Remdesivir-Related Cardiac Adverse Effects in COVID-19 Patients: A Case-Control Study.

BACKGROUND: There have been reports of serious side effects of Remdesivir, including cardiovascular complications. The present study aimed to determine the adverse cardiovascular effects of Remdesivir and the factors affecting them in COVID-19 patients. METHODS: The patients were classified into two groups: those receiving Remdesivir without cardiac complications and those receiving Remdesivir with cardiovascular complications. After reviewing the patient's medical records, the relationship of some factors with the incidence of adverse cardiovascular effects was measured. RESULTS: Chi-square test showed that the distribution of complications in men was significantly higher than in women (P=0.001). The independent t-test revealed that the mean age in the group with complications was significantly higher than the group without complications (P=0.013). Fisher's exact test demonstrated a significant relationship between smoking and cardiovascular complications (P=0.05). According to the Mann-Whitney test, a significant difference was found in the mean changes of Bilirubin (P=0.02) and ALKP (P=0.01) before and after treatment in the groups with and without heart complications. CONCLUSION: Our findings indicated that most of the COVID-19 patients suffered from sinus bradycardia, and the distribution of complications was more pronounced in men than in women. The mean age in the group with complications was higher than the group without complications. Smoking was found to be associated with the occurrence of cardiovascular complications and the mean changes of Bilirubin and ALKP before and after treatment were significantly different in the groups with and without cardiovascular complications.

Notice of retraction: Auraptene-induced cytotoxicity mechanisms in human malignant glioblastoma (U87) cells: role of reactive oxygen species (ROS).

[This retracts the article DOI: 10.17179/excli2019-1136.].

Harmaline exerts potentially anti-cancer effects on U-87 human malignant glioblastoma cells in vitro.

BACKGROUND: Harmaline is a ß-carboline alkaloid that can be extracted from the seeds of Peganum harmala. Harmaline has been shown to exhibit a potent cytotoxic effect against tumor cells. In this study, the anti-glioblastoma activity of harmaline was investigated in vitro. METHODS AND RESULTS: Cell viability, apoptosis, and cell cycle arrest were assessed in U-87 cells treated with harmaline at different doses. Reactive oxygen species (ROS) generation and the mRNA expression of apoptosis-associated genes were assessed. The anti-metastatic effect of harmaline on U-87 cells was evaluated by gelatin zymography assay where matrix metalloproteinase [MMP]-2/-9 enzymatic activity was measured, and the scratch assay was used to assess migratory responses. Flow cytometry demonstrated that harmaline could suppress the proliferation and induce sub-G1 cell cycle arrest and apoptotic cell death in glioblastoma cells. Harmaline treatment was also associated with an upregulation of the cell cycle-related genes, p21 and p53, and pro-apoptotic Bax, as well as the induction of ROS. The zymography assay indicated that the essential steps of metastasis were potently suppressed by harmaline through inhibiting the expression of MMP-2 and - 9. In addition, the migration of U-87 cells was significantly reduced after harmaline treatment. CONCLUSION: Our data suggest a basis for further research of harmaline which has potential cytotoxic activities in glioblastoma cells; inducing cell cycle arrest and apoptosis, repression of migration, possibly invasion, and metastasis.

Therapeutic Potential of Saffron (Crocus sativus L.) in Ischemia Stroke.

Stroke is the second leading cause of death and a main cause of disability worldwide. The majority (approximately 80%) of strokes are ischemic. Saffron (Crocus sativus L.) has been considered for medicinal purposes since ancient times. Pharmacological effects of saffron are attributed to the presence of crocin, crocetin, picrocrocin, and safranal. In the present review, we summarized the reported neuroprotective effects of saffron and its active constituents against cerebral ischemia stroke. Saffron and its components exert its beneficial effects as an antioxidant, anti-inflammatory, and antiapoptotic agent though inhibition of biochemical, inflammatory, and oxidative stress markers. Taken together, this review indicates that saffron and its ingredients could be a potent candidate in the process of new drug production for the treatment of ischemia stroke.

Protective Role of Natural Products in Glioblastoma Multiforme: A Focus on Nitric Oxide Pathway.

In spite of therapeutic modalities such as surgical resection, chemotherapy, and radiotherapy, Glioblastoma Multiforme (GBM) remains an incurable fatal disease. This necessitates further therapeutic options that could enhance the efficacy of existing modalities. Nitric Oxide (NO), a short-lived small molecule, has been revealed to play a crucial role in the pathophysiology of GBM. Several studies have demonstrated that NO is involved in apoptosis, metastasis, cellular proliferation, angiogenesis, invasion, and many other processes implicated in GBM pathobiology. Herein, we elaborate on the role of NO as a therapeutic target in GBM and discuss some natural products affecting the NO signaling pathway.

Hypnotic Activity of Capparis spinosa Hydro-alcoholic Extract in Mice.

BACKGROUND: Sleep disorders are among the most common psychiatric and medical conditions. Herbal medicine appears to be effective in the treatment of sleep disorders which have been valued by many of publications and patents. OBJECTIVE: The present study aimed at investigating the hypnotic activity of the hydro-alcoholic extract of Capparis spinosa (HAE) in mice. METHODS: Three doses of HAE (30, 60 and 120 mg/kg) and three fractions of it, namely n-hexane fraction (NHF), water fraction (WF), and ethyl acetate fraction (EAF), were given in comparison with diazepam (3 mg/kg body weight i.p.) as a positive control and saline as a negative control. After 30 min, pentobarbital (30 mg/kg body weight i.p.) was administered. In addition, LD50 of HAE was examined and the cytotoxicity of HAE was assessed in l929 cells using the MTT assay. Moreover, for motorcoordination ability, 30 mins after administration of HAE, the rotarod test was performed. RESULTS: The results exhibited that the HAE and all the fractions significantly augmented pentobarbital induced sleeping time, which was comparable to that of induced by diazepam. The LD50 value was 2.4 g/kg. The extract did not induce any cytotoxic effects in L929 fibroblast cells. HAE did not affect the animals' performance on the rotarod test. CONCLUSION: Our finding suggests that the hydro-alcoholic extract of C. spinosa possesses a hypnotic potential that may require further scientific investigations.

Natural products as promising targets in glioblastoma multiforme: a focus on NF-κB signaling pathway.

BACKGROUND: Glioblastoma multiforme (GBM), as the broadest cerebrum tumor, is resistant to current medical interventions, particularly chemo/radiation. Hence, it necessitates further therapeutic options that could enhance the efficacy of existing modalities. METHODS: A comprehensive and systematic review of literature on the NF-κB signaling pathway-contributed in the pathogenesis of GBM with a focus on natural products was carried out. RESULTS: Several examinations have shown that nuclear factor (NF)-κB is participated in apoptosis, cellular proliferation, angiogenesis, metastasis, invasion, and many other processes implicated in GBM pathobiology. Recent studies have provided that NF-κB regulation is the primary pharmacological target for GBM therapy. Specific natural products are involved in several signaling pathways implicated in tumor growth and apoptosis of GBM cells. CONCLUSION: In the current review, we elaborate on the role of NF-κB as a promising target in GBM and discuss some natural products affecting the NF-κB signaling pathway.

Tanacetum parthenium enhances pentobarbital-induced sleeping behaviors.

OBJECTIVE: Sleep disorders are among the most common psychiatric and medical conditions. In the present study, the hypnotic effect of Tanacetum parthenium was studied in mice. MATERIALS AND METHODS: The hydro-alcoholic extract (HAE) of T. parthenium and three fractions of it, namely water fraction (WF), ethyl acetate fraction (EAF), and n-hexane fraction (NHF), were intraperitoneally (ip) administrated to mice 30 min before injection of sodium pentobarbital (30 mg/kg, ip). Then, 30 min after administration of HAE, motor coordination (rota-rod test) was evaluated. Besides, LD50 of HAE was determined and the cytotoxicity of HAE was evaluated in PC12 cells using the MTT assay. RESULTS: HAE 50-200 mg/kg increased the sleeping time. EAF was the only fraction which could prolong the sleep duration and decrease sleep latency. The LD50 value was 4.8 g/kg. The extract induced no cytotoxic effects in PC12 cell line. CONCLUSION: The results suggested that T. parthenium potentiates pentobarbital hypnosis without causing toxic effects. Probably, its effects are mediated by the components present in EAF of this plant.

Auraptene-induced cytotoxicity mechanisms in human malignant glioblastoma (U87) cells: role of reactive oxygen species (ROS).

Glioblastoma multiforme (GBM), like the devastating type of astrocytic tumors, is one of the most challenging cancers to treat owing to its aggressive nature. Auraptene, as a prenyloxy coumarin from citrus species, represents antioxidant and antitumor activities; however, the underlying antitumor mechanisms of auraptene against GBM remain unclear. The present study aimed to evaluate the cytotoxic and apoptogenic effects of auraptene, as a promising natural product, and the possible signaling pathways affected in human malignant GBM (U87) cells. Reactive oxygen species (ROS) production significantly decreased in the first 2, and 6 hours after treatment with auraptene however, ROS levels increased in other incubation times (8 and 24 hours), dramatically. N-acetyl-cysteine (NAC) markedly attenuated auraptene-induced ROS production, and consequently reversed auraptene-induced cytotoxicity in 8 and 24 hours after treatment, as well. Induction of apoptosis occurred in the first 24- and 48-hours concentration-dependently. The qRT-PCR showed an up-regulation in p21, CXCL3, and a down-regulation in Cyclin D1 genes expression. Western blot analysis confirmed the up-regulation of the Bax/Bcl-2 ratio protein levels concentration-dependently. Hence, this study collectively revealed that the increase in ROS level is at least one of the mechanisms associated with auraptene-induced GBM cell toxicity as well as the induction of apoptosis through Bax/Bcl-2 modulation and genes expression involved that contribute to the cytotoxicity of auraptene in U87 cells. So, auraptene might be utilized as a potential novel anti-GBM agent after further studies.

Cytotoxic Effects of Ferula Latisecta on Human Glioma U87 Cells.

Glioblastoma multiforme (GBM) is the fatal type of astrocytic tumors with a survival rate of 12 months. The present study, for the first time, evaluated the cytotoxic impacts of Ferula latisecta (F. latisecta) hydroalcoholic extract on U87 GBM cell line. The MTT assay measured the cellular toxicity following 24- and 48 h treatment with various doses of F. latisecta (0-800 µg/mL). Apoptosis was evaluated by an Annexin V/propidium iodide (PI) staining 24 h after treatment by F. latisecta. Moreover, to determine the cellular metastasis of U87 cells, we used a gelatin zymography assay (matrix metalloproteinase [MMP]-2/-9 enzymatic activity). The outcomes showed that F. latisecta mitigated the viability of U87 cells in a concentration- and time-dependent manner with IC50 values of 145.3 and 192.3 µg/mL obtained for 24- and 48 h treatments, respectively. F. latisecta induced apoptosis in a concentration-dependent manner after 24 h. Also, MMP-9 activity was significantly decreased following 24 h after treatment concentration-dependently with no change in MMP-2 enzymatic activity. This study showed that F. latisecta induced cytotoxicity and apoptosis, and mitigated metastasis of U87 GBM cells. Hence, F. latisecta could be beneficial as a promising natural herb against GBM after further studies.

Cytotoxic effects of auraptene against a human malignant glioblastoma cell line.

OBJECTIVE: Glioblastoma multiforme (GBM) is the deadliest type of primary brain tumors, and the survival of patients is estimated to be only about one year. This study, for the first time, investigated the cytotoxic effects of auraptene on U87 GBM cell line. MATERIALS AND METHODS: The cellular toxicity was measured by the MTT assay following 24 and 48-hr treatment with different concentrations of auraptene (0-400µg/ml). Apoptosis was evaluated by sub-G1 peak in cell cycle analysis of propidium-iodide- stained nuclei. Moreover, to determine the Bax, Bcl-2, MCP-1, NF-κB, IL-1ß, and p53 genes expression, we used real-time polymerase chain reaction (RT-PCR). RESULTS: The results revealed that auraptene reduced the viability of U87 cells concentration- and time-dependently with IC50 values of 108.9 and 79.17µg/ml obtained for 24 and 48-hr treatments, respectively. Also, sub-G1 population was significantly increased following 24 (p<0.05 and p<0.001) and 48 (p<0.001) hours of treatment. The quantitative real-time RT-PCR showed an up-regulation in Bax, NF-κB, IL-1ß, and p53 but a down-regulation in MCP-1 and Bcl-2 genes expression. CONCLUSION: This study showed that auraptene triggered apoptosis probably through Bax/Bcl-2 regulation, blocked cell cycle progression and inhibited proliferation in U87 GBM cells. Taken together, auraptene can be utilized as an effective natural medicine against GBM, after complementary studies.

A comparison between the effects of Portulaca oleracea seeds extract and valsartan on echocardiographic and hemodynamic parameters in rats with levothyroxine-induced thyrotoxicosis.

OBJECTIVE: The aim of the present study was to compare the effects of Portulaca oleracea (Po) seeds extract and those of valsartan on cardiac function in levothyroxine (T4)-treated rats. MATERIALS AND METHODS: Forty Wistar rats were divided into four groups (n=10): control, levothyroxine (T4), T4 plus valsartan (T4-Val) and T4 plus hydro-alcoholic extract of the P. oleracea seeds (T4-Po). Control group received normal saline. Levothyroxine (100µg/kg/day, i.p.) was administered to three other groups for 4 weeks. Valsartan (8 mg/kg/day, orally) and Po seeds extract (400 mg/kg/day, orally) were administered during the last two weeks of treatment period. At the end of the experiment, echocardiographic and hemodynamic parameters were measured and serum free T4, T3, and T4 were measured. RESULTS: Administration of T4 for 4 weeks significantly increased serum free T4 levels in T4 group but elevations of free T4 levels in T4-Val group were not significant. Free T4 level decreased in T4-Po (p<0.01) compared to T4 group. Heart rate (HR), heart weight (HW), and left ventricular systolic pressure (LVSP) were significantly increased in T4 group compared to control group while these parameters in the other groups were not significantly different from those of control group. The reduction in HR, HW, and LVSP were more prominent in T4-Po group. Ejection fraction (EF) and fraction shortening (FS) were insignificantly decreased in T4 group compared to control group. CONCLUSION: These results showed that treatment of hyperthyroid rats with P. oleracea seeds extract was more effective than valsartan in reducing cardiac changes induced by levothyroxine.

Toxicity assessment of Ferula gummosa administration during pregnancy, lactation, and juvenile period in rat.

Ferula gummosa is widely used in traditional medicine to treat a variety of ailments. This work evaluated the safety of F. gummosa root in pregnancy, lactation, and juvenile periods. This study was performed in three parts: (1) pregnant rats were received diet containing 0 (control), 150 , or 700 mg/kg of F. gummosa root during pregnancy; (2) Lactating rats were treated with diet containing the root (0, 150, or 700 mg/kg) during lactation period; (3) juvenile rats were received 4 weeks diet containing the root (0, 150, or 700 mg/kg). F. gummosa at both doses had no significant effects on the duration of pregnancy, maternal weight, and the number of delivered pups, but at dose of 700 mg/kg decreased birthweight of the pups. In lactation period, F. gummosa had no significant effects on mortality, body weight, body length, the weight of organs, and blood biochemical parameters of offspring. In juvenile rats, food consumption, body weight, and WBCs number were decreased in treated groups. No histopathological lesions were detected in the brain, heart, liver, lungs and kidney of offspring, and juvenile rats in treated groups. LC/MS/MS analysis confirmed systemic absorption of active constituents of the root by the oral route of administration. In conclusion, F. gummosa root did not produce significant toxic effects during pregnancy, lactation, and juvenile period. But, decrease in birthweight of delivered pups and in weight gain of juvenile rats should be considered in the long-term consumption of this plant.

Effects of pomegranate seed oil on oxidant/antioxidant balance in heart and kidney homogenates and mitochondria of diabetic rats and high glucose-treated H9c2 cell line.

OBJECTIVE: Oxidative stress is a major cause of diabetes complications. The present study aimed to investigate the beneficial effects of Pomegranate Seed Oil (PSO) on diabetes-induced changes in oxidant/antioxidant balance of the kidney, heart and mitochondria from rats and H9c2 cell line. MATERIALS AND METHODS: In these in vivo and in vitro studies, male rats were divided into four groups (twelve each): group 1 served as control, group 2-4 received a single dose of streptozotocin (60 mg/kg, i.p), groups 3 and 4 received PSO (0.36 and 0.72 mg/kg/daily, gavage), respectively. After three weeks, six rats of each group and one week later the remaining animals were anaesthetized and the hearts and kidneys were removed and homogenized. Mitochondrial fractions were separated and enzyme activities were measured in each sample. H9c2 cells were pretreated with high levels of glucose (35 mM), and then, incubated with PSO. Finally, cell viability test, reactive oxygen species production and lipid peroxidation were evaluated. RESULTS: Significant reduction in enzymes activity (Superoxide dismutase, Glutathione S-transferase and Paraoxonase 1), compensatory elevation in Glutathione Reductase, Glutathione Peroxidase and Catalase activity followed by reduction after one week and significant elevation in Oxidative Stress Index (OSI) were observed in diabetic group. PSO treatment resulted in a significant increase in enzymes activity and decreased OSI values compared to diabetic group in both tissue and mitochondrial fractions. PSO remarkably decreased glucose-induced toxicity, ROS level and lipid peroxidation in H9c2 cells. CONCLUSION: Results suggested that PSO has a protective effect against diabetes-induced alterations in oxidant/antioxidant balance in tissues, mitochondrial and H9c2 cell line.

A comprehensive review on the potential therapeutic benefits of phosphodiesterase inhibitors on cardiovascular diseases.

Phosphodiesterases are a group of enzymes that hydrolyze cyclic nucleotides, which assume a key role in directing intracellular levels of the second messengers' cAMP and cGMP, and consequently cell function. The disclosure of 11 isoenzyme families and our expanded knowledge of their functions at the cell and molecular level stimulate the improvement of isoenzyme selective inhibitors for the treatment of various diseases, particularly cardiovascular diseases. Hence, future and new mechanistic investigations and carefully designed clinical trials could help reap additional benefits of natural/synthetic PDE inhibitors for cardiovascular disease in patients. This review has concentrated on the potential therapeutic benefits of phosphodiesterase inhibitors on cardiovascular diseases.

Toxicity evaluation of hydroalcoholic extract of Ferula gummosa root.

Traditionally, people use harvested Ferula gummosa for medicinal purposes. However, no information about its safety and toxicity is available. In the present study, the toxicological profile of sub-chronic oral administration of hydroalcoholic extract of F. gummosa radix is evaluated in rats. The extract was orally administrated at 100 and 600 mg/kg to male rats for 28 days. After 28 days, clinical signs, mortality, body weights, food and water consumption, organ weights, hematology, serum biochemistry, as well as histopathological and neurobehavioral changes were examined. Also, the sedative effect of this extract was evaluated in mice at the doses of 100, 600, and 800 mg/kg. Its cytotoxicity against human stroma-vascular cells and human renal epithelial cells were also evaluated. No lethality or adverse toxic signs were seen during the experimental period. There were no significant changes in body and organ weights, hematology, serum biochemistry, and histopathological examination. The extract decreased the rotarod performance, but did not increase pentobarbital-induced hypnosis. Also, F. gummosa extract significantly decreased cell viability at the concentrations of higher than 400 µg/mL. In conclusion, the sub-chronic toxicity study of F. gummosa hydroalcoholic extract demonstrated the extract to be safe for the tested dosage and route of administration.