Picroside II alleviates DSS-induced ulcerative colitis by suppressing the production of NLRP3 inflammasomes through NF-κB signaling pathway.

CONTEXT: Ulcerative colitis (UC) is a common acute or chronic intestinal disease with an imbalance of inflammation. Picroside II (P-II) exerts a protective role in various inflammation-related diseases. However, the effect of P-II on UC is still unclear. OBJECTIVE: To explore the effect of P-II on UC and its potential mechanism. MATERIALS AND METHODS: Human monocytic leukemia cell line THP-1 was treated with phorbol ester (PMA) to differentiate into a macrophage. The differentiated THP-1 cells were hatched with LPS combined with ATP or Nigericin to activate the NLRP3 inflammasome in vitro. The UC model was constructed by injection of DSS into mice. RESULTS: The maximum nontoxic concentration of P-II on THP-1 cells was 60 µM. LPS combined with ATP or Nigericin stimulated the production of IL-1ß, which was antagonized by P-II treatment. Meanwhile, P-II administration interfered with the aggregation of ASC and the assembly of NLRP3 inflammasomes. Also, P-II treatment reduced the LPS and ATP-induced elevation of the relative protein expression of NLRP3, pro-caspase-1, IL-1ß and p-p65/p65, and the concentration of TNF-α and IL-6. Besides, the NF-κB specific inhibitor BAY-117082 notably repressed the LPS together with ATP-enhanced the relative protein expression of NLRP3, caspase-1 and IL-1ß. Moreover, in vivo results showed that P-II relieved the DDS-induced UC, as evidenced by the improvement of mice weight, DAI and pathological scores. In addition, P-II treatment notably decreased DDS-promoted expression of NLRP3 inflammasomes and inflammatory factors in vivo. CONCLUSION: P-II alleviated DSS-induced UC by repressing the production of NLRP3 inflammasomes via the NF-κB signaling pathway.

Identification and Characterization of Small-Molecule Inhibitors to Selectively Target the DFG-in over the DFG-out Conformation of the B-Raf Kinase V600E Mutant in Colorectal Cancer.

V600E is the most common mutation in the B-Raf kinase domain and the B-RafV600E mutant has been recognized as an attractive target of colorectal cancer. Here, the structural dynamics of V600E-induced conformational conversion in the B-Raf activation loop (A-loop) was characterized in detail using a computational simulation strategy. The simulations revealed that the V600E mutation would induce A-loop flipping from DFG-out to DFG-in, and the approved B-Raf inhibitor vemurafenib exhibits strong selectivity for the mutant over the wild-type kinase. The selectivity is closely associated with the kinase conformation, which can be influenced directly by the V600E mutation. The molecular structure of vemurafenib was applied to a chemical similarity search against a large library of drug/lead-like compounds, from which three hits with high structural similarity were identified, and their inhibitory activities against both the wild-type and mutant kinases were measured by in vitro kinase assay, from which two compounds were determined to possess higher selectivity for the B-RafV600E mutant than for the wild type (5.2- and 3.1-fold, respectively). They can potently inhibit the kinase mutant with IC50 = 54 and 76 nM, respectively. Structural analysis suggested that specific noncovalent interactions play a crucial role in the selectivity of B-Raf inhibitors.

Matrine protects against DSS-induced murine colitis by improving gut barrier integrity, inhibiting the PPAR-α signaling pathway, and modulating gut microbiota.

Matrine is a naturally occurring quinolizidine alkaloid with various bioactivities. However, little is known of its function on ulcerative colitis (UC). Here, we investigated the effect and underlying mechanisms of matrine on dextran sulfate sodium (DSS)-induced UC mice. In this study, different concentrations of matrine were given to mice with DSS-induced colitis for a week. The symptoms of colitis, colonic pathology, inflammation-related indicators, and intestinal mucosal barrier function were detected and analyzed. Moreover, RNA-seq analysis in colon tissues was conducted, and 16S rDNA sequencing was carried out to evaluate the gut microbiota of colon contents. The results showed that matrine significantly alleviated clinical activity and histological changes of UC mice, inhibited the production of the pro-inflammatory cytokines, and improved gut barrier integrity. Moreover, RNA-seq analysis and experimental verification showed that matrine significantly inhibited the peroxisome proliferator-activated receptor-α (PPAR-α) signaling pathway. 16S rDNA sequencing revealed that matrine altered the composition and functions of gut microbiota, increased the abundance of Barnesiella intestinihominis and decreased the abundance of Helicobacter ganmani at the species level. In conclusion, matrine ameliorated DSS-induced colitis by improving gut barrier integrity, inhibiting the PPAR-α signaling pathway, and modulating gut microbiota. These suggested that matrine may be a therapeutic agent for UC treatment.

miR-1271 enhances the sensitivity of colorectal cancer cells to cisplatin.

The high mortality of colorectal cancer (CRC) is likely caused by early invasion and metastasis. The chemoresistance of tumor cells is the critical reason for treatment failure. The present study aimed to develop targeted solutions to overcome chemotherapy drug resistance in CRC. CCK-8 assay was used to examine SW480 cell viability. SW480 cell apoptosis was examined using flow cytometry. The present study demonstrated that the expression of miR-1271 was significantly decreased in CRC tumors and cell lines compared with control tissues. Furthermore, the expression of microRNA (miR)-1271 was increased and decreased following the transfection of miR-1271 mimics and an inhibitor, respectively. Furthermore, miR-1271 regulated mammalian target of rapamycin (mTOR) expression by directly binding to the mTOR 3'-untranslated region and the relative luciferase activity of mTOR was decreased following miR-1271 overexpression. The results of the present study indicate that miR-1271 may be a potential target for anti-CRC therapy, particularly in the sensitivity of chemotherapeutic drugs. miR-1271 may therefore enhance the sensitivity of CRC cells to chemotherapy drugs and provide a novel approach for the gene therapy of CRC.

Curcumin prevents the non-alcoholic fatty hepatitis via mitochondria protection and apoptosis reduction.

BACKGROUND: Non-alcoholic fatty hepatitis (NASH) is highly prevalent, mitochondria damage is the main pathophysiological characteristic of NASH. However, treatment for mitochondria damage is rarely reported. METHODS: NASH model was established in rats, the protective effects of curcumin were evaluated by histological observation; structure and function assessments of mitochondria; and apoptotic genes expression. RESULTS: NASH rats treated with curcumin displayed relatively slight liver damage when compared with NASH livers. The average mitochondrial length and width of NASH (12.0 ± 3.2 and 5.1 ± 1.1 micrometers) were significantly longer than that of normal (6.2 ± 2.1 and 2.1 ± 1.5 micrometers) and NASH treated with curcumin (7.4 ± 1.2 and 3.2 ± 1.5 micrometers) rats. The average malondialdehyde (MDA) and 4-hydroxy nonyl alcohol (HNE) levels in liver homogenates of NASH rats (4.23 ± 0.22 and 19.23 ± 2.3 nmol/Ml) were significantly higher than these in normal (1.32 ± 0.12 and 3.52 ± 0.43 nmol/mL) and NASH treated with curcumin (1.74 ± 0.11 and 4.66 ± 0.99 nmol/mL) rats. The expression levels of CytC, Casp3 and Casp8 of the NASH livers were significantly higher than normal and NASH treated with curcumin rats livers. CONCLUSION: Our data demonstrated that curcumin prevents the NASH by mitochondria protection and apoptosis reduction and provided a possible novel treatment for NASH.