Insulin Receptor Substrates Regulation and Clinical Responses Following Vanadium-Enriched Yeast Supplementation in Obese Type 2 Diabetic Patients: a Randomized, Double-Blind, Placebo-Controlled Clinical Trial.

Increasing evidence suggests that organic vanadium compounds are bioavailable and safe therapeutic agents with insulin-mimetic and insulin-enhancing features. The objective of the current study was to examine the effect of vanadium-enriched yeast (VEY) supplementation on the gene expression level of insulin receptor substrates and clinical manifestations of obese type 2 diabetic mellitus (T2DM) patients. In this randomized, double-blind, placebo-controlled clinical trial, 44 obese T2DM patients were randomly allocated into either VEY (0.9 mg/day vanadium pentoxide) or placebo group for 12 weeks. The mRNA expression level of protein tyrosine phosphatase 1B (PTP1B), phosphatase and tensin homolog (PTEN), mitogen-activated protein kinase (MAPK), ribosomal protein S6 kinase (S6K), and nuclear factor kappa-light-chain-enhancer of activated B cells (NFƘB) genes in the peripheral blood mononuclear cells, serum levels of metabolic parameters, anthropometric indices, as well as the quality of life, and dietary intake were collected at pre- and post-intervention phases. Analysis of covariance was performed to obtain the corresponding effect size. Results showed that VEY administration significantly decreased anthropometric indices and glycemic parameters and increased insulin sensitivity after adjusting for potential covariates (p < 0.05), in comparison to the placebo group. Additionally, VEY supplementation was significantly effective on MAPK, PTP1B, and NFƘB gene expression level, compared to the placebo group. No significant changes were noticed for dietary intake, quality of life, and lipid profile in the VEY group, compared to the placebo group. Overall, VEY supplementation can be considered as a promising safe adjunct therapy for improving anthropometric indices and glycemic parameters in T2DM patients.

Artificial photoactive chlorophyll conjugated vanadium carbide nanostructure for synergistic photothermal/photodynamic therapy of cancer.

Optically active nanostructures consisting of organic compounds and metallic support have shown great promise in phototherapy due to their increased light absorption capacity and high energy conversion. Herein, we conjugated chlorophyll (Chl) to vanadium carbide (V2C) nanosheets for combined photodynamic/photothermal therapy (PDT/PTT), which reserves the advantages of each modality while minimizing the side effects to achieve an improved therapeutic effect. In this system, the Chl from Leptolyngbya JSC-1 extracts acted as an efficient light-harvest antenna in a wide NIR range and photosensitizers (PSs) for oxygen self-generation hypoxia-relief PDT. The available large surface of two-dimensional (2D) V2C showed high Chl loading efficiency, and the interaction between organic Chl and metallic V2C led to energy conversion efficiency high to 78%. Thus, the Chl/ V2C nanostructure showed advanced performance in vitro cell line killing and completely ablated tumors in vivo with 100% survival rate under a single NIR irradiation. Our results suggest that the artificial optical Chl/V2C nanostructure will benefit photocatalytic tumor eradication clinic application.

Vanadium and insulin: Partners in metabolic regulation.

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.

Synthesis, crystal structures and insulin-like activity of three new oxidovanadium(V) complexes with aroylhydrazone ligand.

Three new oxidovanadium(V) complexes were designed, synthesized and characterized by C, H, N elemental analysis, single crystal X-ray diffraction，UV/Vis and IR spectra. Complex 1: [VOL1X] (H2L1 = (E)-N'-(2-hydroxybenzylidene)-3-methbenzohydrazide, HX = ethylmaltol = 2-ethyl-3-hydroxy-4-pyrone), Complex 2: [VOL2(CH3O)(CH3OH)], (H2L2 = C16H16N2O4 = (E)-N'-(2-hydroxybenzylidene)-3,5-dimethoxybenzohydrazide, CH3OH = methanol), Complex 3: [VOL3X] (H2L3 = (E)-N'-(3-ethoxy-2-hydroxybenzylidene)-3,5-dimethoxybenzohydrazide). The insulin-like activity of the three complexes was tested. Both normal and streptozotocin (STZ)-diabetic mice were administered intragastrically for two weeks. It was found that the complexes at doses of 10.0 and 5.0 mg V·kg-1 can significantly decrease the blood glucose level in STZ-diabetic mice, and the blood glucose level in the treated normal mice was not altered. The lesions of kidney and liver caused by diabetes have varying degrees of improvement.

Induction of apoptosis in human colorectal cancer cell line, HCT-116 by a vanadium- Schiff base complex.

Vanadium compounds are well known for their therapeutic interventions against several diseases. Various biochemical attributes of vanadium complexes inspired us to evaluate the cancer cell killing efficacy of the vanadium complex, viz., vanadyl N-(2-hydroxyacetophenone) glycinate [VO(NG)2]. Previously we showed that VO(NG)2 is an effective anticancer agent in in vitro and in vivo cancer models and imposed miniscule side effects. Herein we report that VO(NG)2 is significantly cytotoxic to various cancer cell lines. Furthermore, this redox active vanadyl complex altered the redox homeostatsis of many human cancer cell lines significantly. VO(NG)2 actuates programmed cell death in human colorectal carcinoma cells(HCT-116) through mitochondrial outer membrane permeabilization but in caspase independent manner, possibly by altering cellular redox status and by inflicting DNA damage. Thus, the present work is an attempt to provide many evidences regarding the potent and selective chemotherapeutic efficacy of the novel VO(NG)2.

Speciation of potential anti-diabetic vanadium complexes in real serum samples.

In this work the speciation in real serum samples of five VIVO complexes with potential application in the therapy of diabetes was studied through EPR spectroscopy as a function of V concentration (45.4, 90.9 and 454.5µM) and time (0-180min). [VO(dhp)2], [VO(ma)2], [VO(acac)2], [VO(pic)2(H2O)], and [VO(mepic)2], where Hdhp indicates 1,2-dimethyl-3-hydroxy-4(1H)-pyridinone, Hma maltol, Hacac acetylacetone, Hpic picolinic acid, and Hmepic 6-methylpicolinic acid, were examined. The distribution of VIVO2+ among the serum bioligands was calculated from the thermodynamic stability constants in the literature and compared with the experimental results. EPR results, which confirm the prediction, depend on the strength of the ligand L and geometry assumed by the bis-chelated species at physiological pH, cis-octahedral or square pyramidal. With dhp, the strongest chelator, the system is dominated by [VO(dhp)2] and/or cis-VO(dhp)2(Protein); with intermediate strength chelators, i.e. maltolate, acetylacetonate and picolinate, by cis-VO(ma)2(Protein), [VO(acac)2] or [VO(pic)(citrH-1)]3-/[VO(pic)(lactH-1)]- (citr=citrate and lact=lactate) when the V concentration overcomes 100-200µM and by (VO)(hTf)/(VO)2(hTf) when concentration is lower than 100µM; with the weakest chelator, 6-methylpicolinate, (VO)(hTf)/(VO)2(hTf), (VO)(HSA) (hTf = human serum transferrin and HSA = human serum albumin), and VO(mepic)(Protein)(OH) are the major species at concentration higher than 100-200µM, whereas hydrolytic processes are observed for lower concentrations. For [VO(dhp)2], [VO(ma)2], [VO(acac)2] and [VO(pic)2(H2O)], the EPR spectra remain unaltered with elapsing time, while for mepic they change significantly because the hydrolyzed VIVO species are complexed by the serum bioligands, in particular by lactate. The rate of oxidation in the serum is [VO(dhp)2]>[VO(ma)2]>[VO(acac)2] and reflects the order of E1/2 values.

Selenium, Vanadium, and Chromium as Micronutrients to Improve Metabolic Syndrome.

Trace metals play an important role in the proper functioning of carbohydrate and lipid metabolism. Some of the trace metals are thus essential for maintaining homeostasis, while deficiency of these trace metals can cause disorders with metabolic and physiological imbalances. This article concentrates on three trace metals (selenium, vanadium, and chromium) that may play crucial roles in controlling blood glucose concentrations possibly through their insulin-mimetic effects. For these trace metals, the level of evidence available for their health effects as supplements is weak. Thus, their potential is not fully exploited for the target of metabolic syndrome, a constellation that increases the risk for cardiovascular disease and type 2 diabetes. Given that the prevalence of metabolic syndrome is increasing throughout the world, a simpler option of interventions with food supplemented with well-studied trace metals could serve as an answer to this problem. The oxidation state and coordination chemistry play crucial roles in defining the responses to these trace metals, so further research is warranted to understand fully their metabolic and cardiovascular effects in human metabolic syndrome.

Selective speciation improves efficacy and lowers toxicity of platinum anticancer and vanadium antidiabetic drugs.

Improving efficacy and lowering resistance to metal-based drugs can be addressed by consideration of the coordination complex speciation and key reactions important to vanadium antidiabetic drugs or platinum anticancer drugs under biological conditions. The methods of analyses vary depending on the specific metal ion chemistry. The vanadium compounds interconvert readily, whereas the reactions of the platinum compounds are much slower and thus much easier to study. However, the vanadium species are readily differentiated due to vanadium complexes differing in color. For both vanadium and platinum systems, understanding the processes as the compounds, Lipoplatin and Satraplatin, enter cells is needed to better combat the disease; there are many cellular metabolites, which may affect processing and thus the efficacy of the drugs. Examples of two formulations of platinum compounds illustrate how changing the chemistry of the platinum will result in less toxic and better tolerated drugs. The consequence of the much lower toxicity of the drug, can be readily realized because cisplatin administration requires hospital stay whereas Lipoplatin can be done in an outpatient manner. Similarly, the properties of Satraplatin allow for development of an oral drug. These forms of platinum demonstrate that the direct consequence of more selective speciation is lower side effects and cheaper administration of the anticancer agent. Therefore we urge that as the community goes forward in development of new drugs, control of speciation chemistry will be considered as one of the key strategies in the future development of anticancer drugs.

Effect of Vanadyl Rosiglitazone, a New Insulin-Mimetic Vanadium Complexes, on Glucose Homeostasis of Diabetic Mice.

Diabetes has been cited as the most challenging health problem in the twenty-first century. Accordingly, it is urgent to develop a new type of efficient and low-toxic antidiabetic medication. Since vanadium compounds have insulin-mimetic and potential hypoglycemic activities for type 1 and type 2 diabetes, a new trend has been developed using vanadium and organic ligands to form a new compound in order to increase the intestinal absorption and reduce the toxicity of vanadium compound. In the current investigation, a new organic vanadium compounds, vanadyl rosiglitazone, was synthesized and determined by infrared spectra. Vanadyl rosiglitazone and three other organic vanadium compounds were administered to the diabetic mice through oral administration for 5 weeks. The results of mouse model test indicated that vanadyl rosiglitazone could regulate the blood glucose level and relieve the symptoms of polydipsia, polyphagia, polyuria, and weight loss without side effects and was more effective than the other three organic vanadium compounds including vanadyl trehalose, vanadyl metformin, and vanadyl quercetin. The study indicated that vanadyl rosiglitazone presents insulin-mimetic activities, and it will be a good potential candidate for the development of a new type of oral drug for type 2 diabetes.

Insulin and vanadium protect against osteoarthritis development secondary to diabetes mellitus in rats.

OBJECTIVE: Diabetic complications such as cardiovascular disease and osteoarthritis (OA) are among the common public health problems. The effect of insulin on OA secondary to diabetes has not been investigated before in animal models. Therefore, we sought to determine whether insulin and the insulin-mimicking agent, vanadium can protect from developing OA in diabetic rats. METHODS: Type 1 diabetes mellitus (T1DM) was induced in Sprague-Dawley rats and treated with insulin and/or vanadium. Tissues harvested from the articular cartilage of the knee joint were examined by scanning electron microscopy, and blood samples were assayed for oxidative stress and inflammatory biomarkers. RESULTS: Eight weeks following the induction of diabetes, a profound damage to the knee joint compared to the control non-diabetic group was observed. Treatment of diabetic rats with insulin and/or vanadium differentially protected from diabetes-induced cartilage damage and deteriorated fibrils of collagen fibers. The relative biological potencies were insulin + vanadium >> insulin > vanadium. Furthermore, there was about 2- to 5-fold increase in TNF-α (from 31.02 ± 1.92 to 60.5 ± 1.18 pg/ml, p < 0.0001) and IL-6 (from 64.67 ± 8.16 to 338.0 ± 38.9 pg/ml, p < 0.0001) cytokines and free radicals measured as TBARS (from 3.21 ± 0.37 to 11.48 ± 1.5 µM, p < 0.0001) in the diabetic group, which was significantly reduced with insulin and or vanadium. Meanwhile, SOD decreased (from 17.79 ± 8.9 to 8.250.29, p < 0.0001) and was increased with insulin and vanadium. The relative potencies of the treating agents on inflammatory and oxidative stress biomarkers were insulin + vanadium >> insulin > vanadium. CONCLUSION: The present study demonstrates that co-administration of insulin and vanadium to T1DM rats protect against diabetes-induced OA possibly by lowering biomarkers of inflammation and oxidative stress.