Summary
Hepatitis B virus surface antigen (HBsAg) plays an important role in maintaining the tolerance and may interfere with host innate and adaptive immune responses; therefore, novel therapeutic ...strategies to reduce HBsAg loads in patients infected with hepatitis B virus (HBV) are emerging as an attractive but challenging issue. Metformin could regulate hepatic metabolism while the latter interacts with HBV infection. We hypothesized that metformin could affect HBsAg expression and HBV replication and may work synergistically when combined with current antivirals. In our study, a notably inhibitory effect on HBsAg production, as well as a moderate inhibition in HBV replication and HBeAg expression was observed following metformin treatment. The 50% effective concentration (EC50) for extracellular HBsAg and intracellular HBsAg in HBV‐producing HepG2.2.15 cells was 2.85 mm and 2.75 mm, respectively, with a similarly selective index of about 18. When administered in combination, metformin enhanced the inhibitory effects of interferon‐α2b on HBsAg expression and HBV replication and provided a complimentary role in HBsAg expression for lamivudine (LMV). This novel action of metformin derives partially from its inhibition on multiple HBV cis‐acting elements. By the virtues of preferably hepatocyte distribution and safety profile, collectively, our results suggest that metformin would be potentially clinically helpful as an HBsAg production inhibitor.
Interstitial lung diseases such as idiopathic pulmonary fibrosis (IPF) are caused by persistent micro-injuries to alveolar epithelial tissues accompanied by aberrant repair processes. IPF is ...currently treated with pirfenidone and nintedanib, compounds which slow the rate of disease progression but fail to target underlying pathophysiological mechanisms. The DNA repair protein 8-oxoguanine DNA glycosylase-1 (OGG1) has significant roles in the modulation of inflammation and metabolic syndromes. Currently, no pharmaceutical solutions targeting OGG1 have been utilized in the treatment of IPF. In this study we show Ogg1-targeting siRNA mitigates bleomycin-induced pulmonary fibrosis in male mice, highlighting OGG1 as a tractable target in lung fibrosis. The small molecule OGG1 inhibitor, TH5487, decreases myofibroblast transition and associated pro-fibrotic gene expressions in fibroblast cells. In addition, TH5487 decreases levels of pro-inflammatory mediators, inflammatory cell infiltration, and lung remodeling in a murine model of bleomycin-induced pulmonary fibrosis conducted in male C57BL6/J mice. OGG1 and SMAD7 interact to induce fibroblast proliferation and differentiation and display roles in fibrotic murine and IPF patient lung tissue. Taken together, these data suggest that TH5487 is a potentially clinically relevant treatment for IPF but further study in human trials is required.
Background and Aims
Bunch bagging is a grapevine canopy management strategy to protect bunches from light, heat stress and disease pressure. The aim of this study was to unveil the effects of timing ...and duration of bunch bagging on grape volatile organic compounds (VOCs) at the transcriptomic and metabolic levels.
Methods and Results
Seven bunch bagging treatments of varying timing and duration were implemented with Cabernet Sauvignon grapes. Regardless of timing and duration, bagging significantly reduced nerol, benzaldehyde, benzeneacetaldehyde and p‐cymene, and increased the concentration of phenol and 3,5‐dimethylbenzaldehyde. The decrease of nerol by bagging was associated with the down‐regulation of the gene encoding glycosyltransferase14 at veraison. Bagging and re‐exposing bunches at the preharvest stage inhibited and benefited the accumulation of C6 alcohols. Furthermore, we infer that the higher concentration of total benzenoids in all bagged berries was due to the down‐regulated expression of phenylpropanoid biosynthesis genes. The concentration of the dominant norisoprenoid, β‐damascenone, was not impacted by bunch bagging from veraison to harvest and was increased by bagging from veraison to post‐veraison. All other treatments, however, reduced this compound, which was due to a lower concentration of β‐carotene and lutein, and the down‐regulation of VviCCD4a and VviCCD4b.
Conclusions
Both timing and duration of bunch bagging can affect biosynthesis and accumulation of VOCs.
Significance of the Study
Insights from this study provide new knowledge on bunch bagging, as well as information regarding the sensitivity of VOCs to light and the timing of light exposure during grape ripening.
This study was conducted to explore the regulatory role of methionine (Met) in feather follicle and feather development during the embryonic period of chicks. A total of 280 fertile eggs (40 ...eggs/group) were injected with 0, 5, 10, 20 mg of L-Met or DL-Met/per egg on embryonic day 9 (E9), and whole-body feather and skin tissues were collected on E15 and the day of hatching (DOH). The whole-body feather weight was determined to describe the feather growth, and the skin samples were subjected to hematoxylin and eosin staining and Western blotting for the evaluation of feather follicle development and the expressions of Wingless/Int (Wnt)/β-catenin signaling pathway proteins, respectively. The results showed that L- or DL-Met did not affect the embryo weight (P > 0.05), but increased the absolute and relative whole-body feather weights. Specifically, 5 and 10 mg of L-Met and 5, 10, and 20 mg of DL-Met significantly increased the absolute feather weight at E15 (P < 0.05), and 10 mg of L-Met and 5 and 10 mg of DL-Met significantly increased the absolute and relative feather weight on the DOH (P < 0.05). Moreover, a main effect analysis suggested that changes in the embryo and feather weights were related to the Met levels (P < 0.05) but not the Met source (P > 0.05). The levels of L- and DL-Met were quadratically correlated with the absolute and relative feather weights of chicks on the DOH (P < 0.05). Correspondingly, all doses of L- and DL-Met significantly increased the diameter and density of feather follicles on the DOH (P < 0.05), as well as the activity of Wnt/β-catenin on E15 and the DOH (P < 0.05). In conclusion, injection of either L- or DL-Met can improve feather follicle development by activating Wnt/β-catenin signaling, and thereby promoting feather growth; furthermore, no difference in feather growth was found between L- and DL-Met treatments. Our findings might provide a nutritional intervention for regulating feather growth in poultry production.
ABSTRACT
Leucine (Leu) plays a critical regulatory role in protein synthesis, however, the effects and molecular mechanisms of Leu on crop milk protein in the domestic pigeons (Columba livia) are ...still unknown. Therefore, the study aimed to investigate the effects of dietary Leu supplementation on crop milk protein synthesis and the growth performance of squabs and the possible underlying mechanism. A total of 240 pairs of breeding pigeons (1102.3 ± 9.5 g/pair) were randomly assigned to 1 of 5 treatments, including a positive control (PC) diet that had adequate crude protein (crude protein, CP = 18%; Leu = 1.30%), a negative control (NC) diet that was low in CP (CP = 16%, Leu = 1.30%), and NC diets supplemented with Leu at 0.15%, 0.45%, or 1.05%. Compared with the NC diet, 0.15 to 0.45% Leu supplementation decreased BW loss and increased relative crop weight, crop thickness, and protein levels in the crop tissue and milk of breeding pigeons. However, dietary supplementation with 1.05% Leu inhibited ADFI in breeding pigeons. Dietary supplementation with 0.15 to 0.45% Leu decreased the mortality rate and increased the BW, eviscerated yield, and breast muscle yield of young squabs. The protein expression levels of the target of rapamycin (TOR), ribosomal protein S6 kinase 1 (S6K1), ribosomal protein S6 kinase (S6), eukaryotic initiation factor 4E binding protein 1 (4EBP1), and eukaryotic translation initiation factor 4E (eIF4E) were upregulated in the crop tissue of breeding pigeons in PC, 0.15% and 0.45% Leu-supplemented groups. Collectively, these results indicated that 0.15 to 0.45% Leu supplementation could decrease BW loss, increase milk protein synthesis in the crop of breeding pigeons, and enhance the survival rate and growth performance of young squabs through the TOR signaling pathway.
Summary
Background
Entecavir (ETV) has been shown to be safe and efficacious in randomised controlled trials in highly selected patients with hepatitis B virus (HBV) infection.
Aim
To determine the ...safety and effectiveness of ETV in ‘real‐world’ HBV patients in the United States (US).
Methods
Treatment‐naïve HBV patients ≥18 years old who received ETV for ≥12 months between 2005 and 2013 were included in a retrospective, cohort study. Rates of ALT normalisation, undetectable HBV DNA, HBeAg and HBsAg loss/seroconversion, adverse events (AE) and clinical outcomes were evaluated.
Results
Of 841 patients, 658 65% male, 83% Asian; median age 47 years met the inclusion criteria. 36% were HBeAg+ and 9.3% cirrhotic. 89% had abnormal ALT. Baseline median HBV DNA was 5.8 log 10 IU/mL. Median duration of ETV treatment was 4 years. Rates of ALT normalisation at 1, 3 and 5 years were 37.2%, 48.7% and 56.2% in HBeAg+ and 39.6%, 46.8% and 55.6% in HBeAg‐ patients. HBV DNA was undetectable at 1, 3 and 5 years in 34.6%, 64.7% and 84.6% in HBeAg+ patients, and 81.9%, 90.3% and 96.2% in HBeAg patients. Five‐year cumulative probability of HBeAg loss and seroconversion was 46% and 33.7% and HBsAg loss was 4.6%. ETV was discontinued due to adverse events in 1.2% of patients. Hepatic decompensation occurred in 0.8%, liver cancer in 2.7% and death in 0.6%.
Conclusion
Entecavir treatment was safe in a large cohort of US patients, but ALT normalisation and hepatitis B virus DNA suppression rates were lower than previously reported in clinical trials.
Simultaneous hyperactivation of stress-activated protein kinase/c-Jun N-terminal protein kinase (SAPK/JNK) and mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (MEK/ERK) ...signaling cascades has been reported in carcinogenesis. However, how they are integrated to promote oncogenesis remains unknown. By analyzing breast invasive carcinoma database (The Cancer Genome Altas), we found that the mRNA expression levels of both JNK1 and ERK2 are positively correlated with the mRNA level of EEA1, an endosome associated protein, indicating the potential JNK/ERK crosstalk at endosome. Unbiased screen of different endosome-associated Rab GTPases reveals that late endosome serves as a unique platform to integrate JNK/ERK signaling. Furthermore, we identify that BPGAP1 (a BCH domain-containing, Cdc42GAP-like Rho GTPase-activating protein) promotes MEK partner 1 (MP1)-induced ERK activation on late endosome through scaffolding MP1/MEK1 complex. This regulatory function requires phosphorylation of BPGAP1 by JNK at its C terminal tail (Ser424) to unlock its autoinhibitory conformation. Consequently, phosphorylated BPGAP1 facilitates endosomal ERK signaling transduction to the nucleus, driving cell proliferation and transformation via the ERK-Myc-CyclinA axis. BPGAP1 therefore provides a crucial spatiotemporal checkpoint where JNK and MP1/MEK1 work in concert to regulate endosomal and nuclear ERK signaling in cell proliferation control.
To determine the characteristics of bloodstream infections (BSIs) and to evaluate the impact of BSIs on mortality in severe burn patients.
A retrospective observational study was conducted in 20 ...tertiary hospitals. A total of 185 patients who experienced a massive dust explosion in eastern China were included.
After exclusion, 177 patients were analysed. The median total body surface area (TBSA) burned was 95% (interquartile range 85%–98%). Inhalation injuries occurred in 97.2%. The overall 90-day mortality was 35% (62/177). During the study period, 120 (67.8%) patients developed 253 episodes of BSI with 323 unique causative pathogens. Sixty-six episodes were polymicrobial infections. Catheter-related BSIs (CRBSIs) accounted for 41.5% of the episodes. Acinetobacter baumannii (19.5%), Klebsiella pneumoniae (13.9%) and Candida (12.7%) were the most common organisms. Antimicrobial resistance was found in 63.5% of the isolates, particularly in Gram-negative bacteria. Patients who developed BSIs had a greater illness severity at admission to the intensive care unit, and worse outcomes. After adjusting for demographics, severity of illness and treatment characteristics in a multivariate logistic model, there was a trend toward BSI increasing the risk of 90-day mortality (adjusted OR 3.4; 95% CI 0.9–12.9; p=0.069). In subgroup analyses, CRBSIs (adjusted OR 5.7; 95% CI 1.3–24.9; p=0.021 versus no BSI) and polymicrobial BSIs (adjusted OR 6.1; 95% CI 1.3–28.1; p=0.020 versus no BSI) had greater risk of 90-day mortality.
A strikingly high rate of BSIs was observed in severe burn patients. Gram-negative organisms and fungi were the leading causes. CRBSIs and polymicrobial BSIs were associated with high mortality.
Summary
Background
Hepatitis B virus (HBV) infection is common with major clinical consequences. In Asian Americans, the HBsAg carrier rate ranges from 2% to 16% which approximates the rates from ...their countries of origin. Similarly, HBV is the most important cause of cirrhosis, hepatocellular carcinoma (HCC) and liver related deaths in HBsAg positive Asians worldwide.
Aim
To generate recommendations for the management of Asian Americans infected with HBV.
Methods
These guidelines are based on relevant data derived from medical reports on HBV from Asian countries as well as from studies in the HBsAg positive Asian Americans. The guidelines herein differ from other recommendations in the treatment of both HBeAg positive and negative chronic hepatitis B (CHB), in the approach to HCC surveillance, and in the management of HBV in pregnant women.
Results
Asian American patients, HBeAg positive or negative, with HBV DNA levels >2000 IU/mL (>104 copies/mL) and ALT values above normal are candidates for anti‐viral therapy. HBeAg negative patients with HBV DNA >2000 IU/mL and normal ALT levels but who have either serum albumin <3.5 g/dL or platelet count <130 000 mm3, basal core promoter (BCP) mutations, or who have first‐degree relatives with HCC should be offered treatment. Patients with cirrhosis and detectable HBV DNA must receive life‐long anti‐viral therapy. Indications for treatment include pregnant women with high viraemia, coinfected patients, and those requiring immunosuppressive therapy. In HBsAg positive patients with risk factors, life‐long surveillance for HCC with alpha‐fetoprotein (AFP) testing and abdominal ultrasound examination at 6‐month intervals is required. In CHB patients receiving HCC treatments, repeat imaging with contrast CT scan or MRI at 3‐month intervals is strongly recommended. These guidelines have been assigned to a Class (reflecting benefit vs. risk) and a Level (assessing strength or certainty) of evidence.
Conclusions
Application of the recommendations made based on a review of the relevant literature and the opinion of a panel of Asian American physicians with expertise in HBV treatment will inform physicians and improve patient outcomes.
Linked ContentThis article is linked to Ebel and Rosenthal, and Tong and Pan papers. To view these articles visit https://doi.org/10.1111/apt.14620 and https://doi.org/10.1111/apt.14662.
BACKGROUND AND AIMS: Virus detection is necessary for in vitro production and propagation of virus‐free plants, for in vitro conservation and when material is received from overseas in tissue ...culture. In vitro biological virus indexing is among the reliable techniques. The aim of the present study was to develop an in vitro graft‐free protocol for indexing of Grapevine leafroll‐associated virus‐3 (GLRaV‐3). METHODS AND RESULTS: In vitro GLRaV‐3‐infected shoots were cultured on half‐strength Murashige and Skoog medium supplemented with either 150 mmol NaCl or 4% polyethylene glycol (PEG) 8000 to induce development of the virus symptoms. After 4 weeks of culture, the proportion of the symptom expression was 86 and 81% for Cabernet Sauvignon, 100 for ‘6‐12‐2’, 78 and 72% for Red Globe and 70 and 60% for Kyoho in the diseased shoots stressed by 150 mmol NaCl and 4% PEG, respectively. Expression of virus symptoms was more obvious and reliable when in vitro plantlets were stressed by NaCl than by PEG. CONCLUSIONS: Salt and drought stress induced by NaCl and PEG 8000 can improve in vitro biological indexing of GLRaV‐3 in red grapevine cultivars. SIGNIFICANCE OF THE STUDY: The techniques developed in the present study would have potential application to GLRaV‐3 indexing of red grapevine cultivars.
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