Search Results (1,518)

Highland barley (Hordeum vulgare var. nudum), a member of the genus Hordeum in the family Poaceae, represents a unique cultivated crop adapted to the Qinghai–Tibet Plateau. Weed infestation has long posed a serious threat to the yield and quality of highland barley, and the lack of effective weed management strategies has become a major constraint in its production. Pyroxsulam is an acetolactate synthase (ALS)-inhibiting herbicide widely used for weed control in highland barley fields. This study investigated the molecular mechanisms underlying the response of highland barley to pyroxsulam by integrating physiological, biochemical, and transcriptomic analyses. ALS activity assays showed that the resistant variety ‘Qing0306’ exhibited a significant increase in relative ALS activity within 1–4 days after pyroxsulam treatment. qRT-PCR analysis revealed a rapid induction of HvnALS expression, which was significantly higher in ‘Qing0306’ than in ‘Qing0160’ on the first day after treatment (p < 0.01), indicating that resistance is primarily associated with target-enzyme overexpression rather than target-site mutations. Moreover, transgenic Arabidopsis lines overexpressing HvnP450 and HvnGSTs displayed enhanced tolerance to pyroxsulam, as evidenced by an increased root length and fresh weight compared with wild-type plants. This study provides mechanistic insights that support the genetic improvement of pyroxsulam-resistant highland barley. Full article

We previously demonstrated that HBV promotes liver fibrosis through the enhanced production of pyruvate. Pyruvate kinase M2 (PKM2), a key enzyme in pyruvate metabolism, plays an important role in liver fibrogenesis. Recently, lactylation of PKM2 has been identified, which contributes to stabilize its catalytically active tetrameric conformation. Therefore, we hypothesize that PKM2 lactylation is involved in the regulation of HBV-induced liver fibrosis. In this study, we found that sera lactate levels were increased in CHB patients and HBV-Tg mice. Moreover, the lysine lactylation levels of proteins in liver tissues were significantly increased in the HBV-Tg mice. In LX2 cells, we found that pyruvate treatment significantly increased the profibrotic gene expression and lactylation level of PKM2, which promoted its tetramer-to-dimer transition, inhibited its pyruvate kinase activity, and facilitated its nuclear distribution. Through immunoprecipitation, we identified that pyruvate induced PKM2 lactylation at the K206 site. PKM2 knockdown or K206 mutation reduced PKM2 lactylation and abrogated the induction of profibrotic gene expression by pyruvate. Collectively, our findings indicate that HBV infection stimulated pyruvate production, which increased PKM2 lactylation at K206 to promote the expression of profibrogenic genes in HSCs, leading to liver fibrogenesis. Full article

Plasmid copy number (PCN) is a key factor limiting the expression level of heterologous proteins in yeast. Static strategies for enhancing PCN, such as reducing the transcriptional intensity of selection markers or increasing selection pressure, only maintain PCN at a single fixed level and struggle to achieve dynamic, precise, and reversible copy number regulation. This study established a dynamic plasmid copy number regulation strategy based on CRISPR interference (CRISPRi). Flexible control of PCN was achieved by designing specific guide RNAs (gRNAs) and integrating them into the inducible CRISPRi system. Optimization of the gRNA target site, inducer concentration, and induction timing resulted in a >2-fold increase in the fluorescence intensity of yeast-enhanced green fluorescent protein (yeGFP) compared with the group without induction. Using naringenin synthesis as proof-of-concept, this regulatory tool was applied to modulate the expression of chalcone synthase (CHS), the rate-limiting enzyme in naringenin biosynthesis. Finally, the yield of naringenin increased by 35.62% under the optimal induction conditions. Full article

Extensive use of chemical herbicides has raised serious concerns regarding agricultural sustainability and ecological safety, highlighting the need for environment friendly bioherbicides. In this study, activity-guided fractionation led to the identification of xanthoxylin and α-santonin from the ethanol extract of a dominant desert plant, Seriphidium transiliense, with the phytotoxicity of xanthoxylin being reported for the first time. Petri dish bioassay revealed that both compounds significantly suppressed seedling growth of tested plants in a dose-dependent manner; at 1000 μg/mL, α-santonin inhibited root growth of Amaranthus retroflexus, Setaria viridis, Medicago sativa, and Oxybasis glauca by 98.25%, 79.75%, 71.40%, and 62.75%, respectively, whereas the corresponding inhibition rates for xanthoxylin were 59.15%, 89.71%, 38.80%, and 62.90%. Following pot experiments revealed that both compounds significantly increased MDA content and altered the activities of SOD, CAT, and POD of A. retroflexus seedlings, indicating the induction of oxidative stress. Treated plants also displayed chlorosis and leaf whitening, suggesting possible disturbance of photosynthetic pigment-related processes; subsequent molecular docking further implied that both compounds may interact with protoporphyrinogen IX oxidase (PPO), a key enzyme associated with tetrapyrrole metabolism and chlorophyll biosynthesis. Our results suggests that α-santonin and xanthoxylin have the potential to be developed as bio-herbicides. Full article

Clear cell renal cell carcinoma (ccRCC) is characterized by profound metabolic reprogramming and limited responsiveness to therapeutic stressors, including epigenetic modulation. How glycolytic enzymes contribute to metabolic stress tolerance in ccRCC remains incompletely understood. We investigated the role of the glycolytic enzyme 2,3-bisphosphoglycerate mutase (BPGM) using human tumor specimens, siRNA-mediated gene silencing, functional cell-based assays, and transcriptomic profiling. Epigenetic stress was induced using Vorinostat as a pan-histone deacetylase inhibitor. BPGM expression was consistently elevated in human ccRCC compared with adjacent normal kidney tissue. A498 cells exhibited high basal BPGM levels and limited sensitivity to Vorinostat, whereas BPGM depletion increased cellular stress responses and reduced proliferative capacity. Despite similar phenotypic outcomes, BPGM silencing and Vorinostat treatment triggered distinct transcriptional programs. While HDAC inhibition induced widespread transcriptional changes, BPGM loss elicited a focused stress-associated response, consistent with activation of the unfolded protein response, increased lipid peroxidation, and induction of ER stress-associated genes. Our data identify BPGM as a metabolic player contributing to stress-adaptive transcriptional states in ccRCC and suggest that targeting metabolic stress adaptation may complement epigenetic strategies in renal cancer. Full article

Osteoporosis is characterized by reductions in bone mineral density (BMD) and bone quality. While gut-derived signaling has been increasingly studied in relation to BMD, its contribution to molecular factors associated with bone quality remains less defined. Here, we investigated whether a heat-inactivated, freeze-dried, non-viable preparation of Levilactobacillus brevis AS-1 modulates intestinal epithelial-like cells and thereby promotes lysyl oxidase (LOX), a key enzyme involved in collagen cross-linking. Caco-2 cells were treated using 1 mM sodium butyrate and subsequently stimulated with 100 μg/mL L. brevis AS-1. Supernatants were collected and applied to MG63 cells. Cytokine mRNA expression in Caco-2 cells and LOX responses in MG63 cells were analyzed by qRT-PCR, and bone morphogenetic protein (BMP-1) and transforming growth factor-β (TGF-β)1 protein levels in the supernatant were measured by ELISA. L. brevis AS-1 stimulation up-regulated BMP-1 and TGF-β1 mRNA expression in SB-treated Caco-2 cells and increased BMP-1 protein secretion into the supernatant. LOX mRNA expression and total LOX activity were increased in MG63 cells treated with the conditioned supernatant, and inhibition of BMP-1/procollagen C-proteinase activity (UK383367) attenuated LOX mRNA induction. Collectively, these results suggest that L. brevis AS-1 stimulates intestinal epithelial-like cells to secrete BMP-1, which in turn promotes LOX mRNA expression in osteoblast precursor cells. This in vitro mechanism supports the concept of gut–bone crosstalk regulating molecular factors associated with bone quality. Full article

Acute kidney injury (AKI) is a major complication of lupus nephritis and kidney transplantation, inevitably causing ischemia–reperfusion (I/R) injury. We previously confirmed that high-dose voclosporin induces drug nephropathy through aberrant peroxisome accumulation. The latter induces increased renal indole-3-aceticT acid (IAA) production due to the decreased expression of the IAA-degrading enzyme indolethylamine N-methyltransferase (INMT). Conversely, INMT overexpression prevents this nephropathy, suggesting that high-dose voclosporin could enable a novel therapeutic approach. This prompted us to test whether INMT overexpression with high-dose voclosporin could avert nephrotoxicity and protect against I/R injury. Inmt-overexpressing mice treated with high-dose voclosporin exhibited absence of peroxisomal abnormalities and resistance to I/R injury. RNA sequencing revealed the downregulation of tubular injury markers NGAL (Lcn2) and KIM-1 (Havcr1) concurrent with significant cytokine suppression. Mechanistic analysis revealed the robust induction of Regnase-2, an mRNA decay factor, which directly targeted stem–loop structures within the 3′ untranslated region of Lcn2 and Havcr1, thereby promoting their degradation in proximal tubular cells. Importantly, Regnase-2 knockdown mice showed Lcn2 upregulation, mitochondrial dysfunction, and peroxisomal abnormalities culminating in AKI, underscoring its renal protective effects. High-dose voclosporin under Inmt overexpression promoted Regnase-2-mediated mRNA decay to suppress tubular injury. This protective effect extended beyond I/R to rhabdomyolysis- and lipopolysaccharide-induced AKI to prevent nephropathy. Our findings demonstrate the potential transformative therapeutic approach of administering high-dose voclosporin to promote the prophylactic effect of Regnase-2 augmentation against AKI in both native and transplanted human kidneys. Full article

Cancer is an alarming health concern and economic burden in both developed and developing countries. Recently, there has been a growing demand for new alternative medications with more effectiveness and fewer harmful effects. During the past decades, a set of chemotherapeutic agents has been developed to fight against a large spectrum of cancer types. Unfortunately, their use is associated with a high level of toxicity; they are expensive, also, and their deployment is restricted by the emergence of cellular resistance. Plant-based components are garnering attention due to their low toxicity, selectivity, efficiency, and ease of accessibility. Alkaloids are one of these targeted compounds. Indeed, they are a highly diverse group with basic heterocyclic nitrogen-containing alkaloids that exhibit potent anticancer effects against a large panel of solid and liquid tumors, such as lung, breast, leukemia, liver, and colon cancer. The main molecular mechanisms involved in alkaloids’ anticancer effect are the induction of apoptosis via the extrinsic and intrinsic pathways, DNA damage, and the inhibition of cell cycle progression. Amazingly, these auspicious compounds exhibited strenuous inhibitory effects against a whole range of key enzymes involved in cancer progression and metastasis, such as Cytochrome P450 (CYP450), Cyclooxygenase-2 (Cox-2), Lysine-Specific Demethylase 1 (LSD1), Poly [ADP-ribose] polymerase (PARP), and topoisomerase, mainly through two action modes, namely irreversible and reversible inhibition. Furthermore, several conventional extraction methods have been developed to extract bioactive compounds from natural matrices, such as Soxhlet and hot water extraction. However, these techniques have many drawbacks, as they require a large amount of organic solvents, which not only affect human health but also generate severe environmental issues. To overcome these limitations, multiple eco-extraction techniques have emerged as potential alternatives to traditional extraction methods such as ultrasonic extraction, microwave-assisted extraction, and supercritical fluid extraction. In fact, they are considered eco-friendly and efficient technologies with less time and solvent consumption. Overall, this review aims to provide an updated overview of the most prominent anticancer alkaloids that have not been well reviewed already, as well as the main green extraction techniques relevant to the extraction of antineoplastic alkaloids. Full article

Background: Infections caused by multidrug-resistant bacteria and inadequate vaccine coverage against opportunistic pathogens highlight the need for interventions that broadly and durably enhance host defense beyond antigen-specific adaptive immunity. Trained immunity, driven by metabolic and epigenetic reprogramming of innate immune cells, has been predominantly characterized using Bacille Calmette–Guérin and β-glucan, whereas its induction by Gram-negative bacteria remains poorly defined. To address this gap, we aimed to determine whether heat-killed Klebsiella pneumoniae (HK Kp) induces trained immunity through metabolic and hematopoietic reprogramming to confer heterologous antibacterial protection. Methods: HK Kp-trained murine bone marrow-derived macrophages and HK Kp-immunized C57BL/6 mice were employed to interrogate functional, metabolic, and transcriptomic reprogramming in vitro, hematopoietic progenitor remodeling in vivo, and protective efficacy against systemic Salmonella Typhimurium and Staphylococcus aureus infection. Results: HK Kp-trained macrophages showed markedly enhanced IL-1β secretion across all restimulation conditions, stimulus-dependent amplification of TNF-α responses, increased phagocytosis, and improved intracellular control of S. typhimurium, together with sustained upregulation of the glycolytic enzymes-encoding genes Hk2 and Pfkfb3. Transcriptomic profiling revealed extensive reprogramming enriched in glycolysis/gluconeogenesis and hematopoietic cell lineage pathways. In vivo, HK Kp immunization shifted bone marrow stem/progenitor compartments toward a myeloid-biased state. HK Kp-trained mice challenged with lethal S. typhimurium or S. aureus exhibited less weight loss, improved survival rates, and reduced bacterial burdens. Conclusions: Inactivated K. pneumoniae orchestrates metabolic and hematopoietic reprogramming to establish enhanced innate immune responsiveness and confer heterologous protection in murine S. typhimurium and S. aureus sepsis models, supporting its potential as a potent inducer of trained immunity. These findings establish HK Kp-based trained immunity as a promising strategy for combating multidrug-resistant and vaccine-evading pathogens. Full article

Soil salinization has become a major global constraint threatening ecosystem stability and agricultural production. As a prominent salt-tolerant turfgrass, Paspalum vaginatum (seashore paspalum) serves as an excellent material for exploring salt tolerance mechanisms. In this study, PvHAK12, a high-affinity K⁺ transporter (HAK) family gene isolated from seashore paspalum, was functionally characterized. PvHAK12 encodes a 788 amino acid protein with 13 transmembrane domains, belonging to the plasma membrane-localized ion transporters. It exhibits high sequence conservation with other HAK transporters and is predominantly expressed in roots and stems, with distinct tissue- and time-specific induction under salt stress. Yeast complementation assays revealed that PvHAK12 has no obvious K⁺ transport capacity but may mediate Na⁺ transport. Overexpression of PvHAK12 in Arabidopsis thaliana significantly reduced salt tolerance at germination, seedling and rosette stages, as reflected by lower germination rate, fresh weight, survival rate, the maximum quantum yield of photosystem II (Fv/Fm) value and chlorophyll content, accompanied by higher ion leakage. Under salt stress, transgenic plants accumulated more Na⁺ and less K⁺, leading to an elevated Na⁺/K⁺ ratio. Moreover, transgenic lines displayed weaker antioxidant enzyme activities and higher reactive oxygen species (ROS) accumulation. Transcript analysis further demonstrated that PvHAK12 overexpression suppressed the induction of multiple ion-transport and stress-responsive genes under salt conditions. These results indicate that PvHAK12 negatively regulates plant salt tolerance by disrupting ion homeostasis, antioxidant capacity and stress-related gene expression. Full article

As a global environmental problem, biological invasion poses a serious threat to natural ecosystems. To explore the influence mechanism of Alternanthera philoxeroides (Mart.) Griseb on the growth and development of landscape plants, this study systematically analyzed the effects of extracts from different organs (stems, leaves, and roots) of A. philoxeroides on the seed germination and seedling growth of Zinnia elegans Jacq. by combining the Petri dish filter paper method with a pot experiment to reveal the potential mechanism of allelopathy. The results showed that the aqueous extract of A. philoxeroides inhibited the seed germination and seedling growth of Z. elegans. The high concentration (100 mg·mL⁻¹) of stem and leaf extracts significantly reduced the germination rate (by 99.10% and 90.65%) and seedling morphological parameters. The allelopathic inhibition increased with an increase in concentration, and the inhibitory effect of stem and leaf extracts was significantly stronger than that of root extracts. Aqueous extracts from the roots, stems, and leaves of A. philoxeroides at three concentrations (25, 50, and 100 mg·mL⁻¹) induced oxidative stress in seedlings, as evidenced by the elevated malondialdehyde (MDA) content and dysregulated activities of antioxidant enzymes. Specifically, superoxide dismutase (SOD) and catalase (CAT) activities exhibited a concentration-dependent trend of initial induction followed by subsequent inhibition, while root activity was significantly suppressed (p < 0.05), ultimately impairing seedling growth. The aqueous extracts of A. philoxeroides showed a concentration-dependent inhibitory effect on the seed germination and seedling growth of Z. elegans. High concentrations of stem and leaf extracts exerted a significant inhibitory effect on seedling growth, and this growth suppression was attributed to the induction of oxidative stress by the extracts. This study elucidated the phytotoxicity degree and physiological response mechanisms underlying the biochemical allelopathy of A. philoxeroides on Z. elegans. The findings provide a theoretical foundation for the selection of horticultural plant cultivars resistant to allelopathic stress and the development of management strategies for invasive plants. Full article

Background: Wild jujube (Ziziphus jujuba var. spinosa) exhibits remarkable tolerance to saline-alkali stress, yet its molecular mechanisms remain poorly understood. 3-ketoacyl-CoA synthase (KCS) is a key enzyme involved in the biosynthesis of very-long-chain fatty acids (VLCFAs), which constitute pivotal precursors for membrane lipids involved in stress adaptation. Methods: Through genome-wide analysis and molecular biology techniques, 20 ZjKCS genes were identified. Results: The ZjKCS genes were grouped into nine subfamilies, exhibiting highly conserved gene structures, motifs, and functional domains within each subfamily. Two pairs of collinear gene pairs were identified, with the ZjKCS12-ZjKCS18 pair retaining core conserved functions despite intense purifying selection. ZjKCS genes are rich in cis-acting elements associated with light transduction, phytohormone responses, and abiotic stress adaptation. Tissue-specific expression patterns of ZjKCS under light, ABA (abscisic acid), and MeJA (methyl jasmonate) treatments were analyzed by quantitative real-time PCR (qRT-PCR). Under saline-alkali stress, ZjKCS genes were significantly upregulated, with most showing strong sustained induction during later treatment stages. Conclusions: These findings indicate that the ZjKCS family participates in saline-alkali stress and abiotic stress adaptation, potentially by enhancing VLCFA synthesis to reinforce and remodel membrane lipid structure. This study provides a foundation for elucidating lipid-mediated stress resistance mechanisms in stress-tolerant fruit trees. Full article

Multiple myeloma (MM) is an incurable plasma cell malignancy characterized by high metabolic activity, chronic endoplasmic reticulum stress, and persistent redox imbalance. Excessive immunoglobulin synthesis and adaptation to the hypoxic bone marrow microenvironment lead to sustained production of reactive oxygen species (ROS). Their excessive accumulation promotes genomic instability, disease progression, osteolytic bone disease, and resistance to therapy. Paradoxically, MM cells adapt to oxidative stress by activating antioxidant and metabolic defense mechanisms, including Nuclear factor erythroid 2-related factor 2 (NRF2)- and Heme Oxygenase 1 (HMOX1)-dependent pathways, metabolic reprogramming, and overexpression of ROS-scavenging enzymes such as peroxiredoxin 6 (PRDX6), allowing survival at the threshold of oxidative toxicity. Evidence indicates that biomarkers of oxidative stress—such as lipid and protein oxidation products, antioxidant enzyme activity, and the Oxidative Stress Score—correlate with disease stage, prognosis, and treatment response. Redox-modulating therapeutic strategies, including pharmacological ROS induction, inhibition of antioxidant defenses, and the use of natural pro-oxidant compounds, are emerging as promising adjuncts to standard MM therapies. Recent studies also highlight the gut microbiota as an indirect regulator of oxidative balance, immune modulation, and metabolic homeostasis in MM. This review summarizes current knowledge on oxidative stress in multiple myeloma, emphasizing its role in pathogenesis, drug resistance, biomarker development, and emerging therapeutic and supportive strategies. Full article

Bladder cancer (BCa) is the second most common cancer of the genitourinary tract globally. It has limited treatment options, high recurrence rate, and acquires resistance to platinum-based therapy. Therefore, identifying novel therapeutic targets is urgently needed. Analysis of the TCGA data revealed that the enzyme galactokinase-1 (GALK1) is overexpressed (p < 0.0001) in bladder tumors compared to normal tissue. Our data also confirmed GALK1 protein upregulation in multiple human BCa cell lines and rodent bladder tumors. However, the precise role of GALK1 in BCa progression and effects of its specific inhibitor remain unexamined. In this study, we demonstrate that GALK1 gene silencing using shRNA resulted in a significant reduction in BCa cell proliferation, migration, and invasion. Pharmacological inhibition of GALK1 using small molecule Cpd36 resulted in anticancer efficacy against BCa. Cpd36 inhibited proliferation, migration, and invasion of BCa cells. Further, Cpd36 induced G1 phase cell cycle arrest, apoptosis, mitochondrial membrane depolarization, and ROS production in the BCa cells. Mechanistically, Cpd36-induced reduction in cell proliferation was associated with a decrease in expression of GALK1, PCNA proteins. Inhibition of metastatic potential was accompanied by decreased migration, invasion, and MMP-9 expression. Cell cycle arrest was associated with decrease in Cyclin D1 and increased expression of p21 and p27. Induction of apoptosis was linked with increased expression of cleaved caspase-3 and cleaved PARP, while downregulating p-AKT. Additionally, Cpd36 in combination with cisplatin or gemcitabine showed a strong synergistic effect on BCa cells. Taken together, our findings suggest that GALK1 plays a significant role in BCa cell survival and validates its inhibitors as promising therapeutic options for managing this disease. Full article

Phenolamides in bee pollen exhibit notable bioactivities, such as antioxidant, anti-inflammatory, and antimicrobial effects. Ulcerative colitis (UC) is a prevalent intestinal disorder, while the potential effects of phenolamides on UC remain unclear. This study aims to investigate the effects and mechanisms of phenolamide extract (PAE) from apricot bee pollen on dextran sulfate sodium (DSS)-induced UC in mice. Firstly, we analyzed the main compounds of PAE. Mice were treated with PAE (100, 200, and 400 mg/kg bw) both during the 7 days preceding 2.5% DSS induction and throughout the induction period (7 days). The results show that the primary compounds of PAE were isomers of tri-p-coumaroyl spermidine (97.78 ± 2.76%). A biochemical analysis showed that PAE decreased the levels of pro-inflammatory cytokines and increased the activities of antioxidant enzymes. Regarding the gut microbiota, PAE reduced the Bacillota/Bacteroidota ratio. Additionally, PAE elevated beneficial bacteria, including norank_f_Muribaculaceae, norank_o_Clostridia_UCG-014, and Lachnospiraceae_NK4A136_group, while reducing harmful bacteria, including Escherichia-Shigella, Clostridium, and Romboutsia. A quantitative analysis of short-chain fatty acids (SCFAs) demonstrated that PAE intervention promotes the biosynthesis of SCFAs in UC mice. This study first demonstrates that PAE attenuates DSS-induced colitis by modulating gut microbiota and SCFAs, suggesting its potential as a functional dietary supplement for colitis. Full article