International Journal of Molecular Sciences

3 pages, 169 KiB

Open AccessEditorial

by Domenico Galati and Serena Zanotta

Int. J. Mol. Sci. 2023, 24(4), 4253; https://doi.org/10.3390/ijms24044253 - 20 Feb 2023

Cited by 11 | Viewed by 3861

Dendritic cells (DCs) are acknowledged as the most potent professional antigen-presenting cells (APCs), able to induce adaptive immunity and support the innate immune response [...] Full article

(This article belongs to the Special Issue Dendritic Cell and Cancer Therapy)

16 pages, 1894 KiB

Open AccessArticle

Vx-809, a CFTR Corrector, Acts through a General Mechanism of Protein Folding and on the Inflammatory Process

by Michela Pecoraro, Adele Serra, Maria Pascale and Silvia Franceschelli

Int. J. Mol. Sci. 2023, 24(4), 4252; https://doi.org/10.3390/ijms24044252 - 20 Feb 2023

Cited by 5 | Viewed by 2693

Abstract

Correct protein folding is the basis of cellular well-being; thus, accumulation of misfolded proteins within the endoplasmic reticulum (ER) leads to an imbalance of homeostasis that causes stress to the ER. Various studies have shown that protein misfolding is a significant factor in [...] Read more.

Correct protein folding is the basis of cellular well-being; thus, accumulation of misfolded proteins within the endoplasmic reticulum (ER) leads to an imbalance of homeostasis that causes stress to the ER. Various studies have shown that protein misfolding is a significant factor in the etiology of many human diseases, including cancer, diabetes, and cystic fibrosis. Misfolded protein accumulation in the ER triggers a sophisticated signal transduction pathway, the unfolded protein response (UPR), which is controlled by three proteins, resident in ER: IRE1α, PERK, and ATF6. Briefly, when ER stress is irreversible, IRE1α induces the activation of pro-inflammatory proteins; PERK phosphorylates eIF2α which induces ATF4 transcription, while ATF6 activates genes encoding ER chaperones. Reticular stress causes an alteration of the calcium homeostasis, which is released from the ER and taken up by the mitochondria, leading to an increase in the oxygen radical species production, and consequently, to oxidative stress. Accumulation of intracellular calcium, in combination with lethal ROS levels, has been associated with an increase of pro-inflammatory protein expression and the initiation of the inflammatory process. Lumacaftor (Vx-809) is a common corrector used in cystic fibrosis treatment which enhances the folding of mutated F508del-CFTR, one of the most prevalent impaired proteins underlying the disease, promoting a higher localization of the mutant protein on the cell membrane. Here, we demonstrate that this drug reduces the ER stress and, consequently, the inflammation that is caused by such events. Thus, this molecule is a promising drug to treat several pathologies that present an etiopathogenesis due to the accumulation of protein aggregates that lead to chronic reticular stress. Full article

(This article belongs to the Special Issue Research on Protein Misfolding)

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25 pages, 2584 KiB

Open AccessReview

Potential Novel Role of Membrane-Associated Carbonic Anhydrases in the Kidney

by Seong-Ki Lee, Walter F. Boron and Rossana Occhipinti

Int. J. Mol. Sci. 2023, 24(4), 4251; https://doi.org/10.3390/ijms24044251 - 20 Feb 2023

Cited by 5 | Viewed by 3816

Abstract

Carbonic anhydrases (CAs), because they catalyze the interconversion of carbon dioxide (CO₂) and water into bicarbonate (HCO₃⁻) and protons (H⁺), thereby influencing pH, are near the core of virtually all physiological processes in the body. In [...] Read more.

Carbonic anhydrases (CAs), because they catalyze the interconversion of carbon dioxide (CO₂) and water into bicarbonate (HCO₃⁻) and protons (H⁺), thereby influencing pH, are near the core of virtually all physiological processes in the body. In the kidneys, soluble and membrane-associated CAs and their synergy with acid–base transporters play important roles in urinary acid secretion, the largest component of which is the reabsorption of HCO₃⁻ in specific nephron segments. Among these transporters are the Na⁺-coupled HCO₃⁻ transporters (NCBTs) and the Cl⁻-HCO₃⁻ exchangers (AEs)—members of the “solute-linked carrier” 4 (SLC4) family. All of these transporters have traditionally been regarded as “HCO₃⁻“ transporters. However, recently our group has demonstrated that two of the NCBTs carry CO₃²⁻ rather than HCO₃⁻ and has hypothesized that all NCBTs follow suit. In this review, we examine current knowledge on the role of CAs and “HCO₃⁻” transporters of the SLC4 family in renal acid–base physiology and discuss how our recent findings impact renal acid secretion, including HCO₃⁻ reabsorption. Traditionally, investigators have associated CAs with producing or consuming solutes (CO₂, HCO₃⁻, and H⁺) and thus ensuring their efficient transport across cell membranes. In the case of CO₃²⁻ transport by NCBTs, however, we hypothesize that the role of membrane-associated CAs is not the appreciable production or consumption of substrates but the minimization of pH changes in nanodomains near the membrane. Full article

(This article belongs to the Special Issue Carbonic Anhydrase and Carbonic Anhydrase Inhibitors)

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18 pages, 2063 KiB

Open AccessReview

Extracellular Vesicles as “Very Important Particles” (VIPs) in Aging

by Cristina Mas-Bargues and Matilde Alique

Int. J. Mol. Sci. 2023, 24(4), 4250; https://doi.org/10.3390/ijms24044250 - 20 Feb 2023

Cited by 13 | Viewed by 6005

Abstract

In recent decades, extracellular vesicles have been recognized as “very important particles” (VIPs) associated with aging and age-related disease. During the 1980s, researchers discovered that these vesicle particles released by cells were not debris but signaling molecules carrying cargoes that play key roles [...] Read more.

In recent decades, extracellular vesicles have been recognized as “very important particles” (VIPs) associated with aging and age-related disease. During the 1980s, researchers discovered that these vesicle particles released by cells were not debris but signaling molecules carrying cargoes that play key roles in physiological processes and physiopathological modulation. Following the International Society for Extracellular Vesicles (ISEV) recommendation, different vesicle particles (e.g., exosomes, microvesicles, oncosomes) have been named globally extracellular vesicles. These vesicles are essential to maintain body homeostasis owing to their essential and evolutionarily conserved role in cellular communication and interaction with different tissues. Furthermore, recent studies have shown the role of extracellular vesicles in aging and age-associated diseases. This review summarizes the advances in the study of extracellular vesicles, mainly focusing on recently refined methods for their isolation and characterization. In addition, the role of extracellular vesicles in cell signaling and maintenance of homeostasis, as well as their usefulness as new biomarkers and therapeutic agents in aging and age-associated diseases, has also been highlighted. Full article

(This article belongs to the Special Issue Molecular Biology of Senescence)

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Graphical abstract

16 pages, 4573 KiB

Open AccessArticle

Metabolomic Insights of Biosurfactant Activity from Bacillus niabensis against Planktonic Cells and Biofilm of Pseudomonas stutzeri Involved in Marine Biofouling

by Ilse Sánchez-Lozano, Luz Clarita Muñoz-Cruz, Claire Hellio, Christine J. Band-Schmidt, Yair Cruz-Narváez, Elvia Becerra-Martínez and Claudia J. Hernández-Guerrero

Int. J. Mol. Sci. 2023, 24(4), 4249; https://doi.org/10.3390/ijms24044249 - 20 Feb 2023

Cited by 2 | Viewed by 2449

Abstract

In marine environments, biofilm can cause negative impacts, including the biofouling process. In the search for new non-toxic formulations that inhibit biofilm, biosurfactants (BS) produced by the genus Bacillus have demonstrated considerable potential. To elucidate the changes that BS from B. niabensis promote [...] Read more.

In marine environments, biofilm can cause negative impacts, including the biofouling process. In the search for new non-toxic formulations that inhibit biofilm, biosurfactants (BS) produced by the genus Bacillus have demonstrated considerable potential. To elucidate the changes that BS from B. niabensis promote in growth inhibition and biofilm formation, this research performed a nuclear magnetic resonance (NMR) metabolomic profile analysis to compare the metabolic differences between planktonic cells and biofilms of Pseudomonas stutzeri, a pioneer fouling bacteria. The multivariate analysis showed a clear separation between groups with a higher concentration of metabolites in the biofilm than in planktonic cells of P. stutzeri. When planktonic and biofilm stages were treated with BS, some differences were found among them. In planktonic cells, the addition of BS had a minor effect on growth inhibition, but at a metabolic level, NADP+, trehalose, acetone, glucose, and betaine were up-regulated in response to osmotic stress. When the biofilm was treated with the BS, a clear inhibition was observed and metabolites such as glucose, acetic acid, histidine, lactic acid, phenylalanine, uracil, and NADP+ were also up-regulated, while trehalose and histamine were down-regulated in response to the antibacterial effect of the BS. Full article

(This article belongs to the Special Issue Biofouling and Antifouling: Application of Omics Technologies)

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25 pages, 6748 KiB

Open AccessArticle

Exopolysaccharide Biosynthesis in Rhizobium leguminosarum bv. trifolii Requires a Complementary Function of Two Homologous Glycosyltransferases PssG and PssI

by Kamil Żebracki, Aleksandra Horbowicz, Małgorzata Marczak, Anna Turska-Szewczuk, Piotr Koper, Klaudia Wójcik, Marceli Romańczuk, Magdalena Wójcik and Andrzej Mazur

Int. J. Mol. Sci. 2023, 24(4), 4248; https://doi.org/10.3390/ijms24044248 - 20 Feb 2023

Cited by 2 | Viewed by 2231

Abstract

The Pss-I region of Rhizobium leguminosarum bv. trifolii TA1 comprises more than 20 genes coding for glycosyltransferases, modifying enzymes, and polymerization/export proteins, altogether determining the biosynthesis of symbiotically relevant exopolysaccharides. In this study, the role of homologous PssG and PssI glycosyltransferases in exopolysaccharide [...] Read more.

The Pss-I region of Rhizobium leguminosarum bv. trifolii TA1 comprises more than 20 genes coding for glycosyltransferases, modifying enzymes, and polymerization/export proteins, altogether determining the biosynthesis of symbiotically relevant exopolysaccharides. In this study, the role of homologous PssG and PssI glycosyltransferases in exopolysaccharide subunit synthesis were analyzed. It was shown that the glycosyltransferase-encoding genes of the Pss-I region were part of a single large transcriptional unit with potential downstream promoters activated in specific conditions. The ΔpssG and ΔpssI mutants produced significantly lower amounts of the exopolysaccharide, while the double deletion mutant ΔpssIΔpssG produced no exopolysaccharide. Complementation of double mutation with individual genes restored exopolysaccharide synthesis, but only to the level similar to that observed for the single ΔpssI or ΔpssG mutants, indicating that PssG and PssI serve complementary functions in the process. PssG and PssI interacted with each other in vivo and in vitro. Moreover, PssI displayed an expanded in vivo interaction network comprising other GTs involved in subunit assembly and polymerization/export proteins. PssG and PssI proteins were shown to interact with the inner membrane through amphipathic helices at their C-termini, and PssG also required other proteins involved in exopolysaccharide synthesis to localize in the membrane protein fraction. Full article

(This article belongs to the Collection State-of-the-Art Molecular Microbiology in Poland)

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19 pages, 2001 KiB

Open AccessReview

Peptide Designs for Use in Caries Management: A Systematic Review

by Olivia Lili Zhang, John Yun Niu, Ollie Yiru Yu, May Lei Mei, Nicholas Stephen Jakubovics and Chun Hung Chu

Int. J. Mol. Sci. 2023, 24(4), 4247; https://doi.org/10.3390/ijms24044247 - 20 Feb 2023

Cited by 7 | Viewed by 2392

Abstract

The objective of this study was to review the design methods that have been used to create peptides for use in caries management. Two independent researchers systematically reviewed many in vitro studies in which peptides were designed for use in caries management. They [...] Read more.

The objective of this study was to review the design methods that have been used to create peptides for use in caries management. Two independent researchers systematically reviewed many in vitro studies in which peptides were designed for use in caries management. They assessed the risk of bias in the included studies. This review identified 3592 publications, of which 62 were selected. Forty-seven studies reported 57 antimicrobial peptides. Among them, 31 studies (66%, 31/47) used the template-based design method; 9 studies (19%, 9/47) used the conjugation method; and 7 studies (15%, 7/47) used other methods, such as the synthetic combinatorial technology method, the de novo design method and cyclisation. Ten studies reported mineralising peptides. Seven of these (70%, 7/10) used the template-based design method, two (20%, 2/10) used the de novo design method, and one study (10%, 1/10) used the conjugation method. In addition, five studies developed their own peptides with antimicrobial and mineralising properties. These studies used the conjugation method. Our assessment for the risk of bias in the 62 reviewed studies showed that 44 publications (71%, 44/62) had a medium risk and that 3 publications had a low risk (5%, 3/62). The two most common methods for developing peptides for use in caries management that were used in these studies were the template-based design method and the conjugation method. Full article

(This article belongs to the Special Issue Microbial Resistance Mechanisms)

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19 pages, 2523 KiB

Open AccessArticle

Nuclear High Mobility Group A2 (HMGA2) Interactome Revealed by Biotin Proximity Labeling

by Antoine Gaudreau-Lapierre, Thomas Klonisch, Hannah Nicolas, Thatchawan Thanasupawat, Laura Trinkle-Mulcahy and Sabine Hombach-Klonisch

Int. J. Mol. Sci. 2023, 24(4), 4246; https://doi.org/10.3390/ijms24044246 - 20 Feb 2023

Cited by 4 | Viewed by 2710

Abstract

The non-histone chromatin binding protein High Mobility Group AT-hook protein 2 (HMGA2) has important functions in chromatin remodeling, and genome maintenance and protection. Expression of HMGA2 is highest in embryonic stem cells, declines during cell differentiation and cell aging, but it is re-expressed [...] Read more.

The non-histone chromatin binding protein High Mobility Group AT-hook protein 2 (HMGA2) has important functions in chromatin remodeling, and genome maintenance and protection. Expression of HMGA2 is highest in embryonic stem cells, declines during cell differentiation and cell aging, but it is re-expressed in some cancers, where high HMGA2 expression frequently coincides with a poor prognosis. The nuclear functions of HMGA2 cannot be explained by binding to chromatin alone but involve complex interactions with other proteins that are incompletely understood. The present study used biotin proximity labeling, followed by proteomic analysis, to identify the nuclear interaction partners of HMGA2. We tested two different biotin ligase HMGA2 constructs (BioID2 and miniTurbo) with similar results, and identified known and new HMGA2 interaction partners, with functionalities mainly in chromatin biology. These HMGA2 biotin ligase fusion constructs offer exciting new possibilities for interactome discovery research, enabling the monitoring of nuclear HMGA2 interactomes during drug treatments. Full article

(This article belongs to the Special Issue Proteomics and Its Applications in Cancers 2.0)

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18 pages, 5017 KiB

Open AccessArticle

Microbiome Dysbiosis Shows Strong Association of Gut-Derived Altered Metabolomic Profile in Gulf War Chronic Multisymptom Illness Symptom Persistence Following Western Diet Feeding and Development of Obesity

by Dipro Bose, Vitalli Stebliankin, Trevor Cickovski, Punnag Saha, Ayushi Trivedi, Subhajit Roy, Madhura More, Ashok Tuteja, Kalai Mathee, Giri Narasimhan and Saurabh Chatterjee

Int. J. Mol. Sci. 2023, 24(4), 4245; https://doi.org/10.3390/ijms24044245 - 20 Feb 2023

Cited by 1 | Viewed by 4896

Abstract

The pathophysiology of Gulf War Illness (GWI) remains elusive even after three decades. The persistence of multiple complex symptoms along with metabolic disorders such as obesity worsens the health of present Gulf War (GW) Veterans often by the interactions of the host gut [...] Read more.

The pathophysiology of Gulf War Illness (GWI) remains elusive even after three decades. The persistence of multiple complex symptoms along with metabolic disorders such as obesity worsens the health of present Gulf War (GW) Veterans often by the interactions of the host gut microbiome and inflammatory mediators. In this study, we hypothesized that the administration of a Western diet might alter the host metabolomic profile, which is likely associated with the altered bacterial species. Using a five-month symptom persistence GWI model in mice and whole-genome sequencing, we characterized the species-level dysbiosis and global metabolomics, along with heterogenous co-occurrence network analysis, to study the bacteriome–metabolomic association. Microbial analysis at the species level showed a significant alteration of beneficial bacterial species. The beta diversity of the global metabolomic profile showed distinct clustering due to the Western diet, along with the alteration of metabolites associated with lipid, amino acid, nucleotide, vitamin, and xenobiotic metabolism pathways. Network analysis showed novel associations of gut bacterial species with metabolites and biochemical pathways that could be used as biomarkers or therapeutic targets to ameliorate symptom persistence in GW Veterans. Full article

(This article belongs to the Special Issue The Microbiota and Its Association with Cellular Transformation and Metabolic Changes)

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13 pages, 2804 KiB

Open AccessArticle

Exogenous Ethylene Alleviates the Inhibition of Sorbus pohuashanensis Embryo Germination in a Saline-Alkali Environment (NaHCO₃)

by Yutong Wang, Caihong Zhao, Xiaodong Wang, Hailong Shen and Ling Yang

Int. J. Mol. Sci. 2023, 24(4), 4244; https://doi.org/10.3390/ijms24044244 - 20 Feb 2023

Cited by 5 | Viewed by 1932

Abstract

Saline-alkali stress is a major environmental stress affecting the growth and development of plants such as Sorbus pohuashanensis. Although ethylene plays a crucial role in plant response to saline-alkaline stress, its mechanism remains elusive. The mechanism of action of ethylene (ETH) may be [...] Read more.

Saline-alkali stress is a major environmental stress affecting the growth and development of plants such as Sorbus pohuashanensis. Although ethylene plays a crucial role in plant response to saline-alkaline stress, its mechanism remains elusive. The mechanism of action of ethylene (ETH) may be related to the accumulation of hormones, reactive oxygen species (ROS), and reactive nitrogen species (RNS). Ethephon is the exogenous ethylene donor. Therefore, for the present study we initially used different concentrations of ethephon (ETH) to treat S. pohuashanensis embryos and identified the best treatment concentration and method to promote the release of dormancy and the germination of S. pohuashanensis embryos. We then analyzed the physiological indexes, including endogenous hormones, ROS, antioxidant components, and reactive nitrogen, in embryos and seedlings to elucidate the mechanism via which ETH manages stress. The analysis showed that 45 mg/L was the best concentration of ETH to relieve the embryo dormancy. ETH at this concentration improved the germination of S. pohuashanensis by 183.21% under saline-alkaline stress; it also improved the germination index and germination potential of the embryos. Further analysis revealed that ETH treatment increased the levels of 1-aminocyclopropane-1-carboxylic acid (ACC), gibberellin (GA), soluble protein, nitric oxide (NO), and glutathione (GSH); increased the activities of superoxide dismutase (SOD), peroxidase (POD), catalase (CAT), nitrate reductase (NR), and nitric oxide synthase (NOS); and decreased the levels of abscisic acid (ABA), hydrogen peroxide (H₂O₂), superoxide anion, and malondialdehyde (MDA) of S. pohuashanensis under saline-alkali stress. These results indicate that ETH mitigates the inhibitory effects of saline-alkali stress and provides a theoretical basis by which to establish precise control techniques for the release of seed dormancy of tree species. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Advances in Biochemistry)

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12 pages, 773 KiB

Open AccessReview

Adjuvant Therapy for Renal Cell Carcinoma: Hype or Hope?

by Federica Cosso, Giandomenico Roviello, Gabriella Nesi, Sonia Shabani, Pietro Spatafora, Donata Villari and Martina Catalano

Int. J. Mol. Sci. 2023, 24(4), 4243; https://doi.org/10.3390/ijms24044243 - 20 Feb 2023

Cited by 9 | Viewed by 4160

Abstract

Renal cell carcinoma (RCC) is the third most common genitourinary cancer accounting for approximately 180,000 deaths worldwide in 2020. Although over two-thirds of patients initially present localized disease, up to 50% of them may progress to metastatic disease. Adjuvant therapy aims to reduce [...] Read more.

Renal cell carcinoma (RCC) is the third most common genitourinary cancer accounting for approximately 180,000 deaths worldwide in 2020. Although over two-thirds of patients initially present localized disease, up to 50% of them may progress to metastatic disease. Adjuvant therapy aims to reduce the recurrence risk and improve outcomes in several types of cancers but is currently an unmet need in RCC. The results achieved with tyrosine kinase inhibitors in metastatic RCC led to the evaluation of these target therapies in an early setting with conflicting results for disease-free survival and no overall survival (OS) benefit. Likewise, the results of immune checkpoint inhibitors (ICIs) in an adjuvant setting are conflicting. Available data did not show an improvement in OS with ICIs in the early phase, although a positive trend for pembrolizumab has been recorded, receiving the Food and Drug Administration’s approval in this setting. However, the disappointing results of several ICIs and the heterogeneous pattern of RCC warrant biomarker identification and subgroup analyses to evaluate which patients could benefit from adjuvant therapy. In this review, we will discuss the rationale for adjuvant treatment in RCC, summarizing the results of the most important adjuvant therapy trials and current applications, to outline possible future directions. Full article

(This article belongs to the Special Issue Cancer Immunotherapy Using Checkpoint Inhibitors: Future Directions 3.0)

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13 pages, 1735 KiB

Open AccessReview

Neuroinflammation and Oxidative Stress in Individuals Affected by DiGeorge Syndrome

by Michela Menghi, Ginevra Micangeli, Francesca Tarani, Carolina Putotto, Federica Pirro, Alessandro Mariani, Carla Petrella, Federica Pulvirenti, Bianca Cinicola, Fiorenza Colloridi, Luigi Tarani and Marco Fiore

Int. J. Mol. Sci. 2023, 24(4), 4242; https://doi.org/10.3390/ijms24044242 - 20 Feb 2023

Cited by 2 | Viewed by 13387

Abstract

DiGeorge syndrome (DGS) is a rare genetic disease caused by microdeletions of the 22q11.2 region (DGS1). A haploinsufficiency at 10p level has been proposed also as a DGS cause (DGS2). Clinical manifestations are variable. The most frequent features are thymic hypoplasia or aplasia [...] Read more.

DiGeorge syndrome (DGS) is a rare genetic disease caused by microdeletions of the 22q11.2 region (DGS1). A haploinsufficiency at 10p level has been proposed also as a DGS cause (DGS2). Clinical manifestations are variable. The most frequent features are thymic hypoplasia or aplasia with consequent immune deficiency, cardiac malformations, hypoparathyroidism, facial and palatine abnormalities, variable degrees of cognitive impairment and psychiatric disorders. The specific aim of this descriptive report is to discuss the correlation between oxidative stress and neuroinflammation in DGS patients with microdeletions of the 22q11.2 region. The deleted chromosomic region maps various genes involved in mitochondrial metabolisms, such as DGCR8 and TXNRD2, that could lead to reactive oxygen species (ROS) increased production and antioxidant depletion. Furthermore, increased levels of ROS in mitochondria would lead to the destruction of the projection neurons in the cerebral cortex with consequent neurocognitive impairment. Finally, the increase in modified protein belonging to the family of sulfoxide compounds and hexoses, acting as inhibitors of the IV and V mitochondria complex, could result in direct ROS overproduction. Neuroinflammation in DGS individuals could be directly related to the development of the syndrome’s characteristic psychiatric and cognitive disorders. In patients with psychotic disorders, the most frequent psychiatric manifestation in DGS, Th-17, Th-1 and Th-2 cells are increased with consequent elevation of proinflammatory cytokine IL-6 and IL1

β

. In patients with anxiety disorders, both CD3 and CD4 are increased. Some patients with autism spectrum disorders (ASDs) have an augmented level of proinflammatory cytokines IL-12, IL-6 and IL-1

β

, while IFN

γ

and the anti-inflammatory cytokine IL-10 seem to be reduced. Other data proposed that altered synaptic plasticity could be directly involved in DGS cognitive disorders. In conclusion, the use of antioxidants for restoring mitochondrial functionality in DGS could be a useful tool to protect cortical connectivity and cognitive behavior. Full article

(This article belongs to the Special Issue The Interplay of Oxidative Stress and Inflammation: From Mechanisms to Therapeutic Approaches)

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10 pages, 846 KiB

Open AccessCommunication

A Model Eumelanin from 5,6-Dihydroxyindole-2-Carboxybutanamide Combining Remarkable Antioxidant and Photoprotective Properties with a Favourable Solubility Profile for Dermo-Cosmetic Applications

by Rita Argenziano, Maria Laura Alfieri, Noemi Gallucci, Gerardino D’Errico, Lucia Panzella and Alessandra Napolitano

Int. J. Mol. Sci. 2023, 24(4), 4241; https://doi.org/10.3390/ijms24044241 - 20 Feb 2023

Viewed by 1867

Abstract

The search for new synthetic melanin-related pigments that maintain the antioxidant and photoprotective properties of naturally occurring dark eumelanins, while overcoming their unfavorable solubility, and molecular heterogeneity is presently a very active issue for dermo-cosmetic purposes. In this work, we explored the potential [...] Read more.

The search for new synthetic melanin-related pigments that maintain the antioxidant and photoprotective properties of naturally occurring dark eumelanins, while overcoming their unfavorable solubility, and molecular heterogeneity is presently a very active issue for dermo-cosmetic purposes. In this work, we explored the potential of a melanin obtained from the carboxybutanamide of a major eumelanin biosynthetic precursor, 5,6-dihydroxyindole-2-carboxylic acid (DHICA), by aerobic oxidation under slightly alkaline conditions. Analysis of the pigment by EPR, ATR-FTIR and MALDI MS indicated a substantial structural similarity to DHICA melanin, while investigation of the early intermediates confirmed unchanged regiochemistry of the oxidative coupling. The pigment exhibited a UVA–visible absorption even more intense than that of DHICA melanin, and a noticeable solubility in polar solvents of dermo-cosmetic relevance. The hydrogen- and/or electron-donor ability, and the iron (III) reducing power as determined by conventional assays provided evidence for marked antioxidant properties not merely ascribable to the more favorable solubility profile, while the inhibitory action of the radical- or photosensitized solar light-induced lipid peroxidation was more marked compared to that of DHICA melanin. Overall, these results hint at this melanin, which remarkable properties are, in part, due to the electronic effects of the carboxyamide functionality as a promising functional ingredient for dermo-cosmetic formulations. Full article

(This article belongs to the Special Issue Melanins and Melanogenesis 3.0: From Nature to Applications)

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21 pages, 4673 KiB

Open AccessArticle

YTHDF1 Attenuates TBI-Induced Brain-Gut Axis Dysfunction in Mice

by Peizan Huang, Min Liu, Jing Zhang, Xiang Zhong and Chunlong Zhong

Int. J. Mol. Sci. 2023, 24(4), 4240; https://doi.org/10.3390/ijms24044240 - 20 Feb 2023

Cited by 11 | Viewed by 2841

Abstract

The brain-gut axis (BGA) is a significant bidirectional communication pathway between the brain and gut. Traumatic brain injury (TBI) induced neurotoxicity and neuroinflammation can affect gut functions through BGA. N⁶-methyladenosine (m⁶A), as the most popular posttranscriptional modification of eukaryotic [...] Read more.

The brain-gut axis (BGA) is a significant bidirectional communication pathway between the brain and gut. Traumatic brain injury (TBI) induced neurotoxicity and neuroinflammation can affect gut functions through BGA. N⁶-methyladenosine (m⁶A), as the most popular posttranscriptional modification of eukaryotic mRNA, has recently been identified as playing important roles in both the brain and gut. However, whether m⁶A RNA methylation modification is involved in TBI-induced BGA dysfunction is not clear. Here, we showed that YTHDF1 knockout reduced histopathological lesions and decreased the levels of apoptosis, inflammation, and oedema proteins in brain and gut tissues in mice after TBI. We also found that YTHDF1 knockout improved fungal mycobiome abundance and probiotic (particularly Akkermansia) colonization in mice at 3 days post-CCI. Then, we identified the differentially expressed genes (DEGs) in the cortex between YTHDF1-knockout and WT mice. These genes were primarily enriched in the regulation of neurotransmitter-related neuronal signalling pathways, inflammatory signalling pathways, and apoptotic signalling pathways. This study reveals that the ITGA6-mediated cell adhesion molecule signalling pathway may be the key feature of m⁶A regulation in TBI-induced BGA dysfunction. Our results suggest that YTHDF1 knockout could attenuate TBI-induced BGA dysfunction. Full article

(This article belongs to the Special Issue The Microbiota-Gut-Brain Axis in Relation to Non-communicable Diseases)

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17 pages, 2450 KiB

Open AccessArticle

Comparative Analysis of miRNA-mRNA Regulation in the Testes of Gobiocypris rarus following 17α-Methyltestosterone Exposure

by Shaozhen Liu, Junliang Zhou, Qiong Yang, Yue Chen, Qing Liu, Weiwei Wang, Jing Song, Xianzong Wang and Yu Liu

Int. J. Mol. Sci. 2023, 24(4), 4239; https://doi.org/10.3390/ijms24044239 - 20 Feb 2023

Cited by 2 | Viewed by 1822

Abstract

17α-Methyltestosterone (17MT), a synthetic organic compound commonly found in sewage waters, can affect reproduction in aquatic animals, such as tilapia and yellow catfish. In the present study, male Gobiocypris rarus were exposed to 25, 50, and 100 ng/L of 17α-methyltestosterone (17MT) for 7 [...] Read more.

17α-Methyltestosterone (17MT), a synthetic organic compound commonly found in sewage waters, can affect reproduction in aquatic animals, such as tilapia and yellow catfish. In the present study, male Gobiocypris rarus were exposed to 25, 50, and 100 ng/L of 17α-methyltestosterone (17MT) for 7 days. We first analyzed miRNA- and RNA-seq results to determine miRNA-target gene pairs and then developed miRNA-mRNA interactive networks after 17MT administration. Total weights, total lengths, and body lengths were not significantly different between the test groups and control groups. The paraffin slice method was applied to testes of G. rarus in the MT exposure and control groups. We found that there were more mature sperm (S) and fewer secondary spermatocytes (SSs) and spermatogonia (SGs) in the testes of control groups. As 17MT concentration increased, fewer and fewer mature sperm (S) were observed in the testes of male G. rarus. The results showed that FSH, 11-KT, and E2 were significantly higher in individuals exposed to 25 ng/L 17MT compared with the control groups. VTG, FSH, LH, 11-KT, and E2 were significantly lower in the 50 ng/L 17MT exposure groups compared to the control groups. VTG, FSH, LH, 11-KT, E2, and T were significantly lower in the groups exposed to 100 ng/L 17MT. High-throughput sequencing revealed 73,449 unigenes, 1205 known mature miRNAs, and 939 novel miRNAs in the gonads of G. rarus. With miRNA-seq, 49 (MT25-M vs. Con-M), 66 (MT50-M vs. Con-M), and 49 (MT100-M vs. Con-M) DEMs were identified in the treatment groups. Five mature miRNAs (miR-122-x, miR-574-x, miR-430-y, lin-4-x, and miR-7-y), as well as seven differentially expressed genes (soat2, inhbb, ihhb, gatm, faxdc2, ebp, and cyp1a1), which may be associated with testicular development, metabolism, apoptosis, and disease response, were assayed using qRT-PCR. Furthermore, miR-122-x (related to lipid metabolism), miR-430-y (embryonic development), lin-4-x (apoptosis), and miR-7-y (disease) were differentially expressed in the testes of 17MT-exposed G. rarus. This study highlights the role of miRNA-mRNA pairs in the regulation of testicular development and immune response to disease and will facilitate future studies on the miRNA-RNA-associated regulation of teleost reproduction. Full article

(This article belongs to the Section Molecular Genetics and Genomics)

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25 pages, 2137 KiB

Open AccessReview

Advances in Liquid Biopsy Technology and Implications for Pancreatic Cancer

by Alexander G. Raufi, Michael S. May, Matthew J. Hadfield, Attila A. Seyhan and Wafik S. El-Deiry

Int. J. Mol. Sci. 2023, 24(4), 4238; https://doi.org/10.3390/ijms24044238 - 20 Feb 2023

Cited by 20 | Viewed by 4991

Abstract

Pancreatic cancer is a highly aggressive malignancy with a climbing incidence. The majority of cases are detected late, with incurable locally advanced or metastatic disease. Even in individuals who undergo resection, recurrence is unfortunately very common. There is no universally accepted screening modality [...] Read more.

Pancreatic cancer is a highly aggressive malignancy with a climbing incidence. The majority of cases are detected late, with incurable locally advanced or metastatic disease. Even in individuals who undergo resection, recurrence is unfortunately very common. There is no universally accepted screening modality for the general population and diagnosis, evaluation of treatment response, and detection of recurrence relies primarily on the use of imaging. Identification of minimally invasive techniques to help diagnose, prognosticate, predict response or resistance to therapy, and detect recurrence are desperately needed. Liquid biopsies represent an emerging group of technologies which allow for non-invasive serial sampling of tumor material. Although not yet approved for routine use in pancreatic cancer, the increasing sensitivity and specificity of contemporary liquid biopsy platforms will likely change clinical practice in the near future. In this review, we discuss the recent technological advances in liquid biopsy, focusing on circulating tumor DNA, exosomes, microRNAs, and circulating tumor cells. Full article

(This article belongs to the Special Issue Liquid Biopsies in Oncology)

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24 pages, 6861 KiB

Open AccessArticle

Identification of and Mechanistic Insights into SARS-CoV-2 Main Protease Non-Covalent Inhibitors: An In-Silico Study

by Jian-Xin Shen, Wen-Wen Du, Yuan-Ling Xia, Zhi-Bi Zhang, Ze-Fen Yu, Yun-Xin Fu and Shu-Qun Liu

Int. J. Mol. Sci. 2023, 24(4), 4237; https://doi.org/10.3390/ijms24044237 - 20 Feb 2023

Cited by 4 | Viewed by 2768

Abstract

The indispensable role of the SARS-CoV-2 main protease (Mpro) in the viral replication cycle and its dissimilarity to human proteases make Mpro a promising drug target. In order to identify the non-covalent Mpro inhibitors, we performed a comprehensive study using a combined computational [...] Read more.

The indispensable role of the SARS-CoV-2 main protease (Mpro) in the viral replication cycle and its dissimilarity to human proteases make Mpro a promising drug target. In order to identify the non-covalent Mpro inhibitors, we performed a comprehensive study using a combined computational strategy. We first screened the ZINC purchasable compound database using the pharmacophore model generated from the reference crystal structure of Mpro complexed with the inhibitor ML188. The hit compounds were then filtered by molecular docking and predicted parameters of drug-likeness and pharmacokinetics. The final molecular dynamics (MD) simulations identified three effective candidate inhibitors (ECIs) capable of maintaining binding within the substrate-binding cavity of Mpro. We further performed comparative analyses of the reference and effective complexes in terms of dynamics, thermodynamics, binding free energy (BFE), and interaction energies and modes. The results reveal that, when compared to the inter-molecular electrostatic forces/interactions, the inter-molecular van der Waals (vdW) forces/interactions are far more important in maintaining the association and determining the high affinity. Given the un-favorable effects of the inter-molecular electrostatic interactions—association destabilization by the competitive hydrogen bond (HB) interactions and the reduced binding affinity arising from the un-compensable increase in the electrostatic desolvation penalty—we suggest that enhancing the inter-molecular vdW interactions while avoiding introducing the deeply buried HBs may be a promising strategy in future inhibitor optimization. Full article

(This article belongs to the Section Molecular Biology)

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15 pages, 1108 KiB

Open AccessReview

Polymorphisms in Lymphotoxin-Alpha as the “Missing Link” in Prognosticating Favourable Response to Omega-3 Supplementation for Dry Eye Disease: A Narrative Review

by Benjamin Paik and Louis Tong

Int. J. Mol. Sci. 2023, 24(4), 4236; https://doi.org/10.3390/ijms24044236 - 20 Feb 2023

Cited by 2 | Viewed by 2589

Abstract

Elements of inflammation are found in almost all chronic ocular surface disease, such as dry eye disease. The chronicity of such inflammatory disease speaks to the dysregulation of innate and adaptive immunity. There has been a rising interest in omega-3 fatty acids to [...] Read more.

Elements of inflammation are found in almost all chronic ocular surface disease, such as dry eye disease. The chronicity of such inflammatory disease speaks to the dysregulation of innate and adaptive immunity. There has been a rising interest in omega-3 fatty acids to attenuate inflammation. While many cell-based (in vitro) studies verify the anti-inflammatory effects of omega-3, different human trials report discordant outcomes after supplementation. This may be due to underlying inter-individual differences in inflammatory cytokine metabolism (such as tumor necrosis factor alpha (TNF-α)), in which genetic differences might play a role, such as polymorphisms in the lymphotoxin alpha (LT-α) gene. Inherent TNF-α production affects omega-3 response and is also associated with LT-α genotype. Therefore, LT-α genotype might predict omega-3 response. Using the NIH dbSNP, we analyzed the relative frequency of LT-α polymorphisms among various ethnicities, each weighted by the genotype’s probability of positive response. While the probability of response for unknown LT-α genotypes are 50%, there is greater distinction in response rates between various genotypes. Hence, there is value in genetic testing to prognosticate an individual’s response to omega-3. Full article

(This article belongs to the Special Issue Metabolism and the Biological Functions of Oxylipins)

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15 pages, 3369 KiB

Open AccessArticle

Hydrogel-Based Pre-Clinical Evaluation of Repurposed FDA-Approved Drugs for AML

by Jenna R. James, Johnathan Curd, Jennifer C. Ashworth, Mays Abuhantash, Martin Grundy, Claire H. Seedhouse, Kenton P. Arkill, Amanda J. Wright, Catherine L. R. Merry and Alexander Thompson

Int. J. Mol. Sci. 2023, 24(4), 4235; https://doi.org/10.3390/ijms24044235 - 20 Feb 2023

Cited by 6 | Viewed by 3491

Abstract

In vivo models of acute myeloid leukemia (AML) are low throughput, and standard liquid culture models fail to recapitulate the mechanical and biochemical properties of the extracellular matrix-rich protective bone marrow niche that contributes to drug resistance. Candidate drug discovery in AML requires [...] Read more.

In vivo models of acute myeloid leukemia (AML) are low throughput, and standard liquid culture models fail to recapitulate the mechanical and biochemical properties of the extracellular matrix-rich protective bone marrow niche that contributes to drug resistance. Candidate drug discovery in AML requires advanced synthetic platforms to improve our understanding of the impact of mechanical cues on drug sensitivity in AML. By use of a synthetic, self-assembling peptide hydrogel (SAPH) of modifiable stiffness and composition, a 3D model of the bone marrow niche to screen repurposed FDA-approved drugs has been developed and utilized. AML cell proliferation was dependent on SAPH stiffness, which was optimized to facilitate colony growth. Three candidate FDA-approved drugs were initially screened against the THP-1 cell line and mAF9 primary cells in liquid culture, and EC50 values were used to inform drug sensitivity assays in the peptide hydrogel models. Salinomycin demonstrated efficacy in both an ‘early-stage’ model in which treatment was added shortly after initiation of AML cell encapsulation, and an ‘established’ model in which time-encapsulated cells had started to form colonies. Sensitivity to Vidofludimus treatment was not observed in the hydrogel models, and Atorvastatin demonstrated increased sensitivity in the ‘established’ compared to the ‘early-stage’ model. AML patient samples were equally sensitive to Salinomycin in the 3D hydrogels and partially sensitive to Atorvastatin. Together, this confirms that AML cell sensitivity is drug- and context-specific and that advanced synthetic platforms for higher throughput are valuable tools for pre-clinical evaluation of candidate anti-AML drugs. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Therapies of Myeloid Leukaemia 2.0)

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17 pages, 17708 KiB

Open AccessArticle

Long Non-Coding RNA BNIP3 Inhibited the Proliferation of Bovine Intramuscular Preadipocytes via Cell Cycle

by Wenzhen Zhang, Jianfang Wang, Bingzhi Li, Bing Sun, Shengchen Yu, Xiaoyu Wang and Linsen Zan

Int. J. Mol. Sci. 2023, 24(4), 4234; https://doi.org/10.3390/ijms24044234 - 20 Feb 2023

Cited by 11 | Viewed by 2321

Abstract

The intramuscular fat (or marbling fat) content is an essential economic trait of beef cattle and improves the flavor and palatability of meat. Several studies have highlighted the correlation between long non-coding RNAs (lncRNAs) and intramuscular fat development; however, the precise molecular mechanism [...] Read more.

The intramuscular fat (or marbling fat) content is an essential economic trait of beef cattle and improves the flavor and palatability of meat. Several studies have highlighted the correlation between long non-coding RNAs (lncRNAs) and intramuscular fat development; however, the precise molecular mechanism remains unknown. Previously, through a high-throughput sequencing analysis, we found a lncRNA and named it a long non-coding RNA BNIP3 (lncBNIP3). The 5′ RACE and 3′ RACE explored 1945 bp total length of lncBNIP3, including 1621 bp of 5′RACE, and 464 bp of 3′RACE. The nucleoplasmic separation and FISH results explored the nuclear localization of lncBNIP3. Moreover, the tissue expression of lncBNIP3 was higher in the longissimus dorsi muscle, followed by intramuscular fat. Furthermore, down-regulation of lncBNIP3 increased the 5-Ethynyl-2′- deoxyuridine (EdU)-EdU-positive cells. The flow cytometry results showed that the number of cells in the S phase was significantly higher in preadipocytes transfected with si-lncBNIP3 than in the control group (si-NC). Similarly, CCK8 results showed that the number of cells after transfection of si-lncBNIP3 was significantly higher than in the control group. In addition, the mRNA expressions of proliferative marker genes CyclinB1 (CCNB1) and Proliferating Cell Nuclear Antigen (PCNA) in the si-lncBNIP3 group were significantly higher than in the control group. The Western Blot (WB) results also showed that the protein expression level of PCNA transfection of si-lncBNIP3 was significantly higher than in the control group. Similarly, the enrichment of lncBNIP3 significantly decreased the EdU-positive cells in the bovine preadipocytes. The results of flow cytometry and CCK8 assay also showed that overexpression of lncBNIP3 inhibited the proliferation of bovine preadipocytes. In addition, the overexpression of lncBNIP3 significantly inhibited the mRNA expressions of CCNB1 and PCNA. The WB results showed that the overexpression of lncBNIP3 significantly inhibited the expression of the CCNB1 protein level. To further explore the mechanism of lncBNIP3 on the proliferation of intramuscular preadipocytes, RNA-seq was performed after interference with si-lncBNIP3, and 660 differentially expressed genes (DEGs) were found, including 417 up-regulated DEGs and 243 down-regulated DEGs. The KEGG pathway analysis showed that the cell cycle was the most significant pathway for the functional enrichment of DEGs, followed by the DNA replication pathway. The RT-qPCR quantified the expression of twenty DEGs in the cell cycle. Therefore, we speculated that lncBNIP3 regulated intramuscular preadipocyte proliferation through the cell cycle and DNA replication pathways. To further confirm this hypothesis, the cell cycle inhibitor Ara-C was used to inhibit DNA replication of the S phase in intramuscular preadipocytes. Herein, Ara-C and si-lncBNIP3 were simultaneously added to the preadipocytes, and the CCK8, flow cytometry, and EdU assays were performed. The results showed that the si-lncBNIP3 could rescue the inhibitory effect of Ara-C in the bovine preadipocyte proliferation. In addition, lncBNIP3 could bind to the promoter of cell division control protein 6 (CDC6), and down-regulation of lncBNIP3 promoted the transcription activity and the expression of CDC6. Therefore, the inhibitory effect of lncBNIP3 on cell proliferation might be understood through the cell cycle pathway and CDC6 expression. This study provided a valuable lncRNA with functional roles in intramuscular fat accumulation and revealed new strategies for improving beef quality. Full article

(This article belongs to the Special Issue The Function and Regulation Mechanism of ncRNAs in Adipogenesis)

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18 pages, 1143 KiB

Open AccessReview

Circular RNAs: Biogenesis, Biological Functions, and Roles in Myocardial Infarction

by Jialei Li, Yu Han, Shuang Wang, Xiaolei Wu, Jimin Cao and Teng Sun

Int. J. Mol. Sci. 2023, 24(4), 4233; https://doi.org/10.3390/ijms24044233 - 20 Feb 2023

Cited by 17 | Viewed by 3626

Abstract

Non-coding RNAs have been excavated as important cardiac function modulators and linked to heart diseases. Significant advances have been obtained in illuminating the effects of microRNAs and long non-coding RNAs. Nevertheless, the characteristics of circular RNAs are rarely mined. Circular RNAs (circRNAs) are [...] Read more.

Non-coding RNAs have been excavated as important cardiac function modulators and linked to heart diseases. Significant advances have been obtained in illuminating the effects of microRNAs and long non-coding RNAs. Nevertheless, the characteristics of circular RNAs are rarely mined. Circular RNAs (circRNAs) are widely believed to participate in cardiac pathologic processes, especially in myocardial infarction. In this review, we round up the biogenesis of circRNAs, briefly describe their biological functions, and summarize the latest literature on multifarious circRNAs related to new therapies and biomarkers for myocardial infarction. Full article

(This article belongs to the Special Issue Non-coding RNAs in Pathogens and Associated Diseases)

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18 pages, 2098 KiB

Open AccessArticle

All-Atom Molecular Dynamics Simulations Indicated the Involvement of a Conserved Polar Signaling Channel in the Activation Mechanism of the Type I Cannabinoid Receptor

by Arijit Sarkar, Argha Mitra and Attila Borics

Int. J. Mol. Sci. 2023, 24(4), 4232; https://doi.org/10.3390/ijms24044232 - 20 Feb 2023

Cited by 2 | Viewed by 2944

Abstract

The type I cannabinoid G protein-coupled receptor (CB1, GPCR) is an intensely investigated pharmacological target, owing to its involvement in numerous physiological functions as well as pathological processes such as cancers, neurodegenerative diseases, metabolic disorders and neuropathic pain. In order to develop modern [...] Read more.

The type I cannabinoid G protein-coupled receptor (CB1, GPCR) is an intensely investigated pharmacological target, owing to its involvement in numerous physiological functions as well as pathological processes such as cancers, neurodegenerative diseases, metabolic disorders and neuropathic pain. In order to develop modern medications that exert their effects through binding to the CB1 receptor, it is essential to understand the structural mechanism of activation of this protein. The pool of atomic resolution experimental structures of GPCRs has been expanding rapidly in the past decade, providing invaluable information about the function of these receptors. According to the current state of the art, the activity of GPCRs involves structurally distinct, dynamically interconverting functional states and the activation is controlled by a cascade of interconnecting conformational switches in the transmembrane domain. A current challenge is to uncover how different functional states are activated and what specific ligand properties are responsible for the selectivity towards those different functional states. Our recent studies of the μ-opioid and β₂-adrenergic receptors (MOP and β₂AR, respectively) revealed that the orthosteric binding pockets and the intracellular surfaces of these receptors are connected through a channel of highly conserved polar amino acids whose dynamic motions are in high correlation in the agonist- and G protein-bound active states. This and independent literature data led us to hypothesize that, in addition to consecutive conformational transitions, a shift of macroscopic polarization takes place in the transmembrane domain, which is furnished by the rearrangement of polar species through their concerted movements. Here, we examined the CB1 receptor signaling complexes utilizing microsecond scale, all-atom molecular dynamics (MD) simulations in order to see if our previous assumptions could be applied to the CB1 receptor too. Apart from the identification of the previously proposed general features of the activation mechanism, several specific properties of the CB1 have been indicated that could possibly be associated with the signaling profile of this receptor. Full article

(This article belongs to the Special Issue Proteins in Drug Research)

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19 pages, 2671 KiB

Open AccessArticle

Increased BAT Thermogenesis in Male Mouse Apolipoprotein A4 Transgenic Mice

by Zachary LaRussa, Hsuan-Chih N. Kuo, Kathryn West, Zhijun Shen, Kevin Wisniewski, Patrick Tso, Karen T. Coschigano and Chunmin C. Lo

Int. J. Mol. Sci. 2023, 24(4), 4231; https://doi.org/10.3390/ijms24044231 - 20 Feb 2023

Cited by 3 | Viewed by 2269

Abstract

Dietary lipids induce apolipoprotein A4 (APOA4) production and brown adipose tissue (BAT) thermogenesis. Administration of exogenous APOA4 elevates BAT thermogenesis in chow-fed mice, but not high-fat diet (HFD)-fed mice. Chronic feeding of HFD attenuates plasma APOA4 production and BAT thermogenesis in wildtype (WT) [...] Read more.

Dietary lipids induce apolipoprotein A4 (APOA4) production and brown adipose tissue (BAT) thermogenesis. Administration of exogenous APOA4 elevates BAT thermogenesis in chow-fed mice, but not high-fat diet (HFD)-fed mice. Chronic feeding of HFD attenuates plasma APOA4 production and BAT thermogenesis in wildtype (WT) mice. In light of these observations, we sought to determine whether steady production of APOA4 could keep BAT thermogenesis elevated, even in the presence of HFD consumption, with an aim toward eventual reduction of body weight, fat mass and plasma lipid levels. Transgenic mice with overexpression of mouse APOA4 in the small intestine (APOA4-Tg mice) produce greater plasma APOA4 than their WT controls, even when fed an atherogenic diet. Thus, we used these mice to investigate the correlation of levels of APOA4 and BAT thermogenesis during HFD consumption. The hypothesis of this study was that overexpression of mouse APOA4 in the small intestine and increased plasma APOA4 production would increase BAT thermogenesis and consequently reduce fat mass and plasma lipids of HFD-fed obese mice. To test this hypothesis, BAT thermogenic proteins, body weight, fat mass, caloric intake, and plasma lipids in male APOA4-Tg mice and WT mice fed either a chow diet or a HFD were measured. When fed a chow diet, APOA4 levels were elevated, plasma triglyceride (TG) levels were reduced, and BAT levels of UCP1 trended upward, while body weight, fat mass, caloric intake, and plasma lipids were comparable between APOA4-Tg and WT mice. After a four-week feeding of HFD, APOA4-Tg mice maintained elevated plasma APOA4 and reduced plasma TG, but UCP1 levels in BAT were significantly elevated in comparison to WT controls; body weight, fat mass and caloric intake were still comparable. After 10-week consumption of HFD, however, while APOA4-Tg mice still exhibited increased plasma APOA4, UCP1 levels and reduced TG levels, a reduction in body weight, fat mass and levels of plasma lipids and leptin were finally observed in comparison to their WT controls and independent of caloric intake. Additionally, APOA4-Tg mice exhibited increased energy expenditure at several time points when measured during the 10-week HFD feeding. Thus, overexpression of APOA4 in the small intestine and maintenance of elevated levels of plasma APOA4 appear to correlate with elevation of UCP1-dependent BAT thermogenesis and subsequent protection against HFD-induced obesity in mice. Full article

(This article belongs to the Special Issue Apolipoproteins in Health and Disease)

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19 pages, 7359 KiB

Open AccessArticle

MitoSNARE Assembly and Disassembly Factors Regulate Basal Autophagy and Aging in C. elegans

by Ilias Gkikas, Ioanna Daskalaki, Konstantinos Kounakis, Nektarios Tavernarakis and Eirini Lionaki

Int. J. Mol. Sci. 2023, 24(4), 4230; https://doi.org/10.3390/ijms24044230 - 20 Feb 2023

Cited by 2 | Viewed by 2691

Abstract

SNARE proteins reside between opposing membranes and facilitate vesicle fusion, a physiological process ubiquitously required for secretion, endocytosis and autophagy. With age, neurosecretory SNARE activity drops and is pertinent to age-associated neurological disorders. Despite the importance of SNARE complex assembly and disassembly in [...] Read more.

SNARE proteins reside between opposing membranes and facilitate vesicle fusion, a physiological process ubiquitously required for secretion, endocytosis and autophagy. With age, neurosecretory SNARE activity drops and is pertinent to age-associated neurological disorders. Despite the importance of SNARE complex assembly and disassembly in membrane fusion, their diverse localization hinders the complete understanding of their function. Here, we revealed a subset of SNARE proteins, the syntaxin SYX-17, the synaptobrevins VAMP-7, SNB-6 and the tethering factor USO-1, to be either localized or in close proximity to mitochondria, in vivo. We term them mitoSNAREs and show that animals deficient in mitoSNAREs exhibit increased mitochondria mass and accumulation of autophagosomes. The SNARE disassembly factor NSF-1 seems to be required for the effects of mitoSNARE depletion. Moreover, we find mitoSNAREs to be indispensable for normal aging in both neuronal and non-neuronal tissues. Overall, we uncover a previously unrecognized subset of SNAREs that localize to mitochondria and propose a role of mitoSNARE assembly and disassembly factors in basal autophagy regulation and aging. Full article

(This article belongs to the Special Issue Mitochondria in Human Health and Disease)

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17 pages, 4769 KiB

Open AccessArticle

Transcriptomic Analysis Revealed Key Defense Genes and Signaling Pathways Mediated by the Arabidopsis thaliana Gene SAD2 in Response to Infection with Pseudomonas syringae pv. Tomato DC3000

by Sha Li, Tiantian Shi, Mingjie Lyu, Rui Wang, Andi Xu, Luoying Chen, Rong Luo, Yinglu Sun, Xiaoying Guo, Jun Liu, Huan Wang and Ying Gao

Int. J. Mol. Sci. 2023, 24(4), 4229; https://doi.org/10.3390/ijms24044229 - 20 Feb 2023

Cited by 4 | Viewed by 3036

Abstract

Nucleocytoplasmic transport receptors play key roles in the nuclear translocation of disease resistance proteins, but the associated mechanisms remain unclear. The Arabidopsis thaliana gene SAD2 encodes an importin β-like protein. A transgenic Arabidopsis line overexpressing SAD2 (OESAD2/Col-0) showed obvious resistance to Pseudomonas syringae [...] Read more.

Nucleocytoplasmic transport receptors play key roles in the nuclear translocation of disease resistance proteins, but the associated mechanisms remain unclear. The Arabidopsis thaliana gene SAD2 encodes an importin β-like protein. A transgenic Arabidopsis line overexpressing SAD2 (OESAD2/Col-0) showed obvious resistance to Pseudomonas syringae pv. tomato DC3000 (Pst DC3000) compared to the wild type (Col-0), but the knockout mutant sad2-5 was susceptible. Transcriptomic analysis was then performed on Col-0, OESAD2/Col-0, and sad2-5 leaves at 0, 1, 2, and 3 days post-inoculation with Pst DC3000. A total of 1825 differentially expressed genes (DEGs) were identified as putative biotic stress defense genes regulated by SAD2, 45 of which overlapped between the SAD2 knockout and overexpression datasets. Gene Ontology (GO) analysis indicated that the DEGs were broadly involved in single-organism cellular metabolic processes and in response to stimulatory stress. Kyoto Encyclopedia of Genes and Genomes (KEGG) biochemical pathway analysis revealed that many of the DEGs were associated with the biosynthesis of flavonoids and other specialized metabolites. Transcription factor analysis showed that a large number of ERF/AP2, MYB, and bHLH transcription factors were involved in SAD2-mediated plant disease resistance. These results provide a basis for future exploration of the molecular mechanisms associated with SAD2-mediated disease resistance and establish a set of key candidate disease resistance genes. Full article

(This article belongs to the Special Issue Signal Transduction Pathways in Plants for Resistance against Plant Pathogens 2022)

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27 pages, 5940 KiB

Open AccessReview

Confinement Effects in Well-Defined Metal–Organic Frameworks (MOFs) for Selective CO₂ Hydrogenation: A Review

by Xiaofei Lu, Chuqiao Song, Xingyu Qi, Duanxing Li and Lili Lin

Int. J. Mol. Sci. 2023, 24(4), 4228; https://doi.org/10.3390/ijms24044228 - 20 Feb 2023

Cited by 4 | Viewed by 3570

Abstract

Decarbonization has become an urgent affair to restrain global warming. CO₂ hydrogenation coupled with H₂ derived from water electrolysis is considered a promising route to mitigate the negative impact of carbon emission and also promote the application of hydrogen. It is [...] Read more.

Decarbonization has become an urgent affair to restrain global warming. CO₂ hydrogenation coupled with H₂ derived from water electrolysis is considered a promising route to mitigate the negative impact of carbon emission and also promote the application of hydrogen. It is of great significance to develop catalysts with excellent performance and large-scale implementation. In the past decades, metal–organic frameworks (MOFs) have been widely involved in the rational design of catalysts for CO₂ hydrogenation due to their high surface areas, tunable porosities, well-ordered pore structures, and diversities in metals and functional groups. Confinement effects in MOFs or MOF-derived materials have been reported to promote the stability of CO₂ hydrogenation catalysts, such as molecular complexes of immobilization effect, active sites in size effect, stabilization in the encapsulation effect, and electron transfer and interfacial catalysis in the synergistic effect. This review attempts to summarize the progress of MOF-based CO₂ hydrogenation catalysts up to now, and demonstrate the synthetic strategies, unique features, and enhancement mechanisms compared with traditionally supported catalysts. Great emphasis will be placed on various confinement effects in CO₂ hydrogenation. The challenges and opportunities in precise design, synthesis, and applications of MOF-confined catalysis for CO₂ hydrogenation are also summarized. Full article

(This article belongs to the Special Issue Current Trends in MOF (Metal-Organic Framework) and Metal X-ides)

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29 pages, 2259 KiB

Open AccessReview

View from the Biological Property: Insight into the Functional Diversity and Complexity of the Gut Mucus

by Chengwei He, Han Gao, Shuzi Xin, Rongxuan Hua, Xueran Guo, Yimin Han, Hongwei Shang and Jingdong Xu

Int. J. Mol. Sci. 2023, 24(4), 4227; https://doi.org/10.3390/ijms24044227 - 20 Feb 2023

Cited by 3 | Viewed by 5442

Abstract

Due to mucin’s important protective effect on epithelial tissue, it has garnered extensive attention. The role played by mucus in the digestive tract is undeniable. On the one hand, mucus forms “biofilm” structures that insulate harmful substances from direct contact with epithelial cells. [...] Read more.

Due to mucin’s important protective effect on epithelial tissue, it has garnered extensive attention. The role played by mucus in the digestive tract is undeniable. On the one hand, mucus forms “biofilm” structures that insulate harmful substances from direct contact with epithelial cells. On the other hand, a variety of immune molecules in mucus play a crucial role in the immune regulation of the digestive tract. Due to the enormous number of microorganisms in the gut, the biological properties of mucus and its protective actions are more complicated. Numerous pieces of research have hinted that the aberrant expression of intestinal mucus is closely related to impaired intestinal function. Therefore, this purposeful review aims to provide the highlights of the biological characteristics and functional categorization of mucus synthesis and secretion. In addition, we highlight a variety of the regulatory factors for mucus. Most importantly, we also summarize some of the changes and possible molecular mechanisms of mucus during certain disease processes. All these are beneficial to clinical practice, diagnosis, and treatment and can provide some potential theoretical bases. Admittedly, there are still some deficiencies or contradictory results in the current research on mucus, but none of this diminishes the importance of mucus in protective impacts. Full article

(This article belongs to the Special Issue New Insights into Molecular Innate Immunity)

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17 pages, 5763 KiB

Open AccessArticle

NUF2 Promotes Breast Cancer Development as a New Tumor Stem Cell Indicator

by Yang Deng, Jiapeng Li, Yingjie Zhang, Hao Hu, Fujian Wan, Hang Min, Hao Zhou, Lixing Gu, Xinghua Liao, Jingjiao Zhou and Jun Zhou

Int. J. Mol. Sci. 2023, 24(4), 4226; https://doi.org/10.3390/ijms24044226 - 20 Feb 2023

Cited by 8 | Viewed by 2374

Abstract

Multiple new subtypes of breast cancer (BRCA) are identified in women each year, rendering BRCA the most common and rapidly expanding form of cancer in females globally. NUF2 has been identified as a prognostic factor in various human cancers, regulating cell apoptosis and [...] Read more.

Multiple new subtypes of breast cancer (BRCA) are identified in women each year, rendering BRCA the most common and rapidly expanding form of cancer in females globally. NUF2 has been identified as a prognostic factor in various human cancers, regulating cell apoptosis and proliferation. However, its role in BRCA prognosis has not been clarified. This study explored the role of NUF2 in breast cancer development and prognosis using informatic analysis combined with in vivo intracellular studies. Through the online website TIMER, we evaluated the transcription profile of NUF2 across a variety of different cancer types and found that NUF2 mRNA was highly expressed in BRCA patients. Its transcription level was found to be related to the subtype, pathological stage, and prognosis of BRCA. The R program analysis showed a correlation of NUF2 with cell proliferation and tumor stemness in the BRCA patient samples. Subsequently, the association between the NUF2 expression level and immune cell infiltration was analyzed using the XIANTAO and TIMER tools. The results revealed that NUF2 expression was correlated with the responses of multiple immune cells. Furthermore, we observed the effect of NUF2 expression on tumor stemness in BRCA cell lines in vivo. The experimental results illuminated that the overexpression of NUF2 statistically upregulated the proliferation and tumor stemness ability of the BRCA cell lines MCF-7 and Hs-578T. Meanwhile, the knockdown of NUF2 inhibited the abilities of both cell lines, a finding which was verified by analyzing the subcutaneous tumorigenic ability in nude mice. In summary, this study suggests that NUF2 may play a key role in the development and progression of BRCA by affecting tumor stemness. As a stemness indicator, it has the potential to be one of the markers for the diagnosis of BRCA. Full article

(This article belongs to the Special Issue Recent Advances in Breast Cancer Research)

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24 pages, 1844 KiB

Open AccessReview

Roles of RNA Methylations in Cancer Progression, Autophagy, and Anticancer Drug Resistance

by Hyein Jo, Kyeonghee Shim and Dooil Jeoung

Int. J. Mol. Sci. 2023, 24(4), 4225; https://doi.org/10.3390/ijms24044225 - 20 Feb 2023

Cited by 8 | Viewed by 3000

Abstract

RNA methylations play critical roles in RNA processes, including RNA splicing, nuclear export, nonsense-mediated RNA decay, and translation. Regulators of RNA methylations have been shown to be differentially expressed between tumor tissues/cancer cells and adjacent tissues/normal cells. N6-methyladenosine (m6A) is the most prevalent [...] Read more.

RNA methylations play critical roles in RNA processes, including RNA splicing, nuclear export, nonsense-mediated RNA decay, and translation. Regulators of RNA methylations have been shown to be differentially expressed between tumor tissues/cancer cells and adjacent tissues/normal cells. N6-methyladenosine (m6A) is the most prevalent internal modification of RNAs in eukaryotes. m6A regulators include m6A writers, m6A demethylases, and m6A binding proteins. Since m6A regulators play important roles in regulating the expression of oncogenes and tumor suppressor genes, targeting m6A regulators can be a strategy for developing anticancer drugs. Anticancer drugs targeting m6A regulators are in clinical trials. m6A regulator-targeting drugs could enhance the anticancer effects of current chemotherapy drugs. This review summarizes the roles of m6A regulators in cancer initiation and progression, autophagy, and anticancer drug resistance. The review also discusses the relationship between autophagy and anticancer drug resistance, the effect of high levels of m6A on autophagy and the potential values of m6A regulators as diagnostic markers and anticancer therapeutic targets. Full article

(This article belongs to the Special Issue Combating Drug Resistance in Cancer—from Novel Biomarkers to Enhanced Therapeutic Efficacy)

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25 pages, 4402 KiB

Open AccessArticle

Polydopamine Incorporation Enhances Cell Differentiation and Antibacterial Properties of 3D-Printed Guanosine-Borate Hydrogels for Functional Tissue Regeneration

by Maria Merino-Gómez, Javier Gil, Roman A. Perez and Maria Godoy-Gallardo

Int. J. Mol. Sci. 2023, 24(4), 4224; https://doi.org/10.3390/ijms24044224 - 20 Feb 2023

Cited by 9 | Viewed by 2374

Abstract

Tissue engineering focuses on the development of materials as biosubstitutes that can be used to regenerate, repair, or replace damaged tissues. Alongside this, 3D printing has emerged as a promising technique for producing implants tailored to specific defects, which in turn increased the [...] Read more.

Tissue engineering focuses on the development of materials as biosubstitutes that can be used to regenerate, repair, or replace damaged tissues. Alongside this, 3D printing has emerged as a promising technique for producing implants tailored to specific defects, which in turn increased the demand for new inks and bioinks. Especially supramolecular hydrogels based on nucleosides such as guanosine have gained increasing attention due to their biocompatibility, good mechanical characteristics, tunable and reversible properties, and intrinsic self-healing capabilities. However, most existing formulations exhibit insufficient stability, biological activity, or printability. To address these limitations, we incorporated polydopamine (PDA) into guanosine-borate (GB) hydrogels and developed a PGB hydrogel with maximal PDA incorporation and good thixotropic and printability qualities. The resulting PGB hydrogels exhibited a well-defined nanofibrillar network, and we found that PDA incorporation increased the hydrogel’s osteogenic activity while having no negative effect on mammalian cell survival or migration. In contrast, antimicrobial activity was observed against the Gram-positive bacteria Staphylococcus aureus and Staphylococcus epidermidis. Thus, our findings suggest that our PGB hydrogel represents a significantly improved candidate as a 3D-printed scaffold capable of sustaining living cells, which may be further functionalized by incorporating other bioactive molecules for enhanced tissue integration. Full article

(This article belongs to the Section Materials Science)

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Int. J. Mol. Sci., Volume 24, Issue 4 (February-2 2023) – 1196 articles

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