Background and AimFunctional dyspepsia (FD) is characterized by chronic and unexplained indigestion at upper abdomen. Because of unsatisfactory effect of conventional treatments, demand is growing for complementary and alternative medicine. Rikkunshito (RKT) is a herbal medicine, which has been widely used for FD in Asia; however, the evidence is lacking. We carried out systematic review and meta‐analysis to evaluate the effect and safety of RKT in the treatment of FD.MethodsElectronic databases were searched in April 2019, including PUBMED, EMBASE, and Cochrane Library. All eligible studies should be randomized controlled trials (RCTs) comparing RKT or combination therapy (RKT and western medicine) group to western medicine group. The primary outcome measure was the total clinical efficacy rate (TCE). The secondary outcomes were total dyspepsia symptom scale, gastric emptying rate, gastrin, motilin, recurrence 6 months after treatment, and Hamilton depression rating scale.ResultsFifty‐two RCTs with 5475 patients were involved in this systematic review and meta‐analysis. Compared with western medicine, RKT showed significant better result, with higher TCE (relative risk = 1.21, 95% confidence interval 1.17 to 1.25, P < 0.001). RKT presented higher reduction of total dyspepsia symptom scale, more improved gastric emptying rate, and lower recurrence 6 months after treatment compared with western medicine. However, there was no significant difference in Hamilton depression rating scale between RKT and western medicine group. Combination therapy brought significant symptom improvement with TCE compared with western medicine alone.ConclusionsRikkunshito and combination therapy might be considered an effective alternative treatment for FD. Further rigorously designed and high‐quality RCTs are needed.

Polyene macrolides such as nystatin A1 and amphotericin B belong to a large family of very valuable antifungal polyketide compounds typically produced by soil actinomycetes. Recently, nystatin-like Pseudonocardia polyene (NPP) A1 has been identified as a unique disaccharide-containing tetraene antifungal macrolide produced by Pseudonocardia autotrophica. Despite its significantly increased water solubility and decreased hemolytic activity, its antifungal activity remains limited compared with that of nystatin A1. In this study, we developed NPP B1, a novel NPP A1 derivative harboring a heptaene core structure, by introducing two amino acid substitutions in the putative NADPH-binding motif of the enoyl reductase domain in module 5 of the NPP A1 polyketide synthase NppC. The low level NPP B1 production yield was successfully improved by eliminating the native plasmid encoding a polyketide biosynthetic gene cluster present in P. autotrophica. In vitro and in vivo antifungal activity and toxicity studies indicated that NPP B1 exhibited comparable antifungal activity against Candida albicans and was less toxic than the most potent heptaene antifungal, amphotericin B. Moreover, NPP B1 showed improved pharmacokinetic parameters compared to those of amphotericin B, suggesting that NPP B1 could be a promising candidate for development into a pharmacokinetically improved and less-toxic polyene antifungal antibiotic.

The precise mechanisms of resistance to camptothecin (CPT)-derived DNA topoisomerase (topo I) inhibitors and the determinants remain unclear. We found that a DNA repair protein, O 6 -methylguanine-DNA methyltransferase (MGMT), participated in resistance to irinotecan hydrochloride (CPT-11), its active metabolite SN-38, and a novel CPT derivative, DX-8951f. In 17 human cancer cell lines, MGMT gene expression level closely correlated with sensitivity to the CPT derivatives, and inhibition of MGMT activity by nontoxic 5 µ µ µ µM O 6 -benzylguanine augmented the drug activity in relation to the MGMT expression levels in 8 cell lines examined. Transfection of pCR/MGMTsense into U-251MG and pCR/MGMT-antisense into T98G and HEC-46 cells revealed that increased MGMT expression decreased the sensitivity to CPT-11, SN-38, and DX-8951f, whereas repressed MGMT expression sensitized cells to the drugs. Western analysis revealed that treatment of MGMT-expressing T98G cells with the drugs caused a decrease of both MGMT and topo I in a dose-dependent manner. Although, in the transfectants, MGMT expression did not so closely correlate with the sensitivity to drugs as to nimustine hydrochloride (ACNU), MGMT is probably an important resistance determinant to CPT derivatives, and may play some role in the topo Imediated DNA damage and/or the repair process.

The Janus kinase (JAK) family comprises four members (JAK1, JAK2, JAK3, and Tyk2) that play a key role in mediating cytokine receptor signaling. JAK inhibition thus modulates cytokine-mediated effects. In particular, selective inhibition of JAK1 or JAK3 may provide an efficient therapeutic agent for the treatment of inflammatory diseases, with minimized side effects. In this study, as part of our continued efforts to develop a selective JAK1 inhibitor, a series of 1,2-disubstituted benzimidazole-5-carboxamide derivatives was prepared and their inhibitory activities against all four JAK isozymes were evaluated. A clear structure-activity relationship was observed with respect to JAK1 selectivity; this highlighted the importance of hydrogen bond donors at both N(1) and R2 positions located within a specific distance from the benzimidazole core. One of the synthesized compounds, 1-(2-aminoethyl)-2-(piperidin-4-yl)-1H-benzo[d]imidazole-5-carboxamide (5c), showed remarkable JAK1 selectivity (63-fold vs JAK2, 25-fold vs JAK3, and 74-fold vs Tyk2). Molecular docking revealed that the 2-aminoethyl and piperidin-4-yl substituents of 5c function as probes to differentiate the ATP-binding site of JAK1 from that of JAK2, resulting in preferential JAK1 binding. A kinase panel assay confirmed the JAK1 selectivity of 5c, which showed no appreciable inhibitory activity against 26 other protein kinases at 10 μM.

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