Biomolecules

11 pages, 249 KiB

Open AccessEditor’s ChoiceReview

Schnitzler Syndrome: Insights into Its Pathogenesis, Clinical Manifestations, and Current Management

by Antoine Braud and Dan Lipsker

Biomolecules 2024, 14(6), 646; https://doi.org/10.3390/biom14060646 - 31 May 2024

Cited by 1 | Viewed by 1507

Schnitzler syndrome is a rare disorder characterized by a chronic urticarial rash associated with immunoglobulin M (IgM) monoclonal gammopathy. Schnitzler syndrome shares strong clinicopathologic similarities with monogenic IL-1-mediated autoinflammatory disorders and is now considered an acquired adult-onset autoinflammatory disease. The spectacular effect of [...] Read more.

Schnitzler syndrome is a rare disorder characterized by a chronic urticarial rash associated with immunoglobulin M (IgM) monoclonal gammopathy. Schnitzler syndrome shares strong clinicopathologic similarities with monogenic IL-1-mediated autoinflammatory disorders and is now considered an acquired adult-onset autoinflammatory disease. The spectacular effect of interleukin-1 inhibitors demonstrates the key role of this cytokine in the pathogenesis of the disease. However, the physiopathology of Schnitzler syndrome remains elusive, and the main question regarding the relationship between autoinflammatory features and monoclonal gammopathy is still unanswered. The purpose of this narrative review is to describe what is currently known about the pathogenesis of this peculiar disease, as well as to address its diagnosis and management. Full article

(This article belongs to the Special Issue Novel Insights into Autoimmune/Autoinflammatory Skin Diseases)

12 pages, 1208 KiB

Open AccessEditor’s ChoiceReview

Duckweed: Beyond an Efficient Plant Model System

by Doni Thingujam, Karolina M. Pajerowska-Mukhtar and M. Shahid Mukhtar

Biomolecules 2024, 14(6), 628; https://doi.org/10.3390/biom14060628 - 27 May 2024

Cited by 3 | Viewed by 2922

Abstract

Duckweed (Lemnaceae) rises as a crucial model system due to its unique characteristics and wide-ranging utility. The significance of physiological research and phytoremediation highlights the intricate potential of duckweed in the current era of plant biology. Special attention to duckweed has [...] Read more.

Duckweed (Lemnaceae) rises as a crucial model system due to its unique characteristics and wide-ranging utility. The significance of physiological research and phytoremediation highlights the intricate potential of duckweed in the current era of plant biology. Special attention to duckweed has been brought due to its distinctive features of nutrient uptake, ion transport dynamics, detoxification, intricate signaling, and stress tolerance. In addition, duckweed can alleviate environmental pollutants and enhance sustainability by participating in bioremediation processes and wastewater treatment. Furthermore, insights into the genomic complexity of Lemnaceae species and the flourishing field of transgenic development highlight the opportunities for genetic manipulation and biotechnological innovations. Novel methods for the germplasm conservation of duckweed can be adopted to preserve genetic diversity for future research endeavors and breeding programs. This review centers around prospects in duckweed research promoting interdisciplinary collaborations and technological advancements to drive its full potential as a model organism. Full article

► Show Figures

Figure 1

23 pages, 6190 KiB

Open AccessFeature PaperEditor’s ChoiceReview

The Functional Significance of High Cysteine Content in Eye Lens γ-Crystallins

by Eugene Serebryany, Rachel W. Martin and Gemma R. Takahashi

Biomolecules 2024, 14(5), 594; https://doi.org/10.3390/biom14050594 - 17 May 2024

Cited by 1 | Viewed by 2101

Abstract

Cataract disease is strongly associated with progressively accumulating oxidative damage to the extremely long-lived crystallin proteins of the lens. Cysteine oxidation affects crystallin folding, interactions, and light-scattering aggregation especially strongly due to the formation of disulfide bridges. Minimizing crystallin aggregation is crucial for [...] Read more.

Cataract disease is strongly associated with progressively accumulating oxidative damage to the extremely long-lived crystallin proteins of the lens. Cysteine oxidation affects crystallin folding, interactions, and light-scattering aggregation especially strongly due to the formation of disulfide bridges. Minimizing crystallin aggregation is crucial for lifelong lens transparency, so one might expect the ubiquitous lens crystallin superfamilies (α and βγ) to contain little cysteine. Yet, the Cys content of γ-crystallins is well above the average for human proteins. We review literature relevant to this longstanding puzzle and take advantage of expanding genomic databases and improved machine learning tools for protein structure prediction to investigate it further. We observe remarkably low Cys conservation in the βγ-crystallin superfamily; however, in γ-crystallin, the spatial positioning of Cys residues is clearly fine-tuned by evolution. We propose that the requirements of long-term lens transparency and high lens optical power impose competing evolutionary pressures on lens βγ-crystallins, leading to distinct adaptations: high Cys content in γ-crystallins but low in βB-crystallins. Aquatic species need more powerful lenses than terrestrial ones, which explains the high methionine content of many fish γ- (and even β-) crystallins. Finally, we discuss synergies between sulfur-containing and aromatic residues in crystallins and suggest future experimental directions. Full article

(This article belongs to the Special Issue Physiological and Pathological Functions of Crystallins)

► Show Figures

Figure 1

25 pages, 2029 KiB

Open AccessEditor’s ChoiceReview

Oncogenic Pathways and Targeted Therapies in Ovarian Cancer

by Carolina Lliberos, Gary Richardson and Antonella Papa

Biomolecules 2024, 14(5), 585; https://doi.org/10.3390/biom14050585 - 15 May 2024

Cited by 2 | Viewed by 2301

Abstract

Epithelial ovarian cancer (EOC) is one of the most aggressive forms of gynaecological malignancies. Survival rates for women diagnosed with OC remain poor as most patients are diagnosed with advanced disease. Debulking surgery and platinum-based therapies are the current mainstay for OC treatment. [...] Read more.

Epithelial ovarian cancer (EOC) is one of the most aggressive forms of gynaecological malignancies. Survival rates for women diagnosed with OC remain poor as most patients are diagnosed with advanced disease. Debulking surgery and platinum-based therapies are the current mainstay for OC treatment. However, and despite achieving initial remission, a significant portion of patients will relapse because of innate and acquired resistance, at which point the disease is considered incurable. In view of this, novel detection strategies and therapeutic approaches are needed to improve outcomes and survival of OC patients. In this review, we summarize our current knowledge of the genetic landscape and molecular pathways underpinning OC and its many subtypes. By examining therapeutic strategies explored in preclinical and clinical settings, we highlight the importance of decoding how single and convergent genetic alterations co-exist and drive OC progression and resistance to current treatments. We also propose that core signalling pathways such as the PI3K and MAPK pathways play critical roles in the origin of diverse OC subtypes and can become new targets in combination with known DNA damage repair pathways for the development of tailored and more effective anti-cancer treatments. Full article

► Show Figures

Figure 1

23 pages, 4279 KiB

Open AccessEditor’s ChoiceArticle

Disruption of Transmembrane Phosphatidylserine Asymmetry by HIV-1 Incorporated SERINC5 Is Not Responsible for Virus Restriction

by Gokul Raghunath, Elizabeth H. Abbott, Mariana Marin, Hui Wu, Judith Mary Reyes Ballista, Melinda A. Brindley and Gregory B. Melikyan

Biomolecules 2024, 14(5), 570; https://doi.org/10.3390/biom14050570 - 10 May 2024

Cited by 2 | Viewed by 1200

Abstract

Host restriction factor SERINC5 (SER5) incorporates into the HIV-1 membrane and inhibits infectivity by a poorly understood mechanism. Recently, SER5 was found to exhibit scramblase-like activity leading to the externalization of phosphatidylserine (PS) on the viral surface, which has been proposed to be [...] Read more.

Host restriction factor SERINC5 (SER5) incorporates into the HIV-1 membrane and inhibits infectivity by a poorly understood mechanism. Recently, SER5 was found to exhibit scramblase-like activity leading to the externalization of phosphatidylserine (PS) on the viral surface, which has been proposed to be responsible for SER5’s antiviral activity. This and other reports that document modulation of HIV-1 infectivity by viral lipid composition prompted us to investigate the role of PS in regulating SER5-mediated HIV-1 restriction. First, we show that the level of SER5 incorporation into virions correlates with an increase in PS levels in the outer leaflet of the viral membrane. We developed an assay to estimate the PS distribution across the viral membrane and found that SER5, but not SER2, which lacks antiviral activity, abrogates PS asymmetry by externalizing this lipid. Second, SER5 incorporation diminished the infectivity of pseudoviruses produced from cells lacking a flippase subunit CDC50a and, therefore, exhibited a higher baseline level of surface-accessible PS. Finally, exogenous manipulation of the viral PS levels utilizing methyl-alpha-cyclodextrin revealed a lack of correlation between external PS and virion infectivity. Taken together, our study implies that the increased PS exposure to SER5-containing virions itself is not directly linked to HIV-1 restriction. Full article

► Show Figures

Figure 1

23 pages, 1045 KiB

Open AccessFeature PaperEditor’s ChoiceArticle

Risk and Resilience Variants in the Retinoic Acid Metabolic and Developmental Pathways Associated with Risk of FASD Outcomes

by Leo McKay, Berardino Petrelli, Molly Pind, James N. Reynolds, Richard F. Wintle, Albert E. Chudley, Britt Drögemöller, Abraham Fainsod, Stephen W. Scherer, Ana Hanlon-Dearman and Geoffrey G. Hicks

Biomolecules 2024, 14(5), 569; https://doi.org/10.3390/biom14050569 - 10 May 2024

Cited by 1 | Viewed by 1427

Abstract

Fetal Alcohol Spectrum Disorder (FASD) is a common neurodevelopmental disorder that affects an estimated 2–5% of North Americans. FASD is induced by prenatal alcohol exposure (PAE) during pregnancy and while there is a clear genetic contribution, few genetic factors are currently identified or [...] Read more.

Fetal Alcohol Spectrum Disorder (FASD) is a common neurodevelopmental disorder that affects an estimated 2–5% of North Americans. FASD is induced by prenatal alcohol exposure (PAE) during pregnancy and while there is a clear genetic contribution, few genetic factors are currently identified or understood. In this study, using a candidate gene approach, we performed a genetic variant analysis of retinoic acid (RA) metabolic and developmental signaling pathway genes on whole exome sequencing data of 23 FASD-diagnosed individuals. We found risk and resilience alleles in ADH and ALDH genes known to normally be involved in alcohol detoxification at the expense of RA production, causing RA deficiency, following PAE. Risk and resilience variants were also identified in RA-regulated developmental pathway genes, especially in SHH and WNT pathways. Notably, we also identified significant variants in the causative genes of rare neurodevelopmental disorders sharing comorbidities with FASD, including STRA6 (Matthew–Wood), SOX9 (Campomelic Dysplasia), FDG1 (Aarskog), and 22q11.2 deletion syndrome (TBX1). Although this is a small exploratory study, the findings support PAE-induced RA deficiency as a major etiology underlying FASD and suggest risk and resilience variants may be suitable biomarkers to determine the risk of FASD outcomes following PAE. Full article

(This article belongs to the Special Issue New Insight into the Molecular Genetics of Neurodevelopmental Disorders)

► Show Figures

Figure 1

12 pages, 1148 KiB

Open AccessFeature PaperEditor’s ChoiceArticle

Synthesis of the Antimicrobial Peptide Murepavadin Using Novel Coupling Agents

by Júlia García-Gros, Yolanda Cajal, Ana Maria Marqués and Francesc Rabanal

Biomolecules 2024, 14(5), 526; https://doi.org/10.3390/biom14050526 - 27 Apr 2024

Cited by 1 | Viewed by 2207

Abstract

The problem of antimicrobial resistance is becoming a daunting challenge for human society and healthcare systems around the world. Hence, there is a constant need to develop new antibiotics to fight resistant bacteria, among other important social and economic measures. In this regard, [...] Read more.

The problem of antimicrobial resistance is becoming a daunting challenge for human society and healthcare systems around the world. Hence, there is a constant need to develop new antibiotics to fight resistant bacteria, among other important social and economic measures. In this regard, murepavadin is a cyclic antibacterial peptide in development. The synthesis of murepavadin was undertaken in order to optimize the preparative protocol and scale-up, in particular, the use of new activation reagents. In our hands, classical approaches using carbodiimide/hydroxybenzotriazole rendered low yields. The use of novel carbodiimide and reagents based on OxymaPure^® and Oxy-B is discussed together with the proper use of chromatographic conditions for the adequate characterization of peptide crudes. Higher yields and purities were obtained. Finally, the antimicrobial activity of different synthetic batches was tested in three Pseudomonas aeruginosa strains, including highly resistant ones. All murepavadin batches yielded the same highly active MIC values and proved that the chiral integrity of the molecule was preserved throughout the whole synthetic procedure. Full article

(This article belongs to the Special Issue Development, Characterization, and Application of Bioactive Peptides, Diagnostic Biomarkers, and Pharmaceutical Proteins)

► Show Figures

Figure 1

14 pages, 2485 KiB

Open AccessEditor’s ChoiceReview

Caspase-5: Structure, Pro-Inflammatory Activity and Evolution

by Leopold Eckhart and Heinz Fischer

Biomolecules 2024, 14(5), 520; https://doi.org/10.3390/biom14050520 - 26 Apr 2024

Cited by 1 | Viewed by 1737

Abstract

Caspase-5 is a protease that induces inflammation in response to lipopolysaccharide (LPS), a component of the cell envelope of Gram-negative bacteria. The expression level of the CASP5 gene is very low in the basal state, but strongly increases in the presence of LPS. [...] Read more.

Caspase-5 is a protease that induces inflammation in response to lipopolysaccharide (LPS), a component of the cell envelope of Gram-negative bacteria. The expression level of the CASP5 gene is very low in the basal state, but strongly increases in the presence of LPS. Intracellular LPS binds to the caspase activation and recruitment domain (CARD) of caspase-5, leading to the formation of a non-canonical inflammasome. Subsequently, the catalytic domain of caspase-5 cleaves gasdermin D and thereby facilitates the formation of cell membrane pores through which pro-inflammatory cytokines of the interleukin-1 family are released. Caspase-4 is also able to form a non-canonical inflammasome upon binding to LPS, but its expression is less dependent on LPS than the expression of caspase-5. Caspase-4 and caspase-5 have evolved via the duplication of a single ancestral gene in a subclade of primates, including humans. Notably, the main biomedical model species, the mouse, has only one ortholog, namely caspase-11. Here, we review the structural features and the mechanisms of regulation that are important for the pro-inflammatory roles of caspase-5. We summarize the interspecies differences and the evolution of pro-inflammatory caspases in mammals and discuss the potential roles of caspase-5 in the defense against Gram-negative bacteria and in sepsis. Full article

(This article belongs to the Section Cellular Biochemistry)

► Show Figures

Figure 1

18 pages, 806 KiB

Open AccessEditor’s ChoiceReview

The Exploitation of the Glycosylation Pattern in Asthma: How We Alter Ancestral Pathways to Develop New Treatments

by Angelika Muchowicz, Agnieszka Bartoszewicz and Zbigniew Zaslona

Biomolecules 2024, 14(5), 513; https://doi.org/10.3390/biom14050513 - 24 Apr 2024

Cited by 1 | Viewed by 1587

Abstract

Asthma has reached epidemic levels, yet progress in developing specific therapies is slow. One of the main reasons for this is the fact that asthma is an umbrella term for various distinct subsets. Due to its high heterogeneity, it is difficult to establish [...] Read more.

Asthma has reached epidemic levels, yet progress in developing specific therapies is slow. One of the main reasons for this is the fact that asthma is an umbrella term for various distinct subsets. Due to its high heterogeneity, it is difficult to establish biomarkers for each subset of asthma and to propose endotype-specific treatments. This review focuses on protein glycosylation as a process activated in asthma and ways to utilize it to develop novel biomarkers and treatments. We discuss known and relevant glycoproteins whose functions control disease development. The key role of glycoproteins in processes integral to asthma, such as inflammation, tissue remodeling, and repair, justifies our interest and research in the field of glycobiology. Altering the glycosylation states of proteins contributing to asthma can change the pathological processes that we previously failed to inhibit. Special emphasis is placed on chitotriosidase 1 (CHIT1), an enzyme capable of modifying LacNAc- and LacdiNAc-containing glycans. The expression and activity of CHIT1 are induced in human diseased lungs, and its pathological role has been demonstrated by both genetic and pharmacological approaches. We propose that studying the glycosylation pattern and enzymes involved in glycosylation in asthma can help in patient stratification and in developing personalized treatment. Full article

(This article belongs to the Special Issue Biomarkers of Severe Asthma: From Pathogenetic Mechanisms to Clinical Application)

► Show Figures

Figure 1

17 pages, 3825 KiB

Open AccessEditor’s ChoiceArticle

Metformin Induces MeCP2 in the Hippocampus of Male Mice with Sex-Specific and Brain-Region-Dependent Molecular Impact

by Khatereh Saei Arezoumand, Chris-Tiann Roberts and Mojgan Rastegar

Biomolecules 2024, 14(4), 505; https://doi.org/10.3390/biom14040505 - 21 Apr 2024

Viewed by 1953

Abstract

Rett Syndrome (RTT) is a progressive X-linked neurodevelopmental disorder with no cure. RTT patients show disease-associated symptoms within 18 months of age that include developmental regression, progressive loss of useful hand movements, and breathing difficulties, along with neurological impairments, seizures, tremor, and mental [...] Read more.

Rett Syndrome (RTT) is a progressive X-linked neurodevelopmental disorder with no cure. RTT patients show disease-associated symptoms within 18 months of age that include developmental regression, progressive loss of useful hand movements, and breathing difficulties, along with neurological impairments, seizures, tremor, and mental disability. Rett Syndrome is also associated with metabolic abnormalities, and the anti-diabetic drug metformin is suggested to be a potential drug of choice with low or no side-effects. Previously, we showed that in vitro exposure of metformin in a human brain cell line induces MECP2E1 transcripts, the dominant isoform of the MECP2 gene in the brain, mutations in which causes RTT. Here, we report the molecular impact of metformin in mice. Protein analysis of specific brain regions in the male and female mice by immunoblotting indicated that metformin induces MeCP2 in the hippocampus, in a sex-dependent manner. Additional experiments confirm that the regulatory role of metformin on the MeCP2 target “BDNF” is brain region-dependent and sex-specific. Measurement of the ribosomal protein S6 (in both phosphorylated and unphosphorylated forms) confirms the sex-dependent role of metformin in the liver. Our results can help foster a better understanding of the molecular impact of metformin in different brain regions of male and female adult mice, while providing some insight towards its potential in therapeutic strategies for the treatment of Rett Syndrome. Full article

(This article belongs to the Special Issue Brain-Derived Neurotrophic Factor in Health and Diseases)

► Show Figures

Figure 1

14 pages, 2283 KiB

Open AccessEditor’s ChoiceArticle

Conformational Modulation of Tissue Transglutaminase via Active Site Thiol Alkylating Agents: Size Does Not Matter

by Pauline Navals, Alana M. M. Rangaswamy, Petr Kasyanchyk, Maxim V. Berezovski and Jeffrey W. Keillor

Biomolecules 2024, 14(4), 496; https://doi.org/10.3390/biom14040496 - 19 Apr 2024

Cited by 1 | Viewed by 1270

Abstract

TG2 is a unique member of the transglutaminase family as it undergoes a dramatic conformational change, allowing its mutually exclusive function as either a cross-linking enzyme or a G-protein. The enzyme’s dysregulated activity has been implicated in a variety of pathologies (e.g., celiac [...] Read more.

TG2 is a unique member of the transglutaminase family as it undergoes a dramatic conformational change, allowing its mutually exclusive function as either a cross-linking enzyme or a G-protein. The enzyme’s dysregulated activity has been implicated in a variety of pathologies (e.g., celiac disease, fibrosis, cancer), leading to the development of a wide range of inhibitors. Our group has primarily focused on the development of peptidomimetic targeted covalent inhibitors, the nature and size of which were thought to be important features to abolish TG2’s conformational dynamism and ultimately inhibit both its activities. However, we recently demonstrated that the enzyme was unable to bind guanosine triphosphate (GTP) when catalytically inactivated by small molecule inhibitors. In this study, we designed a library of models targeting covalent inhibitors of progressively smaller sizes (15 to 4 atoms in length). We evaluated their ability to inactivate TG2 by measuring their respective kinetic parameters k_inact and K_I. Their impact on the enzyme’s ability to bind GTP was then evaluated and subsequently correlated to the conformational state of the enzyme, as determined via native PAGE and capillary electrophoresis. All irreversible inhibitors evaluated herein locked TG2 in its open conformation and precluded GTP binding. Therefore, we conclude that steric bulk and structural complexity are not necessary factors to consider when designing TG2 inhibitors to abolish G-protein activity. Full article

(This article belongs to the Special Issue Transglutaminases: Regulation, Imaging, and Applications)

► Show Figures

Figure 1

13 pages, 972 KiB

Open AccessEditor’s ChoiceReview

Technical Advances in Circulating Cell-Free DNA Detection and Analysis for Personalized Medicine in Patients’ Care

by Monica Sorbini, Tullia Carradori, Gabriele Maria Togliatto, Tiziana Vaisitti and Silvia Deaglio

Biomolecules 2024, 14(4), 498; https://doi.org/10.3390/biom14040498 - 19 Apr 2024

Cited by 3 | Viewed by 2424

Abstract

Circulating cell-free DNA (cfDNA) refers to small fragments of DNA molecules released after programmed cell death and necrosis in several body fluids such as blood, saliva, urine, and cerebrospinal fluid. The discovery of cfDNA has revolutionized the field of non-invasive diagnostics in the [...] Read more.

Circulating cell-free DNA (cfDNA) refers to small fragments of DNA molecules released after programmed cell death and necrosis in several body fluids such as blood, saliva, urine, and cerebrospinal fluid. The discovery of cfDNA has revolutionized the field of non-invasive diagnostics in the oncologic field, in prenatal testing, and in organ transplantation. Despite the potential of cfDNA and the solid results published in the recent literature, several challenges remain, represented by a low abundance, a need for highly sensitive assays, and analytical issues. In this review, the main technical advances in cfDNA analysis are presented and discussed, with a comprehensive examination of the current available methodologies applied in each field. Considering the potential advantages of cfDNA, this biomarker is increasing its consensus among clinicians, as it allows us to monitor patients’ conditions in an easy and non-invasive way, offering a more personalized care. Nevertheless, cfDNA analysis is still considered a diagnostic marker to be further validated, and very few centers are implementing its analysis in routine diagnostics. As technical improvements are enhancing the performances of cfDNA analysis, its application will transversally improve patients’ quality of life. Full article

(This article belongs to the Special Issue Recent Developments in the Biology of Extracellular or Cell-Free DNA)

► Show Figures

Figure 1

24 pages, 3946 KiB

Open AccessEditor’s ChoiceReview

Adenosine Triphosphate: The Primordial Molecule That Controls Protein Homeostasis and Shapes the Genome–Proteome Interface

by Jianxing Song

Biomolecules 2024, 14(4), 500; https://doi.org/10.3390/biom14040500 - 19 Apr 2024

Cited by 2 | Viewed by 1845

Abstract

Adenosine triphosphate (ATP) acts as the universal energy currency that drives various biological processes, while nucleic acids function to store and transmit genetic information for all living organisms. Liquid–liquid phase separation (LLPS) represents the common principle for the formation of membrane-less organelles (MLOs) [...] Read more.

Adenosine triphosphate (ATP) acts as the universal energy currency that drives various biological processes, while nucleic acids function to store and transmit genetic information for all living organisms. Liquid–liquid phase separation (LLPS) represents the common principle for the formation of membrane-less organelles (MLOs) composed of proteins rich in intrinsically disordered regions (IDRs) and nucleic acids. Currently, while IDRs are well recognized to facilitate LLPS through dynamic and multivalent interactions, the precise mechanisms by which ATP and nucleic acids affect LLPS still remain elusive. This review summarizes recent NMR results on the LLPS of human FUS, TDP-43, and the viral nucleocapsid (N) protein of SARS-CoV-2, as modulated by ATP and nucleic acids, revealing the following: (1) ATP binds to folded domains overlapping with nucleic-acid-binding interfaces; (2) ATP and nucleic acids interplay to biphasically modulate LLPS by competitively binding to overlapping pockets of folded domains and Arg/Lys within IDRs; (3) ATP energy-independently induces protein folding with the highest efficiency known so far. As ATP likely emerged in the prebiotic monomeric world, while LLPS represents a pivotal mechanism to concentrate and compartmentalize rare molecules for forming primordial cells, ATP appears to control protein homeostasis and shape genome–proteome interfaces throughout the evolutionary trajectory, from prebiotic origins to modern cells. Full article

► Show Figures

Graphical abstract

17 pages, 3733 KiB

Open AccessEditor’s ChoiceArticle

Mitochondrial Transplantation’s Role in Rodent Skeletal Muscle Bioenergetics: Recharging the Engine of Aging

by Tasnim Arroum, Gerald A. Hish, Kyle J. Burghardt, James D. McCully, Maik Hüttemann and Moh H. Malek

Biomolecules 2024, 14(4), 493; https://doi.org/10.3390/biom14040493 - 18 Apr 2024

Viewed by 2740

Abstract

Background: Mitochondria are the ‘powerhouses of cells’ and progressive mitochondrial dysfunction is a hallmark of aging in skeletal muscle. Although different forms of exercise modality appear to be beneficial to attenuate aging-induced mitochondrial dysfunction, it presupposes that the individual has a requisite level [...] Read more.

Background: Mitochondria are the ‘powerhouses of cells’ and progressive mitochondrial dysfunction is a hallmark of aging in skeletal muscle. Although different forms of exercise modality appear to be beneficial to attenuate aging-induced mitochondrial dysfunction, it presupposes that the individual has a requisite level of mobility. Moreover, non-exercise alternatives (i.e., nutraceuticals or pharmacological agents) to improve skeletal muscle bioenergetics require time to be effective in the target tissue and have another limitation in that they act systemically and not locally where needed. Mitochondrial transplantation represents a novel directed therapy designed to enhance energy production of tissues impacted by defective mitochondria. To date, no studies have used mitochondrial transplantation as an intervention to attenuate aging-induced skeletal muscle mitochondrial dysfunction. The purpose of this investigation, therefore, was to determine whether mitochondrial transplantation can enhance skeletal muscle bioenergetics in an aging rodent model. We hypothesized that mitochondrial transplantation would result in sustained skeletal muscle bioenergetics leading to improved functional capacity. Methods: Fifteen female mice (24 months old) were randomized into two groups (placebo or mitochondrial transplantation). Isolated mitochondria from a donor mouse of the same sex and age were transplanted into the hindlimb muscles of recipient mice (quadriceps femoris, tibialis anterior, and gastrocnemius complex). Results: The results indicated significant increases (ranging between ~36% and ~65%) in basal cytochrome c oxidase and citrate synthase activity as well as ATP levels in mice receiving mitochondrial transplantation relative to the placebo. Moreover, there were significant increases (approx. two-fold) in protein expression of mitochondrial markers in both glycolytic and oxidative muscles. These enhancements in the muscle translated to significant improvements in exercise tolerance. Conclusions: This study provides initial evidence showing how mitochondrial transplantation can promote skeletal muscle bioenergetics in an aging rodent model. Full article

(This article belongs to the Special Issue Skeletal Muscle Homeostasis and Regeneration)

► Show Figures

Figure 1

9 pages, 820 KiB

Open AccessEditor’s ChoiceArticle

Development of Improved Spectrophotometric Assays for Biocatalytic Silyl Ether Hydrolysis

by Yuqing Lu, Chisom S. Egedeuzu, Peter G. Taylor and Lu Shin Wong

Biomolecules 2024, 14(4), 492; https://doi.org/10.3390/biom14040492 - 18 Apr 2024

Cited by 2 | Viewed by 1308

Abstract

Reported herein is the development of assays for the spectrophotometric quantification of biocatalytic silicon−oxygen bond hydrolysis. Central to these assays are a series of chromogenic substrates that release highly absorbing phenoxy anions upon cleavage of the sessile bond. These substrates were tested with [...] Read more.

Reported herein is the development of assays for the spectrophotometric quantification of biocatalytic silicon−oxygen bond hydrolysis. Central to these assays are a series of chromogenic substrates that release highly absorbing phenoxy anions upon cleavage of the sessile bond. These substrates were tested with silicatein, an enzyme from a marine sponge that is known to catalyse the hydrolysis and condensation of silyl ethers. It was found that, of the substrates tested, tert-butyldimethyl(2-methyl-4-nitrophenoxy)silane provided the best assay performance, as evidenced by the highest ratio of enzyme catalysed reaction rate compared with the background (uncatalysed) reaction. These substrates were also found to be suitable for detailed enzyme kinetics measurements, as demonstrated by their use to determine the Michaelis−Menten kinetic parameters for silicatein. Full article

(This article belongs to the Section Enzymology)

► Show Figures

Graphical abstract

13 pages, 3079 KiB

Open AccessEditor’s ChoiceArticle

Radiolabelled FGF-2 for Imaging Activated Fibroblasts in the Tumor Micro-Environment

by Valeria Bentivoglio, Filippo Galli, Michela Varani, Danilo Ranieri, Pallavi Nayak, Annunziata D’Elia, Andrea Soluri, Roberto Massari, Chiara Lauri and Alberto Signore

Biomolecules 2024, 14(4), 491; https://doi.org/10.3390/biom14040491 - 18 Apr 2024

Viewed by 1641

Abstract

Tumor associated fibroblasts (TAFs) play a key role in tumor growth and metastatization. TAFs overexpress different biomarkers that are usually expressed at low levels in physiological conditions. Among them are the fibroblast growth factor receptors (FGFRs) that bind the fibroblast growth factors (FGFs). [...] Read more.

Tumor associated fibroblasts (TAFs) play a key role in tumor growth and metastatization. TAFs overexpress different biomarkers that are usually expressed at low levels in physiological conditions. Among them are the fibroblast growth factor receptors (FGFRs) that bind the fibroblast growth factors (FGFs). In particular, the overexpression of FGFR-2c in tumors has been associated with advanced clinical stages and increased metastatization. Here, we developed a non-invasive tool to evaluate, in vivo, the expression of FGFR-2c in metastatic cancer. This is based on ^99mTc-labelled FGF-2. Methods: ^99mTc-FGF-2 was tested in vitro and in vivo in mice bearing allografts of sarcoma cells. Images of ^99mTc-FGF-2 were acquired using a new portable high-resolution ultra-sensitive gamma camera for small animal imaging. Results: FGF-2 was labeled with high specific activity but low labelling efficiency, thus requiring post-labeling purification by gel-filtration chromatography. In vitro binding to 2C human keratinocytes showed a Kd of 3.36 × 10⁻⁹ M. In mice bearing J774A.1 cell allografts, we observed high and rapid tumor uptake of ^99mTc-FGF-2 with a high Tumor/Blood ratio at 24 h post-injection (26.1 %ID/g and 12.9 %ID) with low kidney activity and moderate liver activity. Conclusions: we labeled FGF-2 with ^99mTc and showed nanomolar Kd in vitro with human keratinocytes expressing FGF-2 receptors. In mice, ^99mTc-FGF-2 rapidly and efficiently accumulated in tumors expressing FGF-2 receptors. This new radiopharmaceutical could be used in humans to image TAFs. Full article

(This article belongs to the Section Molecular Medicine)

► Show Figures

Figure 1

56 pages, 3906 KiB

Open AccessEditor’s ChoiceReview

Metabolic Syndrome and Biotherapeutic Activity of Dairy (Cow and Buffalo) Milk Proteins and Peptides: Fast Food-Induced Obesity Perspective—A Narrative Review

by Kenbon Beyene Abdisa, Emőke Szerdahelyi, Máté András Molnár, László Friedrich, Zoltán Lakner, András Koris, Attila Toth and Arijit Nath

Biomolecules 2024, 14(4), 478; https://doi.org/10.3390/biom14040478 - 14 Apr 2024

Viewed by 2277

Abstract

Metabolic syndrome (MS) is defined by the outcome of interconnected metabolic factors that directly increase the prevalence of obesity and other metabolic diseases. Currently, obesity is considered one of the most relevant topics of discussion because an epidemic heave of the incidence of [...] Read more.

Metabolic syndrome (MS) is defined by the outcome of interconnected metabolic factors that directly increase the prevalence of obesity and other metabolic diseases. Currently, obesity is considered one of the most relevant topics of discussion because an epidemic heave of the incidence of obesity in both developing and underdeveloped countries has been reached. According to the World Obesity Atlas 2023 report, 38% of the world population are presently either obese or overweight. One of the causes of obesity is an imbalance of energy intake and energy expenditure, where nutritional imbalance due to consumption of high-calorie fast foods play a pivotal role. The dynamic interactions among different risk factors of obesity are highly complex; however, the underpinnings of hyperglycemia and dyslipidemia for obesity incidence are recognized. Fast foods, primarily composed of soluble carbohydrates, non-nutritive artificial sweeteners, saturated fats, and complexes of macronutrients (protein-carbohydrate, starch-lipid, starch-lipid-protein) provide high metabolic calories. Several experimental studies have pointed out that dairy proteins and peptides may modulate the activities of risk factors of obesity. To justify the results precisely, peptides from dairy milk proteins were synthesized under in vitro conditions and their contributions to biomarkers of obesity were assessed. Comprehensive information about the impact of proteins and peptides from dairy milks on fast food-induced obesity is presented in this narrative review article. Full article

(This article belongs to the Special Issue Nutrition, Metabolism, and Obesity: Novel Strategies and Molecular Mechanisms—Future Perspectives)

► Show Figures

Figure 1

13 pages, 682 KiB

Open AccessEditor’s ChoiceReview

Innate Immunity and MASLD

by Moritz Meyer, Julian Schwärzler, Almina Jukic and Herbert Tilg

Biomolecules 2024, 14(4), 476; https://doi.org/10.3390/biom14040476 - 13 Apr 2024

Cited by 2 | Viewed by 2252

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) has emerged as the most common liver disease worldwide in recent years. MASLD commonly presents as simple hepatic steatosis, but ~25% of patients develop liver inflammation, progressive fibrosis, liver cirrhosis and related hepatocellular carcinoma. Liver inflammation and [...] Read more.

Metabolic dysfunction-associated steatotic liver disease (MASLD) has emerged as the most common liver disease worldwide in recent years. MASLD commonly presents as simple hepatic steatosis, but ~25% of patients develop liver inflammation, progressive fibrosis, liver cirrhosis and related hepatocellular carcinoma. Liver inflammation and the degree of fibrosis are key determinants of the prognosis. The pathophysiology of liver inflammation is incompletely understood and involves diverse factors and specifically innate and adaptive immune responses. More specifically, diverse mediators of innate immunity such as proinflammatory cytokines, adipokines, inflammasomes and various cell types like mononuclear cells, macrophages and natural killer cells are involved in directing the inflammatory process in MASLD. The activation of innate immunity is driven by various factors including excess lipids and lipotoxicity, insulin resistance and molecular patterns derived from gut commensals. Targeting pathways of innate immunity might therefore appear as an attractive therapeutic strategy in the future management of MASLD and possibly its complications. Full article

(This article belongs to the Special Issue Honorary Special Issue Dedicated to Prof. Giovanni Targher–the Metabolic Fatty Liver Syndromes: MASLD/MAFLD/NAFLD)

► Show Figures

Figure 1

13 pages, 1564 KiB

Open AccessEditor’s ChoiceArticle

Enhancement of Acetate-Induced Apoptosis of Colorectal Cancer Cells by Cathepsin D Inhibition Depends on Oligomycin A-Sensitive Respiration

by Sara Alves, Cátia Santos-Pereira, Cláudia S. F. Oliveira, Ana Preto, Susana R. Chaves and Manuela Côrte-Real

Biomolecules 2024, 14(4), 473; https://doi.org/10.3390/biom14040473 - 12 Apr 2024

Viewed by 1360

Abstract

Colorectal cancer (CRC) is a leading cause of death worldwide. Conventional therapies are available with varying effectiveness. Acetate, a short-chain fatty acid produced by human intestinal bacteria, triggers mitochondria-mediated apoptosis preferentially in CRC but not in normal colonocytes, which has spurred an interest [...] Read more.

Colorectal cancer (CRC) is a leading cause of death worldwide. Conventional therapies are available with varying effectiveness. Acetate, a short-chain fatty acid produced by human intestinal bacteria, triggers mitochondria-mediated apoptosis preferentially in CRC but not in normal colonocytes, which has spurred an interest in its use for CRC prevention/therapy. We previously uncovered that acetate-induced mitochondrial-mediated apoptosis in CRC cells is significantly enhanced by the inhibition of the lysosomal protease cathepsin D (CatD), which indicates both mitochondria and the lysosome are involved in the regulation of acetate-induced apoptosis. Herein, we sought to determine whether mitochondrial function affects CatD apoptotic function. We found that enhancement of acetate-induced apoptosis by CatD inhibition depends on oligomycin A-sensitive respiration. Mechanistically, the potentiating effect is associated with an increase in cellular and mitochondrial superoxide anion accumulation and mitochondrial mass. Our results provide novel clues into the regulation of CatD function and the effect of tumor heterogeneity in the outcome of combined treatment using acetate and CatD inhibitors. Full article

(This article belongs to the Special Issue Advances in the Role of Mitochondria in Regulated Cell Death Dysfunctions Associated with Human Pathologies)

► Show Figures

Figure 1

27 pages, 17475 KiB

Open AccessEditor’s ChoiceArticle

Small Spleen Peptides (SSPs) Shape Dendritic Cell Differentiation through Modulation of Extracellular ATP Synthesis Profile

by Viktor Wixler, Rafael Leite Dantas, Georg Varga, Yvonne Boergeling and Stephan Ludwig

Biomolecules 2024, 14(4), 469; https://doi.org/10.3390/biom14040469 - 11 Apr 2024

Cited by 2 | Viewed by 1592

Abstract

Restoring peripheral immune tolerance is crucial for addressing autoimmune diseases. An ancient mechanism in maintaining the balance between inflammation and tolerance is the ratio of extracellular ATP (exATP) and adenosine. Our previous research demonstrated the effectiveness of small spleen peptides (SSPs) in inhibiting [...] Read more.

Restoring peripheral immune tolerance is crucial for addressing autoimmune diseases. An ancient mechanism in maintaining the balance between inflammation and tolerance is the ratio of extracellular ATP (exATP) and adenosine. Our previous research demonstrated the effectiveness of small spleen peptides (SSPs) in inhibiting psoriatic arthritis progression, even in the presence of the pro-inflammatory cytokine TNFα, by transforming dendritic cells (DCs) into tolerogenic cells and fostering regulatory Foxp3⁺ Treg cells. Here, we identified thymosins as the primary constituents of SSPs, but recombinant thymosin peptides were less efficient in inhibiting arthritis than SSPs. Since Tβ4 is an ecto-ATPase-binding protein, we hypothesized that SSPs regulate exATP profiles. Real-time investigation of exATP levels in DCs revealed that tolerogenic stimulation led to robust de novo exATP synthesis followed by significant degradation, while immunogenic stimulation resulted in a less pronounced increase in exATP and less effective degradation. These contrasting exATP profiles were crucial in determining whether DCs entered an inflammatory or tolerogenic state, highlighting the significance of SSPs as natural regulators of peripheral immunological tolerance, with potential therapeutic benefits for autoimmune diseases. Finally, we demonstrated that the tolerogenic phenotype of SSPs is mainly influenced by adenosine receptors, and in vivo administration of SSPs inhibits psoriatic skin inflammation. Full article

(This article belongs to the Special Issue Diet and Immune Response)

► Show Figures

Figure 1

21 pages, 3686 KiB

Open AccessEditor’s ChoiceArticle

Mice Mutated in the First Fibronectin Domain of Adhesion Molecule L1 Show Brain Malformations and Behavioral Abnormalities

by Viviana Granato, Ludovica Congiu, Igor Jakovcevski, Ralf Kleene, Benjamin Schwindenhammer, Luciana Fernandes, Sandra Freitag, Melitta Schachner and Gabriele Loers

Biomolecules 2024, 14(4), 468; https://doi.org/10.3390/biom14040468 - 11 Apr 2024

Cited by 1 | Viewed by 1386

Abstract

The X-chromosome-linked cell adhesion molecule L1 (L1CAM), a glycoprotein mainly expressed by neurons in the central and peripheral nervous systems, has been implicated in many neural processes, including neuronal migration and survival, neuritogenesis, synapse formation, synaptic plasticity and regeneration. L1 consists of extracellular, [...] Read more.

The X-chromosome-linked cell adhesion molecule L1 (L1CAM), a glycoprotein mainly expressed by neurons in the central and peripheral nervous systems, has been implicated in many neural processes, including neuronal migration and survival, neuritogenesis, synapse formation, synaptic plasticity and regeneration. L1 consists of extracellular, transmembrane and cytoplasmic domains. Proteolytic cleavage of L1’s extracellular and transmembrane domains by different proteases generates several L1 fragments with different functions. We found that myelin basic protein (MBP) cleaves L1’s extracellular domain, leading to enhanced neuritogenesis and neuronal survival in vitro. To investigate in vivo the importance of the MBP-generated 70 kDa fragment (L1-70), we generated mice with an arginine to alanine substitution at position 687 (L1/687), thereby disrupting L1’s MBP cleavage site and obliterating L1-70. Young adult L1/687 males showed normal anxiety and circadian rhythm activities but enhanced locomotion, while females showed altered social interactions. Older L1/687 males were impaired in motor coordination. Furthermore, L1/687 male and female mice had a larger hippocampus, with more neurons in the dentate gyrus and more proliferating cells in the subgranular layer, while the thickness of the corpus callosum and the size of lateral ventricles were normal. In summary, subtle mutant morphological changes result in subtle behavioral changes. Full article

(This article belongs to the Section Biological Factors)

► Show Figures

Graphical abstract

10 pages, 1652 KiB

Open AccessEditor’s ChoiceArticle

Applying Machine Learning for Enhanced MicroRNA Analysis: A Companion Risk Tool for Oral Squamous Cell Carcinoma in Standard Care Incisional Biopsy

by Neha Pruthi, Tami Yap, Caroline Moore, Nicola Cirillo and Michael J. McCullough

Biomolecules 2024, 14(4), 458; https://doi.org/10.3390/biom14040458 - 9 Apr 2024

Cited by 1 | Viewed by 1589

Abstract

Machine learning analyses within the realm of oral cancer outcomes are relatively underexplored compared to other cancer types. This study aimed to assess the performance of machine learning algorithms in identifying oral cancer patients, utilizing microRNA expression data. In this study, we implemented [...] Read more.

Machine learning analyses within the realm of oral cancer outcomes are relatively underexplored compared to other cancer types. This study aimed to assess the performance of machine learning algorithms in identifying oral cancer patients, utilizing microRNA expression data. In this study, we implemented this approach using a panel of oral cancer-associated microRNAs sourced from standard incisional biopsy specimens to identify cases of oral squamous cell carcinomas (OSCC). For the model development process, we used a dataset comprising 30 OSCC and 30 histologically normal epithelium (HNE) cases. We initially trained a logistic regression prediction model using 70 percent of the dataset, while reserving the remaining 30 percent for testing. Subsequently, the model underwent hyperparameter tuning resulting in enhanced performance metrics. The hyperparameter-tuned model exhibited high accuracy (0.894) and ROC AUC (0.898) in predicting OSCC. Testing the model on cases of potentially malignant disorders (OPMDs) revealed that leukoplakia with mild dysplasia was predicted as having a high risk of progressing to OSCC, emphasizing machine learning’s advantage over histopathology in detecting early molecular changes. These findings underscore the necessity for further refinement, incorporating a broader set of variables to enhance the model’s predictive capabilities in assessing the risk of oral potentially malignant disorders. Full article

(This article belongs to the Special Issue Biomolecules and Biomarkers in Head and Neck Medicine (Volume II))

► Show Figures

Figure 1

22 pages, 3397 KiB

Open AccessEditor’s ChoiceArticle

Neurosteroid Modulation of Synaptic and Extrasynaptic GABA_A Receptors of the Mouse Nucleus Accumbens

by Scott J. Mitchell, Grant D. Phillips, Becks Tench, Yunkai Li, Delia Belelli, Stephen J. Martin, Jerome D. Swinny, Louise Kelly, John R. Atack, Michael Paradowski and Jeremy J. Lambert

Biomolecules 2024, 14(4), 460; https://doi.org/10.3390/biom14040460 - 9 Apr 2024

Cited by 1 | Viewed by 1725

Abstract

The recent approval of formulations of the endogenous neurosteroid allopregnanolone (brexanolone) and the synthetic neuroactive steroid SAGE-217 (zuranolone) to treat postpartum depression (PPD) has encouraged further research to elucidate why these potent enhancers of GABA_AR function are clinically effective in this [...] Read more.

The recent approval of formulations of the endogenous neurosteroid allopregnanolone (brexanolone) and the synthetic neuroactive steroid SAGE-217 (zuranolone) to treat postpartum depression (PPD) has encouraged further research to elucidate why these potent enhancers of GABA_AR function are clinically effective in this condition. Dopaminergic projections from the ventral tegmental area (VTA) to the nucleus accumbens are associated with reward/motivation and brain imaging studies report that individuals with PPD show reduced activity of this pathway in response to reward and infant engagement. However, the influence of neurosteroids on GABA-ergic transmission in the nucleus accumbens has received limited attention. Here, we investigate, in the medium spiny neurons (MSNs) of the mouse nucleus accumbens core, the effect of allopregnanolone, SAGE-217 and other endogenous and synthetic steroids of interest on fast phasic and tonic inhibition mediated by synaptic (α1/2βγ2) and extrasynaptic (α4βδ) GABA_ARs, respectively. We present evidence suggesting the resident tonic current results from the spontaneous opening of δ-GABA_ARs, where the steroid-enhanced tonic current is GABA-dependent. Furthermore, we demonstrate local neurosteroid synthesis in the accumbal slice preparation and reveal that GABA-ergic neurotransmission of MSNs is influenced by an endogenous neurosteroid tone. Given the dramatic fluctuations in allopregnanolone levels during pregnancy and postpartum, this neurosteroid-mediated local fine-tuning of GABAergic transmission in the MSNs will probably be perturbed. Full article

(This article belongs to the Special Issue Role of Neuroactive Steroids in Health and Disease)

► Show Figures

Figure 1

16 pages, 13158 KiB

Open AccessEditor’s ChoiceArticle

Intact Transition Epitope Mapping—Force Interferences by Variable Extensions (ITEM-FIVE)

by Cornelia Koy, Claudia Röwer, Hans-Jürgen Thiesen, Andrei Neamtu and Michael O. Glocker

Biomolecules 2024, 14(4), 454; https://doi.org/10.3390/biom14040454 - 8 Apr 2024

Cited by 1 | Viewed by 1096

Abstract

Investigations on binding strength differences of non-covalent protein complex components were performed by mass spectrometry. T4 fibritin foldon (T4Ff) is a well-studied miniprotein, which together with its biotinylated version served as model system to represent a compactly folded protein to which an Intrinsically [...] Read more.

Investigations on binding strength differences of non-covalent protein complex components were performed by mass spectrometry. T4 fibritin foldon (T4Ff) is a well-studied miniprotein, which together with its biotinylated version served as model system to represent a compactly folded protein to which an Intrinsically Disordered Region (IDR) was attached. The apparent enthalpies of the gas phase dissociation reactions of the homo-trimeric foldon F-F-F and of the homo-trimeric triply biotinylated foldon bF-bF-bF have been determined to be rather similar (3.32 kJ/mol and 3.85 kJ/mol) but quite distinct from those of the singly and doubly biotinylated hetero-trimers F-F-bF and F-bF-bF (1.86 kJ/mol and 1.08 kJ/mol). Molecular dynamics simulations suggest that the ground states of the (biotinylated) T4Ff trimers are highly symmetric and well comparable to each other, indicating that the energy levels of all four (biotinylated) T4Ff trimer ground states are nearly indistinguishable. The experimentally determined differences and/or similarities in enthalpies of the complex dissociation reactions are explained by entropic spring effects, which are noticeable in the T4Ff hetero-trimers but not in the T4Ff homo-trimers. A lowering of the transition state energy levels of the T4Ff hetero-trimers seems likely because the biotin moieties, mimicking intrinsically disordered regions (IDRs), induced asymmetries in the transition states of the biotinylated T4Ff hetero-trimers. This transition state energy level lowering effect is absent in the T4Ff homo-trimer, as well as in the triply biotinylated T4Ff homo-trimer. In the latter, the IDR-associated entropic spring effects on complex stability cancel each other out. ITEM-FIVE enabled semi-quantitative determination of energy differences of complex dissociation reactions, whose differences were modulated by IDRs attached to compactly folded proteins. Full article

(This article belongs to the Special Issue Feature Papers in the Natural and Bio-Derived Molecules Section)

► Show Figures

Graphical abstract

24 pages, 908 KiB

Open AccessEditor’s ChoiceReview

Krill Oil and Its Bioactive Components as a Potential Therapy for Inflammatory Bowel Disease: Insights from In Vivo and In Vitro Studies

by Yingying Liu, Ainsley M. Robinson, Xiao Qun Su and Kulmira Nurgali

Biomolecules 2024, 14(4), 447; https://doi.org/10.3390/biom14040447 - 6 Apr 2024

Cited by 1 | Viewed by 2346

Abstract

Krill oil is extracted from krill, a small crustacean in the Antarctic Ocean. It has received growing attention because of krill oil’s unique properties and diverse health benefits. Recent experimental and clinical studies suggest that it has potential therapeutic benefits in preventing the [...] Read more.

Krill oil is extracted from krill, a small crustacean in the Antarctic Ocean. It has received growing attention because of krill oil’s unique properties and diverse health benefits. Recent experimental and clinical studies suggest that it has potential therapeutic benefits in preventing the development of a range of chronic conditions, including inflammatory bowel disease (IBD). Krill oil is enriched with long-chain n-3 polyunsaturated fatty acids, especially eicosapentaenoic and docosahexaenoic acids, and the potent antioxidant astaxanthin, contributing to its therapeutic properties. The possible underlying mechanisms of krill oil’s health benefits include anti-inflammatory and antioxidant actions, maintaining intestinal barrier functions, and modulating gut microbiota. This review aims to provide an overview of the beneficial effects of krill oil and its bioactive components on intestinal inflammation and to discuss the findings on the molecular mechanisms associated with the role of krill oil in IBD prevention and treatment. Full article

(This article belongs to the Collection Feature Papers in Section 'Molecular Medicine')

► Show Figures

Figure 1

14 pages, 1048 KiB

Open AccessEditor’s ChoiceReview

Emerging Insights into the Role of BDNF on Health and Disease in Periphery

by Mayuko Ichimura-Shimizu, Khuleshwari Kurrey, Misaki Miyata, Takuya Dezawa, Koichi Tsuneyama and Masami Kojima

Biomolecules 2024, 14(4), 444; https://doi.org/10.3390/biom14040444 - 5 Apr 2024

Viewed by 2069

Abstract

Brain-derived neurotrophic factor (BDNF) is a growth factor that promotes the survival and growth of developing neurons. It also enhances circuit formation to synaptic transmission for mature neurons in the brain. However, reduced BDNF expression and single nucleotide polymorphisms (SNP) are reported to [...] Read more.

Brain-derived neurotrophic factor (BDNF) is a growth factor that promotes the survival and growth of developing neurons. It also enhances circuit formation to synaptic transmission for mature neurons in the brain. However, reduced BDNF expression and single nucleotide polymorphisms (SNP) are reported to be associated with functional deficit and disease development in the brain, suggesting that BDNF is a crucial molecule for brain health. Interestingly, BDNF is also expressed in the hypothalamus in appetite and energy metabolism. Previous reports demonstrated that BDNF knockout mice exhibited overeating and obesity phenotypes remarkably. Therefore, we could raise a hypothesis that the loss of function of BDNF may be associated with metabolic syndrome and peripheral diseases. In this review, we describe our recent finding that BDNF knockout mice develop metabolic dysfunction-associated steatohepatitis and recent reports demonstrating the role of one of the BDNF receptors, TrkB-T1, in some peripheral organ functions and diseases, and would provide an insight into the role of BDNF beyond the brain. Full article

(This article belongs to the Special Issue Brain-Derived Neurotrophic Factor in Health and Diseases)

► Show Figures

Figure 1

25 pages, 3866 KiB

Open AccessEditor’s ChoiceArticle

Morphological Changes Induced by TKS4 Deficiency Can Be Reversed by EZH2 Inhibition in Colorectal Carcinoma Cells

by Mevan Jacksi, Eva Schad and Agnes Tantos

Biomolecules 2024, 14(4), 445; https://doi.org/10.3390/biom14040445 - 5 Apr 2024

Cited by 1 | Viewed by 1830

Abstract

Background: The scaffold protein tyrosine kinase substrate 4 (TKS4) undergoes tyrosine phosphorylation by the epidermal growth factor receptor (EGFR) pathway via Src kinase. The TKS4 deficiency in humans is responsible for the manifestation of a genetic disorder known as Frank–Ter Haar syndrome (FTHS). [...] Read more.

Background: The scaffold protein tyrosine kinase substrate 4 (TKS4) undergoes tyrosine phosphorylation by the epidermal growth factor receptor (EGFR) pathway via Src kinase. The TKS4 deficiency in humans is responsible for the manifestation of a genetic disorder known as Frank–Ter Haar syndrome (FTHS). Based on our earlier investigation, the absence of TKS4 triggers migration, invasion, and epithelial–mesenchymal transition (EMT)-like phenomena while concurrently suppressing cell proliferation in HCT116 colorectal carcinoma cells. This indicates that TKS4 may play a unique role in the progression of cancer. In this study, we demonstrated that the enhancer of zeste homolog 2 (EZH2) and the histone methyltransferase of polycomb repressive complex 2 (PRC2) are involved in the migration, invasion, and EMT-like changes in TKS4-deficient cells (KO). EZH2 is responsible for the maintenance of the trimethylated lysine 27 on histone H3 (H3K27me3). Methods: We performed transcriptome sequencing, chromatin immunoprecipitation, protein and RNA quantitative studies, cell mobility, invasion, and proliferation studies combined with/without the EZH2 activity inhibitor 3-deazanoplanocine (DZNep). Results: We detected an elevation of global H3K27me3 levels in the TKS4 KO cells, which could be reduced with treatment with DZNep, an EZH2 inhibitor. Inhibition of EZH2 activity reversed the phenotypic effects of the knockout of TKS4, reducing the migration speed and wound healing capacity of the cells as well as decreasing the invasion capacity, while the decrease in cell proliferation became stronger. In addition, inhibition of EZH2 activity also reversed most epithelial and mesenchymal markers. We investigated the wider impact of TKS4 deletion on the gene expression profile of colorectal cancer cells using transcriptome sequencing of wild-type and TKS4 knockout cells, particularly before and after treatment with DZNep. Additionally, we observed changes in the expression of several protein-coding genes and long non-coding RNAs that showed a recovery in expression levels following EZH2 inhibition. Conclusions: Our results indicate that the removal of TKS4 causes a notable disruption in the gene expression pattern, leading to the disruption of several signal transduction pathways. Inhibiting the activity of EZH2 can restore most of these transcriptomics and phenotypic effects in colorectal carcinoma cells. Full article

(This article belongs to the Special Issue Histone Modifications in Health and Diseases)

► Show Figures

Figure 1

22 pages, 2432 KiB

Open AccessEditor’s ChoiceReview

The Impact of Inorganic Systems and Photoactive Metal Compounds on Cytochrome P450 Enzymes and Metabolism: From Induction to Inhibition

by Dmytro Havrylyuk, David K. Heidary and Edith C. Glazer

Biomolecules 2024, 14(4), 441; https://doi.org/10.3390/biom14040441 - 4 Apr 2024

Cited by 2 | Viewed by 1509

Abstract

While cytochrome P450 (CYP; P450) enzymes are commonly associated with the metabolism of organic xenobiotics and drugs or the biosynthesis of organic signaling molecules, they are also impacted by a variety of inorganic species. Metallic nanoparticles, clusters, ions, and complexes can alter CYP [...] Read more.

While cytochrome P450 (CYP; P450) enzymes are commonly associated with the metabolism of organic xenobiotics and drugs or the biosynthesis of organic signaling molecules, they are also impacted by a variety of inorganic species. Metallic nanoparticles, clusters, ions, and complexes can alter CYP expression, modify enzyme interactions with reductase partners, and serve as direct inhibitors. This commonly overlooked topic is reviewed here, with an emphasis on understanding the structural and physiochemical basis for these interactions. Intriguingly, while both organometallic and coordination compounds can act as potent CYP inhibitors, there is little evidence for the metabolism of inorganic compounds by CYPs, suggesting a potential alternative approach to evading issues associated with rapid modification and elimination of medically useful compounds. Full article

(This article belongs to the Special Issue Novel Insights into Cytochrome P450 Enzymes in Drug Metabolism)

► Show Figures

Figure 1

20 pages, 2583 KiB

Open AccessEditor’s ChoiceArticle

A High-Throughput Screening of a Natural Products Library for Mitochondria Modulators

by Emmanuel Makinde, Linlin Ma, George D. Mellick and Yunjiang Feng

Biomolecules 2024, 14(4), 440; https://doi.org/10.3390/biom14040440 - 4 Apr 2024

Viewed by 1516

Abstract

Mitochondria, the energy hubs of the cell, are progressively becoming attractive targets in the search for potent therapeutics against neurodegenerative diseases. The pivotal role of mitochondrial dysfunction in the pathogenesis of various diseases, including Parkinson’s disease (PD), underscores the urgency of discovering novel [...] Read more.

Mitochondria, the energy hubs of the cell, are progressively becoming attractive targets in the search for potent therapeutics against neurodegenerative diseases. The pivotal role of mitochondrial dysfunction in the pathogenesis of various diseases, including Parkinson’s disease (PD), underscores the urgency of discovering novel therapeutic strategies. Given the limitations associated with available treatments for mitochondrial dysfunction-associated diseases, the search for new potent alternatives has become imperative. In this report, we embarked on an extensive screening of 4224 fractions from 384 Australian marine organisms and plant samples to identify natural products with protective effects on mitochondria. Our initial screening using PD patient-sourced olfactory neurosphere-derived (hONS) cells with rotenone as a mitochondria stressor resulted in 108 promising fractions from 11 different biota. To further assess the potency and efficacy of these hits, the 11 biotas were subjected to a subsequent round of screening on human neuroblastoma (SH-SY5Y) cells, using 6-hydroxydopamine to induce mitochondrial stress, complemented by a mitochondrial membrane potential assay. This rigorous process yielded 35 active fractions from eight biotas. Advanced analysis using an orbit trap mass spectrophotometer facilitated the identification of the molecular constituents of the most active fraction from each of the eight biotas. This meticulous approach led to the discovery of 57 unique compounds, among which 12 were previously recognized for their mitoprotective effects. Our findings highlight the vast potential of natural products derived from Australian marine organisms and plants in the quest for innovative treatments targeting mitochondrial dysfunction in neurodegenerative diseases. Full article

(This article belongs to the Special Issue Biomolecular Approaches and Drugs for Neurodegeneration)

► Show Figures

Figure 1

17 pages, 4125 KiB

Open AccessEditor’s ChoiceArticle

Transient Receptor Potential Canonical 5 (TRPC5): Regulation of Heart Rate and Protection against Pathological Cardiac Hypertrophy

by Pratish Thakore, James E. Clark, Aisah A. Aubdool, Dibesh Thapa, Anna Starr, Paul A. Fraser, Keith Farrell-Dillon, Elizabeth S. Fernandes, Ian McFadzean and Susan D. Brain

Biomolecules 2024, 14(4), 442; https://doi.org/10.3390/biom14040442 - 4 Apr 2024

Viewed by 1622

Abstract

TRPC5 is a non-selective cation channel that is expressed in cardiomyocytes, but there is a lack of knowledge of its (patho)physiological role in vivo. Here, we examine the role of TRPC5 on cardiac function under basal conditions and during cardiac hypertrophy. Cardiovascular parameters [...] Read more.

TRPC5 is a non-selective cation channel that is expressed in cardiomyocytes, but there is a lack of knowledge of its (patho)physiological role in vivo. Here, we examine the role of TRPC5 on cardiac function under basal conditions and during cardiac hypertrophy. Cardiovascular parameters were assessed in wild-type (WT) and global TRPC5 knockout (KO) mice. Despite no difference in blood pressure or activity, heart rate was significantly reduced in TRPC5 KO mice. Echocardiography imaging revealed an increase in stroke volume, but cardiac contractility was unaffected. The reduced heart rate persisted in isolated TRPC5 KO hearts, suggesting changes in basal cardiac pacing. Heart rate was further investigated by evaluating the reflex change following drug-induced pressure changes. The reflex bradycardic response following phenylephrine was greater in TRPC5 KO mice but the tachycardic response to SNP was unchanged, indicating an enhancement in the parasympathetic control of the heart rate. Moreover, the reduction in heart rate to carbachol was greater in isolated TRPC5 KO hearts. To evaluate the role of TRPC5 in cardiac pathology, mice were subjected to abdominal aortic banding (AAB). An exaggerated cardiac hypertrophy response to AAB was observed in TRPC5 KO mice, with an increased expression of hypertrophy markers, fibrosis, reactive oxygen species, and angiogenesis. This study provides novel evidence for a direct effect of TRPC5 on cardiac function. We propose that (1) TRPC5 is required for maintaining heart rate by regulating basal cardiac pacing and in response to pressure lowering, and (2) TRPC5 protects against pathological cardiac hypertrophy. Full article

(This article belongs to the Special Issue TRP Channels in Cardiovascular and Inflammatory Disease)

► Show Figures

Figure 1

19 pages, 3153 KiB

Open AccessEditor’s ChoiceArticle

The Antioxidant Drug Edaravone Binds to the Aryl Hydrocarbon Receptor (AHR) and Promotes the Downstream Signaling Pathway Activation

by Caterina Veroni, Stefania Olla, Maria Stefania Brignone, Chiara Siguri, Alessia Formato, Manuela Marra, Rosa Manzoli, Maria Carla Macario, Elena Ambrosini, Enrico Moro and Cristina Agresti

Biomolecules 2024, 14(4), 443; https://doi.org/10.3390/biom14040443 - 4 Apr 2024

Viewed by 1721

Abstract

A considerable effort has been spent in the past decades to develop targeted therapies for the treatment of demyelinating diseases, such as multiple sclerosis (MS). Among drugs with free radical scavenging activity and oligodendrocyte protecting effects, Edaravone (Radicava) has recently received increasing attention [...] Read more.

A considerable effort has been spent in the past decades to develop targeted therapies for the treatment of demyelinating diseases, such as multiple sclerosis (MS). Among drugs with free radical scavenging activity and oligodendrocyte protecting effects, Edaravone (Radicava) has recently received increasing attention because of being able to enhance remyelination in experimental in vitro and in vivo disease models. While its beneficial effects are greatly supported by experimental evidence, there is a current paucity of information regarding its mechanism of action and main molecular targets. By using high-throughput RNA-seq and biochemical experiments in murine oligodendrocyte progenitors and SH-SY5Y neuroblastoma cells combined with molecular docking and molecular dynamics simulation, we here provide evidence that Edaravone triggers the activation of aryl hydrocarbon receptor (AHR) signaling by eliciting AHR nuclear translocation and the transcriptional-mediated induction of key cytoprotective gene expression. We also show that an Edaravone-dependent AHR signaling transduction occurs in the zebrafish experimental model, associated with a downstream upregulation of the NRF2 signaling pathway. We finally demonstrate that its rapid cytoprotective and antioxidant actions boost increased expression of the promyelinating Olig2 protein as well as of an Olig2:GFP transgene in vivo. We therefore shed light on a still undescribed potential mechanism of action for this drug, providing further support to its therapeutic potential in the context of debilitating demyelinating conditions. Full article

(This article belongs to the Collection Feature Papers in Section 'Molecular Medicine')

► Show Figures

Figure 1

13 pages, 2393 KiB

Open AccessEditor’s ChoiceArticle

LXR Agonist T0901317′s Hepatic Impact Overrules Its Atheroprotective Action in Macrophages, Driving Early Atherogenesis in Chow-Diet-Fed Male Apolipoprotein E Knockout Mice

by Menno Hoekstra, Laura M. de Jong, Rick van der Geest, Lidewij R. de Leeuw, Rani Krisnamurthi, Janine J. Geerling and Miranda Van Eck

Biomolecules 2024, 14(4), 429; https://doi.org/10.3390/biom14040429 - 2 Apr 2024

Viewed by 1387

Abstract

Preclinical studies regarding the potential of liver X receptor (LXR) agonists to inhibit macrophage foam cell formation and the development of atherosclerotic lesions are generally executed in mice fed with Western-type diets enriched in cholesterol and fat. Here, we investigated whether LXR agonism [...] Read more.

Preclinical studies regarding the potential of liver X receptor (LXR) agonists to inhibit macrophage foam cell formation and the development of atherosclerotic lesions are generally executed in mice fed with Western-type diets enriched in cholesterol and fat. Here, we investigated whether LXR agonism remains anti-atherogenic under dietary conditions with a low basal hepatic lipogenesis rate. Hereto, atherosclerosis-susceptible male apolipoprotein E knockout mice were fed a low-fat diet with or without 10 mg/kg/day LXR agonist T0901317 supplementation for 8 weeks. Importantly, T0901317 significantly stimulated atherosclerosis susceptibility, despite an associated increase in the macrophage gene expression levels of cholesterol efflux transporters ABCA1 and ABCG1. The pro-atherogenic effect of T0901317 coincided with exacerbated hypercholesterolemia, hypertriglyceridemia, and a significant rise in hepatic triglyceride stores and macrophage numbers. Furthermore, T0901317-treated mice exhibited elevated plasma MCP-1 levels and monocytosis. In conclusion, these findings highlight that the pro-atherogenic hepatic effects of LXR agonism are dominant over the anti-atherogenic effects in macrophages in determining the overall atherosclerosis outcome under low-fat diet feeding conditions. A low-fat diet experimental setting, as compared to the commonly used high-fat-diet-based preclinical setup, thus appears more sensitive in uncovering the potential relevance of the off-target liver effects of novel anti-atherogenic therapeutic approaches that target macrophage LXR. Full article

(This article belongs to the Section Molecular Medicine)

► Show Figures

Figure 1

18 pages, 10449 KiB

Open AccessEditor’s ChoiceReview

Utilization of Diverse Molecules as Receptors by Cry Toxin and the Promiscuous Nature of Receptor-Binding Sites Which Accounts for the Diversity

by Ryoichi Sato

Biomolecules 2024, 14(4), 425; https://doi.org/10.3390/biom14040425 - 1 Apr 2024

Cited by 3 | Viewed by 1550

Abstract

By 2013, it had been shown that the genes cadherin-like receptor (Cad) and ATP-binding cassette transporter subfamily C2 (ABCC2) were responsible for insect resistance to several Cry1A toxins, acting as susceptibility-determining receptors, and many review articles have been published. Therefore, this review focuses [...] Read more.

By 2013, it had been shown that the genes cadherin-like receptor (Cad) and ATP-binding cassette transporter subfamily C2 (ABCC2) were responsible for insect resistance to several Cry1A toxins, acting as susceptibility-determining receptors, and many review articles have been published. Therefore, this review focuses on information about receptors and receptor-binding sites that have been revealed since 2014. Since 2014, studies have revealed that the receptors involved in determining susceptibility vary depending on the Cry toxin subfamily, and that binding affinity between Cry toxins and receptors plays a crucial role. Consequently, models have demonstrated that ABCC2, ABCC3, and Cad interact with Cry1Aa; ABCC2 and Cad with Cry1Ab and Cry1Ac; ABCC2 and ABCC3 with Cry1Fa; ABCB1 with Cry1Ba, Cry1Ia, Cry9Da, and Cry3Aa; and ABCA2 with Cry2Aa and Cry2Ba, primarily in the silkworm, Bombyx mori. Furthermore, since 2017, it has been suggested that the binding sites of BmCad and BmABCC2 on Cry1Aa toxin overlap in the loop region of domain II, indicating that Cry toxins use various molecules as receptors due to their ability to bind promiscuously in this region. Additionally, since 2017, several ABC transporters have been identified as low-efficiency receptors that poorly induce cell swelling in heterologously expressing cultured cells. In 2024, research suggested that multiple molecules from the ABC transporter subfamily, including ABCC1, ABCC2, ABCC3, ABCC4, ABCC10, and ABCC11, act as low-efficiency receptors for a single Cry toxin in the midgut of silkworm larvae. This observation led to the hypothesis that the presence of such low-efficiency receptors contributes to the evolution of Cry toxins towards the generation of highly functional receptors that determine the susceptibility of individual insects. Moreover, this evolutionary process is considered to offer valuable insights for the engineering of Cry toxins to overcome resistance and develop countermeasures against resistance. Full article

(This article belongs to the Special Issue Identification and Characterization of Receptors for Bacillus thuringiensis Pesticidal Toxins)

► Show Figures

Graphical abstract

18 pages, 5206 KiB

Open AccessEditor’s ChoiceArticle

Corinthian Currants Promote the Expression of Paraoxonase-1 and Enhance the Antioxidant Status in Serum and Brain of 5xFAD Mouse Model of Alzheimer’s Disease

by Dimitris Lymperopoulos, Anastasia-Georgia Dedemadi, Maria-Lydia Voulgari, Eirini Georgiou, Ioannis Dafnis, Christina Mountaki, Eirini A. Panagopoulou, Michalis Karvelas, Antonia Chiou, Vaios T. Karathanos and Angeliki Chroni

Biomolecules 2024, 14(4), 426; https://doi.org/10.3390/biom14040426 - 1 Apr 2024

Viewed by 2698

Abstract

Paraoxonase-1 (PON1), a serum antioxidant enzyme, has been implicated in Alzheimer’s disease (AD) pathogenesis that involves early oxidative damage. Corinthian currants and their components have been shown to display antioxidant and other neuroprotective effects in AD. We evaluated the effect of a Corinthian [...] Read more.

Paraoxonase-1 (PON1), a serum antioxidant enzyme, has been implicated in Alzheimer’s disease (AD) pathogenesis that involves early oxidative damage. Corinthian currants and their components have been shown to display antioxidant and other neuroprotective effects in AD. We evaluated the effect of a Corinthian currant paste-supplemented diet (CurD), provided to 1-month-old 5xFAD mice for 1, 3, and 6 months, on PON1 activity and levels of oxidation markers in serum and the brain of mice as compared to a control diet (ConD) or glucose/fructose-matched diet (GFD). Administration of CurD for 1 month increased PON1 activity and decreased oxidized lipid levels in serum compared to ConD and GFD. Longer-term administration of CurD did not, however, affect serum PON1 activity and oxidized lipid levels. Furthermore, CurD administered for 1 and 3 months, but not for 6 months, increased PON1 activity and decreased free radical levels in the cortex of mice compared to ConD and GFD. To probe the mechanism for the increased PON1 activity in mice, we studied the effect of Corinthian currant polar phenolic extract on PON1 activity secreted by Huh-7 hepatocytes or HEK293 cells transfected with a PON1-expressing plasmid. Incubation of cells with the extract led to a dose-dependent increase of secreted PON1 activity, which was attributed to increased cellular PON1 expression. Collectively, our findings suggest that phenolics in Corinthian currants can increase the hepatic expression and activity of antioxidant enzyme PON1 and that a Corinthian currant-supplemented diet during the early stages of AD in mice reduces brain oxidative stress. Full article

(This article belongs to the Collection Feature Papers in Section 'Molecular Medicine')

► Show Figures

Graphical abstract

11 pages, 993 KiB

Open AccessEditor’s ChoiceArticle

Microbiota Metabolite Profiles and Dietary Intake in Older Individuals with Insomnia of Short vs. Normal Sleep Duration

by Carmel Even, Faiga Magzal, Tamar Shochat, Iris Haimov, Maayan Agmon and Snait Tamir

Biomolecules 2024, 14(4), 419; https://doi.org/10.3390/biom14040419 - 30 Mar 2024

Cited by 2 | Viewed by 1757

Abstract

Recent evidence suggests that the gut microbiota plays a role in insomnia pathogenesis. This study compared the dietary habits and microbiota metabolites of older adults with insomnia of short vs. normal sleep duration (ISSD and INSD, respectively). Data collection included sleep assessment through [...] Read more.

Recent evidence suggests that the gut microbiota plays a role in insomnia pathogenesis. This study compared the dietary habits and microbiota metabolites of older adults with insomnia of short vs. normal sleep duration (ISSD and INSD, respectively). Data collection included sleep assessment through actigraphy, dietary analysis using the Food Frequency Questionnaire, and metabolomic profiling of stool samples. The results show that ISSD individuals had higher body mass index and a greater prevalence of hypertension. Significant dietary differences were observed, with the normal sleep group consuming more kilocalories per day and specific aromatic amino acids (AAAs) phenylalanine and tyrosine and branch-chain amino acid (BCAA) valine per protein content than the short sleep group. Moreover, metabolomic analysis identified elevated levels of the eight microbiota metabolites, benzophenone, pyrogallol, 5-aminopental, butyl acrylate, kojic acid, deoxycholic acid (DCA), trans-anethole, and 5-carboxyvanillic acid, in the short compared to the normal sleep group. The study contributes to the understanding of the potential role of dietary and microbial factors in insomnia, particularly in the context of sleep duration, and opens avenues for targeted dietary interventions and gut microbiota modulation as potential therapeutic approaches for treating insomnia. Full article

(This article belongs to the Special Issue Advances in Metabolites Produced by Microbiota)

► Show Figures

Figure 1

25 pages, 1968 KiB

Open AccessEditor’s ChoiceReview

Alcohol-Associated Liver Disease Outcomes: Critical Mechanisms of Liver Injury Progression

by Natalia A. Osna, Irina Tikhanovich, Martí Ortega-Ribera, Sebastian Mueller, Chaowen Zheng, Johannes Mueller, Siyuan Li, Sadatsugu Sakane, Raquel Carvalho Gontijo Weber, Hyun Young Kim, Wonseok Lee, Souradipta Ganguly, Yusuke Kimura, Xiao Liu, Debanjan Dhar, Karin Diggle, David A. Brenner, Tatiana Kisseleva, Neha Attal, Iain H. McKillop, Shilpa Chokshi, Ram Mahato, Karuna Rasineni, Gyongyi Szabo and Kusum K. Kharbanda Show full author list Hide full author list

Biomolecules 2024, 14(4), 404; https://doi.org/10.3390/biom14040404 - 27 Mar 2024

Cited by 1 | Viewed by 4201

Abstract

Alcohol-associated liver disease (ALD) is a substantial cause of morbidity and mortality worldwide and represents a spectrum of liver injury beginning with hepatic steatosis (fatty liver) progressing to inflammation and culminating in cirrhosis. Multiple factors contribute to ALD progression and disease severity. Here, [...] Read more.

Alcohol-associated liver disease (ALD) is a substantial cause of morbidity and mortality worldwide and represents a spectrum of liver injury beginning with hepatic steatosis (fatty liver) progressing to inflammation and culminating in cirrhosis. Multiple factors contribute to ALD progression and disease severity. Here, we overview several crucial mechanisms related to ALD end-stage outcome development, such as epigenetic changes, cell death, hemolysis, hepatic stellate cells activation, and hepatic fatty acid binding protein 4. Additionally, in this review, we also present two clinically relevant models using human precision-cut liver slices and hepatic organoids to examine ALD pathogenesis and progression. Full article

(This article belongs to the Section Molecular Medicine)

► Show Figures

Figure 1

14 pages, 1318 KiB

Open AccessEditor’s ChoiceReview

Fragile X Messenger Ribonucleoprotein Protein and Its Multifunctionality: From Cytosol to Nucleolus and Back

by Mohamed S. Taha and Mohammad Reza Ahmadian

Biomolecules 2024, 14(4), 399; https://doi.org/10.3390/biom14040399 - 26 Mar 2024

Cited by 1 | Viewed by 2004

Abstract

Silencing of the fragile X messenger ribonucleoprotein 1 (FMR1) gene and a consequent lack of FMR protein (FMRP) synthesis are associated with fragile X syndrome, one of the most common inherited intellectual disabilities. FMRP is a multifunctional protein that is involved [...] Read more.

Silencing of the fragile X messenger ribonucleoprotein 1 (FMR1) gene and a consequent lack of FMR protein (FMRP) synthesis are associated with fragile X syndrome, one of the most common inherited intellectual disabilities. FMRP is a multifunctional protein that is involved in many cellular functions in almost all subcellular compartments under both normal and cellular stress conditions in neuronal and non-neuronal cell types. This is achieved through its trafficking signals, nuclear localization signal (NLS), nuclear export signal (NES), and nucleolar localization signal (NoLS), as well as its RNA and protein binding domains, and it is modulated by various post-translational modifications such as phosphorylation, ubiquitination, sumoylation, and methylation. This review summarizes the recent advances in understanding the interaction networks of FMRP with a special focus on FMRP stress-related functions, including stress granule formation, mitochondrion and endoplasmic reticulum plasticity, ribosome biogenesis, cell cycle control, and DNA damage response. Full article

(This article belongs to the Section Biomacromolecules: Proteins)

► Show Figures

Figure 1

10 pages, 692 KiB

Open AccessEditor’s ChoiceReview

Mitochondrial Dysfunction as the Major Basis of Brain Aging

by Stephen C. Bondy

Biomolecules 2024, 14(4), 402; https://doi.org/10.3390/biom14040402 - 26 Mar 2024

Cited by 5 | Viewed by 2336

Abstract

The changes in the properties of three biological events that occur with cerebral aging are discussed. These adverse changes already begin to develop early in mid-life and gradually become more pronounced with senescence. Essentially, they are reflections of the progressive decline in effectiveness [...] Read more.

The changes in the properties of three biological events that occur with cerebral aging are discussed. These adverse changes already begin to develop early in mid-life and gradually become more pronounced with senescence. Essentially, they are reflections of the progressive decline in effectiveness of key processes, resulting in the deviation of essential biochemical trajectories to ineffective and ultimately harmful variants of these programs. The emphasis of this review is the major role played by the mitochondria in the transition of these three important processes toward more deleterious variants as brain aging proceeds. The immune system: the shift away from an efficient immune response to a more unfocused, continuing inflammatory condition. Such a state is both ineffective and harmful. Reactive oxygen species are important intracellular signaling systems. Additionally, microglial phagocytic activity utilizing short lived reactive oxygen species contribute to the removal of aberrant or dead cells and bacteria. These processes are transformed into an excessive, untargeted, and persistent generation of pro-oxidant free radicals (oxidative stress). The normal efficient neural transmission is modified to a state of undirected, chronic low-level excitatory activity. Each of these changes is characterized by the occurrence of continuous activity that is inefficient and diffused. The signal/noise ratio of several critical biological events is thus reduced as beneficial responses are gradually replaced by their impaired and deleterious variants. Full article

(This article belongs to the Collection Molecular Mechanisms of Obesity, Diabetes, Inflammation and Aging)

► Show Figures

Figure 1

21 pages, 1696 KiB

Open AccessEditor’s ChoiceReview

Biomarkers for Managing Neurodegenerative Diseases

by Lara Cheslow, Adam E. Snook and Scott A. Waldman

Biomolecules 2024, 14(4), 398; https://doi.org/10.3390/biom14040398 - 26 Mar 2024

Cited by 3 | Viewed by 2595

Abstract

Neurological disorders are the leading cause of cognitive and physical disability worldwide, affecting 15% of the global population. Due to the demographics of aging, the prevalence of neurological disorders, including neurodegenerative diseases, will double over the next two decades. Unfortunately, while available therapies [...] Read more.

Neurological disorders are the leading cause of cognitive and physical disability worldwide, affecting 15% of the global population. Due to the demographics of aging, the prevalence of neurological disorders, including neurodegenerative diseases, will double over the next two decades. Unfortunately, while available therapies provide symptomatic relief for cognitive and motor impairment, there is an urgent unmet need to develop disease-modifying therapies that slow the rate of pathological progression. In that context, biomarkers could identify at-risk and prodromal patients, monitor disease progression, track responses to therapy, and parse the causality of molecular events to identify novel targets for further clinical investigation. Thus, identifying biomarkers that discriminate between diseases and reflect specific stages of pathology would catalyze the discovery and development of therapeutic targets. This review will describe the prevalence, known mechanisms, ongoing or recently concluded therapeutic clinical trials, and biomarkers of three of the most prevalent neurodegenerative diseases, including Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), and Parkinson’s disease (PD). Full article

(This article belongs to the Special Issue Advances in Biomarkers for Neurodegenerative Diseases)

► Show Figures

Figure 1

14 pages, 298 KiB

Open AccessEditor’s ChoiceReview

Small-Cell Lung Cancer: Is Liquid Biopsy a New Tool Able to Predict the Efficacy of Immunotherapy?

by Rossella Fasano, Simona Serratì, Tania Rafaschieri, Vito Longo, Roberta Di Fonte, Letizia Porcelli and Amalia Azzariti

Biomolecules 2024, 14(4), 396; https://doi.org/10.3390/biom14040396 - 25 Mar 2024

Cited by 3 | Viewed by 1997

Abstract

Small-cell lung cancer (SCLC) cases represent approximately 15% of all lung cancer cases, remaining a recalcitrant malignancy with poor survival and few treatment options. In the last few years, the addition of immunotherapy to chemotherapy improved clinical outcomes compared to chemotherapy alone, resulting [...] Read more.

Small-cell lung cancer (SCLC) cases represent approximately 15% of all lung cancer cases, remaining a recalcitrant malignancy with poor survival and few treatment options. In the last few years, the addition of immunotherapy to chemotherapy improved clinical outcomes compared to chemotherapy alone, resulting in the current standard of care for SCLC. However, the advantage of immunotherapy only applies to a few SCLC patients, and predictive biomarkers selection are lacking for SCLC. In particular, due to some features of SCLC, such as high heterogeneity, elevated cell plasticity, and low-quality tissue samples, SCLC biopsies cannot be used as biomarkers. Therefore, the characterization of the tumor and, subsequently, the selection of an appropriate therapeutic combination may benefit greatly from liquid biopsy. Soluble factors, circulating tumor DNA (ctDNA), circulating tumor cells (CTCs), and extracellular vesicles (EVs) are now useful tools in the characterization of SCLC. This review summarizes the most recent data on biomarkers detectable with liquid biopsy, emphasizing their role in supporting tumor detection and their potential role in SCLC treatment choice. Full article

(This article belongs to the Special Issue Cancer Immunotherapy and the PD-1/PD-L1 Checkpoint Pathway)

► Show Figures

Graphical abstract

21 pages, 2000 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Inflammation and Organic Cation Transporters Novel (OCTNs)

by Lorena Pochini, Michele Galluccio, Lara Console, Mariafrancesca Scalise, Ivano Eberini and Cesare Indiveri

Biomolecules 2024, 14(4), 392; https://doi.org/10.3390/biom14040392 - 25 Mar 2024

Cited by 3 | Viewed by 2173

Abstract

Inflammation is a physiological condition characterized by a complex interplay between different cells handled by metabolites and specific inflammatory-related molecules. In some pathological situations, inflammation persists underlying and worsening the pathological state. Over the years, two membrane transporters namely OCTN1 (SLC22A4) and OCTN2 [...] Read more.

Inflammation is a physiological condition characterized by a complex interplay between different cells handled by metabolites and specific inflammatory-related molecules. In some pathological situations, inflammation persists underlying and worsening the pathological state. Over the years, two membrane transporters namely OCTN1 (SLC22A4) and OCTN2 (SLC22A5) have been shown to play specific roles in inflammation. These transporters form the OCTN subfamily within the larger SLC22 family. The link between these proteins and inflammation has been proposed based on their link to some chronic inflammatory diseases such as asthma, Crohn’s disease (CD), and rheumatoid arthritis (RA). Moreover, the two transporters show the ability to mediate the transport of several compounds including carnitine, carnitine derivatives, acetylcholine, ergothioneine, and gut microbiota by-products, which have been specifically associated with inflammation for their anti- or proinflammatory action. Therefore, the absorption and distribution of these molecules rely on the presence of OCTN1 and OCTN2, whose expression is modulated by inflammatory cytokines and transcription factors typically activated by inflammation. In the present review, we wish to provide a state of the art on OCTN1 and OCTN2 transport function and regulation in relationships with inflammation and inflammatory diseases focusing on the metabolic signature collected in different body districts and gene polymorphisms related to inflammatory diseases. Full article

► Show Figures

Figure 1

16 pages, 2618 KiB

Open AccessEditor’s ChoiceArticle

Molecular Profiling of Axial Spondyloarthritis Patients Reveals an Association between Innate and Adaptive Cell Populations and Therapeutic Response to Tumor Necrosis Factor Inhibitors

by Daniel Sobral, Ana Filipa Fernandes, Miguel Bernardes, Patrícia Pinto, Helena Santos, João Lagoas-Gomes, José Tavares-Costa, José A. P. Silva, João Madruga Dias, Alexandra Bernardo, Jean-Charles Gaillard, Jean Armengaud, Vladimir Benes, Lúcia Domingues, Sara Maia, Jaime C. Branco, Ana Varela Coelho and Fernando M. Pimentel-Santos

Biomolecules 2024, 14(3), 382; https://doi.org/10.3390/biom14030382 - 21 Mar 2024

Viewed by 1989

Abstract

This study aims at identifying molecular biomarkers differentiating responders and non-responders to treatment with Tumor Necrosis Factor inhibitors (TNFi) among patients with axial spondyloarthritis (axSpA). Whole blood mRNA and plasma proteins were measured in a cohort of biologic-naïve axSpA patients (n = [...] Read more.

This study aims at identifying molecular biomarkers differentiating responders and non-responders to treatment with Tumor Necrosis Factor inhibitors (TNFi) among patients with axial spondyloarthritis (axSpA). Whole blood mRNA and plasma proteins were measured in a cohort of biologic-naïve axSpA patients (n = 35), pre and post (14 weeks) TNFi treatment with adalimumab. Differential expression analysis was used to identify the most enriched pathways and in predictive models to distinguish responses to TNFi. A treatment-associated signature suggests a reduction in inflammatory activity. We found transcripts and proteins robustly differentially expressed between baseline and week 14 in responders. C-reactive protein (CRP) and Haptoglobin (HP) proteins showed strong and early decrease in the plasma of axSpA patients, while a cluster of apolipoproteins (APOD, APOA2, APOA1) showed increased expression at week 14. Responders to TNFi treatment present higher levels of markers of innate immunity at baseline, and lower levels of adaptive immunity markers, particularly B-cells. A logistic regression model incorporating ASDAS-CRP, gender, and AFF3, the top differentially expressed gene at baseline, enabled an accurate prediction of response to adalimumab in our cohort (AUC = 0.97). In conclusion, innate and adaptive immune cell type composition at baseline may be a major contributor to response to adalimumab in axSpA patients. A model including clinical and gene expression variables should also be considered. Full article

(This article belongs to the Special Issue Advances in the Molecular Mechanisms of Inflammatory Arthritis and Inflammation-Related Bone Changes)

► Show Figures

Figure 1

13 pages, 3299 KiB

Open AccessEditor’s ChoiceArticle

Sporadic Amyotrophic Lateral Sclerosis Skeletal Muscle Transcriptome Analysis: A Comprehensive Examination of Differentially Expressed Genes

by Elisa Gascón, Pilar Zaragoza, Ana Cristina Calvo and Rosario Osta

Biomolecules 2024, 14(3), 377; https://doi.org/10.3390/biom14030377 - 20 Mar 2024

Cited by 1 | Viewed by 2347

Abstract

Amyotrophic lateral sclerosis (ALS) that comprises sporadic (sALS) and familial (fALS) cases, is a devastating neurodegenerative disorder characterized by progressive degeneration of motor neurons, leading to muscle atrophy and various clinical manifestations. However, the complex underlying mechanisms affecting this disease are not yet [...] Read more.

Amyotrophic lateral sclerosis (ALS) that comprises sporadic (sALS) and familial (fALS) cases, is a devastating neurodegenerative disorder characterized by progressive degeneration of motor neurons, leading to muscle atrophy and various clinical manifestations. However, the complex underlying mechanisms affecting this disease are not yet known. On the other hand, there is also no good prognosis of the disease due to the lack of biomarkers and therapeutic targets. Therefore, in this study, by means of bioinformatics analysis, sALS-affected muscle tissue was analyzed using the GEO GSE41414 dataset, identifying 397 differentially expressed genes (DEGs). Functional analysis revealed 320 up-regulated DEGs associated with muscle development and 77 down-regulated DEGs linked to energy metabolism. Protein–protein interaction network analysis identified 20 hub genes, including EIF4A1, HNRNPR and NDUFA4. Furthermore, miRNA target gene networks revealed 17 miRNAs linked to hub genes, with hsa-mir-206, hsa-mir-133b and hsa-mir-100-5p having been previously implicated in ALS. This study presents new potential biomarkers and therapeutic targets for ALS by correlating the information obtained with a comprehensive literature review, providing new potential targets to study their role in ALS. Full article

(This article belongs to the Special Issue Advances in Biomarkers for Neurodegenerative Diseases)

► Show Figures

Figure 1

14 pages, 1139 KiB

Open AccessEditor’s ChoiceArticle

Role of Polyunsaturated Fatty Acids (PUFAs) and Eicosanoids on Dry Eye Symptoms and Signs

by Simran Mangwani-Mordani, Amanda Prislovsky, Daniel Stephenson, Charles E. Chalfant, Anat Galor and Nawajes Mandal

Biomolecules 2024, 14(3), 376; https://doi.org/10.3390/biom14030376 - 20 Mar 2024

Cited by 1 | Viewed by 1658

Abstract

Polyunsaturated fatty acids (PUFAs) generate pro- and anti-inflammatory eicosanoids via three different metabolic pathways. This study profiled tear PUFAs and their metabolites and examined the relationships with dry eye (DE) and meibomian gland dysfunction (MGD) symptoms and signs. A total of 40 individuals [...] Read more.

Polyunsaturated fatty acids (PUFAs) generate pro- and anti-inflammatory eicosanoids via three different metabolic pathways. This study profiled tear PUFAs and their metabolites and examined the relationships with dry eye (DE) and meibomian gland dysfunction (MGD) symptoms and signs. A total of 40 individuals with normal eyelids and corneal anatomies were prospectively recruited. The symptoms and signs of DE and MGD were assessed, and tear samples (from the right eye) were analyzed by mass spectrometry. Mann–Whitney U tests assessed differences between medians; Spearman tests assessed correlations between continuous variables; and linear regression models assessed the impact of potential confounders. The median age was 63 years; 95% were male; 30% were White; and 85% were non-Hispanic. The symptoms of DE/MGD were not correlated with tear PUFAs and eicosanoids. DE signs (i.e., tear break-up time (TBUT) and Schirmer’s) negatively correlated with anti-inflammatory eicosanoids (11,12-dihydroxyeicosatrienoic acid (11,12 DHET) and 14,15-dihydroxyicosatrienoic acid (14,15, DHET)). Corneal staining positively correlated with the anti-inflammatory PUFA, docosahexaenoic acid (DHA). MGD signs significantly associated with the pro-inflammatory eicosanoid 15-hydroxyeicosatetranoic acid (15-HETE) and DHA. Several relationships remained significant when potential confounders were considered. DE/MGD signs relate more to tear PUFAs and eicosanoids than symptoms. Understanding the impact of PUFA-related metabolic pathways in DE/MGD may provide targets for new therapeutic interventions. Full article

(This article belongs to the Special Issue Biomarkers of Ocular Allergy and Dry Eye Disease)

► Show Figures

Figure 1

17 pages, 1019 KiB

Open AccessEditor’s ChoiceReview

Immunologic Aspects in Fibrodysplasia Ossificans Progressiva

by Anastasia Diolintzi, Mst Shaela Pervin and Edward C. Hsiao

Biomolecules 2024, 14(3), 357; https://doi.org/10.3390/biom14030357 - 16 Mar 2024

Cited by 3 | Viewed by 2231

Abstract

Background: Inflammation is a major driver of heterotopic ossification (HO), a condition of abnormal bone growth in a site that is not normally mineralized. Purpose of review: This review will examine recent findings on the roles of inflammation and the immune system in [...] Read more.

Background: Inflammation is a major driver of heterotopic ossification (HO), a condition of abnormal bone growth in a site that is not normally mineralized. Purpose of review: This review will examine recent findings on the roles of inflammation and the immune system in fibrodysplasia ossificans progressiva (FOP). FOP is a genetic condition of aggressive and progressive HO formation. We also examine how inflammation may be a valuable target for the treatment of HO. Rationale/Recent findings: Multiple lines of evidence indicate a key role for the immune system in driving FOP pathogenesis. Critical cell types include macrophages, mast cells, and adaptive immune cells, working through hypoxia signaling pathways, stem cell differentiation signaling pathways, vascular regulatory pathways, and inflammatory cytokines. In addition, recent clinical reports suggest a potential role for immune modulators in the management of FOP. Future perspectives: The central role of inflammatory mediators in HO suggests that the immune system may be a common target for blocking HO in both FOP and non-genetic forms of HO. Future research focusing on the identification of novel inflammatory targets will help support the testing of potential therapies for FOP and other related conditions. Full article

(This article belongs to the Special Issue Fibrodysplasia Ossificans Progressiva (FOP): From Molecular Mechanisms to Therapeutic Strategies)

► Show Figures

Figure 1

13 pages, 4011 KiB

Open AccessEditor’s ChoiceArticle

Hedgehog Signaling Controls Chondrogenesis and Ectopic Bone Formation via the Yap-Ihh Axis

by Qian Cong and Yingzi Yang

Biomolecules 2024, 14(3), 347; https://doi.org/10.3390/biom14030347 - 14 Mar 2024

Cited by 3 | Viewed by 1744

Abstract

Fibrodysplasia ossificans progressiva (FOP) is a rare congenital disorder characterized by abnormal bone formation due to ACVR1 gene mutations. The identification of the molecular mechanisms underlying the ectopic bone formation and expansion in FOP is critical for the effective treatment or prevention of [...] Read more.

Fibrodysplasia ossificans progressiva (FOP) is a rare congenital disorder characterized by abnormal bone formation due to ACVR1 gene mutations. The identification of the molecular mechanisms underlying the ectopic bone formation and expansion in FOP is critical for the effective treatment or prevention of HO. Here we find that Hh signaling activation is required for the aberrant ectopic bone formation in FOP. We show that the expression of Indian hedgehog (Ihh), a Hh ligand, as well as downstream Hh signaling, was increased in ectopic bone lesions in Acvr1^R206H; ScxCre mice. Pharmacological treatment with an Ihh-neutralizing monoclonal antibody dramatically reduced chondrogenesis and ectopic bone formation. Moreover, we find that the activation of Yap in the FOP mouse model and the genetic deletion of Yap halted ectopic bone formation and decreased Ihh expression. Our mechanistic studies showed that Yap and Smad1 directly bind to the Ihh promoter and coordinate to induce chondrogenesis by promoting Ihh expression. Therefore, the Yap activation in FOP lesions promoted ectopic bone formation and expansion in both cell-autonomous and non-cell-autonomous manners. These results uncovered the crucial role of the Yap-Ihh axis in FOP pathogenesis, suggesting the inhibition of Ihh or Yap as a potential therapeutic strategy to prevent and reduce HO. Full article

(This article belongs to the Special Issue Fibrodysplasia Ossificans Progressiva (FOP): From Molecular Mechanisms to Therapeutic Strategies)

► Show Figures

Figure 1

16 pages, 2285 KiB

Open AccessEditor’s ChoiceReview

Advances in AI for Protein Structure Prediction: Implications for Cancer Drug Discovery and Development

by Xinru Qiu, Han Li, Greg Ver Steeg and Adam Godzik

Biomolecules 2024, 14(3), 339; https://doi.org/10.3390/biom14030339 - 12 Mar 2024

Cited by 5 | Viewed by 10018

Abstract

Recent advancements in AI-driven technologies, particularly in protein structure prediction, are significantly reshaping the landscape of drug discovery and development. This review focuses on the question of how these technological breakthroughs, exemplified by AlphaFold2, are revolutionizing our understanding of protein structure and function [...] Read more.

Recent advancements in AI-driven technologies, particularly in protein structure prediction, are significantly reshaping the landscape of drug discovery and development. This review focuses on the question of how these technological breakthroughs, exemplified by AlphaFold2, are revolutionizing our understanding of protein structure and function changes underlying cancer and improve our approaches to counter them. By enhancing the precision and speed at which drug targets are identified and drug candidates can be designed and optimized, these technologies are streamlining the entire drug development process. We explore the use of AlphaFold2 in cancer drug development, scrutinizing its efficacy, limitations, and potential challenges. We also compare AlphaFold2 with other algorithms like ESMFold, explaining the diverse methodologies employed in this field and the practical effects of these differences for the application of specific algorithms. Additionally, we discuss the broader applications of these technologies, including the prediction of protein complex structures and the generative AI-driven design of novel proteins. Full article

(This article belongs to the Special Issue Protein Structure Prediction in Drug Discovery: 2nd Edition)

► Show Figures

Graphical abstract

29 pages, 3906 KiB

Open AccessEditor’s ChoiceReview

LL-37: Structures, Antimicrobial Activity, and Influence on Amyloid-Related Diseases

by Surajit Bhattacharjya, Zhizhuo Zhang and Ayyalusamy Ramamoorthy

Biomolecules 2024, 14(3), 320; https://doi.org/10.3390/biom14030320 - 8 Mar 2024

Cited by 9 | Viewed by 3534

Abstract

Antimicrobial peptides (AMPs), as well as host defense peptides (HDPs), constitute the first line of defense as part of the innate immune system. Humans are known to express antimicrobial precursor proteins, which are further processed to generate AMPs, including several types of α/β [...] Read more.

Antimicrobial peptides (AMPs), as well as host defense peptides (HDPs), constitute the first line of defense as part of the innate immune system. Humans are known to express antimicrobial precursor proteins, which are further processed to generate AMPs, including several types of α/β defensins, histatins, and cathelicidin-derived AMPs like LL37. The broad-spectrum activity of AMPs is crucial to defend against infections caused by pathogenic bacteria, viruses, fungi, and parasites. The emergence of multi-drug resistant pathogenic bacteria is of global concern for public health. The prospects of targeting antibiotic-resistant strains of bacteria with AMPs are of high significance for developing new generations of antimicrobial agents. The 37-residue long LL37, the only cathelicidin family of AMP in humans, has been the major focus for the past few decades of research. The host defense activity of LL37 is likely underscored by its expression throughout the body, spanning from the epithelial cells of various organs—testis, skin, respiratory tract, and gastrointestinal tract—to immune cells. Remarkably, apart from canonical direct killing of pathogenic organisms, LL37 exerts several other host defense activities, including inflammatory response modulation, chemo-attraction, and wound healing and closure at the infected sites. In addition, LL37 and its derived peptides are bestowed with anti-cancer and anti-amyloidogenic properties. In this review article, we aim to develop integrative, mechanistic insight into LL37 and its derived peptides, based on the known biophysical, structural, and functional studies in recent years. We believe that this review will pave the way for future research on the structures, biochemical and biophysical properties, and design of novel LL37-based molecules. Full article

(This article belongs to the Special Issue Development, Characterization, and Application of Bioactive Peptides, Diagnostic Biomarkers, and Pharmaceutical Proteins)

► Show Figures

Figure 1

17 pages, 900 KiB

Open AccessEditor’s ChoiceReview

Post-Translational Modifications and Diabetes

by Chiranjeev Sharma, Abu Hamza, Emily Boyle, Dickson Donu and Yana Cen

Biomolecules 2024, 14(3), 310; https://doi.org/10.3390/biom14030310 - 6 Mar 2024

Cited by 5 | Viewed by 2968

Abstract

Diabetes and its associated complications have increasingly become major challenges for global healthcare. The current therapeutic strategies involve insulin replacement therapy for type 1 diabetes (T1D) and small-molecule drugs for type 2 diabetes (T2D). Despite these advances, the complex nature of diabetes necessitates [...] Read more.

Diabetes and its associated complications have increasingly become major challenges for global healthcare. The current therapeutic strategies involve insulin replacement therapy for type 1 diabetes (T1D) and small-molecule drugs for type 2 diabetes (T2D). Despite these advances, the complex nature of diabetes necessitates innovative clinical interventions for effective treatment and complication prevention. Accumulative evidence suggests that protein post-translational modifications (PTMs), including glycosylation, phosphorylation, acetylation, and SUMOylation, play important roles in diabetes and its pathological consequences. Therefore, the investigation of these PTMs not only sheds important light on the mechanistic regulation of diabetes but also opens new avenues for targeted therapies. Here, we offer a comprehensive overview of the role of several PTMs in diabetes, focusing on the most recent advances in understanding their functions and regulatory mechanisms. Additionally, we summarize the pharmacological interventions targeting PTMs that have advanced into clinical trials for the treatment of diabetes. Current challenges and future perspectives are also provided. Full article

► Show Figures

Figure 1

15 pages, 2511 KiB

Open AccessEditor’s ChoiceArticle

Menthol Pretreatment Alleviates Campylobacter jejuni-Induced Enterocolitis in Human Gut Microbiota-Associated IL-10^−/− Mice

by Markus M. Heimesaat, Luis Q. Langfeld, Niklas Schabbel, Nizar W. Shayya, Soraya Mousavi and Stefan Bereswill

Biomolecules 2024, 14(3), 290; https://doi.org/10.3390/biom14030290 - 29 Feb 2024

Cited by 1 | Viewed by 1595

Abstract

Human Campylobacter jejuni infections are of worldwide importance and represent the most commonly reported bacterial enteritis cases in middle- and high-income countries. Since antibiotics are usually not indicated and the severity of campylobacteriosis is directly linked to the risk of developing post-infectious complications, [...] Read more.

Human Campylobacter jejuni infections are of worldwide importance and represent the most commonly reported bacterial enteritis cases in middle- and high-income countries. Since antibiotics are usually not indicated and the severity of campylobacteriosis is directly linked to the risk of developing post-infectious complications, non-toxic antibiotic-independent treatment approaches are highly desirable. Given its health-promoting properties, including anti-microbial and anti-inflammatory activities, we tested the disease-alleviating effects of oral menthol in murine campylobacteriosis. Therefore, human gut microbiota-associated IL-10^−/− mice were orally subjected to synthetic menthol starting a week before C. jejuni infection and followed up until day 6 post-infection. Whereas menthol pretreatment did not improve campylobacteriosis symptoms, it resulted in reduced colonic C. jejuni numbers and alleviated both macroscopic and microscopic aspects of C. jejuni infection in pretreated mice vs. controls. Menthol pretreatment dampened the recruitment of macrophages, monocytes, and T lymphocytes to colonic sites of infection, which was accompanied by mitigated intestinal nitric oxide secretion. Furthermore, menthol pretreatment had only marginal effects on the human fecal gut microbiota composition during the C. jejuni infection. In conclusion, the results of this preclinical placebo-controlled intervention study provide evidence that menthol application constitutes a promising way to tackle acute campylobacteriosis, thereby reducing the risk for post-infectious complications. Full article

(This article belongs to the Special Issue The Value of Natural Compounds as Therapeutic Agents: 2nd Edition)

► Show Figures

Figure 1

Journal Menu

Journal Browser

Editor’s Choice Articles

Further Information

Guidelines

MDPI Initiatives

Follow MDPI