Effects of exogenous melatonin supplementation on health outcomes: An umbrella review of meta-analyses based on randomized controlled trials.

Various melatonin supplementations have been developed to improve health outcomes in various clinical conditions. Thus, we sought to evaluate and summarize the effect of melatonin treatments in clinical settings for health outcomes. We searched PubMed/Medline, Embase, and Cochrane Library from inception to 4 February 2021. We included meta-analyses of randomized controlled trials investigating the melatonin intervention for any health outcome. Based on the different effect sizes of each meta-analysis, we calculated random models' standardized mean differences or risk ratios. We observed robust evidence supported by statistical significance with non-considerable heterogeneity between studies for sleep-related problems, cancer, surgical patients, and pregnant women. Patients with sleep disorder, sleep onset latency (SMD 0.33, 95% CI: 0.10 - 0.56, P < 0.01) were significantly improved whereas no clear evidence was shown with sleep efficiency (1.10, 95% CI: -0.26 to 2.45). The first analgesic requirement time (SMD 5.81, 95% CI: 2.57-9.05, P < 0.001) of surgical patients was distinctly improved. Female patients under artificial reproductive technologies had significant increase in the top-quality embryos (SMD 0.53, 95% CI: 0.27 - 0.79, P < 0.001), but no statistically clear evidence was found in the live birth rate (SMD 1.20, 95% CI: 0.83 - 1.72). Survival at one year (RR 1.90, 95% CI: 1.28 - 2.83, P < 0.005) significantly increased with cancer patients. Research on melatonin interventions to treat clinical symptoms and sleep problems among diverse health conditions was identified and provided considerable evidence. Future well-designed randomized clinical trials of high quality and subgroup quantitative analyses are essential.

Treatment of severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), and coronavirus disease 2019 (COVID-19): a systematic review of in vitro, in vivo, and clinical trials.

Rationale: Coronavirus disease 2019 (COVID-19) has spread worldwide and poses a threat to humanity. However, no specific therapy has been established for this disease yet. We conducted a systematic review to highlight therapeutic agents that might be effective in treating COVID-19. Methods: We searched Medline, Medrxiv.org, and reference lists of relevant publications to identify articles of in vitro, in vivo, and clinical studies on treatments for severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), and COVID-19 published in English until the last update on October 11, 2020. Results: We included 36 studies on SARS, 30 studies on MERS, and 10 meta-analyses on SARS and MERS in this study. Through 12,200 title and 830 full-text screenings for COVID-19, eight in vitro studies, 46 randomized controlled trials (RCTs) on 6,886 patients, and 29 meta-analyses were obtained and investigated. There was no therapeutic agent that consistently resulted in positive outcomes across SARS, MERS, and COVID-19. Remdesivir showed a therapeutic effect for COVID-19 in two RCTs involving the largest number of total participants (n = 1,461). Other therapies that showed an effect in at least two RCTs for COVID-19 were sofosbuvir/daclatasvir (n = 114), colchicine (n = 140), IFN-ß1b (n = 193), and convalescent plasma therapy (n = 126). Conclusions: This review provides information to help establish treatment and research directions for COVID-19 based on currently available evidence. Further RCTs are required.

Tea Consumption and Risk of Cancer: An Umbrella Review and Meta-Analysis of Observational Studies.

Tea is one of the most widely consumed beverages, but its association with cancer risk remains controversial and unclear. We performed an umbrella review to clarify and determine the associations between tea consumption and various types of cancer by summarizing and recalculating the existing meta-analyses. Meta-analyses of observational studies reporting associations between tea consumption and cancer risk were searched on PubMed and Embase. Associations found to be statistically significant were further classified into levels of evidence (convincing, suggestive, or weak), based on P value, between-study heterogeneity, prediction intervals, and small study effects. Sixty-four observational studies (case-control or cohort) corresponding to 154 effect sizes on the incidence of 25 types of cancer were included. Forty-three (27.9%) results in 15 different types of cancer were statistically significant. When combining all studies on the same type of cancer, 19 results in 11 different types of cancer showed significant associations with lower risk of gastrointestinal tract organ cancer (oral, gastric, colorectal, biliary tract, and liver cancer), breast cancer, and gynecological cancer (endometrial and ovarian cancer) as well as leukemia, lung cancer, and thyroid cancer. Only the reduced risk of oral cancer in tea-consuming populations (OR = 0.62; 95% CI: 0.55, 0.72; P value < 10-6) was supported by convincing evidence. Suggestive evidence was found for 6 results on biliary tract, breast, endometrial, liver, and oral cancer. To summarize, tea consumption was shown to have protective effects on some types of cancer, particularly oral cancer. More well-designed prospective studies are needed with consideration of other factors that can cause biases.

Recirculating peritoneal dialysis system using urease-fixed silk fibroin membrane filter with spherical carbonaceous adsorbent.

The chronic kidney disease (CKD) patients are undergoing continuous ambulatory peritoneal dialysis (CAPD). However, there are some constraints, the frequent exchange of the dialysate and limitation of outside activity, associated with CAPD remain to be solved. In this study, we designed the wearable artificial kidney (WAK) system for peritoneal dialysis (PD) using urease-immobilized silk fibroin (SF) membrane and polymer-based spherical carbonaceous adsorbent (PSCA). We evaluated this kit's removal abilities of uremic toxins such as urea, creatinine, uric acid, phosphorus, and ß2-microglobulin from the dialysate of end-stage renal disease (ESRD) patients in vitro. The uremic toxins including urea, creatinine, uric acid, and phosphorus were removed about 99% by immobilized SF membrane and PSCA filter after 24 h treatment. However, only 50% of ß2-microglobulin was removed by this filtering system after 24 h treatment. In vivo study result shows that our filtering system has more uremic toxins removal efficiency than exchanged dialysate at every 6 h. We suggest that recirculating PD system using urease-immobilized SF membrane with PSCA could be more efficient than traditional dialysate exchange system for a WAK for PD.

Triterpenoid Saponins Isolated from Platycodon grandiflorum Inhibit Hepatitis C Virus Replication.

Hepatitis C virus (HCV) infection is a major cause of liver disease, including cirrhosis and hepatocellular carcinoma. Due to significant adverse effects and emergence of resistant strains of currently developed anti-HCV agents, plant extracts have been considered to be potential sources of new bioactive compounds against HCV. The aim of this study was to evaluate the functional effects of triterpenoid saponins contained in the root extract of Platycodon grandiflorum (PG) on viral enzyme activities and replication in both HCV replicon cells and cell culture grown HCV- (HCVcc-) infected cells. Inhibitory activities of triterpenoid saponins from PG were verified by NS5B RNA-dependent RNA polymerase assay and were further confirmed in the context of HCV replication. Six triterpenoid saponins (platycodin D, platycodin D2, platycodin D3, deapioplatycodin D, deapioplatycodin D2, and platyconic acid A), PG saponin mixture (PGSM), were identified as active components exerting anti-HCV activity. Importantly, PGSM exerted synergistic anti-HCV activity in combination with either interferon- α or NS5A inhibitors. We demonstrated that combinatorial treatment of PGSM and IFN- α efficiently suppressed colony formation with significant reduction in drug resistant variant of HCV. These data suggest that triterpenoid saponin may represent a novel anti-HCV therapeutic agent.

Hepatoprotective and anti-hepatitis C viral activity of Platycodon grandiflorum extract on carbon tetrachloride-induced acute hepatic injury in mice.

The present study aims to evaluate the anti-HCV activity of hotwater extract from Platycodon grandiflorum (BC703) with HCV genotype 1b subgenomic replicon system and investigate its hepatoprotective activity on carbon tetrachloride (CCl(4))-induced acute liver damage in mice. BC703 produced significant hepatoprotective effects against CCl(4)-induced acute hepatic injury by decreasing the activities of serum enzymes, nitric oxide and lipid peroxidation. Histopathological studies further substantiated the protective effect of BC703. Furthermore, BC703 inhibited the HCV RNA replication with an EC(50) value and selective index (CC(50)/EC(50)) of 2.82 µg/mL and above 35.46, respectively. However, digested BC703 using a simulated gastric juice showed poor protective effect against CCl(4)-induced hepatotoxicity in mice and decreased anti-HCV activity as compared to the intact BC703. Although further studies are necessary, BC703 may be a beneficial agent for the management of acute hepatic injury and chronic HCV infection.

Discovery of novel HCV polymerase inhibitors using pharmacophore-based virtual screening.

We report the use of pharmacophore-based virtual screening as an efficient tool for the discovery of novel HCV polymerase inhibitors. A three-dimensional pharmacophore model for the HCV-796 binding site, NNI site IV inhibitor, to the enzyme was built by means of the structure-based focusing module in Cerius2 program. Using these models as a query for virtual screening, we produced a successful example of using pharmacophore-based virtual screening to identify novel compounds with HCV replicon assay through inhibition of HCV polymerization. Among the hit compounds, compounds 1 and 2 showed 56% and 48% inhibition of NS5B polymerization activity at 20 µM, respectively. In addition, compound 1 also exhibited replicon activity with EC(50) value of 2.16 µM. Following up the initial hit, we obtained derivatives of compound 1 and evaluated polymerization inhibition activity and HCV replicon assay. These results provide information necessary for the development of more potent NS5B inhibitors.

Changes in brain protein expression are linked to magnesium restriction-induced depression-like behavior.

There is evidence to suggest that low levels of magnesium (Mg) are associated with affective disorders, however, causality and central neurobiological mechanisms of this link are largely unproven. We have recently shown that mice fed a low Mg-containing diet (10% of daily requirement) display enhanced depression-like behavior sensitive to chronic antidepressant treatment. The aim of the present study was to utilize this model to gain insight into underlying mechanisms by quantifying amygdala/hypothalamus protein expression using gel-based proteomics and correlating changes in protein expression with changes in depression-like behavior. Mice fed Mg-restricted diet displayed reduced brain Mg tissue levels and altered expression of four proteins, N(G),N(G)-dimethylarginine dimethylaminohydrolase 1 (DDAH1), manganese-superoxide dismutase (MnSOD), glutamate dehydrogenase 1 (GDH1) and voltage-dependent anion channel 1. The observed alterations in protein expression may indicate increased nitric oxide production, increased anti-oxidant response to increased oxidative stress and potential alteration in energy metabolism. Aberrant expressions of DDAH1, MnSOD and GDH1 were normalized by chronic paroxetine treatment which also normalized the enhanced depression-like behavior, strengthening the link between the changes in these proteins and depression-like behavior. Collectively, these findings provide first evidence of low magnesium-induced alteration in brain protein levels and biochemical pathways, contributing to central dysregulation in affective disorders.