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Human immunodeficiency virus-1 (HIV-1) infects the central nervous system (CNS) and causes HIV-associated neurocognitive disorders (HAND) in about half of the population living with the virus despite combination anti-retroviral therapy (cART). HIV-1 activates the innate immune system, including the production of type 1 interferons (IFNs) α and β. Transgenic mice expressing HIV-1 envelope glycoprotein gp120 (HIVgp120tg) in the CNS develop memory impairment and share key neuropathological features and differential CNS gene expression with HIV patients, including the induction of IFN-stimulated genes (ISG). Here we show that knocking out IFNβ (IFNβKO) in HIVgp120tg and non-tg control mice impairs recognition and spatial memory, but does not affect anxiety-like behavior, locomotion, or vision. The neuropathology of HIVgp120tg mice is only moderately affected by the KO of IFNβ but in a sex-dependent fashion. Notably, in cerebral cortex of IFNβKO animals presynaptic terminals are reduced in males while neuronal dendrites are reduced in females. The IFNβKO results in the hippocampal CA1 region of both male and female HIVgp120tg mice in an ameliorated loss of neuronal presynaptic terminals but no protection of neuronal dendrites. Only female IFNβ-deficient HIVgp120tg mice display diminished microglial activation in cortex and hippocampus and increased astrocytosis in hippocampus compared to their IFNβ-expressing counterparts. RNA expression for some immune genes and ISGs is also affected in a sex-dependent way. The IFNβKO abrogates or diminishes the induction of MX1, DDX58, IRF7 and IRF9 in HIVgp120tg brains of both sexes. Expression analysis of neurotransmission related genes reveals an influence of IFNβ on multiple components with more pronounced changes in IFNβKO females. In contrast, the effects of IFNβKO on MAPK activities are independent of sex with pronounced reduction of active ERK1/2 but also of active p38 in the HIVgp120tg brain. In summary, our findings show that the absence of IFNβ impairs memory dependent behavior and modulates neuropathology in HIVgp120tg brains, indicating that its absence may facilitate development of HAND. Moreover, our data suggests that endogenous IFNβ plays a vital role in maintaining neuronal homeostasis and memory function.

Macrophages (MΦ) infected with human immunodeficiency virus (HIV)-1 or activated by its envelope protein gp120 exert neurotoxicity. We found previously that signaling via p38 mitogen-activated protein kinase (p38 MAPK) is essential to the neurotoxicity of HIVgp120-stimulated MΦ. However, the associated downstream pathways remained elusive. Here we show that cysteinyl-leukotrienes (CysLT) released by HIV-infected or HIVgp120 stimulated MΦ downstream of p38 MAPK critically contribute to neurotoxicity. SiRNA-mediated or pharmacological inhibition of p38 MAPK deprives MΦ of CysLT synthase (LTC4S) and, pharmacological inhibition of the cysteinyl-leukotriene receptor 1 (CYSLTR1) protects cerebrocortical neurons against toxicity of both gp120-stimulated and HIV-infected MΦ. Components of the CysLT pathway are differentially regulated in brains of HIV-infected individuals and a transgenic mouse model of NeuroHIV (HIVgp120tg). Moreover, genetic ablation of LTC4S or CysLTR1 prevents neuronal damage and impairment of spatial memory in HIVgp120tg mice. Altogether, our findings suggest a novel critical role for cysteinyl-leukotrienes in HIV-associated brain injury.

Background: The global incidence of frozen shoulder (FS) (2% ~ 5%) and osteoporosis (OP) is high (9.1%-12.1%). Clinically, postmenopausal women are particularly at risk for both diseases. The main objective of this current research is to investigate the pathogenesis mechanism of FS and explore the connection between FS and OP. Methods: We obtained FS and OP datasets from GEO and identified crosstalk genes. Following KEGG and GO enrich analysis, the p38 MAPK signaling pathway was focused and the specific p38α inhibitor TAK715 was screened out. We conducted flow cytometry, western blot, and PCR analyses to assess the treatment effect of TAK715 on FS synovium fibroblasts at different concentrations. Additionally, we employed SD rats to validate the treatment effects of TAK715 in vivo. Results: TAK715 was useful in reversing fibrosis at the concentration of 1 μM, 5 μM and 10 μM. The unbalanced apoptosis process in frozen shoulder cell and the activation of osteoclast were inhibited at the concentration of 5 μM by TAK715. Then we successfully established a FS and OP rat model, with the FS with OP rat displaying less range of motion (ROM) and thicker shoulder capsule. In FS rat that was treated with TAK715, the frozen shoulder side was corrected in ROM and bone loss. Conclusions: The frozen shoulder with osteoporosis may exhibit more severe symptoms, and TAK715 is effective in protecting fibrosis and osteoporosis both in vitro and vivo. The therapy to correct FS and OP simultaneously by TAK715 provides novel approach in FS treatment and study. [ABSTRACT FROM AUTHOR]

Background: To explore new modulatory intervention targets for radiation-induced lung injury, bioinformatics analysis technology was used to search for the core driving genes in the pathogenesis of radiation pneumonitis, and the results were verified by a radiation-induced murine lung injury model to find possible new targets for the treatment of radiation lung injury. Method: Gene Expression Omnibus Database was used to identify differentially expressed genes in radiation pneumonitis. DAVID database was used for gene ontology (GO) and Kyoto Encyclopedia of Genes and Genome (KEGG) enrichment analysis. Gene Set Enrichment Analysis was used to analyze abnormal expressions. Protein–protein interaction networks were constructed using STRING and Cytoscape. Discovery Studio 4.5 software was used to find the preferred inhibitor of the specific gene. A radiation-induced lung injury model was induced in female C57BL/6N mice. The specific inhibitors were administered by intraperitoneal injection 24 h before and for 7 consecutive days after radiation. Lungs were harvested for further analysis 14 days and 10 weeks post-irradiation. Results: We screened Syk as one of the most important driver genes of radiation pneumonitis by bioinformatics analysis and screened the preferred Syk inhibitor fostamatinib from the drug database. Syk was highly expressed in irradiated lung tissue, and fostamatinib inhibited the level of Syk expression. Syk inhibitor significantly alleviated the radiation-induced lung injury and downregulated the increased expression of p38 MAPK, p53, IL-1β, and IL-6 in lung tissue at 2 weeks after radiation. The levels of TGF-β, COL1A1, and α-SMA and degree of pulmonary fibrosis at 10 weeks after radiation were also decreased by Syk inhibitor. Conclusion: Syk inhibitor may have a potential to be used as a targeted drug to mitigate radiation pneumonitis and inhibit radiation-induced pulmonary fibrosis. [ABSTRACT FROM AUTHOR]

Epithelial-immune cell communication is pivotal to control microbial infections. We show that glycosylphosphatidylinositol-linked aspartyl proteases (Yapsins) of the human opportunistic pathogenic yeast Candida glabrata (Cg) thwart epithelial cell (EC)-neutrophil signalling by targeting the EC protein, Arpc1B (actin nucleator Arp2/3 complex subunit), which leads to actin disassembly and impeded IL-8 secretion by ECs. Further, the diminished IL-8 secretion inhibits neutrophil migration, and protects Cg from the neutrophil-mediated killing. CgYapsin-dependent Arpc1B degradation requires Arginine-142 in Arpc1B, and leads to reduced Arpc1B-p38 MAPK interaction and downregulated p38 signalling. Consistently, Arpc1B or p38 deletion promotes survival of the Cg aspartyl protease-deficient mutant in ECs. Importantly, kidneys of the protease-deficient mutant-infected mice display elevated immune cell infiltration and cytokine secretion, implicating CgYapsins in immune response suppression in vivo. Besides delineating Cg-EC interplay, our results uncover a novel target, Arpc1B, that pathogens attack to constrain the host signalling networks, and link Arpc1B mechanistically with p38 activation. Synopsis: Candida glabrata (Cg) suppresses IL-8 secretion to escape from neutrophil killing. Cg engages cell surface-associated aspartyl proteases to target Arpc1B, a subunit of the Arp2/3 complex, to restrain p38 MAPK activation and IL-8 secretion. The Yapsin family of cell surface-associated aspartyl proteases targets Arpc1B in host epithelial cells. Arpc1B degradation inhibits p38 signalling activation and IL-8 secretion. Reduced IL-8 levels hamper neutrophil migration towards Candida glabrata. Candida glabrata (Cg) suppresses IL-8 secretion to escape from neutrophil killing. Cg engages cell surface-associated aspartyl proteases to target Arpc1B, a subunit of the Arp2/3 complex to restrain p38 MAPK activation and IL-8 secretion. [ABSTRACT FROM AUTHOR]

Reperfusion therapy is the primary treatment strategy for acute myocardial infarction (AMI). Paradoxically, it can lead to myocardial damage, namely myocardial ischemia/reperfusion injury (MIRI). This study explored whether oroxylin A (OA) protects the myocardium after MIRI by inhibiting ferroptosis and the underlying mechanism. In vivo, we established an MIRI model to investigate the protective effect of OA. In vitro, H9C2 cells were used to explore the regulation of ferroptosis by OA through immunofluorescence staining, western blotting, assay kits, etc. Additionally, RNA sequencing analysis (RNA‐seq) and network pharmacology analyses were conducted to elucidate the molecular mechanisms. Our results showed that MIRI caused cardiac structural and functional damage in rats. MIRI promoted ferroptosis, which was consistently observed in vitro. However, pretreatment with OA reversed these effects. The mitogen‐activated protein kinases (MAPK) signaling pathway participated in the MIRI process, with dual‐specificity phosphatase 10 (DUSP10) found to regulate it. Further confirmation was provided by knocking down DUSP10 using small interfering RNA (siRNA), demonstrating the activation of the DUSP10/MAPK‐Nrf2 pathway by OA to protect H9C2 cells from ferroptosis. Our research has demonstrated the mitigating effect of OA on MIRI and the improvement of myocardial function for the first time. The inhibition of ferroptosis has been identified as one of the mechanisms through which OA exerts its myocardial protective effects. Moreover, we have first unveiled that DUSP10 serves as an upstream target involved in mediating ferroptosis, and the regulation of the DUSP10/MAPK‐Nrf2 pathway by OA is crucial in inhibiting ferroptosis to protect the myocardium. [ABSTRACT FROM AUTHOR]

Background: C3H10T1/2 is a mesenchymal cell line capable of differentiating into osteoblasts, adipocytes and chondrocytes. The differentiation of these cells into osteoblasts is modulated by various transcription factors, such as RUNX2. Additionally, several interconnected signaling pathways, including the NOTCH pathway, play a crucial role in modulating their differentiation into mature bone cells. We have investigated the roles of DLK1 and DLK2, two non-canonical inhibitory ligands of NOTCH receptors, in the osteogenic differentiation of C3H10T1/2 cells. Results: Our results corroborate existing evidence that DLK1 acts as an inhibitor of osteogenesis. In contrast, we demonstrate for the first time that DLK2 enhances this differentiation process. Additionally, our data suggest that NOTCH2, 3 and 4 receptors may promote osteogenesis, as indicated by their increased expression during this process, whereas NOTCH1 expression, which decreases during cell differentiation, might inhibit osteogenesis. Moreover, treatment with DAPT, a NOTCH signaling inhibitor, impeded osteogenic differentiation. We have confirmed the increase in ERK1/2 MAPK and p38 MAPK phosphorylation in C3H10T1/2 cells induced to differentiate to osteoblasts. Our new findings reveal increased ERK1/2 MAPK phosphorylation in differentiated C3H10T1/2 cells with a decrease in DLK1 expression or an overexpression of DLK2, which is coincident with the behavior of those transfectants where we have detected an increase in osteogenic differentiation. Additionally, p38 MAPK phosphorylation increases in differentiated C3H10T1/2 cells with reduced DLK1 levels. Conclusions: Our results suggest that DLK1 may inhibit osteogenesis, while DLK2 may promote it, by modulating NOTCH signaling and the phosphorylation of ERK1/2 and p38 MAPK pathways. Given the established inhibitory effect of DLK proteins on NOTCH signaling, these new insights could pave the way for developing future therapeutic strategies aimed at treating bone diseases. [ABSTRACT FROM AUTHOR]

Idiopathic pulmonary fibrosis (IPF) is a progressive, irreversible respiratory disease with limited therapeutic options. A hallmark of IPF is excessive fibroblast activation and extracellular matrix (ECM) deposition. The resulting increase in tissue stiffness amplifies fibroblast activation and drives disease progression. Dampening stiffness-dependent activation of fibroblasts could slow disease progression. We performed an unbiased, next-generation sequencing (NGS) screen to identify signaling pathways involved in stiffness-dependent lung fibroblast activation. Adipocytokine signaling was downregulated in primary lung fibroblasts (PFs) cultured on stiff matrices. Re-activating adipocytokine signaling with adiponectin suppressed stiffness-dependent activation of human PFs. Adiponectin signaling depended on CDH13 expression and p38 mitogen-activated protein kinase gamma (p38MAPKγ) activation. CDH13 expression and p38MAPKγ activation were strongly reduced in lungs from IPF donors. Our data suggest that adiponectin-signaling via CDH13 and p38MAPKγ activation suppresses profibrotic activation of fibroblasts in the lung. Targeting of the adiponectin signaling cascade may provide therapeutic benefits in IPF. NEW & NOTEWORTHY: A hallmark of idiopathic pulmonary fibrosis (IPF) is excessive fibroblast activation and extracellular matrix (ECM) deposition. The resulting increase in tissue stiffness amplifies fibroblast activation and drives disease progression. Dampening stiffness-dependent activation of fibroblasts could slow disease progression. We found that activation of the adipocytokine signaling pathway halts and reverses stiffness-induced, profibrotic fibroblast activation. Specific targeting of this signaling cascade may therefore provide therapeutic benefits in IPF. [ABSTRACT FROM AUTHOR]

The effects of trehalose, an autophagy-inducing disaccharide with neuroprotective properties, on the neurotoxicity of parkinsonian mimetics 6-hydroxydopamine (6-OHDA) and 1-methyl-4-phenylpiridinium (MPP+) are poorly understood. In our study, trehalose suppressed 6-OHDA-induced caspase-3/PARP1 cleavage (detected by immunoblotting), apoptotic DNA fragmentation/phosphatidylserine externalization, oxidative stress, mitochondrial depolarization (flow cytometry), and mitochondrial damage (electron microscopy) in SH-SY5Y neuroblastoma cells. The protection was not mediated by autophagy, autophagic receptor p62, or antioxidant enzymes superoxide dismutase and catalase. Trehalose suppressed 6-OHDA-induced activation of c-Jun N-terminal kinase (JNK), p38 mitogen-activated protein kinase (MAPK), and AMP-activated protein kinase (AMPK), as revealed by immunoblotting. Pharmacological/genetic inhibition of JNK, p38 MAPK, or AMPK mimicked the trehalose-mediated cytoprotection. Trehalose did not affect the extracellular signal-regulated kinase (ERK) and mechanistic target of rapamycin complex 1 (mTORC1)/4EBP1 pathways, while it reduced the prosurvival mTORC2/AKT signaling. Finally, trehalose enhanced oxidative stress, mitochondrial damage, and apoptosis without decreasing JNK, p38 MAPK, AMPK, or AKT activation in SH-SY5Y cells exposed to MPP+. In conclusion, trehalose protects SH-SY5Y cells from 6-OHDA-induced oxidative stress, mitochondrial damage, and apoptosis through autophagy/p62-independent inhibition of JNK, p38 MAPK, and AMPK. The opposite effects of trehalose on the neurotoxicity of 6-OHDA and MPP+ suggest caution in its potential development as a neuroprotective agent. [ABSTRACT FROM AUTHOR]

Introduction: Previous research has shown that an aqueous extract of Humulus japonicus (EH) can ameliorate hypertension, nonalcoholic fatty liver disease, and oxidative stress in adipocytes by activating the thermogenic pathway. However, the effects of an ethanol (30%) extract of EH on obesity are unknown. Methods: Various protein expression levels in fully differentiated 3T3-L1 adipocytes were assessed by Western blotting. Lipid deposition in 3T3-L1 adipocytes was examined by oil red O staining. The MTT assay was used to evaluate adipocyte viability. Caspase 3 activity and glycerol release were determined using commercial assay kits. Results: In this study, we discovered that EH treatment inhibited lipogenesis and promoted lipolysis in both differentiated 3T3-L1 adipocytes and adipose tissue of mice fed a high-fat diet. EH treatment also increased phosphorylated protein kinase A (PKA) levels while reducing p38 phosphorylation. When H89, a PKA inhibitor, was used, the effects of EH on lipogenic lipid accumulation and lipolysis in 3T3-L1 adipocytes were eliminated. Treatment with luteolin 7-O-β-d-glucoside (LU), the major active compound in EH, also suppressed lipid deposition and p38 phosphorylation but enhanced lipolysis in 3T3-L1 adipocytes. These changes were abrogated by H89. Conclusion: These findings indicate that EH containing LU reduces lipogenesis and stimulates lipolysis via the PKA/p38 signaling pathway, leading to an improvement in obesity in mice. Therefore, our study suggested that EH could be a promising therapeutic agent for treating obesity. [ABSTRACT FROM AUTHOR]

Doxorubicin is a frequently used chemotherapeutic agent for treating various malignancies. However, it leads to severe cardiotoxic side effects, such as heart failure, and elevates the risk of sudden cardiac death among cancer patients. While oxidative stress has been identified as the primary cause of doxorubicin-induced cardiotoxicity, therapeutic antioxidant approaches have yielded unsatisfactory outcomes. The aim of this study is to explore the therapeutic potential of vaccarin, an active flavonoid glycoside extracted from traditional Chinese herbal agent Semen Vaccariae, in doxorubicin-induced cardiotoxicity. We observed that vaccarin significantly ameliorates doxorubicin-induced heart dysfunction in mouse model and suppresses oxidative stress mediated cell apoptosis via specifically inhibiting the activation of p38 MAPK pathway. In vitro, we observed that vaccarin alleviates doxorubicin-induced mitochondrial membrane depolarization and ROS generation in H9c2 cell, but the p38 MAPK agonist anisomycin reverses these effects. Our findings provide a promising natural antioxidant to protect against DOX-induced cardiotoxicity. [ABSTRACT FROM AUTHOR]

Abstract Background The global incidence of frozen shoulder (FS) (2% ~ 5%) and osteoporosis (OP) is high (9.1%-12.1%). Clinically, postmenopausal women are particularly at risk for both diseases. The main objective of this current research is to investigate the pathogenesis mechanism of FS and explore the connection between FS and OP. Methods We obtained FS and OP datasets from GEO and identified crosstalk genes. Following KEGG and GO enrich analysis, the p38 MAPK signaling pathway was focused and the specific p38α inhibitor TAK715 was screened out. We conducted flow cytometry, western blot, and PCR analyses to assess the treatment effect of TAK715 on FS synovium fibroblasts at different concentrations. Additionally, we employed SD rats to validate the treatment effects of TAK715 in vivo. Results TAK715 was useful in reversing fibrosis at the concentration of 1 μM, 5 μM and 10 μM. The unbalanced apoptosis process in frozen shoulder cell and the activation of osteoclast were inhibited at the concentration of 5 μM by TAK715. Then we successfully established a FS and OP rat model, with the FS with OP rat displaying less range of motion (ROM) and thicker shoulder capsule. In FS rat that was treated with TAK715, the frozen shoulder side was corrected in ROM and bone loss. Conclusions The frozen shoulder with osteoporosis may exhibit more severe symptoms, and TAK715 is effective in protecting fibrosis and osteoporosis both in vitro and vivo. The therapy to correct FS and OP simultaneously by TAK715 provides novel approach in FS treatment and study.

Abstract Background C3H10T1/2 is a mesenchymal cell line capable of differentiating into osteoblasts, adipocytes and chondrocytes. The differentiation of these cells into osteoblasts is modulated by various transcription factors, such as RUNX2. Additionally, several interconnected signaling pathways, including the NOTCH pathway, play a crucial role in modulating their differentiation into mature bone cells. We have investigated the roles of DLK1 and DLK2, two non-canonical inhibitory ligands of NOTCH receptors, in the osteogenic differentiation of C3H10T1/2 cells. Results Our results corroborate existing evidence that DLK1 acts as an inhibitor of osteogenesis. In contrast, we demonstrate for the first time that DLK2 enhances this differentiation process. Additionally, our data suggest that NOTCH2, 3 and 4 receptors may promote osteogenesis, as indicated by their increased expression during this process, whereas NOTCH1 expression, which decreases during cell differentiation, might inhibit osteogenesis. Moreover, treatment with DAPT, a NOTCH signaling inhibitor, impeded osteogenic differentiation. We have confirmed the increase in ERK1/2 MAPK and p38 MAPK phosphorylation in C3H10T1/2 cells induced to differentiate to osteoblasts. Our new findings reveal increased ERK1/2 MAPK phosphorylation in differentiated C3H10T1/2 cells with a decrease in DLK1 expression or an overexpression of DLK2, which is coincident with the behavior of those transfectants where we have detected an increase in osteogenic differentiation. Additionally, p38 MAPK phosphorylation increases in differentiated C3H10T1/2 cells with reduced DLK1 levels. Conclusions Our results suggest that DLK1 may inhibit osteogenesis, while DLK2 may promote it, by modulating NOTCH signaling and the phosphorylation of ERK1/2 and p38 MAPK pathways. Given the established inhibitory effect of DLK proteins on NOTCH signaling, these new insights could pave the way for developing future therapeutic strategies aimed at treating bone diseases.

G protein-coupled receptors (GPCRs) are highly druggable and implicated in numerous diseases, including vascular inflammation. GPCR signals are transduced from the plasma membrane as well as from endosomes and controlled by posttranslational modifications. The thrombin-activated GPCR protease-activated receptor-1 is modified by ubiquitin. Ubiquitination of protease-activated receptor-1 drives recruitment of transforming growth factor-β-activated kinase-1-binding protein 2 (TAB2) and coassociation of TAB1 on endosomes, which triggers p38 mitogen-activated protein kinase-dependent inflammatory responses in endothelial cells. Other endothelial GPCRs also induce p38 activation via a noncanonical TAB1-TAB2-dependent pathway. However, the regulatory processes that control GPCR ubiquitin-driven p38 inflammatory signaling remains poorly understood. We discovered mechanisms that turn on GPCR ubiquitin-dependent p38 signaling, however, the mechanisms that turn off the pathway are not known. We hypothesize that deubiquitination is an important step in regulating ubiquitin-driven p38 signaling. To identify specific deubiquitinating enzymes (DUBs) that control GPCR-p38 mitogen-activated protein kinase signaling, we conducted a siRNA library screen targeting 96 DUBs in endothelial cells and HeLa cells. We identified nine DUBs and validated the function two DUBs including cylindromatosis and ubiquitin-specific protease-34 that specifically regulate thrombin-induced p38 phosphorylation. Depletion of cylindromatosis expression by siRNA enhanced thrombin-stimulated p38 signaling, endothelial barrier permeability, and increased interleukin-6 cytokine expression. Conversely, siRNA knockdown of ubiquitin-specific protease-34 expression decreased thrombin-promoted interleukin-6 expression and had no effect on thrombin-induced endothelial barrier permeability. These studies suggest that specific DUBs distinctly regulate GPCR-induced p38-mediated inflammatory responses.

Abstract One of the most common causes of peritoneal dialysis withdrawal is ultrafiltration failure which is characterized by peritoneal membrane thickening and fibrosis. Although previous studies have demonstrated the inhibitory effect of p38 MAPK inhibitors on peritoneal fibrosis in mice, it was unclear which specific cells contribute to peritoneal fibrosis. To investigate the role of p38 MAPK in peritoneal fibrosis more precisely, we examined the expression of p38 MAPK in human peritoneum and generated systemic inducible p38 MAPK knockout mice and macrophage-specific p38 MAPK knockout mice. Furthermore, the response to lipopolysaccharide (LPS) was assessed in p38 MAPK-knocked down RAW 264.7 cells to further explore the role of p38 MAPK in macrophages. We found that phosphorylated p38 MAPK levels were increased in the thickened peritoneum of both human and mice. Both chlorhexidine gluconate (CG)-treated systemic inducible and macrophage-specific p38 MAPK knockout mice ameliorated peritoneal thickening, mRNA expression related to inflammation and fibrosis, and the number of αSMA- and MAC-2-positive cells in the peritoneum compared to CG control mice. Reduction of p38 MAPK in RAW 264.7 cells suppressed inflammatory mRNA expression induced by LPS. These findings suggest that p38 MAPK in macrophages plays a critical role in peritoneal inflammation and thickening.

Skin Exposure of skin to ionizing radiation can induce acute or chronic biological effects, resulting in radiation-induced skin injury (RSI). Premature cellular senescence, caused by oxidative stress and/or DNA damage from chemical or physical agents, leads to the decrease of cellular proliferation and physiological function. Persistent DNA damage and accumulation of senescent cells are associated with the progression of radiation-induced injury. Atopic dermatitis and RSI have similar inflammatory symptoms. The treatment of tacrolimus (TAC) in atopic dermatitis may be associated with premature cellular senescence. TAC can prevent the onset of cellular senescence by inactivating the p38 mitogen-activated protein kinase (p38 ​MAPK). The activation of p38 ​MAPK can induce the senescence-associated secretory phenotype (SASP) by enhancing the transcriptional activity of nuclear factor kappa-B (NF-κB), which ultimately leads to premature cellular senescence. FK506 binding protein 51 (FKBP51) exhibits resistance to ionizing radiation, but the mechanism of TAC regulation of ionizing radiation-induced premature senescence still needs further study. This review discusses the mechanism of cellular senescence in RSI and the role of TAC in both dermatitis and RSI.

Plumbagin (PLB), a naphthoquinone compound, has been proven to have anti-cancer properties in different types of cancers. However, the anti-tumor actions as well as molecular processes in osteosarcoma (OS) remain unclear. This study investigates the underlying mechanisms of PLB in human OS cells in vitro. Our study showed that PLB significantly inhibited the proliferation of human OS cells in a time- and dosage-dependent manner. RNA sequencing data revealed that the efficacy of PLB is related to cell cycle, cell death, and p38 MAPK signaling pathway in KHOS-240S cells. Further studies indicated that PLB triggers G2/M phase arrest, mitochondrial-dependent apoptosis, as well as ferroptosis in human OS cells. Mechanistically, PLB treatment increased ROS generation that activates the p38 MAPK signaling pathway. BIRB 796, a p38 MAPK inhibitor, partly reversed PLB-induced phase arrest of G2/M and cell death. Furthermore, N-acetylcysteine (NAC), a ROS scavenger, significantly decreased G2/M phase arrest and cell death and reversed p38 MAPK activation caused by PLB. In conclusion, PLB induces arrest G2/M arrest, apoptosis as well as ferroptosis in human OS cells via ROS generation and p38 MAPK activation. There is potential for PLB to be an effective treatment for OS.

Introduction: Previous research has shown that an aqueous extract of Humulus japonicus (EH) can ameliorate hypertension, nonalcoholic fatty liver disease, and oxidative stress in adipocytes by activating the thermogenic pathway. However, the effects of an ethanol (30%) extract of EH on obesity are unknown. Methods: Various protein expression levels in fully differentiated 3T3-L1 adipocytes were assessed by Western blotting. Lipid deposition in 3T3-L1 adipocytes was examined by oil red O staining. The MTT assay was used to evaluate adipocyte viability. Caspase 3 activity and glycerol release were determined using commercial assay kits. Results: In this study, we discovered that EH treatment inhibited lipogenesis and promoted lipolysis in both differentiated 3T3-L1 adipocytes and adipose tissue of mice fed a high-fat diet. EH treatment also increased phosphorylated protein kinase A (PKA) levels while reducing p38 phosphorylation. When H89, a PKA inhibitor, was used, the effects of EH on lipogenic lipid accumulation and lipolysis in 3T3-L1 adipocytes were eliminated. Treatment with luteolin 7-O-β-d-glucoside (LU), the major active compound in EH, also suppressed lipid deposition and p38 phosphorylation but enhanced lipolysis in 3T3-L1 adipocytes. These changes were abrogated by H89. Conclusion: These findings indicate that EH containing LU reduces lipogenesis and stimulates lipolysis via the PKA/p38 signaling pathway, leading to an improvement in obesity in mice. Therefore, our study suggested that EH could be a promising therapeutic agent for treating obesity.

Xuan Wang,1,* Hanjie Yu,2,* Yunheng Zhang,3,* Xin Chang,1 Chengyi Liu,1 Xiaodong Wen,1 Feng Tian,1 Yi Li1 1Department of Foot and Ankle Surgery, Honghui Hospital, Xi’an Jiaotong University, Xi’an, Shaanxi, People’s Republic of China; 2Laboratory for Functional Glycomics, College of Life Sciences, Northwest University, Xi’an, Shaanxi, People’s Republic of China; 3The Second Clinical Medical College, Shaanxi University of Chinese Medicine, Xianyang, Shaanxi, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yi Li, Email liyidoctor@163.comObjective: Osteoarthritis (OA) is a common degenerative disease worldwide. While curcumin has shown therapeutic effects on OA, its mechanism remains unknown. This study aimed to investigate the molecular mechanism of curcumin in treating OA through network pharmacology and both in vivo and in vitro experiments.Methods: Curcumin-related targets were obtained using the HERB and DrugBank databases. GeneCards and DisGeNET were used to build a target database for OA. The STRING database was employed to construct protein-protein interaction networks and analyze related protein interactions. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and gene ontology enrichment analyses of core targets were performed using Metascape. In addition, Autodock software was utilized for molecular docking validation of curcumin and disease targets. Further validation of the main findings was conducted through in vitro and in vivo experiments. In the in vitro experiments, an inflammation model was constructed through nitric oxide donor (SNP) stimulation of chondrocytes. Subsequently, the regulatory effects of curcumin on core targets and signaling pathways were validated using Western blotting and immunofluorescence staining techniques. In the in vivo experiments, an OA model was established by performing medial meniscectomy on male Sprague–Dawley rats. The therapeutic effects were evaluated using enzyme-linked immunosorbent assays, histologic staining, and micro-computed tomography (micro-CT) techniques.Results: Core targets of curcumin relevant to OA therapy included tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1β, IL-6, matrix metalloproteinase 9 (MMP-9), B-cell lymphoma 2 (BCL-2), and caspase-3. The major biological processes involved oxidative stress and apoptotic processes, among others. The p38 mitogen-activated protein kinase (p38/MAPK) pathway was identified as the most likely pathway involved. In vitro experiments showed that curcumin significantly reduced oxidative stress levels, inhibited the expression of inflammatory factors IL-6 and Cyclooxygenase-2 (COX-2) and downregulated the expression of MMP-9 and MMP-1. In addition, curcumin was found to regulate the expression of BCL-2 and caspase-3 through the p38/MAPK pathway, inhibiting chondrocyte apoptosis. In vivo animal experiments demonstrated that curcumin significantly reduced the expression of OA-related factors (IL-1, IL-6, and TNF-α). Histological analysis and micro-CT results revealed that curcumin treatment significantly increased cartilage thickness, improved cartilage morphology, structure, and function, inhibited cartilage degradation, and enhanced the resorption of subchondral bone in the knee joints of rats with OA.Conclusion: Curcumin regulates oxidative stress and maintains mitochondrial function, thereby protecting chondrocyte guard. In addition, curcumin attenuates the inflammatory response of chondrocytes by inhibiting the phosphorylation of P38MAPK, slowing down the breakdown of the extrachondral matrix while preventing apoptosis of chondrocytes. Additionally curcumin attenuated cartilage degradation and bone damage while helping to boost bone density.Keywords: osteoarthritis, curcumin, molecular mechanism, network pharmacology, p38/MAPK

HBeAg is a non-structural, secreted protein of hepatitis B virus (HBV). Its p25 precursor is post-translationally modified in the endoplasmic reticulum. The G1862T precore mutation leads to the accumulation of P25 in the endoplasmic reticulum and activation of unfolded protein response. Using mass spectrometry, comparative proteome profiling of Huh-7 cells transfected with wildtype (WT) or G1862T revealed significantly differentially expressed proteins resulting in 12 dysregulated pathways unique to WT-transfected cells and 7 shared between cells transfected with either WT or G1862T. Except for the p38 MAPK signalling pathway, WT showed a higher number of DEPs than G1862T-transfected cells in all remaining six shared pathways. Two signalling pathways: oxidative stress and cell cycle signalling were differentially expressed only in cells transfected with G1862T. Fifteen pathways were dysregulated in G1862T-transfected cells compared to WT. The 15 dysregulated pathways were involved in the following processes: MAPK signalling, DNA synthesis and methylation, and extracellular matrix organization. Moreover, proteins involved in DNA synthesis signalling (replication protein A (RPA) and DNA primase (PRIM2)) were significantly upregulated in G1862T compared to WT. This upregulation was confirmed by mRNA quantification of both genes and immunofluorescent confocal microscopy for RPA only. The dysregulation of the pathways involved in these processes may lead to immune evasion, persistence, and uncontrolled proliferation, which are hallmarks of cancer.

Plumbagin (PLB), a naphthoquinone compound, has been proven to have anti-cancer properties in different types of cancers. However, the anti-tumor actions as well as molecular processes in osteosarcoma (OS) remain unclear. This study investigates the underlying mechanisms of PLB in human OS cells in vitro. Our study showed that PLB significantly inhibited the proliferation of human OS cells in a time- and dosage-dependent manner. RNA sequencing data revealed that the efficacy of PLB is related to cell cycle, cell death, and p38 MAPK signaling pathway in KHOS-240S cells. Further studies indicated that PLB triggers G2/M phase arrest, mitochondrial-dependent apoptosis, as well as ferroptosis in human OS cells. Mechanistically, PLB treatment increased ROS generation that activates the p38 MAPK signaling pathway. BIRB 796, a p38 MAPK inhibitor, partly reversed PLB-induced phase arrest of G2/M and cell death. Furthermore, N-acetylcysteine (NAC), a ROS scavenger, significantly decreased G2/M phase arrest and cell death and reversed p38 MAPK activation caused by PLB. In conclusion, PLB induces arrest G2/M arrest, apoptosis as well as ferroptosis in human OS cells via ROS generation and p38 MAPK activation. There is potential for PLB to be an effective treatment for OS. • PLB induces G2/M arrest, apoptosis, and ferroptosis in human osteosarcoma cells. • The anti-osteosarcoma effect of Plumbagin is related to the ROS/p38 MAPK pathway. • PLB could be a promising therapeutic agent for osteosarcoma. [ABSTRACT FROM AUTHOR]

In recent years, a number of studies have demonstrated that hypoxia reoxygenation (HR) induced by ischemia postconditioning (IPC) reduces endothelial barrier dysfunction and inflammation in various models. When HR occurs, the P38 mitogen-activated protein kinase (P38 MAPK) breaks down the endothelial barrier. But no study has clearly clarified the effect of hypoxia postconditioning (HPC) on P38 MAPK in human dermal microvascular endothelial cells. Therefore, we investigated the function of HPC on P38 MAPK during HR in vitro. Human dermal microvascular endothelial cells were cultured in a hypoxic incubator for 8 h. Then cells were reperfused for 12 h (reoxygenation) or postconditioned by 5 min of reoxygenation and 5 min of re-hypoxia 3 times followed by 11.5 h reoxygenation. SB203580 was used as an inhibitor of P38 MAPK. Cell counting kit-8 assay kits were employed to detect cell activity. The corresponding levels of IL-6, IL-8 and IL-1β were examined via Enzyme-Linked ImmunoSorbent Assay. The endothelial barrier was evaluated using fluorescein isothiocyanate-dextran leakage assay. Western blot was used to detect claudin-5, phosphorylation of P38 MAPK (P-P38 MAPK) and P38 MAPK expression. Claudin-5 localization was studied by immunofluorescence. HR induced endothelial barrier hyperpermeability, elevated inflammation levels, and increased the P-P38 MAPK. But HPC reduced cell injury and maintained the integrity of the endothelial barrier while inhibiting P-P38 MAPK and increasing expression of claudin-5. HPC redistributed claudin-5 in a continuous and linear pattern on the cell membrane. HPC protects against HR induced downregulation and redistribution of claudin-5 by inhibiting P-P38 MAPK. [ABSTRACT FROM AUTHOR]

Background: Galectin‐9 (Gal‐9) has been implicated in allergic and autoimmune diseases, but its role and relevance in chronic spontaneous urticaria (CSU) are unclear. Objectives: To characterize the role and relevance of Gal‐9 in the pathogenesis of CSU. Methods: We assessed 60 CSU patients for their expression of Gal‐9 on circulating eosinophils and basophils as well as T cell expression of the Gal‐9 receptor TIM‐3, compared them with 26 healthy controls (HCs), and explored possible links with disease features including disease activity (urticaria activity score, UAS), total IgE, basophil activation test (BAT), and response to omalizumab treatment. We also investigated potential drivers of Gal‐9 expression by eosinophils and basophils. Results: Our CSU patients had markedly increased rates of circulating Gal‐9+ eosinophils and basophils and high numbers of lesional Gal‐9+ cells. High rates of blood Gal‐9+ eosinophils/basophils were linked to high disease activity, IgE levels, and BAT negativity. Serum levels of TNF‐α were positively correlated with circulating Gal‐9+ eosinophils/basophils, and TNF‐α markedly upregulated Gal‐9 on eosinophils. CSU patients who responded to omalizumab treatment had more Gal‐9+ eosinophils/basophils than non‐responders, and omalizumab reduced blood levels of Gal‐9+ eosinophils/basophils in responders. Gal‐9+ eosinophils/basophils were negatively correlated with TIM‐3+TH17 cells. Conclusion: Our findings demonstrate a previously unrecognized involvement of the Gal‐9/TIM‐3 pathway in the pathogenesis CSU and call for studies that explore its relevance. [ABSTRACT FROM AUTHOR]

Background: Microglia, the main innate immune cells in the central nervous system, are key drivers of neuroinflammation, which plays a crucial role in the pathogenesis of neurodegenerative diseases. The Sin3/histone deacetylase (HDAC) complex, a highly conserved multiprotein co-repressor complex, primarily performs transcriptional repression via deacetylase activity; however, the function of SDS3, which maintains the integrity of the complex, in microglia remains unclear. Methods: To uncover the regulatory role of the transcriptional co-repressor SDS3 in microglial inflammation, we used chromatin immunoprecipitation to identify SDS3 target genes and combined with transcriptomics and proteomics analysis to explore expression changes in cells following SDS3 knocking down. Subsequently, we validated our findings through experimental assays. Results: Our analysis revealed that SDS3 modulates the expression of the upstream kinase ASK1 of the p38 MAPK pathway, thus regulating the activation of signaling pathways and ultimately influencing inflammation. Conclusions: Our findings provide important evidence of the contributions of SDS3 toward microglial inflammation and offer new insights into the regulatory mechanisms of microglial inflammatory responses. [ABSTRACT FROM AUTHOR]

Deoxyshikonin (DSK) is a biological component derived from Lithospermum erythrorhizon. Although DSK possesses potential anticancer activities, whether DSK exerts anticancer effects on cervical cancer cells is incompletely explored. This study was aimed to investigate the anticancer activity of DSK against cervical cancer cells and its molecular mechanisms. Cell viability was evaluated by MTT assay. Level of phosphorylation and protein was determined using Western blot. Involvement of signaling kinases was assessed by specific inhibitors. Our results revealed that DSK reduced viability of human cervical cell in a dose‐dependent fashion. Meanwhile, DSK significantly elicited apoptosis of HeLa and SiHa cells. Apoptosis microarray was used to elucidate the involved pathways, and the results showed that DSK dose‐dependently diminished cellular inhibitor of apoptosis protein 1 (cIAP1), cIAP2, and XIAP, and induced cleavage of poly(ADP‐ribose) polymerase (PARP) and caspase‐8/9/3. Furthermore, we observed that DSK significantly triggered activation of ERK, JNK, and p38 MAPK (p38), and only inhibition of p38 diminished the DSK‐mediated pro‐caspases cleavage. Taken together, our results demonstrate that DSK has anti‐cervical cancer effects via the apoptotic cascade elicited by downregulation of IAPs and p38‐mediated caspase activation. This suggests that DSK could act as an adjuvant to facilitate cervical cancer management. [ABSTRACT FROM AUTHOR]

Cognitive dysfunction is one of the serious complications of type 2 diabetes. Exercise intervention has a certain effect on improving diabetes cognition, but the exact process remains ambiguous.This research aims to explore the impact and molecular processes of treadmill exercises in enhancing cognitive impairments in type 2 diabetic mice. Ten m/m 8-week-old male mice were used as the control group. Forty db/db mice, each 8 weeks old and male, were categorized into four distinct groups with each group containing 10 mice, including the db/db group (model group), db+Exe group (exercise group), db+Exe+SB203580 group (exercise combined with the p38 MAPK inhibitor group), db+SB203580 group (p38 MAPK inhibitor group). db+Exe group and db+Exe+SB203580 group were subjected to treadmill running intervention (40min/time, 5 times / week, a total of 8 weeks). db+Exe+SB203580 and db+SB203580 group were intraperitoneally injected with SB203580 (5 mg/kg, 5 times/week, 8 weeks) 2 hours before treadmill exercise. The results of body weights and fasting blood glucose measurement showed that 8-week treadmill exercise could significantly reduce the body mass and fasting blood glucose levels (P<0.01); the results of water maze showed that treadmill exercise improved cognitive dysfunction in diabetic mice (P<0.05). Immunofluorescence staining revealed that treadmill exercise diminished the fluorescence intensity of NLRP3 in hippocampus, and there was a significant difference in CA1 and CA3 regions (P<0.05). Treadmill exercise reduced the fluorescence intensity of PI in the hippocampus, and there was a significant difference in the DG region (P<0.01). The results of qRT-PCR revealed that treadmill exercise decreased IL-1β and IL-18 mRNA levels in hippocampus, with a notable difference in IL-1β mRNA levels(P<0.05). Western blotting analysis revealed that treadmill exercise reduced the concentrations of Caspase3, Caspase9 and Bax in hippocampus (P<0.01), reduced the concentrations of TXNIP, NLRP3, GSDMD-N, IL-1β, IL-18, Cleaved Caspase1 and Caspase1 (P<0.05), decreased the levels of p-RIPK1, RIPK1, p-RIPK3 and RIPK3 (P<0.05). After adding p38 inhibitors, treadmill exercise combined with p38 inhibitor intervention further inhibited the expression of Caspase3, TXNIP, GSDMD-N and IL-18 (P<0.05), and the expression levels of Caspase9, Bax, NLRP3, IL-1β, Cleaved Caspase 1 and Caspase 1 also showed a downward trend. The expression of RIPK1 and p-RIPK3 increased significantly (P<0.05), and the protein expression levels of p-p38, p-RIPK1 and RIPK3 showed an upward trend. In conclusion, treadmill running intervention can effectively improve the cognitive dysfunction in type 2 diabetic mice, and its mechanism is partly through the p38 MAPK signaling pathway to regulate PANoptosis. [ABSTRACT FROM AUTHOR]

Atherosclerosis (AS) is a chronic inflammatory arterial disease, in which abnormal lipid metabolism and foam cell formation play key roles. Histamine is a vital biogenic amine catalyzed by histidine decarboxylase (HDC) from L-histidine. Histamine H1 receptor (H1R) antagonist is a commonly encountered anti-allergic agent in the clinic. However, the role and mechanism of H1R in atherosclerosis have not been fully elucidated. Here, we explored the effect of H1R on atherosclerosis using Apolipoprotein E-knockout (ApoE−/−) mice with astemizole (AST, a long-acting H1R antagonist) treatment. The results showed that AST increased atherosclerotic plaque area and hepatic lipid accumulation in mice. The result of microarray study identified a significant change of endothelial lipase (LIPG) in CD11b+ myeloid cells derived from HDC-knockout (HDC−/−) mice compared to WT mice. Blocking H1R promoted the formation of foam cells from bone marrow-derived macrophages (BMDMs) of mice by up-regulating p38 mitogen-activated protein kinase (p38 MAPK) and LIPG signaling pathway. Taken together, these findings demonstrate that blocking H1R signal aggravates atherosclerosis by promoting abnormal lipid metabolism and macrophage-derived foam cell formation via p38 MAPK-LIPG signaling pathway. Key messages: Blocking H1R signal with AST aggravated atherosclerosis and increased hepatic lipid accumulation in high-fat diet (HFD)-fed ApoE−/− mice. Blocking H1R signal promoted macrophage-derived foam cell formation via p38 MAPK-LIPG signaling pathway. [ABSTRACT FROM AUTHOR]

Aquaporin‐2 (AQP2) is a member of the aquaporin water channel family. In the kidney, AQP2 is expressed in collecting duct principal cells where it facilitates water reabsorption in response to antidiuretic hormone (arginine vasopressin, AVP). AVP induces the redistribution of AQP2 from intracellular vesicles and its incorporation into the plasma membrane. The plasma membrane insertion of AQP2 represents the crucial step in AVP‐mediated water reabsorption. Dysregulation of the system preventing the AQP2 plasma membrane insertion causes diabetes insipidus (DI), a disease characterised by an impaired urine concentrating ability and polydipsia. There is no satisfactory treatment of DI available. This review discusses kinases that control the localisation of AQP2 and points out potential kinase‐directed targets for the treatment of DI. [ABSTRACT FROM AUTHOR]

Metabolic reprogramming in cancer occurs due to interaction of cells with the surrounding tumor microenvironment. In the microenvironment of solid tumors, nutrient deprivation is induced by high consumption of nutrients and insufficient vasculature. Tumor cells alter their metabolic strategies to adapt to the microenvironment. To understand the role of these metabolic changes, in the current study, we have mimicked nutrient deprivation condition in vitro to evaluate the associated signaling pathways in breast cancer cells. In our study, we have shown that nutritional deprivation activated p38 MAPK and activating transcription factor‐2 (ATF‐2) by increased phosphorylation of Thr180/Tyr182 and Thr71, respectively, in breast cancer cells. Pharmacological inhibition of p38 MAPK showed increased cell viability and reduced expression of ATF‐2 and RAD23B under nutrient starvation conditions. Further, silencing of ATF‐2 showed increased cell viability and decreased expression of RAD23B under nutrient starvation conditions. This suggests the involvement of p38 MAPK/ATF‐2/RAD23B axis as a signaling pathway under nutrition starvation in breast cancer cells. The RAD23B mediated proteasome activity was shown to be much higher under stress conditions indicating a crucial role of RAD23B as a target for breast cancer. [ABSTRACT FROM AUTHOR]

Copyright of China Surfactant Detergent & Cosmetics (2097-2806) is the property of China Surfactant Detergent & Cosmetics Editorial Office and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Traditional Chinese Drug Research & Clinical Pharmacology is the property of Traditional Chinese Drug Research & Clinical Pharmacology Editorial Office and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Apigenin (APG) is a plant-based flavonoid that possesses antioxidants, anti-inflammatory, and modulates P38 MAPK as well as tyrosinase. Hydroquinone (HQ), a phenolic compound was used to induce vitiligo in C57BL/6 mice. The present study was performed to check the therapeutic potential of apigenin in HQ-induced vitiligo via targeting P38 MAPK pathway. In the present study, 41 C57BL/6 mice were divided into six groups containing seven animals per group except normal group. (I) normal group, (II) HQ group, (III) to (IV) APG with (1%, 2.5%, 5%), and (VI) tacrolimus (TAC) group. Topical application of HQ was performed from day 1 to day 20 to, (II), (III) to (IV) APG with (1%, 2.5%, 5%), (VI) tacrolimus (TAC) group, and then APG; tacrolimus (TAC) was applied from day 21 to day 60 after removing the hair. In the case of (I) normal group and (II) HQ group, we smeared them with water for 60 days and HQ for 20 days in their individual group. On day 61 after anesthesia, a part of the target skin was peeled and blood serum was taken to check the level of malondialdehyde, cholinesterase, catalase, tyrosinase, pro-inflammatory cytokines, and expression of P38 MAPK, histology of melanin containing hair follicles and depigmentation evaluation. Applying HQ topically had a noticeable impact on depigmentation, inflammatory indicators, oxidative stress, and lowered tyrosinase activity. Further HQ reduced melanin containing hair follicles and increased expression of P38 MAPK was confirmed by histopathology and immunohistochemistry. Furthermore, application of APG and TAC after day 21 to 60 significantly reduced depigmentation, inflammatory markers, oxidative stress, and increased tyrosinase. Furthermore, APG increased melanin containing hair follicles and decreased expression of non-phosphorylated P38 MAPK, as confirmed by histopathology and immunohistochemistry. Our finding demonstrated that APG significantly prevented HQ-induced vitiligo by acting as an anti-inflammatory, increasing tyrosine, and reducing the expression of non-phosphorylated P38 MAPK. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) remains a global health burden, accounting for almost a million deaths annually. Deoxybouvardin (DB), a non-ribosomal peptide originally isolated from Bouvardia ternifolia, has been reported to possess antitumor activity; however, the detailed mechanisms underlying this anticancer activity have not been elucidated. We investigated the anticancer activity of the cyclic hexapeptide, DB, in human CRC HCT116 cells. Cell viability, evaluated by MTT assay, revealed that DB suppressed the growth of both oxaliplatin (Ox)-resistant HCT116 cells (HCT116-OxR) and Ox-sensitive cells in a concentration- and time-dependent manner. Increased reactive oxygen species (ROS) generation was observed in DB-treated CRC cells, and it induced cell cycle arrest at the G2/M phase by regulating p21, p27, cyclin B1, and cdc2 levels. In addition, Western blot analysis revealed that DB activated the phosphorylation of JNK and p38 MAPK in CRC. Furthermore, mitochondrial membrane potential (MMP) was dysregulated by DB, resulting in cytochrome c release and activation of caspases. Taken together, DB exhibited anticancer activity against both Ox-sensitive and Ox-resistant CRC cells by targeting JNK and p38 MAPK, increasing cellular ROS levels, and disrupting MMP. Thus, DB is a potential therapeutic agent for the treatment of Ox-resistant CRC. [ABSTRACT FROM AUTHOR]

This study investigates whether Bacillus pumilus TS1 improves growth performance and alleviates inflammatory damage in broilers and explored its feasibility as an antibiotic alternative. We divided 240 one-day-old AA308 white-finned broilers into five groups (con, LPS, TS1L + LPS, TS1M + LPS and TS1H + LPS). The TS1L + LPS, TS1M + LPS and TS1H + LPS groups were fed TS1 for 15 days by gavage. The LPS, TS1L + LPS, TS1M + LPS and TS1H + LPS groups were injected intraperitoneally with 1 mg/kg LPS for three days. We investigated the probiotic and anti-inflammatory activities by measuring body weight, sequencing the intestinal flora and examining the structure of tissues by using pathological stain, real-time PCR, Western blotting and immunohistochemical detection. TS1 could improve growth performance and intestinal flora composition, also reduced different organ damage and inflammatory cytokine expression in serum and organs. The mechanism may involve upregulating HSP60 and HSP70 expression, targeting and regulating Nrf2 and P38 MAPK and modulating NF-κB and HO-1 expression at the transcriptional level in different organs. B. pumilus TS1 alleviated Inflammatory injury caused by LPS and attenuated the inflammatory response in broilers, and these effects were achieved through MAPK and Nrf2 regulation of HSPs/HO-1 in different organs. The above results suggested broilers fed with TS1 could release the LPS caused organ damage, and the most suggested dosage was 1.4 × 108 CFU/mL.

ABSTRACTHuman fetal membranes (amniochorion) that line the intrauterine cavity consist of two distinct cell layers; single-layer amnion epithelial cells (AEC) and multilayer chorion trophoblast cells (CTC). These layers are connected through a collagen-rich extracellular matrix. Cellular remodeling helps support membrane growth and integrity during gestation and helps to maintain pregnancy. Preterm prelabor rupture of the human amniochorionic (fetal) membrane (pPROM) is antecedent to 40% of all spontaneous preterm birth. Oxidative stress (OS) induced activation of the p38 MAPK due to various maternal risk exposures and the amniochorion cells’ senescence are reported pathological features of pPROM. Our transcriptomics analysis implicated dysregulated autophagy and epithelial-mesenchymal transition (EMT) in fetal membranes from pPROM. The molecular interplay between OS-induced p38 MAPK activation, autophagy, and EMT was investigated in AECs and CTCs to better understand the involvement of autophagy and EMT. We report the differential impact of OS on the autophagic machinery in AECs and CTCs, resulting in distinct cell fates. In AECs, OS-induced p38 MAPK activation causes autophagosome accumulation and reduced autophagic flux mediated by decreased ULK1 activity and kinase activity, leading to senescence. In CTCs, induction of autophagy has a limited effect; however, inhibition of autophagy led to SQSTM1-mediated EMT of trophoblast cells. Autophagy, EMT, and senescence were associated with proinflammatory changes. Thus, AECs and CTCs respond differently to OS via differential autophagy response, partly mediated via p38 MAPK. Besides senescence, OS-induced autophagy dysregulation in amniochorion cells may play a mechanistic role in pPROM pathophysiology.

BackgroundTo explore new modulatory intervention targets for radiation-induced lung injury, bioinformatics analysis technology was used to search for the core driving genes in the pathogenesis of radiation pneumonitis, and the results were verified by a radiation-induced murine lung injury model to find possible new targets for the treatment of radiation lung injury.MethodGene Expression Omnibus Database was used to identify differentially expressed genes in radiation pneumonitis. DAVID database was used for gene ontology (GO) and Kyoto Encyclopedia of Genes and Genome (KEGG) enrichment analysis. Gene Set Enrichment Analysis was used to analyze abnormal expressions. Protein–protein interaction networks were constructed using STRING and Cytoscape. Discovery Studio 4.5 software was used to find the preferred inhibitor of the specific gene. A radiation-induced lung injury model was induced in female C57BL/6N mice. The specific inhibitors were administered by intraperitoneal injection 24 h before and for 7 consecutive days after radiation. Lungs were harvested for further analysis 14 days and 10 weeks post-irradiation.ResultsWe screened Syk as one of the most important driver genes of radiation pneumonitis by bioinformatics analysis and screened the preferred Syk inhibitor fostamatinib from the drug database. Syk was highly expressed in irradiated lung tissue, and fostamatinib inhibited the level of Syk expression. Syk inhibitor significantly alleviated the radiation-induced lung injury and downregulated the increased expression of p38 MAPK, p53, IL-1β, and IL-6 in lung tissue at 2 weeks after radiation. The levels of TGF-β, COL1A1, and α-SMA and degree of pulmonary fibrosis at 10 weeks after radiation were also decreased by Syk inhibitor.ConclusionSyk inhibitor may have a potential to be used as a targeted drug to mitigate radiation pneumonitis and inhibit radiation-induced pulmonary fibrosis.

This study aimed to investigate the effect of apigenin, a flavonoid widely distributed in plants, on AK23-induced desmoglein3 (Dsg3) depletion in pemphigus vulgaris (PV) model using HaCaT cells. Dispase-based dissociation assay showed that the number of cell fragments, which increased compared to the control group due to AK23 treatment, dramatically decreased when HaCaT cells were incubated with AK23 and apigenin. The continuous linear fluorescence intensity of Dsg3 between cells was decreased in the AK23 group, but the treatment of apigenin recovered the fluorescent distribution of Dsg3. Moreover, the addition of apigenin up-regulated the Dsg3 protein expression in AK23-treated HaCaT cells. The phosphorylation level of p38 mitogen-activated protein kinase (MAPK) induced by the AK23 was down-regulated by apigenin. In conclusion, apigenin attenuated AK23-mediated Dsg3 depletion by suppressing the p38 pathway in the PV cell model. Therefore, apigenin could be a functional food material for ameliorating PV.

Background: Cognitive dysfunction, encompassing perioperative psychological distress and cognitive impairment, is a prevalent postoperative complication within the elderly population, and in severe cases, it may lead to dementia. Building upon our prior research that unveiled a connection between postoperative mood fluctuations and cognitive dysfunction with the phosphorylation of P38, this present investigation aims to delve deeper into the involvement of the P38 MAPK/NLRP3 pathway in perioperative neurocognitive disorders (PND) in an abdominal exploratory laparotomy (AEL) aged mice model. Methods: C57BL/6 mice (male, 18-month-old) underwent AEL with 3 % anesthesia. Then, inhibitors targeting P38 MAPK (SB202190, 1 mg/kg) and GSK3β (TWS119, 10 mg/kg) were administered multiple times daily for 7 days post-surgery. The NLRP3-cKO AEL and WT AEL groups only underwent the AEL procedure. Behavioral assessments, including the open field test (OFT), novel object recognition (NOR), force swimming test (FST), and fear conditioning (FC), were initiated on postoperative day 14. Additionally, mice designated for neuroelectrophysiological monitoring had electrodes implanted on day 14 before surgery and underwent novel object recognition while their local field potential (LFP) was concurrently recorded on postoperative day 14. Lastly, after they were euthanasized, pathological analysis and western blot were performed. Results: SB202190, TWS119, and astrocyte-conditional knockout NLRP3 all ameliorated the cognitive impairment behaviors induced by AEL in mice and increased mean theta power during novel location exploration. However, it is worth noting that SB202190 may exacerbate postoperative depressive and anxiety-like behaviors in mice, while TWS119 may induce impulsive behaviors. Conclusions: Our study suggests that anesthesia and surgical procedures induce alterations in mood and cognition, which may be intricately linked to the P38 MAPK/NLRP3 pathway.

Background: Inhibition of p38 alpha mitogen activated protein kinase (p38α) has shown great promise as a treatment for Alzheimer's disease (AD) in preclinical tests. However, previous preclinical studies were performed in “pure” models of AD pathology. A vast majority of AD patients have comorbid dementia-contributing pathologies, particularly some form of vascular damage. The present study therefore aimed to test the potential of p38α inhibition to address dysfunction in the context of comorbid amyloid and vascular pathologies. Methods: An amyloid overexpressing mouse strain (5xFAD) was placed on an 8-week long diet to induce the hyperhomocysteinemia (HHcy) model of small vessel disease. Mice were treated with the brain-penetrant small molecule p38α inhibitor MW150 for the duration of the HHcy diet, and subsequently underwent behavioral, neuroimaging, electrophysiological, or biochemical/immunohistochemical analyses. Results: MW150 successfully reduced behavioral impairment in the Morris Water Maze, corresponding with attenuation of synaptic loss, reduction in tau phosphorylation, and a partial normalization of electrophysiological parameters. No effect of MW150 was observed on the amyloid, vascular, or neuroinflammatory endpoints measured. Conclusions: This study provides proof-of-principle that the inhibition of p38α is able to provide benefit even in the context of mixed pathological contributions to cognitive impairment. Interestingly, the benefit was mediated primarily via rescue of neuronal function without any direct effects on the primary pathologies. These data suggest a potential use for p38 inhibitors in the preservation of cognition across contexts, and in particular AD, either alone or as an adjunct to other AD therapies (i.e. anti-amyloid approaches). Future studies to delineate the precise neuronal pathways implicated in the benefit may help define other specific comorbid conditions amenable to this type of approach or suggest future refinement in pharmacological targeting.

Abstract Acute myeloid leukaemia (AML) is a fatal haematopoietic malignancy and is treated with the conventional combination of cytarabine (Ara-C) and daunorubicin (Dau). The survival rate of AML patients is lower due to the cardiotoxicity of daunorubicin. Clinically, homoharringtonine (HHT) plus Ara-C has been reported to be equally effective as Dau plus Ara-C in some types of AML patients with less toxic effects. We utilized the clinical use of homoharringtonine in combination with Ara-C to test its combination mechanism. We found that the insensitivity of AML cells to cytarabine-induced apoptosis is associated with increased Mcl-1 stability and p38 inactivation. HHT downregulates Mcl-1, phosphorylates H2AX and induces apoptosis by activating p38 MAPK. Inactivation of p38 through inhibitors and siRNA blocks apoptosis, H2AX phosphorylation and Mcl-1 reduction. HHT enhances Ara-C activation of the p38 MAPK signalling pathway, overcoming Ara-C tolerance to cell apoptosis by regulating the p38/H2AX/Mcl-1 axis. The optimal ratio of HHT to Ara-C for synergistic lethality in AML cells is 1:4 (M/M). HHT synergistically induces apoptosis in combination with Ara-C in vitro and prolongs the survival of xenografts. We provide a new mechanism for AML treatment by regulating the p38 MAPK/H2AX/Mcl-1 axis to improve cytarabine therapy.

Mammalian germ cells are derived from primordial germ cells (PGCs) and ensure species continuity through generations. Unlike irreversible committed mature germ cells, migratory PGCs exhibit a latent pluripotency characterized by the ability to derive embryonic germ cells (EGCs) and form teratoma. Here, we show that inhibition of p38 mitogen-activated protein kinase (MAPK) by chemical compounds in mouse migratory PGCs enables derivation of chemically induced Embryonic Germ-like Cells (cEGLCs) that do not require conventional growth factors like LIF and FGF2/Activin-A, and possess unique naïve pluripotentlike characteristics with epiblast features and chimera formation potential. Furthermore, cEGLCs are regulated by a unique PI3K-Akt signaling pathway, distinct from conventional naïve pluripotent stem cells described previously. Consistent with this notion, we show by performing ex vivo analysis that inhibition of p38 MAPK in organ culture supports the survival and proliferation of PGCs and also potentially reprograms PGCs to acquire indefinite proliferative capabilities, marking these cells as putative teratoma-producing cells. These findings highlight the utility of our ex vivo model in mimicking in vivo teratoma formation, thereby providing valuable insights into the cellular mechanisms underlying tumorigenesis. Taken together, our research underscores a key role of p38 MAPK in germ cell development, maintaining proper cell fate by preventing unscheduled pluripotency and teratoma formation with a balance between proliferation and differentiation. [ABSTRACT FROM AUTHOR]

Oyaksoongi-San (OYSGS), which is a combination of 11 herbal ingredients, has long been used in Asia to relieve symptoms of various diseases conditions, including vomiting and diarrhea. In this study, we assessed the protective efficacy of OYSGS in a murine model of asthma induced by ovalbumin (OVA) and explored potential molecular mechanisms. Male C57BL/6 mice were sensitized with OVA and airway challenged with OVA (1% w/v in PBS) for 1 h. OYSGS (100, 300, and 500 mg/kg once daily) was administered for 6 days by oral gavage. Our results revealed that OYSGS significantly decreased the number of inflammatory cells and reduced the concentrations of interleukin (IL)-5 and IL-13 in bronchoalveolar lavage fluid (BALF). Histological analyses showed that OYSGS substantially decreased inflammation and mucus hypersecretion in the airway. Further analyses revealed that OYSGS effectively reduced oxidative stress, as shown by downregulation of malondialdehyde (MDA) and upregulation of total glutathione (GSSG/GSH), and markedly suppressed the phosphorylation of p38 mitogen-activated protein kinase (p38 MAPK). Together, these results suggest that OYSGS effectively inhibits the airway inflammatory responses, mucus secretion, and oxidative stress induced by OVA. [ABSTRACT FROM AUTHOR]

Liver fibrosis occurs in response to chronic damage and inflammation to the liver. Leaving untreated, it can lead to decreased liver function and can eventually progress to cirrhosis, a more advanced and irreversible state of liver damage. Clinical investigations showed that chronic liver disease associated with neurological symptoms including anxiety, depression, and cognitive decline. However, few therapeutic options are available for treating liver and related brain pathologies simultaneously. In this study, we aim to find therapeutic candidates that target the liver-brain axis. Gossypetin, a flavonoid from sedum, shows promising capability in treating liver and brain pathologies in CCl4-induced mouse model. Short term of gossypetin administration is sufficient to ameliorate impaired liver function and pre-existing liver fibrosis, suppress MKK3/6-p38 MAPK and p53 activation, and abolish the activation of hepatic stellate cells and Kupffer cells. Although we observe no neuronal loss in the brain of mice with liver fibrosis, we do observe astrogliosis and microglial activation in certain brain regions, especially the hippocampus. Brief gossypetin administration also shows potential in alleviating neuroinflammation in these regions. These results suggest that gossypetin can target the liver-brain axis and be a promising candidate for treating chronic liver fibrosis patients with neurological symptoms. [ABSTRACT FROM AUTHOR]

G protein-coupled receptors (GPCRs) are ubiquitously expressed cell surface receptors that mediate numerous physiological responses and are highly druggable. Upon activation, GPCRs rapidly couple to heterotrimeric G proteins and are then phosphorylated and internalized from the cell surface. Recent studies indicate that GPCRs not only localize at the plasma membrane but also exist in intracellular compartments where they are competent to signal. Intracellular signaling by GPCRs is best described to occur at endosomes. Several studies have elegantly documented endosomal GPCR-G protein and GPCR-β-arrestin signaling. Besides phosphorylation, GPCRs are also posttranslationally modified with ubiquitin. GPCR ubiquitination has been studied mainly in the context of receptor endosomal-lysosomal trafficking. However, new studies indicate that ubiquitination of endogenous GPCRs expressed in endothelial cells initiates the assembly of an intracellular p38 mitogen-activated kinase signaling complex that promotes inflammatory responses from endosomes. In this mini-review, we discuss emerging discoveries that provide critical insights into the function of ubiquitination in regulating GPCR inflammatory signaling at endosomes. [ABSTRACT FROM AUTHOR]

Apoptotic cell death occurs under normal physiological conditions, such as development, tissue remodeling, and inflammation. Appropriate removal of apoptotic cells by phagocytes and the secretion of anti-inflammatory cytokines such as IL-10 are important mechanisms for maintaining tissue homeostasis. Apoptotic cell phagocytosis is mediated by several phosphatidylserine recognition receptors on non-professional or professional phagocytes, such as neighboring epithelial cells or macrophages. Stabilin-2 is reported as a phosphatidylserine recognition receptor for apoptotic cell phagocytosis, and its downstream signaling pathway for cytoskeletal rearrangement for phagocytosis is well known. However, the mechanisms for stabilin-2-mediated IL-10 production has not yet been reported. In this study, we aimed to investigate stabilin-2 receptor-mediated IL-10 transcription regulation signaling pathway. Highlights: Stabilin-2 receptor mediated phagocytosis promotes IL-10 production. p38 and Pbx1 signaling is mediated to induce IL-10 production. [ABSTRACT FROM AUTHOR]

Background. Glioblastoma multiforme (GBM) is a lethal brain tumor with high mortality and morbidity. Nerolidol (NRD) is a sesquiterpene alcohol sequestered from the essential oils of aromatic florae with potent antioxidant, antiviral, anticancer, cardioprotective, and neuroprotective activity. Objectives. The aim of the study was to investigate the underlying cell-cycle mechanisms of NRD-mediated antiproliferative and apoptosis activities in GBM using human U-251 cells. Materials and methods: The current research investigated the antiproliferative and apoptotic activities of NRD on U-251 cells. The effects of NRD were measured using a Cell Counting Kit-8 (CCK-8) assay, 4',6-diamidino-2-phenylindole (DAPI) staining, messenger ribonucleic acid (mRNA) level assessment, and western blot assay. Results: Nerolidol decreased U-251 viability in a dose-dependent manner, as well as induced apoptotic activity, reduced B-cell lymphoma-2 (BCL-2) levels, and increased mRNA expression of BCL-2-associated X (Bax), caspase-3 and caspase-9. The attenuation of the cyclin-D1, cyclin-dependent kinase 4 (CDK4) and CDK6 mRNA expression confirmed cell cycle regulation. Western blot analysis of CDK1 indicated reductions in cyclin-B1 and p21. Furthermore, NRD prompted apoptosis through p38 amelioration and increased phosphorylated extracellular signal-related kinase 1 (p-ERK1) and phosphorylated c-Jun N-terminal protein kinase 1 (p-JNK1) levels. Conclusions. Nerolidol inhibited GBM cell viability and induced apoptosis through the regulation of cellcycle proteins via p38 mitogen-activated protein kinase (MAPK) signaling pathways. Thus, NRD could be developed as a potential natural therapeutic agent for GBM. [ABSTRACT FROM AUTHOR]

Mogroside V (MV) has anti-inflammatory properties. However, its impact on macrophage polarization under diabetic condition is yet unclear. This study aimed to investigate effects and underlying mechanisms of MV on inflammatory response and M1 polarization of bone marrow-derived macrophages (BMDMs) from diabetic mice. BMDMs were isolated from normal and diabetic C57BL/6 mice. LPS and IFN-γwere used to produce M1-polarized BMDMs. MV treatment was administered throughout the M1 polarization process with or without SB203580 or PDTC. Surface markers CD11b, F4/80 and CD86 of macrophages were identified using flow cytometry or immunofluorescence staining. Inflammatory cytokines IL-1β and IL-6 and phosphorylation levels of p65 and p38 were examined by western blot. High glucose increased proportion of CD11b+F4/80+CD86+ cells, protein levels of inflammatory cytokines IL-1β and IL-6 and phosphorylation levels of p65 and p38 in LPS+IFN-γ-induced BMDMs, while they were decreased upon MV treatment. Additionally, these effects were further downregulated when MV was co-added with SB203580 or PDTC. MV suppressed M1 macrophage polarization and inflammatory response, which was partially through NF-κB and p38 MAPK in LPS+IFN-γ induced BMDMs under high glucose condition, implying the potential of MV in treatment for inflammatory complications of diabetes. [ABSTRACT FROM AUTHOR]

• The CYSLTR1 antagonist montelukast protects neurons from macrophage neurotoxicity induced by HIV-1 or HIVgp120 protein. • HIV-1 infection or exposure to HIVgp120 increases CysLT release by macrophages and inhibition of p38 MAPK abrogates elevated CysLT production. • Cerebral cortex of HIV+ individuals with pathology expresses more CYSLTR1 than that of HIV+ persons without pathology or uninfected individuals. • Genetic ablation of Ltc4s or Cysltr1 in HIVgp120-transgenic mice results in complete neuroprotection and preserved memory function. • Genetic ablation of Ltc4s or Cysltr1 in mice reveals a physiological role of CysLTs in memory function and sexual dimorphisms in glial cells. Macrophages (MΦ) infected with human immunodeficiency virus (HIV)-1 or activated by its envelope protein gp120 exert neurotoxicity. We found previously that signaling via p38 mitogen-activated protein kinase (p38 MAPK) is essential to the neurotoxicity of HIVgp120-stimulated MΦ. However, the associated downstream pathways remained elusive. Here we show that cysteinyl-leukotrienes (CysLT) released by HIV-infected or HIVgp120 stimulated MΦ downstream of p38 MAPK critically contribute to neurotoxicity. SiRNA-mediated or pharmacological inhibition of p38 MAPK deprives MΦ of CysLT synthase (LTC4S) and, pharmacological inhibition of the cysteinyl-leukotriene receptor 1 (CYSLTR1) protects cerebrocortical neurons against toxicity of both gp120-stimulated and HIV-infected MΦ. Components of the CysLT pathway are differentially regulated in brains of HIV-infected individuals and a transgenic mouse model of NeuroHIV (HIVgp120tg). Moreover, genetic ablation of LTC4S or CysLTR1 prevents neuronal damage and impairment of spatial memory in HIVgp120tg mice. Altogether, our findings suggest a novel critical role for cysteinyl-leukotrienes in HIV-associated brain injury. [ABSTRACT FROM AUTHOR]