Metformin ameliorates cardiopulmonary toxicity induced by chlorpyrifos.

Chlorpyrifos (CPF) is a widely used pesticide that can impair body organs. Nonetheless, metformin is known for its protective role against dysfunction at cellular and molecular levels led by inflammatory and oxidative stress. This study aimed to investigate the modulatory impacts of metformin on CPF-induced heart and lung damage. Following the treatment of Wistar rats with different combinations of metformin and CPF, plasma, as well as heart and lung tissues, were isolated to examine the level of oxidative stress biomarkers like reactive oxygen species (ROS) and malondialdehyde (MDA), inflammatory cytokines such as tumor necrosis alpha (TNF-α), high mobility group box 1 (HMGB1) gene, deoxyribonucleic acid (DNA) damage, lactate, ADP/ATP ratio, expression of relevant genes (TRADD, TERT, KL), and along with histological analysis. Based on the findings, metformin significantly modulates the impairments in heart and lung tissues induced by CPF.

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.

Advancements in pharmacotherapy options for treating diabetes in children and adolescents.

INTRODUCTION: This study compares diabetes management between pediatric and adult patients and identifies treatment challenges and gaps. AREAS COVERED: We searched PubMed and Clinicaltrails.gov databases for studies published from 2001 to 2023 on diabetes management in different age groups. EXPERT OPINION: Research shows children have lower insulin sensitivity, clearance, and ß cell function than adults. The US FDA only allows insulin, metformin, and liraglutide as antidiabetic medication options for children. However, some off-label drugs, like meglitinides, sulfonylureas, and alogliptin, have demonstrated positive results in treating certain types of diabetes caused by gene mutations. It's crucial to adopt personalized and precise approaches to managing diabetes in pediatrics, which vary from those used for adult patients. New studies support the classification of type 2 diabetes into several subtypes based on age, BMI, glycemia, homeostasis model estimates, varying insulin resistance, different rates of complications , and islet autoantibodies. With this insight, prevention, treatment, and precision medicine of diabetes might be changed. More research is necessary to assess the safety and efficacy of different antidiabetic drugs and improve diabetes treatment for children and adolescents.

Mcl-1 mediates intrinsic resistance to RAF inhibitors in mutant BRAF papillary thyroid carcinoma.

Papillary thyroid carcinoma (PTC) is the most frequent form of thyroid cancer. PTC commonly presents with mutations of the serine/threonine kinase BRAF (BRAFV600E), which drive ERK1/2 pathway activation to support growth and suppress apoptosis. PTC patients often undergo surgical resection; however, since the average age of PTC patients is under 50, adverse effects associated with prolonged maintenance therapy following total thyroidectomy are a concern. The development of mutant-selective BRAF inhibitors (BRAFi), like vemurafenib, has been efficacious in patients with metastatic melanoma, but the response rate is low for mutant BRAF PTC patients. Here, we assay the therapeutic response of BRAFi in a panel of human PTC cell lines and freshly biopsied patient samples. We observed heterogeneous responses to BRAFi, and multi-omic comparisons between susceptible and resistant mutant BRAF PTC revealed overrepresented stress response pathways and the absence of compensatory RTK activation - features that may underpin innate resistance. Importantly, resistant cell lines and patient samples had increased hallmarks of failed apoptosis; a cellular state defined by sublethal caspase activation and DNA damage. Further analysis suggests that the failed apoptotic phenotypes may have features of "minority mitochondrial outer membrane permeabilization (MOMP)" - a stress-related response characterized by fragmented and porous mitochondria known to contribute to cancer aggressiveness. We found that cells presenting with minority MOMP-like phenotypes are dependent on the apoptotic regulator, Mcl-1, as treatment with the Mcl-1 inhibitor, AZD5991, potently induced cell death in resistant cells. Furthermore, PI3K/AKT inhibitors sensitized resistant cells to BRAFi; an effect that was at least in part associated with reduced Mcl-1 levels. Together, these data implicate minority MOMP as a mechanism associated with intrinsic drug resistance and underscore the benefits of targeting Mcl-1 in mutant BRAF PTC.

Dopamine-driven Increase in IL-1ß in Myeloid Cells is Mediated by Differential Dopamine Receptor Expression and Exacerbated by HIV.

The catecholamine neurotransmitter dopamine is classically known for regulation of central nervous system (CNS) functions such as reward, movement, and cognition. Increasing evidence also indicates that dopamine regulates critical functions in peripheral organs and is an important immunoregulatory factor. We have previously shown that dopamine increases NF-κB activity, inflammasome activation, and the production of inflammatory cytokines such as IL-1ß in human macrophages. As myeloid lineage cells are central to the initiation and resolution of acute inflammatory responses, dopamine-mediated dysregulation of these functions could both impair the innate immune response and exacerbate chronic inflammation. However, the exact pathways by which dopamine drives myeloid inflammation are not well defined, and studies in both rodent and human systems indicate that dopamine can impact the production of inflammatory mediators through both D1-like dopamine receptors (DRD1, DRD5) and D2-like dopamine receptors (DRD2, DRD3, and DRD4). Therefore, we hypothesized that dopamine-mediated production of IL-1ß in myeloid cells is regulated by the ratio of different dopamine receptors that are activated. Our data in primary human monocyte-derived macrophages (hMDM) indicate that DRD1 expression is necessary for dopamine-mediated increases in IL-1ß, and that changes in the expression of DRD2 and other dopamine receptors can alter the magnitude of the dopamine-mediated increase in IL-1ß. Mature hMDM have a high D1-like to D2-like receptor ratio, which is different relative to monocytes and peripheral blood mononuclear cells (PBMCs). We further confirm in human microglia cell lines that a high ratio of D1-like to D2-like receptors promotes dopamine-induced increases in IL-1ß gene and protein expression using pharmacological inhibition or overexpression of dopamine receptors. RNA-sequencing of dopamine-treated microglia shows that genes encoding functions in IL-1ß signaling pathways, microglia activation, and neurotransmission increased with dopamine treatment. Finally, using HIV as an example of a chronic inflammatory disease that is substantively worsened by comorbid substance use disorders (SUDs) that impact dopaminergic signaling, we show increased effects of dopamine on inflammasome activation and IL-1ß in the presence of HIV in both human macrophages and microglia. These data suggest that use of addictive substances and dopamine-modulating therapeutics could dysregulate the innate inflammatory response and exacerbate chronic neuroimmunological conditions like HIV. Thus, a detailed understanding of dopamine-mediated changes in inflammation, in particular pathways regulating IL-1ß, will be critical to effectively tailor medication regimens.

Molecular Evidence on the Inhibitory Potential of Metformin against Chlorpyrifos-Induced Neurotoxicity.

Chlorpyrifos (CPF) is an organophosphorus (OP) pesticide, resulting in various health complications as the result of ingestion, inhalation, or skin absorption, and leads to DNA damage and increased oxidative stress. Metformin, derived from Galega officinalis, is reported to have anti-inflammatory and anti-apoptotic properties; thus, this study aimed to investigate the beneficial role of metformin in neurotoxicity induced by sub-acute exposure to CPF in Wistar rats. In this study, animals were divided into nine groups and were treated with different combinations of metformin and CPF. Following the 28 days of CPF and metformin administration, brain tissues were separated. The levels of inflammatory biomarkers such as tumor necrosis factor alpha (TNFα) and interleukin 1ß (IL-1ß), as well as the expression of 5HT1 and 5HT2 genes, were analyzed. Moreover, the levels of malondialdehyde (MDA), reactive oxygen species (ROS), and the ADP/ATP ratio, in addition to the activity of acetylcholinesterase (AChE) and superoxide dismutase (SOD), were tested through in vitro experiments. This study demonstrated the potential role of metformin in alleviating the mentioned biomarkers, which can be altered negatively as a result of CPF toxicity. Moreover, metformin showed protective potential in modulating inflammation, as well as oxidative stress, the expression of genes, and histological analysis, in a concentration-dependent manner.

Targeting dyslipidemia by herbal medicines: A systematic review of meta-analyses.

ETHNOPHARMACOLOGICAL RELEVANCE: The worldwide increasing prevalence of dyslipidemia has become a global health concern. Various herbal remedies have been claimed to be effective for the treatment of dyslipidemia in traditional and folkloric medicine of different regions clinical trials have been conducted to investigate their efficacy. The aim of the current systematic review is to critically assess the meta-analyses of controlled trials (CT) evaluated herb medicines for dyslipidemia. MATERIALS AND METHODS: Relevant studies from Web of Science, PubMed, Scopus, and Cochrane Library databases based on Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist until January 2021 have been searched. All meta-analyses which pooled studies on the effect of herbal medicines on lipid profile including total cholesterol (TC), triglyceride (TG), and low- or high-density lipoprotein cholesterol (LDL-C, HDL-C) were also included. Meta-analyses of in vitro, animal or observational studies were excluded. RESULTS: The overall of 141 meta-analyses were revealed. Vegetable oils, phytosterols, tea, soy protein, nuts, and curcumin have been studied frequently among the herbal medicines. Among 13 meta-analyses on vegetable oils, the greater reduce of TC (18.95 mg/dl), LDL-C (16.24 mg/dl) and TG (13.69 mg/dl) were exhibited from sunflower oil. Furthermore, rice bran oil (6.65 mg/dl) increased HDL-C significantly. Phytosterols in 12 meta-analyses demonstrated significant improvements in reducing TC, LDL-C and TG as 16.4, 23.7, and 8.85 mg/dl, respectively, and rise in HDL-C as 10.6 mg/dl. The highest reduction in serum level of TC, LDL-C and TG was reported while intake Green tea; 27.57, 24.75, and 31.87 mg/dl, accordingly within 9 meta-analyses. Average improvement of lipid profiles by 6 meta-analyses on plant proteins were 23.2, 21.7, 15.06, and 1.55 mg/dl for TC, LDL-C, TG, and HDL-C, respectively. Among 11 meta-analyses on nuts, almond showed better and significant alleviations in TC (10.69 mg/dl), walnut in LDL-C (9.23 mg/dl), pistachio in TG (22.14 mg/dl), and peanut in HDL-C (2.72 mg/dl). Overall, Curcumin, Curcuminoid, and Turmeric have resulted in the reduction of TC (25.13 mg/dl), LDL-C (39.83 mg/dl), TG (33.65 mg/dl), and an increase in the HDL-C (4.31 mg/dl). CONCLUSION: The current systematic review shed light on the use of herbal medicines for the management of dyslipidemia. However, more well-conducted CTs are required to determine effective doses of herbal medicines.

Drug Repurposing for the Management of Depression: Where Do We Stand Currently?

A slow rate of new drug discovery and higher costs of new drug development attracted the attention of scientists and physicians for the repurposing and repositioning of old medications. Experimental studies and off-label use of drugs have helped drive data for further studies of approving these medications. A deeper understanding of the pathogenesis of depression encourages novel discoveries through drug repurposing and drug repositioning to treat depression. In addition to reducing neurotransmitters like epinephrine and serotonin, other mechanisms such as inflammation, insufficient blood supply, and neurotoxicants are now considered as the possible involved mechanisms. Considering the mentioned mechanisms has resulted in repurposed medications to treat treatment-resistant depression (TRD) as alternative approaches. This review aims to discuss the available treatments and their progress way during repositioning. Neurotransmitters' antagonists, atypical antipsychotics, and CNS stimulants have been studied for the repurposing aims. However, they need proper studies in terms of formulation, matching with regulatory standards, and efficacy.

An overview of interventions for constipation in adults.

INTRODUCTION: The increasing global prevalence of the symptoms of constipation adversely affects the quality of life (QOL) of symptomatic patients. An acceptable universal definition of constipation does not exist and a detailed history taking form each patient with various complaints including stool consistency, sensing of incomplete evacuation or a manual need to assist evacuation is required. Complexity of obtaining etiologic diagnosis and the wide range of therapeutic options can mislead physicians in choosing correct treatment. AREAS COVERED: This review, considers the pathophysiology of constipation and the diagnostic approach to identify the etiology of constipation. Available interventions including non-pharmacological, pharmacological, and invasive methods such as acupuncture and surgical management are discussed. This review utilized on PubMed, Google Scholar, Scopus, and clinicaltrials.gov to search for studies and reviews published between 2000 and 2020. EXPERT COMMENTARY: Constipation necessitates careful considerations to detect the exact pathophysiology. Medical history, focused physical assessments, and selected diagnostic tests help choosing the right management. Non-pharmacological methods are beneficial in most of the cases. If a satisfactory response is not achieved, over the counter or prescribed medications are available. Options for patients who failed to respond to available medications are addressed in this review.

Antibiotic resistance propagation through probiotics.

INTRODUCTION: The widespread use of probiotics globally has established an argument against their safety profile. Recent studies investigated the gastrointestinal tract (GIT) as a reservoir for antibiotic resistance genes and horizontal gene transfer (HGT) amongst opportunistic pathogens, probiotics, and the normal microbiota which might cause severe clinical implications. AREAS COVERED: In this review, we aimed to discuss the potential role of probiotics in spreading antibiotic resistance. All relevant data were found through online/updated databases such as PubMed, Google Scholar, and Clinicaltrials.gov. This review is based on the studies undertaken over the past two decades (2000-2020). EXPERT OPINION: Microorganisms are capable of transferring resistance genes to survive against antimicrobial medications. Transference of resistance genes among pathogens, probiotics, and gut microbiota in the GIT through HGT endow probiotics as a possible source for antimicrobial resistance genes, which is responsible for the development of the antibiotic resistance crisis. According to the expression of genes in mechanisms of antibiotics resistance and probiotics HGT, the hypothesis of the role of these microorganisms in personalized medicine and gene therapy could also be considered.

Evaluating naloxegol for the treatment of opioid-induced constipation.

INTRODUCTION: Due to the increased use of opioids for pain and their abuse globally, the rate of restrictive side effects is elevating. Opioid-induced constipation (OIC) is probably the most widespread, underdiagnosed, and yet common adverse effect. Naloxegol, as an opioid antagonist, is associated with beneficial impacts in OIC. Indeed, blocking mu (µ)-opioid receptors in the gastrointestinal tract (GI) may lead to neutralization of the GI adverse events of opioids. AREAS COVERED: This review is based on a PubMed and Clinicaltrials.gov search for studies undertaken over the past 20 years (2000-2020) using the following keywords: Movantik®, Moventig®, Naloxegol, Opioids, Opioid-induced constipation and Opioid antagonists. EXPERT OPINION: Similar to the management of functional constipation, non-pharmacological therapies are applied as the first step of the procedure. However, in most cases, laxative therpaies with or without stool softeners, which may not result in satisfactory relief are applied. In these instances, administration of prokinetic agents is recommended. Furthermore, studies have shown that the best second-line therapy option is a peripherally acting µ-opioid receptor antagonist (PAMORA), which antagonizes GI adverse events.

The pharmacological management of constipation in patients with Parkinson's disease: a much-needed relief.

INTRODUCTION: Constipation is common in patients with Parkinson's disease (PD). Due to the considerable negative outcomes of constipation, significant efforts have been made to prevent and manage chronic constipation in these patients. AREAS COVERED: Herein, the authors review some of the known pathophysiological causes for slow gastrointestinal (GI) transit in PD patients and the different pharmacological options. All relevant clinical and experimental data found through online databases were included. Bulking agents, osmotic and stimulant laxatives, chloride channel activators, ghrelin agonists, 5-HT4 receptor agonists, and probiotics are some of the proposed medicinal agents. of the authors further review the evidence on alpha-synuclein and botulinum neurotoxin in these patients. It should be noted, however, that some of these interventions are required to be further validated. EXPERT OPINION: Reduction of GI transit and dysfunction of the anorectum is obvious in PD, affecting the incidence of constipation and thus, quality of life (QOL). Furthermore, due to an inadequate and delayed absorption of oral anti PD medications, dose adjustments and changes in the route of administration are recommended.

Multi-organ Toxicity Attenuation by Cerium Oxide and Yttrium Oxide Nanoparticles: Comparing the Beneficial Effects on Tissues Oxidative Damage Induced by Sub-acute Exposure to Diazinon.

BACKGROUND: Excessive use of diazinon, as an organophosphate pesticide (OP), contributes to cytotoxic and pathologic cellular damage and, in particular, oxidative stress. However, metal-oxide nanoparticles (NPs), such as cerium oxide (CeO2) and yttrium oxide (Y2O3), with the property of free radical scavenging demonstrated beneficial effects in the alleviation of oxidative stress biomarkers. OBJECTIVE: The aims of this study include evaluating beneficial effects of CeO2 NPs, Y2O3 NPs, and their combination against diazinon-induced oxidative stress in different tissues of brain, heart, lung, kidney, liver, and spleen. METHODS: Eight randomized groups of 6 adult male Wistar rats were formed. Each group of rats administered a different combination of diazinon, CeO2 and Y2O3 NPs daily and levels of oxidative stress markers, such as reactive oxygen species (ROS), lipid peroxidation (LPO), total thiol molecules (TTM) and total anti-oxidant power (TAP) and catalase enzyme, were measured after 2 weeks of the treatment. RESULTS: Measurements of the mentioned markers in the brain, heart, lung, kidney, liver, and spleen showed that the administration of NPs could significantly alleviate the oxidative stress induced by diazinon. However, the findings of this study illustrated that the combination of both CeO2 and Y2O3 NPs led to a better reduction in oxidative stress markers. CONCLUSION: Sub-acute exposure of diazinon in rats led to increased levels of oxidative stress markers in pivotal tissues such as the brain, heart, lung, kidney, liver, and spleen. CeO2 and Y2O3 NPs neutralize the oxidative stress to compensate diazinon-induced tissue damages. Lay Summary: Organophosphate pesticides (OPs), which are mainly used for pest control, are responsible for the entry of pesticides into the human food cycle. Organophosphate such as diazinon increases the molecular biomarkers of oxidative stress inside the cells of vital tissues such as the heart, liver, lungs, etc. Metal oxide nanoparticles (NPs) such as cerium oxide (CeO2) and yitrium oxide (Y2O3) can have free radical scavenging potential under oxidative stress and through various mechanisms. Although these nanoparticles reduce oxidative stress, it should be borne in the design of the study that additional doses of these substances reverse the beneficial effects.

An overview of the efficacy and safety of prucalopride for the treatment of chronic idiopathic constipation.

Introduction: Chronic idiopathic constipation (CIC) is a kind of constipation in which the patient experiences constipation more than 3 months without any identifiable cause. Prucalopride is one such treatment considered for relieving symptoms of CIC regarding due to its selectivity for the 5HT4 receptor.Areas covered: This article is based on a PubMed and clinicaltrials.gov search for studies undertaken over the past 19 years (2000-2019) using the following keywords either alone or in combination: Prucalopride, chronic idiopathic constipation, chronic constipation, 5HT4 receptor, Resolor and Motegrity.Expert opinion: Prucalopride should be considered as one of the safe options for the treatment of CIC especially when previous treatments have failed. It can be helpful in the treatment of constipation caused by irritable bowel syndrome or spinal cord injury, opioid-induced constipation, post-operative ileus, and intestinal/colonic pseudo-obstruction. The major drawback of prucalopride is its high cost, which makes it less accessible to all patients.

Reappraisal of probiotics' safety in human.

Contrary to the safe usage of probiotics for years, their threat is still worthy of attention. Several risks have been explained or mentioned in the case reports, clinical trials and experimental studies. Due to a large number of probiotic products worldwide, the certainty of the safety of such products is a matter of concern. Current review appraises all the available information about a range of adverse effects by probiotics in different populations of consumers and almost all qualified investigations and reports, relevant to the adverse effects of probiotics. Furthermore, the effects of basic or original sources of probiotics were studied. The principally noticed adverse effects of probiotics are systemic infections, gastrointestinal side effects, skin complications, inflammation of endocardium, gene transfer from probiotics to the normal microbial flora, metabolic harmful impacts of probiotics, and immune system stimulation. The most at-risk groups consist of infants, elderly people, patients in hospitalized condition, and those with immunodeficiency due to a genetic or acquired disease. The existing evidence suggests careful evaluation of the risk-benefit ratio of probiotics prior to prescription or recommendation to use.