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Background: Nimbolide, a bioactive compound derived from the neem tree, has garnered attention as a potential breakthrough in the prevention and treatment of chronic diseases. Recent updates in research highlight its multifaceted pharmacological properties, demonstrating anti-inflammatory, antioxidant, and anticancer effects. With a rich history in traditional medicine, nimbolide efficacy in addressing the molecular complexities of conditions such as cardiovascular diseases, diabetes, and cancer positions it as a promising candidate for further exploration. As studies progress, the recent update underscores the growing optimism surrounding nimbolide as a valuable tool in the ongoing pursuit of innovative therapeutic strategies for chronic diseases. Methods: The comprehensive search of the literature was done until September 2020 on the MEDLINE, Embase, Scopus and Web of Knowledge databases. Results: Most studies have shown the Nimbolide is one of the most potent limonoids derived from the flowers and leaves of neem (Azadirachta indica), which is widely used to treat a variety of human diseases. In chronic diseases, nimbolide reported to modulate the key signaling pathways, such as Mitogen-activated protein kinases (MAPKs), Wingless-related integration site-ß (Wnt-ß)/catenin, NF-κB, PI3K/AKT, and signaling molecules, such as transforming growth factor (TGF-ß), Matrix metalloproteinases (MMPs), Vascular Endothelial Growth Factor (VEGF), inflammatory cytokines, and epithelial-mesenchymal transition (EMT) proteins. Nimbolide has anti-inflammatory, anti-microbial, and anti-cancer properties, which make it an intriguing compound for research. Nimbolide demonstrated therapeutic potential for osteoarthritis, rheumatoid arthritis, cardiovascular, inflammation and cancer. Conclusion: The current review mainly focused on understanding the molecular mechanisms underlying the therapecutic effects of nimbolide in chronic diseases.
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Stroke is one of the main causes of mortality and disability, and it is due to be included in monetary implications on wellbeing frameworks around the world. Ischemic stroke is caused by interference in cerebral blood flow, leading to a deficit in the supply of oxygen to the affected region. It accounts for nearly 80-85% of all cases of stroke. Oxidative stress has a significant impact on the pathophysiologic cascade in brain damage leading to stroke. In the acute phase, oxidative stress mediates severe toxicity, and it initiates and contributes to late-stage apoptosis and inflammation. Oxidative stress conditions occur when the antioxidant defense in the body is unable to counteract the production and aggregation of reactive oxygen species (ROS). The previous literature has shown that phytochemicals and other natural products not only scavenge oxygen free radicals but also improve the expressions of cellular antioxidant enzymes and molecules. Consequently, these products protect against ROS-mediated cellular injury. This review aims to give an overview of the most relevant data reported in the literature on polyphenolic compounds, namely, gallic acid, resveratrol, quercetin, kaempferol, mangiferin, epigallocatechin, and pinocembrin, in terms of their antioxidant effects and potential protective activity against ischemic stroke.
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Accidente Cerebrovascular Isquémico , Accidente Cerebrovascular , Humanos , Antioxidantes/farmacología , Especies Reactivas de Oxígeno/metabolismo , Polifenoles/farmacología , Neuroprotección , Accidente Cerebrovascular/metabolismo , Estrés Oxidativo , IsquemiaRESUMEN
In the current scenario of medicinal chemistry, quinoline plays a pivotal role in the design of new heterocyclic compounds with several pharmacological properties, so the search for new synthetic methodologies and their application in drug discovery has been widely studied. So far, many procedures have been performed for the preparation of quinoline scaffolds, among which Friedländer quinoline synthesis plays an important role in obtaining these heterocycles. The Friedländer reaction involves condensation between 2-aminobenzaldehydes and keto-compounds. The quinoline nucleus, once obtained through the Friedländer synthesis, has been extensively modified so that these derivatives can exhibit a large number of biological activities such as anticancer, antimalarial, antimicrobial, antifungal, antituberculosis, and antileishmanial properties. In this work, the focus is on the applicability of the Friedländer reaction in the synthesis of various types of bioactive heterocyclic quinoline compounds, which to date has not been reported in the context of medicinal chemistry. The main part of this review selectively focuses on research from 2010 to date and will present highlights of the Friedländer quinoline synthesis procedures and findings to address biological and pharmacological activities.
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Antiinfecciosos , Quinolinas , Química Farmacéutica , Quinolinas/química , Antiinfecciosos/farmacologíaRESUMEN
Substance abuse affects the central nervous system (CNS) and remains a global health problem. Psychostimulants, such as cocaine and methamphetamine (METH), and opioids affect neuronal function and lead to behavioral impairments via epigenetic modification. Epigenetic changes occur via classical pathways, especially the class III histone deacetylase (HDAC)-sirtuin (SIRT) family, that act as cellular sensors to regulate energy homeostasis and coordinate cellular responses to maintain genome integrity. However, SIRT family (1-7)-associated neurodegeneration has not been elucidated in the context of energy metabolism. The present study examined the effects of psychostimulants, such as cocaine and METH, and opioids, such as morphine, on SIRT family (1-7) [class I, II, III and IV] expression and cellular translocation-mediated dysfunction in astrocytes and microglial cells. The "nootropic" drug piracetam played a preventative role against psychostimulant- and opioid-induced SIRT (1-7) expression in astrocytes. These results indicate that cocaine, METH, and morphine affected deacetylation and cellular function, and these changes were prevented by piracetam in astrocytes.
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Astrocitos/efectos de los fármacos , Cocaína/farmacología , Histona Desacetilasas/metabolismo , Metanfetamina/farmacología , Morfina/farmacología , Neuroglía/efectos de los fármacos , Sirtuinas/metabolismo , Analgésicos Opioides/farmacología , Astrocitos/enzimología , Células Cultivadas , Estimulantes del Sistema Nervioso Central/farmacología , Epigénesis Genética/efectos de los fármacos , Histona Desacetilasas/genética , Humanos , Neuroglía/enzimología , Nootrópicos/farmacología , Piracetam/farmacología , Sirtuinas/genéticaRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: The prevalence of cardiovascular diseases (CVDs) has been increasing worldwide. Despite significant improvements in therapeutics and on-going developments of novel targeted-treatment regimens, cardiac diseases lack effective preventive and curative therapies with minimal side effects. Therefore, there is an urgent need to identify and propagate alternative and complementary therapies against cardiovascular diseases. Some traditional Chinese medicines can contribute to the prevention and treatment of CVDs and other chronic diseases, with few side effects. Hirudo, a medicinal leech, has been acclaimed for improving blood circulation and overcoming blood stagnation; however, the precise molecular mechanisms of leech extract treatment against pathological cardiac remodeling remain elusive. In this study, we aimed to delineate the molecular mechanisms of medicinal leech extract in the treatment of cardiac hypertrophy and fibrosis, using both in vitro and in vivo assessments. MATERIALS AND METHODS: We conducted in vitro and in vivo animal experiments, including cell-viability assays, fluorescence microscopy, immunoblotting, immunohistochemistry, and Masson's trichrome staining. RESULTS: Pre-treatment with leech extract conferred a survival benefit to spontaneously-hypertensive rats (SHRs) and significantly reduced angiotensin II (ANG II)-induced cardiac hypertrophy and fibrosis. ANG II-stimulated cardiac hypertrophy markers were attenuated by leech extract treatment, versus controls. Translational expression of stress-associated mitogen-activated protein kinases (MAPKs) was also repressed. In vivo, leech extract treatment significantly ameliorated the cardiac hypertrophy phenotype in SHRs and diminished interstitial fibrosis, accompanied with reduced fibrosis markers. CONCLUSION: Leech extract treatment under a hypertensive condition exerted significant cardio-protective benefits by reducing the expression of cardiac hypertrophy-related transcription factors, stress-associated MAPKs, and fibrosis mediators. Our findings imply that medicinal leach extract may be effective against hypertension-induced cardiac hypertrophy and fibrosis.
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Cardiomegalia/tratamiento farmacológico , Cardiotónicos/uso terapéutico , Hirudo medicinalis , Hipertensión/tratamiento farmacológico , Miocitos Cardíacos/efectos de los fármacos , Animales , Factores Biológicos , Cardiomegalia/etiología , Cardiomegalia/patología , Cardiotónicos/aislamiento & purificación , Cardiotónicos/farmacología , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/fisiología , Relación Dosis-Respuesta a Droga , Fibrosis , Hipertensión/complicaciones , Hipertensión/patología , Sanguijuelas , Masculino , Miocitos Cardíacos/patología , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas WKYRESUMEN
HIV infection and drugs of abuse induce oxidative stress and redox imbalance, which cause neurodegeneration. The mechanisms by which HIV infection and cocaine consumption affect astrocyte energy metabolism, and how this leads to neurodegenerative dysfunction, remain poorly understood. Presently, we investigated how oxidative injury causes the depletion of energy resources and glutathione synthetase (GSS), which in turn activates 5' AMP-activated protein kinase (AMPK), glycolytic enzymes, and mitochondrial biogenesis, finally resulting in nuclear factor erythroid (NRF) transcription in astrocytes. Both human primary astrocytes incubated with HIV-1 Tat protein in vitro and HIV-inducible Tat (iTat) mice exposed to cocaine showed decreased levels of GSS and increased superoxide dismutase (SOD) levels. These changes, in turn, significantly activated AMPK and raised the concentrations of several glycolytic enzymes, along with oxidative phosphorylation, the mitochondrial biogenesis of peroxisome proliferator-activated receptor-γ coactivator (PGC-1α) and mitochondrial transcription factor (TFAM), and Nrf1 and Nrf2 gene transcription and protein expression. Moreover, neurons exposed to HIV-1Tat/cocaine-conditioned media showed reductions in dendritic formation, spine density, and neuroplasticity compared with control neurons. These results suggest that redox inhibition of GSS altered AMPK activation and mitochondrial biogenesis to influence Nrf transcription. These processes are important components of the astrocyte signaling network regulating brain energy metabolism in HIV-positive cocaine users. In conclusion, HIV-1 Tat alters redox inhibition, thus increasing glycolytic metabolic profiles and mitochondrial biogenesis, leading to Nrf transcription, and ultimately impacting astrocyte energy resource and metabolism. Cocaine exacerbated these effects, leading to a worsening of neurodegeneration.
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Encéfalo/metabolismo , Cocaína/farmacología , Metabolismo Energético/efectos de los fármacos , Factor 2 Relacionado con NF-E2/genética , Degeneración Nerviosa/genética , Factor Nuclear 1 de Respiración/genética , Biogénesis de Organelos , Transcripción Genética , Productos del Gen tat del Virus de la Inmunodeficiencia Humana/farmacología , Proteínas Quinasas Activadas por AMP/metabolismo , Animales , Astrocitos/efectos de los fármacos , Astrocitos/metabolismo , Células Cultivadas , Espinas Dendríticas/efectos de los fármacos , Espinas Dendríticas/metabolismo , Metabolismo Energético/genética , Regulación de la Expresión Génica/efectos de los fármacos , Glucólisis/efectos de los fármacos , Humanos , Masculino , Ratones Transgénicos , Factor 2 Relacionado con NF-E2/metabolismo , Degeneración Nerviosa/patología , Plasticidad Neuronal/efectos de los fármacos , Factor Nuclear 1 de Respiración/metabolismo , Oxidación-Reducción/efectos de los fármacos , Fosforilación Oxidativa/efectos de los fármacos , Transcripción Genética/efectos de los fármacosRESUMEN
Treatment of brain-related diseases is one of the most strenuous challenges in drug delivery research due to numerous hurdles, including poor blood-brain barrier penetration, lack of specificity, and severe systemic toxicities. Our research primarily focuses on the delivery of natural therapeutic compound, α-asarone, for the treatment of brain-related diseases. However, α-asarone has poor aqueous solubility, bioavailability, and stability, all of which are critical issues that need to be addressed. This study aims at formulating a lipid nanoparticulate system of α-asarone (A-LNPs) that could be used as a brain drug delivery system. The physicochemical, solid-state properties, stability, and in vitro and in vivo studies of the A-LNPs were characterized. The release of α-asarone from the A-LNPs was prolonged and sustained. After intravenous administration of A-LNPs or free α-asarone, significantly higher levels of α-asarone from the A-LNPs were detected in murine plasma and brain parenchyma fractions, confirming the ability of A-LNPs to not only maintain a therapeutic concentration of α-asarone in the plasma, but also transport α-asarone across the blood-brain barrier. These findings confirm that lipid nanoparticulate systems enable penetration of natural therapeutic compound α-asarone through the blood-brain barrier and may be a candidate for the treatment of brain-related diseases.
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Anisoles/farmacocinética , Encéfalo/metabolismo , Lípidos/química , Nanopartículas/química , Administración Intravenosa , Derivados de Alilbenceno , Animales , Disponibilidad Biológica , Transporte Biológico , Barrera Hematoencefálica , Ratones , Distribución TisularRESUMEN
Cocaine abuse is known to alter mitochondrial biogenesis and induce epigenetic modification linked with neuronal dysfunction. Cocaine-induced epigenetic modification of DNA methylation and the mitochondrial genome may affect mitochondrial DNA (mtDNA) and nuclear DNA (nDNA), as epigenetic DNA methylation is key to maintaining genomic integrity in the central nervous system (CNS). However, the impact of cocaine-mediated epigenetic changes in astrocytes has not yet been elucidated. In this study, we explored the neuroprotective effect of piracetam against cocaine-induced epigenetic changes in DNA methylation in astrocytes. To study our hypothesis, we exposed human astrocytes to cocaine alone or in combination with the nootropic drug piracetam. We examined the expression of the DNA methyltransferases (DNMTs) DNMT-1, DNMT-3A, and DNMT-3B; global DNA methylation levels of 5-methycytosine (5-mC); and induction of ten-eleven translocation (TET) enzymes in astrocytes. In addition, we analyzed mtDNA methylation by targeted next-generation bisulfite sequencing. Our data provide evidence that cocaine impairs DNMT activity and thereby has impacts on mtDNA, which might contribute to the neurodegeneration observed in cocaine users. These effects might be at least partially prevented by piracetam, allowing neuronal function to be maintained.
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The use of psychostimulants and alcohol disrupts blood-brain barrier (BBB) integrity, resulting in alterations to cellular function, and contributes to neurotoxicity. The BBB is the critical boundary of the central nervous system (CNS) where it maintains intracellular homeostasis and facilitates communication with the peripheral circulation. The BBB is regulated by tight junction (TJ) proteins that closely interact with endothelial cells (EC). The complex TJ protein network consists of transmembrane proteins, including claudins, occludins, and junction adhesion molecules (JAM), as well as cytoskeleton connected scaffolding proteins, zonula occludentes (ZO-1, 2, and 3). The use of psychostimulants and alcohol is known to affect the CNS and is implicated in various neurological disorders through neurotoxicity that partly results from increased BBB permeability. The present mini review primarily focuses on BBB structure and permeability. Moreover, we assess TJ protein and cytoskeletal changes induced by cocaine, methamphetamine, morphine, heroin, nicotine, and alcohol. These changes promote glial activation, enzyme potentiation, and BBB remodeling, which affect neuroinflammatory pathways. Although the effect of drugs of abuse on BBB integrity and the underlying mechanisms are well studied, the present review enhances the understanding of the underlying mechanisms through which substance abuse disorders cause BBB dysfunction.
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Mitochondrial dysfunction and disturbed mitochondrial dynamics were found to be common phenomena in the pathogenesis of Parkinson's disease (PD). Vasicinone is a quinazoline alkaloid from Adhatoda vasica. Here, we investigated the autophagy/mitophagy-enhancing effect of vasicinone and explored its neuroprotective mechanism in paraquat-mimic PD modal in SH-SY5Y cells. Vasicinone rescued the paraquat-induced loss of cell viability and mitochondrial membrane potential. Subsequently, the accumulation of mitochondrial reactive oxygen species (ROS) was balanced by an increase in the expression of antioxidant enzymes. Furthermore, vasicinone restored paraquat-impaired autophagy and mitophagy regulators DJ-1, PINK-1 and Parkin in SH-SY5Y cells. The vasicinone mediated autophagy pathways were abrogated by treatment with the autophagy inhibitor 3-MA, which lead to increases α-synuclein accumulation and decreased the expression of p-ULK and ATG proteins and the autophagy marker LC3-II compared to that observed without 3-MA treatment. These results demonstrated that vasicinone exerted neuroprotective effects by upregulating autophagy and PINK-1/Parkin mediated mitophagy in SH-SY5Y cells.
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Alcaloides/farmacología , Alcaloides/uso terapéutico , Autofagia/efectos de los fármacos , Autofagia/genética , Género Justicia/química , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Mitofagia/efectos de los fármacos , Mitofagia/genética , Fármacos Neuroprotectores , Paraquat/efectos adversos , Enfermedad de Parkinson Secundaria/tratamiento farmacológico , Fitoterapia , alfa-Sinucleína/metabolismo , Alcaloides/aislamiento & purificación , Animales , Células Cultivadas , Ratones , Mitocondrias/metabolismo , Enfermedad de Parkinson Secundaria/inducido químicamente , Enfermedad de Parkinson Secundaria/metabolismo , Proteína Desglicasa DJ-1/metabolismo , Proteínas Quinasas/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Ubiquitina-Proteína Ligasas/metabolismoRESUMEN
Vasicinone is a quinazoline alkaloid isolated from the Adhatoda vasica plant. In this study, we explored the neuroprotective effect and underlying molecular mechanism of vasicinone against paraquat-induced cellular apoptosis in SH-SY5Y cells. Vasicinone reduced the paraquat-induced loss of cell viability, rescued terminal deoxynucleotide transferase-mediated dUTP nick end-labeling (TUNEL)-positive apoptotic nuclei, and suppressed generation of reactive oxygen species (ROS) in a dose-dependent manner. Western blotting analysis revealed that vasicinone increased the phosphorylation of IGF1R/PI3K/AKT cell survival signaling molecules and downregulated the paraquat-induced, mitogen-activated protein kinase (MAPK)/c-Jun N-terminal kinase (JNK)-mediated apoptotic pathways compared to that observed in cells not treated with vasicinone. This protection depended critically on the activation of IGF1R, and the silencing of IGF1R by siRNA completely abrogated the protective effect of vasicinone in SH-SY5Y cells. Our findings indicated that vasicinone is a potential candidate for the treatment of Parkinson's disease and possibly other oxidative stress-related neurodegenerative disorders.
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Alcaloides/farmacología , Apoptosis/efectos de los fármacos , Paraquat/farmacología , Enfermedad de Parkinson , Fosfatidilinositol 3-Quinasas/metabolismo , Receptor IGF Tipo 1/metabolismo , Línea Celular , Supervivencia Celular/efectos de los fármacos , Humanos , Etiquetado Corte-Fin in Situ , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/patología , Fosforilación/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Especies Reactivas de Oxígeno/antagonistas & inhibidores , Receptor IGF Tipo 1/genética , Transducción de Señal/efectos de los fármacos , Proteína p53 Supresora de Tumor/efectos de los fármacos , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
BACKGROUND: Fisetin, a polyphenolic compound, has drawn notable attention owing to its antioxidant, anti-inflammatory, anti-cancer and neuroprotective effects. However, the cardiac effects of fisetin are not clear yet. HYPOTHESIS: The aim of the present study is to examine the cardioprotective effect of fisetin against Ang-II induced apoptosis in H9c2 cells and in spontaneous hypertensive rats (SHR). METHODS/STUDY DESIGN: The in vitro protective effect of fisetin was evaluated after the cells were treated with fisetin (50 µM/ml/ 24⯠h) for 2⯠h prior or after Ang-II administration to induce apoptosis. For in vivo experiments, SHRs were orally administered with fisetin (10⯠mg/kg) twice a week for 6 weeks. Cellular apoptosis was analyzed by TUNEL staining assay and the modulation in the expression levels of proteins involved in apoptosis and cell survival were determined by western blotting. RESULTS: Our results demonstrate the potent cardioprotective efficacy of fisetin against Ang-II induced apoptosis in H9c2 cells and in SHR models. Fisetin administration reduced the apoptotic nuclei considerably And reduced the expression of apoptotic proteins such as TNF- α, Fas L, FADD, Cleaved caspase-3 and Cleaved PARP and increased the cell survival and anti-apoptotic proteins like Bcl-2, Bcl-xL, p-IGF1R, p-PI3K and p-AKT in both in vitro and in vivo models. CONCLUSION: In conclusion, the results of the present study reveal that fisetin activates the IGF-IR-dependent p-PI3K/p-Akt survival signaling pathway and suppresses the caspase dependent apoptosis.
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Angiotensina II/efectos adversos , Apoptosis/efectos de los fármacos , Flavonoides/farmacología , Hipertensión/tratamiento farmacológico , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Angiotensina II/farmacología , Animales , Proteínas Reguladoras de la Apoptosis/metabolismo , Supervivencia Celular/efectos de los fármacos , Flavonoles , Hipertensión/metabolismo , Hipertensión/patología , Masculino , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Sustancias Protectoras/farmacología , Ratas Endogámicas SHR , Ratas Wistar , Receptor IGF Tipo 1 , Receptores de Somatomedina/metabolismo , Transducción de Señal/efectos de los fármacosRESUMEN
Neferine is a bisbenzylisoquinoline alkaloid isolated from the embryos of lotus which has attracted attention for its anti-inflammatory and anti-cancer activities. The aim of this study was to evaluate the anti-cancer effect of neferine against diethylnitrosamine (DEN)-induced lung carcinogenesis in Wistar rats and to explore the underlying molecular mechanism. DEN-induced oxidative stress is mediated by alterations in the levels of pulmonary reactive-oxygen species, lipid peroxidation, protein carbonyl content and antioxidant status. Thus, treatment with neferine restored cellular normalcy, highlighting the antioxidant potential of neferine in mitigating the oxidative stress-mediated damage produced during DEN-induced lung carcinogenesis. Histopathological analysis showed disorganized alveolar structure, thickened alveolar wall, infiltration of inflammatory cells in DEN-induced rats, the damage was significantly reduced upon neferine treatment. DEN-induced rats exhibited increased gene expression of NF-κB, COX-2, CYP2E1, VEGF, Bcl-2, PI3K/AKT/mTOR and significantly decreased the gene expression of p53, Bax, caspase-9 and caspase-3. Neferine treatment restored the DEN- induced alteration of these gene expression levels. Further, blotting analysis also revealed increased expression of NF-κB, COX-2, Bcl-2 and decreased expression of Bax, caspase-9 and caspase-3 proteins in DEN-induced rats. Neferine treatment restored the expression of these proteins in DEN- induced lung carcinogenesis.