Rosamultin from Potentilla anserine L. exhibits nephroprotection and antioxidant activity by regulating the reactive oxygen species/C/EBP homologous protein signaling pathway.

Rosamultin, a major bioactive constituent from Potentilla anserine L., has antioxidative and hepatoprotective activities. However, its protective effects on cisplatin-induced acute renal injury and the underlying mechanisms remain elusive. In this work, rosamultin could enhance the viability of HEK293 cells treated by cisplatin. In vivo experiment showed that rosamultin effectively decreased kidney index, reduced blood urea nitrogen level, decreased urinary protein excretion, and ameliorated the histopathological damage and fibrosis of renal tissue induced by cisplatin. Besides, rosamultin showed no obvious toxicity in mice. SILAC-based quantitative proteomic analysis identified 4,461 proteins and eight proteins including C/EBP homologous protein (CHOP) were markedly decreased in cisplatin-treated HEK293 cells when exposed to rosamultin. Biochemical experiments further discovered that rosamultin could inhibit p38 and JNK activation, and downregulate the levels of CHOP and proteins in its upstream PERK-eIF2α-ATF4 signaling pathway stimulated by cisplatin or tunicamycin. At the same time, rosamultin reduced the generation of intracellular ROS induced by cisplatin and enhanced the activities of antioxidant enzymes such as SOD, GSH, and CAT. Moreover, rosamultin markedly suppressed the expression of CHOP, apoptosis-associated proteins, and activation of p38 and JNK in renal tissue. These findings suggest that rosamultin might be a potential protectant against cisplatin-induced nephrotoxicity.

Optimal target saturation of ligand-blocking anti-GITR antibody IBI37G5 dictates FcγR-independent GITR agonism and antitumor activity.

Glucocorticoid-induced tumor necrosis factor receptor (GITR) is a co-stimulatory receptor and an important target for cancer immunotherapy. We herein present a potent FcγR-independent GITR agonist IBI37G5 that can effectively activate effector T cells and synergize with anti-programmed death 1 (PD1) antibody to eradicate established tumors. IBI37G5 depends on both antibody bivalency and GITR homo-dimerization for efficient receptor cross-linking. Functional analyses reveal bell-shaped dose responses due to the unique 2:2 antibody-receptor stoichiometry required for GITR activation. Antibody self-competition is observed after concentration exceeded that of 100% receptor occupancy (RO), which leads to antibody monovalent binding and loss of activity. Retrospective pharmacokinetics/pharmacodynamics analysis demonstrates that the maximal efficacy is achieved at medium doses with drug exposure near saturating GITR occupancy during the dosing cycle. Finally, we propose an alternative dose-finding strategy that does not rely on the traditional maximal tolerated dose (MTD)-based paradigm but instead on utilizing the RO-function relations as biomarker to guide the clinical translation of GITR and similar co-stimulatory agonists.

Ginsenoside Rb1 is an immune-stimulatory agent with antiviral activity against enterovirus 71.

ETHNOPHARMACOLOGICAL RELEVANCE: According to the theory of traditional Chinese medicine, the main pathogenesis of severe hand, foot and mouth disease (HFMD) is that the heat and wet poisons are deeply trapped in the viscera, which causes the deficiency of Qi and Yin in the patient's body. Ginsenoside Rb1 (Rb1) is the most abundant triterpenoid saponin in Panax quinquefolius L., which has the function of Qi-invigorating and Yin-nourishing. Enterovirus 71 (EV71) is one of the causative pathogens of HFMD, especially the form associated with some lethal complications. Therefore, the therapeutic effect of Rb1 on this disease caused by EV71 infection is worth exploring. AIM OF THE STUDY: We explored the effective antiviral activities of Rb1 against EV71 in vitro and in vivo and investigated its preliminary antiviral mechanisms. MATERIAL AND METHODS: EV71-infected two-day-old suckling mice model was employed to detect the antiviral effects of Rb1 in vivo. To detect the antiviral effects of Rb1 in vitro, cytopathic effect (CPE) reduction assay was performed in EV71-infected Rhabdomyosarcoma (RD) cells. Interferon (IFN)-ß interference experiment was employed to detect the antiviral mechanism of Rb1. RESULTS: In this paper, we first found that Rb1 exhibited strong antiviral activities in EV71-infected suckling mice when compared to those of ribavirin. Administration of Rb1 reduced the CPE of EV71-infected RD cells in a dose-dependent manner. Moreover, EV71-induced viral protein-1 (VP-1) expression was significantly reduced by Rb1 administration in vitro and in vivo. Furthermore, Rb1 treatment could induce high cellular and humoral immune responses in vivo. Meanwhile, Rb1 contributed to the enhanced Type I IFN responses and IFN-ß knockdown reversed the antiviral activity of Rb1 in vitro. CONCLUSION: In summary, our findings suggest that Rb1 is an immune-stimulatory agent and provide an insight into therapeutic potentials of Rb1 for the treatment of EV71 infection.

Anemoside B4 attenuates nephrotoxicity of cisplatin without reducing anti-tumor activity of cisplatin.

BACKGROUND: Cisplatin is a highly effective chemotherapeutic agent commonly used in the treatment of a wide variety of malignancies. However, its clinical usage is severely limited by its serious side effects, especially nephrotoxicity. Anemoside B4, is a major saponins, rich in root of Pulsatilla chinensis (Bunge), has anti-inflammation in vitro. However, the antioxidant or anti-inflammatory effects of anemoside B4 in cisplatin-induced nephrotoxicity have not been clearly demonstrated. PURPOSE: In this study, we investigated whether anemoside B4 exhibits protective effects against cisplatin-induced nephrotoxicity involving antioxidant or anti-apoptosis effects. METHOD: To clarify it, the effects of anemoside B4 on HEK 293 cell viability was measured by CCK8 kits, intracellular antioxidant capacity including glutathione reduced (GSH), catalase (CAT) were estimated using chemical kits, apoptosis rate and intracellular reactive oxygen species (ROS) was analyzed by flow cytometry, apoptosis protein was measured by western blotting. In vivo model of cisplatin-induced mice acute renal failure was performed to evaluate the properties of anemoside B4. Besides, to evaluate the effect of anemoside B4 on the anti-tumor activity of cisplatin, S180 xenograft models were used. RESULTS: Anemoside B4 potently increased cisplatin-treated HEK 293T cells viability on the concentration and time manners and inhibited cells apoptosis, as demonstrated by the decreased cleaved PARP protein expressions. Anemoside B4 decreased reactive oxygen species (ROS) content and improved superoxide dismutase (SOD) activity. In vivo experiment showed that pretreatment with anemoside B4 effectively adjusted body weight and kidney index, and reduced cisplatin-elevated blood urea nitrogen (BUN) and creatinine (CREA) levels, as well as ameliorated the histopathological damage. Further studies showed that anemoside B4 did not reduce antitumor activity of cisplatin in murine S180 cancer xenograft tumor models. In addition, anemoside B4 per set showed low toxicity in mice. CONCLUSION: The strong antioxidant and anti-apoptosis effects of anemoside B4 may provide therapeutic potential for cisplatin-induced nephrotoxicity without compromising its therapeutic efficiency.

Two new xanthones from the pericarp of Garcinia mangostana.

Two new xanthones, designated garcimangosxanthone F (1) and garcimangosxanthone G (2), were isolated from the EtOAc-soluble fraction of ethanolic extract from the pericarp of Garcinia mangostana. Their structures were established as 1,6,7-trihydroxy-5-(3-methylbut-2-enyl)-8-(3-hydroxy-3-methylbutyl)-6',6'-dimethylpyrano[2',3':3,2]xanthone and 1,6,7-trihydroxy-5-(3-methylbut-2-enyl)-8-(3-hydroxy-3-methylbutyl)-6',6'-dimethyl-4',5'-dihydropyrano[2',3':3,2]xanthone, respectively, on the basis of their 1D, 2D NMR and MS data interpretation.

Analysis of clinical and pathological features of minimal deviation adenocarcinoma of the ;cervix / 中国医师进修杂志

Objective To analyze the clinical and pathological data of the minimal deviation adenocarcinoma (MDA) of the cervix, and to provide evidence based medicine for diagnosis and treatment. Methods Clinical case reports about MDA or malignant adenoma during 1980-2014 published on CNKI, WanFang, CBM, WeiPu and Medline were retrieved and combined with 2 case with the same diagnosis and treatment. Results Age of onset was 20-86 years old, and the average age was 44.8 years, with median age of 44.5 years. Clinical symptoms of MDA showed massive vaginal apocenosis or irregular bleeding. Gynecological examination common showed cervical hypertrophic and harden. The positive rate of cervical cytology examination was 9.73% (11/113). MDA diagnosed by cervical biopsy and conization accounted for 58.38% (108/185). Immunohistochemical showed that the positive rates of carcinoembryonic antigen, P53 and Ki-67 were 93.91%(108/115), 75.44%(43/57)and 100.00% (42/42). Main operation assisted with postoperative radiotherapy and chemotherapy, early diagnosis, clinical stage and operation methods played important roles in the prognosis. Conclusions The clinical symptoms and physical signs are not obvious for MDA which is difficult to diagnose, so it is easy to diagnose mistakenly and misdiagnose also. The positive rate of cervical cytology is usually lower, repeated and deep cervical biopsy or conization combined with immunohistochemistry can improve the accuracy of diagnosis. The individualized treatment should be selected according to clinical stage for the patients who were confirmed preoperatively.

A case-control study on the mxA polymorphisms and susceptibility to severe acute respiratory syndromes / 中华流行病学杂志

<p><b>OBJECTIVE</b>To investigate the association between the genetic polymorphisms of myxovirus resistance 1 (MxA) gene and susceptibility to severe acute respiratory syndromes (SARS).</p><p><b>METHODS</b>A case-control study was conducted and polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was used to detect the T/G polymorphism at position-88 in the mxA gene promoter. Information on related factors of SARS was collected using a pre-testing questionnaire. Univariate and multivariate logistic analyses were conducted with SPSS software package.</p><p><b>RESULTS</b>Sixty-six cases and sixty-four controls were selected for the study. Comparing with GG genotype, the proportion of GT genotype were significantly higher in the case group (81.3%) than that in the control group (62.5%)) with an OR (95% CI) of 2.700 (1.208-6.037). Multivariate logistic regression analysis revealed that the significant association remained after factors as wearing masks, protection gowns and eye-protection when contacting with SARS patient etc. were adjusted with an OR (95 % CI) of 2.911 (1.027-8.250).</p><p><b>CONCLUSION</b>mxA promoter-88G/T SNP might be confered to host genetic susceptibility to SARS in Chinese Han population.</p>