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Minimal change disease (MCD) is the common type of nephrotic syndrome in children. There is an urgent need to explore new treatment methods as current treatments have many drawbacks and cause significant side effects. Our group found that Angiopoietin-like protein 3 (Angptl3) is closely related to renal disease and Angptl3 knockout significantly alleviated proteinuria in mice with adriamycin nephropathy (AN), however, some proteinuria was still present. Minnelide is a water-soluble prodrug of triptolide which has been used for the treatment of glomerular diseases. Therefore, this study aimed to investigate whether minnelide, combined with Angptl3 knockout, could completely protect mice with AN and its mechanism. AN was induced in B6;129S5 female mice by tail vein injection of 25 mg/kg of Adriamycin (ADR), and treatment with 200 ug/kg/d of minnelide. The results showed that minnelide combined with Angptl3 knockout completely reduced proteinuria and restored the foot processes in mice with AN. Moreover, in Angptl3 knockout mice with AN, minnelide restored the distribution of nephrin, podocin and cd2ap and reduced inflammatory factors (Tumor necrosis factor alpha (TNF-α), Interleukin-6 (IL-6) and Interleukin-1β (IL-1β)). Through RNA sequencing and related experiments, we found minnelide could ameliorate fibrosis and apoptosis by inhibiting TGF-β1-Smad2 and p53 pathways in Angptl3 knockout mice with AN, respectively. In Angptl3 knockout primary podocytes, triptolide alleviates ADR-induced decreases in nephrin, podocin and cd2ap, upregulation of Bax and downregulation of Bcl-2. Overall, our study shows that minnelide combined with Angptl3 knockout completely protects mice with AN by inhibiting the TGF-β1-smad2 and p53 pathways.

Sophoricoside (SOP), an isoflavone glycoside isolated from seed of Sophora japonica L., has been reported to have various pharmacological activities, including anti-cancer, anti-allergy and anti-inflammation. However, the effect of SOP on lipopolysaccharides (LPS)-acute lung injury (ALI) is completely unclear. Here, we found that SOP pretreatment significantly ameliorated LPS-induced pathological damage, tissue permeability, neutrophil infiltration and the production of pro-inflammatory cytokines (TNF-α, IL-1β and IL-6) in a murine model of ALI. Besides, SOP reduced the production of pro-inflammatory mediators such as iNOS, NO and inflammatory cytokines including TNF-α, IL-1β and IL-6 in LPS-stimulated RAW264.7 cells and bone marrow derived macrophages. Interestingly, treatment with SOP exhibited no effect on the activation of NF-κB and MAPKs in macrophages but prominently accelerated the expression and nuclear translocation of Nrf2. By using ML385, a specific Nrf2 inhibitor, we found that inhibition of Nrf2 abolished the inhibitory effect of SOP on LPS-induced iNOS expression, NO production as well as pro-inflammatory cytokine generation. SOP also activated AMPK, an upstream protein of Nrf2, under LPS stimuli. Furthermore, we demonstrated that the accelerated expression of Nrf2 induced by SOP was reversed by interference with the AMPK inhibitor Compound C. Taken together, our results suggested that SOP attenuated LPS-induced ALI in AMPK/Nrf2 dependent manner and indicated that SOP might be a potential therapeutic candidate for treating ALI/ARDS.

Idiopathic pulmonary fibrosis (IPF) is a chronic and irreversible inflammatory disease with a high mortality rate and limited therapeutic options. This study explored the potential role and mechanisms of Dehydrocostus lactone (DHL) in the inflammatory and fibrotic responses in a bleomycin (BLM) induced model. Treatment with DHL significantly reduced pathological injury and fibrosis, the secretion of BLM-induced pro-fibrotic mediators TGF-β and α-SMA, and components of the extracellular matrix (fibronectin). Additionally, in the early stages of inflammation, DHL administration inhibited the infiltration of inflammatory cells and downregulated the expression of TGF-β, TNF-α, and IL-6, indicating that DHL treatment effectively alleviated BLM-induced pulmonary fibrosis and inflammation in a dose-dependent manner. Furthermore, BLM induced the production of IL-33 in vivo, which initiated and progressed pulmonary fibrosis by activating macrophages and enhancing the production of IL-13 and TGF-β. In contrast, a significant decrease in the expression of IL-33 after DHL treatment in vitro showed that DHL strongly reduced IL-13 and TGF-β. Regarding the mechanism, BLM-induced phosphorylation of JNK, p38 MAPK, and NF-κB were significantly reduced after DHL treatment, which further led to the down-regulation of IL-33 expression, thereby decreasing IL-13 and TGF-β. Collectively, our data suggested that DHL could exert its anti-fibrosis effect via inhibiting the early inflammatory response by downregulating the JNK/p38 MAPK-mediated NF-κB signaling pathway to suppress macrophage activation. Therefore, DHL has therapeutic potential for pulmonary fibrosis.

Background Acute lung injury (ALI) is a common component of systemic inflammatory disease without more effective treatments. However, recent studies have demonstrated that the recombinant human brain natriuretic peptide (rhBNP) has anti-inflammatory effects. Therefore, we found that rhBNP could prevent lipopolysaccharide (LPS)-induced acute lung injury in a dog model. Methods Dogs were injected with LPS and subjected to continuous intravenous infusion (CIV) of saline solution or rhBNP. We detected the protective effects of rhBNP by histological examination and determination of serum cytokine levels and lung myeloperoxidase (MPO) activity and malondialdehyde (MDA) activity. Histological examination indicated marked inflammation, edema and hemorrhage in lung tissue taken 12 h after rhBNP treatment compared with tissue from dogs which received saline treatment after LPS injection. LPS injection induced cytokine (IL-6 and TNF-α) secretion and lung MPO and MDA activities, which were also attenuated by rhBNP treatment. Results Inductions of IL-6 and TNF-α were significantly attenuated in the L-rhBNP and the H-rhBNP groups. The ratios of the L-rhBNP group and H-rhBNP group were lower than that in the lung injury group. Furthermore, MPO and MDA activities were significantly lower in the H-rhBNP group compared to those in the LI group. Conclusion Our data indicate that rhBNP treatment may exert protective effects and may be associated with adjusting endogenous antioxidant enzymes. Thus, rhBNP may be considered as a therapeutic agent for various clinical conditions involving lung injury by sepsis.

Evodiamine has been reported to exhibit anti-inflammatory and anti-nociceptive effects, but the underlying mechanisms remain to be defined. P2X4 receptor (P2X4R) is a subtype of ATP receptors and plays important roles in pain, inflammatory and immune responses. We aimed to investigate whether evodiamine has beneficial effects on endothelial inflammatory injury mediated by chronic high glucose condition. We found that culturing human umbilical vein endothelial cells (HUVECs) with high glucose significantly increased the expression of P2X4 receptor in HUVECs, cytosolic Ca(2+) concentrations and intracellular reactive oxygen species (ROS) while decreasing nitric oxide (NO); these effects could be reversed by evodiamine. High glucose also significantly increased the expression of the pro-inflammatory activators (NF-κB) and TNFR-ɑ, which was accompanied by the elevation of P2X4R levels. Evodiamine was able to down-regulate the elevated NF-κB, TNFR-ɑ, P2X4R and ROS, and up-regulate the decreased NO. Thus the evodiamine may exert the anti-inflammation activity on high-glucose challenge HUVEC via suppressing the P2X4R signaling pathway, exhibiting beneficial ability to protect HUVECs from glucotoxicity.

Sepsis is the leading cause of death in the intensive care units worldwide. Proinflammatory cytokines such as TNF (tumor necrosis factor)-α and IL (interleukin)-6 mediate the pathogenesis of septic shock characterized by hemodynamic instability and end-stage multi-organ functional failure. Brain natriuretic peptide (BNP) has been used as a diagnostic and prognostic biomarker in the cardiovascular disorders. Most recently, plasma level of BNP has also been used to predict outcomes of critical illnesses including sepsis. We have recently reported that human recombinant BNP (rhBNP) could protect lungs from acute proinflammatory injury in response to LPS-injection. In the current study, using LPS (lipopolysaccharide)-induced canine sepsis models, we further investigated the effect of rhBNP on intestinal injury and its potential mechanisms. We have found that rhBNP (5μg or 10μg/kg weight) could significantly reduce intestinal tissue damage in response to LPS-injection in the dog sepsis models through down-regulating proinflammatory cytokines TNF-α and IL-6 (5-10 fold decrease compared to LPS-injection only group) by a mechanism of suppressing IκB phosphorylation and NF-κB expression. These findings suggest that BNP protect intestinal tissues from endotoxin-induced hyper-inflammatory injury and thus, may be used as therapeutic agents for sepsis.