Network pharmacology and molecular docking reveal the immunomodulatory mechanism of rhubarb peony decoction for the treatment of ulcerative colitis and irritable bowel syndrome.

Background: Ulcerative colitis (UC) and irritable bowel syndrome (IBS) share various similarities in clinical symptoms, pathogenesis, and treatment. UC concurrent IBS tends toward more severe symptoms and worse prognosis, and promising feasible therapies for the overlapping symptoms remains a challenge. Rhubarb peony decoction (RPD) is a well-known traditional Chinese medicine that has been widely applied in treating UC. RPD may exert extensive therapeutic effects on both IBS and UC. However, the common mechanism of its treatment remains unclear. We aimed to assess the potential pharmacological mechanism of RPD in the treatment of overlapping IBS and UC. Methods: The active components and targets of RPD were retrieved from ETCM, TCMSP, BATMAN-TCM, and TCM databases. The disease targets were screened by searching the DrugBank, OMIM, TTD, and PharmGKB databases. PPI network analysis was performed and visualized via the STRING platform and Cytoscape software. GO and KEGG enrichment analyses of the hub genes of RPD were predicted to elucidate the potential molecular mechanism. Subsequently, molecular docking was carried out to verify the combination of active compounds with core targets. Results: By integrating all targets of RPD and disease, a total of 31 bioactive ingredients were identified including quercetin, kaempferol, aloe-emodin, beta-sitosterol, and (+)-catechin, etc. JUN, TP53, MAPK1, RELA, MYC, and ESR1 were explored as potential therapeutic targets among 126 common drug-disease-related targets. They were enriched in the AGE-RAGE signaling pathway in diabetic complications, as well as the NF-kappa B signaling pathway and MAPK signaling pathway. Additionally, some active ingredients were identified as candidates for binding to the hub targets via molecular docking, further suggesting their anti-inflammatory and antioxidative properties. Conclusion: RPD may exert the overall treatment effect for UC and IBS overlap syndrome via the biological mechanism of "multi-ingredients, multi-targets, and multi-pathways" on inflammation, oxidative stress, immune, oncogenicity, and gut microbiota dysbiosis.

Chinese medicine formula 'Baipuhuang Keli' inhibits triple-negative breast cancer by hindering DNA damage repair via MAPK/ERK pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Baipuhuang Keli (BPH, constituted by Bai Tou Weng (Pulsatilla chinensis (Bunge) Regel), Pu Gong Ying (Taraxacum mongolicum Hand.-Mazz.), Huang Qin (Scutellaria baicalensis Georgi), Huang Bo (Phellodendron amurense Rupr.)) is a Chinese herbal formula with clearing heat and cooling blood, and removing toxin effects, which is suit for the case of breast cancer. AIM OF THE STUDY: Here, we aim to explore the effects of BPH on triple-negative breast cancer (TNBC) and its potential mechanisms. MATERIALS AND METHODS: In this study, cell viability assay, colony formation assay, soft agar assay, cell proliferation curve assay, and EdU assay were employed to determine the anti-proliferation effect induced by BPH. Cell cycle distribution was detected by flow cytometry. DNA damage in cells treated with BPH was indicated by comet assay, immunofluorescence, and Western Blot. Both the 4T1 orthotopic tumor model and the MDA-MB-231 subcutaneous tumor model were used to assess in vivo effect of BPH (312.5, and 625 mg/kg). The protein expression levels of the DNA damage response (DDR) pathway and the MAPK/ERK pathway were detected by Western Blot. RESULTS: Our results indicated that TNBC cells were more sensitive to BPH than mammary epithelial cells. Cell proliferation of TNBC cells was significantly inhibited by BPH in a dose-dependent manner. Moreover, BPH induced DNA damage in TNBC cells in a concentration and time-dependent manner. DDR of TNBC cells was inhibited by BPH. MAPK/ERK pathway was inhibited in cells treated with BPH, and DNA damage can be reversed while EGF was added to activate MAPK/ERK pathway. The 4T1 orthotopic tumor model and the MDA-MB-231 subcutaneous tumor model further confirmed that BPH inhibited TNBC proliferation via inhibition of DDR and MAPK/ERK pathway in vivo. CONCLUSIONS: Collectively, we proved that BPH is a potential anticancer Chinese herbal formula for TNBC in the manner of in vitro and in vivo experiments.

Effect of hypophosphatemia on prognosis after spontaneous intracerebral hemorrhage: a retrospective study.

OBJECTIVE: Hypophosphatemia often occurs after spontaneous intracerebral hemorrhage, but the effect of hypophosphatemia on its prognosis is under debate. METHODS: Clinical data of patients with spontaneous intracerebral hemorrhage admitted to our neurosurgery department from January 2018 to June 2020 were retrospectively analyzed. The patients were divided into the hypophosphatemia group and the nonhypophosphatemia group according to the serum phosphorus test values obtained three times within 1 week after admission. The incidence of complications during hospitalization, 28-day mortality, and 6-month mRS score were compared between the two groups. The influence of low phosphorus in patients with hypophosphatemia on the 6-month mRS score was explored. RESULTS: A total of 133 patients were included, of which 85 had hypophosphatemia. Forty-two patients (21 in the hypophosphatemia group and 21 in the nonhypophosphatemia group) were enrolled after propensity score matching. There were no statistically significant differences in the incidence of complications during hospitalization, 28-day mortality, and 6-month mRS score between the two groups (P > 0.05). In 85 patients with hypophosphatemia, the minimum serum phosphorus was associated with the 6-month mRS score (B = - 3.153, 95% CI: - 5.842 ~ - 0.463, P = 0.022). The cutoff value of serumphosphorus for predicting 6-month mRS score was 0.505 mmol/l. CONCLUSION: Whether hypophosphatemia occurred during hospitalization in patients with spontaneous intracerebral hemorrhage showed no effect on the incidence of complications, 28-day mortality, and 6-month mRS score. A significant decrease in serum phosphorus during hospitalization (≤ 0.505 mmol/l) might correlate with a poor 6-month mRS score. Maintaining serum phosphorus stability after spontaneous intracerebral hemorrhage may improve prognosis.

Inhibitory effect of tanshinone IIA, resveratrol and silibinin on enterovirus 68 production through inhibiting ATM and DNA-PK pathway.

BACKGROUND: Human enterovirus 68 (EV68) is a primary etiological agent for respiratory illnesses, while no effective drug has yet used in clinics largely because the pathogenesis of EV68 is not clear. DNA damage response (DDR) responds to cellular DNA breaks and is also involved in viral replication. Three DDR pathways includes ataxia telangiectasia mutated (ATM), ATM and Rad3-related (ATR), and DNA-dependent protein kinase (DNA-PK). Natural products proved to be an excellent source for the discovery and isolation of novel antivirals. Among them, tanshinone IIA, resveratrol, silibinin, rutin and quercetin are reported to target DDR, therefore their roles in anti-EV68 are investigated in this study. PURPOSE: This study investigated the anti-EV68 ability of various natural compounds related to DDR. STUDY DESIGN AND METHODS: The methods include cell counting, flow cytometry, western blot, Immunofluorescence staining, comet assays, quantitative real-time RT PCR and short interfering RNAs (siRNAs) for analysis of cell number, cell cycle, protein expression, protein location, DNA damage, mRNA level and knock down target gene, respectively. RESULTS: EV68 infection induced DDR. Down-regulation or inhibition of ATM or DNA-PK lowered DDR in EV68-infected cells and mitigated viral protein expression, however, down-regulation or inhibition of ATR unexpectedly up-regulated DDR, and promoted viral protein expression. Meanwhile tanshinone IIA, resveratrol, and silibinin inhibited ATM and/or DNA-PK activation and decreased viral proliferation, while rutin and quercetin inhibited ATR activation and promoted viral production. The role of them in ATM, DNA-PK and ATR activation was consistent with previous reports. CONCLUSION: Tanshinone IIA, resveratrol and silibinin inhibited EV68 proliferation through inhibiting ATM and/or DNA-PK activation, and they were effective anti-EV68 candidates.

Recognition of potential therapeutic role of 2-hydroxy-3-methylanthraquinones in the treatment of gallbladder carcinoma: A proteomics analysis.

Gallbladder carcinoma (GBC), with early metastasis and high recurrence rates, is an enormous threat to health. As an anthraquinones monomer of traditional Chinese medicine Hedyotis diffusa, 2-hydroxy-3-methylanthraquinone (HMA) has been reported to inhibit the growth of several cancers. But in our preliminary study, HMA could only weakly induce GBC cell apoptosis. To explore other possible mechanism underlying the inhibition effect of HMA on GBC, this proteomics analysis was performed. A proteomics analysis was performed on one GBC cell line bought from the China Life Science Cell Bank. Several computational techniques were merged to develop analysis for those differently expressed proteins. A comparative protein-protein interaction network analysis was carried out among the differently expressed proteins to identify the proteins potentially inhibiting GBC. Thus, a GO and KEGG analysis was performed to identify the signaling pathways underlying a potential therapeutic role for HMA. A total of 285 proteins were affected by HMA, including 187 upregulated and 98 downregulated. The subcellular localization of differently expressed proteins were identified, including 142 in nuclear, 67 in cytoplasm, 67 in extracellular matrix, 46 in plasma membrane, 13 in mitochondrion, 3 in lysosome, and 1 in cytoskeleton. HMA could regulate EGFR, FN1, PLG, PLAUR, LAMA3, HRG, THBS1, PLAT, KNG1, ENAM, SERPINE1, ECM1, interleukin-8, and trypsin in GBC. Most of the regulated proteins involve in cell migration. Pathways including PI3K-Akt, Wnt, HIF-1, focal adhesion, microRNAs were regulated by HMA. HMA was shown to be an inhibition agent for GBC development, and this analysis would contribute to the development of new anti-GBC drugs.

Damage of anodic biofilms by high salinity deteriorates PAHs degradation in single-chamber microbial electrolysis cell reactor.

The anaerobic biodegradation of polycyclic aromatic hydrocarbons (PAHs) in high salinity wastewater is rather hard due to the inhibition of microorganisms by complex and high dosage of salts. Microbial electrolysis cell (MEC), with its excellent characteristic of anodic biofilms, can be an effective way to enhance the PAHs biodegradation. This work evaluated the impact of NaCl concentrations (0 g/L, 10 g/L, 30 g/L, and 60 g/L) on naphthalene biodegradation and analyzed the damage protection mechanism of anodic biofilms in batching MECs. Compared with the open circuit, the degradation efficiency of naphthalene under the closed circuit with 10 g/L NaCl concentration reached the maximum of 95.17% within 5 days. Even when NaCl concentration reached 60 g/L, the degradation efficiency only decreased by 10.02%, compared with the MEC without additional NaCl. Confocal scanning laser microscope (CSLM) proved the superiority of the biofilm states of MEC anode under high salinity in terms of thicker biofilms and higher proportion of live/dead bacteria cells. The highest dehydrogenase activity (DHA) was found in the MEC with 10 g/L NaCl concentration. Moreover, microbial diversity analysis demonstrated the classical electroactive microorganisms Geobacter and Pseudomonas were found on the anodic biofilms of MECs, which have both PAHs degradability and the electrochemical activity. Therefore, this study proved that high salinity had adverse effects on the anodic biofilms, but MEC alleviated the damage caused by high salinity.

Tannins extract from Galla Chinensis can protect mice from infection by Enterotoxigenic Escherichia coli O101.

BACKGROUND: Enterotoxigenic Escherichia coli (ETEC) is classically associated with acute secretory diarrhea, which induces 2 million people death in developing countries over a year, predominantly children in the first years of life. Previously, tannins (47.75%) were extracted from Galla Chinensis and prepared as Galla Chinensis oral solution (GOS) which showed significant antidiarrheal activity in a castor oil-induced diarrhea in mice. Whether the tannins extract were also effective in treatment of ETEC-induced diarrhea was determined in this study. METHODS: Mice were randomly divided into 6 groups (n = 22). The mice in the normal and untreated groups were given normal saline. Three GOS-treated groups were received different concentrations of GOS (5, 10 and 15%, respectively) at a dose of 10 mL/kg. Mice in the positive control group were fed with loperamide (10 mg/kg). The treatment with GOS started 3 days before infection with ETEC and continued for 4 consecutive days after infection. On day 3, mice were all infected with one dose of LD50 of ETEC, except those in the normal group. Survival of mice was observed daily and recorded throughout the study. On days 4 and 7, samples were collected from 6 mice in each group. RESULTS: GOS could increase the survival rate up to 75%, while in the untreated group it is 43.75%. The body weights of mice treated with 15% GOS were significantly increased on day 7 in comparison with the untreated group and the normal group. GOS-treatment recovered the small intestine coefficient enhanced by ETEC-infection. The diarrhea index of mice treated with GOS was significantly decreased. GOS increased the levels of IgG and sIgA in the terminal ileum and decreased the levels of pro-inflammatory cytokines (IFN-γ, TNF-α, IL-1ß, IL-6 and IL-8) in serum. GOS could increase the amount of intestinal probiotics, Lactobacilli and Bifidobacteria. GOS could alleviate colon lesions induced by ETEC-infection. GOS showed higher potency than loperamide. CONCLUSIONS: GOS could be a promising drug candidate for treating ETEC infections.

Effects of nutrition supplementation and physical exercise on muscle mass, muscle strength and fat mass among sarcopenic elderly: a randomized controlled trial.

This study aimed to determine the impact of nutrition supplementation (whey protein, fish oil, vitamin D) and physical exercise (resistance and aerobic exercise) on muscle mass, muscle strength and fat mass among sarcopenic elderly. Participants (N = 241) with sarcopenia (aged ≥ 60 y) enrolled from 2 centers were randomized into groups undergoing nutrition supplementation (Nutr), physical exercise (Ex), nutrition combined with exercise (Nutr+Ex), or routine consultation for 12 weeks. Muscle-related indicators, grip strength as well as fat-related indicators were compared pre- and post-intervention. The per-protocol analysis showed that all indicators were significantly different between groups (P < 0.001). Further pairwise comparisons showed that compared with controls, appendicular muscle mass and grip strength were significantly higher in Nutr (P < 0.001, 95% CI: 0.578, 1.475; P < 0.001, 95% CI: 3.614∼9.118), Ex (P = 0.010, 95% CI: 0.157, 1.153; P < 0.001, 95% CI: 2.904, 8.732), and Nutr+Ex (P < 0.001, 95% CI: 0.564, 1.471; P < 0.001, 95% CI: 3.441, 8.907) groups, while fat mass was significantly lower in the Nutr (P < 0.001, 95% CI: -4.676, -2.358) and Nutr+Ex (P < 0.001, 95% CI: -4.717,-1.790) groups. When compared with Ex, fat mass decreased significantly in the Nutr (P = 0.001, 95% CI: -4.856,-1.359) and Nutr+Ex (P = 0.005, 95% CI: -4.810, -0.878) groups. The findings indicate that nutrition supplementation and physical exercise could improve muscle mass, strength and fat mass among sarcopenic elderly. Nutrition supplementation might be better at decreasing fat mass in this population. ClinicalTrials.gov registration no.: NCT02873676. Novelty: Nutrition supplementation improved muscle mass, strength and fat mass among sarcopenic elderly. Aerobic and resistance exercise improved muscle mass and strength in sarcopenic elderly. Combined nutrition supplementation and physical exercise improved muscle mass, strength and fat mass among sarcopenic elderly.

Association between dietary antioxidants and risk for diabetic retinopathy in a Chinese population.

BACKGROUND: Diabetic retinopathy (DR) is related to oxidative stress and insufficient intake of dietary antioxidants may be associated with the onset and progression of DR. This study aimed to detect the association between main dietary antioxidants intake and the risk for DR. METHODS: This is a cross-sectional study of a Chinese urban population. Four hundred and fifty-five subjects with type 2 diabetes were recruited and divided into diabetic patients without retinopathy (DWR) group and DR group based on their retinal status. CSMO (clinically significant macular oedema) was diagnosed by stereoscopic photography. Demographic and lifestyle characteristics were ascertained by questionnaire. General physical and ophthalmic examinations were completed for all subjects. Dietary antioxidants were assessed by 3-day food records. Subjects who have taken any type of vitamin supplements were excluded from the study. The association of dietary antioxidants with the risk for DR was analysed by logistic regression with adjustment of other factors. The dietary antioxidants levels of the CSMO subjects and non-CSMO subjects were compared using the Wilcoxon rank sum test. RESULTS: One hundred and nineteen subjects in DR group and 336 subjects in DWR group participated in the study. Only ten DR subjects had CSMO. The results showed that higher vitamin E (OR (95% CI):0.97 (0.95, 1.00), P = 0.036) and selenium (OR (95% CI):0.98 (0.96, 1.00), P = 0.017) intake appear to be the protective factors of DR. The dietary antioxidants levels of CSMO and non-CSMO subjects had no statistical differences (P > 0.05). CONCLUSIONS: Dietary antioxidants intake, particularly vitamin E and selenium, were observed to have protective effects on DR.

A fatal myelosuppression, diarrhea and neurotoxicity induced by combination of irinotecan and tegafur-gimeracil-oteracil potassium in the treatment of colon cancer: a case report.

Chemical treatment is the vital pattern for colon cancer patients after surgery. Irinotecan and tegafur-gimeracil-oteracil potassium (S-1) combined chemotherapy is effective on metastatic colorectal cancer (mCRC). Nevertheless, patients receiving this combined chemotherapy might suffer the adverse drug reaction (ADR), such as myelosuppression and/or diarrhea, which could lead to poor prognosis. Here, we report a 76-year-old Chinese female who died due to the toxicity of combined therapy with irinotecan and S-1. This patient received irinotecan and S-1 combined therapy for 6 sessions after laparoscopic radical operation on colon cancer. After 6 sessions of chemotherapy, myelosuppression and severe diarrhea appeared with delirious accompanied. Antineoplastic agents were stopped immediately due to the appearance of III grade myelosuppression and IV grade diarrhea. Loperamide and octreotide were used to stop diarrhea, while granulocyte colony-stimulating factor (G-CSF) and recombinant human IL (IL-11) were used to improve blood cell count. Meanwhile, intravenous fluid replacement was continuously transfused to maintain water electrolyte balance. The patient remained continuous insanity and died 4 days after admission because of multiple organ failure, cardiac insufficiency, sever myelosuppression and ascending colon cancer. Myelosuppression is the principal toxicity associated with chemotherapy. And delayed-onset diarrhea is most frequently reported ADR of irinotecan, which could also be induced by S-1. Moreover, neurotoxicity is rarely reported as ADR for both irinotecan and S-1. Postoperative adjuvant chemotherapy should be carefully selected according to specific condition of patient. Blood routine examination should be monitored, and clinical manifestations should be carefully observed to ensure the safety and effectiveness of chemotherapy during the treatment.

Research on Intra-Operative Indocyanine Green Angiography of the Parathyroid for Predicting Postoperative Hypoparathyroidism: A Noninferior Randomized Controlled Trial.

OBJECTIVE: A noninferiority randomized controlled trial was undertaken to clarify whether the postoperative measurements of serum calcium and parathyroid hormone and oral supplementation of calcium and calcitriol could be omitted if patients had at least one well-perfused parathyroid gland evaluated by intra-operative indocyanine green (ICG) angiography. METHODS: Patients with at least one parathyroid gland well-perfused by ICG angiography (ICG score >2) were randomized to the control group or test group. For the control group, oral calcium and calcitriol were systematically supplemented. For the test group, no oral calcium or calcitriol was supplemented to the patients. Levels of serum calcium and parathyroid hormone of patients on the first and 30th postoperative day were compared between the two groups. RESULTS: Among all 68 selected patients, 56 patients had at least one well-perfused parathyroid gland evaluated by intra-operative ICG angiography. The 56 patients were randomized to the control group or test group. There were no statistically significant differences in the levels of serum calcium and parathyroid hormone between test group and control group on the first or 30th postoperative day. CONCLUSION: The postoperative measurements of serum calcium and parathyroid hormone and oral supplementation of calcium and calcitriol were evaluated as redundant, if patients had at least one well-perfused parathyroid gland evaluated by intra-operative ICG angiography. ABBREVIATIONS: ICG = indocyanine green; NIR = near infrared; POD = postoperative day; PTH = parathyroid hormone; SBR = signal background ratio.

Mixed dye wastewater treatment in a bioelectrochemical system-centered process.

The feasibility of mixed dye wastewater treatment was evaluated with a novel integrated bioprocess that consisted of a hybrid anaerobic reactor (HAR) with a built-in bioelectrochemical system, an aerobic biofilm reactor (ABFR) and a denitrification reactor (DR). The position of the DR significantly affected chemical oxygen demand (COD) and colority in effluent, and placing the DR after the ABFR improved effluent quality probably due to minimization of the undesired autoxidation of aromatic amine in dye wastewater. The optimal integrated process of HAR + ABFR + DR efficiently treated mixed dye wastewater, and concentrations of COD and TN were decreased down to 75 ± 18 mg/L and 12.91 ± 0.31 mg/L, respectively, along with colority 48 ± 4 times. Total phosphorus reduced to below 0.5 mg/L with coagulation using poly aluminum chloride, and the effluent quality fully met the discharge standard. This comprehensive study suggests the feasibility of the BES based process for practical application to mixed dye wastewater treatment.

A Recombinant Rabies Virus Expressing Fms-like Tyrosine Kinase 3 Ligand (Flt3L) Induces Enhanced Immunogenicity in Mice.

Rabies is a zoonotic disease that still causes 59,000 human deaths each year, and rabies vaccine is the most effective way to control the disease. Our previous studies suggested that the maturation of DC plays an important role in enhancing the immunogenicity of rabies vaccine. Flt3L has been reported to own the ability to accelerate the DC maturation, therefore, in this study, a recombinant rabies virus expressing mouse Flt3L, designated as LBNSE-Flt3L, was constructed, and its immunogenicity was characterized. It was found that LBNSE-Flt3L could enhance the maturation of DC both in vitro and in vivo, and significantly more TFH cells and Germinal Center B (GC B) cells were generated in mice immunized with LBNSE-Flt3L than those immunized with the parent virus LBNSE. Consequently, expressing of Flt3L could elevate the level of virus-neutralizing antibodies (VNA) in immunized mice which provides a better protection from a lethal rabies virus challenge. Taken together, our study extends the potential of Flt3L as a good adjuvant to develop novel rabies vaccine by enhancing the VNA production through activating the DC-TFH-GC B axis in immunized mice.

Evaluation of the inhibition of human carboxylesterases (CESs) by the active ingredients from Schisandra chinensis.

1. Schisandra chinensis, also called wuweizi in Chinese, is the fruit of Schisandra chinensis (Turcz.) Baill., and has been officially utilized as an astringent tonic for more than two thousand years in China. This study aims to evaluate the inhibition of carboxylesterases (CESs) by the major ingredients isolated from Schisandra chinensis, including Anwuligan, Schisandrol B, Schisanhenol, deoxyschizandrin, and Schisandrin B. 2. In vitro human liver microsomes (HLMs)-catalyzed hydrolysis of 2-(2-Benzoyl-3-methoxyphenyl) benzothiazole (BMBT) and fluorescein diacetate (FD) was employed as the probe reaction for CES1 and CES2, respectively. Initial screening, inhibition kinetics determination (inhibition type and parameters (Ki)), and in silico docking method were carried out. 3. Schisandrin B showed strong inhibition on the activity of CES1, and the activity of CES2 was strongly inhibited by Anwuligan and Schisandrin B. Schisandrin B exhibited noncompetitive inhibition towards CES1 and CES2. Anwuligan showed competitive inhibition towards CES2. The inhibition kinetic parameters (Ki) were calculated to be 29.8, 0.6, and 8.1 uM for the inhibition of Schisandrin B on CES1, Anwuligan on CES2, and Schisandrin B on CES2. In silico docking showed that hydrogen bonds and hydrophobic interactions contributed to the inhibition of Schisandrin B on CES1, Anwuligan on CES2, and Schisandrin B on CES2. All these information will be helpful for understanding the adverse effects of Schisandra chinensis due to the inhibition of CESs-catalyzed metabolism.

Evaluation of the efficacy and safety of ceftazidime/avibactam in the treatment of Gram-negative bacterial infections: a systematic review and meta-analysis.

Data on the efficacy and safety of ceftazidime/avibactam (CAZ-AVI) are limited. A systematic review and meta-analysis was conducted to clarify the role of CAZ-AVI for patients with serious Gram-negative bacterial infections. The PubMed, EMBASE and Cochrane Library databases were searched for randomised controlled trials (RCTs) and cohort studies involving CAZ-AVI. Summary risk ratios (RRs) and 95% confidence intervals (CIs) were calculated using a fixed- or random-effects model. Twelve articles (4951 patients) were included, consisting of nine RCTs and three observational studies comparing CAZ-AVI with other regimens, e.g. carbapenems or colistin. CAZ-AVI showed a comparable clinical response (RR = 0.99, 95% CI 0.96-1.02; I2 = 0%) and non-inferior bacterial eradication (RR = 1.04, 95% CI 0.93-1.17; I2 = 79.1%) to carbapenems. No significant difference was detected between groups regarding mortality and adverse events. Moreover, subgroup analyses demonstrated that CAZ-AVI improved the clinical response (RR = 1.61, 95% CI 1.13-2.29) with reduced mortality (RR = 0.29, 95% CI 0.13-0.63) in patients infected by carbapenem-resistant Enterobacteriaceae versus comparators. Likewise, CAZ-AVI improved the clinical cure rate of bloodstream infections (RR = 2.11, 95% CI 1.54-2.88). An improved ability of CAZ-AVI in microbiological eradication was also detected in patients with complicated urinary tract infections (RR = 1.13, 95% CI 1.05-1.21). CAZ-AVI exhibited comparable efficacy and safety with carbapenems. Therefore, this agent might be a potential powerful agent for patients with serious Gram-negative bacterial infections.

Engineering a yeast double-molecule carrier for drug screening.

With the advantages of unicellular eukaryotic structure and easy manipulation, yeast becomes a popular tool for biochemical, genetic and medicinal studies. In order to construct an efficient anti-inflammatory drug screening platform, we engineered yeast as a double-molecule carrier, of which an inserted domain (I domain) of lymphocyte function-associated antigen 1 was displayed on yeast surface and a green fluorescent protein (GFP) was expressed inside cytosol. The I domain specifically targeted a surface marker of mammalian cells, intercellular adhesion molecule 1, whose number is correlated with the level of cellular inflammation. Examination of GFP intensity enables swift quantification of the yeast-mammalian cell binding and thus it reflects inflammatory potency, herein the inflammatory index, of a chemical imposed to cells. The inflammatory potency of a total of 1340 chemicals was indexed. Among them, 1 inflammation-inducing and 1 inflammation-reducing compounds were verified both in vitro and in vivo. Our method demonstrated a swift, facile and high-throughput screening platform at the protein level for inflammation and related diseases drug discovery without using sophisticated instruments.

Everolimus-inhibited multiple isoforms of UDP-glucuronosyltransferases (UGTs).

1. Everolimus is an inhibitor of mammalian target of rapamycin (mTOR) and has been clinically utilized to prevent the rejection of organ transplants. This study aims to determine the inhibition of everolimus on the activity of phase-II drug-metabolizing enzymes UDP-glucuronosyltransferases (UGTs). 2. The results showed that 100 µM of everolimus exerted more than 80% inhibition toward UGT1A1, UGT-1A3 and UGT-2B7. UGT1A3 and UGT2B7 were selected to elucidate the inhibition mechanism, and in silico docking showed that hydrogen bonds and hydrophobic interactions mainly contributed to the strong binding of everolimus toward the activity cavity of UGT1A3 and UGT2B7. Inhibition kinetic-type analysis using Lineweaver-Burk plot showed competitive inhibition toward all these UGT isoforms. The inhibition kinetic parameters (Ki) were calculated to be 2.3, 0.07 and 4.4 µM for the inhibition of everolimus toward UGT1A1, UGT-1A3 and UGT-2B7, respectively. 3. In vitro-in vivo extrapolation (IVIVE) showed that [I]/Ki value was calculated to be 0.004, 0.14 and 0.002 for UGT1A1, UGT-1A3 and UGT-2B7, respectively. Therefore, high DDI potential existed between everolimus and clinical drugs mainly undergoing UGT1A3-catalyzed glucuronidation.

Serum 25-hydroxyvitamin D status in pregnant women with chronic hepatitis B virus infection.

INTRODUCTION: Maternal 25-hydroxyvitamin D [25(OH)D] deficiency has a negative influence on the health of the mother and the developing fetus. The aim of this study was to assess serum 25(OH)D status and its relationship to virologic and biochemical parameters in pregnant women with chronic hepatitis B virus (HBV) infection. METHODOLOGY: Serum 25(OH)D levels among 142 pregnant women with chronic HBV infection and 251 healthy pregnant women were measured using enzyme-linked immunosorbent assay. RESULTS: The mean±SD values for serum 25(OH)D levels were 13.63±5.5 ng/mL in healthy pregnant women and 12.05±3.3 ng/mL in pregnant women with chronic HBV infection (p < 0.01). Serum 25(OH)D levels were associated with seasonal variation in healthy pregnant women (p = 0.01); however, similar results were not observed in pregnant women with chronic HBV infection (p = 0.10). Furthermore, multivariate analysis indicated that only ALT level was independently associated with severe vitamin D deficiency (p = 0.01). A significant positive correlation was found between serum 25(OH)D level and ALT level in pregnant women with chronic HBV infection (r = 0.32; p < 0.001). CONCLUSIONS: Vitamin D levels were lower in pregnant women with chronic HBV infection compared with healthy pregnant women. Vitamin D supplementation can be routinely recommended for pregnant women in China.

Strong Specific Inhibition of UDP-glucuronosyltransferase 2B7 by Atractylenolide I and III.

Drug-metabolizing enzymes inhibition-based drug-drug interaction remains to be the key limiting factor for the research and development of efficient herbal components to become clinical drugs. The present study aims to determine the inhibition of uridine 5'-diphospho-glucuronosyltransferases (UGTs) isoforms by two important efficient herbal ingredients isolated from Atractylodes macrocephala Koidz, atractylenolide I and III. In vitro recombinant UGTs-catalysed glucuronidation of 4-methylumbelliferone was used to determine the inhibition capability and kinetics of atractylenolide I and III towards UGT2B7, and in silico docking method was employed to explain the possible mechanism. Atractylenolide I and III exhibited specific inhibition towards UGT2B7, with negligible influence towards other UGT isoforms. Atractylenolide I exerted stronger inhibition potential than atractylenolide III towards UGT2B7, which is attributed to the different hydrogen bonds and hydrophobic interactions. Inhibition kinetic analysis was performed for the inhibition of atractylenolide I towards UGT2B7. Inhibition kinetic determination showed that atractylenolide I competitively inhibited UGT2B7, and inhibition kinetic parameter (Ki) was calculated to be 6.4 µM. In combination of the maximum plasma concentration of atractylenolide I after oral administration of 50 mg/kg atractylenolide I, the area under the plasma concentration-time curve ration AUCi /AUC was calculated to be 1.17, indicating the highly possible drug-drug interaction between atractylenolide I and drugs mainly undergoing UGT2B7-catalysed metabolism.

In vivo (1)H MRS and (31)P MRSI of the response to cyclocreatine in transgenic mouse liver expressing creatine kinase.

Hepatocyte transplantation has been explored as a therapeutic alternative to liver transplantation, but a means to monitor the success of the procedure is lacking. Published findings support the use of in vivo (31)P MRSI of creatine kinase (CK)-expressing hepatocytes to monitor proliferation of implanted hepatocytes. Phosphocreatine tissue level depends upon creatine (Cr) input to the CK enzyme reaction, but Cr measurement by (1)H MRS suffers from low signal-to-noise ratio (SNR). We examine the possibility of using the Cr analog cyclocreatine (CCr, a substrate for CK), which is quickly phosphorylated to phosphocyclocreatine (PCCr), as a higher SNR alternative to Cr. (1)H MRS and (31)P MRSI were employed to measure the effect of incremental supplementation of CCr upon PCCr, γ-ATP, pH and Pi /ATP in the liver of transgenic mice expressing the BB isoform of CK (CKBB) in hepatocytes. Water supplementation with 0.1% CCr led to a peak total PCCr level of 17.15 ± 1.07 mmol/kg wet weight by 6 weeks, while adding 1.0% CCr led to a stable PCCr liver level of 18.12 ± 3.91 mmol/kg by the fourth day of feeding. PCCr was positively correlated with CCr, and ATP concentration and pH declined with increasing PCCr. Feeding with 1% CCr in water induced an apparent saturated level of PCCr, suggesting that CCr quantization may not be necessary for quantifying expression of CK in mice. These findings support the possibility of using (31)P MRS to noninvasively monitor hepatocyte transplant success with CK-expressing hepatocytes.