Search Results (2,646)

Objectives: Aspidopterys obcordata has been traditionally used by the Dai people in Xishuangbanna, China, for the prevention and treatment of renal calculi. This study aimed to investigate the inhibitory effect of A. tomentosa extracts on calcium oxalate stone formation. Methods: The extracts of A. tomentosa (EA) were obtained via 95% ethanol reflux extraction, followed by multi-polar solvent extraction and elution. The HK-2 cell injury model induced by calcium oxalate and the renal calculus mouse model established by intraperitoneal injection of glyoxylic acid were established to assess drug efficacy. EA intervention was performed to evaluate its effects on calcium oxalate crystal deposition, renal tubular injury, cell apoptosis, and serum creatinine (Scr) and blood urea nitrogen (BUN) levels. Furthermore, the potential mechanism underlying, particularly the regulation of PERK/ATF4/CHOP signaling pathway and endoplasmic reticulum stress-mediated apoptosis, was investigated. Results: EA treatment significantly reduced renal calcium oxalate crystal deposition, alleviated renal tubular injury, inhibited cell apoptosis, and decreased Scr and BUN levels. Mechanistically, the protective effects of EA were mediated by the downregulation of the PERK/ATF4/CHOP signaling pathway and the suppression of endoplasmic reticulum stress-mediated apoptosis. Conclusions: These findings provide experimental evidence supporting that A. tomentosa can be developed as a promising agent for the prevention of nephrolithiasis. Full article

White-nose syndrome (WNS), caused by the psychrophilic fungus Pseudogymnoascus destructans, poses a severe threat to wild bat populations. Caves serve as unique microecosystems. Exploring antagonistic microorganisms and their volatile antifungal compounds within these native environments has emerged as a promising ecological control strategy. In this study, we isolated four antagonistic bacterial strains from bat cave soil that completely inhibit P. destructans. Additionally, we identified benzaldehyde (BzH) and 2,5-dimethylpyrazine (2,5-DMP) as their primary antifungal volatile organic compounds (VOCs). Combined physiological, biochemical, and multi-omics analyses revealed that these two VOCs disrupt the structural integrity of the fungal cell wall and membrane. This disruption triggers abnormal energy metabolism and compensatory ATP accumulation, leading to a significant intracellular burst of reactive oxygen species and the impairment of primary antioxidant defenses. This sustained oxidative stress causes irreversible DNA damage, endoplasmic reticulum stress, and basal metabolic dysfunction. Consequently, this cascade induces apoptosis and significantly downregulates the expression of essential virulence genes. In conclusion, this study systematically elucidates the molecular network through which VOCs released by cave soil microorganisms antagonize P. destructans. These findings provide a theoretical foundation and candidate intervention molecules for the contactless biocontrol of WNS. Full article

Grass carp (Ctenopharyngodon idella) is a major freshwater aquaculture species in China, but its growth is limited under intensive high-density farming. This study aimed to investigate the characteristics of plasma exosomes associated with distinct growth performance by isolating and characterizing exosomes from fast- and slow-growing grass carp after nine months of culture. Exosomes showed typical morphology and expressed characteristic markers (CD63, CD81, TSG101). Small RNA sequencing identified 3325 miRNAs, with 177 highly abundant miRNAs differentially expressed: immune-related miRNAs were upregulated, while development-inhibitory miRNAs were downregulated in fast-growing fish. Target gene enrichment highlighted pathways in neural and skeletal development and amino acid metabolism. Integrative analysis across tissues revealed 26 miRNAs with coordinated expression patterns between plasma exosomes and brain, liver, or muscle, validated by qPCR. DIA proteomics quantified 4203 proteins, identifying 843 differentially enriched proteins linked to immune response, energy metabolism, and endoplasmic reticulum stress. Notably, TYMP was upregulated in muscle and exosomes, while several proteins (e.g., GYG2, BHMT) showed coordinated downregulation across tissues and exosomes in large fish. These results provide comprehensive evidence of exosome-mediated cross-tissue communication in teleosts and suggest a potential role for plasma exosomal miRNAs and proteins as non-invasive biomarkers correlated with growth status in aquaculture. Full article

Background/Objectives: Fluoride (F) is widely used in public water fluoridation to prevent dental caries, and an optimal level of F has been linked to improved glucose metabolism in animal models. Per- and polyfluoroalkyl substances (PFAS), including fluorotelomer alcohols (FTOHs), are persistent environmental contaminants with potential effects on pancreatic function. Methods: This in vitro and in vivo study investigated the effects of 8:2 FTOH and F (NaF) on pancreatic β-cells, focusing on Ca²⁺ homeostasis, insulin secretion, and the GPR40 pathway. Results: Results showed that 8:2 FTOH alters Ca²⁺ influx in a dose-dependent, biphasic manner, enhancing it at low doses and inhibiting it at high doses, while F increased Ca²⁺ signaling at high doses. High-dose 8:2 FTOH also downregulated GPR40 protein in βTC-6 pancreatic cells and modulated pathways related to lipid metabolism, endoplasmic reticulum stress, and insulin regulation in the mouse pancreas by proteomic analyses (in vivo). Conclusions: These findings exploratory indicate that both PFAS and F can impact β-cell function through complex mechanisms, potentially affecting Ca²⁺ homeostasis. This work highlights the hormesis effect of F and provides novel insights into the pancreatic effects of environmentally relevant PFAS exposures, emphasizing the need for further mechanistic studies at low, human-relevant doses. Full article

Methotrexate (MTX) is widely used in the treatment of malignancies and inflammatory disorders, but nephrotoxicity remains a major adverse effect. Naringenin (NAR), a natural flavonoid, has antioxidant, anti-inflammatory, and nephroprotective properties. This study investigated the potential protective effects of NAR against MTX-induced nephrotoxicity at biochemical, molecular, and histopathological levels. Forty-two adult male Wistar albino rats were assigned to seven groups (n = 6): Control, CMC (carboxymethyl cellulose), NAR100, MTX, and MTX combined with NAR (25, 50, or 100 mg/kg/day). NAR was administered for 7 days, with MTX given on day 3. Renal function, histopathology, and genes associated with oxidative stress, apoptosis, endoplasmic reticulum stress, and inflammation were evaluated. MTX administration caused marked renal damage, increased creatinine and BUN levels, elevated apoptosis-, inflammation-, and ER stress-related gene expression, and suppressed antioxidant defense-related genes. However, 50 and 100 mg/kg/day NAR attenuated these alterations, with greater effects at 100 mg/kg/day. Histopathological damage was attenuated by NAR treatment, although complete recovery was not observed. These findings suggest that NAR may protect against MTX-induced nephrotoxicity through the modulation of pathways associated with oxidative stress, inflammation, apoptosis, and ER stress. However, the persistence of certain histopathological alterations indicates that structural recovery of renal tissue may take a longer period compared with molecular changes. Full article

Serotonin transporter Slc6a4a functions as a transporter in serotonin reuptake and is tightly linked with serotonergic regulation and stress responses. However, few studies have investigated its role in copper homeostasis and organogenesis in an in vivo vertebrate model. In this study, we demonstrate that slc6a4a deficiency (slc6a4a^−/−) leads to copper accumulation, retinal developmental defects, and locomotor dysfunction in zebrafish specifically. Mechanistically, slc6a4a deficiency is associated with reduced atp7b and copper accumulation, which lead to reactive oxygen species (ROS) and endoplasmic reticulum (ER) stress, and results in Caspase-3-mediated apoptosis and retinal degeneration. Specifically, tetrathiomolybdate (TTM), a pharmacological copper chelator, partially reduces ER stress and restores retinal defects. Additionally, ectopic expression of full-length atp7b mRNA partially restores retinal defects. These findings identify serotonin transporter Slc6a4a as a novel regulator in copper homeostasis and retinal development via the regulation of Atp7b in an in vivo vertebrate model. This study supports a mechanistic link between slc6a4a deficiency, copper overload, and retinal defects and highlights copper chelation as an alternative therapeutic strategy in individuals with Slc6a4 deficiency. Full article

The European perch (Perca fluviatilis) is highly susceptible to heat stress, limiting its sustainable aquaculture. While single-organ thermal responses are partially understood, the systemic, multi-organ cooperative survival mechanisms under acute heat stress remain poorly characterized. To elucidate the underlying tolerance mechanisms and provide genetic markers for breeding, this study investigated the multi-organ responses of European perch (n = 90; body length: 13.15 ± 1.75 cm; body weight: 30.54 ± 7.17 g) transferred from 24 °C to an acute heat stress challenge (31 °C) at an increasing rate of 2 °C/h, and the histopathological changes (liver and gill), hepatic biochemical biomarkers (CAT, SOD, GSH-Px, GST, LDH, and MDA), and transcriptomic changes (liver and kidney) were evaluated over a 24 h period. Heat stress induced progressive structural damage, including gill lamellar edema and hepatocyte necrosis, accompanied by significant hepatic oxidative stress and lipid peroxidation. RNA-seq transcriptome profiling uncovered distinct sets of genes with significant expression changes, comprising 1343 DEGs in liver tissue and 722 DEGs in kidney samples. Both organs shared a systemic endoplasmic reticulum stress response but exhibited highly divergent survival strategies. The liver underwent severe metabolic reprogramming towards anaerobic glycolysis and gluconeogenesis, coupled with vesicle-mediated membrane repair attempts and apoptosis. Conversely, the kidney adopted a strict “energy triage” strategy, suppressing highly energy-consuming immune and osmoregulatory functions while actively silencing pro-apoptotic signals. These findings highlight organ-specific adaptations and identify potential metabolic markers for the future breeding of new heat-tolerant varieties. Full article

The Cytochrome P450 (CYP) superfamily plays an important role in the regulation of plant growth and development. However, the composition, evolutionary characteristics, and potential functions of CYPs in celery remain largely unexplored. Therefore, the objective of this study was to perform a genome-wide characterization of the Apium graveolens Cytochrome P450 (AgCYP) gene family and investigate its potential roles in seed development. In this study, a total of 227 AgCYPs were identified, and phylogenetic analysis classified them into six clades. Conserved motif and domain evaluations indicated that most AgCYP proteins possess conserved P450 domains. Chromosomal localization revealed an unequal distribution of AgCYPs across the 11 celery chromosomes. Duplicated AgCYP gene pairs were identified by synteny and Ka/Ks analyses, indicating that the duplicated AgCYPs have undergone strong purifying selection. Inter-genomic synteny analysis further reflects the closer relationship within Apiaceae. Analysis of cis-acting elements in the promoter regions identified an abundance of elements associated with light, hormone, and environmental stress. Moreover, AgCYPs showed stage-specific expression patterns and were correlated with monoterpene and phthalide accumulation during celery seed development, suggesting their potential functions in secondary metabolism in seed development. Treatment with exogenous auxin and its transport and biosynthesis inhibitors differentially induced distinct expression responses among AgCYPs, indicating their possible participation in auxin-related regulatory pathways. Moreover, candidate genes were selected. They exhibited diverse tissue-specific expression patterns and were potentially localized to the endoplasmic reticulum and interacted with some auxin-related proteins. In conclusion, this study provides the first comprehensive framework for understanding the functional diversification of AgCYPs in celery seeds, providing new insights into the evolutionary features and biological functions of the AgCYP gene family and establishing a foundation for future functional studies and molecular breeding applications. Full article

Lead (Pb) is a persistent aquatic pollutant that disrupts redox homeostasis in fish. This study investigated hepatic Pb accumulation, reactive oxygen species (ROS) production, antioxidant responses, lipid peroxidation, and transcriptomic alterations in juvenile pufferfish (Takifugu obscurus) exposed to waterborne Pb. Juvenile pufferfish were exposed to 5.98 mg/L waterborne Pb, corresponding to 10% of the 96 h LC50, for 96 h. Liver, blood, and hepatocyte samples were collected at 0, 12, 24, 48, and 96 h, with four biological replicates at each sampling time point. Hepatic Pb accumulation increased over time and reached the highest level at 96 h. ROS levels in blood cells and hepatocytes increased rapidly and peaked at 12 h. Superoxide dismutase (SOD) and catalase (CAT) activities showed early activation followed by late suppression, whereas glutathione peroxidase (GSH-Px) displayed partial adaptive recovery. Malondialdehyde (MDA) content increased progressively and reached approximately 2.8-fold of the control level at 96 h, indicating persistent lipid peroxidation. RNA-seq analysis identified 167, 460, 1398, and 2580 differentially expressed genes at 12, 24, 48, and 96 h, respectively. Enrichment, temporal trend, and weighted gene co-expression analyses indicated that Pb exposure shifted hepatic responses from early redox regulation to later metabolic adaptation, protein processing in the endoplasmic reticulum, proteasome function, and oxidative phosphorylation. qRT-PCR validation of 12 hub genes supported the RNA-seq results. These findings provide integrated biochemical and transcriptomic evidence for oxidative-stress-mediated hepatic toxicity in pufferfish exposed to waterborne Pb. Full article

Reticulon-like proteins shape the endoplasmic reticulum (ER) membrane network, yet the developmental and physiological roles of individual plant reticulon isoforms remain poorly understood. Here, we characterize an Arabidopsis RTNLB16 T-DNA allele, rtnlb16-1, that exhibits severe photoperiod-dependent growth retardation and chlorosis. Molecular analysis revealed that rtnlb16-1 is not a simple loss-of-function mutant: the T-DNA insertion deletes the 5′ region required for RTNLB16 splice variant 7, while a CaMV35S enhancer associated with the insertion drives overexpression of the remaining splice variants. This misexpression is enhanced under long-day photoperiods and reduced under continuous low light, paralleling the severity of the mutant phenotype and its partial rescue. RTNLB16.5-GFP localized mainly to the tubular ER network and punctate cell-boundary structures consistent with plasmodesmata-associated ER. Neither overexpression of RTNLB16 isoforms 1–6 nor CRISPR-Cas9 disruption of major RTNLB16 isoforms reproduced the rtnlb16-1 phenotype, supporting a model in which altered splice-variant stoichiometry, rather than simple loss or gain of function, underlies the developmental defects. Transcriptome profiling showed that rtnlb16-1 undergoes extensive photoperiod-dependent transcriptional reprogramming, including changes in defense, hormone-response, senescence, photosynthesis, and iron/redox-associated gene networks. Physiologically, rtnlb16-1 displayed enhanced recovery from dark-induced senescence, while both rtnlb16-1 and rtnlb16-2 showed reduced sensitivity to exogenous abscisic acid during germination. Together, these findings suggest that balanced expression of RTNLB16 splice variants is important for normal growth and for coordinating ER-associated stress, hormone, and senescence responses in Arabidopsis. Full article

Virus infection requires coordinated activation of pathogen-sensing, innate immune, and cellular stress response pathways to mount an effective antiviral defense. Recognition of nucleic acid pathogen-associated molecular patterns (PAMPs) by pattern recognition receptors (PRRs) initiates signaling cascades that drive the production of type I interferons (IFNs) and proinflammatory cytokines. These responses are often accompanied by the activation of integrated stress response pathways that help optimize host defense. Cytosolic double-stranded dsDNA, generated during viral infection or released from damaged mitochondria, is sensed by cyclic GMP-AMP synthase (cGAS), which generates 2′3′-cGAMP to activate stimulator of interferon genes (STING). Activated STING translocates from the endoplasmic reticulum to the Golgi, where it drives TBK1-dependent IFN and cytokine production. Previous reports show that cGAS activity is enhanced by Ras-GAP SH3 domain binding protein 1 (G3BP1), a key nucleator of stress granules (SGs), independent of its role in SG assembly. Here, we identify a non-canonical role of G3BP1 as a regulator of DNA sensing responses at multiple levels, including STING intracellular trafficking, in addition to potentiating cGAS activity. Loss of G3BP1 impaired STING-dependent IFN and cytokine responses to HSV-1 infection and viral DNA. G3BP1-deficient cells showed reduced cGAMP-induced STING translocation to the Golgi, induction of type I IFN and proinflammatory cytokines, and activation of the ER stress kinase PERK and stress granule formation. Together, these findings demonstrate G3BP1-STING as a node linking DNA sensing, innate immunity, and stress signaling with broad implications for antiviral defense and diseases characterized by aberrant DNA sensing and stress responses, including neurodegeneration, fibrosis, and autoimmunity. Full article

Background: Minimal change disease (MCD) is a leading cause of childhood nephrotic syndrome. Endoplasmic reticulum stress (ERS) and autophagy are implicated in its pathogenesis, but the precise mechanisms remain unclear. This study aimed to identify ERS and autophagy-related key genes (ERS-RGs and ARGs) in MCD using bioinformatic and experimental approaches. Methods: Transcriptomic data from GSE216841 and GSE246206 were analyzed. ERS-RGs and ARGs were obtained from prior literature. Candidate genes were selected by integrating weighted gene coexpression network analysis and differential expression analysis. Feature genes were identified via protein–protein interaction network analysis and machine learning (Least Absolute Shrinkage and Selection Operator and Boruta). Key genes were validated by expression analysis and receiver operating characteristic evaluation. A multilayer perceptron (MLP) model was constructed, and regulatory networks, immune infiltration, and chemical compound prediction were analyzed. The expression levels of the identified key genes were preliminarily assessed in peripheral blood samples using reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Results: LIG4 and ZRANB3 were identified as key genes, both significantly downregulated in the MCD group, and the gene-based MLP model effectively predicted MCD probability. Overall, 13 significantly different immune cell types (e.g., CD56⁺ natural killer and activated dendritic cells) were detected. Regulatory networks (transcription factor-messenger RNA (mRNA) and long non-coding RNA-microRNA-mRNA) and 8 common chemical compounds (e.g., bisphenol A, acetaminophen) targeting these genes were predicted. Notably, peripheral blood RT-qPCR analysis revealed significant LIG4 and ZRANB3 downregulation, suggesting a systemic expression signature. Conclusion: LIG4 and ZRANB3 are key genes associated with ERS and autophagy in MCD, providing insights for diagnosis and targeted therapy. Full article

Ryanodine receptor-like (RyR-like) is a key endoplasmic reticulum (ER) Ca²⁺ release channel governing intracellular Ca²⁺ homeostasis and cellular stress responses in invertebrates. However, its function in bivalves under high-temperature stress remains unclear. In the present study, one RyR-like was identified from Yesso scallop Patinopecten yessoensis (PyRyR-like). Its function in regulating intracellular Ca²⁺, IRE1α-mediated unfolded protein response (UPR) and apoptosis in the mantle after high-temperature (25 °C) treatment was investigated using molecular cloning, qRT-PCR, Western blot, pull-down assay, cellular calcium imaging, TUNEL and histology assays; High temperature treatment significantly increased intracellular Ca²⁺ content at 1 and 6 h (p < 0.05), but decreased it at 3, 12 and 24 h (p < 0.05); meanwhile, the cAMP level, PyPKA activity, mRNA expression level of PyRyR-like, and protein expression levels of PyFKBP12 and PyGRP78 were significantly increased at different times. However, high temperature did not affect the expression level of PyNVL and PyXBP1(S). The SPRY and RYR domains of PyRyR-like separately interacted with PyFKBP12 and PyPKA. Moreover, RyR antagonist Dantrolene reversed high-temperature-induced alterations in Ca concentration, PKA activity, and core UPR- and apoptosis-related molecules, and suppressed Caspase-3 activity. These findings suggest that PyRyR-like plays an important role in the high-temperature response of scallops by regulating intracellular Ca²⁺ homeostasis and mediating UPR activation and apoptosis, providing new insight into the molecular mechanism underlying scallop adaptation to high temperature. Full article

Heat and Cd²⁺ stress are major environmental challenges for marine benthic invertebrates. This study examined their combined effects on growth, physiology, and transcriptomic responses in the peanut worm (Sipunculus nudus). After 30 days, Cd²⁺ reduced survival at 26 °C without significantly affecting growth, whereas at 32 °C, both survival and growth declined with increasing Cd²⁺ concentration, indicating that heat stress exacerbates Cd²⁺ toxicity. Cd accumulation increased with exposure concentration but was not affected by temperature. Heat stress increased immune (AKP) and antioxidant (SOD, CAT) enzyme activities, although significant increases in SOD and CAT were observed only under Cd²⁺ exposure. AKP activity rose at low Cd²⁺ concentrations and fell at high Cd²⁺ concentrations at 26 °C, whereas no significant difference occurred at 32 °C between 0 and 0.25 mg/L Cd²⁺. At the same temperature, SOD and CAT activities were significantly higher under high Cd²⁺ exposure than under low Cd²⁺ exposure. Transcriptome analysis showed that Cd²⁺ exposure activated longevity-related pathways, protein processing, and translation initiation. Heat stress activated Jak-STAT signaling and endoplasmic reticulum protein processing while inhibiting the ribosome pathway. Under combined stress, pathways related to xenobiotic metabolism, nutrient digestion and absorption, and amino acid derivative metabolism were broadly suppressed. These results highlight that heat stress exacerbates Cd²⁺ toxicity, affecting growth, enzyme activity, and transcriptomic responses, and provide insights into the adaptive strategies of marine benthic organisms under the combined pressures of climate change and heavy metal pollution. Full article

Neurodegenerative diseases (NDs), such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Amyotrophic lateral sclerosis (ALS), and Huntington’s disease (HD), involve the gradual loss of structure or function of neurons in the nervous system and are an increasing threat to the aging population worldwide. Although these disorders have different clinical features which affect cognition, movement and other vital body functions, they share key underlying molecular and cellular processes. This starts with protein misfolding and aggregation, mitochondrial dysfunction, oxidative stress, dysregulated protein homeostasis, neuroinflammation, and disrupted cell death pathways. Recent findings have added disease-specific processes, like amyloid-β and tau aggregates in AD, α-synuclein aggregation and mitophagy failure in PD’s, TDP-43-related impaired RNA metabolism in ALS, and mutant huntingtin causing transcription aberrations in HD. Protein interactome network analysis showed mechanistic crosstalk between pathogenic proteins of AD and PD. New evidence highlights how lysosomal dysfunction, endoplasmic reticulum stress, and microglial activation, act as a common axis in neurodegeneration. Advancements in genomics and epigenomics have found shared genetic risk loci and regulatory processes that affect how diseases develop and progress. Simultaneously, new biomarkers like circulating microRNAs, exosome-related pathological proteins, neurofilament light chain, inflammatory cytokines, and microglial activation markers are powering early diagnosis tools and disease variations. New imaging techniques also allow for the identification of protein aggregations before symptoms appear. Overall, these findings are accelerating targeted treatments and personalized medicine aimed at disease progression. This review highlights current insights into the molecular mechanisms of NDs and discusses new biomarkers and treatment targets that help future diagnostic and treatment strategies. Full article