P38 MAPK Signaling Pathway Research Articles

MCP-1 Regulates Fractalkine Secretion through p38MAPK Signaling Pathway in Rats with Advanced Bone Cancer Pain

MCP-1 Regulates Fractalkine Secretion through p38MAPK Signaling Pathway in Rats with Advanced Bone Cancer Pain

Investigation on the mechanism of Qiangxinhuoli prescription in the treatment of chronic heart failure based on p38-MAPK signaling pathway

Investigation on the mechanism of Qiangxinhuoli prescription in the treatment of chronic heart failure based on p38-MAPK signaling pathway

Essential Oil of Matricaria chamomilla Alleviate Psoriatic-Like Skin Inflammation by Inhibiting PI3K/Akt/mTOR and p38MAPK Signaling Pathway.

The traditional Matricaria chamomilla L. has been used to treat dermatitis for thousands of years. Due to emerging trends in alternative medicine, patients prefer natural remedies to relieve their symptoms. Therefore, finding safe and effective plant medicines for topical applications on the skin is an important treatment strategy for dermatologists. German chamomile (Matricaria chamomilla L.) from the Compositae family is a famous medicinal plant, often known as the "star of medicinal species."However, the function of Matricaria chamomilla essential oil on skin inflammation has not been thoroughly examined in earlier research. GC-MS analyzed the components of MCEO, and this study explored the anti-inflammation effects of MCEO on psoriasis with network pharmacological pathway prediction. Following this, we used clinical samples of psoriasis patients to confirm the secretory characteristic of relative inflammatory markers. The therapeutic effect of MCEO on skin inflammation was detected by examination of human keratinocytes HaCaT. At the same time, we prepared imiquimod-induced psoriatic-like skin inflammation in mice to investigate thoroughly the potential inhibition functions of MCEO on psoriatic skin injury and inflammation. MCEO significantly reduced interleukin-22/tumor necrosis factor α/lipopolysaccharide-stimulated elevation of HaCaT cell inflammation, which was correlated with downregulating PI3K/Akt/mTOR and p38MAPK pathways activation mediated by MCEO in HaCaT cells treated with IL-22/TNF-α/LPS. Skin inflammation was evaluated based on the PASI score, HE staining, and relative inflammatory cytokine levels. The results showed that MCEO could significantly contribute to inflammatory skin disease treatment. MCEO inhibited inflammation in HaCaT keratinocytes induced by IL-22/TNF-α/LPS, the potential mechanisms associated with inhibiting excessive activation and crosstalk between PI3K/Akt/mTOR and p38MAPK pathways. MCEO ameliorated skin injury in IMQ-induced psoriatic-like skin inflammation of mice by downregulating the levels of inflammatory cytokines but not IL-17A. Thus, anti-inflammatory plant drugs with different targets with combined applications were a potential therapeutic strategy in psoriasis.

Dietary sodium butyrate and forskolin promote cell proliferation to resist Citrobacter rodentium infection by lysozyme upregulation

The invasion of pathogens derived from diet or the environment triggers intestinal inflammation, which is a result of the host intestinal barrier damage and immune dysfunction, such as the decrease of host defense peptides (HDPs) and inhibition of cell proliferation. Herein, the siRNA interference demonstrated that a critical lysozyme, which was mainly induced by dietary supplementations of sodium butyrate and forskolin, improved cell proliferation by inhibiting p38 MAPK and JNK signaling pathways and reinforced the intestinal barrier. Moreover, we established a mouse model of intestinal inflammation with Citrobacter rodentium (C. rodentium). It was found that NaBu and FSK stimulated intestinal epithelial proliferation to repair barrier damage, and performed stronger disease resistance to C. rodentium infection on account of the lysozyme upregulation in colon. Therefore, this study revealed that NaBu and FSK prevented or alleviated the development of foodborne infections by promoting lysozyme expression, which may be mediated by the effect of lysozyme on promoting cell proliferation and improving barrier function.

Absent in melanoma 2 attenuates proliferation and migration and promotes apoptosis of human colorectal cancer cells by activating P38MAPK signaling pathway.

Colorectal cancer (CRC) stands among the top prevalent cancers worldwide and holds a prominent position as a major contributor to cancer-related mortality globally. Absent in melanoma 2 (AIM2), a constituent of the interferon-inducible hematopoietic interferon-inducible nuclear antigens with 200 amino acid repeats protein family, contributes to both cancer progression and inflammasome activation. Despite this understanding, the precise biological functions and molecular mechanisms governed by AIM2 in CRC remain elusive. Consequently, this study endeavors to assess AIM2's expression levels, explore its potential antitumor effects, elucidate associated cancer-related processes, and decipher the underlying signaling pathways in CRC. Our findings showed a reduced AIM2 expression in most CRC cell lines. Elevation of AIM2 levels suppressed CRC cell proliferation and migration, altered cell cycle by inhibiting G1/S transition, and induced cell apoptosis. Further research uncovered the participation of P38 mitogen-activated protein kinase (P38MAPK) in AIM2-mediated modulation of CRC cell apoptosis and proliferation. Altogether, our achievements distinctly underscored AIM2's antitumor role in CRC. AIM2 overexpression inhibited proliferation and migration and induced apoptosis of CRC cells via activating P38MAPK signaling pathway, indicating AIM2 as a prospective and novel therapeutic target for CRC.

Oxidative stress promotes liver fibrosis by modulating the microRNA-144 and SIN3A-p38 pathways in hepatic stellate cells.

Background & Aims: Reactive oxygen species (ROS) act as modulators triggering cellular dysfunctions and organ damage including liver fibrosis in which hepatic stellate cell (HSC) activation plays a key role. Previous studies suggest that microRNA-144 (miR-144) acts as a pro-oxidant molecule; however, whether and how miR-144 affects HSC activation and liver fibrosis remain unknown. Methods: Carbon tetrachloride (CCl4) and bile duct ligation (BDL)-induced experimental liver fibrosis models were used. Hepatic miR-144 expression was analyzed by miRNA in situ hybridization with RNAscope probe. The in vivo effects of silencing or overexpressing miR-144 were examined with an adeno-associated virus 6 (AAV6) carrying miR-144 inhibitor or mimics in fibrotic mouse experimental models. Results: In this study, we demonstrated that ROS treatment significantly upregulated miR-144 in HSCs, which further promoted HSC activation in vitro. Interestingly, miR-144 was preferentially elevated in HSCs of experimental liver fibrosis in mice and in human liver fibrotic tissues. Furthermore, in vivo loss or gain-of-function experiments via AAV6 carrying miR-144 antagomir or agomir revealed that blockade of miR-144 in HSCs mitigated, while overexpression of miR-144 in HSCs accelerated the development of experimental liver fibrosis. Mechanistically, SIN3 transcription regulator family member A (SIN3A), a transcriptional repressor, was identified to be the target of miR-144 in HSCs. MiR-144 downregulated Sin3A, and in line with this result, specific knockdown of Sin3a in HSCs remarkedly activated p38 MAPK signaling pathway to promote HSC activation, eventually exacerbating liver fibrosis. Conclusions: Oxidative stress-driven miR-144 fuels HSC activation and liver fibrogenesis by limiting the SIN3A-p38 axis. Thus, a specific inhibition of miR-144 in HSCs could be a novel therapeutic strategy for the treatment of liver fibrosis.

Rhizoma Dioscoreae Nipponicae Relieves Asthma by Inducing the Ferroptosis of Eosinophils and Inhibiting the p38 MAPK Signaling Pathway.

Rhizoma Dioscoreae Nipponicae (RDN) is a traditional Chinese medicine that widely applied in the treatment of human diseases. This study aims to explore the therapeutic potential of RDN in asthma and the underlying mechanisms. A mouse model of asthma was established by the stimulation of ovalbumin (OVA). HE staining was performed to detect the pathological injuries of tracheal tissues. The protein expression of collagen I, FN1, α-SMA (airway remodeling markers), and p-p38 (a marker of the p38 MAPK pathway) were detected by Western blot. Eosinophils were then isolated from the model mice. Cell viability and ROS level were measured by CCK-8 and Flow cytometry, respectively. The mRNA expression of GPX4 and ACSL4 (ferroptosis markers) in eosinophils were measured by qRT-PCR. RDN significantly reduced the numbers of total cells and eosnophils in bronchoalveolar lavage fluid (BALF), inhibited inflammatory cell infiltration, and down-regulated remodeling markers (Collagen I, FN1, and α-SMA) in OVA-induced mice. The p38 MAPK pathway was blocked by the intervention of RDN in the model mice, and its blocking weakens the poor manifestations of OVA-induced asthma. In addition, RDN induced the ferroptosis of eosnophils both in vitro and in vivo. Blocking of the p38 MAPK pathway also enhanced the ferroptosis of eosnophils in vitro, evidenced by the decreased cell viability and GPX4 expression, and increased ROS level and ACSL4 expression. RDN induced the ferroptosis of eosinophils through inhibiting the p38 MAPK pathway, contributing to the remission of asthma.

Retraction: miR-3188 Regulates Cell Proliferation, Apoptosis, and Migration in Breast Cancer by Targeting TUSC5 and Regulating the p38 MAPK Signaling Pathway.

[This retracts the article DOI: 10.3727/096504017X14953948675421.].

Effects of ivabradine on myocardial autophagia and apoptosis in isoprenaline-induced heart failure in mice.

To investigate the effects and mechanisms of ivabradine (IVA) on isoprenaline-induced cardiac injury. Forty male C57BL/6 mice were randomly divided into control group, model group, high-dose IVA group, and low-dose IVA group. The control group was given saline, other groups were given subcutaneous injections of isoproterenol (ISO) 5 mg/kg/d to make the myocardial remodeling model. A corresponding dose of IVA (high dose 50 mg/kg/d, low dose 10 mg/kg/d) was given by gavage (30 days). A transthoracic echocardiogram was obtained to detect the structure and function of the heart. An electron microscope was used to explore the cardiomyocytes' apoptosis and autophagy. HE staining and Masson's trichrome staining were performed to explore myocardial hypertrophy and fibrosis. Western blot was used to detect Bax, Bcl-2, cleaved caspase-3, Becline-1, LC3, phosphorylated p38 mitogen-activated protein kinase (p-p38MAPK), phosphorylated extracellular regulated protein kinases1/2 (p-ERK1/2), phosphorylated c-Jun N-terminal kinase (p-JNK), and α-smooth muscle actin (α-SMA) in the myocardium. Heart rate in the IVA groups was reduced, and the trend of heart rate reduction was more obvious in the high-dose group. Echocardiography showed that IVA improved the cardiac structure and function compared to the model group. IVA attenuated cardiac fibrosis, decreased cardiomyocyte apoptosis, and increased autophagy. The phosphorylated MAPK in the ISO-induced groups was increased. IVA treatment decreased the p-p38MAPK level. There were no differences in p-ERK and p-JNK levels. The beneficial effects of IVA on myocardial injury are related to blocking the p38MAPK signal pathway, decreasing cardiomyocyte apoptosis, and increasing cardiomyocyte autophagy.

Reversal of Platinum-based Chemotherapy Resistance in Ovarian Cancer by Naringin Through Modulation of The Gut Microbiota in a Humanized Nude Mouse Model.

As a chemotherapy agent, cisplatin (DDP) is often associated with drug resistance and gastrointestinal toxicity, factors that severely limit therapeutic efficacy in patients with ovarian cancer (OC). Naringin has been shown to increase sensitivity to cisplatin, but whether the intestinal microbiota is associated with this effect has not been reported so far. In this study, we applied a humanized mouse model for the first time to evaluate the reversal of cisplatin resistance by naringin, as well as naringin combined with the microbiota in ovarian cancer. The results showed that naringin combined with Bifidobacterium animalis subsp. lactis NCU-01 had an inhibitory effect on the tumor, significantly reducing tumor size (p<0.05), as well as the concentrations of serum tumor markers CA125 and HE4, increased the relative abundance of Bifidobacterium and Bacteroides, inhibit Toll-like receptor 4 (TLR4)/nuclear factor κB (NF-κB)-induced intestinal inflammation and increase the expression of intestinal permeability-associated proteins ZO-1 (p<0.001) and occludin (p<0.01). In conclusion, the above data demonstrate how naringin combined with Bifidobacterium animalis subsp. lactis NCU-01 reverses cisplatin resistance in ovarian cancer by modulating the intestinal microbiota, inhibiting the TLR4/NF-κB signaling pathway and modulating the p38MAPK signaling pathway.

Porcine Placenta Peptide Inhibits UVB-Induced Skin Wrinkle Formation and Dehydration: Insights into MAPK Signaling Pathways from In Vitro and In Vivo Studies.

Excessive exposure to ultraviolet (UV) radiation from sunlight accelerates skin aging, leading to various clinical manifestations such as wrinkles, dryness, and loss of elasticity. This study investigated the protective effects of porcine placenta peptide (PPP) against UVB-induced skin photoaging. Female hairless SKH-1 mice were orally administered PPP for 12 weeks, followed by UVB irradiation. PPP significantly reduced wrinkle formation, improved skin moisture levels, and prevented collagen degradation. Mechanistically, PPP inhibited the expression of matrix metalloproteinases (MMPs) and upregulated collagen production. Moreover, PPP elevated hyaluronic acid levels, contributing to enhanced skin hydration. Additionally, PPP demonstrated antioxidant properties by increasing the expression of the antioxidant enzyme GPx-1, thereby reducing UVB-induced inflammation. Further molecular analysis revealed that PPP suppressed the activation of p38 MAP kinase and JNK signaling pathways, crucial mediators of UV-induced skin damage. These findings highlight the potential of porcine placental peptides as a natural and effective intervention against UVB-induced skin photoaging. The study provides valuable insights into the mechanisms underlying the protective effects of PPP, emphasizing its potential applications in skincare and anti-aging formulations.

A tissue-adhesive F127 hydrogel delivers antioxidative copper-selenide nanoparticles for the treatment of dry eye disease

Dry eye disease (DED) is currently the most prevalent condition seen in ophthalmology outpatient clinics, representing a significant public health issue. The onset and progression of DED are closely associated with oxidative stress-induced inflammation and damage. To address this, an aldehyde-functionalized F127 (AF127) hydrogel eye drop delivering multifunctional antioxidant Cu2−xSe nanoparticles (Cu2−xSe NPs) was designed. The research findings revealed that the Cu2−xSe nanoparticles exhibit unexpected capabilities in acting as superoxide dismutase and glutathione peroxidase. Additionally, Cu2−xSe NPs possess remarkable efficacy in scavenging reactive oxygen species (ROS) and mitigating oxidative damage. Cu2−xSe NPs displayed promising therapeutic effects in a mouse model of dry eye. Detailed investigation revealed that the nanoparticles exert antioxidant, anti-apoptotic, and inflammation-mitigating effects by modulating the NRF2 and p38 MAPK signalling pathways. The AF127 hydrogel eye drops exhibit good adherence to the ocular surface through the formation of Schiff-base bonds. These findings suggest that incorporating antioxidant Cu2−xSe nanoparticles into a tissue-adhesive hydrogel could present a highly effective therapeutic strategy for treating dry eye disease and other disorders associated with reactive oxygen species. Statement of significanceA new formulation for therapeutic eye drops to be used in the treatment of dry eye disease (DED) was developed. The formulation combines copper-selenium nanoparticles (Cu2-xSe NPs) with aldehyde-functionalized Pluronic F127 (AF127). This is the first study to directly examine the effects of Cu2-xSe NPs in ophthalmology. The NPs exhibited antioxidant capabilities and enzyme-like properties. They effectively eliminated reactive oxygen species (ROS) and inhibited apoptosis through the NRF2 and p38 MAPK signalling pathways. Additionally, the AF127 hydrogel enhanced tissue adhesion by forming Schiff-base links. In mouse model of DED, the Cu2-xSe NPs@AF127 eye drops demonstrated remarkable efficacy in alleviating symptoms of DED. These findings indicate the potential of Cu2-xSe NPs as a readily available and user-friendly medication for the management of DED.

Is alteration of ERK1/2 and p38MAPK signaling pathways activity a general mechanism of Alzheimer’s disease and age-related macular degeneration development?

Age is the primary risk factor for Alzheimer’s disease (AD), the most prevalent progressive senile dementia, and age-related macular degeneration (AMD), the main cause of vision loss in individuals over 60. Effective prevention and treatment of these neurodegenerative conditions are lacking due to incomplete knowledge of their pathogenesis. Risk factors such as smoking, hypertension, hypercholesterolemia, atherosclerosis, obesity, and malnutrition intersect with the pathogenesis mechanisms of both AD and AMD. Oxidative stress, inflammation, mitochondrial dysfunction, and impaired proteostasis maintenance are among the pathological factors associated with the aggregation and accumulation of abnormal extracellular deposits — senile plaques in the brains of AD patients and drusen in AMD patients. Alterations in the regulation of MAPK signaling pathways with age may be associated to the emergence of these abnormalities. Impaired MAPK signaling was confirmed as a significant contributor to the pathogenesis of AD through the results of numerous investigations. MAPK is a potential target for therapeutic interventions. Information on its age-related changes, however, is limited. Virtually no data exist on retinal MAPK activity during AD and AMD development. This study aims to compare changes in ERK1/2 and p38MAPK signaling activity in brain and retina structures with age and AD/AMD progression. Wistar and OXYS rats were used as models of accelerated aging that show concomitant signs of AD and AMD. At the initial stage of the study, we examined the gene expression related to ERK1/2 and p38MAPK signaling pathways via comparing the transcriptomes (RNA-seq data) of the retina, prefrontal cortex, and hippocampus of OXYS and Wistar rats. The analysis was conducted when the rats were 20 days old and showed no signs of AMD and AD symptoms, during their manifestation period (age 3–5 months) and active progression stage (age 18 months). Changes in gene expression, involved in EPK1/2 [1] and p38MAPK signaling pathways according to the Rat Genome Database, are tissue-specific and dependent on the animal genotype. In the retina, the number of genes associated with ERK1/2 and p38MAPK decreased in both Wistar and OXYS rats with age and was minimal at 18 months of age. The greatest differences in the expression levels of these genes were detected when the rats were 20 days old, at the preclinical stage of AMD-like pathology development in OXYS rats. Both activators and inhibitors of the EPK1/2 and p38MAPK pathways were present among the differentially expressed genes (DEGs) with increased mRNA levels. At 3 months, the number of DEGs decreased, while activator genes predominated among those with increased mRNA levels. At 18 months, the retina of OXYS rats displayed only signs of decreased activity in signaling pathways at the gene expression level. Age-related changes in gene expression profiles related to the ERK1/2 [2] and p38MAPK [3, 4] signaling pathways in Wistar rats differed between brain structures and the retina. In the prefrontal cortex and hippocampus, the number of genes increased with age, and the expression differed between OXYS and Wistar rats. However, no signs of significant activation of the signaling pathway were observed. The phosphorylation level of ERK1/2 and p38MAPK signaling pathway kinases serves as an objective indicator of their activity. For protein level evaluation via Western blot analysis, we examined these levels in the retina, prefrontal cortex, and hippocampus. In both rat strains, a significant increase in phosphorylated forms of ERK1/2 and p38MAPK was observed with aging in all examined tissues. Simultaneously, accumulation of the substance became more active in OXYS rats and increased with progression of AD and AMD symptoms. Therefore, the results indicate that no significant changes in the activity of ERK1/2 and p38MAPK signaling cascades in the retina and brain structures are observed during normal aging of Wistar rats and accelerated aging of OXYS, both at the gene expression and protein level. AD and AMD pathological signs in OXYS rats were found to be associated with increased phosphorylation of ERK1/2 and p38MAPK, suggesting that enhancement of MAPK pathways may be a common mechanism for the early development of AD and AMD.

Mitochondrial p38 Mitogen-Activated Protein Kinase: Insights into Its Regulation of and Role in LONP1-Deficient Nematodes.

p38 Mitogen-Activated Protein Kinase (MAPK) cascades are central regulators of numerous physiological cellular processes, including stress response signaling. In C. elegans, mitochondrial dysfunction activates a PMK-3/p38 MAPK signaling pathway (MAPKmt), but its functional role still remains elusive. Here, we demonstrate the induction of MAPKmt in worms deficient in the lonp-1 gene, which encodes the worm ortholog of mammalian mitochondrial LonP1. This induction is subjected to negative regulation by the ATFS-1 transcription factor through the CREB-binding protein (CBP) ortholog CBP-3, indicating an interplay between both activated MAPKmt and mitochondrial Unfolded Protein Response (UPRmt) surveillance pathways. Our results also reveal a genetic interaction in lonp-1 mutants between PMK-3 kinase and the ZIP-2 transcription factor. ZIP-2 has an established role in innate immunity but can also modulate the lifespan by maintaining mitochondrial homeostasis during ageing. We show that in lonp-1 animals, ZIP-2 is activated in a PMK-3-dependent manner but does not confer increased survival to pathogenic bacteria. However, deletion of zip-2 or pmk-3 shortens the lifespan of lonp-1 mutants, suggesting a possible crosstalk under conditions of mitochondrial perturbation that influences the ageing process. Furthermore, loss of pmk-3 specifically diminished the extreme heat tolerance of lonp-1 worms, highlighting the crucial role of PMK-3 in the heat shock response upon mitochondrial LONP-1 inactivation.

Sibjotang Protects against Cardiac Hypertrophy In Vitro and In Vivo.

Cardiac hypertrophy is developed by various diseases such as myocardial infarction, valve diseases, hypertension, and aortic stenosis. Sibjotang (, Shizaotang, SJT), a classic formula in Korean traditional medicine, has been shown to modulate the equilibrium of body fluids and blood pressure. This research study sought to explore the impact and underlying process of Sibjotang on cardiotoxicity induced by DOX in H9c2 cells. In vitro, H9c2 cells were induced by DOX (1 μM) in the presence or absence of SJT (1-5 μg/mL) and incubated for 24 h. In vivo, SJT was administrated to isoproterenol (ISO)-induced cardiac hypertrophy mice (n = 8) at 100 mg/kg/day concentrations. Immunofluorescence staining revealed that SJT mitigated the enlargement of H9c2 cells caused by DOX in a dose-dependent way. Using SJT as a pretreatment notably suppressed the rise in cardiac hypertrophic marker levels induced by DOX. SJT inhibited the DOX-induced ERK1/2 and p38 MAPK signaling pathways. In addition, SJT significantly decreased the expression of the hypertrophy-associated transcription factor GATA binding factor 4 (GATA 4) induced by DOX. SJT also decreased hypertrophy-associated calcineurin and NFAT protein levels. Pretreatment with SJT significantly attenuated DOX-induced apoptosis-associated proteins such as Bax, caspase-3, and caspase-9 without affecting cell viability. In addition, the results of the in vivo study indicated that SJT significantly reduced the left ventricle/body weight ratio level. Administration of SJT reduced the expression of hypertrophy markers, such as ANP and BNP. These results suggest that SJT attenuates cardiac hypertrophy and heart failure induced by DOX or ISO through the inhibition of the calcineurin/NFAT/GATA4 pathway. Therefore, SJT may be a potential treatment for the prevention and treatment of cardiac hypertrophy that leads to heart failure.

DDDR-01. P38-MAPK INHIBITOR REVERSED CISPLATIN RESISTANCE IN NON-SMALL CELL LUNG CANCER BRAIN METASTASES BY REGULATING P-GP AND BCRP OF BLOOD-TUMOR BARRIER

Abstract BACKGROUND Previous studies have shown that the blood-brain barrier (BBB) of brain metastases (BMs) is destroyed, and the neovascularization and tumor cells constitute the blood-tumor barrier (BTB). Whether the BTB plays a role in the chemotherapy resistance of BMs is lacking in-depth research. This study aims to elucidate the possible role of BTB in cisplatin resistance of BMs from non-small cell lung cancer (NSCLC). METHODS AND MATERIALS; A multicenter retrospective cohort study including 1177 patients with NSCLC-BMs was conducted to explore the prognosis. Immunohistochemistry and immunofluorescence staining were used to verify the expression of some BBB markers in the BTB. Animal models of BMs were constructed by cardiac injection of A549. NSCLC-BMs cell lines A549-mBrain were selected in vivo. Cisplatin susceptibility tests and CCK8 proliferation tests were performed on A549-mBrain. RNA sequencing, Western Blot and qPCR were used to explore the mechanism that might regulate cisplatin resistance in A549-mBrain. RESULTS Platinum-based chemotherapy did not improve the overall survival time of NSCLC-BMs. BTB in NSCLC-BMs lacked astrocytes and pericytes, but still expressed several molecular markers of BBB, such as tight junction, transcytosis, and efflux pump. The efflux pump P-gp and BCRP expressions were higher in NSCLC-BMs than those in the lung primary lesion by immunohistochemistry in patients' tumor section. The A549-mBrain showed cisplatin resistance compared with the parental A549. Besides, the expression of P-gp and BCRP were also higher in A549-mBrain than parental A549 by Western Blot and qPCR. In A549-mBrain, inhibition of the p38-MAPK signaling pathway decreased the expression of P-gp and BCRP, thus increasing the sensitivity to cisplatin. CONCLUSION BTB may retain some BBB function in NSCLC-BMs, in which efflux pump P-gp and BCRP expression were related to cisplatin resistance. p38-MAPK inhibitor reversed cisplatin resistance in NSCLC-BMs by regulating P-gp and BCRP.

Microplastics induced inflammation in the spleen of developmental Japanese quail (Coturnix japonica) via ROS-mediated p38 MAPK and TNF signaling pathway activation1

Microplastics (MPs) have been found in virtually every environment on earth and become a source of pollution around the world. The toxicology of microplastics on immunity is an emerging area of research, and more studies are needed to fully understand the effects of microplastics exposure on animal health. Therefore, we tried to determine the immunotoxic effects of microplastics on avian spleen by using an animal model- Japanese quail (Coturnix japonica). One-week chicks were exposed to environmentally relevant concentrations of 0.02 mg/kg, 0.4 mg/kg and 8 mg/kg polystyrene microplastics in the feed for 5 weeks. The results demonstrated that microplastics induced microstructural injuries featured by cell disarrangement and vacuolation indicating splenic inflammation. Ultrastructural damages including membrane lysis and mitochondrial vacuolation also suggested inflammatory responses in the spleen by microplastics exposure. Meanwhile, increasing reactive oxygen species (ROS) and Malondialdehyde (MDA) while the inactivation of superoxide dismutase (SOD), catalase (CAT) and glutathione S-transferase (GST) indicated oxidative stress in the spleen. Moreover, the increasing level of proinflammatory cytokines including Tumor necrosis factor alpha (TNF-α), interferon gamma (IFN-γ), interleukin-1β (IL-1β), interleukin-6 (IL-6) and decreasing level of anti-inflammatory cytokine interleukin-10 (IL-10) implied splenic inflammation. Furthermore, transcriptomic analysis showed that microplastics induced inflammatory responses in the spleen through p38 mitogen-activated protein kinases (p38 MAPK) pathway activation and tumor necrosis factor (TNF) signaling stimulation. The signaling stimulation also aggravated cell apoptosis in the spleen. The present study may benefit to understand potential mechanisms of developmental immunotoxicology of microplastics.

The role and mechanism of biological collagen membranes in repairing cartilage injury through the p38MAPK signaling pathway

ObjectiveTo explore the mechanism of the p38MAPK signaling pathway in repairing articular cartilage defects with biological collagen membranes.MethodsThirty-two healthy adult male rabbits were randomly divided into a control group (n = 8), model group (n = 8), treatment group (n = 8) and positive drug group (n = 8). The control group was fed normally, and the models of bilateral knee joint femoral cartilage defects were established in the other three groups. The knee cartilage defects in the model group were not treated, the biological collagen membrane was implanted in the treatment group, and glucosamine hydrochloride was intragastrically administered in the positive drug group. Twelve weeks after the operation, the repair of cartilage defects was evaluated by histological observation (HE staining and Masson staining), the degree of cartilage repair was quantitatively evaluated by the Mankin scoring system, the mRNA expression levels of p38MAPK, MMP1 and MMP13 were detected by real-time fluorescence quantitative PCR (qRT-PCR), and the protein expression levels of p38MAPK, p-p38MAPK, MMP1 and MMP13 were detected by Western blotting. The results after the construction of cartilage defects, histological staining showed that the articular cartilage wound was covered by a large capillary network, the cartilage tissue defect was serious, and a small amount of collagen fibers were formed around the wound, indicating the formation of a small amount of new bone tissue. In the treatment group and the positive drug group, the staining of cartilage matrix was uneven, the cytoplasmic staining was lighter, the chondrocytes became hypertrophic as a whole, the chondrocytes cloned and proliferated, some areas were nest-shaped, the cells were arranged disorderly, the density was uneven, and the nucleus was stained deeply. The Mankin score of the model group was significantly higher than that of the control group, while the Mankin scores of the treatment group and positive drug group were significantly lower than that of the model group. The results of qRT-PCR detection showed that compared with the control group, the expression level of the p38MAPK gene in the model group did not increase significantly, but the gene expression levels of MMP1 and MMP13 in the model group increased significantly, while the gene expression levels of MMP1 and MMP13 decreased significantly in the treatment group and positive drug group compared with the model group. The results of Western blot detection showed that compared with the control group, the expression level of p38MAPK protein in the model group was not significantly increased, but the phosphorylation level of p38MAPK protein and the protein expression levels of MMP1 and MMP13 were significantly increased in the model group, while the phosphorylation level of p38MAPK protein and the protein expression levels of MMP1 and MMP13 in the treatment group and positive drug group were significantly lower than those in the model group.ConclusionThe biological collagen membrane can regulate the expression of MMP1 and MMP13 and repair the activity of chondrocytes by reducing the phosphorylation level of p38MAPK and inhibiting the activation of the p38MAPK signaling pathway, thus improving the repair effect of articular cartilage defects in rabbits. The P38MAPK signaling pathway is expected to become an important molecular target for the clinical treatment of cartilage defects in the future.

Exploring the mechanism of atherosclerosis and the intervention of traditional Chinese medicine combined with mesenchymal stem cells based on inflammatory targets

Atherosclerosis (AS) is a chronic inflammatory vascular disease, which is the common pathological basis of cardiovascular and cerebrovascular diseases. The immune inflammatory response throughout the course of AS has been evidenced by studies, in which a large number of immune cells and inflammatory factors play a crucial role in the pathogenesis of AS. The inflammation related to AS is mainly mediated by inflammatory cytokines (IL-1β, IL-6, IL-18, TNF-α, hs-CRP, SAA), inflammatory enzymes (Lp-PLA2, sPLA2-IIA, MMPs), and inflammatory signaling pathways (P38 MAPK signaling pathway, NF-κB signaling pathway, TLR2/4 signaling pathway). It is involved in the pathophysiological process of AS, and the degree of inflammation measured by it can be used to evaluate the risk of progression of AS plaque instability. In recent years, traditional Chinese medicine (TCM) has shown the advantage of minimal side effects in immune regulation and has made some progress in the prevention and treatment of AS. Mesenchymal stem cells (MSCs), as self-renewal, highly differentiated, and pluripotent stem cells with anti-inflammatory properties and immune regulation, have been widely used for AS treatment. They also play an important inflammation-immune regulatory function in AS. Notably, in terms of regulating immune cells and inflammatory factors, compared with TCM and its compound, the combination therapy has obvious anti-inflammatory advantages over the use of MSCs alone. It is an important means to further improve the efficacy of AS and provides a new way for the prevention and treatment of AS.

Rosmarinic acid treatment protects against lethal H1N1 virus-mediated inflammation and lung injury by promoting activation of the h-PGDS-PGD2-HO-1 signal axis

BackgroundRosmarinic acid (RosA) is a natural phenolic compound that possesses a wide-range of pharmacological properties. However, the effects of RosA on influenza A virus-mediated acute lung injury remain unknown. In this study, we aimed to explore whether RosA could protect against H1N1 virus-mediated lung injury and elucidate the underlying mechanisms.MethodsMice were intragastrically administered with RosA for 2 days before intranasal inoculation of the H1N1 virus (5LD50) for the establishment of an acute lung injury model. At day 7 post-infection (p.i.), gross anatomic lung pathology, lung histopathologic, and lung index (lung weight/body weight) were examined. Luminex assay, multiple immunofluorescence and flow cytometry were performed to detect the levels of pro-inflammatory cytokines and apoptosis, respectively. Western blotting and plasmid transfection with hematopoietic-type PGD2 synthase (h-PGDS) overexpression were conducted to elucidate the mechanisms.ResultsRosA effectively attenuated H1N1 virus-triggered deterioration of gross anatomical morphology, worsened lung histopathology, and elevated lung index. Excessive pro-inflammatory reactions, aberrant alveolar epithelial cell apoptosis, and cytotoxic CD8+ T lung recruitment in the lung tissues induced by H1N1 virus infection were observed to be reduced by RosA treatment. In vitro experiments demonstrated that RosA treatment dose-dependently suppressed the increased levels of pro-inflammatory mediators and apoptosis through inhibition of nuclear factor kappa B (NF-κB) and P38 MAPK signaling pathways in H1N1 virus-infected A549 cells, which was accompanied by promoting activation of the h-PGDS-PGD2-HO-1 signal axis. Furthermore, we strikingly found that h-PGDS inhibition significantly abrogated the inhibitory effects of RosA on H1N1 virus-mediated activation of NF-κB and P38 MAPK signaling pathways, resulting in diminishing the suppressive effects on the increased levels of pro-inflammatory cytokines and chemokines as well as apoptosis. Finally, suppressing h-PGDS prominently abolished the protective effects of RosA on H1N1 virus-mediated severe pneumonia and lung injury.ConclusionsTaken together, our study demonstrates that RosA is a promising compound to alleviate H1N1 virus-induced severe lung injury through prompting the h-PGDS-PGD2-HO-1 signal axis.