Life Sci Space Res (Amst). 2024 Aug;42:117-132. doi: 10.1016/j.lssr.2024.07.001. Epub 2024 Jul 5.

ABSTRACT

Microgravity, as a unique hazardous factor encountered in space, can induce a series of harmful effects on living organisms. The impact of microgravity on the pivotal functional gene modules stemming from gene enrichment analysis via the regulation of miRNAs is not fully illustrated. To explore the microgravity-induced alterations in critical functional gene modules via the regulation of miRNAs, in the present study, we proposed a novel bioinformatics algorithm for the integrated analysis of miRNAome and transcriptome from short-term space-flown C. elegans. The samples of C. elegans were exposed to two space conditions, namely spaceflight (SF) and spaceflight control (SC) onboard the International Space Station for 4 days. Additionally, the samples of ground control (GC) were included for comparative analysis. Using the present algorithm, we constructed regulatory networks of functional gene modules annotated from differentially expressed genes (DEGs) and their associated regulatory differentially expressed miRNAs (DEmiRNAs). The results showed that functional gene modules of molting cycle, defense response, fatty acid metabolism, lysosome, and longevity regulating pathway were facilitated by 25 down-regulated DEmiRNAs (e.g., cel-miR-792, cel-miR-65, cel-miR-70, cel-lsy-6, cel-miR-796, etc.) in the SC vs. GC groups, whereas these modules were inhibited by 13 up-regulated DEmiRNAs (e.g., cel-miR-74, cel-miR-229, cel-miR-70, cel-miR-249, cel-miR-85, etc.) in the SF vs. GC groups. These findings indicated that microgravity could significantly alter gene expression patterns and their associated functional gene modules in short-term space-flown C. elegans. Additionally, we identified 34 miRNAs as post-transcriptional regulators that modulated these functional gene modules under microgravity conditions. Through the experimental verification, our results demonstrated that microgravity could induce the down-regulation of five critical functional gene modules (i.e., molting cycle, defense response, fatty acid metabolism, lysosome, and longevity regulating pathways) via the regulation of miRNAs in short-term space-flown C. elegans.

PMID:39067983 | DOI:10.1016/j.lssr.2024.07.001

Spectrochim Acta A Mol Biomol Spectrosc. 2024 Jul 17;322:124830. doi: 10.1016/j.saa.2024.124830. Online ahead of print.

ABSTRACT

Dopamine (DA) is catecholamine neurotransmitters that play an important role in the central nervous system. In recent years people started to intentionally add DA to animal feed to enhance muscle development and increase their profit margin. Human consumption of the residual DA from animal tissues has been reported to be associated with the development of such diseases as Parkinson's disease, epilepsy, senile dementia, and schizophrenia and pose serious human health risks. These require development of rapid, cheap, and sensitive methods for detection of DA from animal tissue. Compared to other techniques that require access to expensive instruments, skilled human power, and tiresome routine procedures, colorimetric methods provide cheap and reliable options for detection of DA. Here we report a colorimetric method based on the peroxidase-mimic activity of Fe3O4@C@AgNPs for the detection of DA. A simple wet chemical method was employed to synthesize AgNPs on hydrophilic carbon coated Fe3O4. The produced nanocomposites were characterized by transmission electron microscopy (TEM), Fourier Transform infrared spectroscopy (FTIR), and surface-enhanced Raman spectroscopy (SERS). The detection of DA was done based on inhibition of the peroxidase-like activity of Fe3O4@C@AgNPs using 3, 3', 5, 5'-tetramethylbenzidine (TMB) as a substrate. In the presence of DA, however, the peroxidase-like activity started to decrease. The decrease in activity was concentration dependent showing a linear relationship in the range of 0.5-80 µM. In this linear range, the limit of detection (LOD) was computed and found to be as low as 0.12 µM. Therefore, we propose that the peroxidase-like activity of Fe3O4@C@AgNPs could be used for quantitative detection of DA from different samples.

PMID:39067434 | DOI:10.1016/j.saa.2024.124830

Int Immunopharmacol. 2024 Jul 26;139:112758. doi: 10.1016/j.intimp.2024.112758. Online ahead of print.

ABSTRACT

Parkinson's disease (PD), the second most prevalent neurodegenerative disorder, is projected to see a significant rise in incidence over the next three decades. The precise treatment of PD remains a formidable challenge, prompting ongoing research into early diagnostic methodologies. Network pharmacology, a burgeoning field grounded in systems biology, examines the intricate networks of biological systems to identify critical signal nodes, facilitating the development of multi-target therapeutic molecules. This approach systematically maps the components of Parkinson's disease, thereby reducing its complexity. In this review, we explore the application of network pharmacology workflows in PD, discuss the techniques employed in this field, and evaluate the current advancements and status of network pharmacology in the context of Parkinson's disease. The comprehensive insights will pave newer paths to explore early disease biomarkers and to develop diagnosis with a holistic in silico, in vitro, in vivo and clinical studies.

PMID:39067399 | DOI:10.1016/j.intimp.2024.112758

Stem Cell Rev Rep. 2024 Jul 27. doi: 10.1007/s12015-024-10767-7. Online ahead of print.

ABSTRACT

The influence of surface topography on stem cell behavior and differentiation has garnered significant attention in regenerative medicine and tissue engineering. The cell-imprinting method has been introduced as a promising approach to mimic the geometry and topography of cells. The cell-imprinted substrates are designed to replicate the topographies and dimensions of target cells, enabling tailored interactions that promote the differentiation of stem cells towards desired specialized cell types. In fact, by replicating the size and shape of cells, biomimetic substrates provide physical cues that profoundly impact stem cell differentiation. These cues play a pivotal role in directing cell morphology, cytoskeletal organization, and gene expression, ultimately influencing lineage commitment. The biomimetic substrates' ability to emulate the native cellular microenvironment supports the creation of platforms capable of steering stem cell fate with high precision. This review discusses the role of mechanical factors that impact stem cell fate. It also provides an overview of the design and fabrication principles of cell-imprinted substrates. Furthermore, the paper delves into the use of cell-imprinted polydimethylsiloxane (PDMS) substrates to direct adipose-derived stem cells (ADSCs) differentiation into a variety of specialized cells for tissue engineering and regenerative medicine applications. Additionally, the review discusses the limitations of cell-imprinted PDMS substrates and highlights the efforts made to overcome these limitations.

PMID:39066936 | DOI:10.1007/s12015-024-10767-7

Cell Rep Med. 2024 Jul 24:101659. doi: 10.1016/j.xcrm.2024.101659. Online ahead of print.

ABSTRACT

Whether neurodevelopmental defects underlie postnatal neuronal death in neurodegeneration is an intriguing hypothesis only recently explored. Here, we focus on spinal muscular atrophy (SMA), a neuromuscular disorder caused by reduced survival of motor neuron (SMN) protein levels leading to spinal motor neuron (MN) loss and muscle wasting. Using the first isogenic patient-derived induced pluripotent stem cell (iPSC) model and a spinal cord organoid (SCO) system, we show that SMA SCOs exhibit abnormal morphological development, reduced expression of early neural progenitor markers, and accelerated expression of MN progenitor and MN markers. Longitudinal single-cell RNA sequencing reveals marked defects in neural stem cell specification and fewer MNs, favoring mesodermal progenitors and muscle cells, a bias also seen in early SMA mouse embryos. Surprisingly, SMN2-to-SMN1 conversion does not fully reverse these developmental abnormalities. These suggest that early neurodevelopmental defects may underlie later MN degeneration, indicating that postnatal SMN-increasing interventions might not completely amend SMA pathology in all patients.

PMID:39067446 | DOI:10.1016/j.xcrm.2024.101659

Cell Rep. 2024 Jul 26;43(8):114551. doi: 10.1016/j.celrep.2024.114551. Online ahead of print.

ABSTRACT

Ovarian cancer is characterized by early metastatic spread. This study demonstrates that carcinoma-associated mesenchymal stromal cells (CA-MSCs) enhance metastasis by increasing tumor cell heterogeneity through mitochondrial donation. CA-MSC mitochondrial donation preferentially occurs in ovarian cancer cells with low levels of mitochondria ("mito poor"). CA-MSC mitochondrial donation rescues the phenotype of mito poor cells, restoring their proliferative capacity, resistance to chemotherapy, and cellular respiration. Receipt of CA-MSC-derived mitochondria induces tumor cell transcriptional changes leading to the secretion of ANGPTL3, which enhances the proliferation of tumor cells without CA-MSC mitochondria, thus amplifying the impact of mitochondrial transfer. Donated CA-MSC mitochondrial DNA persisted in recipient tumor cells for at least 14 days. CA-MSC mitochondrial donation occurs in vivo, enhancing tumor cell heterogeneity and decreasing mouse survival. Collectively, this work identifies CA-MSC mitochondrial transfer as a critical mediator of ovarian cancer cell survival, heterogeneity, and metastasis and presents a unique therapeutic target in ovarian cancer.

PMID:39067022 | DOI:10.1016/j.celrep.2024.114551

Viruses. 2024 Jul 8;16(7):1093. doi: 10.3390/v16071093.

ABSTRACT

A wide range of virus-like particles (VLPs) is extensively employed as carriers to display various antigens for vaccine development to fight against different infections. The plant-produced truncated variant of the hepatitis E virus (HEV) coat protein is capable of forming VLPs. In this study, we demonstrated that recombinant fusion proteins comprising truncated HEV coat protein with green fluorescent protein (GFP) or four tandem copies of the extracellular domain of matrix protein 2 (M2e) of influenza A virus inserted at the Tyr485 position could be efficiently expressed in Nicotiana benthamiana plants using self-replicating vector based on the potato virus X genome. The plant-produced fusion proteins in vivo formed VLPs displaying GFP and 4M2e. Therefore, HEV coat protein can be used as a VLP carrier platform for the presentation of relatively large antigens comprising dozens to hundreds of amino acids. Furthermore, plant-produced HEV particles could be useful research tools for the development of recombinant vaccines against influenza.

PMID:39066255 | DOI:10.3390/v16071093

Pharmaceuticals (Basel). 2024 Jul 13;17(7):938. doi: 10.3390/ph17070938.

ABSTRACT

Clozapine is an antipsychotic drug whose accumulation in white cells can sometimes prove toxic; understanding the transporters and alleles responsible is thus highly desirable. We used a strategy in which a yeast (Saccharomyces cerevisiae) CRISPR-Cas9 knock-out library was exposed to cytotoxic concentrations of clozapine to determine those transporters whose absence made it more resistant; we also recognised the structural similarity of the fluorescent dye safranin O (also known as safranin T) to clozapine, allowing it to be used as a surrogate marker. Strains lacking the mitochondrial ABC transporter MDL1 (encoded by YLR188W) showed substantial resistance to clozapine. MDL1 overexpression also conferred extra sensitivity to clozapine and admitted a massive increase in the cellular and mitochondrial uptake of safranin O, as determined using flow cytometry and microscopically. Yeast lacking mitochondria showed no such unusual accumulation. Mitochondrial MDL1 is thus the main means of accumulation of clozapine in S. cerevisiae. The closest human homologue of S. cerevisiae MDL1 is ABCB10.

PMID:39065789 | DOI:10.3390/ph17070938

Pharmaceuticals (Basel). 2024 Jul 6;17(7):899. doi: 10.3390/ph17070899.

ABSTRACT

Traditional drug screening methods typically focus on a single protein target and exhibit limited efficiency due to the multifactorial nature of most diseases, which result from disturbances within complex networks of protein-protein interactions rather than single gene abnormalities. Addressing this limitation requires a comprehensive drug screening strategy. Network medicine is rooted in systems biology and provides a comprehensive framework for understanding disease mechanisms, prevention, and therapeutic innovations. This approach not only explores the associations between various diseases but also quantifies the relationships between disease genes and drug targets within interactome networks, thus facilitating the prediction of drug-disease relationships and enabling the screening of therapeutic drugs for specific complex diseases. An increasing body of research supports the efficiency and utility of network-based strategies in drug screening. This review highlights the transformative potential of network medicine in virtual therapeutic screening for complex diseases, offering novel insights and a robust foundation for future drug discovery endeavors.

PMID:39065749 | DOI:10.3390/ph17070899

Plants (Basel). 2024 Jul 10;13(14):1905. doi: 10.3390/plants13141905.

ABSTRACT

In plant hormone signaling, transcription factor regulatory networks (TFRNs), which link the master transcription factors to the biological processes under their control, remain insufficiently characterized despite their crucial function. Here, we identify a TFRN involved in the response to the key plant hormone auxin and define its impact on auxin-driven biological processes. To reconstruct the TFRN, we developed a three-step procedure, which is based on the integrated analysis of differentially expressed gene lists and a representative collection of transcription factor binding profiles. Its implementation is available as a part of the CisCross web server. With the new method, we distinguished two transcription factor subnetworks. The first operates before auxin treatment and is switched off upon hormone application, the second is switched on by the hormone. Moreover, we characterized the functioning of the auxin-regulated TFRN in control of chlorophyll and lignin biosynthesis, abscisic acid signaling, and ribosome biogenesis.

PMID:39065433 | DOI:10.3390/plants13141905

Microorganisms. 2024 Jul 12;12(7):1415. doi: 10.3390/microorganisms12071415.

ABSTRACT

Sepsis is a life-threatening condition arising from a dysregulated host immune response to infection, leading to a substantial global health burden. The accurate identification of bacterial pathogens in sepsis is essential for guiding effective antimicrobial therapy and optimising patient outcomes. Traditional culture-based bacterial typing methods present inherent limitations, necessitating the exploration of alternative diagnostic approaches. This study reports the successful application of Fourier-transform infrared (FT-IR) spectroscopy in combination with chemometrics as a potent tool for the classification and discrimination of microbial species and strains, primarily sourced from individuals with invasive infections. These samples were obtained from various children with suspected sepsis infections with bacteria and fungi originating at different sites. We conducted a comprehensive analysis utilising 212 isolates from 14 distinct genera, comprising 202 bacterial and 10 fungal isolates. With the spectral analysis taking several weeks, we present the incorporation of quality control samples to mitigate potential variations that may arise between different sample plates, especially when dealing with a large sample size. The results demonstrated a remarkable consistency in clustering patterns among 14 genera when subjected to principal component analysis (PCA). Particularly, Candida, a fungal genus, was distinctly recovered away from bacterial samples. Principal component discriminant function analysis (PC-DFA) allowed for distinct discrimination between different bacterial groups, particularly Gram-negative and Gram-positive bacteria. Clear differentiation was also observed between coagulase-negative staphylococci (CNS) and Staphylococcus aureus isolates, while methicillin-resistant S. aureus (MRSA) was also separated from methicillin-susceptible S. aureus (MSSA) isolates. Furthermore, highly accurate discrimination was achieved between Enterococcus and vancomycin-resistant enterococci isolates with 98.4% accuracy using partial least squares-discriminant analysis. The study also demonstrates the specificity of FT-IR, as it effectively discriminates between individual isolates of Streptococcus and Candida at their respective species levels. The findings of this study establish a strong groundwork for the broader implementation of FT-IR and chemometrics in clinical and microbiological applications. The potential of these techniques for enhanced microbial classification holds significant promise in the diagnosis and management of invasive bacterial infections, thereby contributing to improved patient outcomes.

PMID:39065183 | DOI:10.3390/microorganisms12071415

Microorganisms. 2024 Jun 30;12(7):1343. doi: 10.3390/microorganisms12071343.

ABSTRACT

Immortal time bias (ITB) is common in cohort studies and distorts the association estimates between the treated and untreated. We used data from an Italian study on COVID-19 vaccine effectiveness, with a large cohort, long follow-up, and adjustment for confounding factors, affected by ITB, with the aim to verify the real impact of the vaccination campaign by comparing the risk of all-cause death between the vaccinated population and the unvaccinated population. We aligned all subjects on a single index date and considered the "all-cause deaths" outcome to compare the survival distributions of the unvaccinated group versus various vaccination statuses. The all-cause-death hazard ratios in univariate analysis for vaccinated people with 1, 2, and 3/4 doses versus unvaccinated people were 0.88, 1.23, and 1.21, respectively. The multivariate values were 2.40, 1.98, and 0.99. Possible explanations of this trend of the hazard ratios as vaccinations increase could be a harvesting effect; a calendar-time bias, accounting for seasonality and pandemic waves; a case-counting window bias; a healthy-vaccinee bias; or some combination of these factors. With 2 and even with 3/4 doses, the calculated Restricted Mean Survival Time and Restricted Mean Time Lost have shown a small but significant downside for the vaccinated populations.

PMID:39065111 | DOI:10.3390/microorganisms12071343

Microorganisms. 2024 Jun 25;12(7):1288. doi: 10.3390/microorganisms12071288.

ABSTRACT

Domestic ducks (Anas platyrhynchos domesticus) are resistant to most of the highly pathogenic avian influenza virus (HPAIV) infections. In this study, we characterized the lung proteome and phosphoproteome of ducks infected with the HPAI H5N1 virus (A/duck/India/02CA10/2011/Agartala) at 12 h, 48 h, and 5 days post-infection. A total of 2082 proteins were differentially expressed and 320 phosphorylation sites mapping to 199 phosphopeptides, corresponding to 129 proteins were identified. The functional annotation of the proteome data analysis revealed the activation of the RIG-I-like receptor and Jak-STAT signaling pathways, which led to the induction of interferon-stimulated gene (ISG) expression. The pathway analysis of the phosphoproteome datasets also confirmed the activation of RIG-I, Jak-STAT signaling, NF-kappa B signaling, and MAPK signaling pathways in the lung tissues. The induction of ISG proteins (STAT1, STAT3, STAT5B, STAT6, IFIT5, and PKR) established a protective anti-viral immune response in duck lung tissue. Further, the protein-protein interaction network analysis identified proteins like AKT1, STAT3, JAK2, RAC1, STAT1, PTPN11, RPS27A, NFKB1, and MAPK1 as the main hub proteins that might play important roles in disease progression in ducks. Together, the functional annotation of the proteome and phosphoproteome datasets revealed the molecular basis of the disease progression and disease resistance mechanism in ducks infected with the HPAI H5N1 virus.

PMID:39065055 | DOI:10.3390/microorganisms12071288

Molecules. 2024 Jul 11;29(14):3288. doi: 10.3390/molecules29143288.

ABSTRACT

Surfactants are amphiphilic molecules that are capable of mixing water and oil. Biosurfactants are eco-friendly, low-toxicity, and stable to a variety of environmental factors. Optimizing conditions for microorganisms to produce biosurfactants can lead to improved production suitable for scaling up. In this study, we compared heterologous expression levels of the luminescence system luxCDABE operon controlled by regulatable promoters araC-PBAD and its strong version araC-PBAD-SD in Escherichia coli K12, Pseudomonas aeruginosa PAO1, and P. putida KT2440. Real-time monitoring of luminescence levels in the three strains indicated that luxCDABE controlled by araC-PBAD-SD promoter with 0.2% arabinose supplementation in P. putida produced the highest level of luminescence. By using the araC-PBAD-SD promoter-controlled rhlAB expression in P. putida, we were able to produce mono-rhamnolipid at a level of 1.5 g L-1 when 0.02% arabinose was supplemented. With the same system to express olsB, lyso-ornithine lipid was produced at a level of 10 mg L-1 when 0.2% arabinose was supplemented. To our knowledge, this is the first report about optimizing conditions for lyso-ornithine lipid production at a level up to 10 mg L-1. Taken together, our results demonstrate that regulatable araC-PBAD-SD promoter in P. putida KT2440 is a useful system for heterologous production of biosurfactants.

PMID:39064867 | DOI:10.3390/molecules29143288

J Pers Med. 2024 Jul 18;14(7):765. doi: 10.3390/jpm14070765.

ABSTRACT

T cells are essential tumor suppressors in cancer immunology, but their dysfunction induced by cancer cells can result in T cell exhaustion. Exhausted T cells (Tex) significantly influence the tumor immune environment, and thus, there is a need for their thorough investigation across different types of cancer. Here, we address the role of Tex cells in pan-cancer, focusing on the expression, mutations, methylation, immune infiltration, and drug sensitivity of a molecular signature comprising of the genes HAVCR2, CXCL13, LAG3, LAYN, TIGIT, and PDCD1across multiple cancer types, using bioinformatics analysis of TCGA data. Our analysis revealed that the Tex signature genes are differentially expressed across 14 cancer types, being correlated with patient survival outcomes, with distinct survival trends. Pathway analysis indicated that the Tex genes influence key cancer-related pathways, such as apoptosis, EMT, and DNA damage pathways. Immune infiltration analysis highlighted a positive correlation between Tex gene expression and immune cell infiltration in bladder cancer, while mutations in these genes were associated with specific immune cell enrichments in UCEC and SKCM. CNVs in Tex genes were widespread across cancers. We also highlight high LAYN methylation in most tumors and a negative correlation between methylation levels and immune cell infiltration in various cancers. Drug sensitivity analysis identified numerous correlations, with CXCL13 and HAVCR2 expressions influencing sensitivity to several drugs, including Apitolisib, Belinostat, and Docetaxel. Overall, these findings highlight the importance of reviving exhausted T cells to enhance the treatment efficacy to significantly boost anti-tumor immunity and achieve better clinical outcomes.

PMID:39064019 | DOI:10.3390/jpm14070765

Int J Mol Sci. 2024 Jul 18;25(14):7868. doi: 10.3390/ijms25147868.

ABSTRACT

Glioblastoma (GBM), a highly malignant tumour of the central nervous system, presents with a dire prognosis and low survival rates. The heterogeneous and recurrent nature of GBM renders current treatments relatively ineffective. In our study, we utilized an integrative systems biology approach to uncover the molecular mechanisms driving GBM progression and identify viable therapeutic drug targets for developing more effective GBM treatment strategies. Our integrative analysis revealed an elevated expression of CHST2 in GBM tumours, designating it as an unfavourable prognostic gene in GBM, as supported by data from two independent GBM cohorts. Further, we pinpointed WZ-4002 as a potential drug candidate to modulate CHST2 through computational drug repositioning. WZ-4002 directly targeted EGFR (ERBB1) and ERBB2, affecting their dimerization and influencing the activity of adjacent genes, including CHST2. We validated our findings by treating U-138 MG cells with WZ-4002, observing a decrease in CHST2 protein levels and a reduction in cell viability. In summary, our research suggests that the WZ-4002 drug candidate may effectively modulate CHST2 and adjacent genes, offering a promising avenue for developing efficient treatment strategies for GBM patients.

PMID:39063109 | DOI:10.3390/ijms25147868

Int J Mol Sci. 2024 Jul 9;25(14):7531. doi: 10.3390/ijms25147531.

ABSTRACT

CRNDE is an oncogene expressed as a long non-coding RNA. However, our team previously reported that the CRNDE gene also encodes a micropeptide, CRNDEP. The amino acid sequence of CRNDEP has recently been revealed by other researchers, too. This study aimed to investigate genetic alterations within the CRNDEP-coding region of the CRNDE gene, methylation profiling of this gene, and CRNDEP expression analysis. All investigations were performed on clinical material from patients with ovarian tumors of diverse aggressiveness. We found that CRNDEP levels were significantly elevated in highly aggressive tumors compared to benign neoplasms. Consistently, a high level of this micropeptide was a negative, independent, prognostic, and predictive factor in high-grade ovarian cancer (hgOvCa) patients. The cancer-promoting role of CRNDE(P), shown in our recent study, was also supported by genetic and epigenetic results obtained herein, revealing no CRNDEP-disrupting mutations in any clinical sample. Moreover, in borderline ovarian tumors (BOTS), but not in ovarian cancers, the presence of a single nucleotide polymorphism in CRNDE, rs115515594, significantly increased the risk of recurrence. Consistently, in BOTS only, the same genetic variant was highly overrepresented compared to healthy individuals. We also discovered that hypomethylation of CRNDE is associated with increased aggressiveness of ovarian tumors. Accordingly, hypomethylation of this gene's promoter/first exon correlated with hgOvCa resistance to chemotherapy, but only in specimens with accumulation of the TP53 tumor suppressor protein. Taken together, these results contribute to a better understanding of the role of CRNDE(P) in tumorigenesis and potentially may lead to improvements in screening, diagnosis, and treatment of ovarian neoplasms.

PMID:39062774 | DOI:10.3390/ijms25147531

Genes (Basel). 2024 Jul 14;15(7):918. doi: 10.3390/genes15070918.

ABSTRACT

BACKGROUND: Polymorphism rs1049434 characterizes the nonsynonymous exchange of adenosine (A) by thymidine (T) in the gene for monocarboxylate transporter 1 (MCT1). We tested whether T-allele carriers of rs1049434 demonstrate increased accumulation of markers of metabolic strain.

METHODS: Physically active, healthy, young male subjects (n = 22) conducted a power-matched one-legged cycling exercise to exhaustion. Metabolic substrates in capillary blood, selected metabolic compounds, and indices for the slow oxidative phenotype of vastus lateralis muscle were quantified in samples collected before and after exercise. The genotypes of the rs1049434 polymorphism were determined with polymerase chain reactions.

RESULTS: One-legged exercise affected the concentration of muscle metabolites entering the tricarboxylic acid cycle, such as acetyl-co-enzyme A (+448%) and acetyl-L-carnitine (+548%), muscle glycogen (-59%), and adenosine monophosphate (-39%), 30 min post-exercise. Exercise-related variability in the muscular concentration of glycogen, long-chain acyl co-enzyme As and a triglyceride, nicotinamide adenine dinucleotide (NADH), and adenosine monophosphate (AMP) interacted with rs1049434. T-allele carriers demonstrated a 39% lesser reduction in glycogen after exercise than non-carriers when NADH increased only in the non-carriers. Muscle lactate concentration was 150% higher, blood triacyl-glyceride concentration was 53% lower, and slow fiber percentage was 20% lower in T-allele carriers.

DISCUSSION: The observations suggest a higher anaerobic glycolytic strain during exhaustive exercise and a lowered lipid handling in T-allele non-carriers.

PMID:39062697 | DOI:10.3390/genes15070918

Biomolecules. 2024 Jul 15;14(7):853. doi: 10.3390/biom14070853.

ABSTRACT

Finding an effective treatment for traumatic brain injury is challenging for multiple reasons. There are innumerable different causes and resulting levels of damage for both penetrating and non-penetrating traumatic brain injury each of which shows diverse pathophysiological progressions. More concerning is that disease progression can take decades before neurological symptoms become obvious. Currently, the primary treatment for non-penetrating mild traumatic brain injury, also called concussion, is bed rest despite the fact the majority of emergency room visits for traumatic brain injury are due to this mild form. Furthermore, one-third of mild traumatic brain injury cases progress to long-term serious symptoms. This argues for the earliest therapeutic intervention for all mild traumatic brain injury cases which is the focus of this review. Calcium levels are greatly increased in damaged brain regions as a result of the initial impact due to tissue damage as well as disrupted ion channels. The dysregulated calcium level feedback is a diversity of ways to further augment calcium neurotoxicity. This suggests that targeting calcium levels and function would be a strong therapeutic approach. An effective calcium-based traumatic brain injury therapy could best be developed through therapeutic programs organized in professional team sports where mild traumatic brain injury events are common, large numbers of subjects are involved and professional personnel are available to oversee treatment and documentation. This review concludes with a proposal with that focus.

PMID:39062567 | DOI:10.3390/biom14070853

Biomolecules. 2024 Jun 24;14(7):747. doi: 10.3390/biom14070747.

ABSTRACT

In order to understand the coordinated proteome changes associated with differentiation of a cultured cell pluripotency model, protein expression changes induced by treatment of NT2 embryonal carcinoma cells with retinoic acid were monitored by mass spectrometry. The relative levels of over 5000 proteins were mapped across distinct cell fractions. Analysis of the chromatin fraction revealed major abundance changes among chromatin proteins and epigenetic pathways between the pluripotent and differentiated states. Protein complexes associated with epigenetic regulation of gene expression, chromatin remodelling (e.g., SWI/SNF, NuRD) and histone-modifying enzymes (e.g., Polycomb, MLL) were found to be extensively regulated. We therefore investigated histone modifications before and after differentiation, observing changes in the global levels of lysine acetylation and methylation across the four canonical histone protein families, as well as among variant histones. We identified the set of proteins with affinity to peptides housing the histone marks H3K4me3 and H3K27me3, and found increased levels of chromatin-associated histone H3 tail trimming following differentiation that correlated with increased expression levels of cathepsin proteases. We further found that inhibition of cathepsins B and D reduces histone H3 clipping. Overall, the work reveals a global reorganization of the cell proteome congruent with differentiation, highlighting the key role of multiple epigenetic pathways, and demonstrating a direct link between cathepsin B and D activity and histone modification.

PMID:39062462 | DOI:10.3390/biom14070747