Diabetic nephropathy (DN), which is characterized by renal fibrosis, is a major complication of diabetes, a disease that afflicted more than 460 million people worldwide in 2019. Pyroptosis is an essential signaling pathway in DN-related injuries, such as renal fibrosis. Pyrroloquinoline quinone (PQQ) is a naturally occurring bioactive compound that protects human kidney 2 (HK-2) cells from oxidative stress-induced damage caused by high glucose concentrations. However, the nature and underlying mechanism of the effect of PQQ on DN-related renal fibrosis remains unclear. In this study, we evaluated whether PQQ has potential protective effects against renal fibrosis due to DN by establishing type 1 diabetes in mice via streptozotocin treatment and then inhibiting their pyroptosis signaling pathway. We found that compared to control mice, the area of renal fibrosis and injury were significantly increased in diabetic mice, and this was accompanied by increased levels of expression of collagen I and transforming growth factor-beta 1; increased concentrations of the inflammatory cytokines, interleukin (IL)-1 beta, IL-6, and tumor necrosis factor-alpha; and activation of the pyroptosis pathway components nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3), caspase-1, IL-1 beta, and IL-18. All of these changes were reversed by PQQ treatment. Analogously, we treated cultured HK-2 cells with a high concentration of glucose (35 mmol/L), which caused these cells to exhibit significantly increased concentrations of reactive oxygen species (ROS), phosphorylated (p)-nuclear factor kappa B (NF-kappa B), p-IkappaB, NLRP3, caspase-1, IL-1 beta, and IL-18, and the loss of mitochondrial transmembrane potential. However, PQQ treatment significantly blunted these effects. In conclusion, in this study we demonstrated that PQQ attenuates renal fibrosis by alleviating mitochondrial dysfunction, reducing ROS production, and inhibiting the activation of the NF-kappa B/pyroptosis pathway under conditions of DN and hyperglycemia.

BACKGROUND:CHMP1A, a member of the ESCRT-III complex family, has been indicated as a brand-new inhibitor gene of tumors. Our previous research has revealed that CHMP1A plays a vital role in the development and progression of renal cell carcinoma (RCC).OBJECTIVE:To investigate the potential target pathway of the regulation of the tumor cell growth by CHMP1A.METHODS:The effect of CHMP1A on mTOR pathway was elucidated by western blotting. The effect of CHMP1A on the expression of p53 was evaluated, and A498 cell growth was assessed by colony formation and MTT assays. The expression of p53 was knocked down by shRNA-p53, and the effect of CHMP1A on mTOR after knockdown of p53 was evaluated. The effect of CHMP1A on apoptosis and its relationship with MDM2 pathway were detected by western blotting and FCM. Finally, the relationship between the regulation of p53 by CHMP1A and the PI3K/mTOR pathway was detected.RESULTS:This study showed that the mTOR pathway was suppressed significantly in CHMP1A-overexpressing A498 and 786-0 cells; moreover, the enhanced expression of p53 and the reduced proliferation were shown in CHMP1A-overexpressing A498 cells. Furthermore, CHMP1A was able to regulate the PI3K/PTEN/mTOR and MDM2/p53 pathways in order to suppress RCC. In addition, CHMP1A regulated Bax and Bcl-2 via MDM2/p53 to induce the apoptosis of tumor cells and upregulated the expression of p53 via the PI3K/mTOR pathway.CONCLUSIONS:The results convey that CHMP1A-related suppression of RCC is closely related to the PI3K/mTOR/p53 pathway.

Dendrobium polysaccharide exhibits multiple biological activities, such as immune regulation, antioxidation, and antitumor. However, its resistance to viral infection by stimulating immunity is rarely reported. In this study, we explored the effect and mechanism of DVP-1, a novel polysaccharide from Dendrobium devonianum, in the activation of immunity. After being activated by DVP-1, the ability of mice to prevent H1N1 influenza virus infection was investigated. Results of immune regulation showed that DVP-1 significantly improved the immune organ index, lymphocyte proliferation, and mRNA expression level of cytokines, such as IL-1β, IL-4, IL-6, and TNF-α in the spleen. Immunohistochemical results showed that DVP-1 obviously promoted the mucosal immunity in the jejunum tissue. In addition, the expression levels of TLR4, MyD88, and TRAF6 and the phosphorylation levels of TAK1, Erk, JNK, and NF-κB in the spleen were upregulated by DVP-1. The virus infection results showed that the weight loss of mice slowed down, the survival rate increased, the organ index of the lung reduced, and the virus content in the lung decreased after DVP-1 activated immunity. By activating immunity with DVP-1, the production of inflammatory cells and inflammatory factors in BALF, and alveolar as well as peribronchiolar inflammation could be prevented. The results manifested that DVP-1 could resist H1N1 influenza virus infection by activating immunity through the TLR4/MyD88/NF-κB pathway.

Diabetic cardiomyopathy (DCM), a common complication of diabetes mellitus and is characterized by myocardial hypertrophy and myocardial fibrosis. Pyrroloquinoline quinone (PQQ), a natural nutrient, exerts strong protection against various myocardial diseases. Pyroptosis, a type of inflammation-related programmed cell death, is vital to the development of DCM. However, the protective effects of PQQ against DCM and the associated mechanisms are not clear. This study aimed to investigate whether PQQ protected against DCM and to determine the underlying molecular mechanism. Diabetes was induced in mice by intraperitoneal injection of streptozotocin, after which the mice were administered PQQ orally (10, 20, or 40 mg/kg body weight/day) for 12 weeks. AC16 human myocardial cells were divided into the following groups and treated accordingly: control (5.5 mmol/L glucose), high glucose (35 mmol/L glucose), and HG + PQQ groups (1 and 10 nmol/L PQQ). Cells were treated for 24 h. PQQ reduced myocardial hypertrophy and the area of myocardial fibrosis, which was accompanied by an increase in antioxidant function and a decrease in inflammatory cytokine levels. Moreover, myocardial hypertrophy—(ANP and BNP), myocardial fibrosis—(collagen I and TGF-β1), and pyroptosis-related protein levels decreased in the PQQ treatment groups. Furthermore, PQQ abolished mitochondrial dysfunction and the activation of NF-κB/IκB, and decreased NLRP3 inflammation-mediated pyroptosis in AC16 cells under high-glucose conditions. PQQ improved DCM in diabetic mice by inhibiting NF-κB/NLRP3 inflammasome-mediated cell pyroptosis. Long-term dietary supplementation with PQQ may be greatly beneficial for the treatment of DCM. Diagram of the underlying mechanism of the effects of PQQ on DCM. PQQ inhibits ROS generation and NF-κB activation, which stimulates activation of the NLRP3 inflammasome and regulates the expression of caspase-1, IL-1β, and IL-18. The up-regulated inflammatory cytokines trigger myocardial hypertrophy and cardiac fibrosis and promote the pathological process of DCM.

The anti-inflammatory activity of Quzhou Fructus Aurantii Extract (QFAE) has been reported recently. Thus, present study aims to explore the mechanism of anti-inflammation of QFAE in vitro and in vivo to develop a lung phylactic agent. The anti-inflammatory mechanism of QFAE in RAW 264.7 cells and acute lung injury (ALI) mice model was determined by cytokines analysis, histopathological examination, Western blot assay, immunofluorescence, and immunohistochemistry analysis. The results showed that QFAE restrained mitogen-activated protein kinase (MAPK) and nuclear factor-kappa B (NF-κB) signaling pathways in LPS-induced RAW 264.7 cells, whereas AMP-activated protein kinase (AMPK) signaling pathways were activated, as revealed by prominent attenuation of phosphorylation of ERK, JNK, p38, p65, IκBα, RSK and MSK, and overt enhancement of phosphorylation of ACC and AMPKα. The levels of pro-inflammatory cytokines TNF, IL-6, and IL-1β were suppressed, whereas the level of anti-inflammatory cytokine IL-10 increased after pretreatment with QFAE in vivo and in vitro. Moreover, QFAE prevented mice from LPS-provoked ALI, bases on alleviating neutrophils, and macrophages in bronchoalveolar lavage fluid (BALF) and mitigatingpulmonary histological alters, as well as hematological change. The MAPK and NF-κB signaling pathways in LPS-stimulated ALI mice were dampened by QFAE pretreatment, whereas AMPK signaling pathways were accelerated, as testify by significant restraint of phosphorylation of ERK, JNK, p38, p65, and IκBα, and distinct elevation of phosphorylation of ACC and AMPKα. The remarkable anti-inflammatory effect of QFAE is associated with the suppression of MAPK and NF-κB signaling pathways and the initiation of AMPK signaling pathway.

AIMS:Doxorubicin (DOX) is an effective anthracycline anticancer drug. However, the clinical usage of it is limited due to its severe cardiotoxicity side effects. Metformin (Met) is a kind of first-line antihyperglycemic drug which has a potential protective effect on the heart，it is often used for oral treatment of type 2 diabetes. In this study, we explored whether Met could attenuate cardiotoxicity induced by DOX. MATERIALS AND METHODS:For the sake of exploring the Met protective effect and mechanism, we established the DOX-induced cardiotoxicity models both in H9C2 cells incubated with 5 μM DOX in vitro and Sprague-Dawley rats treated with 20 mg/kg cumulative dose of DOX. KEY FINDINGS:Met is able to inhibit growth inhibition and apoptosis of H9C2 cells induced by DOX. The heart indexes of rats were examined to evaluate the Met cardiotoxicity protection. Met improved the abnormal indexes, serum markers of cardiac heart injury, echocardiography, electrocardiogram, cardiac pathology, cardiomyocyte apoptosis, and oxidative stress markers induced by DOX. Furthermore, in vivo and in vitro studies demonstrated that Met protected against DOX-induced increasing cleaved caspase-3 and Bax. Met also prevented the downregulation of Bcl-2, activated the AMPK pathway, and inhibited the MAPK pathway. SIGNIFICANCE:Met showed protective effects on DOX-induced cardiotoxicity by reducing oxidative stress and apoptosis, as well as regulating AMPK and MAPK signaling pathways.

Objective: The research aims to discuss the effects on electro-acupuncture regulate circadian rhythm of mice. Methods: 28 animals which were screened out were divided randomly into 4 groups which were Baihui( GV20) + Changqiang( GV1) group,Ganshu( BL18) + Zhiyang( GV9) group,non-acupoint group and blank group with 7 for each group. Each group received LD domestication( Light 01: 00-13: 00,Dark 13: 00-01: 00) for 14 days. After that,light source was blocked so that the mice were in free movement and they received DD domestication for 10 days. After 10 days begin to elector-acupuncture for 7 days at CT16,using 2 /15 Hz and 0. 5 m A for 15 min each time and one time a day. Black group bind in the same time without elector-acupuncture. Results: After elector-acupuncture,the acrophase of the mice were advance in each group,there were significant differences in Baihui( GV20) + Changqiang( GV1) group,Ganshu( BL18) + Zhiyang( GV9) group( P 0. 05),there were no significant differences in non-acupoint and black group( P 0. 05). The onset of the mice in Baihui( GV20) + Changqiang( GV1) group advanced were significant differences( P 0. 05). The bouts were reduce in each group but there were no significant differences between this groups( P 0. 05). The period were reduced after electro-acupuncture,there were no significant differences between this groups( P 0. 05). Conclusion: There was distinct circadian rhythm with DD domestication in mice。The impact on circadian rhythm of mice was with free-run. Mainly reflected in acrophase and out in advance,the activity,bouts and amplitude reduction,and the period were elongated. There were significant difference in acrophase,onset and activity in Baihui( GV20) + Changqiang( GV1) group,on the other way there were significant difference in the acrophase and activity in Ganshu( BL18) + Zhiyang( GV9) group.

Objective:To explore the mechanism of cognitive dysfunction induced by isoflurane mediated by activated TGFβ/Smad signaling pathway.Methods:A total of 120 patients in our hospital received anesthesia by isoflurane were analyzed.The cognitive function in each patient was assayed by MMSE before anesthesia and after anesthesia induction at different time points.The expression of TGFβ/Smad signaling pathway related proteins were detected by Western Blotting.60 cases of healthy subjects in our hospital at the same period were taken as control.Results:The results showed that the cognitive dysfunction exits in patients received isoflurane anesthesia when compared with control patients.The results also showed that the expression of TGFβ,Smad3 and Smad 7was enhanced dramatically with a statistical difference when compared with control.Conclusion:Activated TGFβ/Smad signaling pathway participates in isoflurane anesthesia induced cognitive dysfunction.