Vanadium: History, chemistry, interactions with α-amino acids and potential therapeutic applications.

In the last 30 years, since the discovery that vanadium is a cofactor found in certain enzymes of tunicates and possibly in mammals, different vanadium-based drugs have been developed targeting to treat different pathologies. So far, the in vitro studies of the insulin mimetic, antitumor and antiparasitic activity of certain compounds of vanadium have resulted in a great boom of its inorganic and bioinorganic chemistry. Chemical speciation studies of vanadium with amino acids under controlled conditions or, even in blood plasma, are essential for the understanding of the biotransformation of e.g. vanadium antidiabetic complexes at the physiological level, providing clues of their mechanism of action. The present article carries out a bibliographical research emphaticizing the chemical speciation of the vanadium with different amino acids and reviewing also some other important aspects such as its chemistry and therapeutical applications of several vanadium complexes.

PTP1B Inhibition Improves Mitochondrial Dynamics to Alleviate Calcific Aortic Valve Disease Via Regulating OPA1 Homeostasis.

There are currently no pharmacological therapies for calcific aortic valve disease (CAVD). Here, we evaluated the role of protein tyrosine phosphatase 1B (PTP1B) inhibition in CAVD. Up-regulation of PTP1B was critically involved in calcified human aortic valve, and PTP1B inhibition had beneficial effects in preventing fibrocalcific response in valvular interstitial cells and LDLR-/- mice. In addition, we reported a novel function of PTP1B in regulating mitochondrial homeostasis by interacting with the OPA1 isoform transition in valvular interstitial cell osteogenesis. Thus, these findings have identified PTP1B as a potential target for preventing aortic valve calcification in patients with CAVD.

Structure-based peptide design targeting intrinsically disordered proteins: Novel histone H4 and H2A peptidic inhibitors.

A growing body of research has demonstrated that targeting intrinsically disordered proteins (IDPs) and intrinsically disordered protein regions (IDPRs) is feasible and represents a new trending strategy in drug discovery. However, the number of inhibitors targeting IDPs/IDPRs is increasing slowly due to limitations of the methods that can be used to accelerate the discovery process. We have applied structure-based methods to successfully develop the first peptidic inhibitor (HIPe - Histone Inhibitory Peptide) that targets histone H4 that are released from NETs (Neutrophil Extracellular Traps). HIPe binds stably to the disordered N-terminal tail of histone H4, thereby preventing histone H4-induced cell death. Recently, by utilisation of the same state-of-the-art approaches, we have developed a novel peptidic inhibitor (CHIP - Cyclical Histone H2A Interference Peptide) that binds to NET-resident histone H2A, which results in a blockade of monocyte adhesion and consequently reduction in atheroprogression. Here, we present comprehensive details on the computational methods utilised to design and develop HIPe and CHIP. We have exploited protein-protein complexes as starting structures for rational peptide design and then applied binding free energy methods to predict and prioritise binding strength of the designed peptides with histone H4 and H2A. By doing this way, we have modelled only around 20 peptides and from these were able to select 4-5 peptides, from a total of more than a trillion candidate peptides, for functional characterisation in different experiments. The developed computational protocols are generic and can be widely used to design and develop novel inhibitors for other disordered proteins.

An overview on medicinal perspective of thiazolidine-2,4-dione: A remarkable scaffold in the treatment of type 2 diabetes.

Diabetes or diabetes mellitus is a complex or polygenic disorder, which is characterized by increased levels of glucose (hyperglycemia) and deficiency in insulin secretion or resistance to insulin over an elongated period in the liver and peripheral tissues. Thiazolidine-2,4-dione (TZD) is a privileged scaffold and an outstanding heterocyclic moiety in the field of drug discovery, which provides various opportunities in exploring this moiety as an antidiabetic agent. In the past few years, various novel synthetic approaches had been undertaken to synthesize different derivatives to explore them as more potent antidiabetic agents with devoid of side effects (i.e., edema, weight gain, and bladder cancer) of clinically used TZD (pioglitazone and rosiglitazone). In this review, an effort has been made to summarize the up to date research work of various synthetic strategies for TZD derivatives as well as their biological significance and clinical studies of TZDs in combination with other category as antidiabetic agents. This review also highlights the structure-activity relationships and the molecular docking studies to convey the interaction of various synthesized novel derivatives with its receptor site.

Vanadium: Risks and possible benefits in the light of a comprehensive overview of its pharmacotoxicological mechanisms and multi-applications with a summary of further research trends.

BACKGROUND: Vanadium (V) is an element with a wide range of effects on the mammalian organism. The ability of this metal to form organometallic compounds has contributed to the increase in the number of studies on the multidirectional biological activity of its various organic complexes in view of their application in medicine. OBJECTIVE: This review aims at summarizing the current state of knowledge of the pharmacological potential of V and the mechanisms underlying its anti-viral, anti-bacterial, anti-parasitic, anti-fungal, anti-cancer, anti-diabetic, anti-hypercholesterolemic, cardioprotective, and neuroprotective activity as well as the mechanisms of appetite regulation related to the possibility of using this element in the treatment of obesity. The toxicological potential of V and the mechanisms of its toxic action, which have not been sufficiently recognized yet, as well as key information about the essentiality of this metal, its physiological role, and metabolism with certain aspects on the timeline is collected as well. The report also aims to review the use of V in the implantology and industrial sectors emphasizing the human health hazard as well as collect data on the directions of further research on V and its interactions with Mg along with their character. RESULTS AND CONCLUSIONS: Multidirectional studies on V have shown that further analyses are still required for this element to be used as a metallodrug in the fight against certain life-threatening diseases. Studies on interactions of V with Mg, which showed that both elements are able to modulate the response in an interactive manner are needed as well, as the results of such investigations may help not only in recognizing new markers of V toxicity and clarify the underlying interactive mechanism between them, thus improving the medical application of the metals against modern-age diseases, but also they may help in development of principles of effective protection of humans against environmental/occupational V exposure.

Small molecules for fat combustion: targeting obesity.

Obesity is increasing in an alarming rate worldwide, which causes higher risks of some diseases, such as type 2 diabetes, cardiovascular diseases, and cancer. Current therapeutic approaches, either pancreatic lipase inhibitors or appetite suppressors, are generally of limited effectiveness. Brown adipose tissue (BAT) and beige cells dissipate fatty acids as heat to maintain body temperature, termed non-shivering thermogenesis; the activity and mass of BAT and beige cells are negatively correlated with overweight and obesity. The existence of BAT and beige cells in human adults provides an effective weight reduction therapy, a process likely to be amenable to pharmacological intervention. Herein, we combed through the physiology of thermogenesis and the role of BAT and beige cells in combating with obesity. We summarized the thermogenic regulators identified in the past decades, targeting G protein-coupled receptors, transient receptor potential channels, nuclear receptors and miscellaneous pathways. Advances in clinical trials were also presented. The main purpose of this review is to provide a comprehensive and up-to-date knowledge from the biological importance of thermogenesis in energy homeostasis to the representative thermogenic regulators for treating obesity. Thermogenic regulators might have a large potential for further investigations to be developed as lead compounds in fighting obesity.

Frequent amplification of PTP1B is associated with poor survival of gastric cancer patients.

The protein tyrosine phosphatase 1B (PTP1B), a non-transmembrane protein tyrosine phosphatase, has been implicated in gastric pathogenesis. Several lines of recent evidences have shown that PTP1B is highly amplified in breast and prostate cancers. The aim of this study was to investigate PTP1B amplification in gastric cancer and its association with poor prognosis of gastric cancer patients, and further determine the role of PTP1B in gastric tumorigenesis. Our data demonstrated that PTP1B was significantly up-regulated in gastric cancer tissues as compared with matched normal gastric tissues by using quantitative RT-PCR (qRT-PCR) assay. In addition, copy number analysis showed that PTP1B was amplified in 68/131 (51.9%) gastric cancer cases, whereas no amplification was found in the control subjects. Notably, PTP1B amplification was positively associated with its protein expression, and was significantly related to poor survival of gastric cancer patients. Knocking down PTP1B expression in gastric cancer cells significantly inhibited cell proliferation, colony formation, migration and invasion, and induced cell cycle arrested and apoptosis. Mechanically, PTP1B promotes gastric cancer cell proliferation, survival and invasiveness through modulating Src-related signaling pathways, such as Src/Ras/MAPK and Src/phosphatidylinositol-3-kinase (PI3K)/Akt pathways. Collectively, our data demonstrated frequent overexpression and amplification PTP1B in gastric cancer, and further determined the oncogenic role of PTP1B in gastric carcinogenesis. Importantly, PTP1B amplification predicts poor survival of gastric cancer patients.

Cysteine proteases as therapeutic targets: does selectivity matter? A systematic review of calpain and cathepsin inhibitors.

Cysteine proteases continue to provide validated targets for treatment of human diseases. In neurodegenerative disorders, multiple cysteine proteases provide targets for enzyme inhibitors, notably caspases, calpains, and cathepsins. The reactive, active-site cysteine provides specificity for many inhibitor designs over other families of proteases, such as aspartate and serine; however, a) inhibitor strategies often use covalent enzyme modification, and b) obtaining selectivity within families of cysteine proteases and their isozymes is problematic. This review provides a general update on strategies for cysteine protease inhibitor design and a focus on cathepsin B and calpain 1 as drug targets for neurodegenerative disorders; the latter focus providing an interesting query for the contemporary assumptions that irreversible, covalent protein modification and low selectivity are anathema to therapeutic safety and efficacy.

Improved metabolic phenotype of hypothalamic PTP1B-deficiency is dependent upon the leptin receptor.

Protein tyrosine phosphatase 1B (PTP1B) is a known regulator of central metabolic signaling, and mice with whole brain-, leptin receptor (LepRb) expressing cell-, or proopiomelanocortin neuron-specific PTP1B-deficiency are lean, leptin hypersensitive, and display improved glucose homeostasis. However, whether the metabolic effects of central PTP1B-deficiency are due to action within the hypothalamus remains unclear. Moreover, whether or not these effects are exclusively due to enhanced leptin signaling is unknown. Here we report that mice with hypothalamic PTP1B-deficiency (Nkx2.1-PTP1B(-/-)) display decreased body weight and adiposity on high-fat diet with no associated improvements in glucose tolerance. Consistent with previous reports, we find that hypothalamic deletion of the LepRb in mice (Nkx2.1-LepRb(-/-)) results in extreme hyperphagia and obesity. Interestingly, deletion of hypothalamic PTP1B and LepRb (Nkx2.1-PTP1B(-/-):LepRb(-/-)) does not rescue the hyperphagia or obesity of Nkx2.1-LepRb(-/-) mice, suggesting that hypothalamic PTP1B contributes to the central control of energy balance through a leptin receptor-dependent pathway.