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AIM: Coronary artery disease (CAD) is the leading cause of mortality. Though percutaneous transluminal angioplasty followed by stenting is still the default treatment of choice for revascularization of obstructive CAD, the high rate of restenosis compromises the outcomes of endovascular procedures. To overcome restenosis, drug-eluting stents (DES) and drug-coated balloons (DCB) are designed that release antiproliferative drugs like sirolimus, paclitaxel, everolimus, etc., over time to inhibit cell growth and proliferation. Our review aims to summarize the challenges and progress of DES/DCBs in clinical settings. MATERIAL AND METHODS: The comprehensive review, search and selection encompasses in relevant articles through Google Scholar, Springer online, Cochrane library and PubMed that includes research articles, reviews, letters and communications, various viewpoints, meta-analyses, randomized trials and quasi-randomized trials. Several preclinical and clinical data have been included from National Institutes of Health and clinicaltrials.gov websites. KEY FINDINGS: Challenges like delayed endothelialization, stent thrombosis (ST), and inflammation was prominent in first-generation DES. Second-generation DES with improved designs and drug coatings enhanced biocompatibility with fewer complications. Gradual absorption of bioresorbable DES over time mitigated long-term issues associated with permanent implants. Polymer-free DES addressed the inflammation concerns but still, they leave behind metallic stents in the vasculature. As an alternative therapeutic strategy, DCB were developed to minimize inflammation in the vessel. Although both DES and DCBs have shown considerable progress, challenges persist. SIGNIFICANCE: This review illustrates the advancements in the designs, preparation technologies, biodegradable materials, and drugs used as well as challenges associated with DES and DCBs in clinical settings.
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Doença da Artéria Coronariana , Stents Farmacológicos , Humanos , Doença da Artéria Coronariana/terapia , Materiais Revestidos Biocompatíveis , Animais , Reestenose Coronária/prevenção & controle , Angioplastia Coronária com Balão/métodos , Paclitaxel/administração & dosagem , Paclitaxel/uso terapêuticoRESUMO
Autism spectrum disorders (ASD) are neurodevelopmental disorders manifested mainly in children, with symptoms ranging from social/communication deficits and stereotypies to associated behavioral anomalies like anxiety, depression, and ADHD. While the patho-mechanism is not well understood, the role of neuroinflammation has been suggested. Nevertheless, the triggers giving rise to this neuroinflammation have not previously been explored in detail, so the present study was aimed at exploring the role of glutamate on these processes, potentially carried out through increased activity of inflammatory cells like astrocytes, and a decline in neuronal health. A novel chlorpyrifos-induced paradigm of ASD in rat pups was used for the present study. The animals were subjected to tests assessing their neonatal development and adolescent behaviors (social skills, stereotypies, sensorimotor deficits, anxiety, depression, olfactory, and pain perception). Markers for inflammation and the levels of molecules involved in glutamate excitotoxicity, and neuroinflammation were also measured. Additionally, the expression of reactive oxygen species and markers of neuronal inflammation (GFAP) and function (c-Fos) were evaluated, along with an assessment of histopathological alterations. Based on these evaluations, it was found that postnatal administration of CPF had a negative impact on neurobehavior during both the neonatal and adolescent phases, especially on developmental markers, and brought about the generation of ASD-like symptoms. This was further corroborated by elevations in the expression of glutamate and downstream calcium, as well as certain cytokines and neuroinflammatory markers, and validated through histopathological and immunohistochemical results showing a decline in neuronal health in an astrocyte-mediated cytokine-dependent fashion. Through our findings, conclusive evidence regarding the involvement of glutamate in neuroinflammatory pathways implicated in the development of ASD-like symptoms, as well as its ability to activate further downstream processes linked to neuronal damage has been obtained. The role of astrocytes and the detrimental effect on neuronal health are also concluded. The significance of our study and its findings lies in the evaluation of the involvement of chlorpyrifos-induced neurotoxicity in the development of ASD, particularly in relation to glutamatergic dysfunction and neuronal damage.
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Astrócitos , Transtorno do Espectro Autista , Clorpirifos , Ácido Glutâmico , Doenças Neuroinflamatórias , Astrócitos/metabolismo , Astrócitos/efeitos dos fármacos , Animais , Transtorno do Espectro Autista/induzido quimicamente , Transtorno do Espectro Autista/metabolismo , Ácido Glutâmico/metabolismo , Clorpirifos/toxicidade , Doenças Neuroinflamatórias/induzido quimicamente , Doenças Neuroinflamatórias/metabolismo , Doenças Neuroinflamatórias/patologia , Masculino , Ratos Wistar , Ratos , Animais Recém-Nascidos , Feminino , Inflamação/induzido quimicamente , Inflamação/metabolismo , Inflamação/patologiaRESUMO
Olanzapine, a widely prescribed atypical antipsychotic, poses a great risk to the patient's health by fabricating a plethora of severe metabolic and cardiovascular adverse effects eventually reducing life expectancy and patient compliance. Its heterogenous receptor binding profile has made it difficult to point out a specific cause or treatment for the related side effects. Growing body of evidence suggest that transient receptor potential (TRP) channel subfamily Ankyrin 1 (TRPA1) has pivotal role in pathogenesis of type 2 diabetes and obesity. With this background, we aimed to investigate the role of pharmacological manipulations of TRPA1 channels in antipsychotic (olanzapine)-induced metabolic alterations in female mice using allyl isothiocyanate (AITC) and HC-030031 (TRPA1 agonist and antagonist, respectively). It was found that after 6 weeks of treatment, AITC prevented olanzapine-induced alterations in body weight and adiposity; serum, and liver inflammatory markers; glucose and lipid metabolism; and hypothalamic appetite regulation, nutrient sensing, inflammatory and TRPA1 channel signaling regulating genes. Furthermore, several of these effects were absent in the presence of HC-030031 (TRPA1 antagonist) indicating protective role of TRPA1 agonism in attenuating olanzapine-induced metabolic alterations. Supplementary in-depth studies are required to study TRPA1 channel effect on other aspects of olanzapine-induced metabolic alterations.
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Acetanilidas , Antipsicóticos , Diabetes Mellitus Tipo 2 , Purinas , Canais de Potencial de Receptor Transitório , Camundongos , Humanos , Feminino , Animais , Canal de Cátion TRPA1 , Olanzapina , Antipsicóticos/toxicidade , Isotiocianatos/farmacologia , Obesidade/induzido quimicamente , Obesidade/tratamento farmacológico , Fígado/metabolismoRESUMO
Autism Spectrum Disorders (ASD) are a complex set of neurodevelopmental manifestations which present in the form of social and communication deficits. Affecting a growing proportion of children worldwide, the exact pathogenesis of this disorder is not very well understood, and multiple signaling pathways have been implicated. Among them, the ERK/MAPK pathway is critical in a number of cellular processes, and the normal functioning of neuronal cells also depends on this cascade. As such, recent studies have increasingly focused on the impact this pathway has on the development of autistic symptoms. Improper ERK signaling is suspected to be involved in neurotoxicity, and the same might be implicated in autism spectrum disorders (ASD), through a variety of effects including mitochondrial dysfunction and oxidative stress. Niclosamide, an antihelminthic and anti-inflammatory agent, has shown potential in inhibiting this pathway, and countering the effects shown by its overactivity in inflammation. While it has previously been evaluated in other neurological disorders like Alzheimer's Disease and Parkinson's Disease, as well as various cancers by targeting ERK/MAPK, it's efficacy in autism has not yet been evaluated. In this article, we attempt to discuss the potential role of the ERK/MAPK pathway in the pathogenesis of ASD, specifically through mitochondrial damage, before moving to the therapeutic potential of niclosamide in the disorder, mediated by the inhibition of this pathway and its detrimental effects of neuronal development.
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Transtorno do Espectro Autista , Transtorno Autístico , Doenças Mitocondriais , Criança , Humanos , Transtorno do Espectro Autista/tratamento farmacológico , Transtorno do Espectro Autista/metabolismo , Niclosamida/farmacologia , Niclosamida/uso terapêutico , Estresse OxidativoRESUMO
BACKGROUND: Morbidity and mortality rates associated with acute lung injury/acute respiratory distress syndrome (ALI/ARDS) are high (30-40%). Nuclear factor-kappa B (NF-κB) is a transcription factor, associated with transcription of numerous cytokines leading to cytokine storm, and thereby, plays a major role in ALI/ARDS and in advanced COVID-19 syndrome. METHODS: Considering the role of NF-κB in ALI, cost-effective in silico approaches were utilized in the study to identify potential NF-κB inhibitor based on the docking and pharmacokinetic results. The identified compound was then pharmacologically validated in lipopolysaccharide (LPS) rodent model of acute lung injury. LPS induces ALI by altering alveolar membrane permeability, recruiting activated neutrophils and macrophages to the lungs, and compromising the alveolar membrane integrity and ultimately impairs the gaseous exchange. Furthermore, LPS exposure is associated with exaggerated production of various proinflammatory cytokines in lungs. RESULTS: Based on in silico studies Olopatadine Hydrochloride (Olo), an FDA-approved drug was found as a potential NF-κB inhibitor which has been reported for the first time, and considered further for the pharmacological validation. Intraperitoneal LPS administration resulted in ALI/ARDS by fulfilling 3 out of the 4 criteria described by ATS committee (2011) published workshop report. However, treatment with Olo attenuated LPS-induced elevation of proinflammatory markers (IL-6 and NF-κB), oxidative stress, neutrophil infiltration, edema, and damage in lungs. Histopathological studies also revealed that Olo treatment significantly ameliorated LPS-induced lung injury, thus conferring improvement in survival. Especially, the effects produced by Olo medium dose (1 mg/kg) were comparable to dexamethasone standard. CONCLUSION: In nutshell, inhibition of NF-κB pathway by Olo resulted in protection and reduced mortality in LPS- induced ALI and thus has potential to be used clinically to arrest disease progression in ALI/ARDS, since the drug is already in the market. However, the findings warrant further extensive studies, and also future studies can be planned to elucidate its role in COVID-19-associated ARDS or cytokine storm.
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Lesão Pulmonar Aguda , COVID-19 , Síndrome do Desconforto Respiratório , Humanos , NF-kappa B , Lipopolissacarídeos/farmacologia , Cloridrato de Olopatadina , Síndrome da Liberação de Citocina , Transdução de Sinais , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/tratamento farmacológico , Proteínas I-kappa B , CitocinasRESUMO
Autism spectrum disorders (ASD) are a complex sequelae of neurodevelopmental disorders which manifest in the form of communication and social deficits. Currently, only two agents, namely risperidone and aripiprazole have been approved for the treatment of ASD, and there is a dearth of more drugs for the disorder. The exact pathophysiology of autism is not understood clearly, but research has implicated multiple pathways at different points in the neuronal circuitry, suggesting their role in ASD. Among these, the role played by neuroinflammatory cascades like the NF-KB and Nrf2 pathways, and the excitotoxic glutamatergic system, are said to have a bearing on the development of ASD. Similarly, the GPR40 receptor, present in both the gut and the blood brain barrier, has also been said to be involved in the disorder. Consequently, molecules which can act by interacting with one or multiple of these targets might have a potential in the therapy of the disorder, and for this reason, this study was designed to assess the binding affinity of taurine, a naturally-occurring amino acid, with these target molecules. The same was scored against these targets using in-silico docking studies, with Risperidone and Aripiprazole being used as standard comparators. Encouraging docking scores were obtained for taurine across all the selected targets, indicating promising target interaction. But the affinity for targets actually varied in the order NRF-KEAP > NF-κB > NMDA > Calcium channel > GPR 40. Given the potential implication of these targets in the pathogenesis of ASD, the drug might show promising results in the therapy of the disorder if subjected to further evaluations.
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NSP16 is one of the structural proteins of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) necessary for its entrance to the host cells. It exhibits 2'O-methyl-transferase (2'O-MTase) activity of NSP16 using methyl group from S-adenosyl methionine (SAM) by methylating the 5-end of virally encoded mRNAs and shields viral RNA, and also controls its replication as well as infection. In the present study, we used in silico approaches of drug repurposing to target and inhibit the SAM binding site in NSP16 using Food and Drug Administration (FDA)-approved small molecules set from Drug Bank database. Among the 2 456 FDA-approved molecules, framycetin, paromomycin, and amikacin were found to be significant binders against the SAM binding cryptic pocket of NSP16 with docking score of -13.708, -14.997 and -15.841 kcal/mol, respectively. Classical molecular dynamics (MD) simulation and molecular mechanics Poisson-Boltzmann surface area (MM/PBSA)-based binding free energy calculation depicted that all these three framycetin, paromomycin, and amikacin might be promising therapeutic leads towards SARS-CoV-2 infections via host immune escape inhibition pathway.
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BACKGROUND: Major depressive disorder is a mental health disorder that is characterized by a persistently low mood and loss of interest. MDD is affecting over 3.8% of the global population as a major health problem. Its etiology is complex, and involves the interaction between a number of factors, including genetic predisposition and the presence of environmental stresses. AREAS COVERED: The role of the immune and inflammatory systems in depression has been gaining interest, with evidence suggesting the potential involvement of pro-inflammatory molecules like TNF, interleukins, prostaglandins, and other cytokines, among others, has been put forth. Along with this, the potential of agents, from NSAIDs to antibiotics, are being evaluated in therapy for depression. The current review will discuss emerging immune targets at the preclinical level. EXPERT OPINION: With increasing evidence to show that immune and inflammatory mediators are implicated in MDD, increasing research toward their potential as drug targets is encouraged. At the same time, agents acting on these mediators and possessing anti-inflammatory potential are also being evaluated as future therapeutic options for MDD, and increasing focus toward non-conventional drugs which can act through these mechanisms is important as regards the future prospects of the use of anti-inflammatory agents in depression.
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Transtorno Depressivo Maior , Humanos , Transtorno Depressivo Maior/tratamento farmacológico , Citocinas , Anti-Inflamatórios , Mediadores da Inflamação , AntibacterianosRESUMO
BACKGROUND & AIM: Obesity is a worldwide epidemic leading to decreased quality of life, higher medical expenses and significant morbidity. Enhancing energy expenditure and substrate utilization in adipose tissues through dietary constituents and polypharmacological approaches is gaining importance for the prevention and therapeutics of obesity. An important factor in this regard is Transient Receptor Potential (TRP) channel modulation and resultant activation of "brite" phenotype. Various dietary TRP channel agonists like capsaicin (TRPV1), cinnamaldehyde (TRPA1), and menthol (TRPM8) have shown anti-obesity effects, individually and in combination. We aimed to determine the therapeutic potential of such combination of sub-effective doses of these agents against diet-induced obesity, and explore the involved cellular processes. KEY FINDINGS: The combination of sub-effective doses of capsaicin, cinnamaldehyde and menthol induced "brite" phenotype in differentiating 3T3-L1 cells and subcutaneous white adipose tissue of HFD-fed obese mice. The intervention prevented adipose tissue hypertrophy and weight gain, enhanced the thermogenic potential, mitochondrial biogenesis and overall activation of brown adipose tissue. These changes observed in vitro as well as in vivo, were linked to increased phosphorylation of kinases, AMPK and ERK. In the liver, the combination treatment enhanced insulin sensitivity, improved gluconeogenic potential and lipolysis, prevented fatty acid accumulation and enhanced glucose utilization. SIGNIFICANCE: We report on the discovery of therapeutic potential of TRP-based dietary triagonist combination against HFD-induced abnormalities in metabolic tissues. Our findings indicate that a common central mechanism may affect multiple peripheral tissues. This study opens up avenues of development of therapeutic functional foods for obesity.
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Capsaicina , Mentol , Animais , Camundongos , Capsaicina/farmacologia , Capsaicina/metabolismo , Mentol/metabolismo , Mentol/farmacologia , Mentol/uso terapêutico , Qualidade de Vida , Dieta Hiperlipídica/efeitos adversos , Obesidade/tratamento farmacológico , Obesidade/etiologia , Obesidade/metabolismo , Tecido Adiposo Marrom/metabolismo , Fenótipo , Tecido Adiposo Branco/metabolismo , Metabolismo Energético , Camundongos Endogâmicos C57BLRESUMO
Schizophrenia is a neurological disorder that alters the behavior and affects the quality of life of a patient. It is characterized by hallucinations, disorganized behavior, cognitive dysfunction, hyperlocomotion, and loss of the reward system. Schizophrenia constitutes three symptoms' domains, viz. positive, negative and cognitive. Typical and atypical antipsychotics do not fully resolve all the symptoms' domains thus paving the way to the genesis of the glutamatergic hypothesis, i.e. N-methyl-D-aspartate (NMDA) receptor hypofunction in the pathophysiology of schizophrenia. Positive modulation of NMDA receptors by enhancing co-agonist, glycine effect is proposed to produce a therapeutic effect in schizophrenia. Hence, sarcosine (N-methyl glycine), natural amino acid, and a glycine transporter inhibitor (GlyT-1) which also acts on NMDA receptors were used in the present study. The present study unravels the role of sarcosine in the attenuation of ketamine-induced three symptom domains in a rat model through modulation of oxidative stress, mitochondrial dysfunction, and neuroinflammatory pathways. The animal model of schizophrenia was established by injecting ketamine intraperitoneal (ip) at a 30 mg/kg dose for 10 consecutive days, after which sarcosine (300, 600 mg/kg, ip) as a treatment was given for 7 days followed by behavioral, biochemical, molecular, and histopathological analysis. It was revealed that sarcosine reversed ketamine-induced behavioral impairments. Moreover, sarcosine ameliorated oxidative and nitrosative stress, mitochondrial dysfunction, and neuroinflammation and showed protective effects in histopathological examination by hematoxylin and eosin staining. Hence, conclusively, sarcosine was regarded to attenuate the behavioural symptoms of schizophrenia by alleviating oxidative stress, neuroinflammation, and mitochondrial dysfunction established by the ketamine.
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Ketamina , Esquizofrenia , Ratos , Animais , Sarcosina/farmacologia , Sarcosina/uso terapêutico , Esquizofrenia/induzido quimicamente , Esquizofrenia/tratamento farmacológico , Proteínas da Membrana Plasmática de Transporte de Glicina , Ketamina/farmacologia , Ketamina/uso terapêutico , Receptores de N-Metil-D-Aspartato , Doenças Neuroinflamatórias , Qualidade de VidaRESUMO
BACKGROUND: Neuroinflammation resulting from oxidative and nitrosative stress is associated with various neurological disorders and involves the generation of pro-inflammatory cytokines and microglial activation. Dietary phytochemicals are safer and more valuable adjunct neurotherapeutic agents which can be added to the therapeutic regimen. These compounds provide neuroprotection by the modulation of various signaling pathways. INTRODUCTION: Naringenin (NGN) is a phytochemical having low oral bioavailability because of poor solubility, and adding to this limitation is enhanced efflux by P-glycoprotein transporters in neuroinflammatory diseases. METHODS: Hence, as a solution for these limitations, naringenin encapsulated poly-lactic-co-glycolic acid (PLGA) nanocarriers were developed using the nanoprecipitation technique and coated with 1% glutathione (GSH) and 1% Tween 80 to enhance brain delivery. RESULTS: Coated and uncoated NGN-PLGA nanoparticles (NGN-PLGA-NPs) were spherical, monodispersed, stable, and non-toxic, with a particle size of less than 200 nm. They had negative zeta-potential values, 80% entrapment efficiency, and sustained drug release of 81.8% (uncoated), 80.13%, and 78.43% (coated) in 24 hours. FT-IR, DSC, PXRD, and NMR confirmed the drug encapsulation and coating over nanoparticles. In vivo brain uptake showed greater fluorescence intensity of the coated nanoparticles in the brain than uncoated nanoparticles. In addition, there was a 2.33-fold increase in bioavailability after coating compared to naringenin suspension and enhanced brain uptake. CONCLUSION: Present studies indicate sustained and targeted brain delivery of naringenin via the ligandcoated delivery system by inhibiting enhanced P-glycoprotein (P-gp) efflux occurring in autism spectrum disorders due to neuroinflammation.
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Transtorno do Espectro Autista , Nanopartículas , Humanos , Disponibilidade Biológica , Doenças Neuroinflamatórias , Espectroscopia de Infravermelho com Transformada de Fourier , Encéfalo , Subfamília B de Transportador de Cassetes de Ligação de ATP , Glicóis , Tamanho da Partícula , Portadores de FármacosRESUMO
Huntington disease (HD), an autosomal dominant neurodegenerative disorder characterized by involuntary choreatic movements with cognitive and behavioral disturbances. HD striatum has increased conversion of kynurenine to quinolinic acid (QA) which activates NMDA receptors leading to activation of microglia and increased levels of nuclear factor kappa B (NF-κB) leading to elevated transcription of inducible nitric oxide synthase (iNOS) and various cytokines causing neuronal death via neuroinflammation, oxidative stress, mitochondrial dysfunction and apoptosis. Therefore, inhibiting IKK-NF-κB pathway induced excitotoxicity, oxidative stress and neuroinflammation could be a potential intervention in slowing down the disease progression. QA injection intrastriatally (IS-QA) produce damage mimicking HD where neuroinflammation, oxidative stress and mitochondrial dysfunction play crucial role. Ellagic acid (EA) and vanillic acid (VA) are well reported to possess antioxidant and NF-κB inhibiting effect. Hence, in present study, rats administered IS-QA were treated with EA and VA for 21 days to explore their neuroprotective effects. Behavioral studies, biochemical estimations for oxidative stress and acetylcholinesterase assay were performed. Mitochondrial function was determined by estimating mitochondrial enzyme complexes; inflammatory markers like TNF-α, IL-6, NF-κB by ELISA and apoptosis by caspase-3 levels. Brain damage was determined by histopathology which revealed their neuroprotective effects. Various doses of EA and VA produced improved motor and cognitive functions, oxidative stress and neuroinflammation were also reduced and mitochondrial functioning was improved. In a nutshell, these results signify improved motor and cognitive functions by EA and VA in QA model of HD, along with declined oxidative stress, mitochondrial dysfunction and neuroinflammation.
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Doença de Huntington , Fármacos Neuroprotetores , Animais , Ratos , Ácido Quinolínico/efeitos adversos , Doença de Huntington/induzido quimicamente , Doença de Huntington/tratamento farmacológico , Doença de Huntington/metabolismo , NF-kappa B/metabolismo , Caspase 3/metabolismo , Ácido Elágico/farmacologia , Ácido Elágico/uso terapêutico , Ácido Vanílico/farmacologia , Ácido Vanílico/uso terapêutico , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Óxido Nítrico Sintase Tipo II/metabolismo , Acetilcolinesterase/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Antioxidantes/farmacologia , Receptores de N-Metil-D-Aspartato/metabolismo , Interleucina-6/metabolismo , Cinurenina/metabolismo , Estresse Oxidativo , Anti-Inflamatórios/farmacologiaRESUMO
BACKGROUND: The nitric oxide pathway has been \pivotal in exploring neurodevelopmental disorders. Pathogenesis of autism spectrum disorders (ASD) is also suspected to involve a number of biological cascades triggered by nitric oxide-induced neurotoxicity. The excessive nitric oxide levels caused by varied toxicants leads to the formation of reactive nitrogenous species along with ROS leading to mitochondrial dysfunction, oxidative stress, neuroinflammation, and altered NOS expression responsible for worsening of behavioral complications. AREAS COVERED: In this article, we will discuss the plausible role of the nitric oxide pathway in ASD and also discuss the modulation of this pathway by therapeutics, which can be explored in clinics for mitigating nitrosative stress in ASD. Literature was searched utilizing various databases such as Embase, Medline, Web of Science, and Google Scholar from 1966 to 2021. EXPERT OPINION: Nitric oxide pathway is an unexplored domain in the field of ASD and could act as an important therapeutic target in providing relief from behavioral alterations in autistic patients. At present, no major experimental study confirms the role of nitric oxide in autism. However, conclusive preclinical and clinical evidence is needed to evaluate and establish the role of nitric oxide in ASD.
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Transtorno do Espectro Autista , Transtorno do Espectro Autista/tratamento farmacológico , Humanos , Óxido Nítrico/metabolismo , Estresse Nitrosativo , Estresse OxidativoRESUMO
Kynurenine pathway, a neuroimmunological pathway plays a substantial role in depression. Consistently, increased levels of neurotoxic metabolite of kynurenine pathway; quinolinic acid (QA) found in the suicidal patients and remitted major depressive patients. QA, an endogenous modulator of N-methyl-d-aspartate receptor is produced by microglial cells, may serve as a potential candidate for a link between antioxidant defence system and immune changes in depression. Further, nuclear factor (erythroid-derived 2) like 2 (Nrf2), an endogenous antioxidant transcription factor plays a significant role in maintaining antioxidant homeostasis during basal and stress conditions. The present study was designed to explore the effects of KMO-inhibition (Kynurenine monooxygenase) and association of reduced QA on Keap1/Nrf2/ARE pathway activity in olfactory bulbectomized mice (OBX-mice). KMO catalysis the neurotoxic branch of kynurenine pathway directing the synthesis of QA. KMO inhibitionshowed significant reversal of depressive-like behaviour, restored Keap-1 and Nrf2 mRNA expression, and associated antioxidant levels in cortex and hippocampus of OBX-mice. KMO inhibition also increased PI3K/AKT mRNA expression in OBX-mice. KMO inhibition and associated reduced QA significantly decreased inflammatory markers, kynurenine and increased the 5-HT, 5-HIAA and tryptophan levels in OBX-mice. Furthermore, molecular docking studies has shown good binding affinity of QA towards ubiquitin proteasome complex and PI3K protein involved in Keap-1 dependent and independent proteasome degradation of Nrf2 respectively supporting our in-vivo findings. Hence, QA might act as pro-oxidant through downregulating Nrf2/ARE pathway along with modulating other pathways and KMO inhibition could be a potential therapeutic target for depression treatment.
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Transtorno Depressivo Maior , Ácido Quinolínico , Animais , Antioxidantes , Depressão/tratamento farmacológico , Modelos Animais de Doenças , Humanos , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Cinurenina/metabolismo , Quinurenina 3-Mono-Oxigenase/metabolismo , Camundongos , Simulação de Acoplamento Molecular , Fator 2 Relacionado a NF-E2/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Ácido Quinolínico/metabolismo , RNA MensageiroRESUMO
Cognitive dysfunction is an important complication observed in type 2 diabetes mellitus (T2DM) patients. Tetramethylpyrazine (TMP) is known to exhibit anti-diabetic and neuroprotective properties. Therefore, the present study aimed to investigate the possible therapeutic effects of TMP against type 2 diabetes-associated cognitive impairment in rats. High-fat diet (HFD) followed by a low dose of streptozotocin (35 mg/kg) was used to induce diabetes in Sprague-Dawley rats. TMP (20, 40, and 80 mg/kg) and Pioglitazone (10 mg/kg) were administered for 4 weeks. The Morris water maze (MWM) and novel objective recognition task (NOR) tests were used to assess memory function. Fasting blood glucose (FBG), lipid profile, HOMA-IR, glycosylated hemoglobin (HbA1c), and glucose tolerance were measured. Acetylcholinesterase (AChE) and choline acetytransferase (ChAT) activity, acetylcholine (ACh) levels, oxidative stress, apoptotic (Bcl-2, Bax, caspase-3), and inflammatory markers (TNF-α, IL-1ß, and NF-kß) were assessed. BDNF, p-AKT, and p-CREB levels were also measured. In the present work, we observed that treatment of diabetic rats with TMP alleviated learning and memory deficits, improved insulin sensitivity, and attenuated hyperglycemia and dyslipidemia. Furthermore, treatment with TMP increased BDNF, p-Akt, and p-CREB levels, normalized cholinergic dysfunction, and suppressed oxidative, inflammatory, and apoptotic markers in the hippocampus. Collectively, our results suggest that the TMP may be an effective neuroprotective agent in alleviating type 2 diabetes-associated cognitive deficits.
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Disfunção Cognitiva , Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Acetilcolinesterase , Animais , Apoptose , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Disfunção Cognitiva/tratamento farmacológico , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Aprendizagem em Labirinto , Doenças Neuroinflamatórias , Estresse Oxidativo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Pirazinas , Ratos , Ratos Sprague-DawleyRESUMO
One of the essential organs and protective barricades, the skin, needs to be taken care of early. Skin is affected by several intrinsic and extrinsic factors, and despite their morphological and pathological differences, they have many molecular similarities. As of today, various mechanisms and theories have been recommended for aging, such as cellular anility, reduced proliferative tendency, reduction in length of telomere, mutations in DNA, theory of free radical generation, and many others. In today's society, skin health is often considered an important indicator of health, which has led to an increased demand for anti-aging products. However, numerous conventional cosmetics and phytocompounds (curcumin, Vitamin E, resveratrol) utilized in anti-aging products have inimical physical and chemical attributes, including insufficient chemical stability and inadequate skin penetration bound their effectuality after topical administration. So recently, new novel nanotechnological approaches for preventing skin aging, such as liposomes, niosomes, solid lipid nanoparticles, transferosomes, ethosomes, nanostructured lipid carriers, and carbon nanotubes, are being used. Hence, the field of cosmeceutical nanomaterials is rapidly evolving, and we can look forward to seeing a variety of innovative nanotechnology-based cosmetic products be a game-changer for this multi-million anti-aging cosmetic industry.
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Cosméticos , Nanopartículas , Nanotubos de Carbono , Envelhecimento da Pele , Cosméticos/farmacologia , Cosméticos/uso terapêutico , Humanos , Lipossomos , Nanotecnologia , Pele/metabolismoRESUMO
Depression is a psychiatric disorder characterized by low-esteem, anhedonia, social deficit, and lack of interest. Decreased brain-derived neurotrophic factor (BDNF) and impaired tropomyosin kinase B receptor (TrkB receptor) signaling are associated with depression. In our study, depressive-like behavior was induced in mice by chronic unpredictable mild stress (CUMS) model. Various behavioral tests like tail suspension test (TST), open field test (OFT), sucrose preference test (SPT); biochemical analyses for corticosterone, reduced glutathione (GSH), lipid peroxidation (LPO), superoxide dismutase (SOD), nitric oxide (NO) and enzyme-linked immunosorbent assay (ELISA) for BDNF were performed. Body weight was measured every week. CUMS induced depressive-like behavior was found to be associated with increased oxidative stress in the brain and serum corticisterone with subsequent reduction of BDNF. Sodium orthovanadate (SOV), a protein tyrosine phosphatase inhibitor already reported to elevate BDNF levels, was used as the test drug. Sodium orthovanadate (5 mg/kg, 10 mg/kg) and fluoxetine (FLX-10 mg/kg) was given to mice orally for 21days before 30 min of stress induction. The behavioral tests reflected depressive-like behavior in CUMS, which was attenuated by both SOV and fluoxetine. SOV at 10 mg/kg demonstrated significant results in the present study characterized by decreased malondialdehyde levels (MDA/LPO), NO levels, and increased GSH level and SOD activity in both the cortex and hippocampus. Besides, ELISA has revealed the significant elevation of BDNF levels in the treatment groups (SOV-5 mg/kg, 10 mg/kg and FLX-10 mg/kg) as compared to the disease group (CUMS). Therefore, the treatment with SOV appeared to reverse both oxidative and nitrosative stress. Decreased serum corticosterone levels observed with SOV (5 & 10 mg/kg), FLX-10 mg/kg, FLX (10 mg/kg) + SOV (5 mg/kg); and SOV-10 mg/kg per-se treatment and elevated BDNF level with SOV (5 & 10 mg/kg), FLX-10 mg/kg were associated with attenuation of depressive-like behavior. The findings of this preliminary study indicate that SOV has the potential to restore antidepressant-like effects or prevent stress-induced anhedonia and so further molecular mechanisms are warranted for clinical translation.
Assuntos
Antidepressivos/farmacologia , Estresse Psicológico , Vanadatos/farmacologia , Administração Oral , Animais , Antidepressivos/química , Antidepressivos/uso terapêutico , Comportamento Animal/efeitos dos fármacos , Depressão/tratamento farmacológico , Modelos Animais de Doenças , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Vanadatos/química , Vanadatos/uso terapêuticoRESUMO
BACKGROUND: Bioactive dietary constituents activating Transient receptor potential (TRP) channels have emerged as promising candidates for the prevention of metabolic disorders. OBJECTIVE: The present study is an attempt to evaluate anti-obesity potential of a dietary TRP-based tri-agonist, combination of sub-effective doses of capsaicin (TRPV1 agonist), menthol (TRPM8 agonist), and cinnamaldehyde (TRPA1 agonist) in high-fat diet (HFD)-fed mice. DESIGN: Male C57BL/6 J mice divided into three groups (n = 8), were fed on normal pellet diet (NPD), or high-fat diet (HFD) (60% energy by fat) and HFD + CB (combination of capsaicin 0.4 mg/Kg, menthol 20 mg/Kg, and cinnamaldehyde 2 mg/Kg; p.o) for 12 weeks. Effects on HFD-induced weight gain, biochemical, histological and genomic changes in the WAT, BAT, liver and hypothalamus tissues were studied. RESULTS: Administration of tri-agonist prevented HFD-induced increase in weight gain, improved altered morphometric parameters, glucose homeostasis, and adipose tissue hypertrophy. Tri-agonist supplementation was found to induce browning of white adipose tissue and promote brown adipose tissue activation. Enhanced glucose utilization and prevention of lipid accumulation and insulin resistance in the liver was observed in mice supplemented with a tri-agonist. CONCLUSION: The present work provides evidence that the new approach based on combination of sub-effective doses of TRP channel agonists (TRI-AGONIST) can be employed to develop concept-based functional food for therapeutic and preventive strategies against HFD-associated pathological complications.
Assuntos
Metabolismo Energético/efeitos dos fármacos , Canais de Potencial de Receptor Transitório/agonistas , Acroleína/administração & dosagem , Acroleína/análogos & derivados , Acroleína/uso terapêutico , Animais , Capsaicina/administração & dosagem , Capsaicina/uso terapêutico , Dieta Hiperlipídica/efeitos adversos , Dieta Hiperlipídica/métodos , Modelos Animais de Doenças , Mentol/administração & dosagem , Mentol/uso terapêutico , Camundongos , Camundongos Endogâmicos C57BL/crescimento & desenvolvimento , Camundongos Endogâmicos C57BL/metabolismo , Fenótipo , Canais de Potencial de Receptor Transitório/farmacologiaRESUMO
Neuropsychiatric disorders (NPDs) are a huge burden to the patient, their family, and society. NPDs have been greatly associated with cardio-metabolic comorbidities such as obesity, type-2 diabetes mellitus, dysglycaemia, insulin resistance, dyslipidemia, atherosclerosis, and other cardiovascular disorders. Antipsychotics, which are frontline drugs in the treatment of schizophrenia and off-label use in other NPDs, also add to this burden by causing severe metabolic perturbations. Despite decades of research, the mechanism deciphering the link between neuropsychiatric and metabolic disorders is still unclear. In recent years, transient receptor potential Ankyrin 1 (TRPA1) channel has emerged as a potential therapeutic target for modulators. TRPA1 agonists/antagonists have shown efficacy in both neuropsychiatric disorders and appetite regulation and thus provide a crucial link between both. TRPA1 channels are activated by compounds such as cinnamaldehyde, allyl isothiocyanate, allicin and methyl syringate, which are present naturally in food items such as cinnamon, wasabi, mustard, garlic, etc. As these are present in many daily food items, it could also improve patient compliance and reduce the patients' monetary burden. In this review, we have tried to present evidence of the possible involvement of TRPA1 channels in neuropsychiatric and metabolic disorders and a possible hint towards using TRPA1 modulators to target appetite, lipid metabolism, glucose and insulin homeostasis and inflammation associated with NPDs.