Search Results (506)

Resveratrol (RSV), a polyphenol found in a variety of berries and wines, is known for its anti-inflammatory, anticancer, and antioxidant properties. It has been suggested that RSV may play a role in the regulation of metabolic disorders, including diabetes and insulin resistance. However, in recent years, it has been reported to completely inhibit Akt kinase function in liver cells. Akt is a central protein involved in the metabolic function of insulin and is regulated by the phosphatidylinositol-3-kinase (PI3K) pathway. In this study, we examined the effect of RSV on insulin-induced insulin receptor (IR) phosphorylation and proteins involved in the PI3K/Akt pathway in a hepatic cell model, clone 9 (C9), and in hepatoma cells, Hepa 1-6 (H1-6). In both cell lines, RSV inhibited tyrosine phosphorylation of IR and insulin-induced activation of Akt. We also evaluated the effect of RSV on the activation of protein tyrosine phosphatase 1B (PTP1B), which is associated with IR dephosphorylation, and found that RSV increased PTP1B-Tyr¹⁵² phosphorylation in a time- and concentration-dependent manner. Furthermore, we found that the protein kinase C (PKC) inhibitors BIM and Gö6976 prevented the inhibition of Akt phosphorylation by RSV and increased the phosphorylation of Ser/Thr residues in IR, suggesting that PKC is involved in the inhibition of the insulin pathway by RSV. Thus, classical PKC isoforms impair the PI3K/Akt pathway at the IR and GSK3 and GS downstream levels; however, IRS-Tyr⁶³² phosphorylation remains unaffected. These results suggest that RSV can lead to insulin resistance by activating PTP1B and PKC, consequently affecting glucose homeostasis in hepatic cells. Full article

The white button mushroom (Agaricus bisporus) is a widely cultivated edible and medicinal mushroom, which contains various active substances, and has application value against pathogenic bacteria in aquaculture. Firstly, A. bisporus water extract (AB-WE) was prepared. Through the detection kits, it was found that the polysaccharide, protein, and polyphenol components of AB-WE were 9.11%, 3.3%, and 1.5%, respectively. The 246 compounds were identified in AB-WE, and the major small-molecule components included L-Isoleucine, L-Tyrosine, L-Valine, and Linoleic acid by HPLC-Q Exactive-Orbitrap-MS. Secondly, the AB-WE was evaluated for its immunological activities through dietary administration and pathogen challenge (Aeromonas hydrophila and Vibrio fluvialis) in goldfish (Carassius auratus). The results showed that the levels of immune factors of acid phosphatase (ACP), alkaline phosphatase (AKP), and lysozyme (LZM) increased (p < 0.05) in goldfish, and the relative percentage survival of AB-WE against A. hydrophila and V. fluvialis were 80.00% (p < 0.05) and 81.82% (p < 0.05), respectively. The AB-WE reduced the bacterial content in renal tissue, enhanced the phagocytic activity of leukocytes, and exhibited antioxidant and anti-inflammatory effects by reducing the expression of antioxidant-related factors and inflammatory factors. Through histopathological and immunofluorescence techniques, it was found that AB-WE maintained the integrity of visceral tissues and reduced renal tissue apoptosis and DNA damage. Therefore, AB-WE exhibits immunoprotective activity against A. hydrophila and V. fluvialis infections in fish, and holds promise as an immunotherapeutic agent against major pathogenic bacteria in aquaculture. Full article

Neutrophils play a key role in autoimmune diseases like rheumatoid arthritis, contributing to tissue damage through rapid recruitment and activation. In this study, we investigated the regulatory properties of two receptor-like tyrosine phosphatases (RPTPs), CD45 and CD148, in inflammatory arthritis. Using an in vivo mouse model of K/BxN serum transfer-induced arthritis, we found that CD45 and CD148 feature distinct regulatory properties during inflammatory arthritis. CD45 is required for neutrophil infiltration, cytokine release, and reactive oxygen species production, whereas CD148 deficiency leads to a delayed onset of arthritis but unaltered overall neutrophil infiltration and reduced ROS production. Furthermore, we could demonstrate that activation of Src family kinases in neutrophils is differentially regulated by CD45 and CD148 in a stimulus-dependent manner. Summarizing, our results suggest that CD45 is positively involved, while CD148 is positively and negatively involved in neutrophil recruitment and function during inflammatory arthritis. Full article

Tuberculosis (TB) poses a persistent global health threat exacerbated by the emergence of drug-resistant strains; hence, there is a continuous quest for novel antimicrobial agents. Despite efforts to develop effective therapies, existing treatments require a relatively long duration of therapy to eradicate the pathogen due to its virulence factors, pathogenesis patterns, and ability to enter dormant states. This can lead to a higher risk of treatment failure due to poor patient adherence to the complex regimen. As a result, considerable research is necessary to identify alternative antituberculosis agents. The marine environment, particularly marine-derived fungi, has recently gained interest due to its potential as an abundant source of bioactive natural products. This review covers 19 genera of marine-derived fungi and 139 metabolites, 131 of which exhibit antimycobacterial activity. The integrated dataset pinpoints the fungal genera and chemical classes that most frequently yield potent antimycobacterial hits while simultaneously exposing critical gaps, such as the minimal evaluation of compounds against dormant bacilli and the presence of underexplored ecological niches and fungal genera. Several compounds exhibit potent activity through uncommon mechanisms, including the inhibition of mycobacterial protein tyrosine phosphatases (MptpB/MptpA), protein kinase PknG, ATP synthase and the disruption of mycobacterial DNA via G-quadruplex stabilization. Structure–activity relationship (SAR) trends are highlighted for the most potent agents, illuminating how specific functional groups underpin target engagement and potency. This review also briefly proposes a dereplication strategy and approaches for toxicity mitigation in the exploration of marine-derived fungi’s natural products. Through this analysis, we offer insights into the potency and challenges of marine-derived fungi’s natural products as hit compounds or scaffolds for further antimycobacterial research. Full article

The large yellow croaker, or Larimichthys crocea, is highly prized for its golden color and nutritional content. The purpose of this study was to investigate the differences in body composition, mucus biochemical indices and body color in five strains of large yellow croakers (body weight: 347.01 ± 5.86 g). To conduct genetic diversity analyses of the populations, a total of 50 tailfin samples were randomly chosen from the following populations of large yellow croakers: wild (LYC1), Dai-qu population (LYC2), Yongdai 1 (LYC3), Min-yuedong population (LYC4), and Fufa 1 (LYC5). The findings demonstrated that the LYC3 group’s pigment contents, crude protein, crude lipid, and chromatic values were comparable to those of the LYC1 group (p > 0.05). There was no significant difference between the LYC1 and LYC5 groups’ mucus superoxide dismutase (SOD) and catalase (CAT) activities (p > 0.05). The alkaline phosphatases (ALP), acid phosphatases (ACP), and lysozyme (LYS) activities of the mucus in the LYC1 group were not significantly different from the LYC3 group (p > 0.05). The back skin mRNA expressions of tyrosinase (tyr), tyrosinase-related protein 1 (tyrp1), dopachrome tautomerase (dct), microphtalmia-associated transcription factor (mitf), and melanocortin 1 receptor (mc1r) were significantly up-regulated in the LYC2 and LYC4 groups compared to the LYC1, LYC3, and LYC5 groups (p < 0.05). Forkhead box d3 (foxd3), paired box 3 (pax3), purine nucleoside phosphorylase 4a (pnp4a), aristaless-like homeobox 4a (alx4a), cAMP dependent protein kinase (pka), anaplastic lymphoma kinase (alk), leukocyte receptor tyrosine kinase (ltk), and colony stimulating factor (fms) were among the mRNA expressions of the abdominal skin in the LYC1, LYC3, and LYC5 groups significantly higher than those in the LYC2 and LYC4 groups (p < 0.05). In conclusion, the LYC3 group’s crude protein, crude lipid, carotenoid, and lutein contents were most similar to those of the large yellow croaker found in the wild. Furthermore, the molecular mechanism underlying the variations in body color among the various strains of large yellow croakers was supplied for additional research. Full article

Although some GABA_A receptor subtypes are involved in both the passive permeability of anions and the ATP-dependent recovery of neuronal anion concentrations, the molecular mechanisms that ensure the coordination of passive and active transport processes remain unclear. Here we used fluorescence measurements to investigate the role of genistein (tyrosine kinase inhibitor) and vanadate (tyrosine phosphatase and ATPase inhibitor) in modulating GABA_AR-mediated [Cl⁻]_i/[HCO₃⁻]_i changes and ATPase activity in rat cortical neurons and HEK 293FT cells expressing the heteropentameric α2β3γ2 GABA_AR isoform. We found that genistein plays an important role in the inhibition of passive GABA_AR-mediated Cl⁻ influx and Cl⁻ATPase activity, whereas vanadate plays an important role in the inhibition of Cl⁻, HCO₃⁻ATPase activity and ATP-dependent recovery of [HCO₃⁻]_i via changes in the formation of the phosphorylated intermediate. The effect of blockers was significantly restored in the presence of phenol. In behavioral experiments, the administration of phenol has been established to induce tremors and head twitching in rats, with the involvement of GABA_AR/ATPase in these behavioral responses. Genistein can reduce the adverse effects of phenol, thereby confirming the interaction of these chemicals when binding to binding receptor sites. While our data demonstrate the opposing roles of genistein and vanadate in modulating GABA_AR/ATPase function in a bicarbonate-dependent manner. Such multidirectional systems are considered to be bistable elements involved in the regulatory mechanisms of synaptic plasticity. Full article

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, memory loss and limited therapeutic options. Metal-based drugs have emerged as promising alternatives in the search for effective treatments, and vanadium coordination complexes have shown significant potential due to their neuroprotective and anti-aggregant properties. This review explores the advances in the development of vanadium-based metallodrugs for AD, focusing on their ability to modulate amyloid-beta (Aβ) aggregation, oxidative stress, and neuroinflammation. Recent in vitro and in vivo studies highlight the efficacy of oxovanadium (IV) and peroxovanadium (V) complexes in inhibiting Aβ fibril formation and reducing neuronal toxicity. Additionally, the interaction of vanadium complexes with key biological targets, such as peroxisome proliferator-activated receptor gamma (PPARγ) and protein-tyrosine phosphatase 1B (PTP1B), suggests a multifaceted therapeutic approach. While these findings underscore the potential of vanadium compounds as innovative treatments for AD, further research is needed to optimize their bioavailability, selectivity, and safety for clinical applications. Full article

CD300 family members are immunoglobulin superfamily receptors that regulate immune cell function through either activating or inhibitory signals. Among them, CD300a is a prototypical inhibitory receptor, highly expressed in both myeloid and lymphoid lineages, and plays a pivotal role in the pathogenesis of inflammation and tumor immunity. CD300a transduces inhibitory signals in several immune cells—including mast cells, eosinophils, monocytes, dendritic cells (DCs), neutrophils, and natural killer (NK) cells—by recruiting SHP-1 phosphatase to immunoreceptor tyrosine-based inhibitory motifs (ITIMs) and suppressing activation pathways such as Toll-like receptor (TLR)-MyD88 and FcεRI signaling. Recent studies suggest that tumor cells may hijack CD300a-associated pathways to establish an immunosuppressive microenvironment that facilitates immune evasion, tumor survival, and potentially metastatic spread. Proposed mechanisms include reduced DC-mediated type I interferon (IFN) production, diminished NK cell cytotoxicity, and negative regulation of mast cell– and eosinophil-dependent anti-tumor responses. Although some of these findings are derived from in vivo models, the cumulative evidence positions CD300a as a critical immune checkpoint in tumor-associated immune regulation. In addition to its established roles in hematologic malignancies—including chronic lymphocytic leukemia, acute lymphoblastic leukemia, and acute myeloid leukemia—CD300a has also been implicated in modulating tumor-associated immune responses in other pathological contexts. While most studies emphasize its immune cell–mediated effects, emerging evidence suggests that CD300a may directly influence tumor progression by regulating immune homeostasis, intracellular signaling, and tumor microenvironment interactions. Collectively, these findings establish CD300a as a pleiotropic immunoregulatory molecule in both hematologic and non-hematologic malignancies, underscoring the need to further explore its broader relevance and therapeutic potential in cancer immunology. Full article

Desert environments pose severe challenges to livestock survival. This study examined climate-driven physiological and metabolic adaptations in 258 Mongolian cattle from six regions of the Alxa Desert, China. Serum biochemical indices were measured and analyzed using linear models to assess the effects of climate, sex, and age. Climate significantly affected key blood parameters, including glucose (p < 0.001), creatinine (p < 0.001), alkaline phosphatase (p < 0.001), and lactate (p = 0.034). Additionally, sex significantly influenced lactate dehydrogenase (p = 0.049), bicarbonate (p = 0.0061), urea (p = 0.0055), and triglycerides (p = 0.039), while age affected total protein (p = 0.020), LDL-C (p = 0.0097), and cholesterol (p < 0.001). Glucose levels were negatively correlated with body size traits. Metabolomic profiling showed that cattle in arid, high-radiation areas exhibited reduced TCA cycle and fatty acid metabolism, with concurrent carbohydrate accumulation, including glucose, fructose, and mannose. Enhanced amino acid metabolism increased proline, valine, tyrosine, and tryptophan levels, potentially supporting physiological stability under heat and drought stress. These findings reveal how Mongolian cattle modulate metabolism in response to desert climates, offering insights into livestock adaptation and informing breeding strategies for resilience in harsh environments. Full article

Mycobacterium indicus pranii (MIP), an atypical mycobacterium originally developed as an anti-leprosy vaccine, has emerged as a potent immunomodulator with diverse therapeutic applications. Despite its clinical significance, molecular mechanisms underlying MIP’s immunomodulatory properties remain largely unexplored. Bacterial phosphatases are recognized as crucial virulence factors that enable pathogens to evade host defenses by modulating host immune signaling pathways, including phosphoinositide metabolism. MIP_07528 was identified as a putative protein tyrosine phosphatase B (PtpB) ortholog through in silico analysis, with significant sequence conservation observed within catalytic domains of pathogenic mycobacterial PtpB proteins. Phosphatase activity was detected in both cell lysate and culture filtrate fractions, revealing differential expression patterns between MIP and M. tuberculosis. Upregulation of MIP_07528 was demonstrated under oxidative stress, suggesting involvement in stress adaptation. The recombinant protein exhibited distinctive kinetic properties, characterized by higher substrate affinity yet increased susceptibility to oxidative inactivation compared to its M. tuberculosis counterpart. In macrophages, MIP_07528 suppressed pro-inflammatory cytokines while enhancing anti-inflammatory IL-10 production. These findings establish MIP_07528 as a functional phosphatase that may contribute to MIP’s immunomodulatory properties. This work advances understanding of phosphatase function in non-pathogenic mycobacteria while providing insights into virulence factor evolution and establishing a foundation for novel antimicrobial strategies. Full article

Midkine (MDK) is a multifunctional protein that is secreted into the extracellular space. It functions as a cytokine or growth factor, modulating a variety of signaling pathways implicated in angiogenesis, antitumor immunity, metastasis, and therapy resistance. MDK overexpression has been documented in a variety of cancers, including those that affect women. MDK mediates its effects through activation of key signaling pathways such as MAPK/ERK, PI3K/AKT, and STAT3, which are pivotal for cell cycle progression, survival, and maintenance of stemness. Obesity and estrogen signaling, a known critical driver of women’s cancer, further elevate the levels of MDK. MDK’s effects are mediated by a variety of membrane receptors, such as integrins, protein tyrosine phosphatase ζ (PTPζ), anaplastic lymphoma kinase (ALK), and neurogenic locus notch homolog protein 2 (Notch2). Recently published studies have indicated that MDK is a potential therapeutic target and a biomarker for the progression of women’s cancer. In this review, we have provided a concise summary of the most recent papers that have examined the potential biomarker and therapeutic utility of MDK signaling in women’s cancer. Full article

Background/Objectives: In the tumor microenvironment, hypoxia regulates genes that support tumor cell invasion and angiogenesis under the control of the hypoxia-inducible transcription factors (HIFs). Pleiotrophin (PTN) is a secreted protein that activates cell migration in endothelial and cancer cells that express α_νβ₃ integrin but has inhibitory effects in cells that do not express α_νβ₃ integrin. In both cases, the protein tyrosine phosphatase receptor zeta 1 (PTPRZ1) seems to mediate the effects of PTN. In the present work, we studied the effect of hypoxia on PTN and PTPRZ1 expression and the functional consequences of this effect. Methods: Western blot, quantitative real-time PCR, and luciferase assays were used to study the impact of hypoxia at the protein, mRNA, and transcriptional levels, respectively. Decoy oligonucleotides (ODNs), siRNA technology, and plasmid overexpression were used to study the involvement of the transcription factors studied. Functional assays were used to study the effect of hypoxia on cell proliferation and migration. Results: Hypoxia increases PTN expression through the transcriptional activation of the corresponding gene in α_νβ₃ integrin-expressing cells. The transcription factors HIF-1α, HIF-2α, and AP-1 mediate the up-regulation of PTN by hypoxia. Functional assays in endothelial cells from PTN knockout mice or endothelial and cancer cells following the downregulation of PTN expression showed that PTN negatively affects chemical hypoxia-induced cell proliferation and migration. In cancer cells that do not express α_νβ₃ integrin, hypoxia or chemical hypoxia inhibits PTN expression in a HIF-1α-, HIF-2α-, and AP-1-independent manner. The expression of PTPRZ1 is up-regulated by chemical hypoxia, is HIF-1α- and HIF-2α-dependent, and seems to limit the activation of HIF-1α, at least in endothelial cells. Conclusions: Hypoxia or chemical hypoxia regulates PTN and PTPRZ1 expressions to restrict the stimulatory effects of hypoxia on endothelial and cancer cell migration. Full article

SHP2, a non-receptor protein tyrosine phosphatase, plays a pivotal role in regulating intracellular signaling pathways, particularly the RAS/MAPK and PI3K/AKT cascades, which are critical for cellular proliferation, differentiation, and survival. Aberrant SHP2 activity, often driven by gain-of-function mutations, is implicated in oncogenesis and drug resistance, making it an attractive therapeutic target. Traditional inhibitors targeting SHP2’s catalytic site face limitations such as poor selectivity and low bioavailability. Recent advancements in allosteric inhibitors, specifically targeting SHP2’s tunnel site, offer improved specificity and pharmacokinetics. Natural products, especially saponins with their unique structural diversity, have emerged as promising candidates for SHP2 inhibition. This review explores the structural and functional dynamics of SHP2, highlights the potential of saponin-based inhibitors, and discusses their mechanisms of action, including their interactions with key residues in the tunnel site. The therapeutic potential of saponins is further emphasized by their ability to overcome the limitations of catalytic inhibitors and their applicability in combination therapies. Future directions include structural optimization to improve pharmacokinetics and the development of innovative strategies such as PROTACs to enhance the clinical utility of saponin-based SHP2 inhibitors. Full article

This study evaluated the effects of tea residue combined with complex enzymes on the growth performance, serum biochemistry, meat quality, and intestinal microbiota of Xiangling fattening pigs. A total of 120 healthy Xiangling fattening pigs, with an average weight of 47.93 kg (±15.28 kg), were randomly assigned to five treatment groups, each comprising four replicates of six pigs. The control group (CON) received a basal diet; the experimental groups received a diet containing 5.8% fermented tea residue as an alternative energy and protein source (dry matter basis) and mixed additional 0 (CZ), 200 (M200), 400 (M400), and 800 (M800) complex enzymes. The trial lasted for 83 days. The results showed that tea residue and complex enzymes failed to affect growth performance (p > 0.05). Tea residue reduced the serum aspartate aminotransferase and alkaline phosphatase activities (p < 0.01), and complex enzyme supplementation lowered the total cholesterol levels and reduced the alanine aminotransferase activity (p < 0.05). Additionally, tea residue decreased the pH_24h and b*_1h values (p < 0.05), and complex enzyme supplementation increased the L*_24h value and pork shear force (p < 0.05). In terms of amino acid content, tea residue significantly elevated aspartic acid and inosine monophosphate (p < 0.05), and complex enzyme addition increased the glutamic acid, lysine, alanine, valine, tyrosine, isoleucine, leucine, and phenylalanine levels (p < 0.05). The 800 mg/kg complex enzyme group exhibited a reduction in the C10:0, C15:0, and C17:0 contents (p < 0.05). Microbial analysis showed that tea residue promoted the abundance of Oribacterium and Butyricicoccus, while enzyme supplementation enriched Eggerthellaceae, Oscillospirales, and Peptococcaceae. Overall, the combination of tea residue and complex enzymes improved the pork quality, enhanced metabolic health markers, and modulated the gut microbiota composition, with the 400 mg/kg enzyme dose (M400) achieving the most pronounced benefits. These findings suggest a potential feeding strategy for improving pork quality without compromising growth performance. Full article

Sodium orthovanadate is a non-selective protein tyrosine phosphatase inhibitor that can cause several types of kidney injury, including glomerulosclerosis, inflammation, and tubular damage. Cannabis is widely known for its medicinal use, and several studies have demonstrated its anti-diabetic and anti-inflammatory properties. The current study investigated the therapeutic effect of Lebanese cannabis oil extract (COE) against sodium orthovanadate-induced nephrotoxicity both in vitro and in vivo. Sprague Dawley male rats were intraperitoneally injected with 10 mg/kg sodium orthovanadate for 10 days followed by 5 mg/kg; 10 mg/kg; or 20 mg/kg intraperitoneal injection of cannabis oil extract, starting on day 4 until day 10. The body weight of the rats was monitored during the study, and clinical parameters, including serum urea, creatinine, and electrolytes, as well as kidney and heart pathology, were measured. Conditionally immortalized cultured rat podocytes were exposed to either sodium orthovanadate or selective phosphatase inhibitors, including DUSPi (DUSP1/6 inhibitor) and SF1670 (PTEN inhibitor), in the presence or absence of cannabis oil extract. MTS and an in vitro scratch assay were used to assess podocyte cell viability and migration, respectively. Western blot analysis was used to evaluate the phosphorylation levels of AKT and p38 MAPK. Rats injected with sodium orthovanadate displayed a marked reduction in body weight and an increase in serum creatinine and urea in comparison to the control non-treated group. All doses of COE caused a significant decrease in serum urea, with a significant decrease in serum creatinine observed at a dose of 20 mg/kg. Moreover, the COE treatment of rats injected with orthovanadate (20 mg/kg) showed a marked reduction in renal vascular dilatation, scattered foci of acute tubular necrosis, and numerous mitoses in tubular cells compared to the sodium orthovanadate-treated group. The cell viability assay revealed that COE reversed cytotoxicity induced by sodium orthovanadate and specific phosphatase inhibitors (DUSPi and SF1670) in rat podocytes. The in vitro scratch assay showed that COE partially restored the migratory capacity of podocytes incubated with DUSPi and SF1670. Time-course and dose-dependent experiments showed that COE (1 μg/mL) induced a significant increase in phospho-(S473)-AKT, along with a decrease in phospho (T180 + Y182) P38 levels. The current results demonstrated that Lebanese cannabis oil possesses important kidney protective effects against sodium orthovanadate-induced renal injury. Full article