New method for risk assessment in environmental health: The paradigm of heavy metals in honey.

The release of heavy metals into the natural environment creates problems due to their persistence. They can accumulate in the food chain presenting a dangerous sign for ecosystems and human health. The metals in honey could be of agrochemical or industrial origin. Regular consumption of honey and bee products contaminated with various pollutants in high concentrations can cause serious health problems due accumulation of toxic substances in the body. In the current study, we aimed to determine the concentrations of chromium, cadmium, zinc, copper, lead and nickel in four types of honey (linden, acacia, rapeseed and polyfloral honey) and soil collected from three regions with different degrees of pollution. For the risk characterization, we used a new methodology that calculated the corrected estimated daily intake and the source hazard quotient for each metal and the adversity-specific hazard index. There was a strong influence of the degree of environmental pollution on the level of contaminants in the honey samples. In the case of a single chemical assessment, an HQ above 10 was obtained for Cd in linden, rapeseed and polyfloral honey from area 1 and an HQ above 1 was obtained for Cd in the other honey samples from the 3 areas, for Cu in all honey samples from all the 3 areas, for Pb in linden, rapeseed and polyfloral honey from area 1 and for Cr in linden honey for area 2. HIA calculated as a sum of all HQS of heavy metals in food reveals an increase and moderate risk for nephrotoxicity, bone demineralisation, cardiotoxicity, developmental toxicity, small decrease in body weight or body weight gain after consumption of honey impurified with heavy metals. A strict monitorization of heavy metals in honey samples from farmers should be done in order to protect the consumers.

Evaluation of perinatal exposure of glyphosate and its mixture with 2,4-D and dicamba οn liver redox status in Wistar rats.

Wide-scale emergence of glyphosate-resistant weeds has led to an increase in the simultaneous application of herbicide mixtures exacerbated by the introduction of crops tolerant to glyphosate plus dicamba or glyphosate plus 2,4-D. This raises serious concerns regarding the environmental and health risks resulting from increased exposure to a mixture of herbicide active ingredients. We evaluated hepatotoxic effects following perinatal exposure to glyphosate alone or in combination with 2,4-D and dicamba from gestational day-6 until adulthood in Wistar rats. Animals were administered with glyphosate at the European Union (EU) acceptable daily intake (ADI; 0.5 mg/kg bw/day) and no-observed-adverse-effect level (NOAEL; 50 mg/kg bw/day). A mixture of glyphosate with 2,4-D (0.3 mg/kg bw/day) and dicamba (0.02 mg/kg bw/day) with each at their EU ADI was evaluated. Redox status was determined by measuring levels of reduced glutathione, decomposition rate of Η2Ο2, glutathione reductase, glutathione peroxidase, total antioxidant capacity, thiobarbituric reactive substances, and protein carbonyls. Gene expression analysis of Nr1d1, Nr1d2, Clec2g, Ier3, and Gadd45g associated with oxidative damage to DNA, was also performed. Analysis of liver samples showed that exposure to the mixture of the three herbicides induced a marked increase in the concentration of glutathione and malondialdehyde indicative of a disturbance in redox balance. Nevertheless, the effect of increased lipid peroxidation was not discernible following a 3-month recuperation period where animals were withdrawn from pesticide exposure post-weaning. Interestingly, toxic effects caused by prenatal exposure to the glyphosate NOAEL were present after the same 3-month recovery period. No statistically significant changes in the expression of genes linked with genotoxicity were observed. Our findings reinforce the importance of assessing the combined effects of chemical pollutants at doses that are asserted by regulatory agencies to be safe individually.

Effect of perinatal exposure to glyphosate and its mixture with 2,4-D and dicamba on rat dam kidney and thyroid function and offspring's health.

The increasing use of the herbicide mixture of glyphosate, dicamba and 2-4-D to deal with glyphosate-resistant weeds raises concerns regarding human health and environmental risks. This study aimed to evaluate the effects of developmental exposure to glyphosate and a herbicide mixture containing glyphosate, dicamba and 2-4-D on rat dams' kidney and thyroid function and offspring's health. Pregnant Wistar rats were exposed from day-6 of gestation till weaning to regulatory relevant doses of glyphosate corresponding to the European Union (EU) acceptable daily intake (ADI; 0.5 mg/kg bw/day), and the no-observed-adverse-effect level (NOAEL; 50 mg/kg bw/day), and to a mixture of glyphosate, dicamba and 2,4-D all at the EU ADI (0.5, 0.002 and 0.3 mg/kg bw/day) respectively. After weaning the dams were sacrificed and blood and organs were collected. The pups' health was assessed by measuring viability, gestational and anogenital indices. Perinatal exposure to GLY alone and the herbicide mixture resulted in anti-androgenic effects in male offspring. In dams, exposure to glyphosate resulted in kidney glomerular and tubular dysfunction as well as increased thyroid hormone levels in a dose-dependent manner. Furthermore, exposure to the herbicide mixture resulted in effects similar to those observed with glyphosate at the NOAEL, suggesting at least an additive effect of the herbicide mixture at doses individually considered safe for humans.

A mixture of 13 pesticides, contaminants, and food additives below individual NOAELs produces histopathological and organ weight changes in rats.

The current approach for the risk assessment of chemicals does not account for the complex human real-life exposure scenarios. Exposure to chemical mixtures in everyday life has raised scientific, regulatory, and societal concerns in recent years. Several studies aiming to identify the safety limits of chemical mixtures determined hazardous levels lower than those of separate chemicals. Following these observations, this study built on the standards set by the real-life risk simulation (RLRS) scenario and investigated the effect of long-term exposure (18 months) to a mixture of 13 chemicals (methomyl, triadimefon, dimethoate, glyphosate, carbaryl, methyl parathion, aspartame, sodium benzoate, EDTA, ethylparaben, butylparaben, bisphenol A and acacia gum) in adult rats. Animals were divided into four dosing groups [0xNOAEL (control), 0.0025xNOAEL (low dose-LD), 0.01xNOAEL (medium dose-MD) and 0.05xNOAEL (high dose-HD) (mg/kg BW/day)]. After 18 months of exposure, all animals were sacrificed, and their organs were harvested, weighed, and pathologically examined. While organ weight tended to be higher in males than in females, when sex and dose were taken into account, lungs and hearts from female rats had significantly greater weight than that of males. This discrepancy was more obvious in the LD group. Histopathology showed that long-term exposure to the chemical mixture selected for this study caused dose-dependent changes in all examined organs. The main organs that contribute to chemical biotransformation and clearance (liver, kidneys, and lungs) consistently presented histopathological changes following exposure to the chemical mixture. In conclusion, exposure to very low doses (below the NOAEL) of the tested mixture for 18 months induced histopathological lesions and cytotoxic effects in a dose and tissue-dependent manner.

DNA Damage Estimation after Chronic and Combined Exposure to Endocrine Disruptors: An In Vivo Real-Life Risk Simulation Approach.

Exposure to chemical substances has always been a matter of concern for the scientific community. During the last few years, researchers have been focusing on studying the effects resulting from combined exposure to different substances. In this study, we aimed to determine the DNA damage caused after chronic and combined exposure to substances characterized as endocrine disruptors using comet and micronuclei assays, specifically glyphosate (pure and commercial form), bisphenol A, parabens (methyl-, propyl- and butylparaben), triclosan and bis (2-ethylhexyl) phthalate. The highest mean tail intensity was observed in the group exposed to a high-dose (10 × ADI) mixture of substances (Group 3), with a mean value of 11.97 (11.26-13.90), while statistically significant differences were noticed between the groups exposed to low-dose (1 × ADI) (Group 2) and high-dose (10 × ADI) (Group 3) mixtures of substances (p = 0.003), and between Group 3 and both groups exposed to high doses (10 × ADI) of the pure and commercial forms of glyphosate (Groups 4 (p = 0.014) and 5 (p = 0.007)). The micronuclei assay results were moderately correlated with the exposure period. Group 5 was the most impacted exposure group at all sampling times, with mean MN counts ranging between 28.75 ± 1.71 and 60.75 ± 1.71, followed by Group 3 (18.25 ± 1.50-45.75 ± 1.71), showing that commercial forms of glyphosate additives as well as mixtures of endocrine disruptors can enhance MN formation. All exposure groups showed statistically significant differences in micronuclei counts with an increasing time trend.

Apoptosis evasion via long non-coding RNAs in colorectal cancer.

Long non-coding RNA (LncRNA) is a novel and diverse class of regulatory transcripts that are frequently dysregulated in numerous tumor types. LncRNAs are involved in a complicated molecular network, regulating gene expression, and modulating diverse cellular activities in different cancers including colorectal cancer (CRC). Evidence indicates that lncRNAs can be used as a potential biomarker for the prognosis and diagnosis of CRC as they are aberrantly expressed in CRC cells. The high expression or silencing of lncRNAs is associated with cell proliferation, invasion, metastasis, chemoresistance and apoptosis in CRC. LncRNAs exert both pro-apoptotic and anti-apoptotic functions in CRC. The expression of some oncogene lncRNAs is upregulated which leads to the inhibition of apoptotic pathways, similarly, the tumor suppressor lncRNAs are downregulated in CRC. In this review, we describe the function and mechanisms of lncRNAs to regulate the expression of genes that are involved directly or indirectly in controlling cellular apoptosis in CRC. Furthermore, we also discussed the different apoptotic pathways in normal cells and the mechanisms by which CRC evade apoptosis.

Anticancer potential of alkaloids: a key emphasis to colchicine, vinblastine, vincristine, vindesine, vinorelbine and vincamine.

Cancer, one of the leading illnesses, accounts for about 10 million deaths worldwide. The treatment of cancer includes surgery, chemotherapy, radiation therapy, and drug therapy, along with others, which not only put a tremendous economic effect on patients but also develop drug resistance in patients with time. A significant number of cancer cases can be prevented/treated by implementing evidence-based preventive strategies. Plant-based drugs have evolved as promising preventive chemo options both in developing and developed nations. The secondary plant metabolites such as alkaloids have proven efficacy and acceptability for cancer treatment. Apropos, this review deals with a spectrum of promising alkaloids such as colchicine, vinblastine, vincristine, vindesine, vinorelbine, and vincamine within different domains of comprehensive information on these molecules such as their medical applications (contemporary/traditional), mechanism of antitumor action, and potential scale-up biotechnological studies on an in-vitro scale. The comprehensive information provided in the review will be a valuable resource to develop an effective, affordable, and cost effective cancer management program using these alkaloids.

Targeting Ras-ERK cascade by bioactive natural products for potential treatment of cancer: an updated overview.

MAPK (mitogen-activated protein kinase) or ERK (extracellular-signal-regulated kinase) pathway is an important link in the transition from extracellular signals to intracellular responses. Because of genetic and epigenetic changes, signaling cascades are altered in a variety of diseases, including cancer. Extant studies on the homeostatic and pathologic behavior of MAPK signaling have been conducted; however, much remains to be explored in preclinical and clinical research in terms of regulation and action models. MAPK has implications for cancer therapy response, more specifically in response to experimental MAPK suppression, compensatory mechanisms are activated. The current study investigates MAPK as a very complex cell signaling pathway that plays roles in cancer treatment response, cellular normal conduit maintenance, and compensatory pathway activation. Most MAPK inhibitors, unfortunately, cause resistance by activating compensatory feedback loops in tumor cells and tumor microenvironment components. As a result, innovative combinatorial treatments for cancer management must be applied to limit the likelihood of alternate pathway initiation as a possibility for generating novel therapeutics based on incorporation in translational research. We summarize current knowledge about the implications of ERK (MAPK) in cancer, as well as bioactive products from plants, microbial organisms or marine organisms, as well as the correlation with their chemical structures, which modulate this pathway for the treatment of different types of cancer.

Flavonoids as potential anti-platelet aggregation agents: from biochemistry to health promoting abilities.

Cardiovascular ailments are the number one cause of mortalities throughout the globe with 17.9 million deaths per year. Platelet activation and aggregation play a crucial role in the pathogenesis of arterial diseases, including acute coronary syndrome, acute myocardial infarction, cerebrovascular transient ischemia, unstable angina, among others. Flavonoids-rich plant extracts are gaining interest for treating the heart-related problems due to safe nature of these herbal extracts. Consumption of plant-food-derived bioactives, particularly flavonoids, has shown antithrombotic, and cardiovascular protective effects due to its anti-platelet activity. Preclinical and clinical trials have proven that flavonoid-rich plant extracts are protective against the cardiac ailments through anti-platelet aggregation activity. This review aims to highlight the anti-platelet aggregation potential of flavonoids with a key emphasis on the therapeutic efficacy in humans. The mechanism of flavonoids in preventing and treating cardiovascular diseases is also highlighted based on preclinical and clinical experimental trials. Further studies are the need of time for exploring the exact molecular mechanism of flavonoids as anti-platelet aggregation agents for treating heart-related problems.

Dietary supplements, vitamins and minerals as potential interventions against viruses: Perspectives for COVID-19.

The novel coronavirus (SARS-CoV-2) causing COVID-19 disease pandemic has infected millions of people and caused more than thousands of deaths in many countries across the world. The number of infected cases is increasing day by day. Unfortunately, we do not have a vaccine and specific treatment for it. Along with the protective measures, respiratory and/or circulatory supports and some antiviral and retroviral drugs have been used against SARS-CoV-2, but there are no more extensive studies proving their efficacy. In this study, the latest publications in the field have been reviewed, focusing on the modulatory effects on the immunity of some natural antiviral dietary supplements, vitamins and minerals. Findings suggest that several dietary supplements, including black seeds, garlic, ginger, cranberry, orange, omega-3 and -6 polyunsaturated fatty acids, vitamins (e.g., A, B vitamins, C, D, E), and minerals (e.g., Cu, Fe, Mg, Mn, Na, Se, Zn) have anti-viral effects. Many of them act against various species of respiratory viruses, including severe acute respiratory syndrome-related coronaviruses. Therefore, dietary supplements, including vitamins and minerals, probiotics as well as individual nutritional behaviour can be used as adjuvant therapy together with antiviral medicines in the management of COVID-19 disease.

Polycystic Ovary Syndrome: A Comprehensive Review of Pathogenesis, Management, and Drug Repurposing.

Polycystic ovary syndrome (PCOS) is an endocrine-gynecology disorder affecting many women of childbearing age. Although a part of the involved mechanism in PCOS occurrence is discovered, the exact etiology and pathophysiology are not comprehensively understood yet. We searched PubMed for PCOS pathogenesis and management in this article and ClinicalTrials.gov for information on repurposed medications. All responsible factors behind PCOS were thoroughly evaluated. Furthermore, the complete information on PCOS commonly prescribed and repurposed medications is summarized through tables. Epigenetics, environmental toxicants, stress, diet as external factors, insulin resistance, hyperandrogenism, inflammation, oxidative stress, and obesity as internal factors were investigated. Lifestyle modifications and complementary and alternative medicines are preferred first-line therapy in many cases. Medications, including 3-hydroxy-3-methyl-3-glutaryl-coenzyme A (HMG-CoA) reductase inhibitors, thiazolidinediones, sodium-glucose cotransporter-2 inhibitors, dipeptidyl peptidase-4 inhibitors, glucose-like peptide-1 receptor agonists, mucolytic agents, and some supplements have supporting data for being repurposed in PCOS. Since there are few completed clinical trials with a low population and mostly without results on PCOS repurposed medications, it would be helpful to do further research and run well-designed clinical trials on this subject. Moreover, understanding more about PCOS would be beneficial to find new medications implying the effect via the novel discovered routes.

Back to basics in COVID-19: Antigens and antibodies-Completing the puzzle.

The outbreak of the coronavirus disease 2019 (COVID-19) has gathered 1 year of scientific/clinical information. This informational asset should be thoroughly and wisely used in the coming year colliding in a global task force to control this infection. Epidemiology of this infection shows that the available estimates of SARS-CoV-2 infection prevalence largely depended on the availability of molecular testing and the extent of tested population. Within molecular diagnosis, the viability and infectiousness of the virus in the tested samples should be further investigated. Moreover, SARS-CoV-2 has a genetic normal evolution that is a dynamic process. The immune system participates to the counterattack of the viral infection by pathogen elimination, cellular homoeostasis, tissue repair and generation of memory cells that would be reactivated upon a second encounter with the same virus. In all these stages, we still have knowledge to be gathered regarding antibody persistence, protective effects and immunological memory. Moreover, information regarding the intense pro-inflammatory action in severe cases still lacks and this is important in stratifying patients for difficult to treat cases. Without being exhaustive, the review will cover these important issues to be acknowledged to further advance in the battle against the current pandemia.

Chitosan nanoparticles as a promising tool in nanomedicine with particular emphasis on oncological treatment.

The study describes the current state of knowledge on nanotechnology and its utilization in medicine. The focus in this manuscript was on the properties, usage safety, and potentially valuable applications of chitosan-based nanomaterials. Chitosan nanoparticles have high importance in nanomedicine, biomedical engineering, discovery and development of new drugs. The manuscript reviewed the new studies regarding the use of chitosan-based nanoparticles for creating new release systems with improved bioavailability, increased specificity and sensitivity, and reduced pharmacological toxicity of drugs. Nowadays, effective cancer treatment is a global problem, and recent advances in nanomedicine are of great importance. Special attention was put on the application of chitosan nanoparticles in developing new system for anticancer drug delivery. Pre-clinical and clinical studies support the use of chitosan-based nanoparticles in nanomedicine. This manuscript overviews the last progresses regarding the utilization, stability, and bioavailability of drug nanoencapsulation with chitosan and their safety.

A Pharmacological Perspective on Plant-derived Bioactive Molecules for Epilepsy.

Epilepsy is a related chronic neurological condition of a predisposition for recurrent epileptic seizures, with various manifestations and causes. Although there are antiepileptic drugs, complementary natural therapies are widely used. The purpose of this systematic review was to analyze the antiepileptic/anticonvulsant pharmacological properties of plant-food derived bioactive molecules. In this regard, a systematic review of the PubMed database was made based on the inclusion criteria. Natural compounds/herbs with scientifically proven antiepileptic properties were selected. Experimental pharmacological studies in vitro and in vivo have shown that flavonoids, alkaloids and terpenoids may have anticonvulsant mechanisms similar to the new generation antiepileptic drugs. The relationships of structure-anticonvulsant effect, pharmacological models, seizure-inducing factors and response, effective dose were also analyzed and discussed. The results of in vitro and in vivo pharmacological studies analyzed in this systematic review support the clinical importance of plant-food-derived bioactive molecules for the complementary treatment of epilepsy. Thus, are opened new perspectives to develop new natural anticonvulsant drugs.

Ficus plants: State of the art from a phytochemical, pharmacological, and toxicological perspective.

Ficus genus is typically tropical plants and is among the earliest fruit trees cultivated by humans. Ficus carica L. is the common fig, Ficus benjamina L. is the weeping fig, and Ficus pumila L. is the creeping fig. These species are commonly used in traditional medicine for a wide range of diseases and contain rich secondary metabolites that have shown diverse applications. This comprehensive review describes for Ficus genus the phytochemical compounds, traditional uses and contemporary pharmacological activities such as antioxidant, cytotoxic, antimicrobial, anti-inflammatory, antidiabetic, antiulcer, and anticonvulsant. An extended survey of the current literature (Science Direct, Scopus, PubMed) has been carried out as part of the current work. The trends in the phytochemistry, pharmacological mechanisms and activities of Ficus genus are overviewed in this manuscript: antimicrobial, antidiabetic, anti-inflammatory and analgesic activity, antiseizure and anti-Parkinson's diseases, cytotoxic and antioxidant. Health-promoting effects, recent human clinical studies, safety and adverse effects of Ficus plants also are covered. The medical potential and long-term pharmacotherapeutic use of the genus Ficus along with no serious reported adverse events, suggests that it can be considered as being safe.

The Effect of Silver Nanoparticles on Antioxidant/Pro-Oxidant Balance in a Murine Model.

This study aimed to evaluate the subacute effect of two types of Ag-NPs(EG-AgNPs and PVP-EG-AgNPs) on antioxidant/pro-oxidant balance in rats. Seventy Wistar rats (35 males and 35 females) were divided in 7 groups and intraperitoneally exposed for 28 days to 0, 1, 2 and 4 mg/kg bw/day EG-Ag-NPs and 1, 2 and 4 mg/kg bw/day PVP- EG-Ag-NPs. After 28 days, the blood was collected, and the total antioxidant capacity (TAC), thiobarbituric reactive species (TBARS),protein carbonyl (PROTC) levels, reduced glutathione (GSH) levels and catalase (CAT) activity were determined. EG-Ag-NPs determined protective antioxidant effects in a dose-dependent manner. The exposure to the 4 mg/kg bw/day EG-Ag-NPs determines both in males and females a significant increase in TAC and CAT and a significant decrease in TBARS and PROTC only in females. The PVP-EG-AgNPs showed a different trend compared to EG-AgNPs. At 4 mg/kg bw/day the PVP-EG-AgNPs induce increased PROTC levels and decreased GSH (males and females) and TAC levels (males). The different mechanisms of EG-AgNPs and PVP-EG-AgNPs on antioxidant-/pro-oxidant balance can be explained by the influence of coating agent used for the preparation of the nanoparticles in the formation and composition of protein corona that influence their pathophysiology in the organism.

Probiotics: Versatile Bioactive Components in Promoting Human Health.

The positive impact of probiotic strains on human health has become more evident than ever before. Often delivered through food, dietary products, supplements, and drugs, different legislations for safety and efficacy issues have been prepared. Furthermore, regulatory agencies have addressed various approaches toward these products, whether they authorize claims mentioning a disease's diagnosis, prevention, or treatment. Due to the diversity of bacteria and yeast strains, strict approaches have been designed to assess for side effects and post-market surveillance. One of the most essential delivery systems of probiotics is within food, due to the great beneficial health effects of this system compared to pharmaceutical products and also due to the increasing importance of food and nutrition. Modern lifestyle or various diseases lead to an imbalance of the intestinal flora. Nonetheless, as the amount of probiotic use needs accurate calculations, different factors should also be taken into consideration. One of the novelties of this review is the presentation of the beneficial effects of the administration of probiotics as a potential adjuvant therapy in COVID-19. Thus, this paper provides an integrative overview of different aspects of probiotics, from human health care applications to safety, quality, and control.

The blood-brain barrier and beyond: Nano-based neuropharmacology and the role of extracellular matrix.

Restrained drug delivery due to the blood-brain barrier (BBB) considerably limits options for the treatment of brain pathologies. The utilization of nanoparticulate (NP) carriers has been proposed as a solution. The development strategies need to address the important hurdle of NP passage across the BBB as well as the altered cellular up-take due to the pathophysiological changes of the damaged or diseased tissue as well as immunological and toxicological aspects of nanomedicine penetration. This review therefore scopes to: 1) outline the state-of-the art knowledge on BBB passage, 2) address the significant influence of pathological conditions on nanoparticulate drug delivery, and, 3) highlight the largely neglected role of the extracellular matrix (ECM). Interactions of the nanosystem with biological barriers, cells and ECM in the milieu of brain pathologies are critically discussed in order to present a holistic overview of the advances and pits of nanomedicine applications in brain disease.

Cucurbits Plants: A Key Emphasis to Its Pharmacological Potential.

Cucurbita genus has received a renowned interest in the last years. This plant species, native to the Americas, has served worldwide folk medicine for treating gastrointestinal diseases and intestinal parasites, among other clinical conditions. These pharmacological effects have been increasingly correlated with their nutritional and phytochemical composition. Among those chemical constituents, carotenoids, tocopherols, phenols, terpenoids, saponins, sterols, fatty acids, and functional carbohydrates and polysaccharides are those occurring in higher abundance. However, more recently, a huge interest in a class of triterpenoids, cucurbitacins, has been stated, given its renowned biological attributes. In this sense, the present review aims to provide a detailed overview to the folk medicinal uses of Cucurbita plants, and even an in-depth insight on the latest advances with regards to its antimicrobial, antioxidant and anticancer effects. A special emphasis was also given to its clinical effectiveness in humans, specifically in blood glucose levels control in diabetic patients and pharmacotherapeutic effects in low urinary tract diseases.