Search Results (3,507)

Soil salinity severely impairs plant growth, and polyamines such as spermidine (Spd) are known to bolster stress tolerance by acting as osmoprotectants and signaling molecules. Using TiO₂ enrichment, iTRAQ quantification, and bioinformatics analysis, we identified 870 proteins and 157 differentially phosphorylated proteins. Functional annotation showed that salt stress activated key components of the Salt Overly Sensitive pathway, particularly serine threonine kinases (SOS2) and Ca²⁺ binding sensors (SOS3). Among thirty-six SOS-associated kinases detected, eight SOS2 isoforms, four MAPKs, and two SOS3 homologs were significantly upregulated by NaCl, and Spd further increased the phosphorylation of six SOS2 proteins and one SOS3 protein under salt stress, with no detectable effect on SOS1. qRT PCR revealed enhanced expression of MAPKs and calcium-dependent protein kinases, suggesting a phosphorylation-centered model in which Spd amplifies Ca²⁺-mediated SOS signaling and reinforces ion homeostasis through coordinated transcriptional priming and post-translational control. Additional, proteins involved in protein synthesis and turnover (ribosomal subunits, translation initiation factors, ubiquitin–proteasome components), DNA replication and transcription, and RNA processing showed differential expression under salt or Spd treatment. Central metabolic pathways were reprogrammed, involving glycolysis, the TCA cycle, the pentose phosphate pathway, as well as ammonium transporters and amino acid biosynthetic enzymes. These findings indicate that exogenous Spd regulated phosphorylation-mediated networks involving the SOS signaling pathway, protein homeostasis, and metabolism, thereby enhancing cucumber salt tolerance. Full article

Reactive oxygen species (ROS) act as double-edged swords in cancer biology—facilitating tumor growth, survival, and metastasis at moderate levels while inducing oxidative damage and cell death when exceeding cellular buffering capacity. To survive under chronic oxidative stress, cancer cells rely on robust antioxidant systems such as the glutathione (GSH) and thioredoxin (Trx), and superoxide dismutases (SODs). These systems maintain redox homeostasis and sustain ROS-sensitive signaling pathways including MAPK/ERK, PI3K/Akt/mTOR, NF-κB, STAT3, and HIF-1α. Targeting the antioxidant defense mechanisms of cancer cells has emerged as a promising therapeutic strategy. Inhibiting the glutathione system induces ferroptosis, a non-apoptotic form of cell death driven by lipid peroxidation, with compounds like withaferin A and altretamine showing strong preclinical activity. Disruption of the Trx system by agents such as PX-12 and dimethyl fumarate (DMF) impairs redox-sensitive survival signaling. Trx reductase inhibition by auranofin or mitomycin C further destabilizes redox balance, promoting mitochondrial dysfunction and apoptosis. SOD1 inhibitors, including ATN-224 and disulfiram, selectively enhance oxidative stress in tumor cells and are currently being tested in clinical trials. Mounting preclinical and clinical evidence supports redox modulation as a cancer-selective vulnerability. Pharmacologically tipping the redox balance beyond the threshold of cellular tolerance offers a rational and potentially powerful approach to eliminate malignant cells while sparing healthy tissue, highlighting novel strategies for targeted cancer therapy at the interface of redox biology and oncology. Full article

The peach landrace ‘Liuyefeitao’ exhibits the unique reproductive trait of self-compatibility combined with cross-incompatibility, contrasting with typical Prunus species in this way. In preliminary studies involving controlled pollination assays, we showed complete pollen tube arrest in cross-pollinated styles, whereas self-pollination enabled full tube elongation. S-genotyping identified a homozygous S₂S₂ genotype with intact S₂-RNase but a truncated PpSFB2 due to a frameshift mutation. Transcriptome profiling of the styles revealed 7937 differentially expressed genes (DEGs) between self- and cross-pollination treatments, with significant enrichment in plant MAPK signaling, plant–pathogen interactions, and plant hormone signaling transduction pathways (|Fold Change| ≥ 2, FDR < 0.01). Notably, PpSLFL3 (a pollen F-box gene) showed down-regulation in cross-pollinated styles, as validated by means of qRT-PCR. Protein interaction assays revealed direct binding between PpSLFL3 and S₂-RNase via Y2H and BiFC analysis, suggesting its role in mediating SCF complex-dependent degradation. We propose that insufficient PpSLFL3 expression during cross-pollination disrupts SCF ubiquitin ligase complex-mediated degradation of non-self S₂-RNase, leading to the toxic degradation of RNA in pollen tubes by S₂-RNase. This mechanism is mechanistically similar to unilateral reproductive barriers in Solanaceae but represents a novel regulatory module in Rosaceae. Our findings provide critical insights into the evolution of cross-incompatibility systems and molecular breeding strategies for Prunus species. Full article

Background: Rheumatoid arthritis (RA) is a chronic inflammatory disorder characterized by synovial hyperplasia and joint destruction. Previous studies have demonstrated that the alkaloids of Rushanhu (ARSHs), the dried root and stem of Zanthoxylum nitidum var. tomentosum, exhibit favorable therapeutic effects on RA, and this study aims to investigate the underlying molecular mechanisms involved. Methods: A complete Freund’s adjuvant (CFA)-induced arthritis model in male SD rats (n = 64) was used to evaluate ARSHs. Groups included control, model, methotrexate (MTX), and ARSH-treated. Therapeutic effects were assessed via arthritis index, paw swelling, and serum cytokines (IL-1β, IL-6, IL-17A). Network pharmacology identified bioactive alkaloids and core targets, validated by molecular docking. In vitro mechanisms (proliferation, apoptosis, signaling pathways) were examined in MH7A synovial cells. Results: ARSHs significantly attenuated joint inflammation and damage in CFA rats (* p < 0.01 vs. model), reducing pro-inflammatory cytokines. Fifteen alkaloids (e.g., dihydrochelerythrine, magnoflorine) and 24 targets (e.g., SRC, STAT3, MAPK3) were prioritized. Molecular docking confirmed strong binding (binding energy < −7.0 kcal/mol). In vitro, ARSHs suppressed MH7A proliferation and induced apoptosis via Bcl-2/Bax dysregulation and the inhibition of SRC/STAT3/MAPK3 phosphorylation. Conclusions: ARSHs mitigate RA pathogenesis by targeting the SRC/STAT3/MAPK3 signaling axis in synovial cells. This study provides mechanistic validation of ARSHs as multi-target phytotherapeutic agents against inflammatory arthritis. Full article

Hederagenin, a pentacyclic triterpenoid saponin from various medicinal plants, shows immense therapeutic potential; however, its inherent low bioavailability severely hinders its clinical translation. This comprehensive review synthesizes recent studies on the health benefits of hederagenin and its glycosides, critically the chemical modification strategies and pharmacological mechanisms aimed at optimizing its bioactivity. Key findings reveal that its broad anticancer and anti-inflammatory activities largely stem from its capacity to modulate crucial cellular signaling pathways, including the NF-κB, PI3K/Akt, and MAPK. Structural modification, particularly intelligent derivatization at the C-28 position, is a central strategy to overcome its pharmacokinetic deficiencies and significantly boost cytotoxicity. Furthermore, its unique pro-oxidant function within cancer cells, achieved by inhibiting the Nrf2-ARE antioxidant pathway, offers a novel approach for selective chemotherapeutics. For the clinical translation of hederagenin, we propose a strategic focus on derivatization through multi-target hybrids and sophisticated delivery systems. This approach is essential for addressing its pharmacokinetic barriers while strategically leveraging its context-dependent pro-oxidant effects. Full article

This study aims to develop a gelatin methacryloyl (GelMA)-based ginsenoside Rb3 (G-Rb3) drug delivery system and investigate its application in the treatment of periodontitis and the underlying mechanisms. Periodontal ligament stem cells (PDLSCs) were obtained and identified. The appropriate concentration ranges of G-Rb3 and lipopolysaccharide (LPS) were investigated by the CCK-8 experiments. Quantitative RT-PCR, ELISA, and Western blot were performed to assess the effects of GelMA@G-Rb3 on LPS-treated PDLSCs. The possible mechanisms were determined through network pharmacology analysis and Western blot. The therapeutic effects of GelMA@G-Rb3 in rat periodontitis animal models were systematically evaluated using Micro-CT, H&E staining, Masson staining, and immunofluorescence staining. PDLSCs were successfully isolated and characterized. The in vitro results indicated that GelMA@G-Rb3 significantly alleviated LPS-induced inflammation in PDLSCs by inhibiting the p38/ERK signaling pathway and activating the PI3K/AKT signaling pathway. In vivo experiments confirmed that GelMA@G-Rb3 significantly reduced alveolar bone resorption, and promoted periodontal tissue regeneration, while simultaneously demonstrating significant regulatory effects on the MAPK signaling pathway. This study demonstrated the efficacy of the GelMA@G-Rb3 system in modulating the inflammatory responses of periodontitis and improving the periodontal tissue regeneration, which establish a solid foundation and proposed innovative therapeutic approaches for the treatment of periodontitis. Full article

This study investigates the effect of walnut green husk extract (WE) on gut microbiota, metabolites, and immune-antioxidant changes in fattening pigs through gut microbiota-metabolite interactions. A total of 60 healthy fattening pigs (Duroc × Landrace × Yorkshire) with an initial body weight of 65.2 ± 3.1 kg were randomly assigned to two groups (n = 30 per group): the control group (NC), which was fed a basal diet, and the WE group, which was fed the basal diet supplemented with 0.1% walnut green husk extract (WE). Dietary supplementation with 0.1% WE significantly increased the relative abundances of beneficial bacteria (e.g., Firmicutes, Lactobacillus) and reduced pathogenic bacteria (e.g., Proteobacteria, Shigella). Untargeted metabolomics identified 170 differentially accumulated metabolites, among which propionic acid—a key short-chain fatty acid with immunomodulatory effects—was significantly upregulated by 1.09-fold (p = 0.03) and showed a positive correlation with beneficial microbial abundances. These metabolites were enriched in glycerophospholipid and α-linolenic acid metabolism pathways, where eicosadienoic acid inhibited the nuclear factor kappa-B (NF-κB) pathway for anti-inflammatory effects, and methyl cinnamate synergistically regulated mitogen-activated protein kinase (MAPK) signaling with Lactobacillus. Serum analyses showed that WE significantly enhanced IgA, IgM, and IgG levels by 3.97-fold, 4.67-fold, and 4.43-fold (p < 0.01), reduced malondialdehyde (MDA) concentration by 82.8% (p < 0.01), and trended to improve antioxidant capacity via glutamine. Mechanistically, WE promoted short-chain fatty acid production by beneficial bacteria, forming a “microbiota–metabolite–immunity” cascade to enhance lipid metabolism and alleviate intestinal inflammation. These findings highlight that WE provides multi-omics evidence for its application as a functional feed additive. Full article

Background/Objectives: Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm characterized by the BCR–ABL fusion gene, whose constitutive tyrosine kinase activity drives leukemogenesis. Although tyrosine kinase inhibitors (TKIs) have revolutionized treatment, drug resistance and leukemic stem cell persistence remain major challenges. Natural compounds such as polyphenols have shown potential in modulating key oncogenic pathways in CML. Results: Polyphenols such as resveratrol, quercetin, curcumin, and epigallocatechin gallate (EGCG) demonstrated significant antiproliferative and pro-apoptotic effects in CML cell lines, including imatinib-resistant models. These effects were mediated through the modulation of signaling pathways, including PI3K/Akt, STAT5, and MAPK; inhibition of BCR–ABL expression; induction of oxidative stress; and the enhancement of apoptosis via mitochondrial and caspase-dependent mechanisms. Some polyphenols also showed synergistic activity with TKIs, potentiating their efficacy and overcoming resistance. Conclusions: Preclinical evidence supports the role of polyphenols as potential adjuvants in CML therapy, particularly in drug-resistant contexts. Their pleiotropic molecular actions and low toxicity profile make them promising candidates for integrative oncology. Nonetheless, clinical translation requires further investigation through well-designed trials assessing efficacy, safety, and pharmacokinetics. Full article

Background: Hepatocellular carcinoma is one of the leading causes of cancer-related deaths worldwide. Its high recurrence rate and limited treatment options underscore the urgent need for the development of new and highly effective drugs. Methods: This study systematically explores the molecular mechanism of cinnamic acid against hepatocellular carcinoma through integrated machine learning prediction, network pharmacological analysis and in vitro experimental verification. Results: The prediction of anti-tumor activity based on the random forest model showed that cinnamic acid has significant anti-tumor potential (probability = 0.69). Network pharmacology screened 185 intersection targets of cinnamic acid and liver cancer, of which 39 core targets (such as PIK3R1, AKT1, MAPK1) were identified as key regulatory hubs through protein interaction network and topological analysis. Functional enrichment analysis showed that these targets were mainly enriched in the PI3K/AKT signaling pathway (p = 2.1 × 10⁻¹²), the cancer pathway (p = 3.8 × 10⁻¹⁰), and apoptosis-related biological processes. Molecular docking validation revealed that the binding energies of cinnamic acid with the 19 core targets were all below −5 kcal/mol, a threshold indicating strong binding affinity in molecular docking. The binding modes to PIK3R1 (−5.4 kcal/mol) and AKT1 (−5.1 kcal/mol) stabilized through hydrogen bonding. In vitro, cinnamic acid dose-dependently inhibited Hep3B proliferation/migration, induced apoptosis, downregulated PI3K, p-AKT, and Bcl-2, and upregulated Bax and Caspase-3/8. Conclusions: This study systematically reveals, for the first time, that the multi-target mechanism of cinnamic acid exerts anti-hepatic cancer effects by targeting the PI3K/AKT signaling pathway, supporting its potential as a natural anti-tumor drug. Full article

Investigating the physiological responses and resistance mechanisms in plants under drought stress provides critical insights for optimizing irrigation water utilization efficiency and promoting the development of irrigation science. In this study, cotton seedlings were cultivated in a light incubator. Three drought stress levels were applied: mild (M1, 50–55% field moisture), moderate (M2, 45–50%), and severe (M3, 40–45%). Transcriptome analysis was performed under mild and severe stress. The results revealed that differentially expressed genes (DEGs) related to proline degradation were down-regulated and proline content increased in cotton. Under different stress treatments, cotton exhibited a stress-intensity-dependent regulation of carbohydrate metabolism and soluble sugar content decreased and then increased. And the malondialdehyde content analysis revealed a dose-dependent relationship between stress intensity and membrane lipid peroxidation. Stress activated the antioxidant system, leading to the down-regulation of DEGs for reactive oxygen species production in the mitogen-activated protein kinase (MAPK) signaling pathway. Concurrently, superoxide dismutase activity and peroxidase content increased to mitigate oxidative damage. Meanwhile, the photosynthetic performance of cotton seedlings was inhibited. Chlorophyll content, stomatal conductance, the net photosynthetic rate, the transpiration rate and water use efficiency were significantly reduced; intercellular carbon dioxide concentration and leaf stomatal limitation value increased. But photosynthesis genes (e.g., PSBO (oxygen-evolving enhancer protein 1), RBCS (ribulose bisphosphate carboxylase small chain), and FBA2 (fructose-bisphosphate aldolase 1)) in cotton were up-regulated to coordinate the photosynthetic process. Furthermore, cotton seedlings differentially regulated key biosynthesis and signaling components of phytohormonal pathways including abscisic acid, indoleacetic acid and gibberellin. This study elucidates the significant gene expression of drought-responsive transcriptional networks and relevant physiological response in cotton seedlings and offers a theoretical basis for developing water-saving irrigation strategies. Full article

Carbon monoxide (CO) is generally recognized as a toxic gas; however, it has recently been identified as an endogenous gasotransmitter with significant cytoprotective properties. CO modulates key molecular pathways, including anti-inflammatory, anti-apoptotic, antioxidant, and vasodilatory signaling pathways, by targeting heme- and non-heme-containing proteins. These proteins include soluble guanylate cyclase, cytochrome P450 enzymes, MAPKs, and NLRP3. This review summarizes recent advances in understanding the molecular mechanisms associated with the protective effects of CO, particularly in the context of ischemia–reperfusion injury relevant to organ transplantation. We discuss preclinical data from rodent and large animal models, as well as therapeutic delivery strategies, such as inhalation, CO-releasing molecules, and gas-entrapping materials. We also reviewed early-phase clinical trials. The objective of this review is to provide a thorough exploration of CO as a potential therapeutic gas, with special emphasis on its application in transplantation. Full article

The serine protease kazal-type inhibitor (SPINK) family is central to the regulation of proteolytic function, the establishment of physiological homeostasis, and the development of many disease states, including cancer. Emerging research has identified that members of the SPINK family are commonly overexpressed in most malignancies and are deeply implicated in pivotal oncogenic pathways like cell growth, epithelial-to-mesenchymal transition (EMT), metastasis, and drug resistance. This review provides an in-depth examination of structural and functional characteristics of SPINK proteins and their involvement in the onset and development of multiple cancers, which include prostrate, pancreatic, and colorectal carcinomas. Significantly, SPINK proteins regulate major signalling pathways, including EGFR, NF-κB, and MAPK, highlighting their role as prognostic biomarkers and therapeutic targets. The review underscores the most recent advancements in therapeutic strategies for SPINK-related pathways and outlines the bottlenecks that have restricted their use in the clinic. By integrating current evidence, this work signals the potential of SPINK proteins as good precision oncology candidates with novel options for cancer prognosis, treatment, and management. Full article

Background/Objectives: Hair loss, driven by disrupted hair cycles, age-related hormonal imbalances, and oxidative stress, poses significant psychological challenges, necessitating the development of safe and effective therapies. This research investigates the trichogenic potential and underlying mechanisms of a standardized Ageratum conyzoides extract (ACE) using human follicle dermal papilla cells (HFDPCs) and C57BL/6 mice as models. Methods: HFDPCs were treated with ACE to assess its effects on 5α-reductase activity, estrogen receptor (ERα/ERβ) signaling, and activation of Wnt/β-catenin and MAPK pathways. Reactive oxygen species (ROS) levels and antioxidant enzyme expression were also evaluated. In vivo, C57BL/6 mice were administered ACE orally, and hair regrowth, follicle number and depth, and histological changes were measured. Results: In HFDPCs, ACE inhibited 5α-reductase activity, modulated ERα and ERβ signaling, and activated Wnt/β-catenin and MAPK pathways. ACE treatment at 100 μg/mL significantly increased β-catenin, p-GSK3β, and vascular endothelial growth factor (VEGF) expression (p < 0.01) and decreased Dickkopf-related protein-1 (DKK-)1 expression (p < 0.05). It also upregulated VEGF and other hair-growth-related factors and exhibited substantial antioxidant properties by reducing reactive oxygen species (ROS) and elevating the expression of antioxidant enzymes, notably SOD2 at 100 μg/mL. In C57BL/6 mice, oral administration of ACE significantly increased hair regrowth, with the 50 mg/kg group showing the most prominent effects, including increased hair follicle number and depth compared to the negative control group (p < 0.05). These effects were observed to be dose-dependent and comparable to those of minoxidil. Histological analysis confirmed enhanced anagen-phase follicle development. Conclusions: These findings highlight ACE’s multifaceted biological activity in promoting hair growth through hormonal modulation, pathway activation, and antioxidant protection, positioning it as a promising natural supplement for hair growth and health, although further clinical studies are required to confirm its efficacy in humans. Full article

Astrocytic tumors are a heterogeneous group of glial neoplasms characterized by marked differences in biological behavior and patient prognosis. Transforming growth factor-beta (TGF-β) signaling plays a pivotal role in astrocytoma pathogenesis; however, the extent and mechanisms of its epigenetic regulation remain poorly understood. This study aimed to investigate how promoter methylation and microRNA-mediated mechanisms regulate key genes within the TGF-β signaling pathway across various astrocytoma grades. Tumor tissue samples from 65 patients with WHO grade II–IV astrocytomas were analyzed using Affymetrix gene expression and microRNA microarrays. Promoter methylation of TGF-β signaling genes was assessed using methylation-specific polymerase chain reaction (MSP). Gene expression was validated by reverse transcription quantitative polymerase chain reaction (RT-qPCR), and protein levels were quantified using enzyme-linked immunosorbent assay (ELISA). MicroRNA targets were predicted using bioinformatic tools, and survival analyses were conducted using Kaplan–Meier and Cox regression models. Six genes—SMAD1, SMAD3, SKIL, BMP2, SMAD4, and MAPK1—showed significant upregulation in high-grade tumors (fold change > 5.0, p < 0.05), supported by RT-qPCR and protein-level data. Promoter hypomethylation and reduced expression of regulatory microRNAs (e.g., hsa-miR-145-5p targeting SMAD3) were more common in higher-grade tumors. Protein–protein interaction analysis indicated strong functional interconnectivity among the overexpressed genes. High protein levels of SMAD1, SMAD3, and SKIL were significantly associated with shorter overall survival (p < 0.001). This multi-level analysis reveals that astrocytic tumor progression involves epigenetic derepression and microRNA-mediated dysregulation of TGF-β signaling. Elevated expression of SMAD1, SMAD3, and SKIL emerged as strong prognostic indicators, underscoring their potential as biomarkers and therapeutic targets in astrocytic tumors. Full article

Gastric ulcer (GU) is a common gastrointestinal disorder that impacts quality of life. Currently, several drugs are available for GU treatment, including proton pump inhibitors like omeprazole (OMP); however, their use is limited by numerous potential adverse effects. Glycyrrhizic acid (GLY), a natural anti-inflammatory agent, exhibits promising gastroprotective properties; however, its use is likewise limited by numerous potential adverse effects. This study aimed to synthesize GLY nanoparticles (GLY-NPs) to enhance their therapeutic potential and to comparatively evaluate their efficacy against OMP in an ethanol-induced GU in male Wistar rats. GLY-NPs were synthesized via a hydrothermal method and characterized using TEM, XRD, FTIR, and zeta potential analyses. In vivo, GLY-NPs significantly attenuated gastric mucosal damage compared to OMP, as evidenced by macroscopic and histopathological analyses. Biochemical assays revealed that GLY-NPs markedly improved antioxidant defenses by elevating SOD, catalase, and glutathione peroxidase activities while reducing MDA levels, surpassing the effects of OMP. Furthermore, GLY-NPs modulated inflammatory responses by downregulating p38 MAPK, NF-κB, and TNF-α expression, concomitant with upregulation of the anti-inflammatory cytokine IL-10. Mechanistic insights indicated that GLY-NPs favorably regulated key signaling pathways implicated in gastric mucosal protection, including suppression of the JAK2/STAT3 and TGF-β1/Smad3 pathways, alongside activation of the SIRT1/FOXO1/PGC-1α axis. In conclusion, these findings indicate that GLY-NPs offer higher gastroprotective effects relative to traditional OMP therapy through comprehensive modulation of oxidative stress, inflammation, and molecular signaling pathways. This study highlights GLY-NPs as a potent nanotherapeutic candidate for the effective management of GU. Full article