Search Results (1,154)

Glaesserella parasuis (GPS) is a Gram-negative, pathogenic bacterium that colonizes the upper respiratory tract of piglets and causes Glässer’s disease with peritonitis under stress conditions. The mechanism underlying GPS-induced peritonitis in piglets remains unclear. Baicalin is one of the main active ingredients of Huangqin (Scutellaria baicalensis), which has a significant anti-inflammatory effect on inflammatory diseases. Therefore, this study aimed to elucidate the molecular mechanism by which baicalin alleviates GPS-induced peritonitis in piglets, specifically focusing on the role of the ADAM17/EGFR signaling axis. We investigated the effects of baicalin in vitro using porcine peritoneal mesothelial cells (PPMCs) and in vivo in GPS-infected piglets. Our results showed that baicalin reduced the expression of the pro-inflammatory cytokines tumor necrosis factor alpha (TNF-α), interleukin-1 beta (IL-1β), and interleukin-6 (IL-6) in PPMCs and the peritoneum of piglets after GPS infection. Concurrently, baicalin significantly reduced the upregulation of disintegrin and metalloproteinase 17 (ADAM17), phosphorylated epidermal growth factor receptor (p-EGFR)/EGFR, and phosphorylated extracellular signal-regulated kinase (p-ERK)/ERK induced by GPS infection in PPMCs and the peritoneum of piglets. Crucially, in vitro mechanistic investigations revealed that baicalin can significantly reduce the upregulation of ADAM17, p-EGFR/EGFR, p-ERK/ERK, TNF-α, IL-1β, and IL-6 induced by ADAM17 overexpression in PPMCs. Furthermore, ADAM17 small interfering RNA can significantly reduce the upregulation of ADAM17, p-EGFR/EGFR, p-ERK/ERK, TNF-α, IL-1β, and IL-6 induced by GPS infection in PPMCs. These findings demonstrate that baicalin can inhibit the expression of inflammatory factors TNF-α, IL-1β, and IL-6 through the ADAM17/EGFR axis, and then alleviate the peritonitis caused by GPS in piglets. This provides a theoretical basis for developing novel non-antibiotic strategies, including phytochemical therapeutics and feed additives, for preventing and controlling GPS. Full article

The human airway surface is covered by a mucus layer composed primarily of the mucins MUC5AC and MUC5B. Excessive mucin production and secretion by airway epithelial cells in patients with asthma result in airway obstruction and worsened asthma symptoms. This study investigated the effects of liquiritin, a widely used flavonoid, on intracellular and secreted MUC5AC and MUC5B levels in the NCI-H292 human airway epithelial cell line. Liquiritin treatment suppressed both mucin types in a dose-dependent manner, accompanied by decreased activity of extracellular signal-regulated kinase (ERK) and p38. The effect of liquiritin was further examined in cells stimulated with phorbol 12-myristate 13-acetate (PMA) to induce excessive mucin production and secretion. Liquiritin dose-dependently reduced PMA-induced increases in intracellular and secreted MUC5AC and MUC5B levels as well as PMA-induced ERK and p38 activity. Overall, these results suggest that liquiritin reduces intracellular and secreted MUC5AC and MUC5B levels by suppressing the ERK and/or p38 signaling pathway. Full article

Diabetes mellitus, as a metabolic disorder, has received growing attention for its detrimental effects on the male reproductive system (particularly the testes) manifesting as increased oxidative stress, reduced blood perfusion, heightened inflammation, and germ cell apoptosis under hyperglycemic conditions. Hypoxia-inducible factor (HIF)-1α, a pivotal transcription factor in cellular hypoxia responses, plays a crucial role in regulating metabolism, angiogenesis, and apoptosis. Emerging evidence underscores its significant physiological and pathological roles in diabetic testicular injury. This review outlines the structural domains, activation mechanisms, and key target genes of HIF-1α, and further examines its involvement in diabetes-induced oxidative stress, impaired perfusion, endocrine dysregulation, and the imbalance of apoptosis and autophagy in testicular tissue. Notably, HIF-1α exerts protective effects by activating canonical signaling pathways such as phosphoinositide-3 kinase (PI-3K)/protein kinase B (Akt), mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK), and nuclear factor (NF)-κB, thereby enhancing antioxidant gene expression, promoting angiogenesis, and upregulating anti-apoptotic proteins. Furthermore, HIF-1α may help stabilize androgen levels by preserving Leydig cell function, potentially alleviating diabetes-associated gonadal dysfunction. This review also discusses the feasibility of targeting HIF-1α as a novel therapeutic strategy. In conclusion, a comprehensive understanding of HIF-1α’s mechanistic role in diabetic testicular damage provides valuable insights into the pathogenesis of diabetes-related reproductive disorders and offers new avenues for therapeutic intervention. Full article

Tumor necrosis factor (TNF) receptor-associated factor 7 (TRAF7) is a signal transducer in the TNF receptor superfamily. TRAF7 is unique among its superfamily in that it does not contain a TRAF-C domain but does contain WD-40 domains. TRAF7 interacts with mitogen-activated protein kinases (MAPK), which are known regulators of inflammation and shear stress response. Notably, these molecular interactions have profound implications for the function of brain endothelial cells (ECs), which are pivotal for sustaining the integrity of the blood–brain barrier (BBB), orchestrating neurovascular coupling (NVC), and modulating the vascular architecture. By directly influencing MAPK signaling pathways, particularly the shear stress-responsive MAPK kinase kinase 3 (MEKK3)–MAPK kinase 5 (MEK5)–extracellular-regulated protein kinase 5 (ERK5) cascade, TRAF7 contributes to vascular homeostasis, as exemplified by its role in phosphorylating ERK5. Such molecular events underpin the capacity of brain ECs to regulate substance exchange, adjust blood flow in response to neural activity, and maintain efficient cerebral perfusion, all of which are essential for preserving brain health and cognitive performance. By synthesizing the current evidence regarding TRAF7’s molecular functions and its impact on brain endothelial integrity, cerebrovascular aging, and exploring implications for therapeutic strategies targeting vascular dysfunction in the aging brain, this review fills a crucial gap in the literature. Given the limited number of original studies directly addressing these contexts, the review will integrate broader insights from related literature to provide a foundational overview for future research in this developing field. The culmination of this literature will provide a rationale for the development of novel TRAF7-targeted therapies to restore vascular integrity in the context of aging, which could maintain cognitive health. Although TRAF7 has been implicated in regulating endothelial permeability during inflammation, its precise functions in brain ECs and the subsequent effects on cerebrovascular structure and cognitive function remain to be fully elucidated. Full article

Helicobacter pylori infection causes inflammation in the gastric mucosa, and this has been reported to disrupt the gastric microbiota. Serotonin (5-HT) is a key neurotransmitter in the gut–brain axis and plays key roles in intestinal homeostasis and immune function. We investigated gastric serotonin release in H. pylori-infected mice and observed increased release in vaccinated, challenged mice compared to sham vaccinated controls. We investigated the effects of 5-HT on epithelial responses in an in vitro human gastric cancer cell line model (AGS), as well as inflammatory responses and the gastric microbiota in a C57BL/6 mouse model of H. pylori infection. HTR1A was upregulated in the stomachs of mice chronically infected with H. pylori SS1 (3 weeks) compared to uninfected controls, whereas HTR2B was upregulated only in acutely infected mice (3 days), consistent with a role for 5-HT signalling in the development of gastritis. Exposure to 5-HT did not affect NF-κB activation in H. pylori-exposed AGS cells but did inhibit extracellular signal-regulated kinase 1 (ERK1) translocation. Analysis of the gastric microbiota revealed that while vaccination did not significantly affect the diversity of the microbiota, vaccinated animals had increased abundance of Lactobacilli. Our results suggest that local inflammation caused by H. pylori is responsible for increased 5-HT release. Full article

Sprouty-related proteins with enabled/vasodilator-stimulated phosphoprotein homology 1 (EVH1) domain (SPREDs) are negative regulators of the Ras/MAPK signaling pathway and are known to modulate developmental and endocrine processes. While the roles of SPRED1 and SPRED2 are increasingly understood, the physiological relevance of SPRED3 remains elusive. To elucidate its function, we generated SPRED3 knockout (KO) mice and performed phenotypic, molecular, and hormonal analyses. SPRED3-deficient mice exhibited growth retardation and a non-Mendelian genotype distribution. X-Gal staining revealed Spred3 promoter activity in the thyroid, adrenal gland, pituitary, cerebral cortex, and kidney. Hormonal profiling identified elevated thyroid-stimulating hormone (TSH) and reduced thyroxine (T₄) levels, indicating primary hypothyroidism. Thyroidal extracellular signal-regulated kinase (ERK) signaling was mildly reduced in SPRED3 KO mice, and immunoblotting revealed altered expression of autophagy regulators, including reduced sequestosome 1 (p62), increased autophagy-related gene 5 (ATG5), as well as an elevated microtubule-associated protein 1 light chain 3 (LC3) II/I ratio and a decreased pBeclin/Beclin ratio in SPRED3 KO mice. Our findings indicate that SPRED3 is involved in thyroidal homeostasis and plays a regulatory role in autophagy processes within the thyroid gland. Full article

Post-traumatic stress disorder (PTSD) is a chronic mental health condition resulting from exposure to traumatic events. It is associated with long-term neurobiological changes and disturbances in emotional regulation. Understanding the sociodemographic profiles, biomarkers, and emotional control in patients with PTSD helps to better comprehend the impact of the disorder on the body and its clinical course. An analysis of biomarkers such as Interleukin-18 (IL-18), Inositol-Requiring Enzyme 1 (IRE1), Phosphorylated Extracellular Signal-Regulated Kinase (pERK), and Activating Transcription Factor–6 (ATF-6) in PTSD patients with varying durations of illness (≤5 years and >5 years) and a control group without PTSD revealed significant differences. Patients with recently diagnosed PTSD (≤5 years) showed markedly elevated levels of inflammatory and cellular stress markers, indicating an intense neuroinflammatory response during the acute phase of the disorder. In the chronic PTSD group (>5 years), the levels of these biomarkers were lower than in the recently diagnosed group, but still significantly higher than in the control group. An opposite trend was observed regarding the suppression of negative emotions, as measured by the Courtauld Emotional Control Scale (CECS): individuals with chronic PTSD exhibited a significantly greater suppression of anger, depression, and anxiety than those with recent PTSD or healthy controls. Correlations between biomarkers were strongest in individuals with chronic PTSD, suggesting a persistent neuroinflammatory dysfunction. However, the relationships between biomarkers and emotional suppression varied depending on the stage of PTSD. These findings highlight the critical role of PTSD duration in shaping the neurobiological and emotional mechanisms of the disorder, which may have important implications for therapeutic strategies and patient monitoring. Full article

The aim of this study was to analyze how recombinant rabbit NGF (Nerve Growth Factor) encapsulated in chitosan (rrβNGFch) affects sperm viability, motility, capacitation, acrosome reaction (AR), kinetic traits, and apoptosis after 30 min and 2 h of storage. Specific intracellular signaling pathways associated with either cell survival, such as protein kinase B (AKT) and extracellular signal-regulated kinases 1/2 (ERK1/2), or programmed cell death, such as c-Jun N-terminal kinase (JNK), were also analyzed. The results confirmed the effect of rrβNGFch on capacitation and AR, whereas a longer storage time (2 h) decreased all qualitative sperm traits. AKT and JNK did not show treatment-dependent activation and lacked a correlation with functional traits, as shown by ERK1/2. These findings suggest that rrβNGFch may promote the functional activation of sperm cells, particularly during early incubation. The increase in capacitation and AR was not linked to significant changes in pathways related to cell survival or death, indicating a specific action of the treatment. In contrast, prolonged storage negatively affected all sperm parameters. ERK1/2 activation correlated with capacitation, AR, and apoptosis, supporting its role as an NGF downstream mediator. Further studies should analyze other molecular mechanisms of sperm and the potential applications of NGF in assisted reproduction. Full article

The Sprouty (Spry) proteins modulate signalling and regulate processes like cellular migration and proliferation. Here, we investigated a Spry4 alteration substituting a lysine at position 177 to an arginine, based on a mutation found in Kallmann syndrome, a genetically heterogeneous disease connected to reduced fibroblast growth factor receptor1 (FGFR) signalling. Using growth curves to evaluate proliferative and scratch assays to determine migrative capacities of the cells, in normal fibroblasts as well as in osteosarcoma-derived cells, we demonstrate that the modified Spry4^K177R version hinders both processes, which the unaltered protein cannot do under the same conditions. The inhibition of these processes was accompanied by lower relative phospho-extracellular-signal-regulated kinases (pERK) levels in response to serum induction, indicating that activation of MAPK was less efficient. In contrast to the situation in these cells of mesenchymal origin, in lung cancer-derived cell lines both variants of Spry4 were able to interfere with proliferation of tested cells, and in the cells with elevated FGFR1 expression the Spry4 proteins with an alteration at codon 177 were even more effective. In summary, these data indicate that the lysine at position 177 restricts the ability of Spry4 to inhibit signal transduction at least in cells with high FGFR1 levels. Full article

Equine lutropin hormone/choriogonadotropin receptor (LH/CGR) is a G protein-coupled receptor that binds to both luteinizing hormone and choriogonadotropin, with multiple potential N-linked glycosylation sites in the long extracellular domain region. The roles of these glycosylation sites in hormone binding have been widely studied; however, their relationships with cyclic adenosine monophosphate (cAMP) activation, loss of cell surface receptors, and phosphorylated extracellular signal-regulated kinases1/2 (pERK1/2) expression are unknown. We used site-directed mutagenesis with the substitution of Asn for Gln to alter the consensus sequences for N-linked glycosylation, and cAMP signaling was analyzed in the mutants. Specifically, the N174Q and N195Q mutants exhibited markedly reduced expression levels, reaching approximately 15.3% and 2.5%, respectively, of that observed for wild-type equine LH/CGR. Correspondingly, the cAMP EC₅₀ values were decreased by 7.6-fold and 5.6-fold, respectively. Notably, the N195Q mutant displayed an almost complete loss of cAMP activity, even at high concentrations of recombinant eCG, suggesting a critical role for this glycosylation site in receptor function. Despite these alterations, Western blot analysis revealed that pERK1/2 phosphorylation peaked at 5 min following agonist stimulation across all mutants, indicating that the ERK1/2 signaling pathway remains functionally intact. This study demonstrates that the specific N-linked glycosylation site, N195, in equine LH/CGR is indispensable for cAMP activity but is normally processed in pERK1/2 signaling. Thus, we suggest that in equine LH/CGR, agonist treatment induces biased signaling, differentially activating cAMP signaling and the pERK1/2 pathway. Full article

Naturally occurring prostaglandin E₂ (PGE₂) influences cytokine production regulation in bovine neutrophils exposed to Staphylococcus aureus Rosenbach. Here, we employed bovine neutrophils as the primary experimental system, and administered specific inhibitors targeting various receptors, which were subsequently exposed to S. aureus. Cytokine expression levels in dairy cow neutrophils induced by S. aureus via the endogenous PGE₂-EP2/4 receptor pathway were investigated, and its effects on P38, extracellular signal-regulated kinase (ERK), P65 activation, and phagocytic function in Staphylococcus aureus Rosenbach-induced dairy cow neutrophils, were examined. Blocking cyclooxygenase-2 (COX-2) and microsomal prostaglandin E synthase-1 (mPGES-1) enzymes substantially decreased PGE₂ production and release in S. aureus-exposed bovine neutrophils. Cytokine output showed significant reduction compared to that in SA113-infected controls. Phosphorylation of P38, ERK, and P65 signaling molecules was depressed in the infected group. Pharmacological interference with EP2/EP4 receptors similarly diminished cytokine secretion and phosphorylation patterns of P38, ERK, and P65, with preserved cellular phagocytic function. During S. aureus infection of bovine neutrophils, COX-2 and mPGES-1 participated in controlling PGE₂ biosynthesis, and internally produced PGE₂ molecules triggered NF-κB and MAPK inflammatory pathways via EP2/EP4 receptor activation, later adjusting the equilibrium between cytokine types that promote or suppress inflammation. This signaling mechanism coordinated inflammatory phases through receptor-mediated processes. Full article

This review highlights recent findings on the potent anti-angiogenic serpin protein, pigment epithelium-derived factor (PEDF) as it relates to metabolic disease, diabetes, angiogenesis and cardiovascular disease (CVD), listing a majority of all the publicly available studies reported to date. PEDF is involved in various physiological roles in the body, and when awry, it triggers various disease states clinically. Biomarkers such as insulin, AMP-activated protein kinase alpha (AMPK-α), and peroxisome proliferator-activated receptor gamma (PPAR-γ) are involved in PEDF effects on metabolism. Wnt, insulin receptor substate (IRS), Akt, extracellular signal-regulated kinase (ERK), and mitogen-activated protein kinase (MAPK) are implicated in diabetes effects displayed by PEDF. For CVD, oxidised LDL, Wnt/β-catenin, and reactive oxygen species (ROS) are players intertwined with PEDF activity. The review also presents an outlook on where efforts could be devoted to bring this serpin closer to clinical trials for these diseases and others in general. Full article

Piperine, a phytochemical alkaloid, exhibits notable anticancer properties in several cancer cell types. In this study, we investigated the mechanisms by which piperine induces cell death and apoptosis in colorectal cancer (CRC) cells, focusing on oxidative stress and key signaling pathways. Using MTT assay, flow cytometry, gene overexpression, and Western blot analysis, we observed that piperine significantly reduced cell viability, triggered G1 phase cell cycle arrest, and promoted apoptosis in DLD-1 cells. In addition, piperine effectively suppressed cell viability and induced apoptosis in other CRC cell lines, including SW480, HT-29, and Caco-2 cells. These effects were associated with increased intracellular reactive oxygen species (ROS) generation, mediated by the regulation of mitochondrial complex III, NADPH oxidase, and xanthine oxidase. Additionally, piperine modulated signaling pathways by inhibiting phosphoinositide 3-kinase (PI3K)/Akt, activating p38 and p-extracellular signal-regulated kinase (ERK). Pretreatment with antimycin A, apocynin, allopurinol, and PD98059, and the overexpression of p-Akt significantly recovered cell viability and reduced apoptosis, confirming the involvement of these pathways. This study is the first to demonstrate piperine induces apoptosis in CRC cells through a multifaceted oxidative stress mechanism and by critically modulating PI3K/Akt and ERK signaling pathways. Full article

Acute heart failure (AHF) is a clinical syndrome characterized by the sudden onset or rapid worsening of heart failure signs and symptoms, frequently triggered by myocardial ischemia, pressure overload, or cardiotoxic injury. A central component of its pathophysiology is the activation of intracellular signal transduction cascades that translate extracellular stress into cellular responses. Among these, the mitogen-activated protein kinase (MAPK) pathways have received considerable attention due to their roles in mediating inflammation, apoptosis, hypertrophy, and adverse cardiac remodeling. The canonical MAPK cascades—including extracellular signal-regulated kinases (ERK1/2), p38 MAPK, and c-Jun N-terminal kinases (JNK)—are activated by upstream stimuli such as angiotensin II (Ang II), aldosterone, endothelin-1 (ET-1), and sustained catecholamine release. Additionally, emerging evidence highlights the role of receptor-mediated signaling, cellular stress, and myeloid cell-driven coagulation events in linking MAPK activation to fibrotic remodeling following myocardial infarction. The phosphatidylinositol 3-kinase (PI3K)/Akt signaling cascade plays a central role in regulating cardiomyocyte survival, hypertrophy, energy metabolism, and inflammation. Activation of the PI3K/Akt pathway has been shown to confer cardioprotective effects by enhancing anti-apoptotic and pro-survival signaling; however, aberrant or sustained activation may contribute to maladaptive remodeling and progressive cardiac dysfunction. In the context of AHF, understanding the dual role of this pathway is crucial, as it functions both as a marker of compensatory adaptation and as a potential therapeutic target. Recent reviews and preclinical studies have linked PI3K/Akt activation with reduced myocardial apoptosis and attenuation of pro-inflammatory cascades that exacerbate heart failure. Among the multiple signaling pathways involved, glycogen synthase kinase-3β (GSK-3β) has emerged as a key regulator of apoptosis, inflammation, metabolic homeostasis, and cardiac remodeling. Recent studies underscore its dual function as both a negative regulator of pathological hypertrophy and a modulator of cell survival, making it a compelling therapeutic candidate in acute cardiac settings. While earlier investigations focused primarily on chronic heart failure and long-term remodeling, growing evidence now supports a critical role for GSK-3β dysregulation in acute myocardial stress and injury. This comprehensive review discusses recent advances in our understanding of the MAPK signaling pathway, the PI3K/Akt cascade, and GSK-3β activity in AHF, with a particular emphasis on mechanistic insights, preclinical models, and emerging therapeutic targets. Full article

Over the past decades, bile acids have been recognized as important signaling molecules with significant roles in metabolic health and disease. Many of their beneficial effects are mediated through the activation of the Takeda G protein-coupled receptor 5 (TGR5), a G protein-coupled receptor ubiquitously expressed in both humans and animals. Upon activation, TGR5 stimulates adenylate cyclase, leading to increased cyclic adenosine monophosphate (cAMP) levels and subsequent activation of protein kinase A (PKA). PKA then phosphorylates and activates several downstream signaling pathways, including exchange protein directly activated by cAMP (EPAC), extracellular signal-regulated kinase 1/2 (ERK1/2), and protein kinase B (AKT). Through these pathways, TGR5 acts as a key molecular link between bile acid signaling and the regulation of energy metabolism. TGR5 activation has been associated with body weight loss in obese models, primarily by reducing food intake, enhancing thermogenesis in adipose tissue and muscle to increase energy expenditure, and improving insulin secretion. This review highlights recent advances in our understanding of TGR5 biology and critically examines its therapeutic potential, limitations, and controversies in the context of energy metabolism, offering new perspectives and opportunities for treating metabolic disorders. Full article