Fecal microbiota transplantation combined with prebiotics ameliorates ulcerative colitis in mice.

Aim: To investigate the effect of treatment with fecal microbiota transplantation (FMT) and galacto- and fructo-oligosaccharides on ulcerative colitis (UC) in mice. Materials & methods: A total of 90 mice, divided into nine groups, were administered FMT or prebiotics or combined treatment. The disease activity index scores, gut microbiota and inflammation factors were evaluated. Results: The treatment using FMT combined with galacto- and fructo-oligosaccharides in a 9:1 ratio significantly reduced intestinal barrier damage and alleviated symptoms of UC. Lactobacillus and Bifidobacterium and short-chain fatty acids were significantly increased after the combined treatment. Conclusion: The results demonstrate that FMT with prebiotics is a new method for UC treatment.

Changes in the bacteria that live in the human gut can cause ulcerative colitis, a type of inflammatory disease in the bowel. Using mice, we investigated two possible treatments for ulcerative colitis: fecal microbiota transplantation, in which a sample of feces is taken from a healthy donor, processed and transferred to someone else; and prebiotics, a nondigestible food ingredient that encourages the growth of good bacteria in the gut. We found that the combination of prebiotics with fecal microbiota transplantation can improve symptoms and change the bacteria in the intestines and improves the uptake of nutrients.

Dominant negative TGFß receptor II and truncated TIM3 enhance the antitumor efficacy of CAR-T-cell therapy in prostate cancer.

BACKGROUND: The immune checkpoint molecules, Transforming growth factor beta receptor II (TGFßRII) and T cell immunoglobulin and mucin domain 3 (TIM3), have been identified as contributors to T cell immune suppression in prostate cancer. The objective of this investigation was to improve the tumor killing capability of prostate-specific membrane antigen (PSMA)-chimeric antigen receptor T (CAR-T) cells by targeting TIM3 and TGFßRII simultaneously. METHODS: To generate dnTGFßRII-trTIM3-PSMA-CAR-T (DT-PSMA-CAR-T) cells, the surface of PSMA-CAR-T cells was overexpressed with dominant negative TGFßRII (dnTGFßRII) and truncated extracellular TIM3 (trTIM3). The efficacy of DT-PSMA-CAR-T cells was assessed through in vitro killing experiments and animal experiments. RESULTS: The DT-PSMA-CAR-T cells demonstrated the ability to eradicate PSMA-positive prostate cancer cells, even in the presence of exogenous TGF-ß and/or TIM3 activating antibodies. In addition, the cells demonstrated the ability to eliminate tumor tissue in an immunodeficient mouse model transplanted with GAL9-PSMA-PC3 cells in vitro, prolonging survival without significant toxic side effects. CONCLUSIONS: This study emphasizes that upregulating dnTGFßRII and trTIM3 on the surface of T cells can potentially diminish the inhibitory effects of TGFßRII and TIM3.

Analysis of gut microbiota in patients with acute myocardial infarction by 16S rRNA sequencing.

Background: An increasing number of studies have shown that gut microbiota are associated with human cardiovascular disease, but the characteristics of intestinal flora in patients with acute myocardial infarction (AMI) are still unclear. In this study, we aimed to investigate the difference of intestinal microflora between patients with AMI and healthy people, and to find the effect of percutaneous coronary intervention (PCI) on intestinal microflora. Methods: A total of 60 stool samples and 60 peripheral blood samples were collected from 20 previously diagnosed AMI patients and 20 healthy people serving as controls. Gut microbiota communities were analyzed via 16 ribosomal RNA-sequencing (16S rRNA). Gut microbiota-derived metabolites, trimethylamine N-oxide (TMAO) and short-chain fatty acids (SCFA), in the blood were detected using stable isotope dilution high-performance liquid chromatography with on line electrospray ionization tandem mass spectrometry (LC/MS/MS). Results: The results showed that a distinct pattern of gut microbiota was observed in AMI patients compared to healthy controls. AMI patients had lower microbiological richness but no significant change in diversity. Bacteroidetes and Verrucomicobia showed an upward trend, whereas Proteobacteria showed a downward trend in AMI patients. During a longitudinal study to compare the changes in bacteria before and after treatment, we found routine cardiac admission therapy 1 week after PCI surgery had no effect on the microbial community structure in patients. There were significantly higher levels of plasma TMAO in AMI patients' microbiota than that in the control group. Contrarily, there was no obvious change in SCFA. Conclusions: The gut microbiota of patients with AMI differs from that of normal people, and the metabolic products of microflora are more abundant in the plasma of AMI than control cases. Microflora may act on the cardiovascular system through metabolites, and regulation of the microfloral structure may be used in the future treatment of cardiovascular diseases.

Design, synthesis, and biological evaluation of a novel indoleamine 2,3-dioxigenase 1 (IDO1) and thioredoxin reductase (TrxR) dual inhibitor.

Targeting the Trp-Kyn pathway is an attractive approach for cancer immunotherapy. Thioredoxin reductase (TrxR) enzymes are reactive oxygen species (ROS) modulators that are involved in the tumor cell growth and survival processes. The 4-phenylimidazole scaffold is well-established as useful for indoleamine 2,3-dioxygenase 1 (IDO1) inhibition, while piperlongumine (PL) and its derivatives have been reported to be inhibitors of TrxR. To take advantage of both immunotherapy and TrxR inhibition, we designed a first-generation dual IDO1 and TrxR inhibitor (ZC0101) using the structural combination of 4-phenylimidazole and PL scaffolds. ZC0101 exhibited better dual inhibition against IDO1 and TrxR in vitro and in cell enzyme assays than the uncombined forms of 4-phenylimidazole and PL. It also showed antiproliferative activity in various cancer cell lines, and a selective killing effect between normal and cancer cells. Furthermore, ZC0101 effectively induced apoptosis and ROS accumulation in cancer cells. Knockdown of TrxR1 and IDO1 expression induced cellular enzyme inhibition and ROS accumulation effects during ZC0101 treatment, but only reduced TrxR1 expression was able to improve ZC0101's antiproliferation effect. This proof-of-concept study provides a novel strategy for cancer treatment. ZC0101 represents a promising lead compound for the development of novel antitumor agents that can also be used as a valuable probe to clarify the relationships and mechanisms of cancer immunotherapy and ROS modulators.

Tanshinone IIA Ameliorates Streptozotocin-Induced Diabetic Nephropathy, Partly by Attenuating PERK Pathway-Induced Fibrosis.

PURPOSE: Tanshinone IIA (Tan IIA), a compound extracted from Salvia miltiorrhiza, can improve type II diabetes, while the molecular mechanisms underlying Tan IIA-mediated protective effects in diabetic nephropathy are unclear. This study explored the protective actions of Tan IIA on renal tissues in streptozotocin (STZ)-induced diabetic nephropathy. MATERIALS AND METHODS: Tan IIA (2, 4, 8 mg/kg/day) was daily administered to STZ-treated rats by intraperitoneal injection for 42 days. The morphologic pathology was evaluated by hematoxylin-eosin and Masson's trichrome staining, and transmission electron microscopy. The protein expression levels in renal tissues were evaluated by Western blotting and immunohistochemistry; the mRNA expression level was determined by quantitative real-time PCR. RESULTS: Tan IIA at 2 and 4 mg/kg attenuated the increase in the levels of uric acid and blood urea nitrogen and restored the reduction in the superoxide dismutase activity in the serum of the diabetic rats. Tan IIA at 2 and 4 mg/kg, but not 8 mg/kg, ameliorated the thickening of renal tubule in the diabetic rats; Tan IIA at 2 and 4 and 8 mg/kg attenuated the thickening of glomerular basement membrane and the collagen deposition in the renal tissues of the diabetic rats. Tan IIA treatment at 2, 4, 8 mg/kg decreased the expression levels of transforming growth factor-beta1, TSP-1, Grp78 and CHOP in the diabetic rats. Tan IIA at 2 and 4 and 8 mg/kg attenuated the increase in the protein levels of p-PERK, p-elf2α and ATF-4 from the renal tissues of diabetic rats, while the protein level of AFT-6 and the mRNA expression levels of XBP-1t, XBP-1s and p58IPK in the renal tissues were not affected by STZ or Tan IIA treatment. CONCLUSION: Tan IIA-mediated protective effects on the STZ-induced diabetic nephropathy may be associated with the reduced endoplasmic reticulum stress via attenuating PERK signaling activities.

Piperlongumine Inhibits Akt Phosphorylation to Reverse Resistance to Cisplatin in Human Non-Small Cell Lung Cancer Cells via ROS Regulation.

Resistance is a major concern when administering chemotherapy to patients with non-small cell lung cancer (NSCLC). Chemosensitizer are agents that can reverse resistance to chemotherapeutic drugs, thereby enhancing the chemosensitivity of tumor cells. Thus, their development will improve therapeutic efficacy in cancer. However, few effective chemosensitizer have been identified to date. Piperlongumine (PL) has been shown to effectively reverse resistance to chemotherapeutic drugs in several types of cancers. However, the mechanisms associated with the chemotherapy resistance reversal effect of PL and its regulation of target factors in chemotherapy resistance cells are still unclear. This study investigated the reversal effect of PL both in vitro and in vivo, and provided evidence that PL inhibited the phosphorylation of Akt via the accumulation of reactive oxygen species in chemotherapy resistance cells. Consequently, various Akt activation-dependent genes caused a reduction of drug efflux and induction of apoptosis in cisplatin-resistant A549 NSCLC cells. Our results indicate that Akt phosphorylation may play a functional role in the reversal effect of PL and contribute, at least in part, to the treatment outcomes of patients with chemotherapy resistance.

Shape-based virtual screen for the discovery of novel CDK8 inhibitor chemotypes.

With the aim of discovering novel cyclin-dependent kinase 8 (CDK8) inhibitors, a combined similarity search and molecular docking approach was employed, which led to 32 hits. Biological tests led to the discovery of several novel submicromolar inhibitors. In particular, compound C768-0769 (ZC0201) showed good CDK8 inhibitory activity, and compound ZC0201 effectively suppressed HCT-116 colorectal cancer cell proliferation by inducing G1/S transition arrest. Furthermore, modulation of phosphorylated signal transducer and activator of transcription 1 (Ser 727) (STAT1SER727), a pharmacodynamic biomarker of CDK8 activity, demonstrated that ZC0201 may cause G1/S transition arrest through CDK8 activity inhibition. Due to its good cellular activity, ZC0201 may be an ideal lead compound for further modification as a potential cancer therapeutic agent.

Nrf2 is a key factor in the reversal effect of curcumin on multidrug resistance in the HCT­8/5­Fu human colorectal cancer cell line.

Multidrug resistance (MDR) is a major concern when using chemotherapy for the treatment of patients with colorectal cancer. MDR modulators are agents that can reverse MDR and, thus, enhance the chemosensitivity of tumor cells. The development of MDR modulators can improve the therapeutic efficacies of MDR in cancer. However, few effective MDR modulators have been identified so far. Curcumin has been reported to be an effective compound in the reversal of MDR in colorectal cancer cells. However, the mechanisms associated with the reversal effect of curcumin on MDR and its regulation of target factors in MDR cells remain to be fully elucidated. 3­(4,5­dimethyl­2­thiazol)­2,5­diphenyltetrazolium bromide assays, flow cytometer apoptosis assays as well as mRNA and protein expression assays were performed in the present study, and the results confirmed the reversal effect of curcumin on HCT­8/5­Fu cells and provided evidence that activated nuclear factor erythroid 2­related factor (Nrf2) deficiency induced by the curcumin altered the B­cell lymphoma 2 (Bcl­2) associated X protein/Bcl­2 expression ratio, which led to the induction of apoptosis in HCT­8/5­Fu cells. These results indicated that Nrf2 may have a functional in the reversal effect of curcumin and contribute, at least in part, to the outcomes of chemotherapy in patients with MDR.

Bis(5-amino-4-amino-carbonyl-1H-imid-azol-3-ium) (5-amino-4-amino-carbonyl-1H-imidazol-3-ium-κO)-di-µ-chlorido-hepta-chlorido-dibismuth(III) mono-hydrate.

The title compound, (C(4)H(7)N(4)O)(2)[Bi(2)Cl(9)(C(4)H(7)N(4)O)]·H(2)O, was prepared by the reaction of bis-muth trichloride and 5-amino-1H-imidazole-4-carboxamide in a dilute HCl medium. The asymmetric unit contains two 5-amino-4-amino-carbonyl-1H-imidazol-3-ium cations, one edge-shared non-centrosymmetric biocta-hedral [Bi(2)C1(9)(C(4)H(7)N(4)O)](2-) dianion and a water mol-ecule. In the dianion, the planar 5-amino-4-amino-carbonyl-1H-imidazol-3-ium ligand occupies an equatorial site and is inclined at an angle of 75.7 (2)° to the Bi(2)(µ-C1)(2) plane. The salt forms a three-dimensional network arising from hydrogen bonds between cations, anions and water mol-ecules.