Search Results (2,296)

Background: Chinese Red Steppe cattle (CRS) combine indigenous environmental resilience with moderate dairy performance, whereas Holstein cattle (HOL), despite their high milk yield, suffer reduced genetic diversity and compromised adaptation. A comparative analysis of their population genetic architecture and selection signatures can reveal valuable targets for CRS dairy improvement. Methods: We genotyped 61 CRS and 392 HOL individuals using the Illumina GGP Bovine 100K SNP array and performed stringent quality control. Population structure was assessed via principal component analysis, neighbor-joining trees, and sparse nonnegative matrix factorization. Historical effective population size (Ne) and divergence time were inferred with SMC++. Genome-wide selection scans combined Fixation Index (FST) and Cross-Population Composite Likelihood Ratio test (XP-CLR); overlapping high-confidence regions were annotated and subjected to GO and KEGG enrichment analyses. Results: CRS and HOL were clearly separated along PC1 (explaining 57.48% of variance), with CRS exhibiting high internal homogeneity and weak substructure, versus greater diversity and complex substructure in HOL. SMC++ indicated a split approximately 3500 years ago (700 generations) and a pronounced recent decline in Ne for both breeds. Joint selection mapping identified 767 candidate genes; notably, the ACSM1/2B/3/4 cluster on chromosome 25—key to butanoate metabolism—showed the strongest signal. Enrichment analyses highlighted roles for proteasome function, endoplasmic reticulum stress response, ion homeostasis, and RNA processing in regulating milk fat synthesis and protein secretion. Conclusion: This study delineates the genetic divergence and demographic history of CRS and HOL, and pinpoints core genes and pathways—particularly those governing butanoate metabolism and protein quality control—underlying dairy traits. These findings furnish molecular markers and theoretical guidance for precision breeding and sustainable utilization of Chinese Red Steppe cattle. Full article

The extensive utilization of amorphous silica nanoparticles (SiNPs) has raised concerns regarding the potential health risks. Previous studies have indicated that SiNPs could trigger both the activation of heat shock proteins (HSPs) and epithelial–mesenchymal transition (EMT) in BEAS-2B cells; however, the underlying mechanisms require further elucidation. This study aimed to investigate how SiNPs activate the heat shock response (HSR) in BEAS-2B cells, which subsequently triggers EMT. Firstly, we observed that SiNPs were internalized by BEAS-2B cells and localized in the endoplasmic reticulum (ER), inducing ER stress. The ER stress led to the activation of SIRT1 by phosphorylation, which enhanced the nuclear transcriptional activity of HSF1 via deacetylation. HSF1 was found to upregulate the levels of HSP70 and HSP27 proteins, which further affected EMT-related genes and, ultimately, induced EMT. Additionally, 4-phenylbutyric acid (4-PBA) inhibited ER stress, which attenuated the SIRT1/HSF1 signaling pathway. The knockdown of SIRT1 and HSF1 using siRNA effectively suppressed the EMT progression. In summary, these results suggested that SiNPs activated the SIRT1/HSF1/HSPs pathway through ER stress, thereby triggering EMT in BEAS-2B cells. The present study identified a novel mechanism of SiNP-induced EMT, which has provided valuable insights for future toxicity studies and risk assessments of SiNPs. Full article

Maturity-onset diabetes of the young type 10 (MODY10) is a monogenic diabetes subtype caused by heterozygous mutations in the insulin gene (INS), leading to defective proinsulin processing, endoplasmic reticulum (ER) stress, and β-cell dysfunction. Current management relies on sulfonylureas or insulin therapy, but these fail to address the underlying genetic defect. Recent research has elucidated the molecular mechanisms of MODY10, including ER stress induced by proinsulin misfolding, activation of the unfolded protein response (UPR), and β-cell apoptosis. Emerging therapies such as Adeno-Associated Virus (AAV)-mediated gene delivery to induce the glucose-responsive hepatic insulin expression, plasmid-based single-chain insulin analogs, and cell-based therapies show promise in preclinical studies. However, critical challenges remain, including immune responses to AAV vectors, incomplete correction of dominant-negative mutant effects, and the need for long-term safety data. This review summarizes current knowledge on MODY10 genetics, pathophysiology, and therapeutic innovations, while identifying key gaps for future research to enable precision medicine approaches. Full article

The progression of inflammation during sepsis represents a multifaceted biological cascade that requires effective therapeutic interventions to improve survival. In septic neonatal foals, oxidative stress (OS) arises due to a compromised antioxidant defense system. Oxidative stress may disrupt the functionality of redox-sensitive organelles, such as the endoplasmic reticulum (ER). Endoplasmic reticulum stress disorder affects multiple cellular signaling pathways, including redox balance, inflammation, and apoptosis, and contributes to the pathogenesis of sepsis. The study aimed to elucidate whether OS conditions in sepsis influenced gene expression associated with ER stress. Blood samples were collected from 7 healthy and 21 hospitalized neonatal foals and processed for RNA extraction. RNA sequencing was employed to identify ER stress-responsive genes. Novel findings reported here indicate activation of the ER stress pathway in foals with sepsis. Several genes associated with ER stress, such as clusterin (CLU), BCL2-like 1 (BCL2L1), ubiquitin specific peptidase 14 (USP14), bifunctional apoptosis regulator (BFAR), and optic atrophy 1 (OPA1), were upregulated and positively correlated with sepsis scores and negatively correlated with the combined activities of antioxidant enzymes. In contrast, X-box binding protein 1 (XBP1), homocysteine inducible ER protein with ubiquitin-like domain 1 (HERPUD1), leucine-rich repeat kinase 2 (LRRK2), and selenoprotein S (SELENOS) were negatively correlated with sepsis scores and were downregulated in sepsis and positively correlated with the combined activities of antioxidant enzymes. Furthermore, a positive correlation was observed between cAMP responsive element binding protein 3 like 2 (CREB3L2) and BCL2L1, as well as between the expressions of USP14 and YOD1 deubiquitinase (YOD1) in sepsis. Similarly, the expression levels of XBP1 and Herpud1 demonstrated a positive correlation with each other in sepsis. Additionally, the downregulation of genes with protective function against OS, such as XBP1, HERPUD1, and SELENOS, in septic foals also highlights their significance in mitigating OS in sepsis treatment. The study reported here highlights the potential of ER stress as a promising therapeutic target and prognostic marker in septic foals. Full article

The rapid development of the nuclear industry and mining has increased environmental radioactive contamination, posing potentially ecological risks and health threats to humans. Uranium compounds are known to exhibit selective nephrotoxicity, but their toxicological processes and mechanisms still remain poorly understood and controversial. In this study, the uranyl-induced toxicity in human renal tubular epithelial cells (HK-2) were explored using flow cytometry, DAPI staining, and comet assays. Our results demonstrate that uranium exposure primarily triggers apoptosis. Kyoto Encyclopedia of Genes and Genomes pathway enrichment and protein–protein interaction (PPI) analyses revealed significant associations with DNA damage. Moreover, aberrant expression of ABC transporters (e.g., ABCB7) and mitochondrial-related proteins confirms uranium-induced mitochondrial dysfunction. Gene Ontology functional annotation implicated extrinsic apoptotic signaling pathways in uranium-induced cell death. The downregulation of the UBL5 protein also pointed to endoplasmic reticulum stress-mediated apoptosis. In summary, uranium exposure can induce the apoptosis of HK-2 cells through intrinsic pathways by damaging DNA and mitochondria and disrupting protein synthesis, with secondary contributions from endoplasmic reticulum stress and extrinsic apoptotic signaling. Full article

Mistletoe (Viscum album L.) has been used in complementary cancer therapy for decades, but its mechanisms remained poorly understood until recently. This review synthesizes transformative advances in mistletoe cancer research from 2020 to 2025, focusing on newly discovered molecular mechanisms, immunomodulatory properties, and clinical applications. We conducted a comprehensive analysis of controlled studies, mechanistic investigations, and real-world evidence published between 2020 and 2025. The discovery of mistletoe-induced immunogenic cell death (ICD) represents a paradigm shift in understanding its anticancer effects. Mistletoe extracts trigger endoplasmic reticulum stress, leading to calreticulin exposure in 18–51% of cancer cells and a 7-fold increase in adenosine triphosphate (ATP) release. Three-dimensional culture models revealed enhanced macrophage reprogramming effects, with a 15.8% increase in pro-inflammatory interleukin (IL)-6 and a 26.4% reduction in immunosuppressive IL-10. Real-world evidence from over 400 non-small-cell lung cancer patients shows that combining mistletoe with programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) inhibitors doubles median overall survival (6.8 to 13.8 months), with biomarker-selected populations experiencing up to a 91.2% reduction in death risk. The Johns Hopkins Phase I trial established intravenous administration safety at 600 mg three times weekly. Advanced analytical approaches including metabolomics, chronobiology, and machine learning are enabling precision medicine applications. These findings position mistletoe as a scientifically validated component of integrative oncology, bridging traditional medicine with evidence-based cancer care. Future research should focus on ferroptosis mechanisms, single-cell immune profiling, and standardized clinical protocols. Full article

Kupffer cells (KCs) play a pivotal role in the progression of metabolic-associated steatohepatitis (MASH). This study evaluated the impact of short-term KC depletion induced by gadolinium chloride (GdCl₃) in a rat model of MASH. The intervention with GdCl₃ effectively reduced KC markers CD68 and Clec4f, together with pro-inflammatory cytokines (IL-1β, TNFα, NOS2), without affecting anti-inflammatory markers (IL-10, MRC1). Histologically, GdCl₃ reduced hepatocyte ballooning and NAS despite persistent steatosis. KC depletion was associated with decreased oxidative stress markers (TBARS, 3-nitrotyrosine) and antioxidant enzyme activity (SOD, catalase). Additionally, markers of endoplasmic reticulum stress (ATF4, GRP78, CHOP, P58^IPK) and apoptosis (BAX/BCL2 ratio, cleaved caspase-3) were diminished. Despite these improvements, GdCl₃ had no effect on lipid or glucose metabolism in the liver, associated with persistent elevation of PTP1B expression induced by SRD intake. KC depletion, however, increased FGF21 expression. GdCl₃ treatment improved systemic insulin sensitivity and reduced fasting glucose and NEFA serum levels. In white adipose tissue, the treatment decreased adipocyte size, restored insulin signaling, and inhibited lipolysis (ATGL expression) without altering macrophage infiltration (IBA) or thermogenic protein levels (UCP1) in SRD rats. These findings suggest that KC depletion modulates liver-to-adipose tissue crosstalk, potentially through FGF21 signaling, contributing to improved systemic metabolic homeostasis of SRD animals. Full article

Objectives: This study aimed to establish a transgenic mouse model expressing nucleus-localized human α-synuclein (α-syn) to investigate its impact on the central nervous system and behavior and the underlying mechanisms involved. Methods: A nuclear localization sequence (NLS) was added to the end of the human SNCA (hSNCA) gene. Subsequently, an empty vector and a mammalian lentiviral vector of the hSNCA-NLS were constructed. Transgenic mice were generated via microinjection, with genotyping and protein expression confirmed by PCR and western blotting. Only male mice were used in subsequent behavioral and molecular experiments. Immunofluorescence identified the colocalization of human α-syn with the cell nucleus in mouse brain tissues. Behavioral changes in transgenic mice were assessed using open field, rotarod, and O-maze tests. qPCR and Western blotting detected expression levels of genes and proteins related to inflammation, endoplasmic reticulum stress (ERS), and apoptosis. Bulk RNA sequencing was used to screen for differentially expressed genes and signaling pathways. Results: We successfully constructed a transgenic mouse model expressing human α-syn. Human α-syn was widely expressed in the heart, liver, spleen, kidneys, and brain of the mice, with distinct nuclear localization observed. Behavioral assessments demonstrated that, by 2 months of age, the mice exhibited motor dysfunction alongside astrocyte proliferation and neuroinflammation. At 6 months, the elevated expression of ERS-related genes (ATF6, PERK, and IRE1) and activation of the PERK-Beclin1-LC3II pathway indicated progressive ERS. By 9 months, apoptotic events had occurred, accompanied by significant anxiety-like behaviors. Bulk RNA sequencing further identified key differentially expressed genes, including IL-1α, TNF, PERK, BECLIN, GABA, IL-6α, P53, LC3II, NOS, and SPAG, suggesting their involvement in the observed pathological and behavioral phenotypes. Conclusions: The nuclear localization human α-syn transgenic mice were successfully established. These findings demonstrate that nucleus-localized α-syn induces early motor deficits, which are likely mediated by neuroinflammation, whereas later anxiety-like behaviors may result from ERS-induced apoptosis. This model provides a valuable tool for elucidating the role of nuclear α-syn in Parkinson’s disease and supports further mechanistic and therapeutic research. Full article

Classical swine fever (CSF) is a highly contagious and lethal disease caused by classical swine fever virus (CSFV), and it is also a notifiable disease according to the World Organization for Animal Health. Owing to the continuous growth of the international trade in pigs and pig products, pig farming has become the pillar industry of the global livestock industry and is the most important source of animal protein for mankind. As a single-stranded RNA virus, CSFV can avoid being recognized and cleared by the host immune system through a variety of immune evasion strategies so that it persists in the host body and causes multisystemic pathology. CSF has also become one of the most serious infectious diseases affecting the pig industry, resulting in considerable economic losses to the pig industry. Therefore, understanding the main immune evasion mechanism of CSFV is very important for the prevention and control of CSF infection. This article reviews the main immune evasion mechanisms of CSFV, including the suppression of nonspecific immune responses; evasion of adaptive immune responses; and the regulation of host cell apoptosis and cell autophagy. CSFV affects type I interferon regulatory signals; the JAK-STAT signaling pathway; the RIG-I and NF-κB signaling pathways; immune cell function; the mitochondrial apoptosis pathway; and the endoplasmic reticulum stress apoptosis pathway; the PI3K-Akt signaling mediated AMPK-mTOR macroautophagy pathway through its structural proteins E^rns and E1 and E2; and the nonstructural proteins N^pro, NS4B, and NS5A to achieve immune evasion. As our understanding of CSFV immune strategies continues to deepen, we believe that this understanding will provide new strategies for the development of new vaccines and novel diagnostic methods in the future. Full article

Macrobrachium nipponense represents a commercial decapod species that predominantly inhabits freshwater ecosystems or environments with low salinity. However, the species exhibits normal survival and reproductive capacity in natural aquatic habitats with salinity levels up to 10 parts per thousand (ppt). The present study aimed to elucidate the molecular mechanisms underlying salinity acclimation in M. nipponense by investigating alterations in oxidative stress, morphological adaptations, and hepatopancreatic gene expression profiles following exposure to a salinity level of 10 ppt. The present study demonstrates that glutathione peroxidase and Na⁺/K⁺-ATPase play critical roles in mitigating oxidative stress induced by elevated salinity in M. nipponense. Furthermore, histological analysis revealed distinct pathological alterations in the hepatopancreas of M. nipponense following 7-day salinity exposure, including basement-membrane disruption, luminal expansion, vacuolization, and a marked reduction in storage cells. Transcriptomic profiling of M. nipponense hepatopancreas suggested coordinated activation of both immune (lysosome and protein processing in endoplasmic reticulum pathways) and energy (pyruvate metabolism, glycolysis/gluconeogenesis, and citrate cycle) metabolic processes during salinity acclimation in M. nipponense. Quantitative real-time PCR validation confirmed the reliability of RNA-seq data. This study provides molecular insights into the salinity adaptation mechanisms in M. nipponense, offering potential applications for improving cultivation practices in brackish water environments. Full article

The retina is highly sensitive to oxygen and blood supply, and hypoxia plays a key role in retinal diseases such as diabetic retinopathy (DR) and age-related macular degeneration (AMD). Müller glial cells, which are essential for retinal homeostasis, respond to injury and hypoxia with reactive gliosis, characterized by the upregulation of the glial fibrillary acidic protein (GFAP) and vimentin, cellular hypertrophy, and extracellular matrix changes, which can impair retinal function and repair. The retinal pigment epithelium (RPE) supports photoreceptors, forms part of the blood–retinal barrier, and protects against oxidative stress; its dysfunction contributes to retinal degenerative diseases such as AMD, retinitis pigmentosa (RP), and Stargardt disease (SD). Extracellular vesicles (EVs) play a crucial role in intercellular communication, protein homeostasis, and immune modulation, and have emerged as promising diagnostic and therapeutic tools. Understanding the role of extracellular vesicles’ (EVs’) signaling machinery of glial cells and the retinal pigment epithelium (RPE) is critical for developing effective treatments for retinal degeneration. In this study, we investigated the bidirectional EV-mediated crosstalk between RPE and Müller cells under hypoxic conditions and its impact on cellular metabolism and retinal cell integrity. Our findings demonstrate that RPE-derived extracellular vesicles (RPE EVs) induce time-dependent metabolic reprogramming in Müller cells. Short-term exposure (24 h) promotes pathways supporting neurotransmitter cycling, calcium and mineral absorption, and glutamate metabolism, while prolonged exposure (72 h) shifts Müller cell metabolism toward enhanced mitochondrial function and ATP production. Conversely, Müller cell-derived EVs under hypoxia influenced RPE metabolic pathways, enhancing fatty acid metabolism, intracellular vesicular trafficking, and the biosynthesis of mitochondrial co-factors such as ubiquinone. Proteomic analysis revealed significant modulation of key regulatory proteins. In Müller cells, hypoxic RPE-EV exposure led to reduced expression of Dyskerin Pseudouridine Synthase 1 (DKc1), Eukaryotic Translation Termination Factor 1 (ETF1), and Protein Ser/Thr phosphatases (PPP2R1B), suggesting alterations in RNA processing, translational fidelity, and signaling. RPE cells exposed to hypoxic Müller cell EVs exhibited elevated Ribosome-binding protein 1 (RRBP1), RAC1/2, and Guanine Nucleotide-Binding Protein G(i) Subunit Alpha-1 (GNAI1), supporting enhanced endoplasmic reticulum (ER) function and cytoskeletal remodeling. Functional assays also revealed the compromised barrier integrity of the outer blood–retinal barrier (oBRB) under hypoxic co-culture conditions. These results underscore the adaptive but time-sensitive nature of retinal cell communication via EVs in response to hypoxia. Targeting this crosstalk may offer novel therapeutic strategies to preserve retinal structure and function in ischemic retinopathies. Full article

Cardiopulmonary bypass (CPB) is associated with significant neurological complications, yet the mechanisms underlying brain injury remain unclear. This study investigated the role of interleukin-17A (IL-17A) in exacerbating CPB-induced neuronal apoptosis and identified vulnerable brain regions. Utilizing a rat CPB model and an oxygen–glucose deprivation/reoxygenation (OGD/R) cellular model, we demonstrated that IL-17A levels were markedly elevated in the hippocampus post-CPB, correlating with endoplasmic reticulum stress (ERS)-mediated apoptosis. Transcriptomic analysis revealed the enrichment of IL-17 signaling and apoptosis-related pathways. IL-17A-Neutralizing monoclonal antibody (mAb) and the ERS inhibitor 4-phenylbutyric acid (4-PBA) significantly attenuated neurological deficits and hippocampal neuronal damage. Mechanistically, IL-17A activated the Act1-IRE1-JNK1 axis, wherein heat shock protein 90 (Hsp90) competitively regulated Act1-IRE1 interactions. Co-immunoprecipitation confirmed the enhanced Hsp90-Act1 binding post-CPB, promoting IRE1 phosphorylation and downstream caspase-12 activation. In vitro, IL-17A exacerbated OGD/R-induced apoptosis via IRE1-JNK1 signaling, reversible by IRE1 inhibition. These findings identify the hippocampus as a key vulnerable region and delineate a novel IL-17A/Act1-IRE1-JNK1 pathway driving ERS-dependent apoptosis. Targeting IL-17A or Hsp90-mediated chaperone switching represents a promising therapeutic strategy for CPB-associated neuroprotection. This study provides critical insights into the molecular crosstalk between systemic inflammation and neuronal stress responses during cardiac surgery. Full article

Heat stress in dairy cows, caused by high temperature and humidity during summer, has led to significant declines in milk production and severe economic losses for farms. Exosomes—extracellular vesicles carrying bioactive molecules—are critical for intercellular communication and immunity but remain understudied in heat-stressed Holstein cows. In this study, we extracted exosomes from three heat-stressed (HS) cows and three non-heat-stressed (Ctr) cows and employed proteomics to analyze plasma exosomes. We identified a total of 28 upregulated and 18 downregulated proteins in the HS group compared to the control group. Notably, we observed a significant upregulation of key protein groups, including cytoskeletal regulators, signaling mediators, and coagulation factors, alongside the downregulation of HP-25_1. These differentially expressed proteins demonstrate strong potential as heat stress biomarkers. GO and KEGG analyses linked the differentially expressed proteins to actin cytoskeleton regulation and endoplasmic reticulum pathways. Additionally, protein–protein interaction (PPI) analysis revealed the PI3K-Akt signaling pathway as a central node in the cellular response to heat stress. These findings establish plasma exosomes as valuable biospecimens, provide valuable insights into the molecular mechanisms of heat stress response, and may contribute to the development of precision breeding strategies for enhanced thermal resilience in dairy herds. Full article

Background/Objectives: The aim of this research is to analyze the effect of paclitaxel on endoplasmic reticulum (ER) stress in spermatogenic cells. Methods: In the study, spermatogonium (GC1) and spermatocyte (GC2) cell lines were used. The IC50 dose of paclitaxel was calculated using an MTT assay. Each cell line was separated into two different groups: control (GC1-C, GC2-C) and paclitaxel-treated (GC1-P, GC2-P). The control cells were incubated under standard culture conditions. The paclitaxel group cells were incubated in culture medium containing the paclitaxel IC50 dose for 24 h. After the experiments, all groups were stained with GRP78, p-PERK, and p-eIF2α antibodies using semi-quantitative immunocytochemistry. Results: Paclitaxel showed cytotoxicity. In the experimental model of the paclitaxel-treated cells, all the markers showed elevated levels of immunoreactivity, indicating ER stress. Conclusions: Paclitaxel administration triggered ER stress in spermatogenic cells. Studies of ER-related stress mechanisms in spermatogenic cells with further advanced molecular analyses will be important for therapeutic strategies. Full article

Bisphenol A (BPA), a prevalent endocrine-disrupting chemical, is widely found in various consumer products and poses significant health risks, particularly through hormone receptor interactions, oxidative stress, and mitochondrial dysfunction. BPA exposure is associated with reproductive, metabolic, and neurodevelopmental disorders. Melatonin, a neurohormone with strong antioxidant and anti-inflammatory properties, has emerged as a potential therapeutic agent to counteract the toxic effects of BPA. This review consolidates recent findings from in vitro and animal/preclinical studies, highlighting melatonin’s protective mechanisms against BPA-induced toxicity. These include its capacity to reduce oxidative stress, restore mitochondrial function, modulate inflammatory responses, and protect against DNA damage. In animal models, melatonin also mitigates reproductive toxicity, enhances fertility parameters, and reduces histopathological damage. Melatonin’s ability to regulate endoplasmic reticulum (ER) stress and cell death pathways underscores its multifaceted protective role. Despite promising preclinical results, human clinical trials are needed to validate these findings and establish optimal dosages, treatment durations, and safety profiles. This review discusses the wide range of potential uses of melatonin for treating BPA toxicity and suggests directions for future research. Full article