Search Results (3,356)

Dill, Anethum graveolens L., is a culinary plant used in traditional medicine to treat gastrointestinal conditions; its seeds have been previously reported to exhibit antimicrobial, anti-inflammatory, hypolipidemic, anticancer and antioxidant activities. This study aimed to assess dill seed extracts and essential oil in terms of chemical composition and cytotoxic effects, combined with an exploration of the potential underlying mechanisms. Four hydroethanolic seed extracts were prepared using Soxhlet extraction or maceration and the essential oil (AGEO) was prepared by steam distillation. Extracts were physicochemically analysed via LC-MS and spectrophotometry while the AGEO composition was determined through GC-MS. Their cytotoxic effects were assessed in A375, PANC-1 and SK-OV-3 cancer cells, while HaCaT keratinocytes were used as non-cancerous control. The mechanistic investigations included immunofluorescence assay, high-resolution respirometry, network pharmacology and molecular docking. Ferulic acid and fisetin were identified as major components of the hydroethanolic extracts, while D-limonene and carvotanacetone were the main compounds in the AGEO. All tested products were revealed to induce dose-dependent cytotoxicity (with IC₅₀ values ranging between 619.8 and 810.2 μg/mL), diminished OXPHOS efficiency and a mitochondrial uncoupling effect. Morphological changes consistent with apoptosis were recorded, particularly in PANC-1 and A375 cells. Network pharmacology suggested a multitarget mechanism for EO that involved STAT3 and HSP90AA1, while the molecular docking calculations indicated that D-limonene and carvotanacetone could be accommodated within the ATP-binding pocket of Hsp90α. Full article

Global climate change increases concurrent waterlogging and heat waves, threatening crop production. Tomato, a widely cultivated vegetable crop, is susceptible to both stresses, but their combined effects on tomato responses remain poorly understood. This study analyzed the anatomical, physiological, and molecular responses of two tomato genotypes, ‘NT212’ and ‘NT606’ (sensitive and tolerant to combined waterlogging and heat stresses), under control (C), waterlogging (W), heat stress (H1, H2, and H3) (34/27 °C, 38/31 °C, 42/35 °C), and combined stress (WH1, WH2, and WH3) for 48 h. ‘NT212’ exhibited only abaxial epidermal peeling under H2, but severe anatomical degradation including abaxial epidermal peeling and sponge parenchyma cell lysis under WH2. The superoxide anion (O₂^•−) production rate and PsbS and HSP70 expression were significantly higher in ‘NT212’ under WH2 than W and H2. Moreover, as the stress intensity increased from WH1 to WH2 and WH3, the O₂^•− production rate and PsbS and HSP70 expression were significantly increased in ‘NT212’. In contrast, ‘NT606’ did not exhibit obvious cell lysis under any stress treatments. The O₂^•− production rate was highest in ‘NT606’ under WH3 among all the treatments. HSP70 expression was significantly upregulated in ‘NT606’ under H3 and WH3 compared with the other treatments. Consequently, ‘NT212’ exhibited severe wilting under the H2, H3, and all combined stresses, while ‘NT606’ showed severe wilting only under WH3. Thus, combined stress caused synergistic damage exceeding individual stress, with injury intensifying as temperature increased. This study provided vital knowledge for breeding climate-resilient tomato cultivars, especially under combined waterlogging and heat stress. Full article

Endometriosis is a chronic inflammatory disorder affecting 5–10% of women of reproductive age and is associated with chronic pain and infertility. While research has mainly focused on local lesions, systemic immune dysfunction is increasingly implicated in disease pathogenesis. This study employs single-cell RNA sequencing (scRNA-seq) of peripheral blood mononuclear cells (PBMCs) from women with endometriosis and unaffected controls, combined with integrative analysis of publicly available datasets of menstrual blood and endometrial tissues, to uncover immune dysregulation and therapeutic targets in endometriosis. Cell-type composition and pathway alterations were assessed. Upregulated genes were evaluated using pharmacophore modeling, virtual screening, molecular docking of approved drugs, and molecular dynamics simulations to explore therapeutic potential. Immune profiling revealed increased B- and T-cell subsets and widespread inflammatory dysregulation. Notably, HSP90AA1 and PLCG2 (linked to endometrial cell survival and angiogenesis) were consistently upregulated across datasets, emerging as biologically plausible candidate drug targets for therapeutic intervention. Computational drug repurposing analysis prioritized upadacitinib, sorafenib, alpelisib, and sulindac as hypothetical candidates for further investigation, with molecular docking identifying favorable predicted binding affinity scores, particularly for HSP90AA1. These results reinforce a systemic, immune-mediated view of endometriosis and nominate HSP90AA1 and PLCG2 as novel candidate targets that now require biochemical, chemical, and in vivo validation. Full article

Hypoxia poses a significant threat to hippocampal neurons, but the temporal dynamics of mitophagy pathways in neuronal models remain incompletely characterized. This study aims to delineate time-dependent mitochondrial structural damage, fragmentation, and mitophagic responses in hippocampal neuronal cells under sustained hypoxia and to explore the key mitophagy receptors involved. Murine HT22 immortalized hippocampal neuronal cells were exposed to 1% O₂ for 6–72 h. Mitochondrial integrity was assessed using Western blot and transmission electron microscopy. Mitochondrial fragmentation was quantified via HSP60 intensity, mitochondrial length, and number of fragments per cell using immunofluorescence and MitoTracker live-cell labeling. Mitophagic activity was evaluated using LC3B puncta quantification, LC3B–Tom20 colocalization, and mitochondria–lysosome proximity via LysoTracker co-labeling. The transcriptional responses of five mitophagy-related genes (Bnip3, Bnip3l, Pink1, Fundc1, and Atg5) were screened using RT-qPCR, with protein validation by Western blot and immunofluorescence. Prolonged hypoxia progressively reduced Tim23 and Tom20, with ultrastructural damage and mitochondrial fragmentation seen. Mitophagy-associated phenotypes were evident, as shown by increased LC3B puncta, LC3B–Tom20 colocalization, and mitochondria–lysosome proximity. Bnip3 and Bnip3l showed the earliest and most pronounced transcriptional upregulation, with BNIP3 and BNIP3L protein levels elevated from 12 to 48 h. BNIP3 and BNIP3L intensities increased after 48 h, exhibiting granular and filamentous morphologies, respectively. This study provides a temporal framework for hypoxia-induced mitophagy in hippocampal neurons, identifying BNIP3/BNIP3L as early and prominent responders, which may inform therapeutic targeting in hypoxic brain injury. Full article

FK506-binding protein 4 (FKBP4), also known as FKBP52, is an HSP90 co-chaperone associated with poor outcomes in lung adenocarcinoma (LUAD). We evaluated FKBP4 using TCGA-LUAD, cBioPortal, CellMiner, and H1299 cell data. Among 535 primary tumors, the 20 displayed FKBP4 correlations from each of the HALLMARK_APOPTOSIS and HALLMARK_PEROXISOME sets remained significant after set-wise Bonferroni correction. cBioPortal identified two FKBP4 coding alterations among 511 tumors (0.39%), without a recurrent hotspot. No CellMiner association remained significant after Benjamini–Hochberg correction across 263 activity profiles. Three siRNAs reduced FKBP4 transcript abundance in an archived qPCR screen, although independent transfections could not be confirmed. Only si-FKBP4-3 was assessed by CCK-8, and FKBP4 protein depletion was not confirmed during the assay window. In one archived experiment, mean OD450 values were higher at 48 and 72 h across five technical wells. Because CCK-8 reflects WST-8 reduction, this observation does not establish proliferation, survival, or another defined phenotype. The study therefore identifies tumor-level co-expression associations and a preliminary cellular observation requiring independent and orthogonal validation. Full article

Rice (Oryza sativa L.) is a staple food crop globally, and identifying genes governing grain yield is critical for food security. Although heat shock proteins (HSPs) are known for their roles in stress tolerance, the molecular mechanisms by which they regulate yield formation remain unclear. In this study, we generated knockout and overexpression lines for OsHSP20 which is encoding a member of the Hsp20/alpha crystallin family, LOC_Os10g30162.1 (It is also one of the four candidate genes discovered during our fine mapping of major QTLs for photosynthetic rate in rice.), and performed integrated analyses combining field phenotyping, multi-stress assays, and transcriptomics. Phenotypic analyses revealed that OsHSP20 deficiency resulted in compromised plant architecture, leaf morphology, tillering, and panicle development, leading to a significant reduction in grain setting rate. Conversely, OsHSP20 overexpression enhanced drought tolerance. Mechanistically, transcriptomic and functional analyses demonstrated that OsHSP20 maintains protein homeostasis under drought stress via its chaperone activity; this function orchestrates a coordinated regulatory network involving lipid barrier formation, antioxidant defense, and carbon allocation. Our findings establish OsHSP20 as a positive regulator of both yield and drought resilience, improving crop adaptability by balancing growth and stress responses. In addition, our previous research has shown that OsHSP20 is actually one of the important components of the main QTL for rice photosynthetic rate. Therefore, this study can provide new genetic resources and a theoretical basis for cultivating rice varieties with high yield, stress resistant, and a high photosynthetic rate. Full article

Cardio-oncology explores the complex interplay between cancer biology and cardiovascular health, particularly the cardiotoxic effects of cancer therapies. Both microRNAs (miRNAs) and alarmins have emerged as key molecular mediators linking tumor progression and cardiac stress, representing promising biomarkers and therapeutic targets. In skin and breast cancer, specific miRNAs, including miR-21, miR-155, miR-34a, and the miR-200 family, regulate tumor proliferation, invasion, metastasis, and therapy resistance. Alarmins such as NPM, HMGB1, HSPs, IL-33, and S100 proteins modulate inflammatory signaling, oxidative stress, and tissue remodeling, contributing to both tumor progression and cardiomyocyte dysfunction. These molecules are also implicated in chemotherapy- and targeted therapy-induced cardiotoxicity, including apoptosis, fibrosis, and impaired cardiac function. This review highlights the dual role of miRNAs and alarmins in tumor biology and cardiovascular toxicity, emphasizing their potential as circulating biomarkers for early detection and monitoring. Therapeutic strategies targeting this axis—including miRNA mimics/inhibitors and alarmin modulators—may provide synergistic benefits by reducing cardiotoxicity while suppressing tumor growth. Understanding miRNA–alarmin relationships, including direct interactions such as the NPM/miR-200c axis, as well as their broader regulatory networks in cardio-oncology, offers novel avenues for precision medicine, enabling integrated approaches to monitor, prevent, and treat therapy-related cardiac complications in patients with skin and breast cancers. Full article

Alkylcyclohexanes are vital components of aviation kerosene. Intramolecular H−migration of •OOQOOH radicals controls ketohydroperoxide (KHP) formation, the primary pathway responsible for low-temperature chain-branching during low−temperature oxidation. Available chemical kinetic models for alkylcyclohexanes generally lack directly computed kinetic data for H−migration reactions of •OOQOOH in cyclic fuels; relevant rate constants are commonly transferred from analogous alkane reactions, introducing systematic uncertainties in low−temperature ignition predictions. In this work, quantum chemical calculations are performed for 13 representative •OOQOOH intramolecular H−migration pathways originating from alkylcyclohexanes, covering six structural subclasses: 1,5−H−(s)(p), 1,5−H−(s)(s), 1,5−H−(t)(p), 1,5−H−(t)(s), 1,6−H−(t)(p), and 1,6−H−(t)(s). Modified Arrhenius parameters are fitted from high−pressure−limit rate constants over 500–1500 K. Further comparison between the present computed rate data and parameters adopted in existing mechanisms demonstrates that the literature values transferred from alkanes are systematically lower. Ring strain and distinct transition−state entropy originating from cyclic structures make the alkane kinetic parameters inappropriate for alkylcyclohexane systems. The kinetic parameters and lumped subclass rate rules obtained in this study provide fundamental data for improving low-temperature oxidation models of alkylcyclohexanes. Full article

Heat stress is a critical environmental factor that compromises reproductive performance in dairy cattle, primarily through deleterious effects on ovarian follicular cells. Granulosa cells (GCs), which provide essential nutritional and hormonal support for oocyte maturation, are particularly vulnerable to hyperthermic insult. However, the early molecular and subcellular events that precede overt cellular dysfunction remain inadequately characterized. This study aimed to investigate the temporal dynamics of mitochondrial morphological alterations and transcriptomic reprogramming in bovine GCs subjected to acute in vitro heat stress. Bovine GCs were exposed to 43 °C for 10, 20, 30, or 40 min, with untreated cells serving as controls. Heat shock protein expression (HSP90 and HSPA1A) was evaluated by qRT-PCR. Intracellular calcium concentration was measured using the Fluo-3 AM fluorescent probe. Mitochondrial ultrastructure was examined via transmission electron microscopy (TEM). Global transcriptional changes were profiled by RNA sequencing (RNA-seq) at 20 and 40 min post-treatment, followed by bioinformatics analysis. Nine selected differentially expressed genes (DEGs) were validated by qRT-PCR. HSP90 and HSPA1A expression was significantly upregulated at 30 and 40 min of heat exposure (p < 0.05). Intracellular Ca²⁺ concentration exhibited a biphasic pattern—markedly elevated at 20 min but significantly reduced at 40 min. TEM revealed progressive mitochondrial swelling and cristae disruption at both time points, with more severe damage at 40 min. RNA-seq identified 185 DEGs at 20 min and 831 DEGs at 40 min, with 285 genes commonly dysregulated across both time points. Functional enrichment analysis demonstrated that the 20-min response was dominated by heat shock protein-related pathways, whereas the 40-min response expanded to encompass apoptosis, inflammation, steroidogenesis, and ciliogenesis pathways. qRT-PCR validation confirmed the reliability of the RNA-seq data. These findings provide a mechanistic framework for understanding heat stress-induced ovarian dysfunction and may inform strategies to preserve fertility in dairy cattle during thermal challenge. Full article

Breast cancer remains the most prevalent malignancy among middle-aged and elderly women with underlying health conditions, with triple-negative breast cancer (TNBC) representing a notably aggressive subtype associated with poorer clinical outcomes. Prunus africana (P. africana) has been reported to contain bioactive compounds with notable antioxidant and anticancer properties. Bark extracts obtained using water, as well as single (100%) and binary (50% v/v) solvents of methanol and ethanol (MeOH-100, EtOH-100, MeOH-50, and EtOH-50), were evaluated for their antioxidant activity, apoptosis-inducing effects, and modulation of signaling pathways in selected breast cancer cell lines. Antioxidant activity was measured via FRAP, DPPH radical scavenging, and TEAC assays; cytotoxic activity and pathway modulation were assessed using MTS, human apoptosis, and phospho-RTK array assays. While the EtOH-100 extract presented the lowest extraction yield of 3.22%, it showed the highest total phenolic (505.96 mg GAE/g) and total flavonoid (2.53 mg RU/g) contents and antioxidant activities (2.25 mM Fe²⁺/g and 311.68 mM TE/g), and the lowest EC₅₀ (0.21 mg/mL), comparable to ascorbic acid (0.18 mg/mL). EtOH-100 also notably induced apoptosis in HCC1806 as shown by increased cleaved caspase-3, HSP60, and HSP27 expression, and sustained catalase levels. Phospho-RTK array analysis revealed early silencing of HGF and transient upregulation of EGF and Insulin R following EtOH-100 extract treatment, suggesting modulation of oncogenic signaling. These findings highlight the therapeutic potential of P. africana, particularly the EtOH-100 extract, as a viable treatment for TNBC. Full article

The study was conducted to establish the thermoneutral zone (TNZ) of Murrah buffalo calves under precisely regulated environmental conditions. Six healthy calves (8–10 months) were exposed to progressively decreasing (24–15 °C; Temperature-Humidity Index (THI): 72.45–58.98) and increasing (25–40 °C; THI: 73.49–90.32) ambient temperatures with 3 °C intervals in a psychrometric chamber. Each exposure was maintained for 10 consecutive days under cyclic conditions (12 h exposure and 12 h thermoneutral recovery). Physiological responses and body surface temperature (BST) were recorded, and blood samples were collected on day 10 at 1500 h. Segmented regression analysis was performed using the SegReg (Oosterbaan, 2017) software program to identify lower and upper critical temperatures (LCT, UCT) and corresponding THI thresholds. LCTs ranged from 18.06 to 19.14 °C across different responsive parameters, with breakpoints (BPs) at 18.60 °C (SE_BP = 0.634) for pulse rate (PR), 18.15 °C (SE_BP = 0.945) for haemoglobin, 18.15 °C (SE_BP = 0.189) for lymphocytes, 18.24 °C (SE_BP = 0.404) for granulocytes, 19.14 °C (SE_BP = 1.09) for reactive oxygen species (ROS), 18.15 °C (SE_BP = 23.9) for superoxide dismutase (SOD), and 18.06 °C (SE_BP = 4.2) for cortisol; no distinct LCT was detected for respiratory rate (RR), rectal temperature (RT), total leukocyte count (TLC), or heat shock protein (HSP) 70/HSP90 expression. BST at different locations exhibited an LCT between ~20 and 21 °C. UCTs for PR, RR and RT were observed at 28.9 °C (SE_BP = 0.892), 28.6 °C (SE_BP = 0.843) and 29.2 °C (SE_BP = 1.16), respectively. Neither BST nor erythrocytic parameters exhibited a distinct UCT; however, BST increased progressively with increasing exposure temperature. TLC, lymphocyte and granulocyte % showed UCTs of 28.15 °C (SE_BP = 0.753), 28.15 °C (SE_BP = 0.497) and 32.65 °C (SE_BP = 14.20), respectively. The UCT for cortisol was observed at 28.15 °C (SE_BP = 5.52), whereas ROS and SOD showed UCTs of 28.75 °C (SE_BP = 4.67) and 34.15 °C (SE_BP = 6.55), respectively. HSP70 and HSP90 exhibited breakpoints at 35.35 °C (SE_BP = 1.32) and 34.30 °C (SE_BP = 2.11), respectively. Integration of key physiological and systemic responses (excluding BST) indicated a TNZ ranging from 19.14 °C to 28.15 °C. These findings provide a multi-level characterization of thermophysiological responses in buffalo calves and support the use of integrated biological indicators for defining thermoneutral conditions under controlled environments. The estimated TNZ of 19.14–28.15 °C provides a practical reference for managing Murrah buffalo calves. Producers should monitor housing temperature and consider ventilation, shade and air movement when temperatures approach or exceed ~28 °C while providing protection from cold when temperatures fall below ~19 °C. This may help reduce thermal strain and maintain normal physiological function. Full article

Diabetes and hypertension are closely interlinked and among the most prevalent diseases that significantly increase cardiovascular risks. They can be caused by a wide range of factors, which often affect overlapping molecular pathways, resulting in vascular dysfunction. Hyperglycemia in diabetes and increased angiotensin II levels in hypertension act similarly to promote vascular dysfunction by triggering pathways leading to oxidative stress, low-grade inflammation, and vessel remodeling. In this context, Heat Shock Protein 70 (HSP70), a ubiquitous molecular chaperone that exists locally (iHSP70) and systemically (eHSP70) and has opposing biological effects, is emerging as a new component associated with vascular dysfunction in chronic conditions. While elevated levels of eHSP70 in diabetes and hypertension have been associated with low-grade inflammation, iHSP70 appears to regulate intracellular calcium handling—a hallmark mechanism disrupted in both pathologies. This review focuses on the role of HSP70 as an evolving component of the intricate mechanisms underlying vascular dysfunction in these two pervasive diseases, which are very likely to coexist and represent a growing burden worldwide, while addressing whether HSP70 actively contributes to the vascular dysfunction or reflects an adaptive response to disease-associated stress across tissues and experimental models. Finally, we discuss emerging evidence on the pharmacological modulation of HSP70 and the challenges remaining in defining its role as a biomarker and therapeutic target. Full article

Alcoholic liver injury (ALI) represents a significant global health burden with limited therapeutic options. Xanthoxylin, a natural flavonoid compound, has demonstrated potential hepatoprotective properties, yet its underlying molecular mechanisms against ALI remain poorly elucidated. This study employed an integrated strategy combining network pharmacology, molecular docking, molecular dynamics (MD) simulations, and in vitro experimental validation to systematically investigate the protective mechanisms of xanthoxylin against ALI. Network pharmacology screening identified 52 intersection targets between xanthoxylin and ALI, with the top 10 core targets comprising ALB, PPARG, BCL2, PTGS2, ESR1, HIF1A, EGFR, HSP90AA1, GSK3B, and PARP1. GO enrichment analysis highlighted mitochondrion and mitochondrial outer membrane among the top 10 cellular component (CC) terms. KEGG pathway analysis revealed PI3K-Akt signaling within the top 10 pathways. Molecular docking suggested potential binding of xanthoxylin to the key targets. Subsequent MD simulations further confirmed the formation of stable complexes between xanthoxylin and EGFR, PPARG, and PTGS2. In vitro, xanthoxylin significantly ameliorated ethanol-induced HepG2 cell injury, attenuated TC and TG elevations, suppressed mitochondrial ROS accumulation, and enhanced SOD activity. Mechanistically, xanthoxylin upregulated HSP90, p-EGFR, EGFR, p-AKT, AKT, and PPARG protein expression, and suppressed the expression levels of PTGS2. Erlotinib, an EGFR inhibitor, reversed the cytoprotective effects of xanthoxylin. Xanthoxylin protects against alcoholic liver injury through regulating the EGFR/AKT pathway, with concurrent modulation of PPARG and PTGS2. These findings provide compelling evidence for xanthoxylin as a promising therapeutic candidate for ALI and establish a foundation for subsequent preclinical development. Full article

Chronic pain, a devastatingly prevalent condition, is increasingly understood not merely as a disorder of neuronal signaling but as a failure of the neuronal infrastructure itself. Central to this paradigm is the microtubule (MT) cytoskeleton, which functions not as a passive scaffold but as a dynamic regulatory hub and the primary railway for intracellular transport. This review provides a comprehensive mechanistic analysis of how the dysregulation of microtubule dynamics drives the initiation and maintenance of chronic pain. We dissect the change in microtubule dynamics across diverse pain etiologies, summarizing how diverse insults lead to either pathological hyper-stabilization or catastrophic disassembly of the microtubule network. Finally, we explore emerging therapeutic strategies that move beyond broad-spectrum microtubule modulators to target specific regulatory proteins such as Histone deacetylase 6 (HDAC6), Collapsin Response Mediator Protein 2 (CRMP2), Heat Shock Protein 27 (HSP27), and motor proteins (kinesins and dyneins). We propose that restoring cytoskeletal homeostasis, by which we recalibrate the tubulin code or rescue motor-driven transport, represents a paradigm-shifting approach to pain management. By moving the therapeutic focus from blocking electrical signals to repairing the structural and logistical integrity of the nociceptive neuron, these strategies hold the potential to modify the underlying disease process, offering a new frontier for analgesic development. Full article

This study evaluated the effects of dietary SYNSEA Premium postbiotics on growth, immunity, disease resistance, intestinal microbiota, and host metabolism in Asian seabass (Lates calcarifer). Fish were fed a control diet or diets supplemented with heat-killed Lactiplantibacillus plantarum LP28, L. plantarum LP1008, and Bacillus subtilis at 10⁸ (LSP) or 10⁹ (HSP) cells kg⁻¹ diet for 56 days. Postbiotic supplementation did not significantly affect growth performance, feed efficiency, production, condition factor, or dorsal muscle composition, but significantly improved survival. Fish receiving postbiotics also exhibited higher survival following Vibrio alginolyticus and iridovirus challenges. These protective effects were accompanied by enhanced superoxide dismutase, phagocytic, and lysozyme activities and modulation of immune-related genes, including tgf-β1, tnf, ifn-γ1, c3, and mx. Exploratory microbiome and metabolome analyses, which were restricted to the control and LSP groups, identified differences in the relative abundance of specific intestinal microbial taxa and associations between microbial composition and host metabolic profiles. The LSP group showed lower relative abundances of potential pathogens such as Salmonella enterica, Lactococcus garvieae, and Staphylococcus warneri, although the overall microbial community structure did not differ significantly between groups. Metabolomic analysis of the LSP group further showed changes in D-glucose, pentose phosphate pathway intermediates, reduced glutathione, CoA, and 2-methylacetoacetyl-CoA relative to the control. Collectively, SYNSEA Premium improved survival, immune responses, and resistance to bacterial and viral infections without significantly affecting growth performance, while exploratory omics analysis of the LSP treatment identified associated microbial and metabolic changes. Full article