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Amyotrophic lateral sclerosis (ALS) is a severe adult motor neuron disease that causes progressive neuromuscular atrophy, muscle wasting, weakness, and depressive-like symptoms. Our previous research suggests that mercury levels are directly associated with ALS progression. MeHg+-induced ALS is characterised by oligodendrocyte destruction, myelin basic protein (MBP) depletion, and white matter degeneration, leading to demyelination and motor neuron death. The selection of MeHg+ as a potential neurotoxicant is based on our evidence that it has been connected to the development of ALS-like characteristics. It causes glutamate-mediated excitotoxicity, calcium-dependent neurotoxicity, and an ALS-like phenotype. Dysregulation of IGF-1/GLP-1 signalling has been associated with ALS progression. The bioactive amino acid 4-hydroxyisoleucine (HI) from Trigonella foenum graecum acts as an insulin mimic in rodents and increases insulin sensitivity. This study examined the neuroprotective effects of 4-HI on MeHg+-treated adult Wistar rats with ALS-like symptoms, emphasising brain IGF1/GLP-1 activation. Furthermore, we investigated the effect of 4-HI on MBP levels in rat brain homogenate, cerebrospinal fluid (CSF), blood plasma, and cell death indicators such as caspase-3, Bax, and Bcl-2. Rats were assessed for muscular strength, locomotor deficits, depressed behaviour, and spatial learning in the Morris water maze (MWM) to measure neurobehavioral abnormalities. Doses of 4-HI were given orally for 42 days in the MeHg+ rat model at 50 mg/kg or 100 mg/kg to ameliorate ALS-like neurological dysfunctions. Additionally, neurotransmitters and oxidative stress markers were examined in rat brain homogenates. Our findings suggest that 4-HI has neuroprotective benefits in reducing MeHg+-induced behavioural, neurochemical, and histopathological abnormalities in ALS-like rats exposed to methylmercury.
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Esclerose Lateral Amiotrófica , Compostos de Metilmercúrio , Esclerose Lateral Amiotrófica/tratamento farmacológico , Esclerose Lateral Amiotrófica/genética , Animais , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Isoleucina/análogos & derivados , Compostos de Metilmercúrio/toxicidade , Neurônios Motores , Ratos , Ratos WistarRESUMO
Parkinson's disease (PD) is characterised by dopaminergic neuronal loss in the brain area. PD is a complex disease that deteriorates patients' motor and non-motor functions. In experimental animals, the neurotoxin 6-OHDA induces neuropathological, behavioural, neurochemical and mitochondrial abnormalities and the formation of free radicals, which is related to Parkinson-like symptoms after inter-striatal 6-OHDA injection. Pathological manifestations of PD disrupt the cAMP/ATP-mediated activity of the transcription factor CREB, resulting in Parkinson's-like symptoms. Forskolin (FSK) is a direct AC/cAMP/CREB activator isolated from Coleus forskohlii with various neuroprotective properties. FSK has already been proven in our laboratory to directly activate the enzyme adenylcyclase (AC) and reverse the neurodegeneration associated with the progression of Autism, Multiple Sclerosis, ALS, and Huntington's disease. Several behavioural paradigms were used to confirm the post-lesion effects, including the rotarod, open field, grip strength, narrow beam walk (NBW) and Morris water maze (MWM) tasks. Our results were supported by examining brain cellular, molecular, mitochondrial and histopathological alterations. The FSK treatment (15, 30 and 45 mg/kg, orally) was found to be effective in restoring behavioural and neurochemical defects in a 6-OHDA-induced experimental rat model of PD. As a result, the current study successfully contributes to the investigation of FSK's neuroprotective role in PD prevention via the activation of the AC/cAMP/PKA-driven CREB pathway and the restoration of mitochondrial ETC-complex enzymes.
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Adenilil Ciclases , Doença de Parkinson , Animais , Ratos , Oxidopamina/efeitos adversos , Colforsina/farmacologia , Adenilil Ciclases/metabolismo , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/etiologia , Doença de Parkinson/metabolismo , Mitocôndrias/metabolismoRESUMO
Cannabis has long been used for healing and recreation in several regions of the world. Over 400 bioactive constituents, including more than 100 phytocannabinoids, have been isolated from this plant. The non-psychoactive cannabidiol (CBD) and the psychoactive Δ9-tetrahydrocannabinol (Δ9-THC) are the major and widely studied constituents from this plant. Cannabinoids exert their effects through the endocannabinoid system (ECS) that comprises cannabinoid receptors (CB1, CB2), endogenous ligands, and metabolizing enzymes. Several preclinical studies have demonstrated the potential of cannabinoids against leukemia, lymphoma, glioblastoma, and cancers of the breast, colorectum, pancreas, cervix and prostate. Cannabis and its constituents can modulate multiple cancer related pathways such as PKB, AMPK, CAMKK-ß, mTOR, PDHK, HIF-1α, and PPAR-γ. Cannabinoids can block cell growth, progression of cell cycle and induce apoptosis selectively in tumour cells. Cannabinoids can also enhance the efficacy of cancer therapeutics. These compounds have been used for the management of anorexia, queasiness, and pain in cancer patients. Cannabinoid based products such as dronabinol, nabilone, nabiximols, and epidyolex are now approved for medical use in cancer patients. Cannabinoids are reported to produce a favourable safety profile. However, psychoactive properties and poor bioavailability limit the use of some cannabinoids. The Academic Institutions across the globe are offering training courses on cannabis. How cannabis and its constituents exert anticancer activities is discussed in this article. We also discuss areas that require attention and more extensive research.
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Antineoplásicos/uso terapêutico , Canabinoides/uso terapêutico , Cannabis , Maconha Medicinal , Neoplasias/tratamento farmacológico , Animais , Antineoplásicos/farmacologia , Canabinoides/farmacologia , Cannabis/química , História do Século XIX , História do Século XX , História do Século XXI , Humanos , Maconha Medicinal/química , Maconha Medicinal/história , Maconha Medicinal/farmacologia , Maconha Medicinal/uso terapêutico , Neoplasias/metabolismo , Receptores de Canabinoides/metabolismoRESUMO
Matrine, a quinolizidine alkaloid, is commonly employed for treating various viral and inflammatory disorders. Here, we have evaluated matrine for its activity on C-X-C chemokine receptor type 4 (CXCR4) and matrix metalloproteinases (MMP-9/2) expression, and its potential to affect tumor metastasis and invasion. The effects of matrine on CXCR4, MMP-9/2, and nuclear factor κB (NF-κB) activation in lung (A549), prostate (DU145), and pancreas (MIA PaCa-2) cells were investigated by diverse techniques. The expression level of CXCR4 and MMP-9/2 was analyzed by western blot analysis and reverse transcription polymerase chain reaction. NF-κB activation was also evaluated by western blot analysis, electrophoretic mobility shift assay as well as immunocytochemical experiments. Furthermore, we monitored cell invasion and metastasis activities by wound healing and Boyden chamber assays. We noted that matrine induced a down-regulation of CXCR4 and MMP-9/2 at both protein and mRNA levels. In addition, matrine negatively regulated human epidermal growth factor receptor 2 (HER2) and C-X-C Motif Chemokine Ligand 12 (CXCL12)-induced CXCR4 expression. Moreover, NF-κB suppression by matrine led to inhibition of metastatic potential of tumor cells. Our results suggest that matrine can block the cancer metastasis through the negative regulation of CXCR4 and MMP-9/2 and consequently it can be considered as a potential candidate for cancer therapy.
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Alcaloides/metabolismo , Alcaloides/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Quinolizinas/metabolismo , Quinolizinas/farmacologia , Células A549 , Antineoplásicos Fitogênicos/farmacologia , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Metaloproteinases da Matriz/metabolismo , NF-kappa B/metabolismo , Invasividade Neoplásica/genética , Neoplasias/metabolismo , Receptores CXCR4/metabolismo , Receptores CXCR4/fisiologia , Transdução de Sinais/efeitos dos fármacos , MatrinasRESUMO
Evodiamine (EVO) is an indoloquinazoline alkaloid that exerts its various anti-oncogenic actions by blocking phosphatidylinositol-3-kinase/protein kinase B (PI3K/Akt), mitogen-activated protein kinase (MAPK), c-Met, and nuclear factor kappa B (NF-κB) signaling pathways, thus leading to apoptosis of tumor cells. We investigated the ability of EVO to affect hepatocyte growth factor (HGF)-induced c-Met/Src/STAT3 activation cascades in castration-resistant prostate cancer (CRPC). First, we noted that EVO showed cytotoxicity and anti-proliferation activities in PC-3 and DU145 cells. Next, we found that EVO markedly inhibited HGF-induced c-Met/Src/STAT3 phosphorylation and impaired the nuclear translocation of STAT3 protein. Then, we noted that EVO arrested the cell cycle, caused apoptosis, and downregulated the expression of various carcinogenic markers such as B-cell lymphoma 2 (Bcl-2), B-cell lymphoma-extra large (Bcl-xL), cyclin D1, cyclooxygenase 2 (COX-2), survivin, vascular endothelial growth factor (VEGF), and matrix metallopeptidases 9 (MMP-9). Moreover, it was observed that in cPC-3 and DU145 cells transfected with c-Met small interfering RNA (siRNA), Src/STAT3 activation was also mitigated and led to a decrease in EVO-induced apoptotic cell death. According to our results, EVO can abrogate the activation of the c-Met/Src/STAT3 signaling axis and thus plays a role as a robust suppressor of tumor cell survival, proliferation, and angiogenesis.
Assuntos
Apoptose/efeitos dos fármacos , Neoplasias da Próstata/patologia , Proteínas Proto-Oncogênicas c-met/metabolismo , Quinazolinas/farmacologia , Transdução de Sinais , Apoptose/genética , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Dano ao DNA/genética , Regulação para Baixo/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Inativação Gênica , Fator de Crescimento de Hepatócito/farmacologia , Humanos , Masculino , Modelos Biológicos , Proteínas de Neoplasias/metabolismo , Fosforilação/efeitos dos fármacos , Neoplasias da Próstata/genética , Quinazolinas/química , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos , Quinases da Família src/metabolismoRESUMO
COVID-19 is known as one of the deadliest pandemics of the century. The rapid spread of this deadly virus at incredible speed has stunned the planet and poses a challenge to global scientific and medical communities. Patients with COVID-19 are at an increased risk of co-morbidities associated with liver dysfunction and injury. Moreover, hepatotoxicity induced by antiviral therapy is gaining importance and is an area of great concern. Currently, alternatives therapies are being sought to mitigate hepatic damage, and there has been growing interest in the research on bioactive phytochemical agents (nutraceuticals) due to their versatility in health benefits reported in various epidemiological studies. Therefore, this review provides information and summarizes the juncture of antiviral, immunomodulatory, and hepatoprotective nutraceuticals that can be useful during the management of COVID-19.
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Antivirais , Tratamento Farmacológico da COVID-19 , COVID-19 , Doença Hepática Induzida por Substâncias e Drogas , Suplementos Nutricionais , Pandemias , SARS-CoV-2 , Antivirais/efeitos adversos , Antivirais/uso terapêutico , COVID-19/epidemiologia , Doença Hepática Induzida por Substâncias e Drogas/dietoterapia , Doença Hepática Induzida por Substâncias e Drogas/epidemiologia , HumanosRESUMO
Oxymatrine (OMT) is a quinolizidine alkaloid derived from the roots of the Sophora genus plants. It has been widely used as a treatment for chronic hepatitis infections and inflammatory diseases due to its effective immunomodulatory and anti-inflammatory properties. Recently, the potential anti-cancer effects of OMT have been actively studied in various cancers. It can induce apoptosis and inhibit the proliferation of tumor cells, including those of colorectal cancer, gall bladder carcinoma, and leukemia. Moreover, it reduces tumor growth in different in vivo models as well as augments the anti-cancer effects of existing chemotherapeutics on tumor cells. OMT regulates various oncogenic signaling pathways such as the Akt, epidermal growth factor receptor (EGFR), and nuclear factor kappa B (NF-κB) cascades to exert its cytotoxicity against cancer cells. This review provides an overview of the current knowledge on the potential of OMT as an anti-cancer therapeutic through the modulation of diverse oncogenic molecular targets.
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Alcaloides/uso terapêutico , Antineoplásicos Fitogênicos/uso terapêutico , Neoplasias/tratamento farmacológico , Quinolizinas/uso terapêutico , Alcaloides/química , Alcaloides/farmacologia , Animais , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Modelos Animais de Doenças , Humanos , Quinolizinas/química , Quinolizinas/farmacologiaRESUMO
Amyotrophic lateral sclerosis (ALS) is a paralytic disease that damages the brain and spinal cord motor neurons. Several clinical and preclinical studies have found that methylmercury (MeHg+) causes ALS. In ALS, MeHg+-induced neurotoxicity manifests as oligodendrocyte destruction; myelin basic protein (MBP) deficiency leads to axonal death. ALS development has been connected to an increase in signal transducer and activator of transcription-3 (STAT-3), a mammalian target of rapamycin (mTOR), and a decrease in peroxisome proliferator-activated receptor (PPAR)-gamma. Guggulsterone (GST), a plant-derived chemical produced from Commiphorawhighitii resin, has been found to protect against ALS by modulating these signaling pathways. Vitamin D3 (VitD3) deficiency has been related to oligodendrocyte precursor cells (OPC) damage, demyelination, and white matter deterioration, which results in motor neuron death. As a result, the primary goal of this work was to investigate the therapeutic potential of GST by altering STAT-3, mTOR, and PPAR-gamma levels in a MeHg+-exposed experimental model of ALS in adult rats. The GST30 and 60 mg/kg oral treatments significantly improved the behavioral, motor, and cognitive dysfunctions and increased remyelination, as proven by the Luxol Fast Blue stain (LFB), and reduced neuroinflammation as measured by histological examinations. Furthermore, the co-administration of VitD3 exhibits moderate efficacy when administered in combination with GST60. Our results show that GST protects neurons by decreasing STAT-3 and mTOR levels while increasing PPAR-gamma protein levels in ALS rats.
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Encéfalo , Compostos de Metilmercúrio , PPAR gama , Pregnenodionas , Fator de Transcrição STAT3 , Transdução de Sinais , Serina-Treonina Quinases TOR , Animais , Serina-Treonina Quinases TOR/metabolismo , PPAR gama/metabolismo , Fator de Transcrição STAT3/metabolismo , Compostos de Metilmercúrio/toxicidade , Masculino , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Encéfalo/metabolismo , Transdução de Sinais/efeitos dos fármacos , Ratos , Pregnenodionas/farmacologia , Ratos WistarRESUMO
Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease that causes significant neurodegeneration. Methylmercury (MeHg+) is a neurotoxin that induces axonal neurodegeneration and motor nerve degeneration by destroying oligodendrocytes, degenerating white matter, inducing apoptosis, excitotoxicity, and reducing myelin basic protein (MBP). This study examines the inhibition of SIRT-1 (silence information regulator 1), Nrf-2 (nuclear factor E2-related factor 2), HO-1 (heme oxygenase 1), and TDP-43 (TAR-DNA-binding protein 43) accumulation in the context of ALS, as well as the modulation of these proteins by icariin (15 and 30 mg/kg, orally), a glycoside flavonoid with neuroprotective properties. Neuroprotective icariin activates SIRT-1, Nrf-2, and HO-1, mitigating inflammation and neuronal injury in neurodegenerative disorders. In-vivo and in-silico testing of experimental ALS models confirmed icariin efficacy in modulating these cellular targets. The addition of sirtinol 10 mg/kg, an inhibitor of SIRT-1, helps determine the effectiveness of icariin. In this study, we also examined neurobehavioral, neurochemical, histopathological, and LFB (Luxol fast blue) markers in various biological samples, including Cerebrospinal fluid (CSF), blood plasma, and brain homogenates (Cerebral Cortex, Hippocampus, Striatum, mid-brain, and Cerebellum). These results demonstrate that the administration of icariin ameliorates experimental ALS and that the mechanism underlying these benefits is likely related to regulating the SIRT-1, Nrf-2, and HO-1 signaling pathways.
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Multiple sclerosis (MS), a prevalent neurological disorder, predominantly affects young adults and is characterized by chronic autoimmune activity. The study explores the immune system dysregulation in MS, highlighting the crucial roles of immune and non-neuronal cells in the disease's progression. This review examines the dual role of cytokines, with some like IL-6, TNF-α, and interferon-gamma (IFN-γ) promoting inflammation and CNS tissue injury, and others such as IL-4, IL-10, IL-37, and TGF-ß fostering remyelination and protecting against MS. Elevated chemokine levels in the cerebrospinal fluid (CSF), including CCL2, CCL5, CXCL10, CXCL13, and fractalkine, are analyzed for their role in facilitating immune cell migration across the blood-brain barrier (BBB), worsening inflammation and neurodegeneration. The study also delves into the impact of auto-antibodies targeting myelin components like MOG and AQP4, which activate complement cascades leading to further myelin destruction. The article discusses how compromised BBB integrity allows immune cells and inflammatory mediators to infiltrate the CNS, intensifying MS symptoms. It also examines the involvement of astrocytes, microglia, and oligodendrocytes in the disease's progression. Additionally, the effectiveness of immunomodulatory drugs such as IFN-ß and CD20-targeting monoclonal antibodies (e.g., rituximab) in modulating immune responses is reviewed, highlighting their potential to reduce relapse rates and delaying MS progression. These insights emphasize the importance of immune system dysfunction in MS development and progression, guiding the development of new therapeutic strategies. The study underscores recent advancements in understanding MS's molecular pathways, opening avenues for more targeted and effective treatments.
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Progressão da Doença , Esclerose Múltipla , Humanos , Esclerose Múltipla/imunologia , Esclerose Múltipla/patologia , Animais , Barreira Hematoencefálica/imunologia , Barreira Hematoencefálica/metabolismo , Citocinas/metabolismo , Citocinas/imunologia , Sistema Imunitário/imunologiaRESUMO
Dementia, an international health issue distinguished by the impairment of daily functioning due to cognitive decline, currently affects more than 55 million people worldwide, with the majority residing in low-income and middle-income countries. Globally, dementia entails significant economic burdens in 2019, amounting to a cost of 1.3 trillion US dollars. Informal caregivers devote considerable hours to providing care for those affected. Dementia imposes a greater caregiving and disability-adjusted life-year burden on women. A recent study has established a correlation between prolonged Proton Pump Inhibitor (PPI) usage and dementia, in addition to other neurodegenerative conditions. PPIs are frequently prescribed to treat peptic ulcers and GERD (gastroesophageal reflux disease) by decreasing stomach acid secretion. They alleviate acid-related symptoms through the inhibition of acid-secreting H+-K+ ATPase. In a number of observational studies, cognitive decline and dementia in the elderly have been linked to the use of PPIs. The precise mechanism underlying this relationship is unknown. These drugs might also alter the pH of brain cells, resulting in the accumulation of amyloid-beta (Aß) peptides and the development of Alzheimer's disease (AD). Despite the compelling evidence supporting the association of PPIs with dementia, the results of studies remain inconsistent. The absence of a correlation between PPI use and cognitive decline in some studies emphasizes the need for additional research. Chronic PPI use can conceal underlying conditions, including cancer, celiac disease, vitamin B12 deficiency, and renal injury, highlighting dementia risk and the need for further investigations on cognitive health.
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Demência , Inibidores da Bomba de Prótons , Humanos , Inibidores da Bomba de Prótons/efeitos adversos , Inibidores da Bomba de Prótons/uso terapêutico , Demência/epidemiologia , Comorbidade , Disfunção Cognitiva/epidemiologiaRESUMO
Multiple sclerosis [MS] is a progressive autoimmune condition that primarily affects young people and is characterized by demyelination and neurodegeneration of the central nervous system [CNS]. This in-depth review explores the complex involvement of oligodendrocytes, the primary myelin- producing cells in the CNS, in the pathophysiology of MS. It discusses the biochemical processes and signalling pathways required for oligodendrocytes to function and remain alive, as well as how they might fail and cause demyelination to occur. We investigate developing therapeutic options that target remyelination, a fundamental component of MS treatment. Remyelination approaches promote the survival and differentiation of oligodendrocyte precursor cells [OPCs], restoring myelin sheaths. This improves nerve fibre function and may prevent MS from worsening. We examine crucial parameters influencing remyelination success, such as OPC density, ageing, and signalling pathway regulation [e.g., Retinoid X receptor, LINGO-1, Notch]. The review also examines existing neuroprotective and antiinflammatory medications being studied to see if they can assist oligodendrocytes in surviving and reducing the severity of MS symptoms. The review focuses on medicines that target the myelin metabolism in oligodendrocytes. Altering oligodendrocyte metabolism has been linked to reversing demyelination and improving MS patient outcomes through various mechanisms. We also explore potential breakthroughs, including innovative antisense technologies, deep brain stimulation, and the impact of gut health and exercise on MS development. The article discusses the possibility of personalized medicine in MS therapy, emphasizing the importance of specific medicines based on individual molecular profiles. The study emphasizes the need for reliable biomarkers and improved imaging tools for monitoring disease progression and therapy response. Finally, this review focuses on the importance of oligodendrocytes in MS and the potential for remyelination therapy. It also underlines the importance of continued research to develop more effective treatment regimens, taking into account the complexities of MS pathology and the different factors that influence disease progression and treatment.
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Obsessive-Compulsive Disorder (OCD), a prevalent neuropsychiatric condition, affects approximately 2%-3% of the global population. This paper provides an extensive overview of OCD, detailing its clinical manifestations, neurobiological underpinnings, and therapeutic approaches. It examines OCD's classification shift in the DSM-5, the role of the cortico-striatothalamo- cortical pathway in its development, and the various factors contributing to its etiology, such as genes, environmental factors, and genetic predispositions. The challenges in diagnosing OCD and the effectiveness of both psychological and pharmacotherapeutic treatments are discussed. The paper also highlights the significant overlap between OCD and other mental health disorders, emphasizing its impact on global disability. Moreover, the role of genetic factors in OCD, including twin studies and gene association studies, is elaborated, underscoring the complex interplay of hereditary and environmental influences in its manifestation. The review further delves into the polygenic nature of OCD, illustrating how multiple genes contribute to its development, and explores the implications of genetic studies in understanding the disorder's complexity. Additionally, this research study delves into the concept of polygenic inheritance in complex diseases, highlighting the role of multiple genes in increasing OCD risk. A Genome-wide Association Study (GWAS) is employed to assess Single Nucleotide Polymorphisms (SNPs) to unearth genetic associations with OCD. This comprehensive analysis provides valuable insights into OCD's genetic landscape, paving the way for enhanced diagnostic approaches and treatment modalities.
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Neurodegenerative and neuropsychiatric disorders are two broad categories of neurological disorders characterized by progressive impairments in movement and cognitive functions within the central and peripheral nervous systems, and have emerged as a significant cause of mortality. Oxidative stress, neuroinflammation, and neurotransmitter imbalances are recognized as prominent pathogenic factors contributing to cognitive deficits and neurobehavioral anomalies. Consequently, preventing neurodegenerative and neuropsychiatric diseases has surfaced as a pivotal challenge in contemporary public health. This review explores the investigation of neurodegenerative and neuropsychiatric disorders using both synthetic and natural bioactive compounds. A central focus lies on melatonin, a neuroregulatory hormone secreted by the pineal gland in response to light-dark cycles. Melatonin, an amphiphilic molecule, assumes multifaceted roles, including scavenging free radicals, modulating energy metabolism, and synchronizing circadian rhythms. Noteworthy for its robust antioxidant and antiapoptotic properties, melatonin exhibits diverse neuroprotective effects. The inherent attributes of melatonin position it as a potential key player in the pathophysiology of neurological disorders. Preclinical and clinical studies have demonstrated melatonin's efficacy in alleviating neuropathological symptoms across neurodegenerative and neuropsychiatric conditions (depression, schizophrenia, bipolar disorder, and autism spectrum disorder). The documented neuroprotective prowess of melatonin introduces novel therapeutic avenues for addressing neurodegenerative and psychiatric disorders. This comprehensive review encompasses many of melatonin's applications in treating diverse brain disorders. Despite the strides made, realizing melatonin's full neuroprotective potential necessitates further rigorous clinical investigations. By unravelling the extended neuroprotective benefits of melatonin, future studies promise to deepen our understanding and augment the therapeutic implications against neurological deficits.
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Melatonina , Transtornos Mentais , Doenças Neurodegenerativas , Fármacos Neuroprotetores , Melatonina/farmacologia , Melatonina/uso terapêutico , Humanos , Doenças Neurodegenerativas/tratamento farmacológico , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/fisiopatologia , Transtornos Mentais/tratamento farmacológico , Transtornos Mentais/fisiopatologia , Transtornos Mentais/metabolismo , Animais , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/fisiopatologiaRESUMO
The cytokine-activated Janus kinase (JAK)-signal transducer and activator of transcription (STAT) cascade is a pleiotropic pathway that involves receptor subunit multimerization. The mammalian target of rapamycin (mTOR) is a ubiquitously expressed serine-threonine kinase that perceives and integrates a variety of intracellular and environmental stimuli to regulate essential activities such as cell development and metabolism. Peroxisome proliferator-activated receptor-gamma (PPARγ) is a prototypical metabolic nuclear receptor involved in neural differentiation and axon polarity. The JAK-STAT, mTOR, and PPARγ signaling pathways serve as a highly conserved signaling hub that coordinates neuronal activity and brain development. Additionally, overactivation of JAK/STAT, mTOR, and inhibition of PPARγ signaling have been linked to various neurocomplications, including neuroinflammation, apoptosis, and oxidative stress. Emerging research suggests that even minor disruptions in these cellular and molecular processes can have significant consequences manifested as neurological and neuropsychiatric diseases. Of interest, target modulators have been proven to alleviate neuronal complications associated with acute and chronic neurological deficits. This research-based review explores the therapeutic role of JAK-STAT, mTOR, and PPARγ signaling modulators in preventing neuronal dysfunctions in preclinical and clinical investigations.
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Janus Quinases , PPAR gama , Janus Quinases/metabolismo , PPAR gama/metabolismo , Transdução de Sinais/fisiologia , Serina-Treonina Quinases TOR/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Fatores de Transcrição STAT/metabolismoRESUMO
Multiple sclerosis (MS) is a debilitating, inflammatory, and demyelinating disease of the central nervous system influenced by environmental and genetic factors. Around 2.8 million people worldwide are affected by MS due to its challenging diagnosis and treatment. Our study investigates the role of the JAK/STAT and PPAR-gamma signaling pathways in the progression of multiple sclerosis. Inflammation and demyelination can be caused by dysregulation of these pathways. Modulating the STAT-3, mTOR, and PPAR-gamma signaling pathways may offer therapeutic potential for multiple sclerosis. Matrine (40 and 80 mg/kg, i.p.), a quinolizidine alkaloid derived from Sophora flavescens, has been investigated for its therapeutic potential in our laboratory. Matrine has been studied for its neuroprotective effect in neurodegenerative diseases. It inhibits inflammatory responses and promotes regeneration of damaged myelin sheaths, indicating its potential efficacy in treating multiple sclerosis. Matrine exerts its neuroprotective effect by inhibiting STAT-3 and mTOR and promoting PPAR-gamma expression.GW9662, a PPAR-gamma antagonist (2 mg/kg, i.p.), was administered to evaluate the involvement of PPAR-gamma and to compare the efficacy of matrine's potential neuroprotective effect. Matrine's interaction with the STAT-3, mTOR, and PPAR-gamma pathways in multiple Sclerosis was also validated and confirmed through insilico investigation. In addition, matrine altered the CBC profile, intensifying the clinical presentation of multiple sclerosis. In addition, we evaluated the diagnostic potential of various biological samples, including CSF, blood plasma, and brain homogenates (striatum, cortex, hippocampus, and midbrain). These samples were used to evaluate the neurochemical changes caused by neurobehavioral alterations during the progression of multiple sclerosis. These results indicate that matrine treatment ameliorated multiple sclerosis and that the mechanism underlying these effects may be closely related to the modulation of the STAT-3/mTOR/PPAR-gamma signaling pathway.
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Esclerose Múltipla , Fármacos Neuroprotetores , Humanos , Esclerose Múltipla/tratamento farmacológico , Matrinas , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Receptores Ativados por Proliferador de Peroxissomo , Encéfalo , Serina-Treonina Quinases TORRESUMO
Obsessive-compulsive disorder (OCD) is a neuropsychiatric condition characterized by intrusive, repetitive thoughts and behaviors. Our study uses a validated 8-OH-DPAT-induced experimental model of OCD in rodents. We focus on the modulatory effects of Insulin-like growth factor-1 (IGF-1) and glucagon-like peptide-1 (GLP-1), which are linked to neurodevelopment and survival. Current research investigates melatonin, a molecule with neuroprotective properties and multiple functions. Melatonin has beneficial effects on various illnesses, including Alzheimer's, Parkinson's, and depression, indicating its potential efficacy in treating OCD. In the present study, we employed two doses of melatonin, 5 mg/kg and 10 mg/kg, demonstrating a dose-dependent effect on 8-OH-DPAT-induced rat changes. In addition, the melatonin antagonist luzindole 5 mg/kg was utilized to compare and validate the efficacy of melatonin. In-silico studies alsocontribute to understanding the activation of IGF-1/GLP-1 pathways by melatonin. Current research indicates restoring neurochemical measurements on various biological samples (brain homogenates, CSF, and blood plasma) and morphological and histological analyses. In addition, the current research seeks to increase understanding of OCD and investigate potential new treatment strategies. Therefore, it is evident from the aforementioned research that the protective effect of melatonin can serve as a strong basis for developing a new OCD treatment by upregulating IGF-1 and GLP-1 levels. The primary focus of current study revolves around the examination of melatonin as an activator of IGF-1/GLP-1, with the aim of potentially mitigating behavioral, neurochemical, and histopathological abnormalities in an experimental model of obsessive-compulsive disorder caused by 8-OH-DPAT in adult Wistar rats.
Assuntos
Melatonina , Transtorno Obsessivo-Compulsivo , Ratos , Animais , Fator de Crescimento Insulin-Like I/metabolismo , Melatonina/farmacologia , Melatonina/uso terapêutico , Peptídeo 1 Semelhante ao Glucagon , 8-Hidroxi-2-(di-n-propilamino)tetralina/uso terapêutico , Ratos Wistar , Transtorno Obsessivo-Compulsivo/diagnóstico , Transtorno Obsessivo-Compulsivo/tratamento farmacológico , Transtorno Obsessivo-Compulsivo/etiologia , Encéfalo/metabolismo , Plasma/metabolismoRESUMO
This study focuses on the fabrication, characterization and anticancer properties of biocompatible and biodegradable composite nanofibers consisting of poly(vinyl alcohol) (PVA), oxymatrine (OM), and citric acid (CA) using a facile and high-yield centrifugal spinning process known as Forcespinning. The effects of varying concentrations of OM and CA on fiber diameter and molecular cross-linking are investigated. The morphological and thermo-physical properties, as well as water absorption of the developed nanofiber-based mats are characterized using microscopical analysis, energy dispersive X-ray spectroscopy, Fourier transform infrared spectroscopy, differential scanning calorimetry, and thermogravimetric analysis. In vitro anticancer studies are conducted with HCT116 colorectal cancer cells. Results show a high yield of long fibers embedded with beads. Fiber average diameters range between 462 and 528 nm depending on OM concentration. The thermal analysis results show that the fibers are stable at room temperature. The anticancer study reveals that PVA nanofiber membrane with high concentrations of OM can suppress the proliferation of HCT116 colorectal cancer cells. The study provides a comprehensive investigation of OM embedded into nanosized PVA fibers and the prospective application of these membranes as a drug delivery system.
Assuntos
Neoplasias Colorretais , Matrinas , Nanofibras , Humanos , Nanofibras/química , Álcool de Polivinil/farmacologia , Álcool de Polivinil/química , Alicerces Teciduais/química , Neoplasias Colorretais/tratamento farmacológicoRESUMO
Background: Nephrotoxicity refers to the toxigenic impact of compounds and medications on kidney function. There are a variety of drug formulations, and some medicines that may affect renal function in multiple ways via nephrotoxins production. Nephrotoxins are substances that are harmful to the kidneys. Purpose: This investigation examines the renoprotective effect of gymnemic acid (GA) on Wistar rats in gentamicin-induced nephrotoxicity by analyzing serum, kidney, and histopathological markers. Study-design/methods: The current study investigated the protective effect of GA at doses of 20, 40, and 60 mg/kg against gentamicin-induced nephrotoxicity in rats. Vitamin E was administered to compare the antioxidant capacity and efficacy of GA. In addition to the treatment groups, 100 mg/kg of gentamicin was administered intraperitoneal for 14 days. At the end of the study protocol, kidney homogenate, blood, and serum were evaluated biochemically. Serum creatinine, blood urea, glomerular filtration rate (GFR), mitochondrial dysfunctions, inflammatory cytokines, and renal oxidative stress were examined to assess gentamicin-induced nephrotoxicity. In addition, the impact of GA on the above-mentioned nephrotoxic markers were evaluated and further confirmed by histological analysis. Results: This study establishes a correlation between antibiotic use, especifically aminoglycosides and acute renal failure. The research demonstrates the nephrotoxic effects of aminoglycosides, inducing mitochondrial ETC-complex dysfunction, and renal tissue inflammation in experimental rats. GA's antioxidant properties restored renal oxidative stress markers, reducing kidney inflammation and injury. Histopathological analysis revealed a significant reduction in renal injury with GA treatment. Additionally, GA demonstrated greater efficacy than Vitamin E in restoring antioxidant potential and mitochondrial enzymes. Conclusion: Consequently, our findings imply that long-term use of GA may be a suitable therapeutic strategy for reducing aminoglycoside toxicity. The current study suggests GA's potential in treating gentamicin-induced nephrotoxicity and acute renal failure, meriting further investigation using advanced techniques.
RESUMO
This study investigates the feasibility of centrifugal spinning for producing fibrous membranes containing pullulan, chitosan, and danshen extract. The danshen extract is composed of 20 wt% salvianolic acid B (SA). Citric acid was added to the mixture as a crosslinking agent to promote its use in the aqueous medium. The influence of the danshen concentration (25 wt% and 33 wt%) on fiber morphology, thermal behavior, and the biochemical effect was analyzed. Developed fiber-based membranes consist of long, continuous, and uniform fibers with a sparse scattering of beads. Fiber diameter analysis shows values ranging from 384 ± 123 nm to 644 ± 141 nm depending on the concentration of danshen. The nanofibers show adequate aqueous stability after crosslinking. Thermal analysis results prove that SA is loaded into nanofibers without compromising their structural integrity. Cell-based results indicate that the developed nanofiber membranes promote cell growth and are not detrimental to fibroblast cells. Anticancer studies reveal a promising inhibition to the proliferation of HCT116 colon cancer cells. The developed systems show potential as innovative systems to be used as a bioactive chemotherapeutic drug that could be placed on the removed tumor site to prevent development of colon cancer microdeposits.