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The mechanisms by which retinoic acid-inducible gene I (RIG-I), a critical RNA virus sensor, is regulated in many biological and pathological processes remain to be determined. Here, we demonstrate that T cell immunoglobulin and mucin protein-3 (Tim-3), an immune checkpoint inhibitor, mediates infection tolerance by suppressing RIG-I-type I interferon pathway. Overexpression or blockade of Tim-3 affects type I interferon expression, virus replication, and tissue damage in mice following H1N1 infection. Tim-3 signaling decreases RIG-I transcription via STAT1 in macrophages and promotes the proteasomal dependent degradation of RIG-I by enhancing K-48-linked ubiquitination via the E3 ligase RNF-122. Silencing RIG-I reversed Tim-3 blockage-mediated upregulation of type I interferon in macrophages. We thus identified a new mechanism through which Tim-3 mediates the immune evasion of H1N1, which may have clinical implications for the treatment of viral diseases.

Danshen (Salvia miltiorrhiza) and prednisone are extensively applied in the treatment of kidney disease. Salvianolic acid A (SAA), the major biologically active component of Danshen, which has various biological effects. Our previous findings have demonstrated the renoprotective effect of SAA in various kidney disease rodent models. Here, we explore the therapeutic potential and possible mechanisms of SAA in combination with low-dose prednisone in adriamycin (ADR)-induced minimal change disease (MCD) rat model and mouse podocyte injury cell model. SAA was injected via tail vein at 10 mg/kg/day and prednisone at 5 mg/kg/day via gavage. Each drug was administered daily alone or in combination for 3 weeks. Combination therapy showed significant therapeutic efficacy as manifested by relieved urinary proteins, improved blood biochemical indicators including serum total protein, albumin, triglyceride, cholesterol, the indices of renal function i.e. blood urea nitrogen and serum creatinine levels, and ameliorated pathological lesions. Particularly, co-administration showed a significant anti-proteinuria effect in MCD rats. Further studies suggested that co-administration effectively ameliorated the podocyte injury as indicated by the reduction of podocyte foot processes fusion, up-regulation of synaptopodin and down-regulation of desmin. These beneficial effects are accompanied by activation of the Nrf2/HO-1 and PPARγ/Angptl4 pathways in vivo, and the effect of SAA on PPARγ/Angptl4 is also demonstrated in vitro. These findings suggested that SAA exerted podocyte-protection against MCD injury through PPARγ/Angptl4 and Nrf2/HO-1 pathways, and combined with low-dose prednisone possessed a significant anti-proteinuria and therapeutic effects in MCD rats.

Background Ulcerative colitis (UC) is a chronic inflammatory condition of the intestines and is difficult to cure once diagnosed. The efficacy of the current clinical treatment for UC is limited. Common anti-inflammatory drugs are prone to adverse effects, while novel biological agents are expensive, although tolerated by patients. Therefore, an urgency exists to find more safe and effective drugs to treat UC. Osthole is an active constituent isolated from the fruit of Cnidium monnieri (L.) Cuss. Osthole has anti-inflammatory activities and offers certain intestinal protection. These characteristics indicate that osthole has the potential to inhibit UC. Purpose The study was conducted to investigate the anti-inflammatory potential of osthole in LPS-induced RAW 264.7 cells and dextran sulphate sodium (DSS)-induced ulcerative colitis in mice. Methods In in vitro experiments, mouse monocyte-macrophage RAW 264.7 cells were stimulated by 1 μg/ml LPS to produce inflammatory mediators. Griess reagent was used to determine Nitric Oxide (NO) production, and ELISA kits were used to determine the levels of PGE2, TNF-α, and IL-6. The anti-inflammatory mechanisms of osthole were detected using western blot. In in vivo experiments, UC was induced via the intragastric administration of 3.5% DSS to BALB/C mice for 7 days. During the experiment, clinical signs and body weight were monitored and recorded daily to calculate the DAI score. At the end of the experiment, the colon lengths were measured. The colonic histopathological lesions were evaluated. MPO activity and TNF-α levels were determined using the corresponding kits. The protein expression of TNF-α and NF-κB pathways were analysed using western blot. Results In an in vitro study, osthole inhibited the production of NO, PGE2, TNF-α, and IL-6 in LPS-induced RAW 264.7 cells. The results of western blot showed that osthole inhibited the expression of iNOS, COX-2, p38 MAPK and IκB α in RAW 264.7 cells. On this basis, in DSS-induced UC mice, it was found that osthole relieved the symptoms of UC by inhibiting weight loss, colon shortening and the DAI score, and simultaneously alleviating colon tissue lesions. It was also found that osthole reduced the levels of TNF-α in serum and colon tissues and effectively inhibited the activity of MPO. The western blot results showed that osthole reduced the expression of NF-κB p65 and p-IκB α and increased the content of IκB α in colon tissues. Conclusion Osthole exerted anti-inflammatory effects by blocking the activation of the NF-κB and MAPK/p38 pathways. Additionally, osthole possesses therapeutic potential in the treatment of UC.

Ulcerative colitis (UC) is a type of inflammatory bowel disease (IBD), which is characterized by chronic intestinal inflammation and leads to an increased risk of colon cancer. There are many studies using phyto-ingredients as a novel approach for the treatment of UC. The plant Andrographis paniculata (Acanthaceae) is a safe and edible vegetable that has been extensively adopted in traditional Chinese medicine for conditions involving inflammation, and the most active phytochemical agent is andrographolide. The andrographolide derivative 3,14,19-triacetyl andrographolide, which is known as CX-10 (a hemi chemical synthesized from andrographolide), has been found to possess strong anti-inflammatory properties. In the present study, we investigated the therapeutic potential of CX-10 as a complementary and alternative medicine against dextran sulphate sodium (DSS)-induced ulcerative colitis in mice. Our results revealed that CX-10 treatment reduced body weight loss, reduced colon length shortening, decreased colon weight, decreased the spleen index, decreased the disease activity index (DAI), and alleviated histological damage in the colon. The expression of TNF-α and IL-6 and the activity of myeloperoxidase (MPO) in colonic tissues were significantly reduced in CX-10 supplemented mice. It is noteworthy that the efficacy of 200 mg/kg of CX-10 was equivalent to that of the mesalazine positive control (200 mg/kg). Furthermore, western blot analysis revealed that CX-10 treatment reduced the expression of nuclear factor-κB (NF-κB) p65 and p-IκBα, increased the expression of IκBα and down-regulated the phosphorylation of p38 mitogen-activated protein kinase (MAPK), ERK and JNK. In conclusion, CX-10 treatment attenuated DSS-induced UC in mice through inhibiting the activation of NF-κB and MAPK pathways and reducing TNF-α and IL-6 levels, suggesting that CX-10 is a potential therapeutic drug for UC.

Renal ischaemia-reperfusion (I/R) injury is the most common cause of acute kidney injury (AKI). Peritubular capillary (PTC) endothelium damages are an important pathogenesis during I/R AKI. Salvianolic acid A (SAA) possesses various pharmacological activities. The study investigated whether SAA ameliorated I/R AKI through protecting against PTC endothelium damages. Male Sprague-Dawley rats were divided into 6 groups: control, sham, I/R, and I/R plus SAA (2.5, 5, 10 mg/kg) groups. Rats were subjected to bilateral renal pedicle clamping for 60 min, and killed at 24 hr after reperfusion. Kidney injury, PTC endothelium damages and factors affecting PTC endothelium were evaluated. SAA significantly decreased blood urea nitrogen and serum creatinine levels, and reduced urine kidney injury molecule-1 concentration. Simultaneously, SAA alleviated histological damages, prevented PTC endothelium damages, preserved the density of PTC and improved renal hypoxia. Furthermore, SAA inhibited platelet activation, elevated Klotho protein expression and up-regulated vascular endothelial growth factor A expression. Overall, SAA has protective effects on AKI induced by I/R. Preventing PTC endothelium damages and preserving PTC integrity to improve the renal hypoxia may be the ways for SAA to ameliorate AKI. All these indicate that SAA is likely to be a promising agent for AKI.