Cardioprotective Effects of PARP Inhibitors: A Re-Analysis of a Meta-Analysis and a Real-Word Data Analysis Using the FAERS Database.

Objective: This study aimed to assess the potential of PARP inhibitors to prevent cardiotoxicity. Methods: First, a re-analysis and update of a previously published study was conducted. Additional searches were conducted of the PubMed and Cochrane Central Register of Controlled Trials databases on 2 June 2023. After the selection process, the pooled odds ratio (OR) for cardiac adverse events (AEs) was calculated. Second, the FAERS database was examined for 10 frequently co-administered anticancer agents. The reporting odds ratio (ROR) was calculated based on the occurrence of cardiac AEs depending on the co-administration of PARP inhibitors. Results: Seven studies were selected for the meta-analysis. Although not statistically significant, co-administration of PARP inhibitors with chemotherapy/bevacizumab decreased the risk of cardiac AEs (Peto OR = 0.61; p = 0.36), while co-administration with antiandrogens increased the risk of cardiac AEs (Peto OR = 1.83; p = 0.18). A total of 19 cases of cardiac AEs were reported with co-administration of PARP inhibitors in the FAERS database. Co-administration of PARP inhibitors with chemotherapy/bevacizumab significantly decreased the risk of cardiac AEs (ROR = 0.352; 95% confidence interval (CI), 0.194-0.637). On the other hand, for antiandrogens co-administered with PARP inhibitors, the ROR was 3.496 (95% CI, 1.539-7.942). The ROR for immune checkpoint inhibitors co-administered with PARP inhibitors was 0.606 (95% CI, 0.151-2.432), indicating a non-significant effect on cardiac AEs. Conclusion: This study reports that PARP inhibitors show cardioprotective effects when used with conventional anticancer agents.

Integration of the Natural Language Processing of Structural Information Simplified Molecular-Input Line-Entry System Can Improve the In Vitro Prediction of Human Skin Sensitizers.

Natural language processing (NLP) technology has recently used to predict substance properties based on their Simplified Molecular-Input Line-Entry System (SMILES). We aimed to develop a model predicting human skin sensitizers by integrating text features derived from SMILES with in vitro test outcomes. The dataset on SMILES, physicochemical properties, in vitro tests (DPRA, KeratinoSensTM, h-CLAT, and SENS-IS assays), and human potency categories for 122 substances sourced from the Cosmetics Europe database. The ChemBERTa model was employed to analyze the SMILES of substances. The last hidden layer embedding of ChemBERTa was tested with other features. Given the modest dataset size, we trained five XGBoost models using subsets of the training data, and subsequently employed bagging to create the final model. Notably, the features computed from SMILES played a pivotal role in the model for distinguishing sensitizers and non-sensitizers. The final model demonstrated a classification accuracy of 80% and an AUC-ROC of 0.82, effectively discriminating sensitizers from non-sensitizers. Furthermore, the model exhibited an accuracy of 82% and an AUC-ROC of 0.82 in classifying strong and weak sensitizers. In summary, we demonstrated that the integration of NLP of SMILES with in vitro test results can enhance the prediction of health hazard associated with chemicals.

Zinc Deficiency Promotes Calcification in Vascular Smooth Muscle Cells Independent of Alkaline Phosphatase Action and Partly Impacted by Pit1 Upregulation.

Inorganic phosphate (Pi) is a critical determinant of calcification, and its concentration is regulated by alkaline phosphatase (ALP) and Pit1. ALP is a key regulator of osteogenic calcification and acts by modulating local inorganic phosphate (Pi) concentrations through hydrolyzing pyrophosphate in the extracellular matrix (ECM). Pit1, a sodium-dependent phosphate transporter, regulates calcification via facilitating phosphate uptake within the cells. To investigate whether zinc differentially regulates osteoblastic and vascular calcifications, we examined ALP activity and Pit1 in osteoblastic and vascular smooth muscle cells (VSMCs). Our findings demonstrate that calcification in osteoblastic MC3T3-E1 cells is decreased via diminished ALP action under zinc deficiency. In contrast, zinc-deficiency-induced calcification in VSMCs is independent of ALP action, as demonstrated by very weak ALP activity and expression in calcified VSMCs. In zinc-deficient A7r5 VSMC, P accumulation increased with increasing Na phosphate concentration (3-7 mM) but not with ß-GP treatment, which requires ALP activity to generate Pi. Ca deposition also increased with Na phosphate in a dose-dependent manner; in contrast, ß-GP did not affect Ca deposition. In osteoblastic cells, Pit1 expression was not affected by zinc treatments. In contrast, Pit1 expression is highly upregulated in A7r5 VSMC under zinc deficiency. Using phosphonoformic acid, a competitive inhibitor of Pit1, we showed that calcification is inhibited in both A7r5 and MC3T3-E1 cells, indicating a requirement for Pit1 in both calcifications. Moreover, the downregulation of VSMC markers under zinc deficiency was restored by blocking Pit1. Taken together, our results imply that zinc-deficiency-induced calcification in VSMC is independent of ALP action in contrast to osteoblastic calcification. Moreover, Pit1 expression in VSMCs is a target for zinc deficiency and may mediate the inhibition of VSMC marker expression under zinc deficiency.

Ellagic Acid Prevented Dextran-Sodium-Sulfate-Induced Colitis, Liver, and Brain Injury through Gut Microbiome Changes.

Inflammatory bowel disease (IBD) affects millions of people worldwide and is considered a significant risk factor for colorectal cancer. Recent in vivo and in vitro studies reported that ellagic acid (EA) exhibits important antioxidant and anti-inflammatory properties. In this study, we investigated the preventive effects of EA against dextran sulfate sodium (DSS)-induced acute colitis, liver, and brain injury in mice through the gut-liver-brain axis. Acute colitis, liver, and brain injury were induced by treatment with 5% (w/v) DSS in the drinking water for 7 days. Freshly prepared EA (60 mg/kg/day) was orally administered, while control (CON) group mice were treated similarly by daily oral administrations with a vehicle (water). All the mice were euthanized 24 h after the final treatment with EA. The blood, liver, colon, and brain samples were collected for further histological and biochemical analyses. Co-treatment with a physiologically relevant dose (60 mg/kg/day) of EA for 7 days significantly reduced the DSS-induced gut barrier dysfunction; endotoxemia; and inflammatory gut, liver, and brain injury in mice by modulating gut microbiota composition and inhibiting the elevated oxidative and nitrative stress marker proteins. Our results further demonstrated that the preventive effect of EA on the DSS-induced IBD mouse model was mediated by blocking the NF-κB and mitogen-activated protein kinase (MAPK) pathway. Therefore, EA co-treatment significantly attenuated the pro-inflammatory and oxidative stress markers by suppressing the activation of NF-κB/MAPK pathways in gut, liver, and brain injury. These results suggest that EA, effective in attenuating IBD in a mouse model, deserves further consideration as a potential therapeutic for the treatment of inflammatory diseases.

Hepatitis Risk in Diabetes Compared to Non-Diabetes and Relevant Factors: A Cross-Sectional Study with National Health and Nutrition Examination Survey (NHANES), 2013-2018.

This study aimed to identify the development of hepatitis B or C infection in diabetes patients compared to those without and to elucidate factors associated with the prevalence of hepatitis B or C infection in diabetes. We conducted a cross-sectional study using data from the National Health and Nutrition Examination Survey (NHANES) 2013-2018. As evaluation factors, we included variables such as age, race, illicit drug use, and poverty. The diabetic group had a significantly higher prevalence of hepatitis B or C infection than the non-diabetic group (odds ratio (OR) = 1.73; 95% confidence interval (CI), 1.36-2.21, p < 0.01). In multivariate Cox regression, non-poverty and non-illicit drug use were lower risk factors contributing to hepatitis development in diabetes (hazard ratio (HR) = 0.50; 95% CI, 0.32-0.79, p < 0.01, and HR = 0.05; 95% CI, 0.03-0.08, p < 0.01, respectively). Logistic regression also showed that these factors were significant contributors to hepatitis development in the diabetic group (p < 0.01). In patients with diabetes, the development of hepatitis was higher than that in those without, and hepatitis development was influenced by poverty and illicit drug use. This may provide supporting evidence of response strategies for diabetes to care for hepatitis development in advance.

The Effect of Apple-Derived Nanovesicles on the Osteoblastogenesis of Osteoblastic MC3T3-E1 Cells.

Osteoporosis is characterized by low bone mass and elevated structural deterioration of the bone tissue, resulting in bone weakness with an increased risk of fracture. Considering biological activities of various phytochemicals extracted from apples, we herein demonstrated the potential antiosteoporotic effects of apple-derived nanovesicles (apple NVs) using osteoblastic MC3T3-E1 cells. Apple NVs significantly stimulated the growth of MC3T3-E1 cells. The cellular alkaline phosphatase (ALP) activity was significantly upregulated in the 5 µg/mL apple NVs-treated group. In addition, the concentrarion of mineralized nodules was significantly increased in the apple NVs-treated groups. Furthermore, apple NVs increased the expression of the genes and proteins associated with osteoblast growth and differentiation, such as Runx2, ALP, OPN, and BMP2/4, which further activated ERK- and JNK-related mitogen-activated protein kinase signaling. These results demonstrate that apple NVs have a potential to prevent osteoporosis by promoting osteoblastogenesis in osteoblastic MC3T3-E1 cells through regulating the BMP2/Smad1 pathways.

Comparative impact of repositioned anticancer therapies on non-cancer COVID-19 patient treatment: A systematic review and network meta-analysis of randomized controlled trials.

PURPOSE: Coronavirus disease 2019 (COVID-19) has emerged as a serious threat to public health; anticancer-repositioning treatment strategy has been formulated to treat the disease. However, evidence supporting the efficacy and safety of repositioned anticancer treatment in treating COVID-19-infected non-cancer patients (CINPs) is limited. Therefore, this study analyzed published randomized controlled trials (RCTs) evaluating the impact of anticancer drugs compared to current standards of care (SOCs) on CINP treatment. MATERIALS AND METHODS: The PubMed and Embase databases were searched to identify eligible RCTs. Outcome measures included mortality, the use of mechanical ventilation (MV), and serious adverse events (SAEs). RESULTS: 25 RCTs were reviewed in our study. Compared to SOCs, repositioned anticancer therapy for treating CINPs was associated with mortality reduction (odds ratio (OR) = 0.78, 95% confidence interval (CI) = 0.65 - 0.94, p = 0.01). Using the repositioned anticancer treatment exhibited statistically significant reduction, in both the number of CINPs using MV (OR = 0.67, 95% CI = 0.51 - 0.88, p = 0.004) and experiencing SAEs (OR = 0.79, 95% CI = 0.69 - 0.91, p = 0.0009). CONCLUSION: Conclusively, repositioned anticancer treatment was shown significant differences from SOCs in treating CINPs, which appears to be more associated with mortality, MV use, and SAE development reduction in CINPs.

Comparative Impact of Pharmacological Therapies on Cluster Headache Management: A Systematic Review and Network Meta-Analysis.

It is important to find effective and safe pharmacological options for managing cluster headache (CH) because there is limited evidence from studies supporting the general efficacy and safety of pharmacological therapies. This systematic review and network meta-analysis (NMA) analyzed published randomized controlled trials (RCTs) to evaluate the efficacy and safety of pharmacological treatments in patients with CH. The PubMed and Embase databases were searched to identify RCTs that evaluated the efficacy and safety of pharmacological treatments for CH. Efficacy outcomes included frequency and duration of attacks, pain-free rate, and the use of rescue agents. Safety outcomes were evaluated based on the number of patients who experienced adverse events. A total of 23 studies were included in the analysis. The frequency of attacks was reduced (mean difference (MD) = −1.05, 95% confidence interval (CI) = −1.62 to −0.47; p = 0.0004), and the pain-free rate was increased (odds ratio (OR) = 3.89, 95% CI = 2.76−5.48; p < 0.00001) in the pharmacological treatment group, with a lower frequency of rescue agent use than the placebo group. Preventive, acute, and triptan or non-triptan therapies did not show significant differences in efficacy (p > 0.05). In the NMA, different results were shown among the interventions; for example, zolmitriptan 5 mg was more effective than zolmitriptan 10 mg in the pain-free outcome (OR = 0.40, 95% CI = 0.19−0.82; p < 0.05). Pharmacological treatment was shown to be more effective than placebo to manage CH with differences among types of therapies and individual interventions, and it was consistently shown to be associated with the development of adverse events. Thus, individualized therapy approaches should be applied to treat CH in real-world practice.

Depletion of Zinc Causes Osteoblast Apoptosis with Elevation of Leptin Secretion and Phosphorylation of JAK2/STAT3.

Zinc (Zn) has been reported to mediate leptin secretion, and thus leptin can be an important candidate molecule linking Zn with bone formation. The present study investigated whether zinc deficiency induces leptin secretion by activating a JAK2/STAT3 signaling pathway and leads to osteoblastic apoptosis. MC3T3-E1 cells were incubated for 24 h in normal osteogenic differentiation medium (OSM) or OSM treated with either 1 µM (Low Zn) or 15 µM (High Zn) of ZnCl2 containing 5 µM TPEN (Zn chelator). Our results demonstrated that low Zn stimulated extracellular leptin secretion and increased mRNA and protein expression of leptin in osteoblastic MC3T3-E1 cells. The OB-Rb (long isoform of leptin receptor) expressions were also elevated in osteoblasts under depletion of Zn. Leptin-signaling proteins, JAK2 and p-JAK2 in the cytosol of low Zn osteoblast conveyed leptin signaling, which ultimately induced higher p-STAT3 expression in the nucleus. Apoptotic effects of JAK2/STAT3 pathway were shown by increased caspase-3 in low Zn osteoblasts as well as apoptotic morphological features observed by TEM. Together, these data suggest that low Zn modulates leptin secretion by activating JAK2/STAT3 signaling pathway and induces apoptosis of osteoblastic MC3T3-E1 cells.