Cannabisin A and B from hemp seed hulls improve glucose homeostasis by re-engaging insulin, leptin, and AMPK pathways via selective PTP1B inhibition.

The induction of somatic embryogenesis is controlled by various genes and proteins involved in hormonal pathways and stress responses, which act as key regulators of in vitro cellular reprogramming. In this study, we employed a temporal proteomic approach to investigate the underlying molecular mechanisms governing sugarcane (Saccharum spp.) embryogenic callus formation in response to 2,4-dichlorophenoxyacetic acid (2,4-D) during induction. Proteomic profiling revealed 996 differentially accumulated proteins (DAPs) across at least one pairwise comparison among time points (0, 7, 14 and 21days) during callus induction. These DAPs were classified into different clusters on the basis of their accumulation profile. Proteins involved in embryogenesis, histone epigenetic regulation, hormone responses and protein post-translational modification accumulate during callus induction. The predicted interactions between the TOPLESS protein and auxin response proteins (SKP1, CUL1 and CAND1) are associated with increased accumulation of the histone deacetylase HDT2 protein, a regulator of chromatin condensation, during embryogenic callus initiation. Moreover, proteomic analysis revealed a temporal reduction in methylation cycle enzymes during callus induction, whereas global DNA methylation showed only a slight, non-significant increase, suggesting that additional regulatory layers are present. The identified protein dynamics provide valuable targets for refining somatic embryogenesis protocols and advancing their biotechnological applications in sugarcane. SIGNIFICANCE: Genetic engineering and plant cloning usually involve the induction of embryogenic competence using 2,4-dichlorophenoxyacetic acid (2,4-D). This study presents protein-protein interaction (PPI) networks regulated during the induction of sugarcane callus using 2,4-D, in addition to the morphological aspects of the explant during the process. Proteomic analysis of time series shows the regulation of protein kinases and transcriptional regulators TOPLESS, CUL1, SKP1, CAND1, and ARGONAUTE kinases, revealing mechanisms of activation of induction and multiplication of embryogenic callus. Furthermore, the possible interaction between GH3.8 and SnRK/SAPK kinases suggests a link between hormonal responses.

TRPC1 channel modulates mechanical stretch-induced bone marrow mesenchymal stem cell proliferation through Ca2+-dependent ERK1/2 activation.

An adaptor protein CRK mediates antiviral immunity against white spot syndrome virus via JAK/STAT signaling pathway in Cherax quadricarinatus.

Metabolic dysfunction-associated fatty liver disease (MAFLD), a globally prevalent condition, can lead to serious complications, such as liver cirrhosis, hepatocellular carcinoma, and an increased risk of hepatic failure and mortality. MAFLD progression is influenced by various factors, including lipid overload, mitochondrial dysfunction, reactive oxygen species (ROS) production, and inflammation. Corylin, a flavonoid extracted from Psoralea corylifolia L., possesses multiple beneficial properties, including anti-inflammatory, antiproliferative, antiobesity, and antioxidant effects, and can alleviate hyperglycemia, hyperlipidemia, and insulin resistance. However, the beneficial potential of corylin for MAFLD has not been explored. Herein, we investigated the effects of corylin on MAFLD. Corylin reduced plasma hyperglycemia, ROS levels, lipid accumulation, inflammation, and fibrosis in livers of high-fat diet (HFD)-fed mice; additionally, it improved insulin resistance and enhanced glycogen synthesis. In palmitic acid (PA)-treated HepG2 cells, corylin decreased excessive lipogenesis, ROS production, and mitochondrial dysfunction while promoting glucose uptake, glycogen synthesis, and mitochondrial activation. Furthermore, corylin reduced inflammation in PA-treated RAW264.7 macrophages and decreased fibrotic protein expression in TGF-β-treated LX-2 hepatic stellate cells (HSCs). The regulatory effects of corylin on PA-treated HepG2 cells and RAW264.7 macrophages were mediated through adenosine 5'-monophosphate-activated protein kinase regulation; however, similar effects were not observed in transforming growth factor beta-stimulated LX-2 HSCs. These findings suggest that corylin has anti-ROS, anti-inflammatory, antilipogenic, and antifibrotic properties. Consequently, corylin is a promising beneficial candidate for the treatment of MAFLD. Antioxid. Redox Signal. 00, 000-000.

A stimulating effect induced by Bisphenol A bis (diphenylphosphate) in HepG2 cells via vascular endothelial growth factor (VEGF)/VEGF receptor axis.

This study reveals that inhibiting the protein CK2α forces blood stem cells into a stressed, immune-primed state. These tissue-specific findings highlight potential side effects for cancer therapies targeting this essential regulatory kinase.

The stability and activity of CRAF/Raf1 kinase are stringently regulated by heat shock protein 90 (Hsp90). Hsp90-mediated client folding and maturation are governed by its co-chaperones, but their functionality in chaperoning CRAF kinase to support signaling under physiological conditions remains poorly understood. Here, we show that Hsp70/Hsp90 organizing protein (HOP) associates with CRAF kinase tomaintain its activity and facilitates MAPK pathway activation. This activation is mediated by TPR2A-2B-DP2 domain of HOP and requires efficient binding to Hsp90. Although Cdc37 recruits Hsp90, it cannot compensate for HOP function. Downregulation of HOP/Sti1 in yeast and mammalian cell culture significantly reduces the CRAF signaling. Our data suggest that Hsp90 is recruited to CRAF in two distinct steps: first during folding/maturation via HOP and Cdc37, and later during activation mediated by HOP. Therefore, HOP is a regulator of CRAF kinase during activation of MAPK pathway and serves as a modulator of growth signaling beyond its client folding and maturation function.

Triple negative breast cancer (TNBC) is associated with poor prognosis and is mainly treated with chemotherapy-based regimens, often including carboplatin. Resistance to carboplatin is a common clinical issue that is either initially present or develops with treatment. Overcoming this resistance is a significant clinical challenge, which highlights the need for novel therapeutic strategies. We used a pooled shRNA screening approach with a chemoresistant TNBC patient-derived xenograft (PDX) cell (PDXC) line to identify targets whose knockdown would enhance the efficacy of carboplatin. This screening led to the identification of the ATR (ataxia telangiectasia and Rad3-related) gene as a key therapeutic vulnerability. Inhibiting ATR with BAY1895344 or AZD6738 re-sensitized carboplatin-resistant PDXCs and PDXs to carboplatin, resulting in an increase in DNA damage, and apoptosis. ATR inhibition prevents carboplatin-resistant cells from effectively engaging the S and G2/M checkpoints required for DNA repair, leading to mitotic catastrophe. We further identified that the addition of ATR inhibitors to carboplatin enabled FOXM1-targeted gene program leading to premature passage into mitosis. Moreover, targeting PKMYT1, a regulator of cyclin-dependent kinase 1 (CDK1) controlling the G2/M checkpoint, through knockdown or with the novel PKMYT1 inhibitor RP-6306, also enhanced carboplatin efficacy in our TNBC PDXC. Molecular factors associated with response to the ATR inhibitor/carboplatin combination included low RNA levels of PKMYT1. These results underscore the pivotal roles of ATR and PKMYT1 in mediating resistance to carboplatin in TNBC and support targeting these pathways to overcome carboplatin resistance in this disease.

Plasma-activated gas, an emerging technology derived from non-thermal plasma, demonstrates considerable promise in wound management through its rich repertoire of reactive oxygen and nitrogen species. Plasma-activated gas exerts broad-spectrum antimicrobial activity through multi-target mechanisms, effectively eliminating multidrug-resistant pathogens, including methicillin-resistant Staphylococcus aureus and Pseudomonas aeruginosa, as well as disrupting bacterial biofilm architecture. In tissue repair, plasma-activated gas orchestrates the entire wound healing cascade. It accelerates platelet activation and coagulation, enhances proliferation and migration of epithelial cells and fibroblasts by activating vascular endothelial growth factor receptor-extracellular regulated protein kinases 1/2 and transforming growth factor-β/Smad signaling pathways, promotes angiogenesis via the endothelial nitric oxide synthase- vascular endothelial growth factor axis, and optimizes tissue remodeling by fine-tuning the matrix metalloproteinases and their tissue inhibitors balance. Preclinical and early clinical studies confirm that plasma-activated gas significantly shortens healing time, mitigates scar formation, and effectively controls wound infection. Although challenges remain in standardization, safety profiling, and clinical translation, advances in precise dosing strategies and intelligent device design position plasma-activated gas as a transformative approach for managing refractory chronic wounds. The results and cutting-edge advancements summarized in this review are expected to provide a valuable and forward-looking reference for the subsequent research and development upgrading and clinical translational application of plasma-activated gas. JOURNAL/mgres/04.03/01612956-990000000-00092/figure1/v/2026-04-11T111231Z/r/image-tiff.

Dual-specificity phosphatase 5 (DUSP5) is a key regulator of the mitogen-activated protein kinase (MAPK) pathway, with established roles in various types of cancer. However, its function in esophageal squamous cell carcinoma (ESCC) remains unclear. This study combines single-cell transcriptomics with in vitro and in vivo models to investigate the role of DUSP5 in ESCC. Single-cell RNA sequencing revealed tumor-infiltrating myeloid populations, including apolipoprotein C-positive (APOC⁺) macrophages, which interact with tumor cells via the amphiregulin-epidermal growth factor receptor (AREG-EGFR) axis, activating MAPK/extracellular signal-regulated kinase (ERK) signaling to promote tumor growth and immune modulation. We identified a prognostic gene signature linked to these macrophages. DUSP5 expression was downregulated in ESCC tissues, and its overexpression inhibited cell proliferation, induced senescence and apoptosis, and suppressed migration and invasion. In mouse xenografts, overexpression of DUSP5 reduced tumor growth and metastasis. Mechanistically, DUSP5 inhibited ERK1/2 activation, and its tumor-suppressive effects were reversed by ERK1/2 activation. Moreover, ETS Like-1 protein (ELK1), an ERK1/2 downstream transcription factor, was identified as a negative regulator of DUSP5. In a carcinogen-induced model, DUSP5 knockout increased tumor burden, effects reversed by ERK1/2 inhibition. Our findings indicate that the DUSP5-ERK1/2-ELK1 signaling axis, modulated by tumor-infiltrating myeloid cells, contributes to ESCC progression and represents a promising source of biomarkers and therapeutic targets.

Cardiovascular diseases remain the leading global cause of death and disability, prompting the need for precise mapping of molecular drivers that couple ionic flux to signaling. Because of its regulatory role in ionic balance and signaling, transient receptor potential melastatin 7 (TRPM7) channel-kinase has emerged as a key molecular determinant of cardiovascular physiology and pathophysiology. Following an overview of Ca2+ signaling in cardiovascular biology, we summarize current knowledge of TRPM7 from its structure to its function, including channel architecture, gating properties, and kinase regulation by metabolic and redox signals with a diverse substrate repertoire. Integration of evidence across cardiovascular systems biology shows that TRPM7 acts in a context-dependent manner. In the vasculature, TRPM7 shapes endothelial function, smooth muscle phenotype and remodeling, and participates in neurogenic control of blood pressure through carotid body glomus cells. In the heart, TRPM7 regulates pacemaking and conduction through transcription control of ion channel genes, contributes to atrial fibrogenesis via Ca2+-dependent fibroblast activation, and worsens ischemia-reperfusion injury through ionic overload and inflammasome signaling. In metabolic heart disease, TRPM7 kinase activity links mitochondrial oxidative stress to diastolic dysfunction, suggesting relevance to heart failure with preserved ejection fraction (HFpEF). Finally, we appraise pharmacological tools that target TRPM7, including natural and synthetic channel and kinase modulators, and outline translational considerations for organ- and disease-specific modulation. Overall, TRPM7 is a central integrator of ionic homeostasis and kinase signaling in cardiovascular biology and represents a promising, yet nuanced, therapeutic target that requires context-aware strategies.

Ly6Chigh monocytes, previously recognized as a pro-inflammatory subset, play critical roles in secondary neuroinflammation in the stroke brain. Growing evidence reveals increased infiltration of myeloid cells with substantial heterogeneity, raising the question of how Ly6Chigh monocyte-derived macrophages in the stroke brain adapt to the ischemic environment. Here, by combining analysis of stroke patient samples with in vivo and in vitro murine studies and single-cell transcriptomic profiling, we identify hypoxia-inducible lipid droplet-associated protein (Hilpda)/hypoxia-inducible protein 2 (HIG2) as a critical mediator of anti-inflammatory property of Ly6ChighLy6Glow monocyte-derived macrophages in the stroke brain. Mechanistically, HIG2 promotes phosphatidylcholine synthesis via Hif1α-dependent transcriptional regulation of choline kinase α, initiating lipid metabolism reprogramming that underpins the anti-inflammatory phenotype of Ly6ChighLy6Glow monocyte-derived macrophages in the ischemic brain after stroke. Intranasal delivery of recombinant HIG2 protein improves neurological outcomes after stroke. These findings suggest that targeting HIG2 might represent a novel immunometabolic strategy to mitigate poststroke neuroinflammation.

The excessive use of antibiotics has driven β-lactam resistance in Escherichia coli, with the two-component system (TCS) playing a key role in regulating virulence and resistance genes. The EnvZ/OmpR TCS, involving the histidine kinase EnvZ and regulator OmpR, influences porin genes ompC and ompF. The authors' previous work suggested that EnvZ may regulate β-lactam antibiotic resistance, but the mechanism remains unclear. This study aimed to explore how EnvZ regulates β-lactam antibiotic resistance and virulence mechanisms in E. coli. An envZ deletion mutant (ΔenvZ) was constructed from an imipenem-resistant E. coli strain (Sx181-128). Phenotypic assays evaluated antibiotic susceptibility, environmental tolerance, adhesion and motility. RNA sequencing (RNA-seq) compared transcriptional profiles between Sx181-128 and ΔenvZ. The envZ deletion mutant exhibited a 2-fold increase in susceptibility to six β-lactam antibiotics (cefoxitin, meropenem, imipenem, cefepime, amoxicillin and aztreonam) compared with the resistant strain Sx181-128, along with compromised tolerance especially under hypertonic condition. RNA-seq analysis revealed 338 differentially expressed genes (116 up-regulated, 222 down-regulated), primarily associated with porins, transporters, amino sugar and nucleotide sugar metabolism and flagellar assembly. Mechanistically, envZ deletion increased membrane permeability by dysregulating ompC and ompF expression, enhancing β-lactam antibiotic uptake. Additionally, ΔenvZ displayed increased adhesion to HeLa cells, bacterial motility and biofilm-forming capacity, suggesting a dual role for EnvZ in modulating both antibiotic resistance and virulence. EnvZ regulates β-lactam resistance by modulating porin expression and membrane permeability, while also influencing virulence traits like adhesion and motility. These findings highlight TCS-mediated resistance mechanisms and offer potential targets for novel antimicrobials or vaccines against E. coli.

Root hairs at the frontline: Tiny architects of adaptive responses to salinity stress.

DUSP1 interacts with BIP to regulate Staphylococcus aureus-induced apoptosis through the MAPK signaling pathway.

S-nitrosylation of Dexras1 attenuates fear memory generalization in the infralimbic cortex.

Delivery growth factors by layer-by-layer assembly in nanofibers for enhancing bone defect repairment along with neurogenesis.

Persistent facial and oral discomfort, particularly trigeminal neuralgia (TN), is frequently accompanied by anxiety, which has been closely linked to increased excitability of neurons in the lateral habenula (LHb). However, the mechanisms underlying this hyperexcitability remain unclear. Here, we show that partial transection of the infraorbital nerve (pT-ION) significantly upregulated the expression of transient receptor potential canonical 6 (TRPC6), β isoform of calcium/calmodulin-dependent protein kinase II (βCaMKII), phosphorylated extracellular regulated kinase (p-ERK), and phosphorylated cyclic adenosine monophosphate response element-binding protein (p-CREB) in the LHb. Pharmacological blockade of either TRPC6 or βCaMKII effectively reversed pT-ION-induced mechanical hypersensitivity and anxiety-like behaviors. TRPC6 overexpression in the LHb reproduced the behavioral and electrophysiological phenotypes observed in pT-ION mice, including increased LHb neuronal excitability. In contrast, bilateral knockdown of TRPC6 attenuated both pain- and anxiety-like behaviors and normalized neuronal activity in the LHb. Our study identified TRPC6 as a key mediator of LHb neuronal hyperexcitability, contributing to trigeminal neuralgia-associated pain and anxiety via the βCaMKII/ERK/CREB pathway, and suggests its potential as a target for treatment.

Objective: To investigate the role of Rap1GAP in myocardial hypertrophy and fibrosis and its potential mechanism. Methods: In animal experiments, 20 cardiac-specific Rap1GAP knockout mice (Rap1GAPΔ/Δ) and 20 Rap1GAP homozygous floxed mice (Rap1GAPfl/fl), aged 6-8 weeks, were divided into four groups: Rap1GAPfl/fl+saline group, Rap1GAPΔ/Δ+saline group, Rap1GAPfl/fl+AngⅡ group, and Rap1GAPΔ/Δ+AngⅡ group. Echocardiography was used to assess cardiac function in each group. HE staining was performed to observe the overall structure and cellular morphology of myocardial tissue. Wheat germ agglutinin staining was used to measure the cross-sectional area of cardiomyocytes. Masson staining and Sirius red staining were employed for quantitative analysis of myocardial fibrosis levels and collagen proportion. Western blot was used to detect the protein expression levels of Rap1GAP, α-smooth muscle actin (α-SMA), atrial natriuretic peptide (ANP), β-myosin heavy chain (β-MHC), collagen type Ⅰ, collagen type Ⅲ, transforming growth factor-β1 (TGF-β1), phosphorylated extracellular regulated kinase (p-ERK), extracellular regulated kinase (ERK), phosphorylated c-Jun N-terminal kinase (p-JNK), c-Jun N-terminal kinase (JNK), phosphorylated p38 mitogen-activated protein kinase (p-p38), p38 mitogen-activated protein kinase (p38), phosphorylated nuclear factor κB (p-NF-κB), and nuclear factor κB (NF-κB) in myocardial tissue. In cell experiments, primary cardiomyocytes and cardiac fibroblasts were isolated from 1-3-day-old Wistar rat neonates. Rap1GAP expression was knocked down by transfecting Rap1GAP small interfering RNA (si-Rap1GAP), and cells were divided into si-control (negative control siRNA)+saline group, si-Rap1GAP+saline group, si-control+AngⅡ group, and si-Rap1GAP+AngⅡ group. Rap1GAP was overexpressed by infecting with Rap1GAP adenovirus (Ad-Rap1GAP), and cells were divided into Ad-GFP (GFP empty vector adenovirus)+saline group, Ad-Rap1GAP+saline group, Ad-GFP+AngⅡ group, and Ad-Rap1GAP+AngⅡ group. For inhibitor rescue experiments, cardiac fibroblasts infected with Ad-Rap1GAP or Ad-GFP were treated with 10 μmol/L p38 inhibitor (SB203580) or TGF-β1 inhibitor (pirfenidone), forming Ad-Rap1GAP+AngⅡ+SB203580 group, Ad-Rap1GAP+Ang+pirfenidone group, Ad-GFP+AngⅡ+SB203580 group and Ad-GFP+Ang+pirfenidone group. Immunofluorescence staining was used to detect the expression levels of Rap1GAP, α-SMA, and proliferating cell nuclear antigen (PCNA) in cells. Dihydroethidium staining was employed to measure reactive oxygen species (ROS) levels. Western blot was used to detect the expression levels of target proteins (consistent with animal experiments). Results: In animal experiments, compared with the Rap1GAPfl/fl+AngⅡ group, the Rap1GAPΔ/Δ+AngⅡ group showed larger left ventricular end-diastolic diameter and left ventricular end-systolic diameter, while the cardiomyocyte surface area, myocardial fibrosis ratio and myocardial collagen volume ratio were smaller. Additionally, the expression levels of ANP, β-MHC, collagen type Ⅰ, collagen type Ⅲ, and α-SMA were lower (all P<0.05). Proteomic analysis revealed differences in the protein expression profiles of myocardial tissue between the Rap1GAPΔ/Δ+AngⅡ group and the Rap1GAPfl/fl+AngⅡ group at biological process, cellular component, and molecular function. In cell experiments, compared with the si-Rap1GAP+AngⅡ group, the si-control+AngⅡ group exhibited larger cardiomyocyte cross-sectional area, as well as higher expression levels of ANP, β-MHC, collagen type Ⅰ, collagen type Ⅲ and α-SMA, and a higher proportion of PCNA-positive cells (all P<0.05). Compared with the Ad-GFP+AngⅡ group, the Ad-Rap1GAP+AngⅡ group showed larger cardiomyocyte cross-sectional area, higher expression levels of the aforementioned proteins, and a higher proportion of PCNA-positive cells (all P<0.05). Furthermore, the relative expression levels of p-ERK/ERK, p-JNK/JNK, p-p38/p38, p-NF-κB/NF-κB proteins, and ROS levels in cardiomyocytes or cardiac fibroblasts were higher in the si-control+AngⅡ group than in the si-Rap1GAP+AngⅡ group (all P<0.05), while these indices were higher in the Ad-Rap1GAP+AngⅡ group than in the Ad-GFP+AngⅡ group (all P<0.05). Meanwhile, the ROS level, proportion of PCNA-positive cells, and expression levels of TGF-β1, p-ERK/ERK, p-JNK/JNK, p-p38/p38, collagen type Ⅰ, collagen type Ⅲ, and α-SMA proteins in cardiac fibroblasts were lower in the Ad-GFP+Ang+SB203580 group than in the Ad-GFP+AngⅡ group (all P<0.05). The same trend was observed in the Ad-GFP+AngⅡ+pirfenidone group, with all aforementioned indices lower than those in the Ad-GFP+AngⅡ group (all P<0.05). Conclusions: Rap1GAP may mediate cardiomyocyte hypertrophy by regulating the mitogen-activated protein kinase signaling pathway and the expression of its downstream target NF-κB. Meanwhile, Rap1GAP may promote myocardial fibrosis by inducing ROS production and activating the TGF-β1/mitogen-activated protein kinase signaling pathway.