Evaluation of Antioxidant, Anti-Tyrosinase, and Anti-Melanoma Activities of Phlomis Rigida

The aim of this study is to evaluate in vitro cytotoxicity of Phlomis rigida (P. rigida) aerial parts on the malignant melanoma cells as well as assess its antioxidant and anti-tyrosinase activities. The total phenolic and flavonoid contents along with in vitro antioxidant and anti-tyrosinase activities of P. rigida MeOH (80%) extract were determined using Folin-Ciocalteu, aluminum chloride, DPPH radical scavenging, and mushroom tyrosinase assays, respectively. The cytotoxicity of the extract was investigated by determination of the cell viability using MTT assay on the normal fibroblast (NIH3T3) and malignant melanoma (SKMEL-3) cells. The extract showed a weak scavenging activity with SC50 value higher than 5 mg/mL and the tyrosinase inhibitory activity with an IC50 value of 1.092 mg/mL. Interestingly, the extract was not toxic on NIH3T3 cells at all tested concentrations (0.0001-0.1 mg/mL), however, it could significantly reduce cell viability on SKMEL-3 cells, particularly at higher concentrations than 0.01 mg/mL (the IC50 ≈ 0.148 mg/mL). Based on our results, a selective cytotoxic effect against SKMEL-3 cells was found for the extract of P. rigida compared with NIH3T3 cells. Therefore, it is recommended as a good candidate for further investigation to discover bioactive natural agents in melanoma treatmen

Mechanistic assessment of cadmium toxicity in association with the functions of estrogen receptors in the Langerhans islets

Objective(s): Diabetes is a metabolic disease with an increasing prevalence for which finding new and efficient therapeutic approaches has always been a challenge. Preserving integrity and functionality of pancreatic β-cells as the only source of insulin in the body is such a case. To achieve this goal different cellular targets have been proposed among which pancreatic estrogen receptors have gotten much attention. In this work, we evaluated the integrity and function of islets of Langerhans under the influence of factors known to intervene with estrogen receptors. Cadmium, a toxic heavy metal, has been recently shown to interact with estrogen receptors but its toxicity in the pancreatic islets regarding this mechanism remains unclear. Materials and Methods: Isolated islets of Langerhans from the pancreas of rats were grouped and treated with cadmium chloride and also cadmium chloride plus β-estradiol. After 24 hr incubation, parameters of cellular viability, oxidative stress, apoptosis, and insulin secretion were measured. Results: The results indicated that cadmium reduced viability of the islets along with an increase in the formation of reactive oxygen species and apoptosis markers, and β-estradiol, in turn, was able to alleviate these disturbances to some extent, implicating the protective role of β-estradiol against pancreatic toxicity of cadmium. Conclusion: It can be concluded that modification of estrogen receptors in the endocrine pancreas and especially β-cells may be a promising target to find a new therapeutic strategy for diabetes and even uncovering mechanisms of environmental toxicants that have been known as risk factors of diabetes

Endo-cannabinoids system and the toxicity of cannabinoids with a biotechnological approach

Cannabinoids have shown diverse and critical effects on the body systems, which alter the physiological functions. Synthetic cannabinoids are comparatively innovative misuse drugs with respect to their nature of synthesis. Synthetic cannabinoids therapy in healthy, chain smokers, and alcoholic individuals cause damage to the immune and nervous system, eventually leading to intoxication throughout the body. Relevant studies were retrieved using major electronic databases such as PubMed, EMBASE, Medline, Scopus, and Google Scholar. The extensive use of Cannabis Sativa L. (C. Sativa) and its derivatives/analogues such as the nonpsychoactive dimethyl heptyl homolog (CBG-DMH), and tetrahydrocannabivarin (THCV) amongst juveniles and adults have been enhanced in recent years. Cannabinoids play a crucial role in the induction of respiratory, reproductive, immune and carcinogenic effects; however, potential data about mutagenic and developmental effects are still insufficient. The possible toxicity associated with the prolong use of cannabinoids acts as a tumor promoter in animal models and humans. Particular synthetic cannabinoids and analogues have low affinity for CB1 or CB2 receptors, while some synthetic members like Δ9-THC have high affinity towards these receptors. Cannabinoids and their derivatives have a direct or indirect association with acute and long-term toxicity. To reduce/attenuate cannabinoids toxicity, pharmaceutical biotechnology and cloning methods have opened a new window to develop cannabinoids encoding the gene tetrahydrocannabinolic acid (THCA) synthase. Plant revolution and regeneration hindered genetic engineering in C. Sativa. The genetic culture suspension of C. Sativa can be transmuted by the use of Agrobacterium tumefaciens to overcome its toxicity. The main aim of the present review was to collect evidence of the endo-cannabinoid system (ECS), cannabinoids toxicity, and the potential biotechnological approach of cannabinoids synthesis

Beneficial Effects of Trachyspermum ammi (L.) Sprague on Rat Irritable Bowel Syndrome

Background and objective: Trachyspermum ammi (T. ammi) has been used for the treatment of various digestive disorders with considerable therapeutic effects such as anticholinergic and anti-oxidant activities.This study aimed to evaluate the efficacy of the hydro-alcoholic extract of the fruits of T. ammi in an experimental model of irritable bowel syndrome (IBS). Methods: The rats were classified into seven groups, including sham (no stress), control (saline recipients), loperamide and fluoxetine (10 mg/kg/day) (positive controls), and the plant groups at the doses of 150, 250 and 500 mg/kg/day for 5 days under restrictive stress, 2 days before receiving the treatment. All medicines were given as gavage. The effect of the plant extract on gastric emptying and the transit of the small intestine was evaluated. The levels of the inflammatory and oxidative related biomarkers, tumor necrosis factor alpha (TNF-α) and lipid peroxidation (LPO), also the myeloperoxidase (MPO) activity were measured. Results: The gastric emptying and the transit of the small intestine were significantly reduced in all T. ammi treated groups, and no significant difference was observed at the dose of 500 mg/kg/day compared with the loperamide group. The levels of TNF-α and MPO activities decreased in the treatment groups compared with the control, and the LPO level was decreased at the concentrations of 250 and 500 mg/kg/day compared to the control. The antioxidant levels significantly increased in the rats treated with T. ammi at the doses of 250 and 500 mg/kg/day. Conclusions: The severity of stress-induced IBS was reduced in a dose-dependent manner by the hydro-alcoholic extract of the fruits of T. ammi, confirming the effectiveness of this plant in the management of IBS.  </strong

Global, regional, and national burden of disorders affecting the nervous system, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

BackgroundDisorders affecting the nervous system are diverse and include neurodevelopmental disorders, late-life neurodegeneration, and newly emergent conditions, such as cognitive impairment following COVID-19. Previous publications from the Global Burden of Disease, Injuries, and Risk Factor Study estimated the burden of 15 neurological conditions in 2015 and 2016, but these analyses did not include neurodevelopmental disorders, as defined by the International Classification of Diseases (ICD)-11, or a subset of cases of congenital, neonatal, and infectious conditions that cause neurological damage. Here, we estimate nervous system health loss caused by 37 unique conditions and their associated risk factors globally, regionally, and nationally from 1990 to 2021.MethodsWe estimated mortality, prevalence, years lived with disability (YLDs), years of life lost (YLLs), and disability-adjusted life-years (DALYs), with corresponding 95% uncertainty intervals (UIs), by age and sex in 204 countries and territories, from 1990 to 2021. We included morbidity and deaths due to neurological conditions, for which health loss is directly due to damage to the CNS or peripheral nervous system. We also isolated neurological health loss from conditions for which nervous system morbidity is a consequence, but not the primary feature, including a subset of congenital conditions (ie, chromosomal anomalies and congenital birth defects), neonatal conditions (ie, jaundice, preterm birth, and sepsis), infectious diseases (ie, COVID-19, cystic echinococcosis, malaria, syphilis, and Zika virus disease), and diabetic neuropathy. By conducting a sequela-level analysis of the health outcomes for these conditions, only cases where nervous system damage occurred were included, and YLDs were recalculated to isolate the non-fatal burden directly attributable to nervous system health loss. A comorbidity correction was used to calculate total prevalence of all conditions that affect the nervous system combined.FindingsGlobally, the 37 conditions affecting the nervous system were collectively ranked as the leading group cause of DALYs in 2021 (443 million, 95% UI 378–521), affecting 3·40 billion (3·20–3·62) individuals (43·1%, 40·5–45·9 of the global population); global DALY counts attributed to these conditions increased by 18·2% (8·7–26·7) between 1990 and 2021. Age-standardised rates of deaths per 100 000 people attributed to these conditions decreased from 1990 to 2021 by 33·6% (27·6–38·8), and age-standardised rates of DALYs attributed to these conditions decreased by 27·0% (21·5–32·4). Age-standardised prevalence was almost stable, with a change of 1·5% (0·7–2·4). The ten conditions with the highest age-standardised DALYs in 2021 were stroke, neonatal encephalopathy, migraine, Alzheimer's disease and other dementias, diabetic neuropathy, meningitis, epilepsy, neurological complications due to preterm birth, autism spectrum disorder, and nervous system cancer.InterpretationAs the leading cause of overall disease burden in the world, with increasing global DALY counts, effective prevention, treatment, and rehabilitation strategies for disorders affecting the nervous system are needed

Discovery approaches for novel dyslipidemia drugs

Introduction: Dyslipidemia is increased fasting level of total cholesterol (TC), LDL cholesterol (LDL-C), and triglycerides (TG), along with decreased levels of HDL cholesterol (HDL-C). Owing to effect on the cardiovascular system and increased chances of metabolic diseases, it is needed to review novel under development drugs and new approaches in drug discovery for dyslipidemia. Areas Covered: This article reviews all phases I to IV clinical trials and preclinical trials with results associated with novel treatment of dyslipidemia. Drug discovery for dyslipidemia, toward newer targets has been addressed. Findings: Statins are, currently available, best choice of drugs for treating dyslipidemia and coronary diseases. In addition to this, lipid lowering drugs support treatment to a great extent, either as monotherapy or in combinations with other groups. Pravastatin used in combination with cholesteryl ester, transfers protein inhibitors (CETP) to produce efficient results. Peroxisome proliferator-activated receptor agonists (PPAR) like muraglitazar, aleglitazar and tesaglitazar are PPAR a/y receptor agonist, dual in action performs better in phase 3 clinical study and reduces renal and cardiovascular events. By targeting both receptors, a better treatment for cardiovascular and diabetic problems can be achieved. Proprotein convertase subtilisin/kexin type 9 (PCSK-9) inhibitors like humanized monoclonal antibodies, are newly discovered inhibitors that reduce the risk of cardiovascular diseases. During the past few years, nucleic acid-based therapies targeting lipid and lipoprotein metabolism, such as microsomal TG transfer protein (MTP) may be a promising therapeutic approach to treat vascular diseases. Gene regulating transcription factors involved in bile acids and cholesterol metabolism can be controlled by FXR agonists in dyslipidemia. To overcome these drawbacks, many thyroid hormone analogues have been developed to lower down cholesterol level by targeting specifically thyroid hormone β receptors abundantly present in the liver without severe side effects. Virtual screening, an important tool in screening databases of the lead compounds, provides a good platform to access new compounds. In this review, examples of novel FXR modulators, thyromimetic agents, cholesterol absorption inhibitors and other new anti hyperlipidemia scaffolds have been addressed

Multiple protective mechanisms of alpha-lipoic acid in oxidation, apoptosis and inflammation against hydrogen peroxide induced toxicity in human lymphocytes

The naturally antioxidant and coenzyme, alphalipoic acid (alpha-LA), has gained considerable attention regarding different functions and therapeutically effective in treating oxidative stress-associated diseases in the human body. This study was designed to examine the protective effect of alpha-LA against H2O2-induced oxidative stress and apoptosis in human lymphoid cells. Human peripheral blood lymphocytes were preincubated with alpha-LA and then exposed to H2O2. After that, the viability of the cells, rate of apoptosis, oxidative stress biomarkers such as reactive oxygen species (ROS) and level of lipid peroxidation (LPO), and also tumor necrosis factor-alpha (TNF-alpha) were studied. Pretreatment of lymphocytes with alpha-LA, dramatically enhanced viability of the cells and decreased apoptosis. Investigation of caspases gives a clear picture of the mechanism by which alpha-LA decreases ROS and causes a reduction in apoptosis through caspase-9-dependent mitochondrial pathway. Furthermore, alpha-LA dose dependently decreased oxidative stress by a reduction in level of LPO, and the dose of 1000 mu M indicates a significant decrease (p < 0.01) in TNF-alpha level. Collectively, the present data show that alpha-LA is an ideal compound which has profound protective effects on oxidation, inflammation, and apoptosis. As a result, alpha-LA may indicate a new way toward the development of antioxidant therapy

Biochemical and molecular evidences on the protection by magnesium oxide nanoparticles of chlorpyrifos-induced apoptosis in human lymphocytes

Background: Chlorpyrifos (CP) is one of the most widely used organophosphate (OP) insecticides in agricultural and residential pest control with its attendant adverse health effect. In the present study, it is proposed to investigate the possible modulatory role of magnesium oxide nanoparticles (MgO NPs) against CP-induced toxicity in human lymphocytes and determine the mechanisms lying behind this protection by viability and biochemical assays. Materials and Methods: Isolated lymphocytes were exposed to 12 μg/mL CP either alone or in combination with different concentrations of MgO NPs (0.1 μg/mL, 1 μg/mL, 10 μg/mL, and 100 μg/mL). After a 3-day incubation, the viability and oxidative stress markers including cellular mitochondrial activity, caspase-3 and -9 activities, total antioxidant power, lipid peroxidation, and myeloperoxidase (MPO) activity were measured. Also, the levels of tumor necrosis factor-α (TNF-α) as inflammatory index, along with acetylcholinesterase (AChE) activity were measured. Statistical differences were determined using one-way analysis of variance (ANOVA) and Dunnett′s multiple comparison tests. Results: It is indicated that CP-exposed lymphocytes treated with MgO NPs resulted in a substantial reduction in the pace of mortality as well as the stages of oxidative stress in a dose-dependent manner. Also, MgO NPs (100 μg/mL) meaningfully restored CP-induced increase of TNF-α (P < 0.001) and decrease of AChE activity (P < 0.001) and were capable of preventing CP-treated human lymphocytes from apoptosis (P < 0.001). Conclusion: Our results demonstrate that MgO NPs in approximate 100 nm diameter not only make cells resistant to the toxic properties of CP but also attenuate toxic effects of CP, which is demonstrating the potential of MgO NPs to be applied in future immune deficiency therapeutic strategies

Polysaccharide-based hydrogel enriched by epidermal growth factor peptide fragment for improving the wound healing process

Wounds represent a ''silent epidemic'' in the global population that impact significantly people's quality of life and the economy of societies. Owing to the numerous therapies, the pursuit of a perfect wound dressing with superior performance for treating all sorts of wounds is still underway. Several studies have shown the potential of integrating restorative peptides into the scaffolds as potential therapeutic candidates for wound healing. So far, there is little information about the wound-healing effect of S-acetamidomethyl Cys 20-31-EGF peptide, a main fragment of epidermal growth factor. In this regard, the effectiveness of this peptide in the alginate-gum arabic polysaccharide hydrogel was evaluated as a wound dressing (AG-P). Physicochemical evaluation of the hydrogels demonstrated that the incorporation of the peptide compressed the hydrogel network due to the presence of hydrogen and electrostatic bonds without significant effect on the mechanical, viscoelastic properties, swelling and degradation rate of the hydrogel. The hydrogel could continuously release the peptide and prevent rapid attenuation of its concentration. Cellular assessment of AG-P by scratch test and CFSE cytoplasmic dye/flow cytometry technique encouraged the migration and proliferation of human fibroblast cells, respectively. The effect of the AG-P on the expression of IL-6, TNF-α, NF-kB1 and VEGF genes indicated that this hydrogel reduced inflammation, and significantly increased angiogenesis compared to the control group based on the Real-time PCR results. In vitro assessment indicated that this structure can promote efficient and faster wound regeneration by altering the microenvironment of the wound. The hydrogel showed interesting features to be more equipped with other therapeutic agents making it as suitable dressing for various type of the wounds

Curcumin increases insulin sensitivity in C2C12 muscle cells via AKT and AMPK signaling pathways

Background: Diabetes is an enduring condition that causes impaired, peripheral insulin resistance. Curcumin was shown to exert notable anti-diabetic effects, which might be possible by overexpression of certain glucose transporter genes and glycoprotein content within the cells. Objectives: To investigate the effect of curcumin alone and in concomitant with insulin on glucose translocation from intracellular compartments of nuclear or endoplasmic reticulum membranes into the cytoplasmic membrane (CM) and key kinases involved in insulin signaling pathways. Materials and Methods: C2C12 myoblast cells were cultured and differentiated to the myotubes. Later, the cells were treated with curcumin alone or a combination of curcumin and insulin, so their viability was measured by MTT assay. The expression level of GLUT 4 gene was examined by Real Time-reverse Transcription Polymerase Chain Reaction (qRT-PCR). To evaluate the activity of curcumin and curcumin/insulin synergistic effect on stimulated GLUT4 translocation, kinases AKT, P-AKT, AMP-activated protein kinase (AMPK) and P-AMPK were assessed and detected via Western Blotting (WB). Results: Curcumin significantly induced GLUT 4 expression and its translocation from intra-cell space into the cell surface and showed a synergic effect on GLUT 4 translocation in presence of insulin. This synergistic effect was inhibited by the insulin receptor inhibitor AG1024 and the inhibitor of AMPK signaling, compound C. Conclusion: Curcumin demonstrated a synergistic effect with insulin and could be a choice of type 2 diabetes mellitus (T2DM) treatment, which may be affected by both AKT and AMPK signaling pathways, hereby facilitates glucose uptake into the cells