Single-Cell Transcriptomics Reveals the Ameliorative Effect of Oridonin on Septic Liver Injury.

Sepsis is a life-threatening syndrome leading to hemodynamic instability and potential organ dysfunction. Oridonin, commonly used in Traditional Chinese Medicine (TCM), exhibits significant anti-inflammation activity. To explore the protective mechanisms of oridonin against the pathophysiological changes, the authors conducted single-cell transcriptome (scRNA-seq) analysis on septic liver models induced by cecal ligation and puncture (CLP). They obtained a total of 63,486 cells, distributed across 11 major cell clusters, and concentrated their analysis on four specific clusters (hepatocytes/Heps, macrophages, endothelial/Endos and T/NK) based on their changes in proportion during sepsis and under oridonin treatment. Firstly, biological changes in Hep, which are related to metabolic dysregulation and pro-inflammatory signaling, are observed during sepsis. Secondly, they uncovered the dynamic profiles of macrophage's phenotype, indicating that a substantial number of macrophages exhibited a M1-skewed phenotype associated with pro-inflammatory characteristics in septic model. Thirdly, they detected an upregulation of both inflammatory cytokines and transcriptomic factor Nfkb1 expression within Endo, along with slight capillarization during sepsis. Moreover, excessive accumulation of cytotoxic NK led to an immune imbalance. Though, oridonin ameliorated inflammatory-related responses and improved the liver dysfunction in septic mice. This study provides fundamental evidence of the protective effects of oridonin against sepsis-induced cytokine storm.

Combined Administration of Vitamin D3 and Geniposide Is Less Effective than Single Use of Vitamin D3 or Geniposide in the Treatment of Ulcerative Colitis.

With the increasing incidence of ulcerative colitis (UC) in China, Chinese medicinal herbs or relatively active compounds are widely applied in treating UC. These medicines may be combined with other therapeutic agents such as vitamin D3. Nevertheless, the efficacy of these combinations for UC is unclear. Geniposide is an active component in many Chinese herbal medicines. It could ameliorate dextran sulfate sodium (DSS)-induced colitis in mice. This study was designed to determine the efficacy and mechanism of the single use and combination of geniposide and vitamin D3 on a mouse model of acute colitis. Data showed that a single administration of geniposide (2 mg/kg) or vitamin D3 (4 IU/day) could significantly improve the symptoms of UC and relieve colon damage. Geniposide and vitamin D could significantly decrease the levels of TNF-α and IL-6 in serum and colon, and increase the level of IL-10 in the colon. However, the combined treatment of geniposide (2 mg/kg) and vitamin D3 (4 IU/day) exerted less beneficial effects on UC in mice, indicating by less improvement of UC symptoms, colon damage, and inflammatory infiltration. The combination only downregulated the level of TNF-α in serum and IL-6 in the colon. Our data further demonstrated that geniposide could inhibit the activation of p38 MAPK and then restrict the vitamin D receptor signaling stimulated by vitamin D3. These results implied that the combination of geniposide and vitamin D3 might not be an ideal combined treatment for acute colitis, and the combination of vitamin D supplementary and geniposide (or herbal medicines rich in geniposide) need more evaluation before being applied to treat UC in clinic.

2,3,5,4'-Tetrahydroxystilbene-2-O-ß-D-glucoside, a major bioactive component from Polygoni multiflori Radix (Heshouwu) suppresses DSS induced acute colitis in BALb/c mice by modulating gut microbiota.

BACKGROUND: Inflammatory bowel disease (IBD) includes ulcerative colitis (UC) and Crohn's disease (CD), which is a common idiopathic digestive disease without a specific cure or treatment for improvement. Because Polygoni multiflori Radix has a traditional medicinal use to treat intestinal diseases, and the water extract of this herbal medicine had a positive influence on dextran sulfate sodium (DSS) induced UC model in our study. Meanwhile 2,3,5,4'-tetrahydroxystilbene-2-O-ß-D-glucoside (TSG) as the major component of the water extract of Polygoni multiflori Radix with yield of more than 10% exhibited the remarkable anti-inflammatory activity in vivo and in vitro, we predicted that TSG may contribute to benefit intestinal tract presented by the water extract of Polygoni multiflori Radix. Therefore, the present study aims to explore the pharmacological effect of this compound on UC model and its possible mechanism to regulate intestinal function through gut microbiota. METHODS: Ulcerative colitis model was established in BALb/c mice by continuously administrating 3% (w/v) DSS aqueous solution for one week. The disease activity index (DAI), colon length, histopathological examination by H&E and the levels of tight junction proteins (TJP) by immunofluorescence staining were performed in ulcerative colitis model following the protocol. Furthermore, the levels of main inflammatory factors like TNF-α, IL-ß, IL-6, and IL-10 were analyzed by the ELIZA kits for the further confirmation of anti-inflammatory activity of TSG on ulcerative colitis model. Finally, 16S rDNA sequencing technology was conducted to explore the composition and relative abundance of gut microbiota of different treatment groups. RESULTS: TSG treatments effectively increased body weight about 5% of those in DSS group (p < 0.001) as well remarkably reduced the DAI scores to the 50% of those in DSS group (p < 0.001) in the UC model. TSG treatments of either 25 mg/kg (TSG-25) or 100 mg/kg (TSG-100) dosage restored epithelial barrier structure and exhibited obviously intact colon histology with reduced signs of inflammatory cells infiltration, preserved epithelia barrier, restored crypt structure, and increased numbers of goblet cells. TSG treatments could markedly lessen the histopathologic score two or three times than those in DSS group (p < 0.001). Especially for TSG-100 treatment, the fluorescence intensity of ZO-1 and Occludin were nearly back to 80% of those in normal group, and were 1.5 times more than those in the DSS group (p < 0.001). Additionally, direct evidence pointed to TSG as a therapeutically active molecule in the prevention and treatment of UC by significantly reducing the production of these pro-inflammatory cytokines like TNF-α, IL-1ß, and IL-6 (p < 0.05-0.001) and increasing the levels of anti-inflammatory cytokine IL-10 (p < 0.05-0.001). Finally, it was found TSG treatments significantly raised the relative abundances of Firmicutes and Bacteroidetes with a dose-dependently and improved the homeostasis of the gut microbiota composition which disrupted by DSS through increasing genus level Lachnospiraceae_NK4A136 and decreasing genus level of Helicobacter, Bacteroides, Parabacteroides. CONCLUSION: The present results suggested that TSG treatments had a desirable pharmacological effect on acute colitis induced by DSS in the mice as well showed the possible mechanism relate to improve the intestinal function through balancing the gut microbiota of intestinal flora.