Search Results (599)

Sepsis remains a leading cause of global mortality and is characterized by a dysregulated host immune response to infection. Early deaths often result from hyperinflammation and organ dysfunction, whereas late-stage mortality is increasingly attributed to sepsis-induced immunosuppression, leading to secondary infections and viral reactivation. Challenges persist in the identification and management of sepsis-induced immunosuppression, including the lack of standardized immune monitoring methods, the absence of reliable immune biomarkers to guide therapy, and the limited success of immunomodulatory therapies in clinical trials. This review comprehensively summarizes the pathophysiology of sepsis-induced immunosuppression, encompassing immune cell apoptosis and exhaustion, the expansion and activation of immunomodulatory cells, metabolic reprogramming, epigenetic alterations, and iatrogenic factors. We also discuss current diagnostic challenges and explore emerging immunomodulatory strategies, such as cytokine therapies, immune checkpoint inhibitors, and metabolic modulators, as potential approaches to restore immune function. Finally, we highlight the importance of immune phenotyping and individualized precision medicine in the future management of sepsis, and integrating multidisciplinary approaches from mechanistic research to targeted therapies holds promise for improving patient outcomes. Full article

Chronic stress and sustained hypothalamic–pituitary–adrenal (HPA) axis activation are major contributors to metabolic bone diseases, including osteoporosis. However, the precise molecular mechanisms by which chronic stress-induced HPA axis dysregulation drives bone deterioration remain unclear. A Chronic Unpredictable Mild Stress (CUMS) model was established in male rats to simulate prolonged stress exposure. Animals were randomly allocated into three groups: control, 10-week CUMS, and 20-week CUMS (n = 10/group). Model validity was confirmed via behavioral assessments. Bone mineral density (BMD) and trabecular microarchitecture were quantified using micro-computed tomography (micro-CT). Serum corticosterone (CORT) levels, HPA axis negative feedback function, and the expression of pro-inflammatory cytokines (IL-1β, TNF-α) in HPA-regulatory brain regions (hippocampus, prefrontal cortex, hypothalamus) were assessed. Critically, glucocorticoid receptor (GR) expression and nuclear translocation in these brain regions and bone tissue were examined by immunofluorescence and Western blot analysis. CUMS exposure induced progressive, time-dependent bone loss, with the 20-week group exhibiting significantly greater reductions in BMD and trabecular quality compared to the 10-week and control groups. While the HPA axis showed initial hyperactivation, the 20-week group displayed adrenal exhaustion (reduced serum CORT) alongside elevated ACTH, indicating feedback failure. Mechanistically, stress significantly impaired GR nuclear translocation in both brain and bone tissues, coinciding with the upregulation of FKBP5 and pro-inflammatory cytokines. Notably, despite low systemic CORT at late stages, skeletal 11β-HSD1 expression was significantly upregulated, creating a local microenvironment of glucocorticoid toxicity that aggravated osteoblast apoptosis. Our findings demonstrate that chronic stress induces progressive, time-dependent bone loss through a cascade of HPA axis dysregulation and impaired GR signaling. The FKBP5-mediated impairment of GR nuclear translocation in both central and peripheral tissues fosters glucocorticoid resistance, perpetuating hypercortisolemia and a pro-inflammatory milieu that directly accelerates osteoblast apoptosis and bone deterioration. These findings identify the HPA-GR axis as a critical pathway linking chronic stress to osteoporosis and suggest that restoring GR signaling offers a potential therapeutic strategy. Full article

The article presents the current state of knowledge on genetic modifiers of ovarian cancer risk in women carrying pathogenic variants (PVs) in the BRCA1 and BRCA2 genes, which are major contributors to hereditary susceptibility to this malignancy. Although PV carriers have high disease penetrance (BRCA1: ~40% and BRCA2: 11–27%), substantial variability in individual risk is observed, suggesting the influence of additional genetic variants. Background: Ovarian cancer is characterized by late detection and high mortality, and a significant portion of risk among BRCA1/2 carriers is shaped by reproductive and environmental factors as well as genetic modifiers. The article emphasizes that carriers of the same BRCA PV can exhibit markedly different risk levels depending on additional variants that modulate key biological processes, such as DNA repair, cell cycle regulation, and apoptosis. Methods: A systematic literature search covering the years 1996–2025 was conducted in the PubMed database. Initially, 734 publications were identified; after removing duplicates, thematically irrelevant articles, non-full-text papers, and studies not meeting the inclusion criteria, 47 articles were included in the review. These studies covered candidate gene analyses, GWAS, and data from the CIMBA consortium, which enables the examination of large cohorts of PV carriers. Results: The review identified numerous variants associated with increased or decreased ovarian cancer risk in BRCA1 carriers, including the following: OGG1, DR4, MDM2, CYP2A7, CASP8, ITGB3, HRAS1, TRIM61, and MTHFR. The reviewed studies also identified both protective and risk-increasing variants among BRCA2 PV carriers: UNG, TDG, and PARP2, and haplotypes in ATM, BRIP1, BARD1, MRE11, RAD51, and 9p22.2. The analysis identified 11 variants affecting both BRCA1 and BRCA2 carriers, most of which increase risk, including the following: IRS1, RSPO1, SYNPO2, BABAM1, MRPL34, PLEKHM1, and TIPARP. Protective variants include BNC2 and LINC00824. The only SNP reaching genome-wide significance (p < 5 × 10⁻⁸) was in BNC2. Conclusions: The article summarizes the growing number of genetic modifiers of ovarian cancer risk among BRCA1/2 carriers and highlights their potential to improve individualized risk assessment, enhance patient stratification, support personalized prevention and surveillance strategies, deepen the understanding of disease biology, and identify potential therapeutic targets. Full article

Embryonic diapause, a state of developmental arrest in silkworm (Bombyx mori) eggs, poses a challenge for year-round sericulture. While physical stimuli like corona discharge can effectively terminate diapause, the underlying molecular mechanisms, particularly the initial events, remain poorly understood. This study employed an integrated transcriptomic and proteomic approach to analyze silkworm eggs within 48 h after corona treatment. Our time-series analysis revealed that the Hippo and Wnt signaling pathways were specifically activated as early as 1 h post-treatment, preceding the previously reported FoxO pathway response. We identified two temporally distinct gene clusters within the Hippo pathway, including immediate–early genes (e.g., Dachs_17/25/29, Ft_10) and late-phase effector genes, coordinating the exit from cell cycle arrest. Concurrently, the Wnt pathway was rapidly initiated, marked by the sustained upregulation of key regulators Notum and Pontin52, suggesting its role in unlocking the cell cycle. We propose a synergistic model wherein corona discharge triggers the concurrent, early activation of Hippo and Wnt signaling, which collectively reprogram the cell cycle and reinstate the developmental trajectory by promoting proliferation and suppressing apoptosis. These findings provide crucial insights into the initial molecular events of diapause termination, identifying Hippo and Wnt pathways as master regulators in transducing the physical corona stimulus into a developmental signal. Full article

Chinese rice-field eel rhabdovirus (CrERV) is a serious epidemic pathogen of Chinese rice-field eel and causes severe economic losses to aquaculture. However, there are no commercial drugs presently available to control CrERV infection. Eugenol is a bioactive compound extracted from clove plants and exhibits potential antiviral activity. In the study, the antiviral activity of eugenol against CrERV was investigated in Chinese rice-field eel (Monopterus albus). Eugenol reached the highest inhibition rate of 96.6% at 40 mg/L in Chinese rice-field eel kidney cells (CrEK). Notably, eugenol exhibits antiviral activity by directly targeting CrERV and additionally confers prophylactic effects against infection via its action on CrEK cells. The results of exploring the viral invasion cycle demonstrated that eugenol primarily exerted its antiviral effect during the middle stage and late stage (12 h and 24 h) of viral infection. In addition, eugenol inhibited CrERV-induced apoptosis of CrEK cells, maintained mitochondrial membrane potential levels, maintained physiological cellular morphology and structure, and protected cells from loss of cellular morphology, formation of apoptotic vesicles, and cell fragmentation. For the in vivo study, eugenol increased the survival rate of CrERV-infected rice-field eel by 56% and 48%, in prevention experiments and treatment experiments, respectively. Concurrently, eugenol significantly reduced viral loads and induced the upregulation of anti-inflammatory and antioxidant genes, indicating its potential for immunoregulation. In summary, eugenol holds potential for both preventing and treating CrERV infections in the aquaculture context. Full article

Ovarian cancer remains a top mortality contributor within gynecological cancers because patients receive diagnoses late in the disease course and conventional treatment resistance along with high recurrence rates cause poor outcomes. Aberrant regulation of autophagy and apoptosis has a critical role in the development, progression, chemoresistance, and immune escape from ovarian cancer. Recent evidence has demonstrated a complicated and dynamic crosstalk between autophagy and apoptosis, during which autophagy can act as a cytoprotective or cell death-promoting process depending on tumor stage and therapeutic context. In parallel, apoptosis functions as a tightly regulated form of programmed cell death that is essential for eliminating damaged or malignant cells and serves as a major tumor-suppressive mechanism in ovarian cancer. The PI3K/AKT/mTOR signaling pathway is the most active and clinically relevant pathway in the management of ovarian cancer as a master regulator of both autophagy and apoptosis, suppressing apoptotic cell death while promoting cytoprotective autophagy under chemotherapeutic stress. Bioactive natural products derived from plants, marine sources, and dietary intake have emerged as potential modulators of the autophagy-apoptosis crosstalk. Curcumin, resveratrol, quercetin, berberine, and epigallocatechin gallate are known to have the ability to restore apoptotic signaling, block pro-survival autophagy, and sensitize ovarian cancer cells to chemotherapy through the regulation of key pathways including PI3K/AKT/mTOR, AMPK, MAPK, p53, and Bcl-2 family proteins. In this review, we provide an updated understanding of the molecular mechanisms through which bioactive natural products modulate autophagy–apoptosis crosstalk in ovarian cancer. We also highlight the translational challenges, therapeutic potential, and future directions for the integration of natural product-based strategies in precision medicine for ovarian cancer. Full article

Declining Leydig cell steroidogenesis contributes to late-onset hypogonadism and to age-associated impairment of male reproductive health. Determinants of dysfunction extend beyond chronological aging. This review synthesizes recent experimental and translational evidence on cellular and molecular processes that compromise Leydig cell endocrine output and the interstitial niche that supports spermatogenesis. Evidence spanning environmental endocrine-disrupting chemicals (EDCs), obesity and metabolic dysfunction, and testicular aging is integrated with emphasis on oxidative stress, endoplasmic reticulum stress, mitochondrial dysregulation, apoptosis, disrupted autophagy and mitophagy, and senescence-associated remodeling. Across model systems, toxicant exposure and metabolic stress converge on impaired organelle quality control and altered redox signaling, with downstream loss of steroidogenic capacity and, in some settings, premature senescence within the Leydig compartment. Aging further reshapes the testicular microenvironment through inflammatory shifts and biomechanical remodeling and may erode stem and progenitor Leydig cell homeostasis, thereby constraining regenerative potential. Single-cell transcriptomic atlases advance the field by resolving Leydig cell heterogeneity, nominating subsets that appear more vulnerable to stress and aging, and mapping age-dependent rewiring of interstitial cell-to-cell communication with Sertoli cells, peritubular myoid cells, vascular cells, and immune cells. Many mechanistic insights derive from rodent in vivo studies and in vitro platforms that include immortalized Leydig cell lines, and validation in human tissue and human clinical cohorts remains uneven. Together, these findings frame mechanistically informed opportunities to preserve endogenous androgen production and fertility through exposure mitigation, metabolic optimization, fertility-preserving endocrine stimulation, and strategies that target inflammation, senescence, and regenerative capacity. Full article

Tibetan sheep, a dominant livestock species on the Qinghai–Tibet Plateau, is characterized by late sexual maturity and low reproductive efficiency. Although long non-coding RNAs (lncRNAs) are known to play critical regulatory roles in mammalian testicular development and spermatogenesis, their expression dynamics and functions in Tibetan sheep remain poorly understood. In this study, we integrated histological and transcriptomic analyses to profile testicular lncRNAs across three developmental stages: pre-pubertal (3 months), sexually mature (1 year), and adult (3 years). Histological examination showed progressive structural maturation of seminiferous tubules, accompanied by significant increases in testicular weight and serum testosterone levels. RNA sequencing identified 10,857 high-confidence lncRNAs and uncovered extensive reprogramming of the lncRNA transcriptome during sexual maturation, with 7784 lncRNAs differentially expressed between pre-pubertal and post-pubertal stages. Functional enrichment analyses of cis- and antisense-target genes indicated that these lncRNAs were involved in key biological processes, including cell cycle regulation, TGF-β and Hippo signaling pathways, extracellular matrix organization, glycolysis, and apoptosis. Co-expression network analysis further linked upregulated lncRNAs to spermatogenesis-related genes involved in processes such as sperm nuclear condensation (e.g., TNP1) and metabolic support (e.g., PFKP). Our findings demonstrated that lncRNAs coordinate testicular development and spermatogenesis in Tibetan sheep by modulating transcriptional networks, remodeling the cellular microenvironment, and reprogramming energy metabolism. This study provides the first comprehensive atlas of testicular lncRNAs in Tibetan sheep and offers novel insights into the epigenetic regulation of male reproduction in high-altitude mammals. Full article

Chagas disease remains a major public health challenge due to the limited effectiveness and considerable side effects of existing treatments, particularly during the chronic stage. Açaí (Euterpe oleracea) seeds have gained increasing attention as a source of bioactive compounds with potential therapeutic applications. In this study, hydroalcoholic extracts and solvent fractions obtained from açaí seeds were chemically characterized by ESI/MS and HPLC–MS/MS and evaluated for their cytotoxicity and antiparasitic activity against different developmental stages of Trypanosoma cruzi (Y strain). Chemical profiling revealed a predominance of phenolic compounds, particularly catechins and procyanidins, which were identified as major constituents of the hydroalcoholic extract and the ethyl acetate fraction. Cytotoxicity assays performed on murine peritoneal macrophages demonstrated low toxicity, with CC₅₀ values exceeding 500 µg/mL for most samples, indicating a favorable in vitro safety profile. Antiparasitic assays showed weak activity against epimastigote forms; however, significant inhibitory effects were observed against bloodstream trypomastigotes, cell culture-derived trypomastigotes, and intracellular amastigotes. Notably, the hydroalcoholic extract exhibited the highest selectivity against intracellular amastigotes, with a selectivity index greater than 10, fulfilling key criteria proposed by the Drugs for Neglected Diseases initiative (DNDi) for early-stage hit compounds. Flow cytometry analysis showed that both the hydroalcoholic extract and the ethyl acetate fraction induced parasite cell death through late apoptosis-like and necrosis. Together, these findings highlight the antiparasitic potential of E. oleracea seed extracts, particularly against clinically relevant stages of T. cruzi, and support further investigation of these bioproducts as promising candidates for the development of new therapeutic strategies for Chagas disease. Full article

Background/Objectives: Colon cancer is the third most common type of cancer in the world, characterized by a high risk of metastasis, resistance to various drugs, and late diagnosis. In addition, the drugs used for treatment are associated with serious neurological damage, causing acute and chronic pain and compromising the patient’s quality of life. Meanwhile, lectins are proteins capable of exerting cytotoxic action on cells from various tumors in a selective manner, without exerting significant toxicity on healthy cells. Despite this, studies on the potential of lectins obtained from microalgae are still scarce in the literature. In this sense, the objective of this study was to evaluate the antitumor activity of lectin isolated from the microalgae Chlorella vulgaris (CvL) on colorectal cancer cells, HT-29. Methods: The purified lectin was tested for cytotoxicity using MTT colorimetric methods, in addition to clonogenicity, cell cycle, apoptosis, and necrosis tests, analyzed by flow cytometry. Results: The assays demonstrated that the lectin was able to induce cell death in the HT-29 tumor line by approximately 83.75% with an IC₅₀ value of 21.5 µg/mL⁻¹, reduced colony formation by more than 90%, was able to regulate the cell cycle by apoptosis, and did not present significant necrosis. These results show that microalgae lectins have the potential to be exploited in the control of neoplastic cells. Full article

Background: The intensification of aquaculture has led to increased use of chemical agents, such as trichlorfon, for controlling parasitic infections in farmed fish. While effective, this organophosphate compound may exert toxic effects even at sublethal concentrations, posing risks to economically important species such as tambaqui (C. macropomum). This study investigated the molecular effects of trichlorfon on the expression of genes involved in stress response, energy metabolism, and apoptosis in juvenile tambaqui. Methods: Fish were exposed to two sublethal concentrations of trichlorfon (30% and 50% LC_{50–96 h}, equivalent to 0.261 and 0.435 mg/L) for 48, 72, and 96 h. Expression levels of fkbp5, p53, pim-2, pir, me1, bbox1, and higd1a were quantified in liver tissue using qPCR. Results: fkbp5 and p53 were strongly upregulated at 48 h, indicating acute stress and genotoxic activation. me1 and pim-2 were also upregulated, reflecting activation of compensatory energy metabolism and anti-apoptotic survival pathways. bbox1 showed an early induction followed by collapse at 96 h, while higd1a and pir exhibited delayed overexpression at 96 h, suggesting mitochondrial hypoxia and inflammation. Conclusions: Trichlorfon triggers a multifaceted toxic response characterized by initial activation of compensatory pathways (stress response, antioxidant defense, and anti-apoptotic mechanisms) followed by late-phase metabolic collapse, mitochondrial hypoxia, and inflammation, with both time- and dose-dependent effects. These findings demonstrate that even sublethal concentrations disrupt hepatic homeostasis and support the use of these genes as molecular biomarkers for environmental monitoring in aquaculture. Full article

This study explores the effects of exogenous SELENOV on cellular migration, viability, mitochondrial function, ROS production, and Ca²⁺ signaling in mouse fibroblast L-929 and testicular teratoma F-9 cells. In scratch assays, 50–100 µg/mL SELENOV significantly inhibited F-9 cell migration after 48 h, while in L-929 fibroblasts, only 100 µg/mL had a suppressive effect. Viability assays revealed strong cytotoxicity in F-9 cells. Critically, at a dose of 50 µg/mL (where the corresponding volume of solvent buffer alone was non-toxic), SELENOV reduced survival to 19%, triggering late apoptosis in 76% of cells, whereas in L-929 cells, comparable effects required 100 µg/mL. Mitochondrial depolarization (JC-1/Rhodamine-123 assays) was pronounced in F-9 cells even at 50 µg/mL, while L-929 cells responded only to 100 µg/mL. Similarly, 50 µg/mL SELENOV induced significant ROS overproduction in F-9 but not in L-929 cells, correlating with upregulated NOX1, NOX4, GPX3, and GPX4 expression. Ca²⁺ imaging showed dose-dependent [Ca²⁺]ᵢ elevation, with 50 µg/mL SELENOV inducing a sustained rise in F-9 cells, whereas L-929 cells required higher doses. Strikingly, 50 µg/mL SELENOV in F-9 cells downregulated BCL-2 and BCL-xL while upregulating pro-apoptotic BAX and PUMA, suggesting selective activation of intrinsic apoptosis. These results demonstrate that F-9 cancer cells are significantly more sensitive to SELENOV than normal fibroblasts, with 50 µg/mL sufficient to trigger mitochondrial dysfunction, oxidative stress, and apoptosis. The findings highlight SELENOV’s potential as a targeted anticancer agent, particularly for germ cell tumors. Full article

The primary reason of dental restoration failure is the recurrence of caries, driving research to incorporate quaternary ammonium salts (QASs) into resin-based composites (RBCs). Given the prolonged contact of these materials with oral tissue, this in vitro study assessed the biocompatibility (cytotoxicity and genotoxicity) profiles of experimental RBCs modified with cetyltrimethylammonium bromide (CTAB) and dimethyldioctadecylammonium bromide (DODAB), using two restorative materials: an unmodified–experimental composite, KE, and Flow-Art (FA) as comparative standards. The primarily novelty of this study is the direct comparison of the cellular safety profiles of CTAB vs. DODAB when incorporated into RBCs. Human fibroblast BJ cells were exposed to composite eluates for 24 h, and cell viability (MTT assay), the percentage of apoptotic and necrotic cells (the Annexin V/Propidium Iodide (PI) flow cytometry method), and DNA damage (the alkaline comet assay) were quantified. Among the compounds evaluated, only CTAB caused a significant, dose-dependent decrease in BJ cell viability, primarily by inducing late apoptosis or necrosis. Cell viability was severely reduced, dropping by 84% at 2 wt% CTAB (p < 0.001) compared to control. Consistent with this effect, CTAB also induced a dose-dependent increase in DNA damage. In contrast, the DODAB-modified composites, along with the KE and FA controls, exhibited non-cytotoxic and non-genotoxic profiles across all tested concentrations. This innovative comparative assessment highlights that DODAB exhibits superior cellular safety, offering vital guidance to prioritize its use for developing safe and effective next-generation antibacterial dental composites. Conversely, CTAB is precluded for clinical use at these concentrations due to its observed toxicity. Full article

Ganoderma lucidum has long been recognized for its medicinal properties, particularly due to its antioxidant, anti-inflammatory, and pro-apoptotic components such as polysaccharides and triterpenoids. This study aimed to evaluate the cytotoxic and molecular effects of ethanol and methanol extracts of G. lucidum as well as doxorubicin on MCF-7 breast cancer cells. The cytotoxicity was assessed via MTT assay. The methanol extract showed stronger cytotoxicity (IC₅₀: 62.37 µg/mL) than the ethanol extract, while doxorubicin exhibited an IC₅₀ value of 0.66 mM. Phenolic profiling by HPLC revealed high levels of vanillic acid, gallic acid and (−)-epicatechin in the methanol extract, while volatile compounds such as hexanal and acetic acid were identified by GC-MS. Flow cytometric analysis demonstrated G0/G1 phase cell cycle arrest and an increase in early and late apoptotic populations. Gene expression studies using RT-qPCR showed significant downregulation of ACAT1, ADCY3, and NME2, key regulators of energy metabolism and epigenetic modification. On the other hand, doxorubicin treatment upregulated ACAT1 and ADCY3, while a slight downregulation was observed in NME2. These molecular changes suggest that G. lucidum induces apoptosis and impairs cancer cell proliferation through metabolic disruption and gene modulation. Full article

Coccidiosis is one of the most serious parasitic diseases in poultry, with Eimeria-induced apoptosis of IECs recognized as a key pathogenic mechanism. This review systematically delineates the molecular mechanisms governing this apoptotic process. The invasion process of Eimeria app. is mediated by the AMA1-RON2 moving junction complex and secreted effector proteins. An integrated model of apoptotic regulation is proposed. This model comprises the mitochondrial, death receptor, and endoplasmic reticulum stress pathways, which are coordinated by signaling hubs, such as PI3K/Akt, NF-κB, and JNK/p38 MAPK, and is further finely modulated by non-coding RNA networks. It is notable that the apoptosis during coccidial infection exhibits a biphasic pattern, where early inhibition supports parasite development and late activation facilitates parasite release and dissemination. Although potential therapeutic targets have emerged for these signaling pathways, how the host precisely switches between different apoptotic pathways remains a current core knowledge gap. Future research needs to thoroughly analyze the molecular logic of host–parasite interaction and ultimately lay a theoretical foundation for developing new strategies targeting the process of cell apoptosis for coccidiosis prevention and control. Full article