Biomolecules

15 pages, 13257 KiB

Open AccessArticle

Revealing the Mechanism of Esculin in Treating Renal Cell Carcinoma Based on Network Pharmacology and Experimental Validation

by Zixuan Chen, Cunzhou Wang, Yuesong Cai, An Xu, Chengtao Han, Yanjun Tong, Sheng Cheng and Min Liu

Biomolecules 2024, 14(8), 1043; https://doi.org/10.3390/biom14081043 - 22 Aug 2024

Viewed by 921

Abstract

Purpose: This study aims to explore the potential mechanisms of esculin in the treatment of renal cell carcinoma (RCC). Methods: We employed network pharmacology to predict the potential mechanisms and targets of esculin in RCC. Molecular docking techniques were then employed to validate [...] Read more.

Purpose: This study aims to explore the potential mechanisms of esculin in the treatment of renal cell carcinoma (RCC). Methods: We employed network pharmacology to predict the potential mechanisms and targets of esculin in RCC. Molecular docking techniques were then employed to validate the predicted targets. Additionally, a series of in vitro experiments were conducted to verify the anticancer effects of esculin on RCC cells, including the CCK-8 assay, EdU assay, wound healing assay, apoptosis assay, and Western blot. Results: Network pharmacology and molecular docking results identified GAPDH, TNF, GSK3B, CCND1, MCL1, IL2, and CDK2 as core targets. GO and KEGG analyses suggested that esculin may influence apoptotic processes and target the PI3K/Akt pathway in RCC. Furthermore, the CCK-8 assay demonstrated that esculin inhibited RCC cell viability. Microscopic observations revealed that following esculin treatment, there was an increase in cell crumpling, a reduction in cell density, and an accumulation of floating dead cells. Additionally, with increasing esculin concentrations, the proportion of EdU-positive cells decreased, the wound closure ratio decreased, the proportion of PI-positive cells increased, the expression levels of BAX and cleaved-caspase-3 proteins increased, and the expression level of Bcl2 protein decreased. These findings suggested that esculin inhibits the proliferation and migration of RCC cells while promoting apoptosis. Moreover, esculin was found to target GAPDH and inhibit the PI3K/Akt pathway. Conclusions: This study is the first to elucidate the therapeutic effects of esculin on RCC cells. The results provide evidence supporting the clinical application of esculin and introduce a promising new candidate for RCC treatment. Full article

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37 pages, 3773 KiB

Open AccessReview

The Role of m6A Methylation in Tumor Immunity and Immune-Associated Disorder

by Siyu Mu, Kaiyue Zhao, Shanshan Zhong and Yanli Wang

Biomolecules 2024, 14(8), 1042; https://doi.org/10.3390/biom14081042 - 22 Aug 2024

Viewed by 1542

Abstract

N6-methyladenosine (m6A) represents the most prevalent and significant internal modification in mRNA, with its critical role in gene expression regulation and cell fate determination increasingly recognized in recent research. The immune system, essential for defense against infections and maintaining internal stability through interactions [...] Read more.

N6-methyladenosine (m6A) represents the most prevalent and significant internal modification in mRNA, with its critical role in gene expression regulation and cell fate determination increasingly recognized in recent research. The immune system, essential for defense against infections and maintaining internal stability through interactions with other bodily systems, is significantly influenced by m6A modification. This modification acts as a key post-transcriptional regulator of immune responses, though its effects on different immune cells vary across diseases. This review delineates the impact of m6A modification across major system-related cancers—including those of the respiratory, digestive, endocrine, nervous, urinary reproductive, musculoskeletal system malignancies, as well as acute myeloid leukemia and autoimmune diseases. We explore the pathogenic roles of m6A RNA modifications within the tumor immune microenvironment and the broader immune system, highlighting how RNA modification regulators interact with immune pathways during disease progression. Furthermore, we discuss how the expression patterns of these regulators can influence disease susceptibility to immunotherapy, facilitating the development of diagnostic and prognostic models and pioneering new therapeutic approaches. Overall, this review emphasizes the challenges and prospective directions of m6A-related immune regulation in various systemic diseases throughout the body. Full article

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28 pages, 11854 KiB

Open AccessArticle

Preparation of Time-Sequential Functionalized ZnS-ZnO Film for Modulation of Interfacial Behavior of Metals in Biological Service Environments

by Jianwen Zhang, Yujie Tang, Xiaowa Gao, Xinyu Pei, Yajun Weng and Junying Chen

Biomolecules 2024, 14(8), 1041; https://doi.org/10.3390/biom14081041 - 22 Aug 2024

Viewed by 700

Abstract

Blood-contact devices are prone to inflammation, endothelial dysfunction, coagulation, and the uncontrolled release of metal ions during implantation and service. Therefore, it is essential to make these multifunctional. Herein, a superhydrophobic DE@ZnS-ZnO@SA film (composed of dabigatran ester, zinc sulfite, zinc oxide, and stearic [...] Read more.

Blood-contact devices are prone to inflammation, endothelial dysfunction, coagulation, and the uncontrolled release of metal ions during implantation and service. Therefore, it is essential to make these multifunctional. Herein, a superhydrophobic DE@ZnS-ZnO@SA film (composed of dabigatran ester, zinc sulfite, zinc oxide, and stearic acid, respectively) is produced. The prepared film has non-adhesion and antibacterial properties, superior mechanical stability, durability, corrosion resistance, and is self-cleaning and blood-repellent. The results of the hemolysis, cytotoxicity, and other anticoagulant experiments revealed that the film had good blood compatibility, no cytotoxicity, and excellent anticoagulant properties. The film displays anticoagulant properties even after being immersed in Phosphate-Buffered Saline (PBS) for 7 days. Furthermore, the film can spontaneously release H₂S gas for 90 h after soaking in an acidic environment (pH = 6) for 90 h. This property improves the acidic microenvironment of the lesion and promotes the proliferation of endothelial cells by using H₂S gas. In addition, the film can inhibit the uncontrollable release of Zn²⁺ ions, avoiding its toxicity even when immersed in an acid environment for 35 days. This time-sequential functionalized surface has the potential to typify the future of blood-contacting scaffolds for long-lasting use. Full article

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21 pages, 5025 KiB

Open AccessArticle

Targeting Grb2 SH3 Domains with Affimer Proteins Provides Novel Insights into Ras Signalling Modulation

by Anna A. S. Tang, Andrew Macdonald, Michael J. McPherson and Darren C. Tomlinson

Biomolecules 2024, 14(8), 1040; https://doi.org/10.3390/biom14081040 - 22 Aug 2024

Viewed by 1217

Abstract

Src homology 3 (SH3) domains play a critical role in mediating protein–protein interactions (PPIs) involved in cell proliferation, migration, and the cytoskeleton. Despite their abundance in the human proteome, the functions and molecular interactions of many SH3 domains remain unknown, and this is [...] Read more.

Src homology 3 (SH3) domains play a critical role in mediating protein–protein interactions (PPIs) involved in cell proliferation, migration, and the cytoskeleton. Despite their abundance in the human proteome, the functions and molecular interactions of many SH3 domains remain unknown, and this is in part due to the lack of SH3-domain-specific reagents available for their study. Affimer proteins have been developed as affinity reagents targeting a diverse range of targets, including those involved in PPIs. In this study, Affimer proteins were isolated against both the N- and C-terminal SH3 domains (NSH3 and CSH3) of growth-factor-receptor-bound protein 2 (Grb2), an adapter protein that provides a critical link between cell surface receptors and Ras signalling pathways. Targeting the CSH3 alone for the inhibition of PPIs appeared sufficient for curtailing Ras signalling in mammalian cell lines stimulated with human epidermal growth factor (EGF), which conflicts with the notion that the predominant interactions with Ras activating Son of sevenless (SOS) occur via the NSH3 domain. This result supports a model in which allosteric mechanisms involved in Grb2-SOS1 interaction modulate Ras activation. Full article

(This article belongs to the Special Issue The Role of Scaffold Proteins in Human Diseases)

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17 pages, 3083 KiB

Open AccessArticle

MMFSyn: A Multimodal Deep Learning Model for Predicting Anticancer Synergistic Drug Combination Effect

by Tao Yang, Haohao Li, Yanlei Kang and Zhong Li

Biomolecules 2024, 14(8), 1039; https://doi.org/10.3390/biom14081039 - 22 Aug 2024

Cited by 1 | Viewed by 1031

Abstract

Combination therapy aims to synergistically enhance efficacy or reduce toxic side effects and has widely been used in clinical practice. However, with the rapid increase in the types of drug combinations, identifying the synergistic relationships between drugs remains a highly challenging task. This [...] Read more.

Combination therapy aims to synergistically enhance efficacy or reduce toxic side effects and has widely been used in clinical practice. However, with the rapid increase in the types of drug combinations, identifying the synergistic relationships between drugs remains a highly challenging task. This paper proposes a novel deep learning model MMFSyn based on multimodal drug data combined with cell line features. Firstly, to ensure the full expression of drug molecular features, multiple modalities of drugs, including Morgan fingerprints, atom sequences, molecular diagrams, and atomic point cloud data, are extracted using SMILES. Secondly, for different modal data, a Bi-LSTM, gMLP, multi-head attention mechanism, and multi-scale GCNs are comprehensively applied to extract the drug feature. Then, it selects appropriate omics features from gene expression and mutation omics data of cancer cell lines to construct cancer cell line features. Finally, these features are combined to predict the synergistic anti-cancer drug combination effect. The experimental results verify that MMFSyn has significant advantages in performance compared to other popular methods, with a root mean square error of 13.33 and a Pearson correlation coefficient of 0.81, which indicates that MMFSyn can better capture the complex relationship between multimodal drug combinations and omics data, thereby improving the synergistic drug combination prediction. Full article

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19 pages, 2300 KiB

Open AccessReview

The Role of Tripartite Motif Family Proteins in Chronic Liver Diseases: Molecular Mechanisms and Therapeutic Potential

by Xiwen Cao, Yinni Chen, Yuanli Chen and Meixiu Jiang

Biomolecules 2024, 14(8), 1038; https://doi.org/10.3390/biom14081038 - 21 Aug 2024

Viewed by 1146

Abstract

The worldwide impact of liver diseases is increasing steadily, with a consistent upswing evidenced in incidence and mortality rates. Chronic liver diseases (CLDs) refer to the liver function’s progressive deterioration exceeding six months, which includes abnormal clotting factors, detoxification failure, and hepatic cholestasis. [...] Read more.

The worldwide impact of liver diseases is increasing steadily, with a consistent upswing evidenced in incidence and mortality rates. Chronic liver diseases (CLDs) refer to the liver function’s progressive deterioration exceeding six months, which includes abnormal clotting factors, detoxification failure, and hepatic cholestasis. The most common etiologies of CLDs are mainly composed of chronic viral hepatitis, MAFLD/MASH, alcoholic liver disease, and genetic factors, which induce inflammation and harm to the liver, ultimately resulting in cirrhosis, the irreversible final stage of CLDs. The latest research has shown that tripartite motif family proteins (TRIMs) function as E3 ligases, which participate in the progression of CLDs by regulating gene and protein expression levels through post-translational modification. In this review, our objective is to clarify the molecular mechanisms and potential therapeutic targets of TRIMs in CLDs and provide insights for therapy guidelines and future research. Full article

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11 pages, 1819 KiB

Open AccessArticle

Glut1 Functions in Insulin-Producing Neurons to Regulate Lipid and Carbohydrate Storage in Drosophila

by Matthew R. Kauffman and Justin R. DiAngelo

Biomolecules 2024, 14(8), 1037; https://doi.org/10.3390/biom14081037 - 20 Aug 2024

Viewed by 1124

Abstract

Obesity remains one of the largest health problems in the world, arising from the excess storage of triglycerides (TAGs). However, the full complement of genes that are important for regulating TAG storage is not known. The Glut1 gene encodes a Drosophila glucose transporter [...] Read more.

Obesity remains one of the largest health problems in the world, arising from the excess storage of triglycerides (TAGs). However, the full complement of genes that are important for regulating TAG storage is not known. The Glut1 gene encodes a Drosophila glucose transporter that has been identified as a potential obesity gene through genetic screening. Yet, the tissue-specific metabolic functions of Glut1 are not fully understood. Here, we characterized the role of Glut1 in the fly brain by decreasing neuronal Glut1 levels with RNAi and measuring glycogen and TAGs. Glut1RNAi flies had decreased TAG and glycogen levels, suggesting a nonautonomous role of Glut1 in the fly brain to regulate nutrient storage. A group of hormones that regulate metabolism and are expressed in the fly brain are Drosophila insulin-like peptides (Ilps) 2, 3, and 5. Interestingly, we observed blunted Ilp3 and Ilp5 expression in neuronal Glut1RNAi flies, suggesting Glut1 functions in insulin-producing neurons (IPCs) to regulate whole-organism TAG and glycogen storage. Consistent with this hypothesis, we also saw fewer TAGs and glycogens and decreased expression of Ilp3 and Ilp5 in flies with IPC-specific Glut1RNAi. Together, these data suggest Glut1 functions as a nutrient sensor in IPCs, controlling TAG and glycogen storage and regulating systemic energy homeostasis. Full article

(This article belongs to the Special Issue Drosophila as a Model System to Study Metabolism)

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25 pages, 4799 KiB

Open AccessReview

Enhancing Vaccine Efficacy and Stability: A Review of the Utilization of Nanoparticles in mRNA Vaccines

by Nargish Parvin, Sang Woo Joo and Tapas Kumar Mandal

Biomolecules 2024, 14(8), 1036; https://doi.org/10.3390/biom14081036 - 20 Aug 2024

Viewed by 1907

Abstract

The development of vaccines has entered a new era with the advent of nanotechnology, particularly through the utilization of nanoparticles. This review focuses on the role of nanoparticles in enhancing the efficacy and stability of mRNA vaccines. Nanoparticles, owing to their unique properties [...] Read more.

The development of vaccines has entered a new era with the advent of nanotechnology, particularly through the utilization of nanoparticles. This review focuses on the role of nanoparticles in enhancing the efficacy and stability of mRNA vaccines. Nanoparticles, owing to their unique properties such as high surface area, tunable size, and their ability to be functionalized, have emerged as powerful tools in vaccine development. Specifically, lipid nanoparticles (LNPs) have revolutionized the delivery of mRNA vaccines by protecting the fragile mRNA molecules and facilitating their efficient uptake by cells. This review discusses the various types of nanoparticles employed in mRNA vaccine formulations, including lipid-based, polymer-based, and inorganic nanoparticles, highlighting their advantages and limitations. Moreover, it explores the mechanisms by which nanoparticles improve immune responses, such as enhanced antigen presentation and the prolonged release of mRNA. This review also addresses the challenges and future directions in nanoparticle-based vaccine development, emphasizing the need for further research to optimize formulations for broader applications. By providing an in-depth analysis of the current advancements in and potential of nanoparticles in mRNA vaccines, this review aims to shed light on their critical role in combating infectious diseases and improving public health outcomes. Full article

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19 pages, 2857 KiB

Open AccessReview

CAR-NK Cell Therapy: A Transformative Approach to Overcoming Oncological Challenges

by Wangshu Li, Xiuying Wang, Xu Zhang, Aziz ur Rehman Aziz and Daqing Wang

Biomolecules 2024, 14(8), 1035; https://doi.org/10.3390/biom14081035 - 20 Aug 2024

Cited by 1 | Viewed by 1935

Abstract

The use of chimeric antigen receptor (CAR) in natural killer (NK) cells for cancer therapy is gaining momentum, marking a significant shift in cancer treatment. This review aims to explore the potential of CAR-NK cell therapy in cancer immunotherapy, providing a fresh perspective. [...] Read more.

The use of chimeric antigen receptor (CAR) in natural killer (NK) cells for cancer therapy is gaining momentum, marking a significant shift in cancer treatment. This review aims to explore the potential of CAR-NK cell therapy in cancer immunotherapy, providing a fresh perspective. It discusses the innovative approaches in CAR-NK cell design and engineering, particularly targeting refractory or recurrent cancers. By comparing CAR-NK cells with traditional therapies, the review highlights their unique ability to tackle tumor heterogeneity and immune system suppression. Additionally, it explains how novel cytokines and receptors can enhance CAR-NK cell efficacy, specificity, and functionality. This review underscores the advantages of CAR-NK cells, including reduced toxicity, lower cost, and broader accessibility compared to CAR-T cells, along with their potential in treating both blood cancers and solid tumors. Full article

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3 pages, 496 KiB

Open AccessCorrection

Correction: Thangameeran et al. Examining Transcriptomic Alterations in Rat Models of Intracerebral Hemorrhage and Severe Intracerebral Hemorrhage. Biomolecules 2024, 14, 678

by Shaik Ismail Mohammed Thangameeran, Sheng-Tzung Tsai, Hock-Kean Liew and Cheng-Yoong Pang

Biomolecules 2024, 14(8), 1034; https://doi.org/10.3390/biom14081034 - 20 Aug 2024

Viewed by 398

Abstract

In the original publication [...] Full article

(This article belongs to the Special Issue Intracerebral Hemorrhage: Advances in Preclinical Studies: 2nd Edition)

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19 pages, 11217 KiB

Open AccessArticle

Neglected Tropical Diseases: A Chemoinformatics Approach for the Use of Biodiversity in Anti-Trypanosomatid Drug Discovery

by Marilia Valli, Thiago H. Döring, Edgard Marx, Leonardo L. G. Ferreira, José L. Medina-Franco and Adriano D. Andricopulo

Biomolecules 2024, 14(8), 1033; https://doi.org/10.3390/biom14081033 - 20 Aug 2024

Cited by 1 | Viewed by 1666

Abstract

The development of new treatments for neglected tropical diseases (NTDs) remains a major challenge in the 21st century. In most cases, the available drugs are obsolete and have limitations in terms of efficacy and safety. The situation becomes even more complex when considering [...] Read more.

The development of new treatments for neglected tropical diseases (NTDs) remains a major challenge in the 21st century. In most cases, the available drugs are obsolete and have limitations in terms of efficacy and safety. The situation becomes even more complex when considering the low number of new chemical entities (NCEs) currently in use in advanced clinical trials for most of these diseases. Natural products (NPs) are valuable sources of hits and lead compounds with privileged scaffolds for the discovery of new bioactive molecules. Considering the relevance of biodiversity for drug discovery, a chemoinformatics analysis was conducted on a compound dataset of NPs with anti-trypanosomatid activity reported in 497 research articles from 2019 to 2024. Structures corresponding to different metabolic classes were identified, including terpenoids, benzoic acids, benzenoids, steroids, alkaloids, phenylpropanoids, peptides, flavonoids, polyketides, lignans, cytochalasins, and naphthoquinones. This unique collection of NPs occupies regions of the chemical space with drug-like properties that are relevant to anti-trypanosomatid drug discovery. The gathered information greatly enhanced our understanding of biologically relevant chemical classes, structural features, and physicochemical properties. These results can be useful in guiding future medicinal chemistry efforts for the development of NP-inspired NCEs to treat NTDs caused by trypanosomatid parasites. Full article

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6 pages, 1087 KiB

Open AccessEditorial

Molecular Aspects of Cardiovascular Risk Factors

by Shang-Zhong Xu and Thozhukat Sathyapalan

Biomolecules 2024, 14(8), 1032; https://doi.org/10.3390/biom14081032 - 20 Aug 2024

Viewed by 1161

Abstract

Cardiovascular diseases (CVDs) are the leading cause of death [...] Full article

(This article belongs to the Special Issue Molecular Aspect of Cardiovascular Risk Factors)

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30 pages, 9634 KiB

Open AccessReview

Nano-Formulations of Natural Antioxidants for the Treatment of Liver Cancer

by Mariateresa Cristani, Andrea Citarella, Federica Carnamucio and Nicola Micale

Biomolecules 2024, 14(8), 1031; https://doi.org/10.3390/biom14081031 - 19 Aug 2024

Viewed by 1327

Abstract

Oxidative stress is a key factor in the pathological processes that trigger various chronic liver diseases, and significantly contributes to the development of hepatocarcinogenesis. Natural antioxidants reduce oxidative stress by neutralizing free radicals and play a crucial role in the treatment of free-radical-induced [...] Read more.

Oxidative stress is a key factor in the pathological processes that trigger various chronic liver diseases, and significantly contributes to the development of hepatocarcinogenesis. Natural antioxidants reduce oxidative stress by neutralizing free radicals and play a crucial role in the treatment of free-radical-induced liver diseases. However, their efficacy is often limited by poor bioavailability and metabolic stability. To address these limitations, recent advances have focused on developing nano-drug delivery systems that protect them from degradation and enhance their therapeutic potential. Among the several critical benefits, they showed to be able to improve bioavailability and targeted delivery, thereby reducing off-target effects by specifically directing the antioxidant to the liver tumor site. Moreover, these nanosystems led to sustained release, prolonging the therapeutic effect over time. Some of them also exhibited synergistic effects when combined with other therapeutic agents, allowing for improved overall efficacy. This review aims to discuss recent scientific advances in nano-formulations containing natural antioxidant molecules, highlighting their potential as promising therapeutic approaches for the treatment of liver cancer. The novelty of this review lies in its comprehensive focus on the latest developments in nano-formulations of natural antioxidants for the treatment of liver cancer. Full article

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13 pages, 2947 KiB

Open AccessArticle

Extracellular Vesicles Induce Nuclear Factor-κB Activation and Interleukin-8 Synthesis through miRNA-191-5p Contributing to Inflammatory Processes: Potential Implications in the Pathogenesis of Chronic Obstructive Pulmonary Disease

by Sara Carpi, Beatrice Polini, Dario Nieri, Stefano Doccini, Maria Conti, Erika Bazzan, Marta Pagnini, Filippo Maria Santorelli, Marco Cecchini, Paola Nieri, Alessandro Celi and Tommaso Neri

Biomolecules 2024, 14(8), 1030; https://doi.org/10.3390/biom14081030 - 19 Aug 2024

Viewed by 925

Abstract

Extracellular vesicles (EVs) play a pivotal role in a variety of physiologically relevant processes, including lung inflammation. Recent attention has been directed toward EV-derived microRNAs (miRNAs), such as miR-191-5p, particularly in the context of inflammation. Here, we investigated the impact of miR-191-5p-enriched EVs [...] Read more.

Extracellular vesicles (EVs) play a pivotal role in a variety of physiologically relevant processes, including lung inflammation. Recent attention has been directed toward EV-derived microRNAs (miRNAs), such as miR-191-5p, particularly in the context of inflammation. Here, we investigated the impact of miR-191-5p-enriched EVs on the activation of NF-κB and the expression of molecules associated with inflammation such as interleukin-8 (IL-8). To this aim, cells of bronchial epithelial origin, 16HBE, were transfected with miR-191-5p mimic and inhibitor and subsequently subjected to stimulations to generate EVs. Then, bronchial epithelial cells were exposed to the obtained EVs to evaluate the activation of NF-κB and IL-8 levels. Additionally, we conducted a preliminary investigation to analyze the expression profiles of miR-191-5p in EVs isolated from the plasma of patients diagnosed with chronic obstructive pulmonary disease (COPD). Our initial findings revealed two significant observations. First, the exposure of bronchial epithelial cells to miR-191-5p-enriched EVs activated the NF-kB signaling and increased the synthesis of IL-8. Second, we discovered the presence of miR-191-5p in peripheral blood-derived EVs from COPD patients and noted a correlation between miR-191-5p levels and inflammatory and functional parameters. Collectively, these data corroborate and further expand the proinflammatory role of EVs, with a specific emphasis on miR-191-5p as a key cargo involved in this process. Consequently, we propose a model in which miR-191-5p, carried by EVs, plays a role in airway inflammation and may contribute to the pathogenesis of COPD. Full article

(This article belongs to the Collection Molecular Biology: Feature Papers)

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18 pages, 3144 KiB

Open AccessArticle

Effects of Interrupting Prolonged Sitting with Light-Intensity Physical Activity on Inflammatory and Cardiometabolic Risk Markers in Young Adults with Overweight and Obesity: Secondary Outcome Analyses of the SED-ACT Randomized Controlled Crossover Trial

by Sascha W. Hoffmann, Janis Schierbauer, Paul Zimmermann, Thomas Voit, Auguste Grothoff, Nadine B. Wachsmuth, Andreas Rössler, Tobias Niedrist, Helmut K. Lackner and Othmar Moser

Biomolecules 2024, 14(8), 1029; https://doi.org/10.3390/biom14081029 - 19 Aug 2024

Viewed by 1445

Abstract

Sedentary behavior (SB) is an essential risk factor for obesity, cardiovascular disease, and type 2 diabetes. Though certain levels of physical activity (PA) may attenuate the detrimental effects of SB, the inflammatory and cardiometabolic responses involved are still not fully understood. The focus [...] Read more.

Sedentary behavior (SB) is an essential risk factor for obesity, cardiovascular disease, and type 2 diabetes. Though certain levels of physical activity (PA) may attenuate the detrimental effects of SB, the inflammatory and cardiometabolic responses involved are still not fully understood. The focus of this secondary outcome analysis was to describe how light-intensity PA snacks (LIPASs, alternate sitting and standing, walking or standing continuously) compared with uninterrupted prolonged sitting affect inflammatory and cardiometabolic risk markers. Seventeen young adults with overweight and obesity participated in this study (eight females, 23.4 ± 3.3 years, body mass index (BMI) 29.7 ± 3.8 kg/m², glycated hemoglobin A1C (HbA_1c) 5.4 ± 0.3%, body fat 31.8 ± 8.2%). Participants were randomly assigned to the following conditions which were tested during an 8 h simulated workday: uninterrupted prolonged sitting (SIT), alternate sitting and standing (SIT-STAND, 2.5 h total standing time), continuous standing (STAND), and continuous walking (1.6 km/h; WALK). Each condition also included a standardized non-relativized breakfast and lunch. Venous blood samples were obtained in a fasted state at baseline (T₀), 1 h after lunch (T₁) and 8 h after baseline (T₂). Inflammatory and cardiometabolic risk markers included interleukin-6 (IL-6), c-reactive protein (CRP), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglycerides (TGs), visceral fat area (VFA), triglyceride-glucose (TyG) index, two lipid ratio measures, TG/HDL-C and TC/HDL-C, albumin, amylase (pancreatic), total protein, uric acid, and urea. We found significant changes in a broad range of certain inflammatory and cardiometabolic risk markers during the intervention phase for IL-6 (p = 0.014), TG (p = 0.012), TC (p = 0.017), HDL-C (p = 0.020), LDL-C (p = 0.021), albumin (p = 0.003), total protein (p = 0.021), and uric acid (p = 0.040) in favor of light-intensity walking compared with uninterrupted prolonged sitting, alternate sitting and standing, and continuous standing. We found no significant changes in CRP (p = 0.529), creatinine (p = 0.199), TyG (p = 0.331), and the lipid ratios TG/HDL-C (p = 0.793) and TC/HDL-C (p = 0.221) in response to the PA snack. During a simulated 8 h work environment replacement and interruption of prolonged sitting with light-intensity walking, significant positive effects on certain inflammatory and cardiometabolic risk markers were found in young adults with overweight and obesity. Full article

(This article belongs to the Special Issue Diabetes, Overweight and Obesity: From Molecular Mechanisms to Therapies Strategies)

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17 pages, 3008 KiB

Open AccessArticle

Central Actions of Leptin Induce an Atrophic Pattern and Improves Heart Function in Lean Normoleptinemic Rats via PPARβ/δ Activation

by Blanca Rubio, Cristina Pintado, Lorena Mazuecos, Marina Benito, Antonio Andrés and Nilda Gallardo

Biomolecules 2024, 14(8), 1028; https://doi.org/10.3390/biom14081028 - 18 Aug 2024

Viewed by 784

Abstract

Leptin, acting centrally or peripherally, has complex effects on cardiac remodeling and heart function. We previously reported that central leptin exerts an anti-hypertrophic effect in the heart via cardiac PPARβ/δ activation. Here, we assessed the impact of central leptin administration and PPARβ/δ inhibition [...] Read more.

Leptin, acting centrally or peripherally, has complex effects on cardiac remodeling and heart function. We previously reported that central leptin exerts an anti-hypertrophic effect in the heart via cardiac PPARβ/δ activation. Here, we assessed the impact of central leptin administration and PPARβ/δ inhibition on cardiac function. Various cardiac properties, including QRS duration, R wave amplitude, heart rate (HR), ejection fraction (EF), end-diastolic left ventricular mass (EDLVM), end-diastolic volume (EDV), and cardiac output (CO) were analyzed. Central leptin infusion increased cardiac PPARβ/δ protein content and decreased HR, QRS duration, and R wave amplitude. These changes induced by central leptin suggested a decrease in the ventricular wall growth, which was confirmed by MRI. In fact, the EDLVM was reduced by central leptin while increased in rats co-treated with leptin and GSK0660, a selective antagonist of PPARβ/δ activity. In summary, central leptin plays a dual role in cardiac health, potentially leading to ventricular atrophy and improving heart function when PPARβ/δ signaling is intact. The protective effects of leptin are lost by PPARβ/δ inhibition, underscoring the importance of this pathway. These findings highlight the therapeutic potential of targeting leptin and PPARβ/δ pathways to combat cardiac alterations and heart failure, particularly in the context of obesity. Full article

(This article belongs to the Special Issue Peroxisome Proliferator-Activated Receptors (PPARs): A Themed Issue in Honor of Prof. Walter Wahli)

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11 pages, 2808 KiB

Open AccessArticle

Facile Splint-Free Circularization of ssDNA with T4 DNA Ligase by Redesigning the Linear Substrate to Form an Intramolecular Dynamic Nick

by Wenhua Sun, Kunling Hu, Mengqin Liu, Jian Luo, Ran An and Xingguo Liang

Biomolecules 2024, 14(8), 1027; https://doi.org/10.3390/biom14081027 - 18 Aug 2024

Viewed by 1238

Abstract

The efficient preparation of single-stranded DNA (ssDNA) rings, as a macromolecular construction approach with topological features, has aroused much interest due to the ssDNA rings’ numerous applications in biotechnology and DNA nanotechnology. However, an extra splint is essential for enzymatic circularization, and by-products [...] Read more.

The efficient preparation of single-stranded DNA (ssDNA) rings, as a macromolecular construction approach with topological features, has aroused much interest due to the ssDNA rings’ numerous applications in biotechnology and DNA nanotechnology. However, an extra splint is essential for enzymatic circularization, and by-products of multimers are usually present at high concentrations. Here, we proposed a simple and robust strategy using permuted precursor (linear ssDNA) for circularization by forming an intramolecular dynamic nick using a part of the linear ssDNA substrate itself as the template. After the simulation of the secondary structure for desired circular ssDNA, the linear ssDNA substrate is designed to have its ends on the duplex part (≥5 bp). By using this permuted substrate with 5′-phosphate, the splint-free circularization is simply carried out by T4 DNA ligase. Very interestingly, formation of only several base pairs (2–4) flanking the nick is enough for ligation, although they form only instantaneously under ligation conditions. More significantly, the 5-bp intramolecular duplex part commonly exists in genomes or functional DNA, demonstrating the high generality of our approach. Our findings are also helpful for understanding the mechanism of enzymatic DNA ligation from the viewpoint of substrate binding. Full article

(This article belongs to the Special Issue Chemical Biology and Biotechnology of Nucleosides, Nucleotides, and Nucleic Acids)

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13 pages, 1430 KiB

Open AccessReview

Advancement and Potential Applications of Epididymal Organoids

by Junyu Nie, Hao Chen and Xiuling Zhao

Biomolecules 2024, 14(8), 1026; https://doi.org/10.3390/biom14081026 - 17 Aug 2024

Viewed by 1296

Abstract

The epididymis, a key reproductive organ, is crucial for sperm concentration, maturation, and storage. Despite a comprehensive understanding of many of its functions, several aspects of the complex processes within the epididymis remain obscure. Dysfunction in this organ is intricately connected to the [...] Read more.

The epididymis, a key reproductive organ, is crucial for sperm concentration, maturation, and storage. Despite a comprehensive understanding of many of its functions, several aspects of the complex processes within the epididymis remain obscure. Dysfunction in this organ is intricately connected to the formation of the microenvironment, disruptions in sperm maturation, and the progression of male infertility. Thus, elucidating the functional mechanisms of the epididymal epithelium is imperative. Given the variety of cell types present within the epididymal epithelium, utilizing a three-dimensional (3D) in vitro model provides a holistic and practical framework for exploring the multifaceted roles of the epididymis. Organoid cell culture, involving the co-cultivation of pluripotent or adult stem cells with growth factors on artificial matrix scaffolds, effectively recreates the in vivo cell growth microenvironment, thereby offering a promising avenue for studying the epididymis. The field of epididymal organoids is relatively new, with few studies focusing on their formation and even fewer detailing the generation of organoids that exhibit epididymis-specific structures and functions. Ongoing challenges in both clinical applications and mechanistic studies underscore the importance of this research. This review summarizes the established methodologies for inducing the in vitro cultivation of epididymal cells, outlines the various approaches for the development of epididymal organoids, and explores their potential applications in the field of male reproductive biology. Full article

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3 pages, 160 KiB

Open AccessEditorial

Facilities in Molecular Biomarkers in Cardiology

by Pietro Scicchitano and Matteo Cameli

Biomolecules 2024, 14(8), 1025; https://doi.org/10.3390/biom14081025 - 17 Aug 2024

Viewed by 708

Abstract

This Special Issue of Biomolecules, entitled “Molecular Biomarkers in Cardiology 2022–2023”, presents a comprehensive collection of research and reviews exploring the rapidly evolving field of cardiovascular biomarkers [...] Full article

(This article belongs to the Special Issue Molecular Biomarkers In Cardiology 2022–2023)

15 pages, 2684 KiB

Open AccessArticle

The Effects of Hypoxia on the Immune–Metabolic Interplay in Liver Cancer

by Yubei He, Han Xu, Yu Liu, Stefan Kempa, Carolina Vechiatto, Robin Schmidt, Emine Yaren Yilmaz, Luisa Heidemann, Jörg Schnorr, Susanne Metzkow, Eyk Schellenberger, Akvile Häckel, Andreas Patzak, Dominik N. Müller and Lynn Jeanette Savic

Biomolecules 2024, 14(8), 1024; https://doi.org/10.3390/biom14081024 - 17 Aug 2024

Cited by 1 | Viewed by 1006

Abstract

M2-like macrophages promote tumor growth and cancer immune evasion. This study used an in vitro model to investigate how hypoxia and tumor metabolism affect macrophage polarization. Liver cancer cells (HepG2 and VX2) and macrophages (THP1) were cultured under hypoxic (0.1% O₂) [...] Read more.

M2-like macrophages promote tumor growth and cancer immune evasion. This study used an in vitro model to investigate how hypoxia and tumor metabolism affect macrophage polarization. Liver cancer cells (HepG2 and VX2) and macrophages (THP1) were cultured under hypoxic (0.1% O₂) and normoxic (21% O₂) conditions with varying glucose levels (2 g/L or 4.5 g/L). Viability assays and extracellular pH (pHe) measurements were conducted over 96 hours. Macrophages were exposed to the tumor-conditioned medium (TCM) from the cancer cells, and polarization was assessed using arginase and nitrite assays. GC-MS-based metabolic profiling quantified TCM meta-bolites and correlated them with M2 polarization. The results showed that pHe in TCMs decreased more under hypoxia than normoxia (p < 0.0001), independent of glucose levels. The arginase assay showed hypoxia significantly induced the M2 polarization of macrophages (control group: p = 0.0120,^0.1%VX2-TCM group: p = 0.0149, ^0.1%HepG2-TCM group: p < 0.0001, ^0.1%VX2-TCM_HG group: p = 0.0001, and ^0.1%HepG2-TCM_HG group: p < 0.0001). TCMs also induced M2 polarization under normoxic conditions, but the strongest M2 polarization occurred when both tumor cells and macrophages were incubated under hypoxia with high glucose levels. Metabolomics revealed that several metabolites, particularly lactate, were correlated with hypoxia and M2 polarization. Under normoxia, elevated 2-amino-butanoic acid (2A-BA) strongly correlated with M2 polarization. These findings suggest that targeting tumor hypoxia could mitigate immune evasion in liver tumors. Lactate drives acidity in hypoxic tumors, while 2A-BA could be a therapeutic target for overcoming immunosuppression in normoxic conditions. Full article

(This article belongs to the Special Issue Tumor Microenvironment, Immunology and Precision Medicine of Liver Cancer)

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21 pages, 3012 KiB

Open AccessArticle

RNA Surveillance Factor SMG5 Is Essential for Mouse Embryonic Stem Cell Differentiation

by Chengyan Chen, Yanling Wei, Xiaoning Jiang and Tangliang Li

Biomolecules 2024, 14(8), 1023; https://doi.org/10.3390/biom14081023 - 17 Aug 2024

Viewed by 1079

Abstract

Nonsense-mediated mRNA decay (NMD) is a highly conserved post-transcriptional gene expression regulatory mechanism in eukaryotic cells. NMD eliminates aberrant mRNAs with premature termination codons to surveil transcriptome integrity. Furthermore, NMD fine-tunes gene expression by destabilizing RNAs with specific NMD features. Thus, by controlling [...] Read more.

Nonsense-mediated mRNA decay (NMD) is a highly conserved post-transcriptional gene expression regulatory mechanism in eukaryotic cells. NMD eliminates aberrant mRNAs with premature termination codons to surveil transcriptome integrity. Furthermore, NMD fine-tunes gene expression by destabilizing RNAs with specific NMD features. Thus, by controlling the quality and quantity of the transcriptome, NMD plays a vital role in mammalian development, stress response, and tumorigenesis. Deficiencies of NMD factors result in early embryonic lethality, while the underlying mechanisms are poorly understood. SMG5 is a key NMD factor. In this study, we generated an Smg5 conditional knockout mouse model and found that Smg5-null results in early embryonic lethality before E13.5. Furthermore, we produced multiple lines of Smg5 knockout mouse embryonic stem cells (mESCs) and found that the deletion of Smg5 in mESCs does not compromise cell viability. Smg5-null delays differentiation of mESCs. Mechanistically, our study reveals that the c-MYC protein, but not c-Myc mRNA, is upregulated in SMG5-deficient mESCs. The overproduction of c-MYC protein could be caused by enhanced protein synthesis upon SMG5 loss. Furthermore, SMG5-null results in dysregulation of alternative splicing on multiple stem cell differentiation regulators. Overall, our findings underscore the importance of SMG5-NMD in regulating mESC cell-state transition. Full article

(This article belongs to the Special Issue New Insights into RNA-Binding Proteins)

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12 pages, 1729 KiB

Open AccessArticle

Neurosteroid Levels in GBA Mutated and Non-Mutated Parkinson’s Disease: A Possible Factor Influencing Clinical Phenotype?

by Francesco Cavallieri, Chiara Lucchi, Sara Grisanti, Edoardo Monfrini, Valentina Fioravanti, Giulia Toschi, Giulia Di Rauso, Jessica Rossi, Alessio Di Fonzo, Giuseppe Biagini and Franco Valzania

Biomolecules 2024, 14(8), 1022; https://doi.org/10.3390/biom14081022 - 17 Aug 2024

Viewed by 782

Abstract

Neurosteroids are pleiotropic molecules involved in various neurodegenerative diseases with neuroinflammation. We assessed neurosteroids’ serum levels in a cohort of Parkinson’s Disease (PD) patients with heterozygous glucocerebrosidase (GBA) mutations (GBA-PD) compared with matched cohorts of consecutive non-mutated PD (NM-PD) patients and healthy subjects [...] Read more.

Neurosteroids are pleiotropic molecules involved in various neurodegenerative diseases with neuroinflammation. We assessed neurosteroids’ serum levels in a cohort of Parkinson’s Disease (PD) patients with heterozygous glucocerebrosidase (GBA) mutations (GBA-PD) compared with matched cohorts of consecutive non-mutated PD (NM-PD) patients and healthy subjects with (GBA-HC) and without (NM-HC) GBA mutations. A consecutive cohort of GBA-PD was paired for age, sex, disease duration, Hoehn and Yahr stage, and comorbidities with a cohort of consecutive NM-PD. Two cohorts of GBA-HC and HC were also considered. Clinical assessment included the Movement Disorder Society revision of the Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) and the Montreal Cognitive Assessment (MoCA). Serum samples were processed and analyzed by liquid chromatography coupled with the triple quadrupole mass spectrometry. Twenty-two GBA-PD (males: 11, age: 63.68), 22 NM-PD (males: 11, age: 63.05), 14 GBA-HC (males: 8; age: 49.36), and 15 HC (males: 4; age: 60.60) were studied. Compared to NM-PD, GBA-PD showed more hallucinations and psychosis (p < 0.05, Fisher’s exact test) and higher MDS-UPDRS part-II (p < 0.05). Most of the serum neurosteroids were reduced in both GBA-PD and NM-PD compared to the respective control cohorts, except for 5α-dihydroprogesterone. Allopregnanolone was the only neurosteroid significantly lower (p < 0.01, Dunn’s test) in NM-PD compared to GBA-PD patients. Only in GBA-PD, allopregnanolone, and pregnanolone levels correlated (Spearman) with a more severe MDS-UPDRS part-III. Allopregnanolone levels also negatively correlated with MoCA scores, and pregnanolone levels correlated with more pronounced bradykinesia. This pilot study provides the first observation of changes in neurosteroid peripheral levels in GBA-PD. The involvement of the observed changes in the development of neuropsychological and motor symptoms of GBA-PD deserves further attention. Full article

(This article belongs to the Special Issue Role of Neuroactive Steroids in Health and Disease: 2nd Edition)

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5 pages, 191 KiB

Open AccessEditorial

The Multifaceted Impact of Environmental Pollutants on Health and Ecosystems

by Marina Piscopo, Carmela Marinaro and Gennaro Lettieri

Biomolecules 2024, 14(8), 1021; https://doi.org/10.3390/biom14081021 - 17 Aug 2024

Viewed by 705

Abstract

Environmental pollutants have pervasive and far-reaching effects on both ecosystems and human health [...] Full article

(This article belongs to the Special Issue Molecular Effects of Environmental Pollutants on Health of Human, Animals and Plants)

21 pages, 7687 KiB

Open AccessArticle

Alterations in the Hypothalamic–Pituitary–Adrenal Axis as a Response to Experimental Autoimmune Encephalomyelitis in Dark Agouti Rats of Both Sexes

by Ana Milosevic, Katarina Milosevic, Anica Zivkovic, Irena Lavrnja, Danijela Savic, Ivana Bjelobaba and Marija M. Janjic

Biomolecules 2024, 14(8), 1020; https://doi.org/10.3390/biom14081020 - 17 Aug 2024

Viewed by 758

Abstract

Multiple sclerosis (MS) is a chronic inflammatory disease that affects the central nervous system, usually diagnosed during the reproductive period. Both MS and its commonly used animal model, experimental autoimmune encephalomyelitis (EAE), exhibit sex-specific features regarding disease progression and disturbances in the neuroendocrine [...] Read more.

Multiple sclerosis (MS) is a chronic inflammatory disease that affects the central nervous system, usually diagnosed during the reproductive period. Both MS and its commonly used animal model, experimental autoimmune encephalomyelitis (EAE), exhibit sex-specific features regarding disease progression and disturbances in the neuroendocrine and endocrine systems. This study investigates the hypothalamic–pituitary–adrenal (HPA) axis response of male and female Dark Agouti rats during EAE. At the onset of EAE, Crh expression in the hypothalamus of both sexes is decreased, while males show reduced plasma adrenocorticotropic hormone levels. Adrenal gland activity is increased during EAE in both males and females, as evidenced by enlarged adrenal glands and increased StAR gene and protein expression. However, only male rats show increased serum and adrenal corticosterone levels, and an increased volume of the adrenal cortex. Adrenal 3β-HSD protein and progesterone levels are elevated in males only. Serum progesterone levels of male rats are also increased, although testicular progesterone levels are decreased during the disease, implying that the adrenal gland is the source of elevated serum progesterone levels in males. Our results demonstrate a sex difference in the response of the HPA axis at the adrenal level, with male rats showing a more pronounced induction during EAE. Full article

(This article belongs to the Special Issue Role of Neuroactive Steroids in Health and Disease: 2nd Edition)

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24 pages, 6028 KiB

Open AccessReview

The Prospect of Hepatic Decellularized Extracellular Matrix as a Bioink for Liver 3D Bioprinting

by Wen Shi, Zhe Zhang and Xiaohong Wang

Biomolecules 2024, 14(8), 1019; https://doi.org/10.3390/biom14081019 - 16 Aug 2024

Cited by 1 | Viewed by 1425

Abstract

The incidence of liver diseases is high worldwide. Many factors can cause liver fibrosis, which in turn can lead to liver cirrhosis and even liver cancer. Due to the shortage of donor organs, immunosuppression, and other factors, only a few patients are able [...] Read more.

The incidence of liver diseases is high worldwide. Many factors can cause liver fibrosis, which in turn can lead to liver cirrhosis and even liver cancer. Due to the shortage of donor organs, immunosuppression, and other factors, only a few patients are able to undergo liver transplantation. Therefore, how to construct a bioartificial liver that can be transplanted has become a global research hotspot. With the rapid development of three-dimensional (3D) bioprinting in the field of tissue engineering and regenerative medicine, researchers have tried to use various 3D bioprinting technologies to construct bioartificial livers in vitro. In terms of the choice of bioinks, liver decellularized extracellular matrix (dECM) has many advantages over other materials for cell-laden hydrogel in 3D bioprinting. This review mainly summarizes the acquisition of liver dECM and its application in liver 3D bioprinting as a bioink with respect to availability, printability, and biocompatibility in many aspects and puts forward the current challenges and prospects. Full article

(This article belongs to the Topic Development and Application of Novel Biomaterials for Tissue Engineering)

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33 pages, 8180 KiB

Open AccessArticle

Novel Insights into the Antimicrobial and Antibiofilm Activity of Pyrroloquinoline Quinone (PQQ); In Vitro, In Silico, and Shotgun Proteomic Studies

by Mai M. Labib, Alaa M. Alqahtani, Hebatallah H. Abo Nahas, Rana M. Aldossari, Bandar Fahad Almiman, Sarah Ayman Alnumaani, Mohammad El-Nablaway, Ebtesam Al-Olayan, Maha Alsunbul and Essa M. Saied

Biomolecules 2024, 14(8), 1018; https://doi.org/10.3390/biom14081018 - 16 Aug 2024

Viewed by 1439

Abstract

Microbial infections pose a significant global health threat, affecting millions of individuals and leading to substantial mortality rates. The increasing resistance of microorganisms to conventional treatments requires the development of novel antimicrobial agents. Pyrroloquinoline quinone (PQQ), a natural medicinal drug involved in various [...] Read more.

Microbial infections pose a significant global health threat, affecting millions of individuals and leading to substantial mortality rates. The increasing resistance of microorganisms to conventional treatments requires the development of novel antimicrobial agents. Pyrroloquinoline quinone (PQQ), a natural medicinal drug involved in various cellular processes, holds promise as a potential antimicrobial agent. In the present study, our aim was, for the first time, to explore the antimicrobial activity of PQQ against 29 pathogenic microbes, including 13 fungal strains, 8 Gram-positive bacteria, and 8 Gram-negative bacteria. Our findings revealed potent antifungal properties of PQQ, particularly against Syncephalastrum racemosum, Talaromyces marneffei, Candida lipolytica, and Trichophyton rubrum. The MIC values varied between fungal strains, and T. marneffei exhibited a lower MIC, indicating a greater susceptibility to PQQ. In addition, PQQ exhibited notable antibacterial activity against Gram-positive and -negative bacteria, with a prominent inhibition observed against Staphylococcus epidermidis, Proteus vulgaris, and MRSA strains. Remarkably, PQQ demonstrated considerable biofilm inhibition against the MRSA, S. epidermidis, and P. vulgaris strains. Transmission electron microscopy (TEM) studies revealed that PQQ caused structural damage and disrupted cell metabolism in bacterial cells, leading to aberrant morphology, compromised cell membrane integrity, and leakage of cytoplasmic contents. These findings were further affirmed by shotgun proteomic analysis, which revealed that PQQ targets several important cellular processes in bacteria, including membrane proteins, ATP metabolic processes, DNA repair processes, metal-binding proteins, and stress response. Finally, detailed molecular modeling investigations indicated that PQQ exhibits a substantial binding affinity score for key microbial targets, including the mannoprotein Mp1P, the transcriptional regulator TcaR, and the endonuclease PvuRTs1I. Taken together, our study underscores the effectiveness of PQQ as a broad-spectrum antimicrobial agent capable of combating pathogenic fungi and bacteria, while also inhibiting biofilm formation and targeting several critical biological processes, making it a promising therapeutic option for biofilm-related infections. Full article

(This article belongs to the Section Bioinformatics and Systems Biology)

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23 pages, 2498 KiB

Open AccessReview

The Influence of Cecal Microbiota Transplantation on Chicken Injurious Behavior: Perspective in Human Neuropsychiatric Research

by Yuechi Fu and Heng-Wei Cheng

Biomolecules 2024, 14(8), 1017; https://doi.org/10.3390/biom14081017 - 16 Aug 2024

Viewed by 1042

Abstract

Numerous studies have evidenced that neuropsychiatric disorders (mental illness and emotional disturbances) with aggression (or violence) pose a significant challenge to public health and contribute to a substantial economic burden worldwide. Especially, social disorganization (or social inequality) associated with childhood adversity has long-lasting [...] Read more.

Numerous studies have evidenced that neuropsychiatric disorders (mental illness and emotional disturbances) with aggression (or violence) pose a significant challenge to public health and contribute to a substantial economic burden worldwide. Especially, social disorganization (or social inequality) associated with childhood adversity has long-lasting effects on mental health, increasing the risk of developing neuropsychiatric disorders. Intestinal bacteria, functionally as an endocrine organ and a second brain, release various immunomodulators and bioactive compounds directly or indirectly regulating a host’s physiological and behavioral homeostasis. Under various social challenges, stress-induced dysbiosis increases gut permeability causes serial reactions: releasing neurotoxic compounds, leading to neuroinflammation and neuronal injury, and eventually neuropsychiatric disorders associated with aggressive, violent, or impulsive behavior in humans and various animals via a complex bidirectional communication of the microbiota–gut–brain (MGB) axis. The dysregulation of the MGB axis has also been recognized as one of the reasons for the prevalence of social stress-induced injurious behaviors (feather pecking, aggression, and cannibalistic pecking) in chickens. However, existing knowledge of preventing and treating these disorders in both humans and chickens is not well understood. In previous studies, we developed a non-mammal model in an abnormal behavioral investigation by rationalizing the effects of gut microbiota on injurious behaviors in chickens. Based on our earlier success, the perspective article outlines the possibility of reducing stress-induced injurious behaviors in chickens through modifying gut microbiota via cecal microbiota transplantation, with the potential for providing a biotherapeutic rationale for preventing injurious behaviors among individuals with mental disorders via restoring gut microbiota diversity and function. Full article

(This article belongs to the Special Issue Prebiotics and Probiotics in Health and Disease: Looking at the Future)

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14 pages, 3676 KiB

Open AccessArticle

Creating Meiotic Recombination-Regulating DNA Sites by SpEDIT in Fission Yeast Reveals Inefficiencies, Target-Site Duplications, and Ectopic Insertions

by Reine U. Protacio, Seth Dixon, Mari K. Davidson and Wayne P. Wahls

Biomolecules 2024, 14(8), 1016; https://doi.org/10.3390/biom14081016 - 16 Aug 2024

Viewed by 816

Abstract

Recombination hotspot-activating DNA sites (e.g., M26, CCAAT, Oligo-C) and their binding proteins (e.g., Atf1-Pcr1 heterodimer; Php2-Php3-Php5 complex, Rst2, Prdm9) regulate the distribution of Spo11 (Rec12)-initiated meiotic recombination. We sought to create 14 different candidate regulatory DNA sites via bp substitutions [...] Read more.

Recombination hotspot-activating DNA sites (e.g., M26, CCAAT, Oligo-C) and their binding proteins (e.g., Atf1-Pcr1 heterodimer; Php2-Php3-Php5 complex, Rst2, Prdm9) regulate the distribution of Spo11 (Rec12)-initiated meiotic recombination. We sought to create 14 different candidate regulatory DNA sites via bp substitutions in the ade6 gene of Schizosaccharomyces pombe. We used a fission yeast-optimized CRISPR-Cas9 system (SpEDIT) and 196 bp-long dsDNA templates with centrally located bp substitutions designed to ablate the genomic PAM site, create specific 15 bp-long DNA sequences, and introduce a stop codon. After co-transformation with a plasmid that encoded both the guide RNA and Cas9 enzyme, about one-third of colonies had a phenotype diagnostic for DNA sequence changes at ade6. PCR diagnostics and DNA sequencing revealed a diverse collection of alterations at the target locus, including: (A) complete or (B) partial template-directed substitutions; (C) non-homologous end joinings; (D) duplications; (E) bp mutations, and (F) insertions of ectopic DNA. We concluded that SpEDIT can be used successfully to generate a diverse collection of DNA sequence elements within a reporter gene of interest. However, its utility is complicated by low efficiency, incomplete template-directed repair events, and undesired alterations to the target locus. Full article

(This article belongs to the Special Issue Two Billion Years of Sex)

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2 pages, 146 KiB

Open AccessEditorial

Integrating Signaling Pathways with Transcription Factor Networks—On the Trail of Sisyphus?

by Kostas A. Papavassiliou and Athanasios G. Papavassiliou

Biomolecules 2024, 14(8), 1015; https://doi.org/10.3390/biom14081015 - 16 Aug 2024

Viewed by 576

Abstract

In the context of health and disease research, cells use signaling pathways that transduce stimuli from the extracellular environment to modulate intracellular gene expression via the activity of transcription factors and cofactors (coactivators and/or corepressors) [...] Full article

(This article belongs to the Special Issue Signal Transduction to Transcription Factors in Health and Disease—Honorary Special Issue Commemorating the Work of Prof. Athanasios G. Papavassiliou)

11 pages, 1974 KiB

Open AccessArticle

Decidualized Endometrial Stromal Cells Promote Mitochondrial Beta-Oxidation to Produce the Octanoic Acid Required for Implantation

by Yumi Mizuno, Shunsuke Tamaru, Hideno Tochigi, Tomomi Sato, Miyuko Kishi, Akira Ohtake, Osamu Ishihara and Takeshi Kajihara

Biomolecules 2024, 14(8), 1014; https://doi.org/10.3390/biom14081014 - 16 Aug 2024

Viewed by 939

Abstract

Decidualization denotes the morphological and biological differentiating process of human endometrial stromal cells (HESCs). Fatty acid pathways are critical for endometrial decidualization. However, the participation of fatty acids as an energy source and their role in endometrial decidualization have received little attention. To [...] Read more.

Decidualization denotes the morphological and biological differentiating process of human endometrial stromal cells (HESCs). Fatty acid pathways are critical for endometrial decidualization. However, the participation of fatty acids as an energy source and their role in endometrial decidualization have received little attention. To identify fatty acids and clarify their role in decidualization, we comprehensively evaluated free fatty acid profiles using liquid chromatography/Fourier transform mass spectrometry (LC/FT-MS). LC/FT-MS analysis detected 26 kinds of fatty acids in the culture medium of decidualized or un-decidualized HESCs. Only the production of octanoic acid, which is an essential energy source for embryonic development, was increased upon decidualization. The expressions of genes related to octanoic acid metabolism including ACADL, ACADM, and ACADS; genes encoding proteins catalyzing the first step of mitochondrial fatty acid beta-oxidation; and ACSL5 and ACSM5; genes encoding fatty acid synthesis proteins were significantly altered upon decidualization. These results suggest that decidualization promotes lipid metabolism, implying that decidualized HESCs require energy metabolism of the mitochondria in embryo implantation. Full article

(This article belongs to the Special Issue Properties and Functions of Endometrial Stromal Cells)

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