RESUMO
Over the last four decades, vanadium compounds have been extensively studied as potential antidiabetic drugs. With the present review, we aim at presenting a general overview of the most promising compounds and the main results obtained with in vivo studies, reported from 1899-2023. The chemistry of vanadium is explored, discussing the importance of the structure and biochemistry of vanadate and the impact of its similarity with phosphate on the antidiabetic effect. The spectroscopic characterization of vanadium compounds is discussed, particularly magnetic resonance methodologies, emphasizing its relevance for understanding species activity, speciation, and interaction with biological membranes. Finally, the most relevant studies regarding the use of vanadium compounds to treat diabetes are summarized, considering both animal models and human clinical trials. An overview of the main hypotheses explaining the biological activity of these compounds is presented, particularly the most accepted pathway involving vanadium interaction with phosphatase and kinase enzymes involved in the insulin signaling cascade. From our point of view, the major discoveries regarding the pharmacological action of this family of compounds are not yet fully understood. Thus, we still believe that vanadium presents the potential to help in metabolic control and the clinical management of diabetes, either as an insulin-like drug or as an insulin adjuvant. We look forward to the next forty years of research in this field, aiming to discover a vanadium compound with the desired therapeutic properties.
Assuntos
Diabetes Mellitus , Compostos de Vanádio , Animais , Humanos , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Hipoglicemiantes/química , Compostos de Vanádio/farmacologia , Compostos de Vanádio/uso terapêutico , Compostos de Vanádio/química , Vanádio/química , Diabetes Mellitus/tratamento farmacológico , Insulina/uso terapêutico , Insulina Regular Humana/uso terapêuticoRESUMO
Despite some significant advancements, breast cancer has become the most prevalent cancer in the world. One of the main reasons for failure in treatment and metastasis has been attributed to the presence of cancer initiating cells-cancer stem cells. Consequently, research is now being focussed on targeting cancer cells along with their stem cell population. Non-oncology drugs are gaining increasing attention for their potent anticancer activities. Metformin, a drug commonly used to treat type 2 diabetes, is the best example in this regard. It exerts its therapeutic action by activating 5' adenosine monophosphate-activated protein kinase (AMPK). Activated AMPK subsequently phosphorylates and targets several cellular pathways involved in cell growth and proliferation and the maintenance of stem-like properties of cancer stem cells. Therefore, AMPK is emerging as a target of choice for developing effective anticancer drugs. Vanadium compounds are well-known PTP inhibitors and AMPK activators. They find extensive applications in treatment of diabetes and obesity via PTP1B inhibition and AMPK-mediated inhibition of adipogenesis. However, their role in targeting cancer stem cells has not been explored yet. This review is an attempt to establish the applications of insulin mimetic vanadium compounds for the treatment of breast cancer by AMPK activation and PTP1B inhibition pathways.
Assuntos
Proteínas Quinases Ativadas por AMP , Neoplasias da Mama , Células-Tronco Neoplásicas , Compostos de Vanádio , Proteínas Quinases Ativadas por AMP/metabolismo , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Feminino , Humanos , Células-Tronco Neoplásicas/metabolismo , Compostos de Vanádio/uso terapêuticoRESUMO
Alzheimer's disease (AD) is an intractable neurodegenerative disease that leads to dementia, primarily in elderly people. The neurotoxicity of amyloid-beta (Aß) and tau protein has been demonstrated over the last two decades. In line with these findings, several etiological hypotheses of AD have been proposed, including the amyloid cascade hypothesis, the oxidative stress hypothesis, the inflammatory hypothesis, the cholinergic hypothesis, et al. In the meantime, great efforts had been made in developing effective drugs for AD. However, the clinical efficacy of the drugs that were approved by the US Food and Drug Association (FDA) to date were determined only mild/moderate. We recently adopted a vanadium compound bis(ethylmaltolato)-oxidovanadium (IV) (BEOV), which was originally used for curing diabetes mellitus (DM), to treat AD in a mouse model. It was shown that BEOV effectively reduced the Aß level, ameliorated the inflammation in brains of the AD mice, and improved the spatial learning and memory activities of the AD mice. These finding encouraged us to further examine the mechanisms underlying the therapeutic effects of BEOV in AD. In this review, we summarized the achievement of vanadium compounds in medical studies and investigated the prospect of BEOV in AD and DM treatment.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Diabetes Mellitus/tratamento farmacológico , Compostos de Vanádio/uso terapêutico , Doença de Alzheimer/patologia , Animais , Diabetes Mellitus/patologia , HumanosRESUMO
Amyotrophic lateral sclerosis (ALS) is the most common motor neuron (MN) disease, with no present cure. The progressive loss of MNs is the hallmark of ALS. We have previously shown the therapeutic effects of the phosphatase and tensin homolog (PTEN) inhibitor, potassium bisperoxo (picolinato) vanadium (bpV[pic]), in models of neurological injury and demonstrated significant neuroprotective effects on MN survival. However, accumulating evidence suggests PTEN is detrimental for MN survival in ALS. Therefore, we hypothesized that treating the mutant superoxide dismutase 1 G93A (mSOD1G93A) mouse model of ALS during motor neuron degeneration and an in vitro model of mSOD1G93A motor neuron injury with bpV(pic) would prevent motor neuron loss. To test our hypothesis, we treated mSOD1G93A mice intraperitoneally daily with 400 µg/kg bpV(pic) from 70 to 90 days of age. Immunolabeled MNs and microglial reactivity were analyzed in lumbar spinal cord tissue, and bpV(pic) treatment significantly ameliorated ventral horn motor neuron loss in mSOD1G93A mice (p = 0.003) while not significantly altering microglial reactivity (p = 0.701). Treatment with bpV(pic) also significantly increased neuromuscular innervation (p = 0.018) but did not affect muscle atrophy. We also cultured motor neuron-like NSC-34 cells transfected with a plasmid to overexpress mutant SOD1G93A and starved them in serum-free medium for 24 h with and without bpV(pic) and downstream inhibitor of Akt signaling, LY294002. In vitro, bpV(pic) improved neuronal viability, and Akt inhibition reversed this protective effect (p < 0.05). In conclusion, our study indicates systemic bpV(pic) treatment could be a valuable neuroprotective therapy for ALS.
Assuntos
Esclerose Lateral Amiotrófica/tratamento farmacológico , Neurônios Motores/efeitos dos fármacos , Fármacos Neuroprotetores/uso terapêutico , Compostos de Vanádio/uso terapêutico , Esclerose Lateral Amiotrófica/patologia , Animais , Células do Corno Anterior/efeitos dos fármacos , Células Cultivadas , Cromonas/farmacologia , Meios de Cultura Livres de Soro/farmacologia , Humanos , Camundongos Transgênicos , Microglia/efeitos dos fármacos , Modelos Animais , Morfolinas/farmacologia , Atrofia Muscular/etiologia , Atrofia Muscular/patologia , Mutação de Sentido Incorreto , Junção Neuromuscular/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , PTEN Fosfo-Hidrolase/antagonistas & inibidores , Mutação Puntual , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Superóxido Dismutase-1/deficiência , Superóxido Dismutase-1/genética , Compostos de Vanádio/farmacologiaRESUMO
In the past few decades, various vanadium compounds have displayed potential in cancer treatment. However, fast clearness in the body and possible toxicity of vanadium compounds has hindered their further development. Vanadium-based nanomaterials not only overcome these limitations, but take advantage of the internal properties of vanadium in photics and magnetics, which enable them as a multimodal platform for cancer diagnosis and treatment. In this paper, we first introduced the basic biological and pharmacological functions of vanadium compounds in treating cancer. Then, the synthesis routes of three vanadium-based nanomaterials were discussed, including vanadium oxides, 2D vanadium sulfides, carbides and nitrides: VmXn (X = S, C, N) and water-insoluble vanadium salts. Finally, we highlighted the applications of these vanadium-based nanomaterials as tumor therapeutic and diagnostic agents.
Assuntos
Nanopartículas Metálicas/química , Nanopartículas Metálicas/uso terapêutico , Neoplasias/diagnóstico , Neoplasias/terapia , Compostos de Vanádio/química , Compostos de Vanádio/uso terapêutico , Animais , Materiais Biocompatíveis/síntese química , Materiais Biocompatíveis/química , Materiais Biocompatíveis/uso terapêutico , Meios de Contraste/química , Humanos , Luminescência , Imageamento por Ressonância Magnética/métodos , Teste de Materiais , Nanopartículas Metálicas/ultraestrutura , Microscopia Eletrônica de Transmissão , Terapia Fototérmica/métodos , Compostos de Vanádio/síntese químicaRESUMO
The chemistry and short lifetimes of metal-based anti-cancer drugs can be turned into an advantage for direct injections into tumors, which then allow the use of highly cytotoxic drugs. The release of their less toxic decomposition products into the blood will lead to decreased toxicity and can even have beneficial effects. We present a ternary VV complex, 1 ([VOL1 L2 ], where L1 is N-(salicylideneaminato)-N'-(2-hydroxyethyl)ethane-1,2-diamine and L2 is 3,5-di-tert-butylcatechol), which enters cells intact to induce high cytotoxicity in a range of human cancer cells, including T98g (glioma multiforme), while its decomposition products in cell culture medium were ≈8-fold less toxic. 1 was 12-fold more toxic than cisplatin in T98g cells and 6-fold more toxic in T98g cells than in a non-cancer human cell line, HFF-1. Its high toxicity in T98g cells was retained in the presence of physiological concentrations of the two main metal-binding serum proteins, albumin and transferrin. These properties favor further development of 1 for brain cancer treatment by intratumoral injections.
Assuntos
Antineoplásicos/química , Neoplasias Encefálicas/tratamento farmacológico , Complexos de Coordenação/química , Compostos de Vanádio/química , Antineoplásicos/uso terapêutico , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Complexos de Coordenação/uso terapêutico , Meios de Cultura , Descoberta de Drogas , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Espectroscopia de Prótons por Ressonância Magnética , Compostos de Vanádio/uso terapêuticoRESUMO
Since the 1970s, the biological role of vanadium compounds has been discussed as insulin-mimetic or insulin-enhancer agents. The action of vanadium compounds has been investigated to determine how they influence the insulin signaling pathway. Khan and coworkers proposed key proteins for the insulin pathway study, introducing the concept "critical nodes". In this review, we also considered critical kinases and phosphatases that participate in this pathway, which will permit a better comprehension of a critical node, where vanadium can act: a) insulin receptor, insulin receptor substrates, and protein tyrosine phosphatases; b) phosphatidylinositol 3'-kinase, 3-phosphoinositide-dependent protein kinase and mammalian target of rapamycin complex, protein kinase B, and phosphatase and tensin homolog; and c) insulin receptor substrates and mitogen-activated protein kinases, each node having specific negative modulators. Additionally, leptin signaling was considered because together with insulin, it modulates glucose and lipid homeostasis. Even in recent literature, the possibility of vanadium acting against metabolic diseases or cancer is confirmed although the mechanisms of action are not well understood because these critical nodes have not been systematically investigated. Through this review, we establish that vanadium compounds mainly act as phosphatase inhibitors and hypothesize on their capacity to affect kinases, which are critical to other hormones that also act on common parts of the insulin pathway.
Assuntos
Glucose/metabolismo , Insulina/uso terapêutico , Metabolismo dos Lipídeos/efeitos dos fármacos , Doenças Metabólicas , Neoplasias , Transdução de Sinais/efeitos dos fármacos , Compostos de Vanádio/uso terapêutico , Vanádio/uso terapêutico , Animais , Humanos , Doenças Metabólicas/tratamento farmacológico , Doenças Metabólicas/metabolismo , Doenças Metabólicas/patologia , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Neoplasias/patologiaRESUMO
Vanadium compounds are promising anti-diabetic agents, and graphene quantum dots (GQDs) are emerging as potential drug delivery systems to improve drug solubility in water and membrane transport. Using highly dispersible and water-soluble GQDs, we herein prepared a novel GQD-VO (p-dmada) complex, in which vanadium coordination compounds [VO(p-dmada)] were packed closely on one side of the GQD sheets possibly via the π-π stacking mechanism. The in vitro tests showed that GQD-VO(p-dmada) exhibited membrane permeability (Papp) as good as that of GQDs with reduced cytotoxicity. In vivo tests on type 2 diabetic mice demonstrated that GQD-VO(p-dmada) exhibited a delayed glucose lowering profile but more profound effects on insulin enhancement and ß-cell protection after three-week treatment compared to VO(p-dmada) alone. In addition, GQD alone was observed for the first time to effectively lower the blood lipid levels of the db/db mice. Overall, GQD-VO(p-dmada) showed improved pharmacokinetic performance and hypoglycemic effects, and using GQD as a nanoplatform for drug delivery may provide vast opportunities for the further design of metal-based pharmaceutical agents.
Assuntos
Grafite/química , Hipoglicemiantes/química , Pontos Quânticos/química , Compostos de Vanádio/química , Animais , Membrana Celular/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Cães , Sistemas de Liberação de Medicamentos , Grafite/farmacocinética , Grafite/uso terapêutico , Hipoglicemiantes/uso terapêutico , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/metabolismo , Lipídeos/sangue , Células Madin Darby de Rim Canino , Camundongos , Camundongos Transgênicos , Pontos Quânticos/uso terapêutico , Solubilidade , Compostos de Vanádio/farmacocinética , Compostos de Vanádio/uso terapêuticoRESUMO
Using metal oxide semiconductor nanomaterials for synergistic cancer treatment has recently attracted the attention of numerous researchers. Herein, oxygen-defective vanadium oxide nanodots (VOx NDs) with ultra-small size and great dispersibility were synthesized via a novel user-friendly method, and then doxorubicin was loaded onto the VOx NDs surfaces. The VOx NDs had great photothermal conversion efficiency and stability. Doxorubicin-loaded VOx NDs can simultaneously serve as therapeutic agent and tumor microenvironment-activable HSP60 inhibitor, resulting in improved efficacy of photothermal therapy and released active doxorubicin for chemotherapy. Finally, we show that synergistic treatment achieved significant therapeutic effects in mice. These results provided a promising strategy for developing novel methods of synthesizing metal oxide semiconductors for enhanced synergistic cancer treatment.
Assuntos
Antineoplásicos/uso terapêutico , Doxorrubicina/uso terapêutico , Nanopartículas/uso terapêutico , Neoplasias/terapia , Compostos de Vanádio/uso terapêutico , Animais , Chaperonina 60/antagonistas & inibidores , Chaperonina 60/metabolismo , Química Verde/métodos , Células HCT116 , Humanos , Hipertermia Induzida/métodos , Camundongos , Camundongos Nus , Nanotecnologia/métodos , Neoplasias/metabolismo , Neoplasias/patologia , Óxidos/uso terapêuticoRESUMO
Vanadium compounds have been primarily investigated as potential therapeutic agents for the treatment of various major health issues, including cancer, atherosclerosis, and diabetes. The translation of vanadium-based compounds into clinical trials and ultimately into disease treatments remains hampered by the absence of a basic pharmacological and metabolic comprehension of such compounds. In this review, we examine the development of vanadium-containing compounds in biological systems regarding the role of the physiological environment, dosage, intracellular interactions, metabolic transformations, modulation of signaling pathways, toxicology, and transport and tissue distribution as well as therapeutic implications. From our point of view, the toxicological and pharmacological aspects in animal models and humans are not understood completely, and thus, we introduced them in a physiological environment and dosage context. Different transport proteins in blood plasma and mechanistic transport determinants are discussed. Furthermore, an overview of different vanadium species and the role of physiological factors (i.e., pH, redox conditions, concentration, and so on) are considered. Mechanistic specifications about different signaling pathways are discussed, particularly the phosphatases and kinases that are modulated dynamically by vanadium compounds because until now, the focus only has been on protein tyrosine phosphatase 1B as a vanadium target. Particular emphasis is laid on the therapeutic ability of vanadium-based compounds and their role for the treatment of diabetes mellitus, specifically on that of vanadate- and polioxovanadate-containing compounds. We aim at shedding light on the prevailing gaps between primary scientific data and information from animal models and human studies.
Assuntos
Diabetes Mellitus/metabolismo , Hipoglicemiantes/uso terapêutico , Compostos de Vanádio/uso terapêutico , Vanádio/química , Vanádio/farmacologia , Animais , Diabetes Mellitus/tratamento farmacológico , Humanos , Hipoglicemiantes/química , Vanádio/sangue , Compostos de Vanádio/químicaRESUMO
Vanadium compounds have been known to have beneficial therapeutic properties since the turn of the century, but it was not until 1965 when it was discovered that those effects could be extended to treating cancer. Some vanadium compounds can combat common markers of cancer, which include metabolic processes that are important to initiating and developing the phenotypes of cancer. It is appropriate to consider vanadium as a treatment option due to the similarities in some of the metabolic pathways utilized by both diabetes and cancer and therefore is among the few drugs that are effective against more than one disease. The development of vanadium compounds as protein phosphatase inhibitors for the treatment of diabetes may be useful for potential applications as an anticancer agent. Furthermore, the ability of vanadium to redox cycle is also important for biological properties and is involved in the pathways of reactive oxygen species. Early agents including vanadocene and peroxovanadium compounds have been investigated in detail, and the results can be used to gain a better understanding of how some vanadium compounds are modifying the metabolic pathways potentially developing cancer. Considering the importance of coordination chemistry to biological responses, it is likely that proper consideration of compound formulation will improve the efficacy of the drug. Future development of vanadium-based drugs should include consideration of drug formulation at earlier stages of drug development.
Assuntos
Anticarcinógenos/uso terapêutico , Antineoplásicos/uso terapêutico , Neoplasias/tratamento farmacológico , Neoplasias/prevenção & controle , Compostos de Vanádio/uso terapêutico , Animais , Anticarcinógenos/efeitos adversos , Anticarcinógenos/química , Anticarcinógenos/metabolismo , Antineoplásicos/efeitos adversos , Antineoplásicos/química , Antineoplásicos/metabolismo , Complexos de Coordenação , Suplementos Nutricionais/efeitos adversos , Composição de Medicamentos , Descoberta de Drogas/métodos , Humanos , Estrutura Molecular , Neoplasias/metabolismo , Neoplasias/patologia , Relação Estrutura-Atividade , Compostos de Vanádio/efeitos adversos , Compostos de Vanádio/química , Compostos de Vanádio/metabolismoRESUMO
Diabetes patients suffer from chronic disorders in the metabolism due to high blood sugar caused by anomalies in insulin excretion. Recently, vanadium compounds have been prepared and functionalized to decrease the level of hyperglycemia. Vitamin A boosts beta cell activity; therefore, the lack of this vitamin plays a role in the development of type 2 diabetes. The aim of this article focused on the synthesis of a new anti-diabetic drug formed from the complexation of a vanadium(IV) salt with vitamin A. Vitamin A acts as a unidentate chelate through the oxygen of its -OH group. The vanadium(IV) compound is surrounded by two vitamin A molecules. The [VO(vitamin A)2(H2O)2] compound was synthesized in a binary solvent system consisting of MeOH/H2O (1:1 ratio) in alkaline media at pH = 8. This compound was characterized using Fourier transform infrared spectra (FT-IR), electronic spectra (UV-vis), effective magnetic moment, electron spin resonance (ESR), scanning electron microscopy (SEM), transmission electron microscopy (TEM), and thermal analysis (thermogravimetry (TG)-differential thermal analysis (DTA)). Anti-diabetic efficiency for the vanadium(IV) compound was assessed in streptozotocin (STZ)-induced diabetic mice. The results of the animal studies demonstrate the ability of the vanadium(IV) complex to act as an anti-diabetic agent, as measured by improvements of lipid profile, antioxidant activity (superoxide dismutase), malondialdehyde (MDA), glutathione, methionine synthase, and kidney and liver functions.
Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Hipoglicemiantes , Compostos de Vanádio , Vitamina A , Animais , Glicemia/efeitos dos fármacos , Creatinina/sangue , Diabetes Mellitus Experimental/sangue , Glucosefosfato Desidrogenase/sangue , Hemoglobinas/análise , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , L-Lactato Desidrogenase/sangue , Masculino , Camundongos , Superóxido Dismutase/sangue , Compostos de Vanádio/química , Compostos de Vanádio/farmacologia , Compostos de Vanádio/uso terapêutico , Vitamina A/química , Vitamina A/farmacologia , Vitamina A/uso terapêuticoRESUMO
Dramatic increase of diabetes over the globe is in tandem with the increase in insulin requirement. This is because destruction and dysfunction of pancreatic ß-cells are of common occurrence in both Type1 diabetes and Type2 diabetes, and insulin injection becomes a compulsion. Because of several problems associated with insulin injection, orally active insulin mimetic compounds would be ideal substitute. Here we report a small molecule, a peroxyvanadate compound i.e. DmpzH[VO(O2)2(dmpz)], henceforth referred as dmp, which specifically binds to insulin receptor with considerable affinity (KD-1.17µM) thus activating insulin receptor tyrosine kinase and its downstream signaling molecules resulting increased uptake of [14C] 2 Deoxy-glucose. Oral administration of dmp to streptozotocin treated BALB/c mice lowers blood glucose level and markedly stimulates glucose and fatty acid uptake by skeletal muscle and adipose tissue respectively. In db/db mice, it greatly improves insulin sensitivity through excess expression of PPARγ and its target genes i.e. adiponectin, CD36 and aP2. Study on the underlying mechanism demonstrated that excess expression of Wnt3a decreased PPARγ whereas dmp suppression of Wnt3a gene increased PPARγ expression which subsequently augmented adiponectin. Increased production of adiponectin in db/db mice due to dmp effected lowering of circulatory TG and FFA levels, activates AMPK in skeletal muscle and this stimulates mitochondrial biogenesis and bioenergetics. Decrease of lipid load along with increased mitochondrial activity greatly improves energy homeostasis which has been found to be correlated with the increased insulin sensitivity. The results obtained with dmp, therefore, strongly indicate that dmp could be a potential candidate for insulin replacement therapy.
Assuntos
Complexos de Coordenação/farmacologia , Diabetes Mellitus Experimental/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Resistência à Insulina , Receptor de Insulina/agonistas , Compostos de Vanádio/uso terapêutico , Células 3T3 , Proteínas Quinases Ativadas por AMP/genética , Proteínas Quinases Ativadas por AMP/metabolismo , Adiponectina/genética , Adiponectina/metabolismo , Tecido Adiposo/metabolismo , Animais , Glicemia/metabolismo , Antígenos CD36/genética , Antígenos CD36/metabolismo , Células Cultivadas , Complexos de Coordenação/uso terapêutico , Diabetes Mellitus Experimental/metabolismo , Ácidos Graxos/sangue , Feminino , Hipoglicemiantes/síntese química , Hipoglicemiantes/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Músculo Esquelético/metabolismo , PPAR gama/genética , PPAR gama/metabolismo , Ligação Proteica , Receptor de Insulina/metabolismo , Triglicerídeos/sangue , Compostos de Vanádio/síntese química , Compostos de Vanádio/farmacologia , Proteína Wnt3A/genética , Proteína Wnt3A/metabolismoRESUMO
OBJECTIVE: The present study was designed to investigate the chemoprotective efficacy of an L-cysteine-based oxovanadium (IV) complex, namely, oxovanadium (IV)-L-cysteine methyl ester complex (VC-IV) against cisplatin (CDDP)-induced renal injury in Swiss albino mice. METHODS: CDDP was administered intraperitoneally (5 mg/kg body weight) and VC-IV was administered orally (1 mg/kg body weight) in concomitant and 7 days pre-treatment schedule. RESULTS: CDDP-treated mice showed marked kidney damage and renal failure. Administration of VC-IV caused significant attenuation of renal oxidative stress and elevation of antioxidant status. VC-IV also significantly decreased serum levels of creatinine and blood urea nitrogen, and improved histopathological lesions. Western blot analysis of the kidneys showed that VC-IV treatment resulted in nuclear translocation of nuclear factor E2-related factor 2 (Nrf2) through modulation of cytosolic Kelch-like ECH-associated protein 1. Thus, VC-IV stimulated Nrf2-mediated activation of antioxidant response element (ARE) pathway and promoted expression of ARE-driven cytoprotective proteins, heme oxygenase 1 and NAD(P)H:quinone oxidoreductase 1, and enhanced activity of antioxidant enzymes. Interestingly, VC-IV did not alter the bioavailability and renal accumulation of CDDP in mice. DISCUSSION: In this study, VC-IV exhibited strong nephroprotective efficacy by restoring antioxidant defense mechanisms and hence may serve as a promising chemoprotectant in cancer chemotherapy.
Assuntos
Cisplatino/toxicidade , Nefropatias/tratamento farmacológico , Rim/efeitos dos fármacos , Rim/metabolismo , Vanadatos/uso terapêutico , Compostos de Vanádio/uso terapêutico , Administração Oral , Animais , Apoptose/efeitos dos fármacos , Feminino , Nefropatias/induzido quimicamente , Camundongos , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Espectrofotometria Atômica , Vanadatos/administração & dosagem , Compostos de Vanádio/administração & dosagemRESUMO
In the second part of the 1980s, and in the 1990s, a number of investigators demonstrated -mainly in streptozotocin-induced (STZ) diabetic rats-that the vanadate and vanadyl forms of vanadium possessed a number of insulin-like effects in various cells. It was hypothesized that oral vanadium could be an alternative treatment to parenteral insulin in the therapy of diabetes mellitus. However, the long-term and/or chronic administration of vanadium compounds should also mean tissue vanadium accumulation and risks of toxicity. The purpose of this review was to revise the current-state-of-the-art on the use of vanadium in the treatment of human diabetes. It has been conducted more than three decades after the first report on the beneficial insulin-mimetic effects of oral vanadium administration in STZ-diabetic rats. Although the antidiabetic effects of vanadium in STZ-diabetic rodents are well supported, in the few studies on human patients with positive results, that are available in the literature, vanadium compounds were administered during very short periods. We conclude that vanadium administration for the treatment of human diabetes is misplaced.
Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Compostos de Vanádio/uso terapêutico , Animais , Humanos , RatosRESUMO
Vanadium is omnipresent in trace amounts in the environment, in food and also in the human body, where it might serve as a regulator for phosphate-dependent proteins. Potential vanadium-based formulations--inorganic and coordination compounds with organic ligands--commonly underlie speciation in the body, that is, they are converted to vanadate(V), oxidovanadium(IV) and to complexes with the body's own ligand systems. Vanadium compounds have been shown to be potentially effective against diabetes Type 2, malign tumors including cancer, endemic tropical diseases (such as trypanosomiasis, leishmaniasis and amoebiasis), bacterial infections (tuberculosis and pneumonia) and HIV infections. Furthermore, vanadium drugs can be operative in cardio- and neuro-protection. So far, vanadium compounds have not yet been approved as pharmaceuticals for clinical use.
Assuntos
Compostos de Vanádio/uso terapêutico , Amebíase/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Infecções por HIV/tratamento farmacológico , Humanos , Leishmaniose/tratamento farmacológico , Neoplasias/tratamento farmacológico , Pneumonia/tratamento farmacológico , Tripanossomíase/tratamento farmacológico , Tuberculose/tratamento farmacológico , Compostos de Vanádio/químicaRESUMO
Patients with diabetes are vulnerable to MI/R (myocardial ischaemia/reperfusion) injury, but are not responsive to IPostC (ischaemic post-conditioning) which activates PI3K (phosphoinositide 3-kinase)/Akt (also known as PKB or protein kinase B) and JAK2 (Janus kinase 2)/STAT3 (signal transducer and activator of transcription 3) pathways to confer cardioprotection. We hypothesized that increased cardiac PTEN (phosphatase and tensin homologue deleted on chromosome 10), a major negative regulator of PI3K/Akt, is responsible for the loss of diabetic heart sensitivity to IPostC cardioprotecton. In STZ (streptozotocin)-induced Type 1 diabetic rats subjected to MI/R (30 min coronary occlusion and 120 min reperfusion), the post-ischaemic myocardial infarct size, CK-MB (creatine kinase-MB) and 15-F2t-isoprostane release, as well as cardiac PTEN expression were significantly higher than those in non-diabetic controls, concomitant with more severe cardiac dysfunction and lower cardiac Akt, STAT3 and GSK-3ß (glycogen synthase kinase 3ß) phosphorylation. IPostC significantly attenuated post-ischaemic infarct size, decreased PTEN expression and further increased Akt, STAT3 and GSK-3ß phosphorylation in non-diabetic, but not in diabetic rats. Application of the PTEN inhibitor BpV (bisperoxovanadium) (1.0 mg/kg) restored IPostC cardioprotection in diabetic rats. HPostC (hypoxic post-conditioning) in combination with PTEN gene knockdown, but not HPostC alone, significantly reduced H/R (hypoxia/reoxygenation) injury in cardiac H9c2 cells exposed to high glucose as was evident from reduced apoptotic cell death and JC-1 monomer in cells, accompanied by increased phosphorylation of Akt, STAT3 and GSK-3ß. PTEN inhibition/gene knockdown mediated restoration of IPostC/HPostC cardioprotection was completely reversed by the PI3K inhibitor wortmannin, and partially reversed by the JAK2 inhibitor AG490. Increased cardiac PTEN, by impairing PI3K/Akt and JAK2/STAT3 pathways, is a major mechanism that rendered diabetic hearts not responsive to post-conditioning cardioprotection.
Assuntos
Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Tipo 1/complicações , Pós-Condicionamento Isquêmico/métodos , Traumatismo por Reperfusão Miocárdica/prevenção & controle , PTEN Fosfo-Hidrolase/antagonistas & inibidores , Animais , Apoptose , Células Cultivadas , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 1/metabolismo , Técnicas de Silenciamento de Genes/métodos , Janus Quinase 2/fisiologia , Masculino , Infarto do Miocárdio/patologia , Traumatismo por Reperfusão Miocárdica/etiologia , Traumatismo por Reperfusão Miocárdica/metabolismo , PTEN Fosfo-Hidrolase/genética , PTEN Fosfo-Hidrolase/metabolismo , Fosfatidilinositol 3-Quinase/fisiologia , Fosforilação , Proteínas Proto-Oncogênicas c-akt/fisiologia , RNA Interferente Pequeno/genética , Ratos Sprague-Dawley , Fator de Transcrição STAT3/fisiologia , Transdução de Sinais/fisiologia , Compostos de Vanádio/farmacologia , Compostos de Vanádio/uso terapêuticoRESUMO
PTEN is a dual specificity phosphatase and is implicated in inflammation and apoptosis of cerebral ischemia and reperfusion (I/R) injury. Bisperoxovanadium (Bpv), a specific inhibitor of PTEN's phosphatase activity, has demonstrated powerful neuroprotective properties. We investigated the neuroprotective roles of Bpv in the rat model of middle cerebral artery occlusion (MCAO) cerebral I/R injury, and explored the modulation of inflammatory mediators and PI3K/Akt/GSK-3ß pathways by Bpv. Our results showed that treatment with Bpv (0.2 mg/kg/day) significantly decreased neurological deficit scores at 7 days after MCAO and infarct volume at 4 days after MCAO. The IL-10 concentration was increased and TNF-α concentration was decreased in the ischemic boundary zone of the cerebral cortex at 4 days after MCAO by Bpv. Furthermore, Bpv (0.2 mg/kg/day) treatment significantly reduced PTEN mRNA and protein levels and increased PI3K, Akt and p-GSK-3ß proteins expression in the ischemic boundary zone of the cerebral cortex at 4 days after MCAO. In conclusions, Bpv treatment demonstrates neuroprotective effects on cerebral ischemia and reperfusion injury of ischemic stroke rats and is associated with its modulation of inflammatory mediator production and up-regulation of PTEN downstream proteins PI3K, Akt and p-GSK-3ß.
Assuntos
Isquemia Encefálica/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Acidente Vascular Cerebral/tratamento farmacológico , Compostos de Vanádio/uso terapêutico , Animais , Infarto Encefálico/tratamento farmacológico , Infarto Encefálico/metabolismo , Infarto Encefálico/patologia , Isquemia Encefálica/metabolismo , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Quinase 3 da Glicogênio Sintase/metabolismo , Glicogênio Sintase Quinase 3 beta , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Interleucina-10/metabolismo , Masculino , PTEN Fosfo-Hidrolase/antagonistas & inibidores , PTEN Fosfo-Hidrolase/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos Sprague-Dawley , Transdução de Sinais , Acidente Vascular Cerebral/metabolismo , Fator de Necrose Tumoral alfa/metabolismoRESUMO
This paper discusses how the activity and expression of cyclooxygenases are influenced by vanadium compounds at anticancer concentrations and recorded in inorganic vanadium poisonings. We refer mainly to the effects of vanadate (orthovanadate), vanadyl and pervanadate ions; the main focus is placed on their impact on intracellular signaling. We describe the exact mechanism of the effect of vanadium compounds on protein tyrosine phosphatases (PTP), epidermal growth factor receptor (EGFR), PLCγ, Src, mitogen-activated protein kinase (MAPK) cascades, transcription factor NF-κB, the effect on the proteolysis of COX-2 and the activity of cPLA2. For a better understanding of these processes, a lot of space is devoted to the transformation of vanadium compounds within the cell and the molecular influence on the direct targets of the discussed vanadium compounds.
Assuntos
Mediadores da Inflamação/farmacologia , Prostaglandina-Endoperóxido Sintases/metabolismo , Compostos de Vanádio/farmacologia , Animais , Relação Dose-Resposta a Droga , Humanos , Mediadores da Inflamação/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Compostos de Vanádio/uso terapêuticoRESUMO
Early postnatal propofol administration has potential detrimental effects on hippocampal synaptic development and memory. Therapeutic method is still lack due to unknown mechanisms. In this study, a 7-day propofol protocol was applied to model anesthesia in neonatal mice. Phosphatase and tensin homolog deleted on chromosome ten (Pten) inhibitor bisperoxovanadium (bpV) was pre-applied before propofol to study its potential protection. After propofol application, Pten level increased while phospho-AKT (p-AKT) (Ser473) decreased in dorsal hippocampus. Interestingly, i.p. injection of Pten inhibitor reversed the decrease of p-AKT. Two months after administration, basal synaptic transmission, hippocampal long-term potentiation (LTP) and long-term memory were reduced in propofol-administrated mice. By contrast, i.p. injection of Pten inhibitor at a dose of 0.2 mg/kg/day before propofol reversed the detrimental effects due to propofol application. Consistently, bpV injection also reversed propofol application-induced decrease of synaptic plasticity-related proteins, including p-CamKIIα, p-PKA and postsynaptic density protein 95. Taken together, our results demonstrate that bpV injection could reverse early propofol exposure-induced decrease of memory and hippocampal LTP. bpV might be a potential therapeutic for memory impairment after early propofol postnatal application.