MUC1 promotes cervical squamous cell carcinoma through ERK phosphorylation-mediated regulation of ITGA2/ITGA3.

In contrast to the decreasing trends in developed countries, the incidence and mortality rates of cervical squamous cell carcinoma in China have increased significantly. The screening and identification of reliable biomarkers and candidate drug targets for cervical squamous cell carcinoma are urgently needed to improve the survival rate and quality of life of patients. In this study, we demonstrated that the expression of MUC1 was greater in neoplastic tissues than in non-neoplastic tissues of the cervix, and cervical squamous cell carcinoma patients with high MUC1 expression had significantly worse overall survival than did those with low MUC1 expression, indicating its potential for early diagnosis of cervical squamous cell carcinoma. Next, we explored the regulatory mechanism of MUC1 in cervical squamous cell carcinoma. MUC1 could upregulate ITGA2 and ITGA3 expression via ERK phosphorylation, promoting the proliferation and metastasis of cervical cancer cells. Further knockdown of ITGA2 and ITGA3 significantly inhibited the tumorigenesis of cervical cancer cells. Moreover, we designed a combination drug regimen comprising MUC1-siRNA and a novel ERK inhibitor in vivo and found that the combination of these drugs achieved better results in animals with xenografts than did MUC1 alone. Overall, we discovered a novel regulatory pathway, MUC1/ERK/ITGA2/3, in cervical squamous cell carcinoma that may serve as a potential biomarker and therapeutic target in the future.

MUC1 is overexpressed in cervical squamous cell carcinoma. MUC1 regulates ERK phosphorylation, and subsequently upregulates ITGA2 and ITGA3 expression to promote tumorigenesis in cervical squamous cell carcinoma. A combination drug regimen targeting MUC1 and ERK achieved better results compared than MUC1 alone.

ELABELA-derived peptide ELA13 attenuates kidney fibrosis by inhibiting the Smad and ERK signaling pathways. / ELABELA衍生肽ELA13通过抑制Smad和ERK信号通路减轻肾纤维化.

Kidney fibrosis is an inevitable result of various chronic kidney diseases (CKDs) and significantly contributes to end-stage renal failure. Currently, there is no specific treatment available for renal fibrosis. ELA13 (amino acid sequence: RRCMPLHSRVPFP) is a conserved region of ELABELA in all vertebrates; however, its biological activity has been very little studied. In the present study, we evaluated the therapeutic effect of ELA13 on transforming growth factor-ß1 (TGF-ß1)-treated NRK-52E cells and unilateral ureteral occlusion (UUO) mice. Our results demonstrated that ELA13 could improve renal function by reducing creatinine and urea nitrogen content in serum, and reduce the expression of fibrosis biomarkers confirmed by Masson staining, immunohistochemistry, real-time polymerase chain reaction (RT-PCR), and western blot. Inflammation biomarkers were increased after UUO and decreased by administration of ELA13. Furthermore, we found that the levels of essential molecules in the mothers against decapentaplegic (Smad) and extracellular signal-regulated kinase (ERK) pathways were reduced by ELA13 treatment in vivo and in vitro. In conclusion, ELA13 protected against kidney fibrosis through inhibiting the Smad and ERK signaling pathways and could thus be a promising candidate for anti-renal fibrosis treatment.

circUSP13 facilitates the fast-to-slow myofiber shift via the MAPK/ERK signaling pathway in goat skeletal muscles.

Understanding how skeletal muscle fiber proportions are regulated is essential for understanding muscle function and improving the quality of mutton. While circular RNA (circRNA) has a critical function in myofiber type transformation, the specific mechanisms are not yet fully understood. Prior evidence indicates that circular ubiquitin-specific peptidase 13 (circUSP13) can promote myoblast differentiation by acting as a ceRNA, but its potential role in myofiber switching is still unknown. Herein, we found that circUSP13 enhanced slow myosin heavy chain (MyHC-slow) and suppressed MyHC-fast expression in goat primary myoblasts (GPMs). Meanwhile, circUSP13 evidently enhanced the remodeling of the mitochondrial network while inhibiting the autophagy of GPMs. We obtained fast-dominated myofibers, via treatment with rotenone, and further demonstrated the positive role of circUSP13 in the fast-to-slow transition. Mechanistically, activation of the mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) pathway significantly impaired the slow-to-fast shift in fully differentiated myotubes, which was restored by circUSP13 or IGF1 overexpression. In conclusion, circUSP13 promoted the fast-to-slow myofiber type transition through MAPK/ERK signaling in goat skeletal muscle. These findings provide novel insights into the role of circUSP13 in myofiber type transition and contribute to a better understanding of the genetic mechanisms underlying meat quality.

Actions of remimazolam on inhibitory transmission of rat spinal dorsal horn neurons.

Remimazolam is an ultra-short benzodiazepine that acts on the benzodiazepine site of γ-aminobutyric acid (GABA) receptors in the brain and induces sedation. Although GABA receptors are found localized in the spinal dorsal horn, no previous studies have reported the analgesic effects or investigated the cellular mechanisms of remimazolam on the spinal dorsal horn. Behavioral measures, immunohistochemistry, and in vitro whole-cell patch-clamp recordings of dorsal horn neurons were used to assess synaptic transmission. Intrathecal injection of remimazolam induced behavioral analgesia in inflammatory pain-induced mechanical allodynia (six rats/dose; p < 0.05). Immunohistochemical staining revealed that remimazolam suppressed spinal phosphorylated extracellular signal-regulated kinase activation (five rats/group, p < 0.05). In vitro whole-cell patch-clamp analysis demonstrated that remimazolam increased the frequency of GABAergic miniature inhibitory post-synaptic currents, prolonged the decay time (six rats; p < 0.05), and enhanced GABA currents induced by exogenous GABA (seven rats; p < 0.01). However, remimazolam did not affect miniature excitatory post-synaptic currents or amplitude of monosynaptic excitatory post-synaptic currents evoked by Aδ- and C-fiber stimulation (seven rats; p > 0.05). This study suggests that remimazolam induces analgesia by enhancing GABAergic inhibitory transmission in the spinal dorsal horn, suggesting its potential utility as a spinal analgesic for inflammatory pain.

Cannabidiol induces ERK activation and ROS production to promote autophagy and ferroptosis in glioblastoma cells.

Small molecule-driven ERK activation is known to induce autophagy and ferroptosis in cancer cells. Herein the effect of cannabidiol (CBD), a phytochemical derived from Cannabis sativa, on ERK-driven autophagy and ferroptosis has been demonstrated in glioblastoma (GBM) cells (U87 and U373 cells). CBD imparted significant cytotoxicity in GBM cells, induced activation of ERK (not JNK and p38), and increased intracellular reactive oxygen species (ROS) levels. It increased the autophagy-related proteins such as LC3 II, Atg7, and Beclin-1 and modulated the expression of ferroptosis-related proteins such as glutathione peroxidase 4 (GPX4), SLC7A11, and TFRC. CBD significantly elevated the endoplasmic reticulum stress, ROS, and iron load, and decreased GSH levels. Inhibitors of autophagy (3-MA) and ferroptosis (Fer-1) had a marginal effect on CBD-induced autophagy/ferroptosis. Treatment with N-acetyl-cysteine (antioxidant) or PD98059 (ERK inhibitor) partly reverted the CBD-induced autophagy/ferroptosis by decreasing the activation of ERK and the production of ROS. Overall, CBD induced autophagy and ferroptosis through the activation of ERK and generation of ROS in GBM cells.

Ergosterol promotes neurite outgrowth, inhibits amyloid-beta synthesis, and extends longevity: In vitro neuroblastoma and in vivo Caenorhabditis elegans evidence.

AIMS: Alzheimer's disease (AD), the most common neurodegenerative disorder associated with aging, is characterized by amyloid-ß (Aß) plaques in the hippocampus. Ergosterol, a mushroom sterol, exhibits neuroprotective activities; however, the underlying mechanisms of ergosterol in promoting neurite outgrowth and preventing Aß-associated aging have never been investigated. We aim to determine the beneficial activities of ergosterol in neuronal cells and Caenorhabditis elegans (C. elegans). MATERIALS AND METHODS: The neuritogenesis and molecular mechanisms of ergosterol were investigated in wild-type and Aß precursor protein (APP)-overexpressing Neuro2a cells. The anti-amyloidosis properties of ergosterol were determined by evaluating in vitro Aß production and the potential inhibition of Aß-producing enzymes. Additionally, AD-associated transgenic C. elegans was utilized to investigate the in vivo attenuating effects of ergosterol. KEY FINDINGS: Ergosterol promoted neurite outgrowth in Neuro2a cells through the upregulation of the transmembrane protein Teneurin-4 (Ten-4) mRNA and protein expressions, phosphorylation of the extracellular signal-regulated kinases (ERKs), activity of cAMP response element (CRE), and growth-associated protein-43 (GAP-43). Furthermore, ergosterol enhanced neurite outgrowth in transgenic Neuro2A cells overexpressing either the wild-type APP (Neuro2a-APPwt) or the Swedish mutant APP (Neuro2a-APPswe) through the Ten-4/ERK/CREB/GAP-43 signaling pathway. Interestingly, ergosterol inhibited Aß synthesis in Neuro2a-APPwt cells. In silico analysis indicated that ergosterol can interact with the catalytic sites of ß- and γ-secretases. In Aß-overexpressing C. elegans, ergosterol decreased Aß accumulation, increased chemotaxis behavior, and prolonged lifespan. SIGNIFICANCE: Ergosterol is a potential candidate compound that might benefit AD patients by promoting neurite outgrowth, inhibiting Aß synthesis, and enhancing longevity.

Particulate matter (PM10) exacerbates on MK-801-induced schizophrenia-like behaviors through the inhibition of ERK-CREB-BDNF signaling pathway.

Particulate matter (PM), released into the air by a variety of natural and human activities, is a key indicator of air pollution. Although PM is known as the extensive health hazard to affect a variety of illness, few studies have specifically investigated the effects of PM10 exposure on schizophrenic development. In the present study, we aimed to investigate the impact of PM10 on MK-801, N-methyl-D-aspartate (NMDA) receptor antagonist, induced schizophrenia-like behaviors in C57BL/6 mouse. Preadolescent mice were exposed PM10 to 3.2 mg/m3 concentration for 4 h/day for 2 weeks through a compartmentalized whole-body inhalation chamber. After PM10 exposure, we conducted behavioral tests during adolescence and adulthood to investigate longitudinal development of schizophrenia. We found that PM10 exacerbated schizophrenia-like behavior, such as psychomotor agitation, social interaction deficits and cognitive deficits at adulthood in MK-801-induced schizophrenia animal model. Furthermore, the reduced expression levels of brain-derived neurotrophic factor (BDNF) and the phosphorylation of BDNF related signaling molecules, extracellular signal-regulated kinase (ERK) and cAMP response element-binding protein (CREB), were exacerbated by PM10 exposure in the adult hippocampus of MK-801-treated mice. Thus, our present study demonstrates that exposure to PM10 in preadolescence exacerbates the cognitive impairment in animal model of schizophrenia, which are considered to be facilitated by the decreased level of BDNF through reduced ERK-CREB expression.

MMPs-related risk model identification and SAA1 promotes clear cell renal cell carcinoma migration via ERK-AP1-MMPs axis.

Matrix Metalloproteinases (MMPs) have been demonstrated to be essential in facilitating the migration and metastasis of clear cell renal cell carcinoma (ccRCC). However, the ability of the MMP family to predict clinical outcomes and guide optimal therapeutic strategies for ccRCC patients remains incompletely understood. In this investigation, we initially conducted a thorough examination of the MMP family in pan-cancer. Notably, MMPs exhibited distinctive significance in ccRCC. Following this, we undertook an extensive analysis to evaluate the clinical value of MMPs and potential mechanisms by which MMPs contribute to the progression of ccRCC. A novel stratification method and prognostic model were developed based on MMPs in order to enhance the accuracy of prognosis prediction for ccRCC patients and facilitate personalized treatment. By conducting multi-omics analysis and transcriptional regulation analysis, it was hypothesized that SAA1 plays a crucial role in promoting ccRCC migration through MMPs. Subsequently, in vitro experiments confirmed that SAA1 regulates ccRCC cell migration via the ERK-AP1-MMPs axis. In conclusion, our study has explored the potential value of the MMP family as prognostic markers for ccRCC and as guides for medication regimens. Additionally, we have identified SAA1 as a crucial factor in the migration of ccRCC.

Stellera chamaejasme L. extract inhibits adipocyte differentiation through activation of the extracellular signal-regulated kinase pathway.

Stellera chamaejasme L. (SCL) is a perennial herb with demonstrated bioactivities against inflammation and metabolic dysfunction. Adipocyte differentiation is a critical regulator of metabolic homeostasis and a promising target for the treatment of metabolic diseases, so we examined the effects of SCL on adipogenesis. A methanol extract of SCL dose-dependently suppressed intracellular lipid accumulation in adipocyte precursors cultured under differentiation induction conditions and reduced expression of the adipogenic transcription factors PPARγ and C/EBPα as well as the downstream lipogenic genes fatty acid binding protein 4, adiponectin, fatty acid synthase, and stearoyl-CoA desaturase. The extract also promoted precursor cell proliferation and altered expression of the cell cycle regulators cyclin-dependent kinase 4, cyclin E, and cyclin D1. In addition, SCL extract stimulated extracellular signal-regulated kinase (ERK) phosphorylation, while pharmacological inhibition of ERK effectively blocked the inhibitory effects of SCL extract on preadipocyte differentiation. These results suggest that SCL extract contains bioactive compounds that can suppress adipogenesis through modulation of the ERK pathway.

The activation of RARα prevents surgery-induced cognitive impairments via the inhibition of neuroinflammation and the restoration of synaptic proteins in elderly mice.

Post-operative cognitive dysfunction (POCD) is a multi-etiological symptom mainly occurred in elderly people after surgery. The activation of retinoic acid receptor α (RARα), a transcriptional factor, was previously predicated to be negatively associated with the occurrence of POCD. However, the mechanisms underlying anti-POCD effects of RARα were still unclear. In this study, AM580, a selective agonist of RARα, and all-trans-retinoic acid (ATRA), a pan agonist of RAR, significantly alleviated cognitive dysfunction and increased the expression of RARα in elderly mice after surgery, which was decreased by RO41-5253, an antagonist of RARα. A bioinformatic study further predicted that the activation of RARα might produce anti-POCD effects via the restoration of synaptic proteins. Both agonists inhibited the expression of Toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (Myd88) and the phosphorylation of nuclear factorkappa-B (NF-κB), leading to the prevention of microglial over-activation and pro-inflammatory cytokines secretion in the hippocampal regions of elderly mice after surgery. Moreover, AM580 and ATRA increased the expression of brain-derived neurotrophic factor (BDNF) and postsynaptic density protein 95 (PSD95), and the phosphorylation of extracellular signal-regulated kinase (ERK) and cAMP-response element binding protein (CREB). All these results suggested that the activation of RARα prevented surgery-induced cognitive impairments via the inhibition of neuroinflammation by the reduction of the TLR4/Myd88/NF-κB pathway and the restoration of synaptic proteins by the activation of the BDNF/ERK/CREB pathway, providing a further support that RARα could be developed as a therapeutic target for POCD.

Enhancement of progesterone biosynthesis via kisspeptin stimulation: Upregulation of steroidogenic transcripts and phosphorylated extracellular signal-regulated kinase (p-ERK1/2) expression in the buffalo luteal cells.

The presence of Kisspeptin (Kp) and its receptors in the corpus luteum (CL) of buffalo has recently been demonstrated. In this study, we investigated the role of Kp in the modulation of progesterone (P4) synthesis in vitro. The primary culture of bubaline luteal cells (LCs) was treated with 10, 50, and 100 nM of Kp and Kp antagonist (KpA) alongside a vehicle control. The combined effect of Kp and KpA was assessed at 100 nM concentration. Intracellular response to Kp treatment in the LCs was assessed by examining transcript profiles (LHR, STAR, CYP11A1, HSD3B1, and ERK1/2) using quantitative polymerase chain reaction (qPCR). In addition, the immunolocalization of ERK1/2 and phosphorylated ERK1/2 (p-ERK1/2) in the LCs was studied using immunocytochemistry. Accumulation of P4 from the culture supernatant was determined using enzyme-linked immunosorbent assay (ELISA). The results indicated that LCs had a greater p-ERK1/2 expression in the Kp treatment groups. A significant increase in the P4 concentration was recorded at 50 nM and 100 nM Kp, while KpA did not affect the basal concentration of P4. However, the addition of KpA to the Kp-treated group at 100 nM concentration suppressed the Kp-induced P4 accumulation into a concentration similar to the control. There was significant upregulation of ERK1/2 and CYP11A1 expressions in the Kp-treated LCs at 100 nM (18.1 and 37fold, respectively, p < 0.01). However, the addition of KpA to Kp-treated LCs modulated ERK1/2, LHR, STAR, CYP11A1, and HSD3B1 at 100 nM concentration. It can be concluded that Kp at 100 nM stimulated P4 production, while the addition of KpA suppressed Kp-induced P4 production in the buffalo LCs culture. Furthermore, an increment in p-ERK1/2 expression in the LCs indicated activation of the Kp signaling pathway was associated with luteal steroidogenesis.

ACA-28, an ERK MAPK Signaling Modulator, Exerts Anticancer Activity through ROS Induction in Melanoma and Pancreatic Cancer Cells.

The extracellular signal-regulated kinase (ERK) MAPK pathway is dysregulated in various human cancers and is considered an attractive therapeutic target for cancer. Therefore, several inhibitors of this pathway are being developed, and some are already used in the clinic. We have previously identified an anticancer compound, ACA-28, with a unique property to preferentially induce ERK-dependent apoptosis in melanoma cells. To comprehensively understand the biological cellular impact induced by ACA-28, we performed a global gene expression analysis of human melanoma SK-MEL-28 cells exposed to ACA-28 using a DNA microarray. The transcriptome analysis identified nuclear factor erythroid 2-related factor 2 (Nrf2), a master transcription factor that combats oxidative stress, as the most upregulated genetic pathway after ACA-28 treatment. Consistently, ACA-28 showed properties to increase the levels of reactive oxygen species (ROS) as well as Nrf2 protein, which is normally repressed by proteasomal degradation and activated in response to oxidative stresses. Furthermore, the ROS scavenger N-acetyl cysteine significantly attenuated the anticancer activity of ACA-28. Thus, ACA-28 activates Nrf2 signaling and exerts anticancer activity partly via its ROS-stimulating property. Interestingly, human A549 cancer cells with constitutively high levels of Nrf2 protein showed resistance to ACA-28, as compared with SK-MEL-28. Transient overexpression of Nrf2 also increased the resistance of cells to ACA-28, while knockdown of Nrf2 exerted the opposite effect. Thus, upregulation of Nrf2 signaling protects cancer cells from ACA-28-mediated cell death. Notably, the Nrf2 inhibitor ML385 substantially enhanced the cell death-inducing property of ACA-28 in pancreatic cancer cells, T3M4 and PANC-1. Our data suggest that Nrf2 plays a key role in determining cancer cell susceptibility to ACA-28 and provides a novel strategy for cancer therapy to combine the Nrf2 inhibitor and ACA-28.

Histamine H1 Receptor-Mediated JNK Phosphorylation Is Regulated by Gq Protein-Dependent but Arrestin-Independent Pathways.

Arrestins are known to be involved not only in the desensitization and internalization of G protein-coupled receptors but also in the G protein-independent activation of mitogen-activated protein (MAP) kinases, such as extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK), to regulate cell proliferation and inflammation. Our previous study revealed that the histamine H1 receptor-mediated activation of ERK is dually regulated by Gq proteins and arrestins. In this study, we investigated the roles of Gq proteins and arrestins in the H1 receptor-mediated activation of JNK in Chinese hamster ovary (CHO) cells expressing wild-type (WT) human H1 receptors, the Gq protein-biased mutant S487TR, and the arrestin-biased mutant S487A. In these mutants, the Ser487 residue in the C-terminus region of the WT was truncated (S487TR) or mutated to alanine (S487A). Histamine significantly stimulated JNK phosphorylation in CHO cells expressing WT and S487TR but not S487A. Histamine-induced JNK phosphorylation in CHO cells expressing WT and S487TR was suppressed by inhibitors against H1 receptors (ketotifen and diphenhydramine), Gq proteins (YM-254890), and protein kinase C (PKC) (GF109203X) as well as an intracellular Ca2+ chelator (BAPTA-AM) but not by inhibitors against G protein-coupled receptor kinases (GRK2/3) (cmpd101), ß-arrestin2 (ß-arrestin2 siRNA), and clathrin (hypertonic sucrose). These results suggest that the H1 receptor-mediated phosphorylation of JNK is regulated by Gq-protein/Ca2+/PKC-dependent but GRK/arrestin/clathrin-independent pathways.

ERK signaling expands mammalian cortical radial glial cells and extends the neurogenic period.

The molecular basis for cortical expansion during evolution remains largely unknown. Here, we report that fibroblast growth factor (FGF)-extracellular signal-regulated kinase (ERK) signaling promotes the self-renewal and expansion of cortical radial glial (RG) cells. Furthermore, FGF-ERK signaling induces bone morphogenic protein 7 (Bmp7) expression in cortical RG cells, which increases the length of the neurogenic period. We demonstrate that ERK signaling and Sonic Hedgehog (SHH) signaling mutually inhibit each other in cortical RG cells. We provide evidence that ERK signaling is elevated in cortical RG cells during development and evolution. We propose that the expansion of the mammalian cortex, notably in human, is driven by the ERK-BMP7-GLI3R signaling pathway in cortical RG cells, which participates in a positive feedback loop through antagonizing SHH signaling. We also propose that the relatively short cortical neurogenic period in mice is partly due to mouse cortical RG cells receiving higher SHH signaling that antagonizes ERK signaling.

L-Methionine accentuates anti-tumor action of Gefitinib in Gefitinib-resistant lung adenocarcinoma: Role of EGFR/ERK/AKT signaling and histone H3K36me2 alteration.

Adenocarcinoma, the predominant subtype of non-small cell lung cancer (NSCLC), poses a significant clinical challenge due to its prevalence and aggressive nature. Gefitinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor is often susceptible to development of resistance despite being the preferred treatment option for NSCLC. In this study, we investigated the potential of L-Methionine in enhancing the cytotoxicity of Gefitinib and preventing resistance development. In vitro experiment employing the H1975 cell line demonstrated a notable enhancement in cytotoxic efficacy when L-Methionine (10 mM) was combined with Gefitinib, as indicated by a substantial reduction in IC50 values (155.854 ± 1.87 µM vs 45.83 ± 4.83 µM). Complementary in vivo investigations in a lung cancer model corroborated these findings. Co-administration of L-Methionine (100 mg/kg and 400 mg/kg) with Gefitinib (15 mg/kg) for 21 days exhibited marked improvements in therapeutic efficacy, which was observed by macroscopic and histopathological assessments. Mechanistic insights revealed that the enhanced cytotoxicity of the combination stemmed from the inhibition of the EGFR, modulating the downstream cascade of ERK/AKT and AMPK pathways. Concurrently inhibition of p-AMPK-α by the combination also disrupted metabolic homeostasis, leading to the increased production of reactive oxygen species (ROS). Notably, L-Methionine, functioning as a methyl group donor, elevated the expression of H3K36me2 (an activation mark), while reducing the p-ERK activity. Our study provides the first evidence supporting L-Methionine supplementation as a novel strategy to enhance Gefitinib chemosensitivity against pulmonary adenocarcinoma.

Protective effect of hygrolansamycin C against corticosterone-induced toxicity and oxidative stress-mediated via autophagy and the MAPK signaling pathway.

BACKGROUND: Excessive stress, a major problem in modern societies, affects people of all ages worldwide. Corticosterone is one of the most abundant hormones secreted during stressful conditions and is associated with various dysfunctions in the body. In particular, we aimed to investigate the protective effects of hygrolansamycin C (HYGC) against corticosterone-induced cellular stress, a manifestation of excessive stress prevalent in contemporary societies. METHODS: We isolated HYGC from Streptomyces sp. KCB17JA11 and subjected PC12 cells to corticosterone-induced stress. The effects of HYGC were assessed by measuring autophagy and the expression of mitogen-activated protein kinase (MAPK) phosphorylation-related genes. We used established cellular and molecular techniques to analyze protein levels and pathways. RESULTS: HYGC effectively protected cells against corticosterone-induced injury. Specifically, it significantly reduced corticosterone-induced oxidative stress and inhibited the expression of autophagy-related proteins induced by corticosterone, which provided mechanistic insight into the protective effects of HYGC. At the signaling level, HYGC suppressed c-Jun N-terminal kinase and extracellular signal-regulated kinase phosphorylation and p38 activation. CONCLUSIONS: HYGC is a promising candidate to counteract corticosterone-induced apoptosis and oxidative stress. Autophagy and MAPK pathway inhibition contribute to the protective effects of HYGC. Our findings highlight the potential of HYGC as a therapeutic agent for stress-related disorders and serve as a stepping stone for further exploration and development of stress management strategies.

Indole-3-acetic acid ameliorates dextran sulfate sodium-induced colitis via the ERK signaling pathway.

Microbiota-derived catabolism of nutrients is closely related to ulcerative colitis (UC). The level of indole-3-acetic acid (IAA), a microbiota-dependent metabolite of tryptophan, was decreased significantly in the feces of UC patients. Thus supplementation with IAA could be a potential therapeutic method for ameliorating colitis. In this work, the protective effect of supplementation with IAA on dextran sulfate sodium (DSS)-induced colitis was evaluated, and the underlying mechanism was elucidated. The results indicated that the administration of IAA significantly relieved DSS-induced weight loss, reduced the disease activity index (DAI), restored colon length, alleviated intestinal injury, and improved the intestinal tight junction barrier. Furthermore, IAA inhibited intestinal inflammation by reducing the expression of proinflammatory cytokines and promoting the production of IL-10 and TGF-ß1. In addition, the ERK signaling pathway is an important mediator of various physiological processes including inflammatory responses and is closely associated with the expression of IL-10. Notably, IAA treatment induced the activation of extracellular signal-regulated kinase (ERK), which is involved in the progression of colitis, while the ERK inhibitor U0126 attenuated the beneficial effects of IAA. In summary, IAA could attenuate the clinical symptoms of colitis, and the ERK signaling pathway was involved in the underlying mechanism. Supplementation with IAA could be a potential option for preventing or ameliorating UC.

Duration of the preemptive analgesic effects of low- and high-frequency transcutaneous electrical nerve stimulation in rats with acute inflammatory pain.

Transcutaneous electrical nerve stimulation (TENS) activates various pathways to induce antinociceptive effects, based on the frequencies used. This study evaluates the preemptive analgesic effects and their duration of low- (LT: 4 Hz) and high-frequency TENS (HT: 100 Hz) using a rat model of acute inflammatory pain. Acute inflammation was induced by injecting 1% formalin into the hind paws of rats. LT or HT was applied for 30 min before formalin injection. Pain-related behaviors, such as licking, flinching, and lifting, were recorded for 60 min postinjection. Immunohistochemistry was used to assess the number of phosphorylated extracellular signal-regulated kinase (pERK)- and c-fos-positive cells in the spinal cord. Naloxone, a µ-opioid receptors (MORs) antagonist, and naltrindole, a δ-opioid receptors (DORs) antagonist, were administered before TENS application. Pain behavior duration and pERK- and c-fos-positive cell expression were then measured. LT and HT pretreatment significantly reduced both pain behaviors and the number of pERK- and c-fos-positive cells postformalin injection. Naloxone and naltrindole partially reversed the effects of LT and HT, respectively. Notably, HT's analgesic effect lasted up to 120 min whereas that of LT persisted for 90 min. LT and HT effectively exerted their preemptive analgesic effects on acute inflammatory pain by inhibiting pERK and c-fos expression in the spinal cord. HT presented a longer-lasting effect compared to LT. MOR and DOR activation may contribute to LT and HT's analgesic mechanisms, respectively.

Periostin in Cancer-Associated Fibroblasts Promotes Esophageal Squamous Cell Carcinoma Progression by Enhancing Cancer and Stromal Cell Migration.

Cancer-associated fibroblasts (CAFs) in the tumor microenvironment are involved in the progression of various cancers, including esophageal squamous cell carcinoma (ESCC). CAF-like cells were generated through direct co-culture of human bone marrow-derived mesenchymal stem cells, one of CAF origins, with ESCC cells. Periostin (POSTN) was found to be highly expressed in CAF-like cells. After direct co-culture, ESCC cells showed increased malignant phenotypes, such as survival, growth, and migration, as well as increased phosphorylation of Akt and extracellular signal-regulated kinase (Erk). Recombinant human POSTN activated Akt and Erk signaling pathways in ESCC cells, enhancing survival and migration. The suppression of POSTN in CAF-like cells by siRNA during direct co-culture also suppressed enhanced survival and migration in ESCC cells. In ESCC cells, knockdown of POSTN receptor integrin ß4 inhibited Akt and Erk phosphorylation, and survival and migration increased by POSTN. POSTN also enhanced mesenchymal stem cell and macrophage migration and endowed macrophages with tumor-associated macrophage-like properties. Immunohistochemistry showed that high POSTN expression in the cancer stroma was significantly associated with tumor invasion depth, lymphatic and blood vessel invasion, higher pathologic stage, CAF marker expression, and infiltrating tumor-associated macrophage numbers. Moreover, patients with ESCC with high POSTN expression exhibited poor postoperative outcomes. Thus, CAF-secreted POSTN contributed to tumor microenvironment development. These results indicate that POSTN may be a novel therapeutic target for ESCC.

IL-6 Up-Regulates Expression of LIM-Domain Only Protein 4 in Psoriatic Keratinocytes through Activation of the MEK/ERK/NF-κB Pathway.

Psoriasis is a chronic inflammatory skin disease characterized by the activation of keratinocytes and the infiltration of immune cells. Overexpression of the transcription factor LIM-domain only protein 4 (LMO4) promoted by IL-23 has critical roles in regulating the proliferation and differentiation of psoriatic keratinocytes. IL-6, an autocrine cytokine in psoriatic epidermis, is a key mediator of IL-23/T helper 17-driven cutaneous inflammation. However, little is known about how IL-6 regulates the up-regulation of LMO4 expression in psoriatic lesions. In this study, human immortalized keratinocyte cells, clinical biopsy specimens, and an animal model of psoriasis induced by imiquimod cream were used to investigate the role of IL-6 in the regulation of keratinocyte proliferation and differentiation. Psoriatic epidermis showed abnormal expression of IL-6 and LMO4. IL-6 up-regulated the expression of LMO4 and promoted keratinocyte proliferation and differentiation. Furthermore, in vitro and in vivo studies showed that IL-6 up-regulates LMO4 expression by activating the mitogen-activated extracellular signal-regulated kinase (MEK)/extracellular signal-regulated kinase (ERK)/NF-κB signaling pathway. These results suggest that IL-6 can activate the NF-κB signaling pathway, up-regulate the expression of LMO4, lead to abnormal proliferation and differentiation of keratinocytes, and promote the occurrence and development of psoriasis.