jsh-23 and Disease-Models--Animal

Topics: Anaplastic Lymphoma Kinase; Animals; Anti-Inflammatory Agents; Chronic Disease; Disease Models, Animal; Diterpenes, Kaurane; Humans; Inflammasomes; Inflammation; Metabolic Diseases; Mice; NIMA-Related Kinases; NLR Family, Pyrin Domain-Containing 3 Protein; Phenylenediamines; Protein Binding; Protein Kinase Inhibitors; Up-Regulation

Peroxisome proliferator-activated receptor-gamma (PPARγ) is critical in protecting against inflammatory and oxidative stresses post brain injury. We have previously reported that rosiglitazone, an agonist of PPARγ, was effective to prevent microglia from apoptosis and ameliorate neuronal injuries post intracerebral hemorrhage (ICH) with suppression of matrix metalloproteinase-9 (MMP9) expression. However, molecular mechanisms linking how PPARγ decreases MMP9 remain unknown. Here, we hypothesize that PPARγ downregulates MMP9 expression post hemorrhage by inhibiting nuclear factor kappa B (NF-κB), an upstream regulator of MMPs gene and also key transcription factor involved in the control of immune and neuroinflammatory responses. We found both in vivo and in vitro that PPARγ was significantly downregulated post ICH with prominent increases of NF-κB and MMP9. Activation of PPARγ using rosiglitazone decreased the expression of both NF-κB and MMP9, while reversed effects were observed when administrating the PPARγ antagonist GW9662. Besides, inhibiting NF-κB by JSH-23 also suppressed the expression of MMP9, with only limited effect on PPARγ. Further studies revealed prominent colocalizations of NF-κB with PPARγ and MMP9, respectively. Finally, direct interactions of NF-κB with PPARγ and MMP9 gene were also confirmed, respectively, by protein and chromatin immunoprecipitations. These results suggested a role of NF-κB in mediating the reduction of MMP9 by PPARγ, potentially providing a new therapeutic target for brain hemorrhage.

Topics: Anilides; Animals; Cell Line; Cerebral Hemorrhage; Disease Models, Animal; Down-Regulation; Humans; Male; Matrix Metalloproteinase 9; Mice; NF-kappa B; Phenylenediamines; PPAR gamma; Rats; Rosiglitazone

Topics: Animals; Apoptosis; Blood Glucose; Diabetes Mellitus, Experimental; Disease Models, Animal; Electroretinography; Humans; Hyperglycemia; Inflammation; Leukocytes; Male; Mice; Mice, Inbred C57BL; Mutation; NF-kappa B; Phenylenediamines; Retina; Retinal Diseases; Retinal Vessels; Tomography, Optical Coherence; Vascular Diseases

Chronic cystitis is characterized by the hyperplasia and fibrosis of the bladder wall as well as attenuated compliance of the bladder. To further unravel its underlying molecular mechanism, the role of NFκB-JMJD3 signaling pathway in cystitis induced bladder fibrosis was investigated. Jmjd3 and Col1/3 expression was detected in a cystitis mouse model that was developed by intraperitoneal injection of cyclophosphamide (CYP). Human bladder smooth muscle cells (hBSMCs) were stimulated in vitro with lipopolysaccharide (LPS), and the cell proliferation and collagen accumulation were detected using EdU, CCK8, flow cytometry, qPCR, western blotting and immunofluorescence assays. Furthermore, the effects of NFκB and JMJD3 on cell proliferation and collagen accumulation were investigated using its selective antagonists, JSH23 and GSK-J4, respectively. CYP induced cystitis significantly increased Jmjd3, Col1 and Col3 expression in the bladder muscle cells. Furthermore, LPS stimulation markedly activated NFκB signaling and elevated JMJD3 expression in hBSMCs, and the activation of NFκB-JMJD3 signaling significantly promoted cell proliferation and collagen accumulation by upregulating CCND1 and COL1/3 expression, respectively. Our study reveals the critical role of NFκB-JMJD3 signaling in cystitis induced bladder reconstruction by regulating hBSMC proliferation and extracellular matrix (ECM) deposition, and these findings provide an avenue for effective treatment of patients with cystitis.

Topics: Animals; Benzazepines; Cell Proliferation; Collagen; Cystitis; Disease Models, Animal; Female; Fibrosis; Humans; Jumonji Domain-Containing Histone Demethylases; Lipopolysaccharides; Mice; Mice, Inbred C57BL; Myocytes, Smooth Muscle; NF-kappa B; Phenylenediamines; Pyrimidines; Signal Transduction; Up-Regulation; Urinary Bladder

Nuclear factor-kappa B (NF-κB), which is reported to play an important role in the pathogenesis of depression, also has a central role in the genesis and progression of inflammation. Here, we have targeted the nuclear translocation of NF-κB using 4-methyl-N1-(3-phenyl-propyl)-benzene-1,2-diamine (JSH-23) to elucidate its role in depression. We investigated the antidepressant-like effects of JSH-23 in the chronic mild stress (CMS) mouse model, which is a valid, reasonably reliable, and useful model of depression. The antidepressant-like effects of JSH-23 were evaluated using the sucrose preference test (SPT) and the forced swimming test (FST). We also assessed inflammatory markers [interleukin (IL)-6 and tumor necrosis factor-α (TNF-α)] and components of antioxidant defense [superoxide dismutase (SOD) and nuclear factor erythroid-2-related factor 2 (Nrf 2)] in the hippocampus. Fluoxetine, a classical antidepressant, was used in this study as a positive control. Administration of JSH-23 significantly prevented the decreased sucrose preference in the SPT and prevented the increased immobility time in the FST caused by CMS, but had no effect on locomotor activity. Expression of NF-κB p65 protein in the hippocampus was decreased, and elevated levels of IL-6 and TNF-α were reduced, after JSH-23 administration. In addition to its anti-inflammatory effect, JSH-23 treatment increased the expression of SOD and Nrf 2 in the hippocampus, suggesting that it strengthens antioxidant defense. The current study demonstrated that inhibiting the NF-κB signaling cascade using JSH-23 prevented depressive-like behaviors by decreasing inflammation and improving antioxidant defense in the hippocampus. We concluded that NF-κB activation plays an important role in the pathophysiology of depression and that targeting NF-κB signaling may provide a novel and effective therapy for depression. Additional preclinical studies and clinical trials are, however, needed to further elucidate the effects of this therapeutic strategy.

Topics: Animals; Antioxidants; Biomarkers; Body Weight; Chronic Disease; Depression; Disease Models, Animal; Hippocampus; Inflammation; Interleukin-6; Locomotion; Male; Mice, Inbred C57BL; NF-kappa B; Phenylenediamines; Stress, Physiological; Superoxide Dismutase; Tumor Necrosis Factor-alpha