Curcumin attenuates isoniazid-induced hepatotoxicity by upregulating the SIRT1/PGC-1α/NRF1 pathway.

As a serious infectious disease, tuberculosis threatens global public health. Isoniazid is the first-line drug not only in active tuberculosis but also in its prevention. Severe hepatotoxicity greatly limits its use. Curcumin, extracted from turmeric, has been found to relieve isoniazid-induced hepatotoxicity. However, the mechanism of isoniazid-induced hepatotoxicity and the protective effects of curcumin are not yet understood completely. We established both cell and animal models about isoniazid-induced hepatotoxicity and investigated the new mechanism of curcumin against isoniazid-induced liver injury. The experimental data in our study demonstrated that curcumin ameliorated isoniazid-mediated liver oxidative stress. The protective effects of curcumin were demonstrated and confirmed to be correlated with upregulating SIRT1/PGC-1α/NRF1 pathway. Western blot revealed that while inhibiting SIRT1 by the siRNA1 (a SIRT1 inhibitor), the expressions of SIRT1, PGC-1α/Ac-PGC-1α, and NRF1 decreased, and the protective effect that curcumin exerted on isoniazid-treated L-02 cells was significantly attenuated. Furthermore, curcumin improved liver functions and reduced necrosis of the isoniazid-treated BALB/c mice, accompanied by downregulating oxidative stress and inflammation in liver. Western blot revealed that curcumin treatment activates the SIRT1/PGC-1α/NRF1 pathway in the isoniazid-treated BALB/c mice. In conclusion, we found one mechanism of isoniazid-induced hepatotoxicity downregulating the SIRT1/PGC-1α/NRF1 pathway, and curcumin attenuated this hepatotoxicity by activating it. Our study provided a novel approach and mechanism for the treatment of isoniazid-induced hepatotoxicity.

Serum biomarkers of isoniazid-induced liver injury: Aminotransferases are insufficient, and OPN, L-FABP and HMGB1 can be promising novel biomarkers.

Isoniazid (INH)-induced liver injury is a great challenge for tuberculosis treatment. Existing biomarkers cannot accurately determine the occurrence of this injury in the early stage. Therefore, developing early specific sensitive biomarkers of INH-induced liver injury is urgent. A rat model of liver injury was established with gastric infusion of INH or INH plus rifampicin (RFP). We examined seven potential novel serum biomarkers, namely, glutamate dehydrogenase (GLDH), liver-fatty acid-binding protein (L-FABP), high-mobility group box-1 (HMGB1), macrophage colony-stimulating factor receptor (MCSF1R), osteopontin (OPN), total cytokeratin 18 (K18), and caspase-cleaved cytokeratin-18 (ccK18), to evaluate their sensitivity and specificity on INH-induced liver injury. With the increase of drug dosage, combining with RFP and prolonging duration of administration, the liver injury was aggravated, showing as decreased weight of the rats, upgraded liver index and oxidative stress level, and histopathological changes of liver becoming marked. But the activity of serum aminotransferases decreased significantly. The area under the curve (AUC) of receiver-operating characteristic (ROC) curve of OPN, L-FABP, HMGB1, MCSF1R, and GLDH was 0.88, 0.87, 0.85, 0.71, and 0.70 (≥0.7), respectively, and 95% confidence interval of them did not include 0.5, with statistical significance, indicating their potential abilities to become biomarkers of INH-induced liver injury. In conclusion, we found traditional biomarkers ALT and AST were insufficient to discover the INH-induced liver injury accurately and OPN, L-FABP, and HMGB1 can be promising novel biomarkers.

Effect of Statins on the Risk of Different Stages of Prostate Cancer: A Meta-Analysis.

INTRODUCTION: The aim of this article was to investigate the relationship between statins and the risk of different stages or grades of prostate cancer. METHODS: A comprehensive literature search was performed for articles published until December 18, 2020, on the PubMed, Embase, and the Cochrane Library databases. The pooled relative risk (RR) and 95% confidence interval (CI) were then analyzed using the STATA.16.0 software. RESULTS: A total of 588,055 patients from 14 studies were included in the analysis. We found that the use of statins expressed a significant correlation with a lower risk of advanced prostate cancer (RR = 0.81, 95% CI: 0.73-0.91; RR = 0.86, 95% CI: 0.75-0.99, respectively). However, no evidence suggested that the use of statins was beneficial for the prevention of localized prostate cancer incidence. Similarly, the pooled results also revealed no association between the use of statins and the risk of high-grade and low-grade prostate cancer. CONCLUSION: It has been found that the use of statins is associated with a lower risk of advanced prostate cancer but was not related to the risk of localized, low-grade, or high-grade prostate cancer.

Identification of Key Aroma Compounds Responsible for the Floral Ascents of Green and Black Teas from Different Tea Cultivars.

Chemicals underlying the floral aroma of dry teas needs multi-dimensional investigations. Green, black, and freeze-dried tea samples were produced from five tea cultivars, and only 'Chunyu2' and 'Jinguanyin' dry teas had floral scents. 'Chunyu2' green tea contained the highest content of total volatiles (134.75 µg/g) among green tea samples, while 'Jinguanyin' black tea contained the highest content of total volatiles (1908.05 µg/g) among black tea samples. The principal component analysis study showed that 'Chunyu2' and 'Jinguanyin' green teas and 'Chunyu2' black tea were characterized by the abundant presence of certain alcohols with floral aroma, while 'Jinguanyin' black tea was discriminated due to the high levels of certain alcohols, esters, and aldehydes. A total of 27 shared volatiles were present in different tea samples, and the contents of 7 floral odorants in dry teas had correlations with those in fresh tea leaves (p < 0.05). Thus, the tea cultivar is crucial to the floral scent of dry tea, and these seven volatiles could be promising breeding indices.

Pharmacokinetics of trazodone sustained-release tablets in healthy subjects: Three open-label, randomized crossover studies
.

OBJECTIVE: To characterize the pharmacokinetics of trazodone hydrochloride (HCl) sustained-release tablets (TSR) and trazodone immediate-release formulation (TIR) and investigate the effects of food on the pharmacokinetics of the drug in healthy subjects. MATERIALS AND METHODS: Three open-label, randomized crossover trials of single-dose, multiple-dose, and food-drug interaction testing were conducted. A validated high-performance liquid chromatography-fluorescence method was used to measure the plasma concentration of trazodone, and a non-compartment model was used to obtain the pharmacokinetic parameters. AUC and Cmax dose proportionality were analyzed using a power model. RESULTS: TSR lacked dose proportionality over a dose range of 25 - 150 mg. In the food-drug interaction study, no significant changes in the pharmacokinetic parameters of the drug under the fed conditions were observed. Multiple dosage of TSR and TIR reached steady state after 7 days, with no accumulation phenomenon observed. The peak time and peak concentrations of TSR were significantly longer and lower, respectively, than those of TIR. CONCLUSION: TSR showed clear sustained-release characteristics, and food exhibited no significant effects on the pharmacokinetic parameters of trazodone. TSR and TIR reached steady state levels after 7 consecutive days of administration, with no accumulation phenomenon observed.

Oxidative Stress Induces Neuronal Apoptosis Through Suppressing Transcription Factor EB Phosphorylation at Ser467.

BACKGROUND/AIMS: This study determined the role and mechanism of action of transcription factor EB (TFEB) in H2O2-induced neuronal apoptosis. METHODS: SH-SY5Y cells were treated with Akt inhibitor/activator and different concentrations of H2O2. Cell apoptosis was detected by flow cytometric analysis. Akt and TFEB phosphorylation and PARP cleavage were determined by Western blotting. HEK293T cells were transfected with different truncated TFEB mutants and HA-Akt-WT; SH-SY5Y cells were transfected with Flag-vector, Flag-TFEB, Flag-TFEB-S467A or Flag-TFEB-S467D; and TFEB interaction with Akt was determined by co-immunoprecipitation and GST pull-down assays. RESULTS: A low concentration of H2O2 induces TFEB phosphorylation at Ser467 and nuclear translocation, facilitating neuronal survival, whereas a high concentration of H2O2 promotes SH-SY5Y cell apoptosis via suppressing TFEB Ser467 phosphorylation and nuclear translocation. The TFEB-S467D mutant is more easily translocated into the nucleus than the non-phosphorylated TFEB-S467A mutant. Further, Akt physically binds to TFEB via its C-terminal tail interaction with the HLH domain of TFEB and phosphorylates TFEB at Ser467. Mutation of TFEB-Ser467 can prevent the phosphorylation of TFEB by Akt, preventing inhibition of oxidative stress-induced apoptosis. CONCLUSIONS: Oxidative stress induces neuronal apoptosis through suppressing TFEB phosphorylation at Ser467 by Akt, providing a novel therapeutic strategy for neurodegenerative diseases.

[Response of radial growth of different timberline species to climate change in Yading Nature Reserve, Sichuan, China]. / å››å·äºšä¸è‡ªç„¶ä¿æŠ¤åŒºä¸åŒæž—çº¿æ ‘ç§å¾„å‘ç”Ÿé•¿å¯¹æ°”å€™å˜åŒ–çš„å“åº”.

The radial growth of trees in alpine timberline is particularly sensitive to climate change. We sampled and disposed tree-ring cores of three coniferous tree species including Juniperus saltuaria, Abies forrestii, and Larix potaninii at alpine timberline in Yading Nature Reserve. The standard tree-ring chronology was used to explore the response of radial growth of different timberline species to climate change. The results showed that radial growth of L. potaninii increased after 2000, while that of A. forrestii declined after 2002, and J. saltuaria showed a significant decreasing growth trend in the past 10 years. Such results indicated divergent growth responses to climate factors among the three tree species at alpine timberline. The radial growth of J. saltuaria was sensitive to temperature, and was positively correlated with the minimum temperature from previous October to current August, the mean tempera-ture from previous November to current April and from current July to October, but was negatively associated with the relative humidity from current July to October. The radial growth of A. forrestii showed negative correlation with mean temperature and the maximum temperature from May to June in the current year, while it exhibited positive association with the relative humidity and the Palmer drought severity index from May to June in the current year. L. potaninii radial growth was positively associated with mean temperature and the maximum temperature of November-December in the previous year, the maximum temperature of current March and mean temperature of current August. The temporal stability of climate-growth relationship varied among different timberline species. The positive correlation between radial growth of A. forrestii and J. saltuaria and temperature gradually decreased, while the posi-tive relationship of L. potaninii radial growth and temperature gradually increased. Under the background of climate warming, rapid rise in surface air temperatures may promote the radial growth of L. potaninii, while inhibit that of J. saltuaria and A. forrestii, which may change the position of regional timberline.

[The clinical analysis of 51 taxi drivers with peptic ulcer].

OBJECTIVE: To explore the main pathogenic factor causing the peptic ulcer of taxi drivers, which provide the basis for its prevention. METHODS: 98 taxi drivers were inspected by electronic endoscopy, according to the inspection all cases were divided into ulcers group and normal group. Then various factors were statuses by the logistic regression analysis according to the results of questionnaire. RESULTS: The prevalence of peptic ulcer of taxi drivers was 52.0%, and logistic regression analysis showed that dining time, taste spicy, meals temperature, smoking,alcohol, mental stress, HP infection and stomach health knowledge were statistically significant (P < 0.05), which would be the risk factors for peptic ulcer of taxi drivers. CONCLUSION: By emphasis on diet and lifestyle adjustments, stress regulation on the basis of eradication of HP infection will help the prevention and treatment of peptic ulcer of the taxi driver.

The Risk of Adverse Effects of TNF-α Inhibitors in Patients With Rheumatoid Arthritis: A Network Meta-Analysis.

OBJECTIVES: To evaluate the safety of each anti-TNF therapy for patients with rheumatoid arthritis (RA) and then make the best choice in clinical practice. METHODS: We searched PUBMED, EMBASE, and the Cochrane Library. The deadline for retrieval is August 2021. The ORs, Confidence Intervals (CIs), and p values were calculated by STATA.16.0 software for assessment. RESULT: 72 RCTs involving 28332 subjects were included. AEs were more common with adalimumab combined disease-modifying anti-rheumatic drugs (DMARDs) compared with placebo (OR = 1.60, 95% CI: 1.06, 2.42), DMARDs (1.28, 95% CI: 1.08, 1.52), etanercept combined DMARDs (1.32, 95% CI: 1.03, 1.67); certolizumab combined DMARDs compared with placebo (1.63, 95% CI: 1.07, 2.46), DMARDs (1.30, 95% CI: 1.10, 1.54), etanercept combined DMARDs (1.34, 95% CI: 1.05, 1.70). In SAEs, comparisons between treatments showed adalimumab (0.20, 95% CI: 0.07, 0.59), etanercept combined DMARDs (0.39, 95% CI: 0.15, 0.96), golimumab (0.19, 95% CI: 0.05, 0.77), infliximab (0.15, 95% CI: 0.03,0.71) decreased the risk of SAEs compared with golimumab combined DMARDs. In infections, comparisons between treatments showed adalimumab combined DMARDs (0.59, 95% CI: 0.37, 0.95), etanercept (0.49, 95% CI: 0.28, 0.88), etanercept combined DMARDs (0.56, 95% CI: 0.35, 0.91), golimumab combined DMARDs (0.51, 95% CI: 0.31, 0.83) decreased the risk of infections compared with infliximab combined DMARDs. No evidence indicated that the use of TNF-α inhibitors influenced the risk of serious infections, malignant tumors. CONCLUSION: In conclusion, we regard etanercept monotherapy as the optimal choice for RA patients in clinical practice when the efficacy is similar. Conversely, certolizumab + DMARDs therapy is not recommended. SYSTEMATIC REVIEW REGISTRATION: identifier PROSPERO CRD42021276176.

Integrative Transcriptomic and Phytohormonal Analyses Provide Insights into the Cold Injury Recovery Mechanisms of Tea Leaves.

Tea plant is susceptible to low temperature, while the cold injury recovery mechanisms of tea leaves are still unclear. Windbreak has an effective and gradient range of protecting tea plants. Tea plants with increasing cold damage degree have varying recovery status accordingly, which are the ideal objects for investigating the cold injury recovery mechanisms of tea leaves. Here, we investigated the transcriptome and phytohormone profiles of tea leaves with different cold injury degrees in recovery (adjacent to the windbreak), and the levels of chlorophylls, malondialdehyde, major phytohormones as well as the activities of peroxidase (POD) and superoxide dismutase (SOD) were also measured. The results showed the content of total chlorophylls and the activity of POD in mature tea leaves gradually decreased with the distance to windbreak, while SOD showed the opposite. The major phytohormones were highly accumulated in the moderately cold-injured tea leaves. The biosynthesis of abscisic acid (ABA) was enhanced in the moderate cold damaged tea leaves, suggesting that ABA plays an important role in the cold response and resistance of tea plants. The transcriptomic result showed that the samples in different rows were well discriminated, and the pathways of plant-pathogen interaction and flavonoid biosynthesis were enriched based on KEGG analysis. WRKY, GRAS and NAC were the top classes of transcription factors differentially expressed in the different cold-injured tea leaves. Thus, windbreak is effective to protect adjacent tea plants from cold wave, and phytohormones importantly participate in the cold injury recovery of tea leaves.

Efficacy of IVIG (intravenous immunoglobulin) for corona virus disease 2019 (COVID-19): A meta-analysis.

BACKGROUND: The benefit of IVIG (Intravenous Immunoglobulin) therapy for COVID-19 remains controversial. We performed a meta-analysis to investigate the efficacy of IVIG treatment in patients with COVID-19. METHODS: We searched articles from Web of Science, PubMed, Embase, the Cochrane Library, MedRxiv between 1 January 2020 and February 17, 2021. We selected randomized clinical trials and observational studies with a control group to assess the efficiency of IVIG in treating patients with COVID-19. Subjects were divided into 'non-severe', 'severe' and 'critical' three subgroups based on the information of the study and the World Health Organization (WHO) definition of severity. We pooled the data of mortality and other outcomes using either a fixed-effect model or a random-effects model. RESULTS: Our meta-analysis retrieved 4 clinical trials and 3 cohort studies including 825 hospitalized patients. The severity of COVID-19 is associated with the efficiency of IVIG. In critical subgroup, IVIG could reduce the mortality compared with the control group [RR = 0.57 (0.42-0.79, I2 = 025%). But there was no significant difference in the severe or non-severe subgroups. CONCLUSION: IVIG has demonstrated clinical efficacy on critical ill patients with COVID-19. There may be a relationship between the efficacy of IVIG and the COVID-19 disease severity. Well-designed clinical trials to identify the clinical and biochemical characteristics in COVID-19 patients' population that could benefit from IVIG are warranted in the future.

[Substructure Characteristics of Combined Acid-Base Modified Sepiolite and Its Adsorption for Cd(â ¡)].

To enhance the adsorption capacity of sepiolite (Sep) on Cd2+ in solution, an acid-base Sep (ABsep) was obtained using the method of combined acid-base modification. The structural properties of Sep and ABsep were analyzed by adsorption-desorption isotherms of N2, scanning electron microscopy with energy dispersive X-ray spectroscopy (SEM-EDS), transmission electron microscopy (TEM), Fourier-transform infrared spectroscopy (FTIR), and X-ray powder diffraction (XRD). Static adsorption experiments were carried out to evaluate the effects of time, mass ratio of ABsep/Cd2+, temperature, adsorbent dose, pH, and co-existing ions on the adsorption of Cd2+ by ABsep. The results showed that the pore structure of the ABsep was more developed than that of Sep. In comparison to Sep, the specific surface area, average pore diameter, and pore volume of ABsep increased by 66.1%, 15.7%, and 34.8%, respectively, and the exchangeable ion contents also increased. The main components of the ABsep were SiO2 and Mg(OH)2. The adsorption process of Cd2+ by Sep and ABsep could be well fitted with a pseudo-second-order kinetic equation and Langmuir isotherm, and both were spontaneous endothermic reactions, which were mainly chemical adsorption along with physical adsorption. The best mass ratio of ABsep:Cd2+ was 3:1, and the maximum saturated adsorption capacity fitted by the Sips model of the ABsep on Cd2+ at 298 K was 142.43 mg·g-1, which was 3.55 times that of Sep. As the adsorbent dose increased, the adsorption amounts of Cd2+ first increased and then decreased, with the optimum dose being 0.3 g·L-1. The amount of Cd2+ adsorption by the ABsep increased with the initial pH of the solution, whereby the best pH was 7. We also found that the presence of K+, Na+, Mg2+, and Ca2+ at different concentrations could inhibit the adsorption of Cd2+, whereby the inhibition of Mg2+ was the highest.

Vitamin D deficiency and Schizophrenia in Adults: A Systematic Review and Meta-analysis of Observational Studies.

Schizophrenia is a heterogeneous disorder in which there is an interaction between genetic and environmental factors. Accumulating data show that there may be an association between vitamin D deficiency and schizophrenia. We conducted an updated meta-analysis to investigate the relationship between schizophrenia and blood vitamin D level. All published observational articles have been searched from five databases until September 2019. In total, 36 articles with a total of 12528 participants were included in this study. Patients with schizophrenia have significantly lower levels of vitamin D than controls. The subgroup analyses based on study design, hospitalization status, quality score, type of biomarker [25-hydroxyvitamin D or 25-hydroxyvitamin D3], and the country did not explain between-study heterogeneity; however, meta-regression on match factors indicted that match of BMI could account for some degree of heterogeneity. No significant differences in publication bias were observed. Also, subjects with schizophrenia were more likely to have vitamin D deficiency or insufficiency compared to controls. In conclusion, our analyses are consistent with the hypothesis that vitamin D deficiency is associated with schizophrenia. More well-designed randomized control trials are needed to determine whether this association is causal.

[Effects of environmental factors at different altitudes on leaves and fruit quality of Fuji apple].

To inquire the different performances of the leaves and fruit quality of Fuji apple tress at various altitudes and their responses to the environmental factors, indices including leaf morphology, anatomy, δ13 C, and fruit quality of the Fuji apple trees at respective altitudes of 1375 m, 1575 m and 1715 m were investigated and their responses to environmental factors were determined following stepwise regression analysis. The results showed that 6 factors like the warmth index, Bailey's index, photosynthetically active radiation (PAR), coldness index, ultraviolet B and the annual precipitation dominantly affected the characteristic parameters of leaves and fruit. Elevation increase was matched by the decreasing warmth index, rising Bailey' s index, intenser PAR, higher coldness index, stronger ultraviolet B and heavier annual precipitation; meanwhile, the leaf structure and fruit quality parameters also displayed evident trends of change accordingly, namely, leaf parameters like leaf thickness, cuticle thickness, ratio of palisade and spongy, maximum conduit diameter, δ13C and nitrogen content per unit area increased gradually, and oppositely, leaf length-width ratio, specific leaf area, stoma length-width ratio and ratio of upper and lower epidermis to the leaf thickness decreased gradually; similarly, fruit parameters such as fruit shape index, fruit hardness, sugar-acid ratio, total color and the a/b-value ascended while the titratable acid and the hue angle descended. With increasing the altitude, the photosynthetic rate and water use efficiency of leaves were enhanced, and the fruit sugar-acid ratio climbed and the fruit flavor and color improved. Therefore, it could be safely concluded that within the altitude range between 1375 and 1715 m, environmental factors at a higher altitude favored Fuji apple growth.