Moderate sedation with single-dose remimazolam tosilate in elderly male patients undergoing transurethral resection of the prostate with spinal anesthesia: a prospective, single-arm, single-centre clinical trial.

BACKGROUND: Remimazolam tosilate (RT) is a newly listed benzodiazepine for sedation and anesthesia featuring quick onset of effects, short maintenance and recovery times, which is currently under research. This trial was conducted to determine the median effective dose (ED50) and the 95% effective dose (ED95) of single-dose remimazolam for moderate sedation in elderly patients undergoing transurethral resection of the prostate (TURP) under spinal anesthesia, and to evaluate its efficacy and safety. METHODS: Thirty male patients aged 65-80 years old were recruited for selective TURP. Remimazolam was administered intravenously to pain-free patients (VAS score < 1) within 1 min of successful spinal anesthesia by the same anesthesiologist. We used modified Dixon's up-and-down sequential allocation method to determine the ED50 and ED95 of the agent with an initial dosage of 0.1 mg/kg. Successful sedation was defined as an MOAA/S score ≤ 3 and above 1. A score of > 3 was deemed as failed sedation. Recruitment continued until ten independent pairs (from successful sedation to failed sedation) would give a reliable estimation of the ED50 and ED95 of RT and their 95% confidence intervals. RESULTS: The ED50 of remimazolam was 0.063 (95% C.I. 0.045-0.073) mg/kg. Its ED95 was 0.079 (95% C.I. 0.07-0.137) mg/kg. Remimazolam was safe in its application. CONCLUSIONS: A single-dose of RT proves to be safe for assisted sedation during TURP in elderly male patients under spinal anesthesia with a lower incidence of adverse events. Its ED50 and ED95 were 0.063 mg/kg and 0.079 mg/kg, respectively. TRIAL REGISTRATION: http://www.chictr.org.cn (ChiCTR2100051912).

New natural compound inhibitors of PDGFRA (platelet-derived growth factor receptor α) based on computational study for high-grade glioma therapy.

Background: High-grade glioma (HGG) is a malignant brain tumor that is common and aggressive in children and adults. In the current medical paradigm, surgery and radiotherapy are the standard treatments for HGG patients. Despite this, the overall prognosis is still very bleak. Studies have shown that platelet-derived growth factor receptor α (PDGFRA) is an essential target to treat tumors and inhibiting the activity of PDGFRA can improve the prognosis of HGG. Thus, PDGFRA inhibitors are critical to developing drugs and cancer treatment. Objective: The purpose of this study was to screen lead compounds and candidate drugs with potential inhibitors against platelet-derived growth factor receptor α (PDGFRA) from the drug library (ZINC database) in order to improve the prognosis of patients with high-grade glioma (HGG). Materials and methods: In our study, we selected Imatinib as the reference drug. A series of computer-aided technologies, such as Discovery Studio 2019 and Schrodinger, were used to screen and assess potential inhibitors of PDGFRA. The first step was to calculate the LibDock scores and then analyze the pharmacological and toxicological properties. Following this, we docked the small molecules selected in the previous steps with PDGFRA to study their docking mechanism and affinity. In addition, molecular dynamics simulation was used to determine whether the ligand-PDGFRA complex was stable in nature. Results: Two novel natural compounds 1 and 2 (ZINC000008829785 and ZINC000013377891) from the ZINC database were found binding to PDGFRA with more favorable interaction energy. Also, they were predicted with less Ames mutagenicity, rodent carcinogenicity, non-developmental toxic potential, and tolerant with cytochrome P450 2D6 (CYP2D6). The dynamic simulation analysis demonstrated that ZINC000008829785-PDGFRA and ZINC000013377891-PDGFRA dimer complex had more favorable potential energy compared with Imatinib, and they can exist in natural environments stably. Conclusion: ZINC000008829785 and ZINC000013377891 might provide a solid foundation for drugs that inhibit PDGFRA in HGG. In addition to being safe drug candidates, these compounds had important implications for improving drugs targeting PDGFRA.

The associations of circulating common and uncommon polyunsaturated fatty acids and modification effects on dietary quality with all-cause and disease-specific mortality in NHANES 2003-2004 and 2011-2012.

BACKGROUND: Associations of dietary or supplementary intake of several unsaturated fatty acids and mortality have been widely studied but the results were still hitherto inconsistent or limited. It is still need to explore the effects of these fatty acids by using the objective biomarkers. OBJECTIVE: We aimed to investigate the relevancy of several serum n-3 and n-6 fatty acids with all-cause and disease-specific mortality to confirm their health effects and effects on the associations between dietary quality and all-cause mortality. METHODS: A total of 4132 people from NHANES 2003-2004 and 2011-2012 and the mortality information was confirmed from the NDI. CPH models adjusted for known risk factors were conducted to explore the associations between circulating n-3 and n-6 fatty acids and all-cause or CVD or cancer mortality under complex sampling. We further evaluated their effects on association between dietary quality and all-cause mortality. RESULTS: A total of 437 deaths occurred during the mean follow-up of 83.34 months, including 157 CVD death and 100 cancer death. Serum LA, ALA, EPA and DHA were associated with all-cause mortality (HR in quintile5: LA:0.584, 95%CI: 0.387-0.882, Ptrend = 0.011; ALA:0.626, 95%CI: 0.432-0.907, Ptrend = 0.008; EPA:0.535, 95%CI: 0.375-0.764, Ptrend = 0.001; DHA:0.669, 95%CI: 0.468-0.955, Ptrend = 0.031). Additionally, serum EPA and ALA were respectively related to CVD and cancer mortality (Q5 HR: EPA:0.450, 95%CI: 0.23-0.854, Ptrend = 0.009; ALA:0.387, 95%CI: 0.167-0.900, Ptrend = 0.022). Serum AA, GLA, DGLA and SDA were not associated with any risk of mortality. The effect on all-cause mortality of the lower AHEI scores can be improved by adherence to a higher serum LA, EPA and DHA (in the lowest AHEI strata, LA in tertile3 compared to tertile1 HR:0.596, 95%CI: 0.366-0.970; EPA:0.660, 95%CI: 0.454-0.959; DHA:0.666, 95%CI; 0.444-1.000). CONCLUSIONS: Our results support the recent dietary recommendations to increase the intake of plant-derived and marine-derived n-6 and n-3 to improve the ability of primary and secondary prevention.

Anticancer Effect of ERM210 on Liver Cancer Cells Through ROS/Mitochondria-dependent Apoptosis Signaling Pathways.

BACKGROUND/AIM: Asian Traditional medicines are renowned for their antitumor properties and are efficacious in the clinical treatment of various cancer types. ERM210 is a Korean traditional medicine comprising nine types of medicinal plants. In the present study, we examined the pro-apoptotic effect and molecular mechanisms of the effects of ERM210 on HepG2 liver cancer cells. MATERIALS AND METHODS: The cytotoxicity of ERM210 on HepG2 cells was investigated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and wound-healing assays, and apoptosis and signaling pathways by fluorescence microscopy flow cytometry and western blotting. RESULTS: ERM210 significantly impaired HepG2 cell viability and enhanced mitochondria-dependent cellular apoptosis in a time- and dose-dependent manner by up-regulating the expression of caspases 3, 7 and 9, and of BCL2 apoptosis regulator (BCL2)-associated X, apoptosis regulator (BAX) proteins, whilst down-regulating that of BCL2 protein. Furthermore, ERM210 treatment increased accumulation of cellular and mitochondrial reactive oxygen species (ROS) and significantly inhibited cell migration. Additionally, all these phenomena were reversed by treating with the ROS scavenger N-acetylcysteine. The analysis of signaling proteins revealed that ERM210 significantly up-regulated the phosphorylation of ROS-dependent mitogen-activated protein kinases (p38, extracellular-regulated kinase, and c-Jun N-terminal kinase in HepG2 liver cancer cells. CONCLUSION: ERM210 exerts anticancer effects in HepG2 liver cancer cells by up-regulating ROS/mitochondria-dependent apoptosis signaling, providing new insight into the possibility of employing this traditional medicine for the clinical treatment of liver cancer.

Ameliorative Effect of Parishin C Against Cerebral Ischemia-Induced Brain Tissue Injury by Reducing Oxidative Stress and Inflammatory Responses in Rat Model.

BACKGROUND: Gastrodia elata Blume (Orchidaceae) is a widely used traditional Chinese herbal medicine in the clinical practice of China, to treat nervous headache, convulsions, dizziness, neurasthenia, and so on. Parishin C (Par C), one of the major bioactive components of Gastrodia elata Blume, is known to exert many different biological activities, including antipsychotic and neuroprotective effects. However, there is little research about its neuroprotective effect in an ischemic stroke model. The objective of the present study is thus to investigate the neuroprotective effects of Par C against cerebral ischemia damage. METHODS: Rats were pretreated with Par C (25, 50, or 100 mg/kg/day, i.p.) for 21 days, then subjected to 2 h of middle cerebral artery occlusion (MCAO) and 22 h of reperfusion. Neurological deficient scores, brain water content, histopathology, TCC staining were performed to assess the neuroprotective effects of Par C. Meanwhile, the oxidative stress, inflammation and apoptosis-related markers of brain tissue were evaluated by corresponding assay kits. Besides, the antioxidant and pro-inflammatory expression was measured by real-time quantification PCR (RT-qPCR). RESULTS: Our findings indicated that the pre-treatment with Par C improved nerve function, suppressed oxidative stress, and pro-inflammatory factors release in rats with cerebral ischemia damage. Besides, Par C significantly increased antioxidant expression and declined pro-inflammatory cytokines expression. CONCLUSION: Par C is shown to exert neuroprotective effects partly via inhibiting oxidative stress and inflammation in a rat model of MCAO.

BRM270 targets cancer stem cells and augments chemo-sensitivity in cancer.

Over the past decade, a number of studies have demonstrated the resistance of cancer cells to conventional drugs and have recognized this as a major challenge in cancer therapy. While attempting to understand the underlying mechanisms of chemoresistance, several studies have suggested that the presence of cancer stem cells (CSCs) in tumors is one of the major pathways contributing toward resistance. Chemoresistance leads to cancer treatment failure and worsens the prognosis of patients. Natural herbal compounds are gaining attention as an alternative treatment strategy for cancer. These compounds may be effective against chemoresistant cells either alone or synergistically alongside conventional drugs, sensitizing cancer cells and enhancing the therapeutic efficacy. BRM270 is a natural compound made from seven herbal plant (Saururus chinensis, Citrus unshiu Markovich, Aloe vera, Arnebia euchroma, Portulaca oleracea, Prunella vulgaris var. lilacina and Scutellaria bacicalensis) extracts used in Asian traditional medicine and has the potential to target CSCs. Several studies have demonstrated the positive effects of BRM270 against chemoresistant cancer and its synergy alongside existing cancer drugs, including paclitaxel and gefitinib. These effects have been observed against various cancer types, including resistant non-small cell lung cancer (NSCLC), glioblastoma, multi-drug resistant osteosarcoma, cervical cancer, pancreatic cancer and hepatocarcinoma. The present review discusses the effects of BRM270 treatment against CSC-associated chemoresistance in common types of cancer.

Picrasma quassioides Extract Elevates the Cervical Cancer Cell Apoptosis Through ROS-Mitochondrial Axis Activated p38 MAPK Signaling Pathway.

BACKGROUND/AIM: Picrasma quassioides (P. quassioides) is used in traditional Asian medicine widely for the treatment of anemopyretic cold, eczema, nausea, loss of appetite, diabetes mellitus, hypertension etc. In this study we aimed to understand the effect of P. quassioides ethanol extract on SiHa cervical cancer cell apoptosis. MATERIALS AND METHODS: The P. quassioides extract-induced apoptosis was analyzed using the MTT assay, fluorescence microscopy, flow cytometry and western blotting. RESULTS: P. quassioides extract induced cellular apoptosis by increasing the accumulation of cellular and mitochondrial reactive oxygen species (ROS) levels and inhibiting ATP synthesis. Pretreatment with N-Acetylcysteine (NAC), a classic antioxidant, decreased the intracellular ROS production and inhibited apoptosis. In addition, the P38 MAPK signaling pathway is a key in the apoptosis of SiHa cells induced by the P. quassioides extract. CONCLUSION: The P. quassioides extract exerts its anti-cancer properties on SiHa cells through ROS-mitochondria axis and P38 MAPK signaling. Our data provide a new insight for P. quassioides as a therapeutic strategy for cervical cancer treatment.

Anti-tumor Properties of Picrasma quassioides Extracts in H-RasG12V Liver Cancer Are Mediated Through ROS-dependent Mitochondrial Dysfunction.

BACKGROUND: Picrasma quassioides (PQ) is a traditional Asian herbal medicine with anti-tumor properties that can inhibit the viability of HepG2 liver cancer cells. H-Ras is often mutated in liver cancer, however, the effect of PQ treatment on H-Ras mutated liver cancer is unclear. This study aimed to investigate the role of PQ on ROS accumulation and mitochondrial dysfunction in H-ras mutated HepG2 (HepG2G12V) cells. MATERIALS AND METHODS: PQ ethanol extract-induced HepG2G12V apoptosis was analyzed by the MTT assay, fluorescence microscopy, flow cytometry and western blotting. RESULTS: PQ treatment affected cell migration and colony formation in HepG2G12V cells. Cleaved-caspase-3, cleaved-caspase-9 and BCL2 associated agonist of cell death (BAD) expression levels were increased, while the levels of B-cell lymphoma-extra large (Bcl-xL) were decreased with PQ treatment. PQ treatment led to a reduction of H-Ras expression levels in liver cancer cells, thus reducing their abnormal proliferation. Furthermore, it led to increased expression levels of Peroxiredoxin VI, which regulates the redox signal in cells. CONCLUSION: Taken together these results provide a new functional significance for the role of PQ in treating HepG2G12V liver cancer.

BRM270 Suppresses Cervical Cancer Stem Cell Characteristics and Progression by Inhibiting SOX2.

BACKGROUND/AIM: Cervical cancer is one of the leading causes of cancer death in women worldwide. BRM270 (BRMLife) has therapeutic potential for cancer treatment owing to its ability to inhibit cell proliferation, and expression of cluster of differentiation (CD) 133 in CD133+ cancer cells. This study was designed to evaluate the therapeutic effects of plant extract formulation BRM270 against cervical cancer progression. MATERIALS AND METHODS: The expression of sex-determining region Y-box 2 (SOX2) was tested in four different cervical cancer cell lines, HeLA, SiHa, Caski and C33A. SOX2-expressing SiHa and C33A cell lines were selected for further experiments on the in vitro and in vivo effects of BRM270 on cervical cancer progression using western blotting, flow cytometry, sphere-formation assay, magnetic-activated cell sorting of CD133+ cervical cancer cells, and xenografts in female athymic BALB/c nude mice. RESULTS: In the present study, in cervical cancer stem cells (CSCs), we found that BRM270 inhibited expression of SOX2, which is associated with cervical cancer initiation and metastasis. BRM270 also inhibited CD133 expression and induced apoptosis of CSCs and suppressed CD133+ CSC proliferation and sphere formation in vitro as well as SiHa and C33A cell xenograft tumor growth in vivo. This was accompanied by down-regulation of markers of epithelial-to-mesenchymal transition. CONCLUSION: BRM270 might be an effective agent for cervical cancer treatment.

Shikonin-induced Apoptosis of Colon Cancer Cells Is Reduced by Peroxiredoxin V Expression.

BACKGROUND/AIM: Colon cancer is the second most common deadliest malignancy in the world and better understanding of its underlying mechanisms is needed to improve clinical management. Natural plant extracts are gaining attention in the development of new therapeutic strategies against various cancer types. Shikonin is a naturally extracted naphthoquinone pigment with effects against cancer, including colon cancer. MATERIALS AND METHODS: In this study, we conducted a series of in vitro experiments to show the effects of Shikonin on colon cancer cell apoptosis. A colon cancer cell line with overexpression of peroxiredoxin V (PrxV) was constructed and the relationship of PrxV expression with Shikonin-induced cell apoptosis was investigated. RESULTS: Shikonin induced colon cancer cell apoptosis via regulation of mammalian target of rapamycin signaling. Shikonin-induced cell apoptosis was abrogated by overexpression of PrxV. CONCLUSION: According to the results obtained in this study, targeting PrxV may provide new insight for the successful management of colon cancer by inducing cell apoptosis.

Efficacy of antioxidant vitamins and selenium supplement in prostate cancer prevention: a meta-analysis of randomized controlled trials.

Several studies have evaluated the possible association between antioxidants vitamins or selenium supplement and the risk of prostate cancer, but the evidence is still inconsistent. We systematically searched PubMed, EMBASE, the Cochrane Library, Science Citation Index Expanded, Chinese biomedicine literature database, and bibliographies of retrieved articles up to January 2009. We included 9 randomized controlled trials with 165,056 participants; methodological quality of included trials was generally high. Meta-analysis showed that no significant effects of supplementation with beta-carotene (RR 0.97, 95% CI 0.90-1.05) (3 trials), vitamin C (RR 0.98, 95% CI 0.91-1.06) (2 trials), vitamin E (RR 0.96, 95% CI 0.85-1.08) (5 trials), and selenium (RR 0.78, 95% CI 0.41-1.48) (2 trials)versus placebo on prostate cancer incidence. The mortality of prostate cancer did not differ significantly by supplement of beta-carotene (RR 1.19, 95% CI 0.87 -1.65) (1 trial), vitamin C (RR 1.45, 95%CI 0.92-2.29) (1 trial), vitamin E (RR 0.85, 95%CI 0.58-1.24) (2 trials), and selenium (RR 2.98, 95% CI 0.12-73.16) (1 trial). Our findings indicate that antioxidant vitamins and selenium supplement did not reduce the incidence and mortality of prostate cancer, these data provide no support for the use of these supplements for the prevention of prostate cancer.

[Effects of paeoniflorin on pathological changes in global brain ischemia model rats].

OBJECTIVE: To explore the effects of paeoniflorin on blood brain barrier and pathological changes in brain ischemia. METHOD: Mice were divided into sham operation group, model group, positive control group-Deng zhanhua tablet group and three different dose (high, middle, low-dose) groups of paeoniflorin. The neurological symptoms of rats were observed. The SOD of ischemic brain tissue, MDA BBB and EAA contents were determined. The ultrastructure on the brain cells was inspected by transmission electron microscope. RESULT: Paeoniflorin had the protetive effects on 4VO model of total cerebral ischemia. Paeoniflorin could obviously increase SOD content, reduce MDA content in rat brain-tissue and alleviate oxidative stress damage by cerebral ischemia on rat brain. Paeoniflorin could improve pathological changes of cell nuclear, perikaryon, mitochondria and myelin sheath, which was the morphologic basis of the protective effect on ischemia. Paeoniflorin could alleviate the incrense of EAA content caused by and hypoxia and inhibit the excitatory neural toxicity by EAA. CONCLUSION: Paeoniflorin has the protection effect on the brain edema after cerebral ischemia, the oxidative stress damage on brain tissue, the ultrastructure lesions of cells and the BBB. The protective mechanism may be related to inhibiting intracellular calcium overload, anti-free radical and reducing EAA content.