Search Results (1,309)

Mulberry (Morus alba) is an economically important forest tree species, yet cutting propagation is constrained by low adventitious rooting efficiency. Although ABT, a composite rooting promoter, can improve cutting survival, its molecular basis remains unclear. Here, cuttings of the cultivar Qiangsang 1 were treated with ABT, NAA, or IAA (200–1000 mg/L) and subjected to transcriptome profiling to elucidate how ABT enhances rooting. Hormone-related analyses showed that ABT upregulated GH3 (auxin-amido synthetase) at days 0 and 20, implicating auxin homeostasis. ERF1/2 (ethylene response factors) exhibited a temporal oscillation, with induction at day 10 followed by repression from days 20 to 30, consistent with a shift from developmental programs to defense-related processes. In parallel, JAZ (jasmonate ZIM-domain) genes were downregulated at day 0 and subsequently upregulated; together with CYP94C1, these changes may attenuate jasmonate-associated defense signaling. For cell remodeling and defense coordination, ABT reduced the expression of genes associated with cell-wall rigidity while inducing EXPA11 (expansin) at day 20, potentially facilitating root primordium emergence. Meanwhile, PR-1 (pathogenesis-related protein 1) was transiently upregulated at days 0, 20, and 30, and the concomitant modulation of WRKY transcription factors and RPM1 suggests enhanced defense readiness. Integrative network analysis further indicated that a GH3–ERF1/2–PR-1 module links hormonal and defense cues and may activate BAT1 (energy metabolism) and RBOHB (ROS production) to support adventitious root elongation. Collectively, these results suggest that ABT improves rooting efficiency by reshaping hormonal homeostasis and coordinating cell-wall reconstruction with a pre-activated defense state, thereby providing a conceptual framework for balancing root induction and defense responses during vegetative propagation in forest trees. Full article

Background/Objectives: Hepatic encephalopathy (HE) is characterized by hyperammonemia, neuroinflammation, oxidative stress, and blood–brain barrier (BBB) dysfunction, with brain endothelial cells being highly vulnerable to ammonia-induced damage. Adiponectin is a cytoprotective adipokine that may enhance endothelial resilience; however, its specific role under hyperammonemic conditions remains unclear. This study aims to investigate the protective effects of adiponectin on brain endothelial function and BBB integrity. Methods: In vivo, male C57BL/6J mice underwent bile duct ligation (BDL) surgery and received daily intraperitoneal adiponectin injections (10 μg/kg/day) for 6 days, starting 5 days post-surgery. On day 11, brain tissues and serum were collected for molecular and cytokine analyses. In vitro, mouse brain endothelial cells (bEnd.3) were pretreated with adiponectin before exposure to ammonia. Assays for tight junction preservation, mitochondrial membrane potential, reactive oxygen species (ROS) generation, and total RNA sequencing were performed. Results: In BDL mice, adiponectin increased the expression of the tight junction protein claudin-5 and synaptic marker PSD95 across the cortex, hippocampus, and striatum, while reducing pro-oxidant (Cyp2e1, Cyp4a1) and apoptotic (Caspase-9) markers. In vitro, adiponectin pretreatment maintained tight junction proteins, suppressed inflammatory markers, restored mitochondrial membrane potential, and decreased ROS generation in ammonia-exposed bEnd.3 cells. Transcriptomic profiling revealed that adiponectin modulates stress-related gene expression under hyperammonemic conditions. Conclusions: Adiponectin enhances cellular stress resistance and maintains BBB structural integrity under ammonia-induced toxicity. These findings suggest that adiponectin serves as a promising therapeutic target for mitigating neurovascular unit dysfunction in hepatic encephalopathy. Full article

Background: Etoricoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, is widely prescribed for the management of inflammatory conditions. Despite its extensive clinical use, evidence regarding its hepatic safety profile remains limited and incompletely characterized. Aims: This study aimed to systematically evaluate the hepatic effects of etoricoxib in a murine model by integrating histopathological assessment with analysis of mRNA expression of key enzymes involved in arachidonic acid metabolism Methods: Male BALB/c mice (n = 7 per group) received either low or high doses of etoricoxib (10.5 or 21 mg/kg/day) or celecoxib (35 or 70 mg/kg/day) for 28 consecutive days. Liver tissues were examined histologically using hematoxylin and eosin staining, while molecular alterations were assessed by quantitative PCR targeting representative cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome P450 (CYP450) isoforms involved in arachidonic acid metabolism. Results: High-dose etoricoxib exposure was associated with pronounced hepatic histopathological alterations, including hepatocellular necrosis, inflammatory cell infiltration, and sinusoidal congestion. In contrast, low-dose treatment resulted in only mild vascular and cellular changes. At the molecular level, etoricoxib administration was associated with marked downregulation of several arachidonic acid–metabolizing genes (including Cyp4a12 and Alox12), whereas Cox2 expression was significantly upregulated (p < 0.05), indicating a shift toward a pro-inflammatory transcriptional profile. Conclusions: Etoricoxib exposure is associated with dose-dependent hepatic injury in mice, accompanied by coordinated transcriptional alterations in arachidonic acid–metabolizing pathways. Notably, molecular changes were detectable even at low doses in the absence of overt histological damage, suggesting potential early indicators of hepatic stress. These findings underscore the importance of cautious dose optimization and further translational studies to clarify the long-term hepatic safety of etoricoxib in clinical settings. Full article

Carbosulfan is a widely used carbamate insecticide, yet its mechanisms of respiratory toxicity remain poorly understood. This study integrated network toxicology, untargeted metabolomics, and molecular docking to systematically investigate the potential mechanisms of carbosulfan-induced respiratory toxicity in male Sprague Dawley rats. Rats were administered a single oral dose of carbosulfan (125 or 250 mg/kg) and assessed after 12 h. Exposure resulted in significant pathological lung damage, characterized by disrupted alveolar architecture, inflammatory cell infiltration, and increased serum levels of the pro-inflammatory cytokines IL-6, IL-1β, and TNF-α. Network toxicology analysis identified 51 potential targets associated with respiratory toxicity, with core targets including SRC, EGFR, PTGS2, CXCL8, CYP3A4, and NR3C1. Enriched pathways were primarily related to neuroactive ligand–receptor interaction, VEGF signaling, and arachidonic acid metabolism. Untargeted metabolomics revealed significant metabolic perturbations in pathways central to antioxidant defense and energy homeostasis, including glutathione metabolism, the tricarboxylic acid cycle, and arginine biosynthesis. Molecular docking confirmed stable in silico binding affinities between carbosulfan and the predicted core targets. Integrative analysis suggests that carbosulfan exposure is associated with respiratory damage, potentially through interconnected mechanisms involving oxidative stress, inflammation, and disruption of cell signaling and metabolic enzyme systems. However, given the acute high-dose nature of the model and the interpretative integration of multi-omics data, these findings should be considered hypothesis-generating. This study provides a novel system-level perspective on carbosulfan-induced respiratory toxicity and highlights key pathways and targets for future validation in chronic exposure models. Full article

Background/Objectives: Losartan, an angiotensin II receptor blocker (ARB) used to treat hypertension and heart failure, shows significant variability in pharmacokinetics (PK) and pharmacodynamics (PD) among individuals. Methods: In this study, we developed a physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) model of losartan and its active metabolite, E3174, using curated data from 25 clinical trials. The model mechanistically describes the processes of absorption, hepatic metabolism, renal and fecal excretion, and pharmacodynamic blood pressure regulation. Simulation studies examined the effects of dose, hepatic and renal impairment, and genetic polymorphisms in cytochrome p450 2C9 (CYP2C9) and P-glycoprotein 1, also known as multidrug resistance protein 1 (MDR1) or ATP-binding cassette sub-family B member 1 (ABCB1), on the model. Results: The model successfully reproduced key PK/PD observations, including dose-dependent receptor blockade, attenuated responses with hepatic impairment, modest enhancement with renal impairment, and substantial variability in E3174 formation dependent on CYP2C9; the effects of ABCB1 were minimal. Specifically, dose dependency simulations confirmed the saturable nature of CYP2C9 metabolism, predicting a decreasing E3174-to-losartan ratio and a stronger, sustained suppression of blood pressure and aldosterone at higher doses. Hepatic impairment was predicted to lead to elevated losartan plasma concentrations (increased AUC) and attenuated metabolite formation, confirming the clinical need for dose reduction. Renal impairment simulations predicted stable losartan AUC but showed an overestimation of E3174 accumulation compared to observed data, where E3174 exposure remained stable. Genetic variability (CYP2C9) was the major determinant of response, with simulations confirming that reduced-function alleles lead to a 1.6- to 3-fold increase in losartan AUC and diminished blood pressure reduction. ABCB1 variability resulted in only minor modulation of systemic exposure and blood pressure effects. Conclusions: This mechanistic digital twin framework provides a quantitative basis for understanding variability in losartan therapy and supports its application in individualized dosing strategies. Full article

APETALA2/ethylene-responsive factor (AP2/ERF) transcription factors integrate phytohormone signalling with developmental programmes and specialised metabolism, yet their family-wide features and potential contributions to phenolic-acid biosynthesis remain to be systematically clarified in Salvia miltiorrhiza. In this study, we conducted a comprehensive genome-wide analysis and identified 169 SmAP2/ERF genes, which were classified into five subfamilies (AP2, ERF, DREB, RAV and Soloist). SmAP2/ERFs were unevenly distributed across chromosomes and expanded predominantly through tandem and segmental duplication, and Ka/Ks analysis indicated that tandem-duplicated pairs have mainly undergone purifying selection. Promoter analysis revealed abundant cis-acting elements related to light, phytohormones and stress responses, indicating extensive regulatory potential. Comparative phylogenetic analysis with Arabidopsis thaliana prioritised four candidates (SmAP2/ERF88, SmAP2/ERF110, SmAP2/ERF121 and SmAP2/ERF122) closely associated with specialised-metabolism regulators. These genes exhibited distinct tissue-preferential expression patterns and divergent hormone responsiveness: SmAP2/ERF88/110 were broadly inducible, whereas SmAP2/ERF121/122 responded mainly to abscisic acid and were repressed by brassinosteroids. Confocal imaging of GFP fusions confirmed nuclear localisation of all four proteins. Phytohormone treatments differentially regulated key phenolic-acid pathway genes (PAL, C4H, 4CL, TAT, HPPR, RAS and CYP98A14) and altered rosmarinic acid and salvianolic acid B accumulation. These results broaden the genome-wide understanding of the SmAP2/ERF family in Salvia miltiorrhiza. Hormone-responsive SmAP2/ERFs show expression patterns associated with hormone-dependent transcriptional changes in phenolic-acid pathway genes and with RA and SAB accumulation, providing candidates for future functional validation and metabolic engineering. Full article

Background/Objectives: Non-steroidal anti-inflammatory drugs (NSAIDs) are widely prescribed to help alleviate pain and treat inflammation, but they are also recognized as common causes of severe cutaneous adverse reactions (SCARs), including Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). Despite their clinical importance, pharmacogenetic markers to predict individual susceptibility to NSAID-induced SJS/TEN remain insufficiently defined. This study investigated associations between HLA class I and II alleles, CYP2C9 polymorphisms, and NSAID-induced SJS/TEN in a Thai population. Methods: A total of 18 patients with NSAID-induced SJS/TEN and 54 NSAID-tolerant controls were enrolled. Genotype data from 183 unrelated Thai individuals without a history of drug allergy were included as a general population control group. Genotyping was performed for HLA class I and II alleles and the CYP2C9*3 variant. Results: HLA-DQB1*03:02 was significantly associated with NSAID-induced SJS/TEN (OR = 9.23, 95% CI = 2.19–38.83, p = 0.0024, Pc = 0.0312), particularly those triggered by piroxicam (OR = 13.71, 95% CI = 2.81–66.86, p = 0.0012, Pc = 0.0156). Additional associations were identified for HLA-B*56:01 and HLA-A*68:01 in the overall NSAID-induced SJS/TEN group. The subgroup analysis suggested that these alleles, along with HLA-DRB1*04:03, were associated with an increased risk of piroxicam-induced SJS/TEN. However, these associations did not remain statistically significant after Bonferroni’s correction. No significant association was identified for CYP2C9*3. Conclusions: This study identified specific HLA alleles, particularly HLA-DQB1*03:02, as candidate pharmacogenetic risk factors for NSAID-induced SJS/TEN in a Thai population, especially in piroxicam-associated cases. However, these associations should be considered exploratory. Larger, multicenter, multi-ethnic studies are required to validate these findings and clarify their potential clinical utility. Full article

Soil salinization poses a major constraint to global agriculture. Apocynum venetum, a salt-tolerant halophyte, provides an effective model for investigating salt-adaptive strategies; however, the temporal dynamics of its tolerance-associated genes and metabolites remain unclear. In this study, integrated transcriptomics, metabolomics (UHPLC-MS), physiological assays, and weighted gene co-expression network analysis (WGCNA) were conducted to characterize early (7-day) and late (18-day) responses to 200 mM NaCl stress. NaCl stress significantly reduced chlorophyll content while increasing Na⁺ accumulation, MDA levels, antioxidant enzyme activities (SOD and CAT), and total flavonoid content. Early responses (NaCl7) were marked by accumulation of ferulic acid, rhamnetin, and 3,4-dihydrocoumarin, with activation of plant hormone (ABA, auxin, zeatin) and MAPK signaling pathways. Late responses (NaCl18) exhibited increased accumulation of scopoletin, formononetin, and caffeyl-alcohol, with enrichment of phenylpropanoid biosynthesis, glutathione metabolism, and photosynthesis-related pathways. WGCNA identified early-response hub genes, including AOC, MAPKKK17/18, CYP98A, and CCoAOMT, coordinating stress signaling and antioxidant metabolism. Late stress responses involved genes like CPK, GST, CYCD3, and ARF, modulating calcium signaling and ROS detoxification. Genes shared across phases included CYP90C1, HD-ZIP, HSP20, and PP2C, regulating protein stabilization and stress signaling. These findings reveal a two-phase salt tolerance strategy in A. venetum, integrating early signaling and late metabolic adaptation. Full article

The present study aims to evaluate the interaction of gliclazide with proteins related to inflammation—{inhibitor of nuclear factor kappa-B kinase subunit beta (IKKα) and NF-kappa-B-inducing kinase (NIK)}; oxidative stress—{kelch domain of Kelch-like ECH-associated protein 1 (KKeap1)} and ER stress—{inositol-requiring enzyme-1alpha (IRE1α)}. X-ray crystal structure of IKKα, (PDB ID: 5EBZ), KKeap1 (PDB ID: 4L7B), NIK (PDB ID: 8YHW) and IRE1α (PDB ID: 4YZ9) were obtained from Protein Data Bank and Open Babel 3.1.1 was used to prepare the ligands. Prior to docking, protein structures were prepared by removing water molecules, adding hydrogen atoms, and optimizing side chain conformations using Maestro (Schrödinger Suite, version 2024-2) along with the OPLS4 force field. Ligand docking was performed using the Glide application. Molecular dynamics simulation was performed with Desmond (Schrödinger Suite) within the Maestro interface for 100 ns for the NPT ensemble at 300 K and 1 atm pressure. Physicochemical and pharmacokinetics properties were analyzed using ADMETlab 3.0 and SwissADME. The binding energies of gliclazide with IKKα, NIK, KKeap1 and IRE1α were −8.3, −7.9, −8.4 and −8.8, respectively. Root mean square displacement (RMSD), root mean square fluctuation (RMSF) and radius of gyration analyses predicted relatively strong and stable interactions between gliclazide and the proteins, with favourable pharmacokinetic properties. It was also observed that CYP3A4 metabolizes gliclazide, in addition to CYP2C9 and CYP2C19. The activity of gliclazide against inflammation, oxidative stress and endoplasmic reticulum stress might be via interaction with these proteins. Full article

Lactic acid bacteria (LAB) and their metabolic derivatives, including exopolysaccharide (EPS), as well as postbiotics (POS), exhibit considerable potential for application as healthy foods and dietary supplements for the host. Evaluating the cholesterol-lowering activities of LAB, EPS and POS, with a focus on their impact on lipid metabolism, has become a hotspot in the development of cholesterol-lowering food products. This study was designed to assess the impacts of Schleiferilactobacillus harbinensis Z171 and its EPS and POS on hepatic cholesterol metabolism of C57BL/6 mice fed a high-fat diet (HFD). Key biomarkers related to cholesterol synthesis, bile acid production, cholesterol transport, and the role of AMPKα activation in inhibiting cholesterol synthesis were studied. The results indicated that Z171, POS, and a high dose of EPS (400 mg/kg) significantly reduced serum total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and triglycerides (TG) by 39.73–41.74%, 34.72–37.43, and 31.74–40.76%, respectively, while simultaneously increasing high-density lipoprotein cholesterol (HDL-C) level by 26.57–31.00%. Furthermore, histopathological analysis revealed that these interventions led to reduced fat accumulation in the liver and an improved liver morphology. Additionally, metabolomic analysis demonstrated that these interventions promoted bile acid synthesis, as evidenced by increased CYP7A1 expression, leading to enhanced cholesterol catabolism. These findings suggested that Z171, POS, and high-dose EPS may be effective in managing hypercholesterolemia by regulating cholesterol synthesis, enhancing bile acid production, and improving lipid metabolism in HFD mice. This work contributes to the understanding of the potential of LAB, POS and EPS as functional ingredients for improving metabolic health. Full article

This study employed an artificial greenhouse-based system to enhance gonadal development in the Manila clam, Ruditapes philippinarum. The dynamics of gonadal development and expression patterns of five regulatory genes were analyzed through histological sections and quantitative PCR. Under the controlled conditions (Chlorophyll a: 18.61 ± 1.36 μg/L; temperature: 27.3 ± 2.0 °C), the clams’ gonads reached full maturity within approximately one month, underscoring the critical importance of appropriate food availability and temperature. Gene expression analysis revealed sex- and stage-specific patterns. The gonadotropin-releasing hormone (GnRH) gene was more expressed in males at day 7, reaching a significant peak at day 7. In contrast, females exhibited synchronized expression peaks for both estrogen-related receptor (ERR) and 17β-hydroxysteroid dehydrogenase (17β-HSD) at day 14 (p < 0.05). Cytochrome P450 17 (CYP17) exhibited a dynamic, sex-specific profile, with significantly higher levels in males at day 7 but elevated expression in females at day 14 and day 21. Furthermore, doublesex and mab-3-related transcription factor 4-like (Dmrt4-like) showed clear sex-dependent temporal patterns: it peaked early during maturation in males, while in females, the peak occurred significantly later, at day 21 (p < 0.05). These dynamic changes in gene expression were closely synchronized with histological alterations, providing mechanistic insights into the regulation of gonadal maturation in R. philippinarum. Full article

The SHOX gene is located on both sex chromosomes, X and Y, within the pseudoautosomal region 1 (PAR1). Gross deletions at the SHOX locus lead to protein insufficiency and are manifested by growth disorders such as Leri-Weill dyschondrosteosis (LWD), Langer mesomelic dysplasia (LMD), and idiopathic short stature (ISS). In cases of the SHOX gene duplication, the phenotype may range from tall to short stature and LWD. This study describes a family with various SHOX locus alterations and diverse phenotypic manifestations. The proband inherited both deletion and duplication in the SHOX locus from her parents and shows typical features of LWD. The proband’s father carries SHOX gene deletion and displays Madelung’s deformity but normal height. The proband’s mother has SHOX gene duplication without any abnormalities in phenotype. One of the proband’s sons inherited deletion, while the other inherited duplication of the gene. Some family members also have the c.845_851dup variant in the CYP26C1 gene, previously described as a modifier of the SHOX gene. It is difficult to assess its effect. At present, it is not possible to predict the future phenotype of the proband’s children due to the high phenotypic variability associated with SHOX locus alterations. Full article

Salt stress is a severe threat to medicinal plants, adversely affecting their growth, yield, and quality. As a key antioxidant tripeptide, glutathione (GSH) confers salinity stress resilience in plants. However, how GSH shapes the plant tolerance to salt stress remains a mystery, especially in medicinal plants, including Pogostemon cablin. In this study, we investigated the regulatory effects of exogenous GSH on P. cablin seedlings under salt conditions. The results showed that GSH significantly improved seedling quality under both normal and salt conditions, evidenced by the increased shoot and root dry weight, plant height, and root length. Moreover, GSH effectively protected the photosynthetic system against salt-mediated damage via raised chlorophyll a, chlorophyll b, carotenoids, quantum yield of photosystem II [Y (II)], and PSII maximum efficiency (Fv/Fm). Furthermore, GSH stimulated the antioxidant defense system, including GSH, AsA, SOD, CAT, APX, POD, and GR, to restrain salt-induced malondialdehyde production and ROS burst. In addition, GSH treatment promoted the biosynthesis of secondary metabolites, including total polyphenol and flavonoid. RNA-seq analysis revealed that the activation of the flavonoid biosynthetic pathway significantly enhanced salt tolerance in P. cablin. Notably, several key regulatory genes within this pathway, including PAL, 4CL, C4H, CHI, ANS, F3′H, and CYP93, were significantly upregulated 24 h following GSH application under salt conditions. Therefore, exogenous GSH alleviates salt-induced oxidative stress in P. cablin via enhancing the antioxidant defense system and flavonoid biosynthetic activation. These findings provide valuable insights into the dual defense strategies of GSH for conferring salt resistance in plants. Full article