jsh-23 and Inflammation

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

The radiation-induced inflammatory response is involved in radiation damage to the cochlea and causes sensorineural hearing loss (SNHL). NF-κB, as the master switch of the inflammatory response, regulates the expression of many inflammation-related genes and thus the inflammatory response. Therefore, in this study we used a mouse model to determine whether radiation-induced NF-κB activation is involved in damage to the cochlea and to investigate the underlying mechanism. Eventually, we found that NF-κB was activated after radiation of the cochleae and the activation reached a maximum at 2-6 h after radiation. And morphological analysis showed severe damage to the cochleae after radiation, but this damage was significantly ameliorated by JSH-23 (an inhibitor of NF-κB) pretreatment. Along with these morphological changes, the expression levels of proinflammatory molecules (including proinflammatory cytokines IL-6, TNF-α, COX-2 and inflammation-related proteins VCAM-1, MIP-1β) in the cochlear tissues were significantly increased after radiation, but were significantly decreased by JSH-23 pretreatment compared to radiation alone. Therefore, these results indicated that radiation-induced NF-κB activation was involved in damage to the cochleae and resultant SNHL via its promotion of the inflammatory response mediated by overexpression of some proinflammatory molecules in cochlear tissues, and inhibition of radiation-induced NF-κB was conducive to preventing such damage.

Topics: Animals; Cochlea; Cytokines; Inflammation; Mice; NF-kappa B; Radiation Injuries; Signal Transduction

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

Mesenchymal stem cells have an important potential in the treatment of age-related diseases. In the last years, small extracellular vesicles derived from these stem cells have been proposed as cell-free therapies. Cellular senescence and proinflammatory activation are involved in the loss of therapeutic capacity and in the phenomenon called inflamm-aging. The regulators of these two biological processes in mesenchymal stem cells are not well-known. In this study, we found that p65 is activated during cellular senescence and inflammatory activation in human umbilical cord-derived mesenchymal stem cell. To demonstrate the central role of p65 in these two processes, we used small-molecular inhibitors of p65, such as JSH-23, MG-132 and curcumin. We found that the inhibition of p65 prevents the cellular senescence phenotype in human umbilical cord-derived mesenchymal stem cells. Besides, p65 inhibition produced the inactivation of proinflammatory molecules as components of a senescence-associated secretory phenotype (SASP) (interleukin-6 and interleukin-8 (IL-6 and IL-8)). Additionally, we found that the inhibition of p65 prevents the transmission of paracrine senescence between mesenchymal stem cells and the proinflammatory message through small extracellular vesicles. Our work highlights the important role of p65 and its inhibition to restore the loss of functionality of small extracellular vesicles from senescent mesenchymal stem cells and their inflamm-aging signature.

Topics: Adolescent; Adult; Cell Proliferation; Cells, Cultured; Cellular Senescence; Curcumin; DNA Damage; Female; Humans; Inflammation; Leupeptins; Mesenchymal Stem Cells; Nanoparticles; Paracrine Communication; Phenotype; Phenylenediamines; Transcription Factor RelA; Umbilical Cord

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

Human β-defensin-2(HBD-2) is one of the two major vertebrate antimicrobial peptide families (α and β), which is highly expressed by proinflammatory induction in the lung and exhibit broad-spectrum antimicrobial activity. We observed that IL-22 receptors high expressed on the membrane of A549 cells; HBD-2 mRNA was expressed in a time- and concentration-dependent manners in A549 cells when treated with IL-22; further studies demonstrated that HBD-2 expression was attenuated by AG490, but to JSH-23, inhibitors of p-STAT3 DNA binding and NF-κB/p65 subunit nuclear translocation, respectively. These results support that IL-22-mediated signalling pathway of HBD-2 gene expression involved STAT3 but not NF-κB in human alveolar epithelium. These findings provide a new insight into how IL-22 may play an important link between innate and adaptive immunity, thereby anti-infection locally in the alveolar epithelium.

Topics: beta-Defensins; Cell Line; DNA-Binding Proteins; Epithelial Cells; Humans; Inflammation; Interleukin-22; Interleukins; Phenylenediamines; Pulmonary Alveoli; Receptors, Interleukin; Respiratory Mucosa; RNA, Messenger; Signal Transduction; STAT3 Transcription Factor; Transcription Factor RelA; Tyrphostins