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To optimize livestock production of integrated farms, dietary crude fat levels are often increased, making efficient fat utilization crucial. Bile acids are known to improve fat utilization, but their impact on growth performance and breast muscle development in Zhijiang ducks remains unclear. In this study, a total of 360 twenty-day-old Zhijiang ducks with similar body weights were divided into three groups: the control group (CN) received a basal diet; the high-fat group (FA) received the basal diet plus 1.25 % rapeseed oil; and the high-fat plus bile acids compound (BA) group (FB) received the FA diet supplemented with 250 mg/kg BA for 30 days. Results indicated that the addition of rapeseed oil and BA significantly increased (P < 0.05) average daily gain (ADG) and reduced (P < 0.05) feed conversion ratio (FCR). Slaughter data showed that BA significantly enhanced (P < 0.05) breast muscle weight and percentage while decreasing (P < 0.05) abdominal fat weight. Additionally, BA increased (P < 0.05) the cross-sectional area of breast muscle fibers, total bile acid content, and levels of insulin-like growth factors 1/2 (IGF1/2). Transcriptomic analysis further revealed that BA significantly upregulated (P < 0.05) the levels of PPARα, CPT1α, NR1H4, and CETP in breast muscle. 16S rRNA analysis showed a significant increase (P < 0.05) in the relative abundances of genera Enorma, [Eubacterium nodatum group], Rikenellaceae RC9 gut group, and SP3-e08. Additionally, the Spearman correlation suggested a positive correlation between the genera Olsenella, SP3-e08, Enorma, Rikenellaceae_RC9_gut_group, and [Eubacterium_nodatum_group] with PPARα, CETP, NR1H4, and CPT1α. In contrast, the genera Christensenellaceae_R₇_group and Sutterella exhibited negative correlations with PPARα. These findings provide new insights into the role of BA in promoting growth performance and skeletal muscle development in Zhijiang ducks fed a high-fat diet, with this effect potentially linked to changes in the gut microbiota. Show less

The development of multi-target directed ligands (MTDLs) amassed great attention to combat the multifactorial nature of Alzheimer's disease (AD). The present study showcases the synthesis of a novel series of 3-hydrazinyl indole phenacetamide derivatives aimed at addressing AD and neuroinflammation by targeting acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and β-secretase (BACE1) enzymes. The primarily in vivo anti-inflammatory screening nominated derivatives 5a-f, 5h, 5j and 5o for the initial in vitro screening against AChE. Compounds 5a-c, 5j, and 5o, exhibited the most potent inhibitory activity against AChE and BChE, were subsequently subjected to further in vivo biological evaluations. Also, 5a-c were inspected for their impact on hallmarks of AD and histopathological changes. N-phenylacetamide indole derivative bearing unsubstituted phenylhydrazinyl side chain 5a depicted the most cognitive enhancement compared to the reference standard donepezil and significantly improved spatial memory capabilities, mitigated histopathological alterations, reduced AD hallmarks, AChE, BACE1, amyloid beta (Aβ), and p-tubulin associated unit (p-Tau), and modulated oxidative and inflammatory markers, GSH and IL-1β. Moreover, in vitro BACE1 enzyme inhibition assay revealed moderate BACE1 inhibitory activity for derivatives 5a-c. Further, in silico docking studies for the most active derivatives 5a-c in AChE and BACE1 binding pockets evidenced interacting with key amino acid residues supporting their remarkable biological activity. Furthermore, molecular dynamics simulations confirmed the stability of derivative 5a within the AChE and BACE1 binding sites throughout the simulation period. Collectively, N-phenylacetamide indole derivative bearing unsubstituted phenylhydrazinyl side chain 5a represents a promising multi-target candidate, combining AChE, BChE and BACE1 inhibition and can be considered as a lead compound for further development in AD therapy. Show less

Dehydroepiandrosterone (DHEA) and DHEA-sulfate (-s) fall with age and are implicated in aging. Observational studies suggest DHEA/DHEA-s could lengthen life in specifically older men. No trial has established the role of DHEA/DHEA-s in aging or lifespan. We assessed the role of DHEA-s in lifespan and key biological determinants, (blood pressure, Apolipoprotein B (ApoB), and haemoglobin A1C (HbA1c)), for men and women in a two-sample mendelian randomization (MR) study using naturally occurring genetic randomization to obviate confounding. We assessed associations of sex-specific DHEA-s from Life-Adult/Life-Heart (men = 4327, women = 3501) with lifespan, based on paternal (n = 415311) and maternal (n = 412937) attained age, and with blood pressure, ApoB and Hba1c (men = 167020, women = 194,174) from the UK Biobank. We used inverse variance weighted (IVW) estimates with sensitivity analysis. DHEA-s was unrelated to lifespan in women using IVW, 0.04 years per logged μmol/L DHEA-s, 95 % confidence interval (CI) -0.50 to 0.58, DHEA-s was associated with shorter lifespan in men (-1.15 years, 95 % CI -1.72 to -0.58) with a difference by sex (p = 0.0017), sensitivity analysis gave similar estimates. DHEA-s was unrelated to blood pressure in women and positively associated with systolic and diastolic blood pressure in men with a difference by sex for diastolic blood pressure. DHEA-s was possibly associated with lower ApoB in men. DHEA-s has different associations with lifespan and blood pressure in men and women. In settings where DHEA is an unregulated supplement, such as the United States, whether public health benefits might accrue from more regulation could be considered. Show less

Due to exploitation of the mineral resource, the Wumeng Mountain region has become one of the most severely polluted areas. This environmental toxicant accumulations threatens the ecosystem, which is vital for ruminant survival, and poses potential health risks to humans through circulation of contaminated product. The present study examined two pastures. Compared to the CON pasture, sulfur (S) and molybdenum (Mo) concentrations were significantly higher in both the soil and forage of the SMO pasture (p < 0.05). Specifically, the S content in SMO forage reached 28.533 g/kg and the Mo content reached 6.18 mg/kg, both of which far exceeded the recommended levels for small ruminants (1-2 g/kg for S and 0.05-0.1 mg/kg for Mo) as outlined by the NRC (2005). Therefore, the SMO pasture was under environmental S and Mo stress. Forty 4-5-month-old male Guizhou black goats were selected (20 from each pasture) for 150 grazing days. Environmental S and Mo stress in SMO goats led to secondary copper (Cu) deficiency (p < 0.05) and lower FW and ADG (p < 0.05). Hematological analysis revealed anemia, with decreased HGB, HCT, MCV, and MCH and increased RDW-CV and RDW-SD (p < 0.05). Serum analysis revealed liver function impairment, with elevated ALT, AST, TBIL, ALP, and CREA (p < 0.05), and inflammatory responses, with increased levels of IL-1β, IL-6, IFN-γ and TNF-α in the serum and increased liver mRNA expression of these cytokines, as well as decreased levels of IL-10 in the serum and decreased liver mRNA expression of IL-10 (p < 0.05). TMT-based proteomics identified 173 differentially expressed proteins (84 upregulated and 89 downregulated). KEGG analysis revealed disruptions in the complement, coagulation, oxidative phosphorylation, and cytochrome P450 pathways. Potential biomarkers include SERPINC1, F2, APOH, APOB, PLG, and AMBP. In conclusion, environmental S and Mo stress impairs the mineral balance, physiological functions, immune system, and growth of goats. Show less

Obesity rates continue to rise in children and adolescents worldwide. The heritability of obesity is estimated to be 40-80 %. Genetic testing for monogenic causes of obesity in the clinical setting is increasing; however, how results of these tests affect family behaviors is unclear. The objective of this study was to understand caregiver intent to change family behaviors following genetic testing for obesity. The sample from this qualitative analysis derives from a larger study identifying mutations on the melanocortin 4 receptor (MC4R) pathway. Inclusion criteria included participation in the main study, aged 2-17 years, and a history of severe obesity and hyperphagia. Caregiver-child dyads were recruited to ensure equal representation of genetic results across racial/ethnic subgroups (Non-Hispanic White, Black, Hispanic). A third of participants in the main study enrolled in the sub-study. Structured caregiver interviews were analyzed using grounded theory. Twenty caregivers were female, 55 % White, 45 % Black, and 5 % Hispanic. Mean caregiver age was 42.3 ± 6.5 years and BMI 40.5 ± 7.9 kg/m Genetic testing for pediatric obesity, regardless of test outcome, motivates caregivers to move forward within the SoC Model or to remain in their current stage. These findings suggest that engaging caregivers to have their child with obesity tested for a genetic cause of obesity does not cause families to stop engaging in behavior change, unless the family was not ready to engage in behavior change prior to genetic testing. Show less

Polyunsaturated fatty acids (PUFAs)-fatty acids containing multiple double bonds within their carbon chain-are an indispensable component of the cell membrane. PUFAs, including the omega-6 PUFA arachidonic acid (ARA; C20:4n-6) and the omega-3 PUFAs eicosapentaenoic acid (EPA; C20:5n-3) and docosahexaenoic acid (DHA; C22:6n-3), have been implicated in various (patho)physiological events. These PUFAs are either obtained from the diet or biosynthesized from the essential fatty acids linoleic acid (LA; C18:2n-6) and α-linolenic acid (ALA; C18:3n-3) via enzymatic reactions that are catalyzed by fatty acid elongases (ELOVL2 and ELOVL5) and fatty acid desaturases (FADS1 and FADS2). In this review, we summarize the recent literature studying the role of PUFAs, placing a special emphasis on the newly discovered functions of PUFAs and their biosynthetic pathway as revealed by studies using animal models targeting the PUFA biosynthetic pathway and genetic approaches including genome-wide association studies. Show less

Neuropathological diseases involve the death of neurons and the aggregation of proteins with altered properties in the brain. Proteins are used at the molecular level to categorize neurodegenerative disorders, emphasizing the importance of protein-processing mechanisms in their development. Natural herbal phytoconstituents, such as icariin, have addressed these neurological complications. Icariin, the principal compound in Epimedium, has been studied for its antineuroinflammatory, anti-oxidative, and antiapoptotic properties. Recent scientific investigations have shown that icariin exhibits promising therapeutic and preventive properties for mental and neurodegenerative disorders. In preclinical, icariin has been shown to inhibit amyloid development and reduce the expression of APP and BACE-1. Previous preclinical studies have demonstrated that icariin can regulate proinflammatory responses in neurological conditions like Parkinson's disease, depression, cerebral ischemia, ALS, and multiple sclerosis. Studies have shown that icariin possesses neuroprotective properties by modulating signaling pathways and crossing the blood-brain barrier, suggesting its potential to address various neurocomplications. This review aims to establish a foundation for future clinical investigations by examining the existing literature on icariin and exploring its potential therapeutic implications in treating neurodegenerative disorders and neuropsychiatric conditions. Future research may address numerous concerns and yield captivating findings with far-reaching implications for various aspects of icariin. Show less

Mayaro virus (MAYV) belongs to the Togaviridae family and is the etiologic agent of Mayaro fever, a disease in which inflammatory responses play a critical role in viral pathogenesis. Macrophages are targets of viral infection and key components of innate immunity and antiviral response. This study analyzed an RNA-sequencing (RNA-seq) dataset to gain insights into inflammatory and antiviral responses in monocyte-derived macrophages (MDMs) infected with the MAYV strain (Venezuelan 2010) at a multiplicity of infection (MOI) of 10. The RNA-seq results were validated by real-time quantitative polymerase chain reaction in MDMs infected with the MAYV strain from Brazil (MOI of 2). In addition, the replication capacity of MAYV and the resulting cell death in infected MDMs were assessed using plaque assays and flow cytometry. At 72 hours post-infection, transcriptomic analysis revealed that MAYV promotes a robust proinflammatory response by upregulating the expression of Toll-like receptors, RIG-I-like receptors, and the nuclear factor-κB complex. This strong inflammatory response was accompanied by a robust antiviral response dependent on type I/III interferon and interleukin-27. Both antiviral responses are mediated through the Janus kinase/signal transducer and activator of transcription signaling pathway, leading to the expression of interferon-stimulated genes. Moreover, MAYV-infected MDMs expressed markers of programmed cell death. These findings highlight the inflammatory response and antiviral activity of MDMs at a late stage in MAYV infection, suggesting a critical role of macrophages in MAYV pathogenesis. Show less

The present study aimed to assess the pharmacological mechanism of Salvia officinalis in Neurodegenerative disorders using a network pharmacology approach followed by molecular docking analysis. Phytoconstituents of S.officinalis were obtained from various databases, followed by the screening of active ingredients using the Swiss ADME web tool. Potential targets of active ingredients were identified using PubChem & SwissTargetPrediction. Genes related to Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD) were gathered using online databases. Besides, the correlation between active ingredient targets and disease-associated genes was linked. Networks were constructed, visualized, and analyzed using Cytoscape. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genome (KEGG) pathway enrichment analysis were performed using DAVID database. Decisively, Autodock was used for molecular docking. The results of network analysis identified 9 key active ingredients based on topological analysis of the active ingredient-candidate targets network. Also, the analysis revealed a shared target of 9 key active ingredients of S. officinalis that interacted with 133 AD-related targets whereas only 6 active ingredients interacted with 85 and 58 targets of PD and HD respectively. The core genes from the network were AKT1, BACE1, CASP3, MAPK1, TNF, and IL6. Furthermore, GO and KEGG enrichment analysis showed that FOXO, TNF, MAPK, PI3K-Akt, Rap 1, and neurotrophin signalling pathways as enriched, which were further evaluated by molecular docking suggesting the protective role of S. officinalis in neurodegenerative diseases. Our research reveals the therapeutic benefits of S. officinalis, which might play a crucial role in modulating neurodegenerative diseases. Show less

Accumulating evidence indicates that neuroinflammation is involved in the pathogenesis of Alzheimer's disease (AD). According to RNA sequencing and quantitative PCR (qPCR), we found that chemokine CCL3 mRNA expression was abnormally upregulated in the brains of AD transgenic mice. Moreover, the levels of CCL3 in the serum of AD patients were significantly elevated and negatively correlated with their cognitive abilities. However, the role of CCL3 in AD neuroinflammation and pathological damages remains elusive. Using behavioral, histological, and biochemical methods, outcomes of CCL3 antibody treatment on neuropathology and cognitive deficits were studied in the APPswe/PS1dE9 mice. In the present study, we reported that CCL3 protein expression was increased in the APPswe/PS1dE9 mice, whereas blockage of CCL3 with neutralizing antibody potently inhibited CCL3 activation in the APPswe/PS1dE9 mice down to the levels of wild-type mice. Specifically, CCL3 antibody significantly improved the learning and memory abilities of APPswe/PS1dE9 mice. In addition, CCL3 antibody treatment decreased cerebral amyloid-β (Aβ) levels and plaque burden via inhibiting amyloid precursor protein (APP) processing by reducing beta-site APP cleaving enzyme 1 (BACE1) expression in the APPswe/PS1dE9 mice. We also found that CCL3 antibody treatment alleviated neuroinflammation and reduced synaptic defects in the APPswe/PS1dE9 mice. Furthermore, the activated NF-κB signaling pathway in APPswe/PS1dE9 mice was inhibited by CCL3 antibody treatment. Collectively, our findings provide evidence that CCL3 activation may contribute to the AD pathogenesis and may serve as a novel therapeutic target in the treatment of AD. Show less

Accelerating ammonium metabolism of hepatocyte like cells (HLCs) is critical for various functions of hepatocytes. The aim of the present study was to investigate whether Farnesoid X receptor (FXR) agonist, obeticholic acid (OCA), accelerated ammonium metabolism of HLCs, which was derived from adipose derived mesenchymal stem cells (ADSCs). Human ADSCs were seed in flat bottom plate, then our differentiation protocol was used for 21 days. OCA treatment had been performed in Step3 for 10days. Then, 1) hepatic maturation, 2) urea cycle genes, 3) urea production, and 4) ammonium metabolism was compared depend on the presence or absence of OCA. HLCs had been successfully produced for 21 days. HLCs with OCA showed significantly higher mRNA expressions of AAT than those without OCA. HLCs with OCA showed significantly higher mRNA expressions of urea cycle genes such as SLC25A13, CPS1, and OTC. Urea production was also tended to be upregulated by OCA addition. HLCs with OCA showed significantly higher clearance of NH4Cl at 6hr and 24 hr after addition of NH4Cl. FXR agonist, OCA, accelerates ammonium metabolism of ADSCs derived HLCs. HLCs could be one of treatment options of hepatic encephalopathy of patients with liver failure or urea cycle disorder in the future. J. Med. Invest. 72 : 54-59, February, 2025. Show less

Coronary artery disease (CAD) is a multifactorial disorder influenced by both genetic and clinical risk factors. Lipid metabolism genes such as apolipoprotein B(APOB) (rs515135) and proprotein convertase subtilisin/kexin type 9 (PCSK9)(rs505151), have been associated with susceptibility to CAD. Study investigates the potential role of these genetic polymorphisms with risk of CAD in the Indian population. A case-control study including 150 CAD cases and 150 controls. Angiographically proven Cases were recruited from the Cardiology Unit, Department of Medicine, Era's Lucknow Medical College. Genotyping was done using specific primers and restriction digestion; statistical analysis included t-tests, odds ratios, and haplotype analysis. CAD cases(mean age 49.93   ±   9.13 years) had higher serum cholesterol and VLDL but lower systolic and diastolic BP compared to controls (mean age 56.47   ±   9.39 years). The APOB G allele showed a significant protective effect against CAD (OR: 0.431, The APOB G allele may serve as a protective factor against CAD, highlighting its potential role in genetic screening for lower disease risk. Further large-scale studies are required to confirm these findings. Show less

The imbalance between osteoblast (OB) -led bone formation and osteoclast (OC) -induced bone resorption is a recognized reason of osteoporosis. However, further gene-related pathogenesis remains to be elucidated. The microarray profile GSE225974 was used to identify the differentially expressed genes (DEGs) between OC and peripheral blood mononuclear cells (PBMC). Bone-marrow-derived macrophages (BMMs) treated with 30 ng/ml macrophage-colony-stimulating factor (M-CSF) and 100 ng/ml receptor activator of NF-kappa B ligand (RANKL) was to induce osteoclastic differentiation in vitro. The expression of lipoprotein lipase (LPL) was measured by quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting methods. Meanwhile, the regulatory role of LPL on osteoclastic differentiation was evaluated by monitoring cathepsin K levels and TRAP staining. Proteins related to LPL were obtained by STRING, and the interaction between proteins was verified by immunoprecipitation (IP) and ubiquitination analysis. LPL was markedly up-expressed in OCs. Inhibition of LPL suppressed osteoclast differentiation of BMMs by inhibiting cathepsin K and number of TRAP-positive cells. Then the results of STRING demonstrated that proteins related to LPL including the lipid synthesis gene ACSL4. Erastin treatment prominently weakened the effects of si-LPL on cathepsin K levels and TRAP staining intensity by activating ferroptosis. Mechanically, inhibition of LPL suppressed osteoclast differentiation by promoting ubiquitination levels of ACSL4, and over-expression of USP14 reversed the effects of LPL knockdown on regulating ubiquitination of ACSL4. Suppression of LPL inhibits the osteoclast differentiation of BMMs in vitro. The mechanism may be related to the LPL knockdown induced USP14 meidated the ACSL4 ubiquitination. Taken together, down-regulation of LPL may be a promising method to suppress osteoclast differentiation to treat osteoporosis. Show less

Aralia continentalis Kitag roots (ACKRs) have been regarded as a nutritional natural resource for treating different diseases, including type 2 diabetes mellitus (T2DM), and its complications (heart attack; HA, diabetic nephropathy; DN). Nonetheless, an extensive investigation of T2DM-derived complications has yet to be performed. Accordingly, we adopted gas chromatography-mass spectrometry (GC-MS) to identify the molecules of ACKRs, followed by the use of cheminformatics (Similarity Ensemble Approach; SEA, SwissTargetPrediction; STP), bioinformatics (STRING, DisGeNET, and OMIM), and computer screening tools to investigate its corresponding targets, in T2DM diseases and its complications. The primary targets (PPARG, and IL6) were confirmed via a protein-protein interaction (PPI) network, suggesting that IL6- Andrographolide, PPARA-Germacrene D, PPARD- Kaurenoic acid, PPARG- Kaurenoic acid, NR1H3- 1-Naphthalenepropanol, α-ethenyldecahydro-5-(hydroxymethyl)-α,2,5,5,8a-pentamethyl-, and FABP4- Kaurenoic acid conformers on PPAR signaling pathway might exert agonistic mode. These findings underline that ACKRs' bioactives filtered by the devised platform could prevent T2DM-derived complications through multiple-target. Show less

Peptide library screening is used to detect optimal sequences for enzymatic cleavage; moreover, the data obtained through this screening are useful for the establishment of a fast screening system and designing of substrate-based enzyme inhibitors. In this study, peptide libraries were prepared and digested with the beta-site amyloid precursor protein cleaving enzyme (BACE1). BACE1 has been used as a target enzyme for drug development against Alzheimer's disease (AD). The library sequences were derived from our previous screening study based on amyloid-beta precursor protein (APP) substrates. Then, newly selected non-natural amino acids were incorporated into several positions on these sequences. After digestion with BACE1, the reaction mixtures were analyzed with high-performance liquid chromatography followed by mass spectrometry to identify the peptides undergoing efficient cleavage. The data obtained from this study can be used for designing drugs against AD in the future. Show less

Remnant cholesterol is receiving increasing attention as a target to reduce residual atherosclerotic cardiovascular disease (ASCVD) risk in individuals already treated with statins. New therapeutic options as antisense oligonucleotides, small interfering RNA, and monoclonal antibodies allow specific targeting of genes and proteins to counter pathological pathways promoted by these genes. Identifying genetic determinants of remnant cholesterol and relating these to risk of ASCVD is thus an appealing path to identifying and evaluating new and existing drug targets. Human genetic epidemiology has identified several genetic variants in genes involved in lipoprotein metabolism with effect on plasma concentrations of remnant cholesterol. Lipoprotein lipase (LPL) is central to the metabolism of remnant lipoproteins and plasma concentrations of remnant cholesterol, and several genes, including APOC3 , ANGPTL3 and ANGPTL4 , whose gene products regulate activity of LPL, are important determinants of remnant cholesterol. Current opinion is that remnant cholesterol is a likely causal factor in the development of ASCVD. Human genetic studies have identified several genes, many involved in LPL function, affecting remnant cholesterol concentrations, some of which are already used as therapeutic targets, and others which are subject to investigation of their remnant cholesterol and triglyceride-lowering effect in clinical trials. Show less

DNA methylation plays a crucial role in species development and environmental adaptation. In mammals, there are significant dietary changes from infancy to adulthood. Notably, the red panda transitions from milk consumption as juveniles to a bamboo-based diet as adults, with significant alterations in food characteristics and nutritional content. However, the regulatory role of DNA methylation in this process remains unclear. In this study, we investigate the regulatory role of DNA methylation on the expression of digestive and metabolic genes in the liver and pancreas during the red panda's dietary transition from suckling stage to adulthood. Our findings reveal significant differences in DNA methylation patterns before and after dietary transition, highlighting the specific alterations in the methylation profiles of genes involved in lipid, carbohydrate, and amino acid metabolism. We found that perilipin-4 (PLIN4) is hypomethylated and highly expressed in the liver of adult red pandas, facilitating lipid droplet formation and storage, crucial for adapting to the low-fat content in bamboo. In contrast, genes like lipoprotein lipase (LPL), crucial for lipid breakdown, exhibited hypermethylated with low-expression patterns, reflecting a reduced lipid metabolism capacity in adults. Carbohydrate metabolism-related genes like ADH4 and FAM3C are hypomethylated and highly expressed in adults, enhancing glycogen production and glucose utilization. Genes involved in protein metabolism like CTSZ and GLDC, exhibit hypomethylated with high-expression and hypermethylated with low-expression patterns in the pancreas of adults, respectively, contributing to protein metabolism balance post-weaning. This study reveals the regulatory role of DNA methylation in the dietary transition of red pandas from milk to bamboo and provides methylation evidence for the molecular regulation of adaptive expression of digestive and metabolic genes in red pandas with specialized diets. Show less

Lung adenocarcinoma (LUAD) remains the leading cause of cancer deaths worldwide. Apurinic/apyrimidinic endonuclease 1 (APE1), an enzyme integral to DNA repair and redox signaling, is notably upregulated in LUAD. Here we reveal that APE1 amplification, primarily via allele duplication, strongly correlates with poor prognosis in LUAD patients. Using human LUAD cell lines and a Show less

Glaucoma is a leading cause of irreversible blindness, often associated with elevated intraocular pressure (IOP) due to trabecular meshwork (TM) dysfunction. Diabetes mellitus (DM) is recognized as a significant risk factor for glaucoma; however, the molecular mechanisms through which hyperglycemia affects TM function remain unclear. This study investigated the impact of high glucose on gene expression in human TM (HTM) cells to uncover pathways that contribute to TM dysfunction and glaucoma pathogenesis under diabetic conditions. Primary HTM cells were cultured under normoglycemic (5.5 mM) and hyperglycemic (30 mM) conditions for seven days, followed by mRNA sequencing (mRNA-seq) to identify differentially expressed genes, with quantitative PCR (qPCR) used for confirmatory analysis. STRING network analysis was performed to predict potential interactions among upregulated and downregulated genes. mRNA-seq analysis revealed 25 significantly differentially expressed genes in high glucose conditions, including upregulated genes associated with oxidative stress, apoptosis, autophagy, immune response, and fibrosis. Notably, TXNIP gene was significantly upregulated, indicating increased oxidative stress and apoptosis in TM cells, while downregulation of autophagy-related genes, such as HSPA6 and LAMP3, suggests compromised protein quality control. Immune response genes, including CCL7 and CHI3L1, were upregulated, suggesting an inflammatory response to oxidative stress. Increased expression of fibrosis-related genes, such as SNAI1, FGF7, and KRT19, and an increase in ECM proteins like Collagen 1 and FN accumulation and fibril formation suggest increased fibrosis of TM in diabetic conditions, potentially elevating IOP. Metabolic changes in diabetic patients could therefore lead to TM dysfunction, impair aqueous humor outflow, and elevate IOP, thereby increasing glaucoma risk. Targeting oxidative stress and fibrosis pathways offers therapeutic strategies to mitigate glaucoma progression in diabetic populations. Show less

Cisplatin is a widely used chemotherapeutic agent in the treatment of non-small cell lung cancer (NSCLC), but cisplatin resistance remains a significant clinical challenge. Lysosomal transmembrane protein 5 (LAPTM5) is a lysosomal membrane protein implicated in macroautophagy/autophagy, although its precise mechanism has yet to be fully elucidated.In this study, we demonstrated that LAPTM5 promotes cisplatin resistance in NSCLC by maintaining lysosomal membrane stability and preserving autophagic flux. Mechanistic investigations showed that LAPTM5 competes with LAMP1 for binding to WWP2, thereby inhibiting LAMP1 ubiquitination and degradation, which ultimately preserves lysosomal membrane stability. LAPTM5 knockdown increases lysosomal membrane permeability, leading to the release of cathepsin D (CTSD), which elevates intracellular reactive oxygen species (ROS) levels; further destabilizing the lysosomal membrane and accelerating cell death. Our findings elucidate the mechanism by which LAPTM5 contributes to cisplatin resistance through lysosomal membrane stabilization and identify LAPTM5 as a potential therapeutic target for overcoming cisplatin resistance in NSCLC. Show less

In the study we investigated how post-hatch preventive administration of Enterococcus faecium AL41 affects growth performance, the intestinal immune parameters and barrier factors, and morphology of jejunum in chickens. Chicks were divided into two groups as control (C) and Enterococcus faecium AL41 (EF). Samples (n=10) from blood and small intestine were taken at days 5, 8, and 11 of the life. Body weight gain increased in EF treated chicks on day 11. From day 8 to 11quantity of IgA in intestinal flush was lower in EF group. Relative expression of occludin gene was up-regulated at day11 in EF group and in same group claudin 1 gene was up-regulated at days 5 and 11. Jejunal CD3 Show less

Depression, a prevalent psychiatric disorder, exerts severe and debilitating impacts on an individual's mental and physical well-being, and it is considered a chronic mental illness. Chronic stress plays an important role in the pathophysiology of depression. Lactobacillus plantarum and Streptococcus thermophilus are psychobiotic bacteria and synthesize some neurotransmitters that play a role in the pathogenesis of depression. In this study, we aimed to investigate the therapeutic effects of Bactolac (Lactobacillus plantarum NBIMCC 8767  + Streptococcus thermophilus NBIMCC 8258) on chronic stress-induced depression in rats. Behavioral tests, including the sucrose preference test, elevated plus maze test, forced swim test, and three-chamber sociability test, were employed to assess depressive and anxiety-like behaviors. The expression level of the 5-HT1A, DRD1, ADRA-2A, GABA-A α1, CNR1, NR3C2, NOD1, NLRP3 and MC4R; BDNF levels, glial activity and intestinal permeability were determined in chronic stress-induced depression in rats. In conclusions, chronic stress decreased the expression levels of 5-HT1A, DRD1, ADRA-2A, GABA-A α1, CNR1, NR3C2, NOD1 and BDNF level; increased the expression levels of NLRP3 and MC4R, caused neurodegeneration and glial activity, ultimately led to depressive effects. Bactolac was effective in reducing depressive-like behaviors according to the results of behavioral tests. Bactolac treatment provided high neuronal survival rate increasing BDNF level, prevented the excessive release of pro-inflammatory cytokines by reducing the expression levels of NLRP3 and MC4R, therefore, prevented the excessive activation of the hypothalamus-pituitary-adrenal (HPA) axis and accordingly, reduced neurodegeneration and glial cell activation in depressed rats. We can suggest that Bactolac supplementation may be beneficial in coping with stress, alleviate the effects of chronic stress and help to protect mental health. Show less

The association between obesity and atrial fibrillation (AF) has garnered increasing attention. Obesity is a significant risk factor for cardiovascular diseases and promotes the occurrence of AF through multiple mechanisms. This study aims to explore the molecular mechanisms of obesity-induced AF using GLP-1R/GIPR dual-target agonist fusion protein (Fc) loaded into adipose-derived mesenchymal stem cell (ADSC) exosome-liposome hybrid nanoparticles (LE@Fc NPs). We successfully constructed and purified the Fc, verifying its purity and functional activity through SDS-PAGE and UV absorption spectroscopy. The fusion protein was then loaded into nanovesicles, and their morphology, size, and stability were assessed using transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), and dynamic light scattering (DLS). In vitro experiments demonstrated that LE@Fc NPs exhibit high fusion efficiency and targeted delivery capability. In vivo experimental results show that LE@Fc NPs significantly inhibit ferroptosis in the epicardial adipose tissue (EAT) of obese mice (iron content: 3.69 ± 0.36 vs. 0.88 ± 0.09), by restoring GSH levels (0.45 ± 0.08 vs. 0.87 ± 0.08) and Gpx4 expression (0.32 ± 0.06 vs. 1.01 ± 0.16), and reducing ROS (12.01 ± 0.95 vs. 2.68 ± 0.17), MDA (3.17 ± 0.29 vs. 0.95 ± 0.09), and 4-HNE (3.74 ± 0.51 vs. 0.91 ± 0.09) levels. Furthermore, LE@Fc NPs treatment significantly improved the inflammatory response (IL-1β: 44.08 ± 3.74 vs. 12.07 ± 0.65, IL-6: 515.59 ± 47.70 vs. 288.43 ± 16.81, MCP-1: 1401.04 ± 194.88 vs. 600.28 ± 45.54, TNF-α: 39.96 ± 2.48 vs. 18.01 ± 0.85). LE@Fc NPs also reduced atrial fibrosis, thereby effectively lowering the incidence of AF. Echocardiography and electrocardiogram monitoring revealed that LE@Fc NPs treatment significantly improved atrial remodeling and reduced the occurrence of AF in obese mice. In addition, LE@Fc NPs significantly improved obesity-induced systemic inflammation and metabolic disorders. In conclusion, LE@Fc NPs show great potential for the treatment of obesity-related AF. Show less

Parkinson's disease (PD) is a genetically complex neurodegenerative disorder. Up to 15% of cases are considered monogenic. However, research on monogenic PD has largely focused on populations of European ancestry, leaving gaps in our understanding of genetic variability in other populations. This study addresses this gap by analysing the allele frequencies of pathogenic and likely pathogenic variants in known monogenic PD genes across eight global populations, using data from the gnomAD database. We compiled a list of 27 genes associated with Mendelian PD from the Online Mendelian Inheritance in Man (OMIM) database, and identified pathogenic and likely pathogenic variants using ClinVar. We then performed pairwise comparisons of allele frequencies across populations included in the gnomAD database. Variants with significant frequency differences were further assessed using in silico pathogenicity predictions. We identified 81 variants across 17 genes with statistically significant allele frequency differences between at least two populations. Variants in Our findings reveal substantial population-specific differences in the allele frequencies of pathogenic variants linked to monogenic PD, emphasising the need for broader genetic studies beyond European populations. These insights have important implications for PD research, genetic screening, and understanding the pathogenesis of PD in diverse populations. Show less

Atherosclerosis is the leading cause of cardiovascular disease-related morbidity and mortality. The traditional Chinese medicine Qingre Sanjie Formula (QRSJF), composed of Prunellae Spica, Sargassum, Fritillariae Thunbergii Bulbus, Leonuri Herba, and Forsythiae Fructus, has shown efficacy in treating cardiovascular diseases, although its mechanisms are unclear. This study aimed to explore the protective effects of QRSJF against atherosclerosis and the mechanisms involved. The composition of QRSJF was analyzed using Ultra Performance Liquid Chromatography Quadrupole Time-of-Flight Mass Spectrometry. An 8-week high-fat diet (HFD)-induced atherosclerosis model was established in ApoE Both low- and high-dose QRSJF effectively attenuated dyslipidemia and decreased serum inflammatory cytokine levels in HFD-fed ApoE QRSJF improves dyslipidemia and reduces atherosclerotic plaque in ApoE Show less

Early-life stress (ELS) increases the risk of major depressive disorder in children and adolescents. However, the molecular and cellular mechanisms of major depressive disorder (MDD) induced by ELS are poorly understood. Here, we establish a stress model in rats in which maternal separation stress (MS) during the postnatal period increases susceptibility to restraint stress (RS) later in life. In terms of mechanism, MS causes long-lasting synaptic plasticity alterations in rats, which is accompanied by reduced branch and spine lengths in the hippocampus. We identified the role of the cell adhesion factor neurexin 3 (NRXN3) and its ligand neuroligin 1 (NLGN1) as mediators of these effects. NRXN3 and NLGN1 downregulation in the hippocampus occurred prior to the observed synaptic changes and depression-related behaviors. In conclusion, NRXN3 is involved in the development of depression induced by maternal separation, and the specific mechanism involves the NRXN3-NLGN1 complex, which can mediate synaptic plasticity and increase susceptibility todepression. Show less

Mutations in four genes encoding the outer ring complex of nuclear pore complexes (NPCs), NUP85, NUP107, NUP133 and NUP160, cause monogenic steroid-resistant nephrotic syndrome (SRNS). Knockout of NUP85, NUP107, or NUP133 in immortalized human podocytes activates CDC42, an important effector of SRNS pathogenesis. However, it is unknown whether or not loss of NUP160 dysregulates CDC42 in the podocytes. Here, we generated a podocyte-specific Nup160 knockout mouse model with double-fluorescent (mT/mG) Cre reporter genes using CRISPR/Cas9 and Cre/loxP technologies. We investigated nephrotic syndrome-associated phenotypes in the Nup160podo-/- mice, and performed single-cell transcriptomic and proteomic analysis of glomerular suspension cells and cultured primary podocytes, respectively. The Nup160podo-/- mice exhibited progressive proteinuria and fusion of podocyte foot processes. We found decreased Cdc42 protein and normal Cdc42 transcriptional level in the podocytes of the Nup160podo-/- mice using analysis of single-cell transcriptomes and proteomes. We subsequently observed that Cdc42 protein decreased in both kidney tissues and cultured primary podocytes of the Nup160podo-/- mice, although Cdc42 mRNA levels were elevated in the cultured primary podocytes of the Nup160podo-/- mice. We also found that Cdc42 activity was significantly reduced in the cultured primary podocytes of the Nup160podo-/- mice. In conclusion, loss of Nup160 dysregulated Cdc42 in the podocytes of the Nup160podo-/- mice with proteinuria and fusion of podocyte foot processes. Our findings suggest that the dysregulation of CDC42 may contribute to the pathogenesis of SRNS in patients with mutations in NUP160. Show less

Hyperlipidemia is a heterogeneous disorder that refers to increased lipid levels in the blood. The purpose of this study was to investigate the molecular effects of novel carboxamide derivatives on a hyperlipidemic male rat model induced by Triton WR-1339 in comparison to fenofibrate using liver, endothelial, and adipose tissue samples. Nitrofuran-2-carboxamide derivatives were compared to fenofibrate to evaluate their molecular hypolipidemic actions. The gene expression profiles of pathways related to triglycerides including PPAR-alpha and beta-oxidation pathways were evaluated in an acute hyperlipidemia rat model using RT-PCR followed by protein-protein interaction networks that were produced using the STRING database. The three novel compounds showed a significant effect on the lipid profile. Several genes were reported to be overexpressed by Triton WR-1339, including CPT1 A in liver tissue and APOE in adipose tissue. Most of the overexpressed genes were downregulated by carboxamide derivatives, with significant decreases in CPT1 A and APOE gene expression levels. On the other hand, several genes were reported to be downregulated by Triton WR-1339, including ACOX1 in liver tissue, LPL, ACADM and ACAA2 in endothelial tissue, and LPL and ACADM in adipose tissue. Most of the downregulated genes were significantly upregulated by carboxamide derivatives. In summary, the three novel compounds were found to improve hypertriglyceridemia with significant changes in gene expression of key enzymes in lipids metabolism, mainly LPL. Show less

Protein-protein interactions (PPIs) mediate many fundamental cellular processes. Control of PPIs through optically or chemically responsive protein domains has had a profound impact on basic research and some clinical applications. Most chemogenetic methods induce the association, i.e., dimerization or oligomerization, of target proteins, whilst the few available dissociation approaches either break large oligomeric protein clusters or heteromeric complexes. Here, we have exploited the controlled dissociation of a homodimeric oxidoreductase from mycobacteria (MSMEG₂₀₂₇₎ by its native cofactor, F Show less