Exercise, exerkines and exercise mimetic drugs: Molecular mechanisms and therapeutics.

Chronic diseases linked with sedentary lifestyles and poor dietary habits are increasingly common in modern society. Exercise is widely acknowledged to have a plethora of health benefits, including its role in primary prevention of various chronic conditions like type 2 diabetes mellitus, obesity, cardiovascular disease, and several musculoskeletal as well as degenerative disorders. Regular physical activity induces numerous physiological adaptations that contribute to these positive effects, primarily observed in skeletal muscle but also impacting other tissues.

Targets, trials and tribulations in Alzheimer therapeutics.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by abnormal accumulation of extracellular amyloid beta senile plaques and intracellular neurofibrillary tangles in the parts of the brain responsible for cognition. The therapeutic burden for the management of AD relies solely on cholinesterase inhibitors that provide only symptomatic relief. The urgent need for disease-modifying drugs has resulted in intensive research in this domain, which has led to better understanding of the disease pathology and identification of a plethora of new pathological targets.

Structural fingerprinting of pleiotropic flavonoids for multifaceted Alzheimer's disease.

Alzheimer's disease has emerged as one of the most challenging neurodegenerative diseases associated with dementia, loss of cognitive functioning and memory impairment. Despite enormous efforts to identify disease modifying technologies, the repertoire of currently approved drugs consists of a few symptomatic candidates that are not capable of halting disease progression. Moreover, these single mechanism drugs target only a small part of the pathological cascade and do not address most of the etiological basis of the disease.

Metallic and polymeric green nanoplatforms in oncology.

Chemotherapy, the cornerstone of cancer treatment, although invaluable, is plagued with unbearable and occasionally life-threatening side effects due to its inability to discriminate between tumorous and healthy cells. Anticancer nanomedicines have gained prominence due to their site-specific delivery of chemotherapeutic agents. In comparison to traditional chemical and physical procedures, which add to the chemical burden of an already ailing body, biosynthesis of nanomaterials by plants and microorganisms has evolved as safer 'green' nano-manufacturing technology.

Therapeutic Peptides: Unravelling Conformational Dynamics by Systematic Application of Biophysical Techniques.

Peptide therapeutics represents one of the fastest-growing sectors in the pharmaceutical drugs pipeline, with an increasing number of regulatory approvals every year. Their pharmacological diversity, biocompatibility, high degree of potency and selectivity make them an attractive choice in several therapeutic areas, such as diabetes, cancer, immune, metabolic, cardiovascular and infectious diseases. However, the development of peptides as drugs presents its own set of challenges, necessitating extensive property optimization aimed at improving their drug-like properties and stability in biological environments.

Smart nanocomposite assemblies for multimodal cancer theranostics.

Despite great strides in anticancer research, performance statistics of current treatment modalities remain dismal, highlighting the need for safe, efficacious strategies for tumour mitigation. Non-invasive fusion technology platforms combining photodynamic, photothermal and hyperthermia therapies have emerged as alternate strategies with potential to meet many of the unmet clinical demands in the domain of cancer. These therapies make use of metallic and magnetic nanoparticles with light absorbing properties, which are manipulated to generate either reactive cytotoxic oxygen species or heat for tumour ablation.

Potential of triazines in Alzheimer's disease: A versatile privileged scaffold.

Triazines are six-membered privileged scaffolds that have been explored in drug discovery programs owing to their stability in biological media and robust reactivity. Their unique chemical properties have led to the exploration of the triazine-containing molecules for multifaceted disorders like Alzheimer's disease (AD). The pathology of AD involves the interplay of multiple biochemical events such as amyloid beta-aggregation, formation of reactive oxygen species, cholinergic degradation, and metal ion dysregulation.

The pleiotropic peroxisome proliferator activated receptors: Regulation and therapeutics.

The Peroxisome proliferator-activated receptors (PPARs) are key regulators of metabolic events in our body. Owing to their implication in maintenance of homeostasis, both PPAR agonists and antagonists assume therapeutic significance. Understanding the molecular mechanisms of each of the PPAR isotypes in the healthy body and during disease is crucial to exploiting their full therapeutic potential.

Design strategies, SAR, and mechanistic insight of Aurora kinase inhibitors in cancer.

Aurora kinases (AURKs) are serine/threonine protein kinases that play a critical role during cell proliferation. Three isoforms of AURKs reported in mammals include AURKA, AURKB, AURKC, and all share a similar C-terminal catalytic domain with differences in their subcellular location, substrate specificity, and function. Recent research reports indicate an elevated expression of these kinases in several cancer types highlighting their role as oncogenes in tumorigenesis.

Docking structurally similar analogues: Dealing with the false-positive.

Analogue design forms one of the mainstays of new drug discovery. A fast-follow on approach is commonly used by modern day drug discoverers on the quest of the best in class. Monitoring close structural analogues of the pioneering drug by an algorithm such as docking is fraught with the risk of returning false positives.

Molecular dynamic simulations on an inhibitor of anti-apoptotic Bcl-2 proteins for insights into its interaction mechanism for anti-cancer activity.

Inhibition of normal cellular apoptosis or programed cell death is the hallmark of all cancers. Apoptotic dysregulation can result in numerous pathological conditions, such as cancers, autoimmune disorders, and neurodegeneration. Members of the BCL-2 family of proteins regulate the process of apoptosis by its promotion or inhibition and overexpression of the pro-survival anti-apoptotic proteins (Bcl-2, Bcl-xL, and Mcl-1) has been associated with tumor maintenance, growth and progression Small molecules and peptides which bind the BH3 binding groove of these proteins have been explored in the recent times for their anticancer potential.

Design, synthesis and biological evaluation of novel inosine 5'-monophosphate dehydrogenase (IMPDH) inhibitors.

This study is based on our attempts to further explore the structure-activity relationship (SAR) of VX-148 (3) in an attempt to identify inosine 5'-mono-phosphate dehydrogenase (IMPDH) inhibitors superior to mycophenolic acid. A five-point pharmacophore developed using structurally diverse, known IMPDH inhibitors guided further design of novel analogs of 3. Several conventional as well as novel medicinal chemistry strategies were tried.

Virtual and experimental high-throughput screening (HTS) in search of novel inosine 5'-monophosphate dehydrogenase II (IMPDH II) inhibitors.

IMPDH (Inosine 5'-monophosphate dehydrogenase) catalyzes a rate-limiting step in the de novo biosynthesis of guanine nucleotides. IMPDH inhibition in sensitive cell types (e.g.

Synthesis and biological evaluation of novel (4 or 5-aryl)pyrazolyl-indoles as inhibitors of interleukin-2 inducible T-cell kinase (ITK).

Interleukin-2 inducible T-cell kinase (ITK) is one of five kinases that belong to the Tec kinase family that plays an important role in T-cell and mast cell signaling. Various reports point to a role of ITK in the treatment of allergic asthma. For example, it was shown that mice lacking ITK have reduced airway hyperresponsiveness, inflammation and tracheal responses in an allergic asthma model.

A comprehensive analysis of the thermodynamic events involved in ligand-receptor binding using CoRIA and its variants.

Quantitative Structure-Activity Relationships (QSAR) are being used since decades for prediction of biological activity, lead optimization, classification, identification and explanation of the mechanisms of drug action, and prediction of novel structural leads in drug discovery. Though the technique has lived up to its expectations in many aspects, much work still needs to be done in relation to problems related to the rational design of peptides. Peptides are the drugs of choice in many situations, however, designing them rationally is a complicated task and the complexity increases with the length of their sequence.

Equilibrium unfolding of DLC8 monomer by urea and guanidine hydrochloride: Distinctive global and residue level features.

We present circular dichroism (CD), steady state fluorescence and multidimensional NMR investigations on the equilibrium unfolding of monomeric dynein light chain protein (DLC8) by urea and guanidine hydrochloride (GdnHCl). Quantitative analysis of the CD and fluorescence denaturation curves reveals that urea unfolding is a two-state process, whereas guanidine unfolding is more complex. NMR investigations in the native state and in the near native states created by low denaturant concentrations enabled residue level characterization of the early structural and dynamic perturbations by the two denaturants.

The amino-terminal domain of human signal transducers and activators of transcription 1: overexpression, purification and characterization.

The dual functional signal transducers and activators of transcription (STAT) proteins are latent cytoplasmic transcription factors that play crucial roles in host defense. Animals that lack these proteins are highly susceptible to microbial and viral infections and chemically induced primary tumours. We have over expressed the amino-terminal domain of human STAT1 (hSTAT1) in Escherichia coli and purified it by affinity chromatography and gel filtration chromatography.

Solution conformation of Substance P antagonists-[D-Arg1, D-Trp7,9, Leu11]-SP, [D-Arg1, D-Pro2, D-Trp7,9, Leu11]-SP and [D-Pro2, D-Trp7,9]-SP by CD, NMR and MD simulations.

Substance P (SP) is an important neuropeptide involved in pain transmission and induction of inflammation. Its antagonists are being extensively investigated for their non-narcotic analgesic and anti-inflammatory activity. With a view towards better understanding the structural requirements of these analogs for efficient interaction with the SP receptor, the conformation of three SP antagonists [D-Arg1, D-Trp7,9, Leu11]-SP, [D-Arg1, D-Pro2, D-Trp7,9, Leu11]-SP and [D-Pro2, D-Trp7,9]-SP has been studied by CD, NMR and molecular dynamics (MD) simulations.

New set of orthogonal protecting groups for the modular synthesis of heparan sulfate fragments.

Six strategically chosen monosaccharide building blocks, which are protected by a novel set of four orthogonal protecting groups (Lev, Fmoc, TBDPS, and All), can be employed for the efficient synthesis of the 20 disaccharide moieties found in heparan sulfate. The properly protected disaccharide building blocks can be converted into glycosyl donors and acceptors, which can be used for the modular synthesis of a wide range of well-defined oligosaccharides that differ in sulfation pattern. [structure: see text]