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Abstract Gut bacterial β-glucuronidase (GUS) can reactivate xenobiotics that exert enterohepatic circulation- triggered gastrointestinal tract toxicity. GUS inhibitors can alleviate drug-induced enteropathy and improve treatment outcomes. We evaluated the inhibitory effect of Polygonum cuspidatum Siebold & Zucc. and its major constituents against Escherichia coli GUS (EcGUS), and characterized the inhibitory mechanism of each of the components. Trans-resveratrol 4'-O-β-D-glucopyranoside (HZ-1) and (-)-epicatechin gallate (HZ-2) isolated from P. cuspidatum were identified as the key components and potent inhibitors. These two components displayed strong to moderate inhibitory effects on EcGUS, with Ki values of 9.95 and 1.95 μM, respectively. Results from molecular docking indicated that HZ-1 and HZ-2 could interact with the key residues Asp163, Ser360, Ile 363, Glu413, Glu504, and Lys 568 of EcGUS via hydrogen bonding. Our findings demonstrate the inhibitory effect of P. cuspidatum and its two components on EcGUS, which supported the further evaluation and development of P. cuspidatum and its two active components as novel candidates for alleviating drug-induced damage in the mammalian gut.

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In this paper, we propose a periodic reaction-diffusion model of Zika virus with seasonal and spatial heterogeneous structure in host and vector population. We introduce the basic reproduction ratio [Formula: see text] for this model and show that the disease-free periodic solution is globally asymptotically stable if [Formula: see text], while the system admits a globally asymptotically stable positive periodic solution if [Formula: see text]. Numerically, we study the Zika transmission in Rio de Janeiro Municipality, Brazil, and investigate the effects of some model parameters on [Formula: see text]. We find that the neglect of seasonality underestimates the value of [Formula: see text] and the maximum carrying capacity affects the spread of Zika virus.

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PURPOSE: Postpartum depression (PPD) is the most common psychiatric condition after childbirth which not only effects the mother's health, but also might have impact on child's development and parenting behaviors. Because the etiology of PPD has not been fully cleared, the efforts towards identification of risk factors are crucial for both the children and mother's health. METHOD: PubMed, EMBASE and PsycINFO databases were searched since inception until July 2019 to collect data about the risk factors of PPD and only systematic review and meta-analysis can be included. RESULT: To identify the real risk factors, protective factors and controversial factors, nineteen parts of the interpretation were adopted. The risk factors are mainly concentrated in the following aspects: violence and abuse, immigration status, gestational diabetes, cesarean section, depressive history, vitamin D deficiency, obese and overweight, postpartum sleep disruption and poor postpartum sleep, lack of social support, traditional dietary pattern (Japanese, Indian, United Kingdom, and Brazilian dietary pattern), multiple births, preterm and low-birth-weight infants, postpartum anemia, negative birth experience. The controversial factors are serum level of cortisol, thyroid peroxidase autoantibodies status, acculturation, traditional confinement practices. Skin-to-skin care, higher concentrations of DHA in mothers' milk, greater seafood consumption, healthy dietary patterns, multivitamin supplementation, fish and PUFA intake, calcium, Vitamin D, zinc and possibly selenium are protective factors. CONCLUSION: Thirteen risk factors were identified, but five factors still controversial due to the insufficient of the evidence. What's more, skin-to-skin care and some nutrition related factors are protective factors against PPD.

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INTRODUCTION: Pressure injury is one of the most prevalent skin injuries and a great challenge in the hospital environment. The implementation of preventive measures contributes to reducing its occurrence. OBJECTIVE: This study compares the protective effect of 2 adhesive dressings used in the prevention of pressure injuries in at-risk patients. MATERIALS AND METHODS: This case series was conducted at a university hospital in southeastern Brazil with 80 hospitalized adult patients at risk for pressure injuries, as per the Braden Scale for Predicting Pressure Sore Risk. Patients were randomized to preventive intervention with either hydrocellular foam (n = 40) or hydrocolloid plate (n = 40) dressing, which was applied to the intact skin over the sacrum and trochanters and changed weekly over 8 weeks. RESULTS: Of the patients, 56.5% were women, 64.5% were 60 years of age or older, 58.1% were admitted to an intensive care unit, and 63.9% were at high risk for pressure injuries. None of the patients developed a pressure injury. However, the presence of blanchable erythema, desquamation, pruritus, discomfort during dressing removal, and skin damage caused by the strong adhesiveness of the dressings were observed in both groups. In the hydrocolloid plate group, patients reported significantly more discomfort during dressing removal due to its strong adhesion to the skin (P = .004) than those in the hydrocellular foam group. CONCLUSIONS: Standard preventive measures combined with the use of either hydrocellular foam or hydrocolloid plate contributed to the prevention of pressure injuries in at-risk patients, with hydrocolloid plate being associated with significantly more discomfort during dressing removal.

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Regional variation in climate can generate differences in population dynamics and stage structure. Where regional differences exist, the best approach to pest management may be region-specific. Salmon lice are a stage-structured marine copepod that parasitizes salmonids at aquaculture sites worldwide, and have fecundity, development and mortality rates that depend on temperature and salinity. We show that in Atlantic Canada and Norway, where the oceans are relatively cold, salmon lice abundance decreases during the winter months, but ultimately increases from year to year, while in Ireland and Chile, where the oceans are warmer, the population size grows monotonically without any seasonal declines. In colder regions, during the winter the stage structure is dominated by the adult stage, which is in contrast to warmer regions where all stages are abundant year round. These differences translate into region-specific recommendations for management: regions with slower population growth have lower critical stocking densities, and regions with cold winters have a seasonal dependence in the timing of follow-up chemotherapeutic treatments. Predictions of our salmon lice model agree with empirical data, and our approach provides a method to understand the effects of regional differences in climate on salmon lice dynamics and management.

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This study aimed to investigate how 6-bromoindirubin-3'-oxime (BIO) increases the osteogenic differentiation of canine bone mesenchymal stem cells (BMSCs) and the role of the Wnt/ß-catenin signaling pathway in this process. We mimicked the effect of Wnt by adding BIO to the culture medium of BMSCs and examined whether canonical Wnt signaling positively affects the differentiation of these cells into osteoblasts. Canine BMSCs were cultured with 0.5 and 1.0 µM BIO under osteogenic conditions and then differentiation markers were investigated. It was found that BIO significantly increased the activity of alkaline phosphatase (ALP), the number of ALP-positive cells, the mineralization level and calcium deposits. Moreover, cells cultured with 0.5 and 1.0 µM BIO exhibited detectable ß-catenin expression in their nuclei, and showed upregulated ß-catenin and glycogen synthase kinase 3 beta(GSK3ß) phosphorylation compared to untreated cells. In addition, BIO enhanced the mRNA expression of osteoblast differentiation markers such as ALP, runt-related transcription factor 2, collagen I, osteocalcin, and osteonectin. In conclusion, BIO upregulated GSK3ß phosphorylation and inhibited its activity, thereby activating the Wnt/ß-catenin signaling pathway and promoting the osteogenic differentiation of canine BMSCs. The effect of 1.0 µM BIO on BMSCs differentiation was stronger than that of 0.5 µM BIO.

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The effect of bisacodyl on the treatment of rats with slow transit constipation (STC) was studied. Forty-five female Wister rats were divided into control group, STC group, and STC bisacodyl group. The immunohistochemical method was used to determine interstitial cells of Cajal (ICC) and the expression of c-Kit protein. Body mass and the number of defecations were significantly decreased in the STC group compared with the control group on the 100th day after diphenoxylate administration, while dry weight of feces was significantly increased and the intestinal transit time was prolonged. There were significant differences in the number of defecations, dry weight of feces, and intestinal transit time among the three groups. The number of defecations was higher, dry weight of feces was lower, and intestinal transit time was shorter in the STC bisacodyl group compared to the STC group. In addition, ICC basement membrane dissolution occurred in the colon wall of the STC group. The connection between ICC and surrounding cells was destroyed, and the nucleus shrunken to different degrees. Moreover, c-Kit expression in the STC group was significantly lower than the control group. The connection between ICC and surrounding cells in the STC bisacodyl group was significantly stronger than the STC group, and the number of ICC and the expression of c-Kit were increased. Bisacodyl could reduce the severity of STC in rats by increasing the number of ICC and the expression of c-Kit.

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The effect of bisacodyl on the treatment of rats with slow transit constipation (STC) was studied. Forty-five female Wister rats were divided into control group, STC group, and STC bisacodyl group. The immunohistochemical method was used to determine interstitial cells of Cajal (ICC) and the expression of c-Kit protein. Body mass and the number of defecations were significantly decreased in the STC group compared with the control group on the 100th day after diphenoxylate administration, while dry weight of feces was significantly increased and the intestinal transit time was prolonged. There were significant differences in the number of defecations, dry weight of feces, and intestinal transit time among the three groups. The number of defecations was higher, dry weight of feces was lower, and intestinal transit time was shorter in the STC bisacodyl group compared to the STC group. In addition, ICC basement membrane dissolution occurred in the colon wall of the STC group. The connection between ICC and surrounding cells was destroyed, and the nucleus shrunken to different degrees. Moreover, c-Kit expression in the STC group was significantly lower than the control group. The connection between ICC and surrounding cells in the STC bisacodyl group was significantly stronger than the STC group, and the number of ICC and the expression of c-Kit were increased. Bisacodyl could reduce the severity of STC in rats by increasing the number of ICC and the expression of c-Kit.

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UNLABELLED: Biliary atresia, the most common indication for pediatric liver transplantation, is a fibrotic disease of unknown etiology affecting the extrahepatic bile ducts of newborns. The recently described toxin biliatresone causes lumen obstruction in mouse cholangiocyte spheroids and represents a new model of biliary atresia. The goal of this study was to determine the cellular changes caused by biliatresone in mammalian cells that ultimately lead to biliary atresia and extrahepatic fibrosis. We treated mouse cholangiocytes in three-dimensional (3D) spheroid culture and neonatal extrahepatic duct explants with biliatresone and compounds that regulate glutathione (GSH). We examined the effects of biliatresone on SOX17 levels and determined the effects of Sox17 knockdown on cholangiocytes in 3D culture. We found that biliatresone caused disruption of cholangiocyte apical polarity and loss of monolayer integrity. Spheroids treated with biliatresone had increased permeability as shown by rhodamine efflux within 5 hours compared with untreated spheroids, which retained rhodamine for longer than 12 hours. Neonatal bile duct explants treated with the toxin showed lumen obstruction with increased subepithelial staining for α-smooth muscle actin and collagen, consistent with fibrosis. Biliatresone caused a rapid and transient decrease in GSH, which was both necessary and sufficient to mediate its effects in cholangiocyte spheroid and bile duct explant systems. It also caused a significant decrease in cholangiocyte levels of SOX17, and Sox17 knockdown in cholangiocyte spheroids mimicked the effects of biliatresone. CONCLUSION: Biliatresone decreases GSH and SOX17 in mouse cholangiocytes. In 3D cell systems, this leads to cholangiocyte monolayer damage and increased permeability; in extrahepatic bile duct explants, it leads to disruption of the extrahepatic biliary tree and subepithelial fibrosis. This mechanism may be important in understanding human biliary atresia. (Hepatology 2016;64:880-893).

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UNLABELLED: Biliatresone is an electrophilic isoflavone isolated from Dysphania species plants that has been causatively linked to naturally occurring outbreaks of a biliary atresia (BA)-like disease in livestock. Biliatresone has selective toxicity for extrahepatic cholangiocytes (EHCs) in zebrafish larvae. To better understand its mechanism of toxicity, we performed transcriptional profiling of liver cells isolated from zebrafish larvae at the earliest stage of biliatresone-mediated biliary injury, with subsequent comparison of biliary and hepatocyte gene expression profiles. Transcripts encoded by genes involved in redox stress response, particularly those involved in glutathione (GSH) metabolism, were among the most prominently up-regulated in both cholangiocytes and hepatocytes of biliatresone-treated larvae. Consistent with these findings, hepatic GSH was depleted at the onset of biliary injury, and in situ mapping of the hepatic GSH redox potential using a redox-sensitive green fluorescent protein biosensor showed that it was significantly more oxidized in EHCs both before and after treatment with biliatresone. Pharmacological and genetic manipulation of GSH redox homeostasis confirmed the importance of GSH in modulating biliatresone-induced injury given that GSH depletion sensitized both EHCs and the otherwise resistant intrahepatic cholangiocytes to the toxin, whereas replenishing GSH level by N-acetylcysteine administration or activation of nuclear factor erythroid 2-like 2 (Nrf2), a transcriptional regulator of GSH synthesis, inhibited EHC injury. CONCLUSION: These findings strongly support redox stress as a critical contributing factor in biliatresone-induced cholangiocyte injury, and suggest that variations in intrinsic stress responses underlie the susceptibility profile. Insufficient antioxidant capacity of EHCs may be critical to early pathogenesis of human BA. (Hepatology 2016;64:894-907).

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