Inhibition Of JNK Activation Research Articles

Monocarbonyl analogs of curcumin C66 and B2BrBC modulate oxidative stress, JNK activity, and pancreatic gene expression in rats with streptozotocin-induced diabetes

The pathogenesis of type 1 diabetes mellitus (T1DM) involves oxidative stress and inflammation. Curcumin, a natural polyphenolic compound found in turmeric, known to exhibit antioxidative and anti-inflammatory properties, is characterized by poor chemical stability, low bioavailability, and rapid metabolism. Monocarbonyl analogs of curcumin (MACs) with a structural absence of β-diketone and enhanced stability and bioavailability present a potential solution to the challenges associated with the use of curcumin. This study aimed to evaluate the effect of two MACs, C66 and B2BrBC, on oxidative stress markers, antioxidant enzyme activity, expression of diabetes-associated genes, and signaling pathway proteins in the context of T1DM. Streptozotocin (STZ)-induced male Wistar rats or rat pancreatic RIN-m cells were used for in vivo and in vitro experiments, respectively. C66 or B2BrBC were given either before or after STZ treatment. Oxidative stress markers and antioxidant enzyme activities were determined in various tissues. Expression of diabetes-associated genes was assessed using RT-qPCR, and the activity of signaling pathway proteins in the pancreas was determined through Western blot analysis. Treatment with C66 and B2BrBC significantly reduced oxidative stress markers and positively influenced antioxidant enzyme activities. Moreover, both compounds inhibited JNK activity in the pancreas while enhancing the expression of genes crucial for β-cell survival and glucose and redox homeostasis. The findings highlight the multifaceted potential of C66 and B2BrBC in ameliorating oxidative stress, influencing gene expression patterns linked to diabetes, and modulating key signaling pathways in the pancreas. The findings suggest that these compounds can potentially address diabetes-related pathological processes.

Delayed treatment with hydro-ethanolic extract of Khaya grandifoliola protects mice from acetaminophen-hepatotoxicity through inhibition of c-Jun N-terminal kinase phosphorylation and mitochondrial dysfunction

The use of N-acetylcysteine against acetaminophen(APAP)-induced hepatotoxicity, a leading cause of liver injury, has several drawbacks, including short therapeutic windows. Khaya grandifoliola (Meliaceae) has been traditionally used to manage liver-related diseases, and many reports have confirmed its hepatoprotective properties. However, its therapeutic potential as an antidote against APAP-induced hepatotoxicity has yet to be proven in a clinically relevant model. This study aimed to verify the efficacy of delayed treatment with the hydroethanolic extract of K. grandifoliola (KgE) in suppressing the early injury phase of APAP pathophysiology. KgE was analyzed using HPLC/UV. Acute oral toxicity tests were conducted in mice to determine the therapeutic dose of KgE. Mice were treated with 300 ​mg/kg APAP; 1h and 12h later, they were treated with either predetermined doses of KgE or 20 ​mg/kg c-Jun N-Terminal Kinase (JNK) inhibitor SP600125, which served as a reference antidote. At 6h and 24h after APAP treatment, the parameters of liver damage and mitochondrial dysfunction, phosphorylation of JNK, and mitochondrial translocation were assessed. KgE at a dose of 5000 ​mg/kg was safe for mice. Accordingly, 100, 200, and 400 ​mg/kg were selected as curative treatments. Delayed administration of KgE reversed the histopathological changes in the liver, inhibited serum levels of alanine aminotransferase, reduced the liver content of nitric oxide and malondialdehyde, and restored hepatic glutathione pools and superoxide dismutase and catalase activities in APAP-intoxicated mice. Moreover, KgE prevented APAP-induced JNK phosphorylation and p-JNK mitochondrial translocation and rescued the activities of mitochondrial enzyme complexes II and V. HPLC/UV analysis revealed the presence of gallic acid, Quercetin and Silibinin, with retention times of 3.77, 11.63 and 11.95 ​min as the major active ingredients present in KgE. Our findings demonstrate that post-treatment with KgE protects the mouse liver from APAP-hepatotoxicity through the inhibition of JNK activation and mitochondrial dysfunction.

Cell-permeable JNK-inhibitory peptide regulates intestinal barrier function and inflammation to ameliorate necrotizing enterocolitis.

Intestinal dysbiosis is believed to play a role in the development of necrotizing enterocolitis (NEC). The efficacy of JNK-inhibitory peptide (CPJIP) in treating NEC was assessed. Treatment with CPJIP led to a notable reduction in p-JNK expression in IEC-6 cells and NEC mice. Following LPS stimulation, the expression of RNA and protein of claudin-1, claudin-3, claudin-4 and occludin was significantly decreased, with this decrease being reversed by CPJIP administration, except for claudin-3, which remained consistent in NEC mice. Moreover, the expression levels of the inflammatory factors TNF-α, IL-1β and IL-6 were markedly elevated, a phenomenon that was effectively mitigated by the addition of CPJIP in both IEC-6 cells and NEC mice. CPJIP administration resulted in improved survival rates, ameliorated microscopic intestinal mucosal injury, and increased the total length of the intestines and colon in NEC mice. Additionally, CPJIP treatment led to a reduction in serum concentrations of FD-4, D-lactate and DAO. Furthermore, our results revealed that CPJIP effectively inhibited intestinal cell apoptosis and promoted cell proliferation in the intestine. This study represents the first documentation of CPJIP's ability to enhance the expression of tight junction components, suppress inflammatory responses, and rescue intestinal cell fate by inhibiting JNK activation, ultimately mitigating intestinal severity. These findings suggest that CPJIP has the potential to serve as a promising candidate for the treatment of NEC.

Docosahexaenoic acid ameliorates autistic‐like behaviors by inhibiting oxidative stress and inflammatory response in neonatal maternal separation rats

AbstractAutism spectrum disorder (ASD) is a pervasive neurodevelopmental disorder characterized by impaired social interactions and communication, repetitive, or stereotyped behavior. Docosahexaenoic acid (DHA), an essential polyunsaturated fatty acid, has been demonstrated to exert anti‐oxidative stress and anti‐inflammatory properties, while also promoting myelin development and neural differentiation and development. However, it remains uncertain whether DHA can ameliorate autistic‐like behaviors, and if so, the underlying mechanisms are still unclear. Here, we established a neonatal maternal separation (NMS) rat model and treated it with DHA (80 mg/kg/day, i.p.). The results showed DHA treatment significantly alleviated autism‐like behaviors in the NMS rats during their juvenile period. Subsequently, we employed network pharmacology analysis and molecular docking methods to screen potential targets of DHA in ASD therapy. Through Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and Wikipedia enrichment analysis, we identified anti‐oxidative stress, anti‐inflammatory and JNK signaling pathway that might be associated with DHA‐mediated improvement of autistic‐like behaviors. Furthermore, western blotting assays showed DHA significantly downregulated the expression levels of p‐JNK and c‐JUN, while upregulating the expression levels of NRF2, HO‐1, SOD1, and CAT. In addition, enzyme‐linked immunosorbent assay results showed DHA effectively reduced the production of pro‐inflammatory factors, such as TNF‐α, IL‐6, and IL‐1β. Collectively, our study predicted and validated that DHA exhibits the potential to improve autistic‐like behaviors induced by NMS in rats by suppressing JNK activation and inhibiting oxidative stress and inflammatory response. These findings suggest that DHA may be a potential therapeutic agent for the treatment of ASD.

Dysfunction of Nrf2-regulated cellular defence system and JNK activation induced by high dose of fly Ash particles are associated with pulmonary injury in mouse lungs

The mechanisms of the exposure to fine particulate matter (PM) as a risk factor for pulmonary injury are not fully understood. The transcription factor, NF-E2-related factor 2 (Nrf2), plays a key role in protection lung against PM insult and cancer chemoprevention. In this study, F3-S fly ash particles from a municipal waste incinerator were evaluated as a PM model. We found that F3-S triggered hierarchical oxidative stress responses involving the prolonged activation of the cytoprotective Nrf2 transcriptional program via Keap1 Cys151 modification, and c-Jun NH2-terminal kinase (JNK) phosphorylation at higher doses. In mouse lungs exposed to fly ash particles at a low dose (10–20 mg/kg), Nrf2 signalling was upregulated, while in those exposed to a high fly ash particle dose (40 mg/kg), there was significant activation of JNK, and this correlated with Nrf2 phosphorylation and the downregulation of antioxidant response element (ARE)-driven genes. The JNK inhibitor, SP600125, reversed Nrf2 phosphorylation, and downregulation of detoxifying enzymes. Silencing JNK expression in mouse lungs using adenoviral shRNA inhibited JNK activation and Nrf2 phosphorylation, promoted ARE-driven gene expression, and reduced pulmonary injury. Furthermore, we found that the 452–515 amino acid region within the Neh1 domain of Nrf2 was required for its interaction with P-JNK. We demonstrated that Nrf2 was an important P-JNK target in fly ash-induced pulmonary toxicity. JNK phosphorylated Nrf2, leading to a dysfunction of the Nrf2-mediated defence system.

Clinacanthus nutans leaf extract reduces pancreatic β-cell apoptosis by inhibiting JNK activation and modulating oxidative stress and inflammation in streptozotocin-induced diabetic rats.

Controlling apoptosis induced by oxidative stress in pancreatic β-cells provides promising strategies for preventing and treating diabetes. Clinacanthus nutans leaves possess bioactive constituents with potential antioxidant and anti-diabetic properties. This study aimed to investigate the molecular mechanisms by which C. nutans extract protects pancreatic β-cells from apoptotic damage in streptozotocin (STZ)-induced diabetic rats. Diabetes was induced in male Wistar rats by intraperitoneal injection of 45 mg/kg STZ, followed by 28 days of treatment with C. nutans leaf extract and Glibenclamide as the standard drug. At the end of the study, blood samples were collected to measure glucose levels, oxidative stress markers, and inflammation. Pancreatic tissue was stained immunohistochemically to detect c-Jun N-terminal kinase (JNK) and Caspase-3 expression. The administration of C. nutans leaf extract to diabetic rats significantly reduced fasting blood glucose, malondialdehyde, and tumor necrosis factor-α levels, while concurrently enhancing the activity of superoxide dismutase. The immunohistochemical studies revealed a decrease in the expression of JNK and caspase-3 in the pancreatic islets of diabetic rats. Clinacanthus nutans exhibits the potential to protect pancreatic β-cells from apoptosis by suppressing oxidative stress and inflammation.

Fine particulate matter exposure disturbs autophagy, redox balance and mitochondrial homeostasis via JNK activation to inhibit proliferation and promote EMT in human alveolar epithelial A549 cells

Epidemiologic studies have demonstrated a direct correlation between fine particulate matter (FPM) exposure and the high risk of respiratory diseases. FPM can penetrate deep into the lung and deposit in the alveoli with breath, where it directly interacts with alveolar epithelial cell (APC). However, we know little about the effects nor mechanisms of FPM on APC. Here, using human APC A549 cells, we found that FPM resulted in blockade of autophagic flux, redox imbalance and oxidative stress, mitochondrial fragmentation, increased mitophagy and impaired mitochondrial respiration. Further we showed that activation of JNK signaling (c-Jun N-terminal kinase) and excessive ROS (reactive oxygen species) release contribute to these adverse effects, with the former being upstream of the latter. More importantly, we found that scavenging ROS or inhibiting JNK activation could restore those effects as well as ameliorate FPM-induced inhibition of cell proliferation, and epithelial-mesenchymal transformation (EMT) in A549 cells. Taken together, our findings indicate that FPM leads to toxicity in alveolar type II cells via JNK activation, and JNK-targeting or antioxidant strategies might be beneficial for prevention or treatment of FPM-related pulmonary diseases.

Design and Synthesis of a Mitochondrial-Targeted JNK Inhibitor and Its Protective Effect on Parkinson's Disease Phenotypes.

C-Jun N-terminal kinase (JNK) is a key mediator involved in a variety of physiological processes. JNK activation is regulated in a complex manner by upstream kinases and phosphatases, and plays an important role in physiological processes such as the immune response and neuronal function. Therefore, JNK has become a therapeutic target for neurodegenerative diseases, ankylosing spondylitis, psoriasis, arthritis and other diseases. Inhibition of JNK activation in mitochondria holds great potential for Parkinson's disease (PD) therapy. However, no specific mitochondrial-targeted JNK inhibitor has been reported. We have developed a mitochondrial-targeted JNK inhibitor, P2, by linking a mitochondrial-specific cell-penetrating peptide to SP600125 (SP), a commercialized specific inhibitor of JNK. We found that P2 specifically inhibited mitochondrial JNK phosphorylation instead of nuclear JNK signaling. Further studies showed that P2 effectively rescued PD phenotypes both in vitro and in vivo, thus indicating that it is a potential therapeutic for PD.

"Adjust Zang and arouse spirit" electroacupuncture ameliorates cognitive impairment by reducing endoplasmic reticulum stress in db/db mice.

Diabetic cognitive impairment (DCI) is a chronic complication of the central nervous system (CNS) caused by diabetes that affects learning and memory capacities over time. Recently, acupuncture has been shown to improve cognitive impairment in streptozotocin-induced diabetic rats. However, the effects of electroacupuncture on DCI and its underlying mechanism have not yet been elucidated in detail. In this study, we used db/db mice as DCI animal models which showed low cognitive, learning and memory functions. Electroacupuncture significantly ameliorated DCI, which is reflected by better spatial learning and memory function using behavioral tests. The db/db mice with cognitive impairment were randomly divided into a model group (Mod) and an electroacupuncture treatment group (Acup), while db/m mice were used as a normal control group (Con). First, the mice were subjected to behavioural tests using the Morris water maze (MWM), and body weight, blood glucose, insulin, triglycerides (TG) and total cholesterol (TC) were observed; HE, Nissl, and TUNEL staining were used to observe the morphological changes and neuronal apoptosis in the mice hippocampus; Finally, Western blot and rt-PCR were applied to detect the essential proteins and mRNA of ERS and insulin signalling pathway, as well as the expression levels of Tau and Aβ. Electroacupuncture significantly ameliorated DCI, which is reflected by better spatial learning and memory function using behavioral tests. Moreover, electroacupuncture attenuated diabetes-induced morphological structure change, neuronal apoptosis in the hippocampus of db/db mice. Our results revealed that electroacupuncture could regulate the expression levels of Tau and Aβ by improving hippocampal ERS levels in db/db mice, inhibiting JNK activation, attenuating IRS1 serine phosphorylation, and restoring normal transduction of the insulin signaling pathway. In summary, ERS and insulin signaling pathway paly causal roles in DCI development. Electroacupuncture can significantly alleviate the pathogenesis of DCI, improve mice's learning and memory ability, and improve cognitive dysfunction. This study adds to our understanding of the effect of acupuncture on DCI and opens the door to further research on DCI.

Construction and validation of a competing endogenous RNA network in the thymus of miR-147-/- mice.

Prior evidence has demonstrated that miR-147 can regulate cellular proliferation, migration, apoptotic death, inflammatory responses, and the replication of viruses through its interactions with specific mRNA targets. LncRNA-miRNA-mRNA interactions are often found in various biological processes. No studies have documented lncRNA-miRNA-mRNA regulatory interactions in miR-147-/- mice. Thymus tissue samples from miR-147-/- mice were systematically analyzed to detect patterns of lncRNA, miRNA, and mRNA dysregulation in the absence of this biologically important miRNA. Briefly, RNA-sequencing was used to analyze samples of thymus tissue from wild-type (WT) and miR-147-/- mice. Radiation damage models of miR-147-/- mice were prepared and prophylactic intervention with the drug trt was performed. The validation of miR-47, PDPK1,AKT and JNK were carried out by qRT-PCR, western blot and fluorescence in situ hybridization. Apoptosis was detected by Hoechst staining, and histopathological changes were detected by HE staining. We showed the identification of 235 mRNAs, 63 lncRNAs, and 14 miRNAs that were significantly upregulated in miR-147-/- mice as compared to WT controls, as well as 267 mRNAs, 66 lncRNAs and 12 miRNAs exhibiting significant downregulation. Predictive analyses of the miRNAs targeted by dysregulated lncRNAs and their associated mRNAs were further performed, highlighting the dysregulation of pathways including the Wnt signaling pathway, Thyroid cancer, Endometrial cancer (include PI3K/AKT) and Acute myeloid leukemia pathway(include PI3K/AKT) pathways. Troxerutin (TRT) upregulated PDPK1 via targeting miR-147 to promote AKT activation and inhibit JNK activation in the lungs of mice in radioprotection. Together, these results highlight the potentially important role of miR-147 as a key regulator of complex lncRNA-miRNA-mRNA interacting networks. Further research focusing on PI3K/AKT pathways in miR-147-/- mice in radioprotection will thus benefit current knowledge of miR-147 while also informing efforts to improve radioprotection.

Curcumin analogue C66 ameliorates mouse cardiac dysfunction and structural disorders after acute myocardial infarction via suppressing JNK activation

Myocardial infarction contributes to the development of cardiovascular disease, and leads to severe inflammation and health hazards. Our previous studies identified C66, a novel curcumin analogue, had pharmacological benefits in suppressing tissue inflammation. Therefore, the present study hypothesized C66 might improve cardiac function and attenuate structural remodeling after acute myocardial infarction. Administration of 5 mg/kg C66 for 4-week significantly improved cardiac function and decreased infarct size after myocardial infarction. C66 also effectively reduced cardiac pathological hypertrophy and fibrosis in non-infarct area. In vitro H9C2 cardiomyocytes, C66 also exerted the pharmacological benefits of anti-inflammatory and anti-apoptosis under hypoxic conditions Mechanistically, C66 inhibited cardiac inflammation and cardiomyocyte apoptosis by targeting on JNK phosphorylation, whereas replenishment of JNK activation abolished the cardioprotective benefits of C66 treatment. Taken together, curcumin analogue C66 inhibited the activation of JNK signaling, and possessed pharmacological benefits in alleviating myocardial infarction-induced cardiac dysfunction and pathological tissue injuries.

Alpha-Pinene Exerts Antiseizure Effects by Preventing Oxidative Stress and Apoptosis in the Hippocampus in a Rat Model of Temporal Lobe Epilepsy Induced by Kainate.

Oxidative stress and apoptosis following seizures play pivotal roles in the consequences of repeated seizures. Beneficial effects of alpha-pinene (APN) have been reported in some experimental models of neurodegenerative diseases. However, its neuroprotective efficacy in a rat model of temporal lobe epilepsy (TLE) induced by kainic acid (KA) has remained unexplored. We aimed to explore the possible antiseizure effects of APN pretreatment and underlying molecular mechanisms in a rat model of TLE induced by KA. TLE was induced in male Wistar rats by intracerebroventricular injection of KA. APN at a dose of 50 mg/kg/day was intraperitoneally injected for 2 weeks before induction of TLE. One day after the induction of TLE, behavioral expressions of seizure were recorded and scored using Racine's scale. Furthermore, the hippocampal levels of oxidative stress markers, B-cell lymphoma 2 (Bcl2), BCL2-associated X protein (BAX), and c-Jun N-terminal kinase (JNK) protein levels were also assessed. Histopathological assessment in the hippocampus was performed with Nissl staining 5 days following induction of TLE. The results revealed that APN pretreatment alleviated epileptic seizures, diminished oxidative stress indicators, blocked the mitochondrial apoptotic pathway via decreasing BAX and raising BCL2 protein levels in the hippocampus at least partly through inhibiting JNK activity, and decreased neuronal death in the CA3 and hilus regions. These findings reveal that APN pretreatment mitigates KA-induced seizures by blocking oxidative stress and neuronal damage factors. It can be concluded that APN has a potent potential to be considered an antiseizure medication, but it needs further investigation.

A small-molecule JNK inhibitor JM-2 attenuates high-fat diet-induced non-alcoholic fatty liver disease in mice.

The prevalence of non-alcoholic fatty liver disease (NAFLD) has been deemed a leading cause of end-stage liver disease. As a member of the mitogen-activated protein kinase family, c-Jun N-terminal kinase (JNK) has been shown to play an important role in the pathogenesis of NAFLD. Here, we identified a novel JNK inhibitor, JM-2, and evaluated its therapeutic effects against NAFLD both in vitro and in vivo. In vitro, JNK was blocked by JM-2 in PA-challenged hepatocytes. C57BL/6 mice were fed a high-fat diet for 6months to develop NAFLD. Mice were treated with JM-2 by intragastric administration. In primary hepatocytes and AML-12 cells, JM-2 treatment significantly suppressed palmitic acid (PA)-induced JNK activation and PA-induced inflammation and cell apoptosis. In addition, JM-2 restricted the production of fibrosis- and lipid metabolism-related genes in PA-challenged hepatocytes. We evaluated the curative effect of JM-2 against NAFLD using a high-fat diet (HFD)-fed mouse model. Based on our findings, JM-2 administration significantly protected the mouse liver from HFD-induced inflammation, lipid accumulation, fibrosis, and apoptosis, accompanied with reduced JNK phosphorylation in the liver tissue. JM-2 affords a significant protective effect against HFD-induced NAFLD by inhibiting JNK activation and is potential to be developed as a candidate drug for NAFLD treatment.

Adipose-Derived Mesenchymal Stem Cells Inhibit JNK-Mediated Mitochondrial Retrograde Pathway to Alleviate Acetaminophen-Induced Liver Injury.

Acetaminophen (APAP) is the major cause of drug-induced liver injury, with limited treatment options. APAP overdose invokes excessive oxidative stress that triggers mitochondria-to-nucleus retrograde pathways, contributing to APAP-induced liver injury (AILI). Mesenchymal stem cell therapy is a promising tool for acute liver failure. Therefore, the purpose of this study was to investigate the beneficial effects of adipose-derived mesenchymal stem cell (AMSC) therapy on AILI and reveal the potential therapeutic mechanisms. C57BL/6 mice were used as the animal model and AML12 normal murine hepatocytes as the cellular model of APAP overdose. Immunohistochemical staining, Western blotting, immunofluorescence staining, and RNA sequencing assays were used for assessing the efficacy and validating mechanisms of AMSC therapy. We found AMSC therapy effectively ameliorated AILI, while delayed AMSC injection lost its efficacy related to the c-Jun N-terminal kinase (JNK)-mediated mitochondrial retrograde pathways. We further found that AMSC therapy inhibited JNK activation and mitochondrial translocation, reducing APAP-induced mitochondrial damage. The downregulation of activated ataxia telangiectasia-mutated (ATM) and DNA damage response proteins in AMSC-treated mouse liver indicated AMSCs blocked the JNK-ATM pathway. Overall, AMSCs may be an effective treatment for AILI by inhibiting the JNK-ATM mitochondrial retrograde pathway, which improves APAP-induced mitochondrial dysfunction and liver injury.

Inhibition of JNK/c-Jun-ATF2 Overcomes Cisplatin Resistance in Liver Cancer through down-Regulating Galectin-1.

Due to drug resistance, the clinical response to cisplatin (CDDP) from patients with liver cancer is unsatisfactory. The alleviation or overcoming of CDDP resistance is an urgent problem to be solved in clinics. Tumor cells rapidly change signal pathways to mediate drug resistance under drug exposure. Here, multiple phosphor-kinase assays were performed and c-Jun N-terminal kinase (JNK) was activated in liver cancer cells treated with CDDP. The high activity of the JNK promotes poor progression and mediates cisplatin resistance in liver cancer, leading to a poor prognosis of liver cancer. Mechanistically, the highly activated JNK phosphorylated c-Jun and ATF2 formed a heterodimer to upregulate the expression of Galectin-1, leading to promoting cisplatin resistance in liver cancer. Importantly, we simulated the clinical evolution of drug resistance in liver cancer by continuous CDDP administration in vivo. In vivo bioluminescence imaging showed the activity of JNK gradually increased during this process. Moreover, the inhibition of JNK activity by small molecular or genetic inhibitors enhanced DNA damage and overcame CDDP resistance in vitro and in vivo. Collectively, our results underline that the high activity of JNK/c-Jun-ATF2/Galectin-1 mediates cisplatin resistance in liver cancer and provides an optional scheme for dynamic monitoring of molecular activity in vivo.

Resveratrol can induce differentiating phenotypes in canine oral mucosal melanoma cells.

This report described the differentiation induction of canine oral mucosal melanoma (OMM) cells by resveratrol. Exposure of canine OMM cells to resveratrol (maximum dose: 50 μM and treatment period: 72 hr) induced differentiating features like melanocytes, and enhanced chemosensitivity against cisplatin, but alone had no influence on cell viability. Additionally, resveratrol significantly enhanced mRNA expression of key melanoma differentiation markers such as microphthalmia-associated transcription factor (MITF). Of several inhibitors against mitogen-activated protein kinase subtypes, only the c-Jun N-terminal kinase (JNK) inhibitor, SP600125, induced melanocyte-like morphological change and enhanced MITF mRNA expression. Furthermore, resveratrol also suppressed JNK activation in OMM cells by approximately 33%. Overall, these findings suggest that resveratrol induces differentiation in canine OMM cells, due to the inhibition of JNK signaling.

Retracted: Tanshinone Protects against Spinal Cord Ischemia-Reperfusion Injury by Inhibiting JNK Activity.

[This retracts the article DOI: 10.1155/2022/7619797.].

Blocking the cytohesin-2/ARF1 axis by SecinH3 ameliorates osteoclast-induced bone loss via attenuating JNK-mediated IRE1 endoribonuclease activity

cytohesin-2 is a guanine nucleotide exchange factor to activate ARF1 and ARF6, which are involved in various biological processes, including signal transduction, cell differentiation, cell structure organization, and survival. Nevertheless, there is a lack of evidence revealing the role of cytohesin-2 in osteoclast differentiation and in the development of osteoporosis. In this study, we find cytohesin-2 and ARF1 positively regulate osteoclast differentiation and function. Blocking the cytohesin-2 /ARF1 axis with SecinH3 or by genetic silencing of cytohesin-2 inhibits osteoclast formation and function in vitro. In vivo treatment with SecinH3 ameliorates ovariectomy-induced osteoporosis. Mechanistically, RNA-sequencing combined with molecular biological methodologies reveal that the regulatory function of cythohesin-2/ARF1 axis in osteoclast differentiation is mainly dependent on activating the JNK pathway. Further, in addition to the common viewpoint that JNK is activated by IRE1 via its kinase activity, we found that JNK can act upstream and regulate the endoribonuclease activity of IRE1 to promote XBP1 splicing. Both SecinH3 and silencing of cytohesin-2 inhibit JNK activation and IRE1 endoribonuclease activity, leading to the suppression of osteoclast differentiation. Taken together, our findings add new insights into the regulation between JNK and IRE1, and reveal that inhibiting the cytohesin-2/ARF1/JNK/IRE1 axis might represent a potential new strategy for the treatment of post-menopause osteoporosis.

Andrographolide promote the growth and immunity of Litopenaeus vannamei, and protects shrimps against Vibrio alginolyticus by regulating inflammation and apoptosis via a ROS-JNK dependent pathway.

Vibrio alginolyticus (V. alginolyticus) is one of the major pathogens causing mass mortality of shrimps worldwide, affecting energy metabolism, immune response and development of shrimps. In the context of the prohibition of antibiotics, it is necessary to develop a drug that can protect shrimp from V. alginolyticus. Andrographolide (hereinafter called Andr), a traditional drug used in Chinese medicine, which possesses diverse biological effects including anti-bacteria, antioxidant, immune regulation. In this study, we investigated the effect of Andr on growth, immunity, and resistance to V. alginolyticus infection of Litopenaeus vannamei (L. vannamei) and elucidate the underlying molecular mechanisms. Four diets were formulated by adding Andr at the dosage of 0 g/kg (Control), 0.5 g/kg, 1 g/kg, and 2 g/kg in the basal diet, respectively. Each diet was randomly fed to one group with three replicates of shrimps in a 4-week feeding trial. The results showed that dietary Andr improved the growth performance and non-specific immune function of shrimps. L. vannamei fed with Andr diets showed lower mortality after being challenged by V. alginolyticus. After 6 h of V. alginolyticus infection, reactive oxygen species (ROS) production, tissue injury, apoptosis, expression of inflammatory factors (IL-1 β and TNFα) and apoptosis-related genes (Bax, caspase3 and p53) were increased in hemocytes and hepatopancreas, while feeding diet with 0.5 g/kg Andr could inhibit the increase. Considering that JNK are important mediators of apoptosis, we examined the influence of Andr on JNK activity during V. alginolyticus infection. We found that Andr inhibited JNK activation induced by V. alginolyticus infection on L. vannamei. The ROS scavenger N-acetyl-l-cysteine (NAC) suppressed V. alginolyticus-induced inflammation and apoptosis, suggesting that ROS play an important role in V. alginolyticus-induced inflammation and apoptosis. Treated cells with JNK specific activator anisomycin, the inflammation and apoptosis inhibited by Andr were counteracted. Collectively, Andr promote the growth and immunity of L. vannamei, and protects shrimps against V. alginolyticus by regulating inflammation and apoptosis via a ROS-JNK dependent pathway. These results improve the understanding of the pathogenesis of V. alginolyticus infection and provide clues to the development of effective drugs against V. alginolyticus.

Exercise inhibits JNK pathway activation and lipotoxicity via macrophage migration inhibitory factor in nonalcoholic fatty liver disease.

The macrophage migration inhibitory factor (MIF) expressed in hepatocytes can limit steatosis during obesity. Lipotoxicity in nonalcoholic fatty liver disease is mediated in part by the activation of the stress kinase JNK, but whether MIF modulates JNK in lipotoxicity is unknown. In this study, we investigated the role of MIF in regulating JNK activation and high-fat fostered liver lipotoxicity during simultaneous exercise treatment. Fifteen mice were equally divided into three groups: normal diet, high-fat diet, and high-fat and exercise groups. High-fat feeding for extended periods elicited evident hyperlipemia, liver steatosis, and cell apoptosis in mice, with inhibited MIF and activated downstream MAPK kinase 4 phosphorylation and JNK. These effects were then reversed following prescribed swimming exercise, indicating that the advent of exercise could prevent liver lipotoxicity induced by lipid overload and might correlate to the action of modulating MIF and its downstream JNK pathway. Similar detrimental effects of lipotoxicity were observed in in vitro HepG2 cells palmitic acid treatment. Suppressed JNK reduced the hepatocyte lipotoxicity by regulating the BCL family, and the excess JNK activation could also be attenuated through MIF supplementation or exacerbated by MIF siRNA administration. The results found suggest that exercise reduces lipotoxicity and inhibits JNK activation by modulating endogenous hepatic MIF in NAFLD. These findings have clinical implications for the prevention and intervention of patients with immoderate diet evoked NAFLD.