Downregulation Of Genes Research Articles

Therapeutic effects of erythropoietin-alginate/chitosan hydrogel on impaired male rat fertility after spinal cord injury.

Infertility is a significant issue in spinal cord injury (SCI) patients. Men with SCI often experience erectile and ejaculatory dysfunctions, and low sperm quality leading to impaired fertility. In this study, we investigated the effectiveness of Erythropoietin (EPO)alginate/chitosan (CH-AL) hydrogel on SCI-induced male rat infertility. Twenty-four male Wistar rats were divided into three groups: Sham, SCI-induced group without any further intervention (Negative control, NC), and a treatment group receiving 10,000 IU/kg EPO-CH/AL hydrogel (EPO group), immediately following SCI induction. Sperm parameters, oxidative stress markers, apoptosis, and histopathological changes in animal testes were analyzed. Sperm viability and motility significantly decreased in the NC group compared to the sham group (p < 0.01). Treatment with 10,000 IU/kg EPO-CH/AL hydrogel significantly improved sperm viability and motility compared to the NC group (p < 0.05). Malondialdehyde (MDA) and Superoxide dismutase (SOD) levels were elevated and reduced, respectively, in the NC group compared to the sham group. Treatment with EPO-CH/AL hydrogel group, significantly decreased MDA level and increased SOD levels compared to the NC group (p < 0.05). Apoptosis analysis revealed upregulation of Bcl-2 and downregulation of Bax genes in EPO-CH/AL hydrogel compared to the NC group (p < 0.05). Histological analysis showed that the EPO-CH/AL hydrogel improved depletion of germ cell population and Luminal spaces compared to NC group but did not fully restore normal histology. EPO-CH/AL hydrogel effectively improves sperm viability and motility, reduces oxidative stress, and mitigates apoptosis, demonstrating its potential as a therapeutic strategy for SCI-induced infertility.

Cobalt oxide nanoparticles induce cytotoxicity and excessive ROS mediated mitochondrial dysfunction and p53-independent apoptosis in melanoma cells

Nanotherapy has emerged as a promising strategy for the targeted and efficient treatment of melanoma, the most aggressive and lethal form of skin cancer, with minimized systemic toxicity. However, the therapeutic efficacy of cobalt oxide nanoparticles (Co3O4NPs) in melanoma treatment remains unexplored. This study aimed to assess the therapeutic potential of Co3O4NPs in melanoma treatment by evaluating their impact on cell viability, genomic DNA and mitochondrial integrity, reactive oxygen species (ROS) generation and apoptosis induction in melanoma A-375 cells. Our findings demonstrated a concentration-dependent reduction in cell viability upon treatment with five Co3O4NP concentrations (0.2, 2, 20, 200, and 2000 µg/ml), with an IC50 value of 303.80 µg/ml. Treatment with this IC50 concentration significantly increased ROS generation, induced dramatic DNA damage, and disrupted mitochondrial membrane potential integrity. Flow cytometric analysis revealed apoptosis and necrosis induction following Co3O4NP exposure at the IC50 concentration value. Results of qRT-PCR analysis demonstrated remarkable dysregulation of apoptotic and mitochondrial genes, including a significant downregulation of apoptotic p53 and mitochondrial ND3 genes and marked upregulation of the anti-apoptotic gene Bcl2. These findings highlight the novel potential of Co3O4NPs as potent inducers of melanoma A-375 cell death in a concentration-dependent manner through excessive ROS production, genomic instability, mitochondrial dysfunction and dysregulation of apoptotic and mitochondrial gene expression, ultimately promoting apoptosis in A-375 cells. This study thus underscores the potential of Co3O4NPs as a promising nanotherapeutic candidate for melanoma treatment, warranting further exploration to elucidate their full biological and clinical applicability.

Optimizing approaches for targeted integration of transgenic cassettes by integrase-mediated cassette exchange in mouse and human stem cells.

To enable robust expression of transgenes in stem cells, recombinase-mediated cassette exchange at safe harbor loci is frequently adopted. The choice of recombinase enzyme is a critical parameter to ensure maximum efficiency and accuracy of the integration event. We have explored the serine recombinase family of site-specific integrases and have directly compared the efficiency of PhiC31, W-beta, and Bxb1 integrase for targeted transgene integration at the Gt(ROSA)26Sor locus in mouse embryonic stem cells. All 3 integrases were found to be suitable for efficient engineering and long-term expression of each integrase was compatible with pluripotency, as evidenced by germline transmission. Bxb1 integrase was found to be 2-3 times more efficient than PhiC31 and W-beta. The Bxb1 system was adapted for cassette exchange at the AAVS1 locus in human induced pluripotent stem (iPS) cells, and the 2 commonly used ubiquitous promoters, CAG and Ef1α (EIF1A), were tested for their suitability in driving expression of the integrated transgenic cargo. AAVS1-integrated Ef1α promoter led to a very mosaic pattern of expression in targeted hiPS cells, whereas the AAVS1-integrated CAG promoter drove consistent and stable expression. To validate the system for the integration of functional machinery, the Bxb1 integrase system was used to integrate CAG-driven CRISPR-activation and CRISPR-inhibition machinery in human iPS cells and robust sgRNA-induced up- and downregulation of target genes was demonstrated.

The molecular mechanism by which heat stress during the grain filling period inhibits maize grain filling and reduces yield

High temperatures significantly impair plant growth and development by restricting maize grain filling; however, the molecular mechanisms underlying heat stress remain poorly understood. In this study, 350 maize inbred lines were evaluated under field conditions, leading to the identification of heat-tolerant Zheng58 and heat-sensitive Qi319. The two inbred lines were exposed to controlled conditions of 30°C/20°C (optimal) and 42°C/30°C (heat stress) during the grain filling period. Heat stress significantly reduced thousand-kernel weight and seed setting rates, with Qi319 experiencing more pronounced declines. In contrast, Zheng58 showed superior performance, with a grain filling rate 48% higher and seed setting rate 57% greater than Qi319. Transcriptome analysis showed that heat stress disrupted starch biosynthesis and hormonal homeostasis, notably affecting abscisic acid and auxin pathways. Additionally, photosynthetic and transpiration rates in panicle leaves were reduced due to the downregulation of genes related to light-harvesting complexes, photosystem I subunits, and water transport. These findings highlight the critical roles of starch metabolism, hormonal regulation, and photosynthetic efficiency in heat tolerance, offering valuable insights for developing heat-resilient maize varieties to mitigate yield losses under high-temperature conditions.

Isolation of Bacillus paralichenifromis BL-1 and Its Potential Application in Producing Bioflocculants Using Phenol Saline Wastewater

Phenolic compounds are harmful organic pollutants found in wastewater from the chemical and pharmaceutical industries, which are frequently accompanied by high saline concentrations. Microorganism-based biodegradation represents an environmentally friendly and cost-effective strategy for phenol removal. In this study, we isolated a bioflocculant-producing Bacillus paralicheniformis BL-1 that is capable of phenol degradation in high-salinity conditions. Differential gene expression analysis revealed the down-regulation of genes related to the synthesis of extracellular polymeric substances and the up-regulation of poly-γ-glutamate biosynthesis in 10% NaCl conditions. These findings indicate that poly-γ-glutamate is the main large biomolecule produced by B. paralicheniformis BL-1. A further investigation suggested that salinity stress resulted in the down-regulated expression of the genes involved in iron homeostasis. Therefore, alleviating iron limitation by supplying excess iron could improve cell growth and, thus, increase the phenol removal rate and flocculating activity. The productivity of poly-γ-glutamate reached 2.23 g/L, and the phenol removal rate reached 73.83% in the synthetic medium supplemented with 10% NaCl, 500 mg/L phenol, and 250 μM FeCl3.

Ameliorative role of camel protein hydrolysates diet against alkaline stress in Oreochrmis niloticus: Hematology, immune responses and their regulating genes expression, and histopathological assays.

This investigation looked at the ameliorative role of camel whey protein hydrolysates-diet (PH) in Oreochromis niloticus stocked under alkaline conditions. One hundred sixty fish (16.02 ± 0.14g) were allocated equally into four groups with four replications for 30 days. The first (control) and second (alkaline) groups were fed basal diets and maintained in fresh and alkaline water, respectively. The third and fourth groups were fed on a PH diet (basal diet containing 75g PH/kg) and maintained in fresh water and alkaline water, respectively. The hematology, immune-antioxidant indices, immune-regulatory genes, histopathological investigation of the spleen, and resistance to Aeromonas sobria were investigated. The results showed that the alkaline condition induced hematological disorders (lowered red blood cells, hemoglobin, packed cell volume, and white blood cell count) and immunosuppression (lowered phagocytic activity and index, lysozyme, nitric oxide, and complement 3) in the exposed fish. Alkaline exposure induced oxidative stress through elevation of the malondialdehyde and reduction in the antioxidant enzymes (superoxide dismutase, catalase, glutathione peroxidase, glutathione S-transferase, glutathione S-reductase, and reduced glutathione). The immune modulatory genes (tolls like receptor-5, interleukin-1beta, interleukin-6, interleukin-8, interleukin-10, interleukin-17, nuclear factor kappa beta, and tumor necrosis factor-alpha) were down-regulated by exposure to alkaline conditions. The microscopic section of the spleen of the fish subjected to alkaline conditions showed notable hyperplasia of the melanomacrophage centers, besides vascular congestion, endothelial cell hypertrophy, and mild hypercellularity in the erythroid and lymphoid elements. In addition, few sections manifested more pronounced erythroid hyperplasia than the lymphoid one. The survival of the fish subjected to alkaline conditions was reduced during the A. sobria challenge. Feeding on a PH diet, the hematology was restored and the immune-antioxidant functions were modulated. Modulation of the immune-regulatory genes and increased survivability of the alkaline-exposed fish were noticed when fed on the PH diet. Consequently, we can recommend enriching the Nile tilapia diet with a 75g PH/kg diet especially when reared under alkaline conditions to support the immune functions of the fish.

Age-Dependent Effects of Butyl Benzyl Phthalate Exposure on Lipid Metabolism and Hepatic Fibrosis in Mice

Endocrine-disrupting chemicals (EDCs), including phthalates, have been implicated in the development of non-alcoholic fatty liver disease (NAFLD) and hepatic fibrosis. This study investigates the age-dependent effects of butyl benzyl phthalate (BBP) exposure on lipid metabolism in the livers of young and aged mice. Young (2-month-old) and aged (20-month-old) male C57BL/6 mice were exposed to BBP through drinking water at a dose of 169 μg/kg/day for 6 and 4 months, respectively. Young mice exposed to BBP showed fatty liver, with downregulation of key fatty acid oxidation genes (CPT1A, CPT1B, CPT2, and Acox1) and elevated pro-inflammatory cytokines (TNF-α and IL-6). In contrast, aged mice exhibited hepatic fibrosis, with increased collagen deposition and upregulation of genes related to fibrosis (Acta2, MMP2, TGF-ß1, and Col1a2), cirrhosis (CXCR4, SOX9, DCN, and MFAP4), and cancer (Bcl2, CDKN2a, c-Myc, and Fn1). Overall, these findings emphasize the importance of age when evaluating the risks of EDC exposure, such as BBP. Future research should focus on understanding the molecular mechanisms behind these age-related differences and explore Grem1 and SOCS3 as potential therapeutic targets for treating EDC-induced and age-related liver diseases.

Establishment and Validation of the Diagnostic Value of Oligodendrocyte-related Genes in Alzheimer's Disease.

AD is a demyelinating disease. Myelin damage initiates the pathological process of AD, resulting in abnormal synaptic function and cognitive decline. The myelin sheath formed by oligodendrocytes (OL) is a crucial component of white matter. Investigating AD from the perspective of OL may offer novel diagnostic and therapeutic perspectives. This study aimed to analyze the association between OL-related genes and Alzheimer's disease (AD) using bioinformatics and verify this association via molecular biology experiments. The AD datasets were acquired from the Gene Expression Omnibus (GEO) database of NCBI. Consensus clustering was employed to determine the subtypes of AD, followed by evaluating the clinical characteristics of these subtypes. Subsequently, immune infiltration analysis of relevant genes and Weighted Gene Co-expression Network Analysis (WGCNA) were conducted to identify modules and hub genes associated with AD progression. The intersection of genes obtained was analyzed using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. To narrow down the scope and identify OL-related genes with diagnostic potential, three machine learning algorithms were utilized. In addition, the eXtreme Sum (XSum) algorithm was used to screen small molecule drug candidates based on the connectivity map (CMAP) database. Finally, these identified genes were validated using Real-time fluorescence quantitative PCR (RT-qPCR). Among the three subtypes of AD, Cluster A and Cluster C exhibited increased levels of Braak and neurofibrillary tangles compared to Cluster B. The proportion of females was greater than that of males among the three subclasses of AD. There were no significant differences in age among the three subclasses, but significant differences in gene expression existed. Through WGCNA analysis, 108 genes were identified. Among these, 16 genes were identified as shared genes by the least absolute shrinkage and selection operator (LASSO), random forest (RF), and support vector machines (SVM) algorithms, and logistic regression further determined 11 genes. The establishment of a nomogram demonstrated the significance of these 11 genes in AD. The "XSum" algorithm revealed five drugs with therapeutic potential for AD. qPCR analysis revealed the upregulation and downregulation of the highlighted genes. According to this study, 11 genes related to OL were also found to be associated with immune cell infiltration in AD patients. These genes demonstrated potential diagnostic value for AD. Additionally, we screened five small molecular drugs that exhibit potential therapeutic effects on AD. This research provides a new perspective for personalized clinical management and treatment of AD.

Seven up regulates reproductive diapause initiation via juvenile hormone biosynthesis in the cabbage beetle Colaphellus bowringi.

Reproductive diapause is an insect survival strategy in which reproduction temporarily halts in response to adverse environmental changes. This process is characterized by arrested ovarian development and lipid accumulation in females. A reduction in juvenile hormone (JH) biosynthesis is known to initiate reproductive diapause, but its regulatory mechanism remains unclear. Seven up (Svp), a transcription factor from the nuclear receptor family, plays a crucial role in various developmental processes in insects. In this study, using the cabbage beetle Colaphellus bowringi as a model, we observed higher expression of Svp in the heads of female adults under reproductive photoperiodic conditions (short-day [SD]) compared to diapause conditions (long-day [LD]). RNA interference-mediated knockdown of Svp in SD females induced typical diapause phenotypes, including ovarian arrest and lipid accumulation. The application of methoprene (ME), a JH receptor agonist, reversed these diapause phenotypes and restored reproduction, indicating that Svp's regulation of reproductive diapause is dependent on JH signaling. Additionally, Svp knockdown led to the downregulation of JH pathway genes and a reduction in JH titers. Further evidence suggested that Svp regulates the expression of JHAMT1, a critical gene in JH biosynthesis, which determines diapause entry in C. bowringi. These findings suggest that diapause-inducing photoperiods suppress Svp expression, blocking JH production and triggering diapause. This work reveals a critical transcription factor that regulates reproductive diapause initiation through modulating JH production, providing a potential target for controlling pests capable of entering reproductive diapause.

Gastrodin Alleviates Lumbar Intervertebral Disc Degeneration by Suppressing the NF-κB and MAPK Pathways.

Intervertebral disc degeneration (IDD) is the main pathological factor resulting in low back pain (LBP), the leading cause of disability globally. Inflammatory response and extracellular matrix (ECM) degradation are critical pathological features in the development of IDD. Gastrodin (GAS), a phenol compound isolated from Gastrodia elata Blume, plays an anti-inflammatory role in experimental models of multiple human diseases. Our study aimed to elucidate whether GAS alleviates TNF-α-induced inflammation in nucleus pulposus (NP) cells and IDD in vivo. The cytotoxicity of GAS was assessed by CCK-8 assay. Rat primary NP cells were stimulated with TNF-α to induce inflammatory response. The expression of proinflammatory cytokines, catabolic genes, and anabolic genes was detected by RT-qPCR, western blotting, and immunofluorescence staining. NF-κB and MAPK pathway activation was determined through western blotting and immunofluorescence staining. The IDD rat model was established by using percutaneous needle puncture. The therapeutic effects of GAS were confirmed by histology analysis. We found that TNF-α stimulation enhanced proinflammatory cytokine (COX2, iNOS, IL-6, and IL-1β) expression in NP cells, which was reversed by GAS treatment. GAS offset TNF-α-induced upregulation in catabolic gene (MMP3, MMP9, and MMP13) expression and downregulation in anabolic gene (Collagen II, SOX9, and Aggrecan) expression. The loss of ECM in TNF-α-treated NP cells was mitigated by GAS treatment. Mechanically, GAS abolished TNF-α-induced increase in p-IKKα, p-IKKβ, p-IκBα, p-p65, p-ERK, p-p38, and p-JNK protein levels in NP cells. In puncture-induced IDD rat models, GAS administration improved intervertebral disc (IVD) structure, increased Collagen II expression, and reduced the levels of proinflammatory factors in IVDs. Overall, GAS alleviates the inflammation and ECM degradation in NP cells via inhibiting NF-κB and MAPK pathway activation and alleviates IDD in vivo, which may be a novel treatment strategy for IDD.

Ferroptosis Transcriptional Regulation and Prognostic Impact in Medulloblastoma Subtypes Revealed by RNA-Seq

Medulloblastoma (MB) is the most common malignant brain tumor in children, typically arising during infancy and childhood. Despite multimodal therapies achieving a response rate of 70% in children older than 3 years, treatment remains challenging. Ferroptosis, a form of regulated cell death, can be induced in medulloblastoma cells in vitro using erastin or RSL3. Using two independent medulloblastoma RNA-sequencing cohorts (MB-PBTA and MTAB-10767), we investigated the expression of ferroptosis-related molecules through multiple approaches, including Weighted Gene Co-Expression Network Analysis (WGCNA), molecular subtype stratification, protein–protein interaction (PPI) networks, and univariable and multivariable overall survival analyses. A prognostic expression score was computed based on a cross-validated ferroptosis signature. In training and validation cohorts, the regulation of the ferroptosis transcriptional program distinguished the four molecular subtypes of medulloblastoma. WGCNA identified nine gene modules in the MB tumor transcriptome; five correlated with molecular subtypes, implicating pathways related to oxidative stress, hypoxia, and trans-synaptic signaling. One module, associated with disease recurrence, included epigenetic regulators and nucleosome organizers. Univariable survival analyses identified a 45-gene ferroptosis prognostic signature associated with nutrient sensing, cysteine and methionine metabolism, and trans-sulfuration within a one-carbon metabolism. The top ten unfavorable ferroptosis genes included CCT3, SNX5, SQOR, G3BP1, CARS1, SLC39A14, FAM98A, FXR1, TFAP2C, and ATF4. Patients with a high ferroptosis score showed a worse prognosis, particularly in the G3 and SHH subtypes. The PPI network highlighted IL6 and CBS as unfavorable hub genes. In a multivariable overall survival model, which included gender, age, and the molecular subtype classification, the ferroptosis expression score was validated as an independent adverse prognostic marker (hazard ratio: 5.8; p-value = 1.04 × 10⁻9). This study demonstrates that the regulation of the ferroptosis transcriptional program is linked to medulloblastoma molecular subtypes and patient prognosis. A cross-validated ferroptosis signature was identified in two independent RNA-sequencing cohorts, and the ferroptosis score was confirmed as an independent and adverse prognostic factor in medulloblastoma.

Identification of Co-Expression Modules of Cotton Plant Height-Related Genes Based on Weighted Gene Co-Expression Network Analysis

Plant height (PH) is a vital agronomic trait that significantly affects cotton yield and facilitates mechanized harvesting. Gaining insights into the genetic regulatory mechanisms governing plant height is fundamental to advancing cotton breeding. In this study, cotton plants were treated with varying concentrations of mepiquat chloride, resulting in significant differences in plant height compared to the control group. Transcriptome data from 18 treated cotton stem tissue samples were analyzed using Weighted Gene Co-expression Network Analysis (WGCNA), leading to the identification of 21 gene co-expression modules. Of these, eight modules exhibited positive correlations, while 13 modules showed negative correlations with plant height. A co-expression network comprising 20,409 valid genes was constructed and visualized using Cytoscape 3.9.1. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses indicated that these modules are associated with biologically significant pathways, including oxidoreductase activity, transcriptional regulator activity, catalytic activity, and phosphate hydrolase activity. Further analysis of gene connectivity within these modules identified 10 core genes (Gohir.D03G105600, Gohir.A03G060400, Gohir.A05G333400, Gohir.D09G243300, Gohir.D12G213500, Gohir.A04G065185, Gohir.A04G039105, Gohir.D08G127760, Gohir.A09G103348, and Gohir.A04G039120) and enabled the establishment of a gene interaction regulation network. Functional predictions suggest that these candidate genes may play key roles in the regulation of cotton plant height. This study offers theoretical insights into the molecular mechanisms underlying cotton plant height and provides valuable references for breeding new cotton varieties with optimized plant heights.

Genetic Risk Profiling Reveals Altered Glycosyltransferase Expression as a Predictor for Patient Outcome in Neuroblastoma

Background/Objectives: Neuroblastoma is a highly aggressive pediatric cancer that arises from immature nerve cells and exhibits a broad spectrum of clinical presentations. While low- and intermediate-risk neuroblastomas often have favorable outcomes, high-risk neuroblastomas are associated with poor prognosis and significant treatment challenges. The complex genetic networks driving these high-risk cases remain poorly understood. This study aims to investigate differences in gene expression patterns that may contribute to disease outcomes. Methods: We employed an in silico approach to analyze a cohort of 493 neuroblastoma tumor samples that underwent mRNA sequencing (GSE49711). This dataset was reanalyzed in depth with a non-hypothesis-driven approach to identify the expression patterns and regulatory mechanisms associated with a poor prognosis. Results: By exploring global gene expression and the integration of clinical parameters, we stratified the samples into two groups with highly distinct gene expression profiles. MYCN amplification emerged as a major driver not only of poor prognosis but also of specific gene regulatory patterns. Notably, tumors with MYCN amplification exhibited the strong regulation of immune response genes and less immune infiltration, suggesting potential immune evasion. However, while we observed only minor changes in immune checkpoint expression, there was a strong modulation of glycosyltransferase genes in MYCN-amplified tumors. Using this information, we were able to construct a risk profile based on 12 glycosylation-related genes, which correlates with the survival outcomes of neuroblastoma patients. Conclusions: This study highlights the role of MYCN amplification in driving a poor prognosis in neuroblastoma through the regulation of immune response and glycosylation-related genes. Based on this finding, we developed a genetic risk profile that correlates with survival outcomes in neuroblastoma patients.

Increased cardiac macrophages in Sorbs2-deficient hearts: revealing a potential role for macrophage in responding to embryonic myocardial abnormalities

Macrophages are known to support cardiac development and homeostasis, contributing to tissue remodeling and repair in the adult heart. However, it remains unclear whether embryonic macrophages also respond to abnormalities in the developing heart. Previously, we reported that the structural protein Sorbs2 promotes the development of the second heart field, with its deficiency resulting in atrial septal defects (ASD). In analyzing RNA-seq data, we noted an upregulation of macrophage-related genes in Sorbs2−/− hearts. Immunostaining and lineage-tracing confirmed an increase in macrophage numbers, underscoring a macrophage response to myocardial abnormalities. Partial depletion of macrophages led to downregulation of genes involved in lipid metabolism, muscle development and organ regeneration, alongside upregulation of genes associated with DNA damage-induced senescence and cardiomyopathy. Additionally, a non-significant increase in septal defects in macrophage-depleted Sorbs2−/− hearts suggests a potential reparative function for macrophages in maintaining structural integrity. Valve formation, however, remained unaffected. Our findings suggest that embryonic macrophages might sense abnormalities in embryonic cardiomyocytes and could adaptively support cardiac structure and function development in response to myocardial abnormalities.

Identifying Novel Aging-Related Biomarkers for Age-related Macular Degeneration with Integrative Bioinformatics Approaches

Age-related macular degeneration (AMD) is the leading cause of visual impairment in older adults worldwide and is a condition that causes visual deprivation. There exist two subcategories of this disease with the wet form of this disease being the focus of our study. Using bioinformatic analysis, this research conducted investigations to uncover the genes related to aging that may be biomarkers for the development of AMD. First, we compared the expression levels of samples from AMD/CNV patients and a control group using the GEO microarrays (GSE29801) in order to obtain differentially expressed genes (DEGs). WGCNA, combined with functional enrichment analysis, is utilized to discover and validate the gene module crucial for AMD. Differentially expressed aging-related genes (DEARGs) were identified by overlapping significant gene sets. The subcellular location of hub DEARGs and their corresponding cell subpopulations were determined and predicted using the Geo dataset GSE155288. Pan-cancer analyses were used to confirm those hub DEARGs function in other diseases. Moreover, both Protein-Protein Interaction (PPI) and AlphaFold prediction were employed to validate the protein interaction among the key DEARGs. Lastly, a potential target drug was selected, with portions of them validated through drug-protein interactions. In further analysis of our result, the collect gene set of 7 DEARGs was divided into the immune-related group and the non-immune-related group. These groups uncovered two distinct pathways of AMD development, with one triggering inflammatory responses by promoting macrophage proliferation and the other inducing choroidal neovascularization formation due to malfunctioning growth regulator genes

Berberine inhibits prostate cancer progression by inducing ferroptosis: evidence from network pharmacology.

The uncertain ferroptosis-related role of berberine in prostate cancer was explored using network pharmacology methodology. Integration of ferroptosis targets in prostate cancer from the Genecard database and berberine targets from the Traditional Chinese Medicine Systems Pharmacology and SwissTargetPrediction databases revealed 17 common targets. Among these, 10 hub genes, including CCNB1, CDK1, AURKA, AR, CDC42, ICAM1, TYMS, NTRK1, PTGS2, and SCD, were identified. Enrichment analyses yielded 799 Gene Ontology terms and 23 Kyoto Encyclopedia of Genes and Genomes pathways associated with berberine-related targets. Molecular docking simulations indicated berberine's binding capacity to all hub genes. In-vitro studies on LNCaP and PC3 cells demonstrated berberine's inhibition of cell proliferation and significant downregulation of TYMS, CCNB1, AURKA, CDK1, and SCD in both cell lines. Berberine exhibited cell line-specific effects by reducing AR expression in LNCaP cells and suppressing ICAM1 in PC3 cells. Overall, berberine shows promise in inhibiting prostate cancer progression through modulation of ferroptosis-related genes, including TYMS, AR, CCNB1, AURKA, CDK1, ICAM1, NTRK1, SCD, and CDC42.

Common and specific gene regulatory programs in zebrafish caudal fin regeneration at single-cell resolution.

Following amputation, zebrafish regenerate their injured caudal fin through lineage-restricted reprogramming. Although previous studies have charted various genetic and epigenetic dimensions of this process, the intricate gene regulatory programs shared by, or unique to, different regenerating cell types remain underinvestigated. Here, we mapped the regulatory landscape of fin regeneration by applying paired snRNA-seq and snATAC-seq on uninjured and regenerating fins. This map delineates the regulatory dynamics of predominant cell populations at multiple stages of regeneration. We observe a marked increase in the accessibility of chromatin regions associated with regenerative and developmental processes at 1 dpa, followed by a gradual closure across major cell types at later stages. This pattern is distinct from that of transcriptomic dynamics, which is characterized by several waves of gene upregulation and downregulation. We identified and in vivo validated cell-type-specific and position-specific regeneration-responsive enhancers and constructed regulatory networks by cell type and stage. Our single-cell resolution transcriptomic and chromatin accessibility map across regenerative stages provides new insights into regeneration regulatory mechanisms and serves as a valuable resource for the community.

Cisplatin exposure dysregulates insulin secretion in male and female mice.

Cancer survivors have an increased risk of developing Type 2 diabetes compared to the general population. Patients treated with cisplatin, a common chemotherapeutic agent, are more likely to develop metabolic syndrome and Type 2 diabetes than age- and sex-matched controls. Surprisingly, the impact of cisplatin on pancreatic islets has not been reported. Our study aimed to determine if mouse islet function is adversely affected by systemic (in vivo) or direct (in vitro) exposure to cisplatin. In vivo cisplatin exposure led to deficits in glucose-stimulated plasma insulin levels in both male and female mice, despite no differences in glucose tolerance. In vitro cisplatin exposure to mouse islets dysregulated insulin release and reduced oxygen consumption in a non-sex specific manner. When shifting our focus to male mouse islets, cisplatin altered the expression of genes related to insulin production, oxidative stress, and the Bcl-2 family as early as 6-hours post-exposure. Genome-wide expression analysis confirmed the pronounced downregulation of genes within the insulin secretion pathway in cisplatin-exposed mouse islets. Data from 3 human organ donors confirms that the detrimental effects of cisplatin on insulin secretion and gene expression are reproduced in human islets. Our findings indicate that cisplatin exposure causes significant defects in insulin secretion and may have lasting effects on islet health.

Precision Prediction of Alzheimer's Disease: Integrating Mitochondrial Energy Metabolism and Immunological Insights.

Alzheimer's disease (AD), a prevalent neurodegenerative disorder, is characterized by mitochondrial dysfunction and immune dysregulation. This study is aimed at developing a risk prediction model for AD by integrating multi-omics data and exploring the interplay between mitochondrial energy metabolism-related genes (MEMRGs) and immune cell dynamics. We integrated four GEO datasets (GSE132903, GSE29378, GSE33000, GSE5281) for differential gene expression analysis, functional enrichment, and weighted gene co-expression network analysis (WGCNA). We identified two key gene modules (turquoise and magenta) significantly correlated with AD. Subsequently, we constructed a risk prediction model incorporating five MEMRGs (MRPL15, RBP4, ABCA1, MPV17, and MRPL37) and clinical factors using LASSO regression. The model demonstrated robust predictive performance (AUC > 0.815) in both internal and external validation (GSE44770) cohorts. Downregulation of MRPL15, RBP4, MPV17, and MRPL37 in AD brain regions (validated using AlzData and qRT-PCR) suggests impaired mitochondrial function. Conversely, ABCA1 upregulation may represent a compensatory response. Furthermore, significant differences in immune cell proportions, particularly gamma delta T cells (p = 0.002) and activated CD4 memory T cells (p = 0.027), were found between AD and non-demented samples. We observed significant correlations between MEMRG expression and specific immune cell fractions, indicating a potential link between mitochondrial dysfunction and immune dysregulation in AD. Our study provides a reliable risk prediction model for AD and highlights the crucial roles of MEMRGs and immune responses in disease pathogenesis, offering potential targets for therapeutic interventions.

Unseen Threats: The Long-term Impact of PET-Microplastics on Development of Male Reproductive Over a Lifetime.

The physical abrasion of plastics from simple everyday entered the food chain, with associated risks recently emphasized. Although many studies have reported the adverse effects of microplastics (MPs) on human, the reproductive implications of continuous exposure to physically abraded polyethylene terephthalate (PET)-MPs remain unexplored. Ingestion of physically abraded PET-MPs (size range: 50-100µm) in mice from 5 to 34 weeks of age at an annual intake relevant dose of MPs (5 mgweek-1) significantly impaired male reproductive function. Reductions in seminiferous tubule diameter and epithelial height are observed (p <0.0001), with 32.2% decrease in Leydig cells and 24.3% reduction in testosterone levels (p <0.05). The epididymis shows marked deterioration in all regions, with total sperm concentration significantly reduce from 17.0 × 10⁶ to 5.3 × 10⁶ (p <0.01) and decrease motility. Transcriptome analysis demonstrates downregulation of genes related with gonadotropin-releasing hormone secretion, testosterone biosynthesis, and Meiosin gene, which is for crucial spermatogenesis. Continuous ingestion of physically abraded PET-MPs from plastic bottles adversely affected testicular and epididymal functions, leading to hormonal imbalances and abnormal sperm production. These findings raise concerns about the impact of commonly used plastics on male reproductive development, highlighting potential risks for future generations.