Biomolecules

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

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

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

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

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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Graphical abstract

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

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

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

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, 1928 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

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)

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

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 Volume)

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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

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

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 Volume)

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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

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

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

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

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

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

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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26 pages, 1385 KiB

Open AccessReview

Unveiling the Impact of BMP9 in Liver Diseases: Insights into Pathogenesis and Therapeutic Potential

by Han Chen, Ying-Yi Li, Kouki Nio and Hong Tang

Biomolecules 2024, 14(8), 1013; https://doi.org/10.3390/biom14081013 - 15 Aug 2024

Abstract

Bone morphogenetic proteins (BMPs) are a group of growth factors belonging to the transforming growth factor β(TGF-β) family. While initially recognized for their role in bone formation, BMPs have emerged as significant players in liver diseases. Among BMPs with various physiological activities, this [...] Read more.

Bone morphogenetic proteins (BMPs) are a group of growth factors belonging to the transforming growth factor β(TGF-β) family. While initially recognized for their role in bone formation, BMPs have emerged as significant players in liver diseases. Among BMPs with various physiological activities, this comprehensive review aims to delve into the involvement of BMP9 specifically in liver diseases and provide insights into the complex BMP signaling pathway. Through an enhanced understanding of BMP9, we anticipate the discovery of new therapeutic options and potential strategies for managing liver diseases. Full article

(This article belongs to the Section Molecular Biomarkers)

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19 pages, 11245 KiB

Open AccessArticle

Impact of Dropping on Postharvest Physiology of Tomato Fruits Harvested at Green and Red Ripeness Stages

by Chy Sophea, Nasratullah Habibi, Naoki Terada, Atsushi Sanada and Kaihei Koshio

Biomolecules 2024, 14(8), 1012; https://doi.org/10.3390/biom14081012 - 15 Aug 2024

Abstract

Dropping during transportation is a critical issue for tomato fruits, as it triggers ethylene production and affects quality parameters, leading to lower quality and a reduced storage life. Thus, this study was conducted to assess the physiological alterations in tomato fruits subjected to [...] Read more.

Dropping during transportation is a critical issue for tomato fruits, as it triggers ethylene production and affects quality parameters, leading to lower quality and a reduced storage life. Thus, this study was conducted to assess the physiological alterations in tomato fruits subjected to dropping. This study involved tomatoes harvested at green and red stages, subjected to the following five dropping treatments: 0 cm, 10 cm, 30 cm, 50 cm, and 100 cm. The results revealed that dropping from 100 cm induced the highest ethylene production, particularly in green fruits, where production began within one hour and peaked within 48 h. Red fruits exhibited a dose-dependent response to mechanical stress, with a notable decrease in ethylene production starting from the second week post-dropping, suggesting a regulatory mechanism. CO₂ production peaked at 350.1 µL g⁻¹ h⁻¹ in green fruits and 338.2 µL g⁻¹ h⁻¹ in red fruits one day after dropping from 100 cm. Dropping also significantly influenced fruit color, firmness, electrolyte leakage, and vitamin C content. Principal component analysis (PCA) revealed distinct changes in metabolite profiles, with methionine and ACC (1-aminocyclopropane-1-carboxylate), key ethylene precursors, increasing in response to dropping, particularly in red fruits. These findings underscore the critical role of mechanical stress in modulating fruit physiology, with implications for post-harvest handling practices aimed at enhancing fruit quality and shelf life. Full article

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