Nootkatone Supplementation Attenuates Carbon Tetrachloride Exposure-Induced Nephrotoxicity in Mice.

Nootkatone (NKT), a major ingredient of Alpinia oxyphylla, exhibited potential nephroprotective effects; however, the precise molecular mechanisms remain poorly understood. This study aimed to study the nephroprotective effects of NKT and the underlying mechanisms in a mouse model. Our results showed that NKT pretreatment at the doses of 5, 10, and 20 mg/kg per day for 7 days significantly attenuates carbon tetrachloride (CCl4)-induced increases of serum BUN and CRE and kidney pathology injury. NKT pretreatment also markedly inhibited oxidative stress, inflammatory response, and the activation of caspases-9 and -3 in kidneys of mice exposed to CCl4. Meanwhile, NKT pretreatment downregulated the expression of NOX4, IL-1ß, IL-6, and TNF-α proteins and NO levels in the kidney tissues. Moreover, NKT pretreatment upregulated the expression of Nrf2 and HO-1 mRNAs, and downregulated the expression of NF-κB, IL-1ß, IL-6, TNF-α, and iNOS mRNAs in the kidneys of mice, compared to those in the CCl4 alone treatment group. In conclusion, our results reveal that NKT supplementation could protect against CCl4 exposure-induced oxidative stress and inflammatory response in the kidneys by inhibiting NOX4 and NF-κB pathways and activating the Nrf2/HO-1 pathway. Our current study highlights the therapeutic application of NKT for kidney diseases.

T-2 toxin and its cardiotoxicity: New insights on the molecular mechanisms and therapeutic implications.

T-2 toxin is one of the most toxic and common trichothecene mycotoxins, and can cause various cardiovascular diseases. In this review, we summarized the current knowledge-base and challenges as it relates to T-2 toxin related cardiotoxicity. The molecular mechanisms and potential treatment approaches were also discussed. Pathologically, T-2 toxin-induced cardiac toxicity is characterized by cell injury and death in cardiomyocyte, increased capillary permeability, necrosis of cardiomyocyte, hemorrhage, and the infiltration of inflammatory cells in the heart. T-2 toxin exposure can cause cardiac fibrosis and finally lead to cardiac dysfunction. Mechanistically, T-2 toxin exposure-induced cardiac damage involves the production of ROS, mitochondrial dysfunction, peroxisome proliferator-activated receptor-gamma (PPAR-γ) signaling pathway, endoplasmic reticulum (ER stress), transforming growth factor beta 1 (TGF-ß1)/smad family member 2/3 (Smad2/3) signaling pathway, and autophagy and inflammatory responses. Antioxidant supplementation (e.g., catalase, vitamin C, and selenium), induction of autophagy (e.g., rapamycin), blockade of inflammatory signaling (e.g., methylprednisolone) or treatment with PPAR-γ agonists (e.g., pioglitazone) may provide protective effects against these detrimental cardiac effects caused by T-2 toxin. We believe that our review provides new insights in understanding T-2 toxin exposure-induced cardiotoxicity and fuels effective prevention and treatment strategies against this important food-borne toxin-induced health problems.

Cost-Effectiveness of Once-Daily, Single-Inhaler Indacaterol Acetate/ Glycopyrronium Bromide/ Mometasone Furoate in Patients with Uncontrolled Moderate-to-Severe Asthma in Canada.

PURPOSE: We evaluated the cost-effectiveness of high-dose indacaterol acetate (IND)/glycopyrronium bromide (GLY)/mometasone furoate (MF) (150/50/160 µg, once daily) compared with high-dose salmeterol/fluticasone (SAL/FLU; 50/500 µg, twice daily)+tiotropium (TIO; 5 µg, once daily) (SAL/FLU+TIO) and with high-dose SAL/FLU (50/500 µg, twice daily) for the treatment of inadequately controlled moderate-to-severe asthma. PATIENTS AND METHODS: A Markov model estimated the incremental cost-effectiveness ratio of treatment with high-dose IND/GLY/MF compared with SAL/FLU+TIO and high-dose IND/GLY/MF compared with SAL/FLU. The model included three health states (day-to-day symptoms without exacerbations, day-to-day symptoms with exacerbations, and death) with a 4-week cycle length. A lifetime time horizon was used. Exacerbation rates and utility values were derived from ARGON and IRIDIUM clinical trials. Canadian dollars (CAD$, 2020) were applied. RESULTS: IND/GLY/MF was the less costly and more effective treatment strategy compared with SAL/FLU+TIO and SAL/FLU in the base-case analyses. IND/GLY/MF had lower costs (CAD $33,501 versus CAD $50,907) and higher quality-adjusted life-years (QALYs) (18.37 versus 18.06 QALYs) compared with SAL/FLU+TIO. Compared with SAL/FLU, IND/GLY/MF had lower costs (CAD $33,408 versus CAD $36,577) and higher QALYs (19.33 versus 19.04 QALYs). IND/GLY/MF was the most cost-effective option in all scenarios tested. CONCLUSION: IND/GLY/MF was cost-effective at a willingness-to-pay threshold of CAD $50,000/QALY in patients with uncontrolled, moderate-to-severe asthma versus SAL/FLU+TIO and SAL/FLU in the base case and all scenarios tested.

Crizanlizumab and comparators for adults with sickle cell disease: a systematic review and network meta-analysis.

OBJECTIVES: Treatment options for preventing vaso-occlusive crises (VOC) among patients with sickle cell disease (SCD) are limited, especially if hydroxyurea treatment has failed or is contraindicated. A systematic literature review (SLR) and network meta-analysis (NMA) were conducted to evaluate the efficacy and safety of crizanlizumab for older adolescent and adult (≥16 years old) SCD patients. METHODS: The SLR included randomised controlled trials (RCTs) and uncontrolled studies. Bayesian NMA of VOC, all-cause hospitalisation days and adverse events were conducted. RESULTS: The SLR identified 51 studies and 9 RCTs on 14 treatments that met the NMA inclusion criteria. The NMA found that crizanlizumab 5.0 mg/kg was associated with a reduction in VOC (HR 0.55, 95% credible interval (0.43, 0.69); Bayesian probability of superiority >0.99), all-cause hospitalisation days (0.58 (0.50, 0.68); >0.99) and no evidence of difference on adverse events (0.91 (0.59, 1.43) 0.66) or serious adverse events (0.93 (0.47, 1.87); 0.59) compared with placebo. The HR for reduction in VOC for crizanlizumab relative to L-glutamine was (0.67 (0.50, 0.88); >0.99). These results were sensitive to assumptions regarding whether patient age is an effect modifier. CONCLUSIONS: This NMA provides preliminary evidence comparing the efficacy of crizanlizumab with other treatments for VOC prevention.

Molecular Mechanisms Underlying Protective Role of Quercetin on Copper Sulfate-Induced Nephrotoxicity in Mice.

Copper overload is an established cause of nephrotoxicity, but the precise molecular mechanism remains unknown. Our study aimed to investigate the molecular mechanism of copper sulfate (CuSO4)-induced nephrotoxicity and the protective effect of the natural compound quercetin using a mouse model. Mice were orally administered CuSO4 only (200 mg/kg per day), or co-administered CuSO4 (200 mg/kg per day) plus quercetin (25, 50, or 100 mg/kg per day), or quercetin only (100 mg/kg per day), or vehicle for 28 days. The blood and kidneys were collected for the examination of serum biomarkers, oxidative stress biomarkers, changes in histopathology and gene and protein expression. Our results show that quercetin supplementation attenuates CuSO4-induced renal dysfunction and tubular necrosis in a dose-dependent manner. Quercetin supplementation at 50 and 100 mg/kg significantly attenuated CuSO4-induced oxidative damage. Quercetin supplementation also inhibited the activities of caspases-9 and-3, and the expression of p53 and Bax mRNAs. Furthermore, quercetin supplementation markedly activated the expression of Nrf2 and HO-1 mRNAs, but inhibited the expression of NF-κB, IL-1ß, IL-6, and TNF-α mRNAs. In conclusion, our results revealed that quercetin supplementation could inhibit CuSO4-induced nephrotoxicity in mice via the inhibition of mitochondrial apoptotic and NF-κB pathways and the activation of Nrf2/HO-1 pathway. Our study highlights quercetin as a potential candidate in treating copper overload-induced nephrotoxicity.

Effect of AcrySof versus other intraocular lens properties on the risk of Nd:YAG capsulotomy after cataract surgery: A systematic literature review and network meta-analysis.

OBJECTIVE: The purpose of this study was to evaluate the impact of different intraocular lens materials (IOL) and optic edge designs on the incidence of Nd:YAG laser capsulotomy. METHODS: Randomized controlled trials (RCTs) reporting incidence of Nd:YAG capsulotomy in patients with monofocal IOLs were identified for systematic literature review (SLR) using Cochrane methodology. A network meta-analysis was conducted under a Bayesian framework. Mean hazard ratios (HRs), 95% credible intervals, and one-sided p-values were estimated for Nd:YAG capsulotomy incidence by comparing AcrySof IOLs with a group of non-AcrySof hydrophobic acrylic, hydrophilic acrylic, silicone, and PMMA IOLs. Sensitivity analysis was conducted comparing the risk of Nd:YAG capsulotomy between sharp- and round-edged designs of the above IOLs. RESULTS: AcrySof IOLs had a lower risk of Nd:YAG capsulotomy compared to hydrophobic acrylic (HR: 2.68; 95% CrI: 1.41, 4.77; p < 0.01), hydrophilic acrylic (HR: 7.54; 95% CrI: 4.24, 14.06; p < 0.001), PMMA (HR: 3.64, 95% CrI: 1.87, 6.33; p < 0.001), and silicone (HR: 1.13; 95% CrI: 0.59, 1.91; p <0.1) IOLs. The risk for Nd:YAG was highest among sharp-edged IOLs for hydrophilic acrylic IOLs (HR: 9.32; 95% CrI: 4.32, 19.29; p < 0.01), followed by other hydrophobic acrylic (HR: 2.91; 95% CrI: 1.27, 5.88; p < 0.01), silicone (HR: 0.838; 95% CrI: 0.328, 1.74; p = 0.69), and PMMA (HR: 0.39; 95% CrI: 0.042, 1.49; p = 0.93) IOLs, compared to AcrySof. Acrysof IOLs had a lower risk of Nd:YAG compared to PMMA (HR: 3.25; 95% CrI: 1.21, 7.37; p < 0.01) and silicone, round edge IOLs (HR: 3.84; 95% CrI: 1.08, 10.64; p = 0.015). CONCLUSION: The risk of Nd:YAG capsulotomy is lower in eyes implanted with AcrySof IOLs compared to non-AcrySof hydrophobic or hydrophilic acrylic IOLs. Sharp-edged AcrySof, PMMA, and silicone IOLs are comparable in terms of reducing the risk of Nd:YAG laser capsulotomy.

Renal Function in Nucleos(t)ide Analog-Treated Patients With Chronic Hepatitis B: A Systematic Literature Review and Network Meta-Analysis.

INTRODUCTION: Renal safety is an important factor in selecting the most appropriate nucleos(t)ide analog (NA) treatment for patients with chronic hepatitis B (CHB). This systematic literature review and network meta-analysis aimed to assess renal function associated with telbivudine treatment compared to other NAs in patients with CHB. METHODS: A systematic literature search via Medline, Medline In-Process, Embase, and the Cochrane library for publications of randomized controlled trials and observational studies was conducted. Network meta-analysis was performed to compare renal function with telbivudine treatment versus other NAs after 1 year of therapy. RESULTS: Overall, 40 (six randomized controlled and 34 observational) studies were included for review. Telbivudine consistently showed an improvement in renal function as measured by an estimated glomerular filtration rate (eGFR) over various time points regardless of the method of measurement. Changes in eGFR (mL/min) from baseline and corresponding 95% credible intervals with various NAs were as follows: monotherapies (telbivudine: 7.78 [6.91, 8.65], entecavir: -1.07 [-4.80, 2.62], lamivudine: -6.08 [-13.35, 1.15], tenofovir: -9.53 [-14.31, -4.89]) and combination therapies (telbivudine + adefovir: 8.37 [-34.00, 50.34], telbivudine + tenofovir: 8.29 [-0.05, 16.64], entecavir + adefovir: 4.15 [-38.55, 46.37], telbivudine + lamivudine: 0.51 [-11.77, 12.96], and lamivudine + adefovir: -0.39 [-42.48, 41.21]). At 1 year, the change in eGFR from baseline was significantly higher with telbivudine compared to other NAs. CONCLUSION: The systematic literature review and network meta-analysis provide evidence that telbivudine is associated with significant improvement in renal function in patients with CHB, either alone or in combination with other NAs. FUNDING: Novartis Pharma AG.

Effect of Telbivudine Versus Other Nucleos(t)ide Analogs on HBeAg Seroconversion and Other Outcomes in Patients with Chronic Hepatitis B: A Network Meta-Analysis.

INTRODUCTION: A comprehensive and up-to-date network meta-analysis (NMA) helps to determine the comparative efficacies of nucleos(t)ide analogs (NAs) in patients with chronic hepatitis B (CHB). The aim of this NMA was to assess the efficacy of telbivudine versus adefovir, entecavir, lamivudine, and tenofovir in nucleos(t)ide-naïve hepatitis B e antigen (HBeAg)-positive patients with CHB. METHODS: A systematic review was conducted to search Medline, Medline-In Process, EMBASE, and the Cochrane Central Register of Controlled Trials databases for publications of randomized controlled trials (RCTs). NMA was performed to compare the efficacy outcomes of telbivudine versus other approved NAs at 1- and 2-year time points. RESULTS: A total of 75 RCTs were included in the systematic review. At the 1-year time point, telbivudine was associated with significantly higher rates of: (1) HBeAg seroconversion than adefovir [odds ratio (OR) 1.99 (95% credible interval (CrI): 1.05, 3.45)], entecavir [OR 2.00 (95% CrI: 1.44, 2.82)] and lamivudine [OR 1.49 (95% CrI: 1.10, 2.03)]; (2) HBeAg loss than entecavir [OR 1.85 (95% CrI: 1.28, 2.76)] and lamivudine [OR 1.62 (95% CrI: 1.20, 2.24)]; (3) alanine aminotransferase (ALT) normalization than lamivudine [OR 1.50 (95% CrI: 1.05, 2.21)]; and (4) hepatitis B virus (HBV) DNA suppression than adefovir [OR 2.77 (95% CrI: 1.28, 5.45)] and lamivudine [OR 2.97 (95% CrI: 1.99, 4.53)]. At the 2-year time point, the relative efficacy outcomes were not statistically significant. CONCLUSION: At 1 year, telbivudine was superior to adefovir, entecavir and lamivudine in HBeAg seroconversion, and to entecavir and lamivudine in HBeAg loss. Telbivudine was also superior to lamivudine in ALT normalization and to adefovir and lamivudine in suppressing HBV DNA levels. FUNDING: Novartis Pharma AG.