Current Drug Targets - Volume 20, Issue 3, 2019

Succumbing to Multi-Drug Resistant (MDR) bacteria is a great distress to the recent health care system. Out of the several attempts that have been made to kill MDR pathogens, a few gained short-lived success. The failures, of the discovered or innovated antimicrobials, were mostly due to their high level of toxicity to hosts and the phenomenal rate of developing resistance by the pathogens against the new arsenal. Recently, a few quantum dots were tested against the pathogenic bacteria and therefore, justified for potential stockpiling of next-generation antibacterial agents. The key players for antimicrobial properties of quantum dots are considered to be Reactive Oxygen Species (ROS). The mechanism of reaction between bacteria and quantum dots needs to be better understood. They are generally targeted towards the cell wall and membrane components as lipoteichoic acid and phosphatidyl glycerol of bacteria have been documented here. In this paper, we have attempted to simulate ZnS quantum dots and have analysed their mechanism of reaction as well as binding potential to the above bacterial membrane components using CDOCKER. Results have shown a high level of antibacterial activity towards several pathogenic bacteria which specify their potentiality for future generation antibacterial drug development.

Memory is an associated part of life without which livelihood of a human being becomes miserable. As the global aged population is increasing tremendously, time has come to concentrate on tail end life stage diseases. Alzheimer's disease (AD) is one of such diseases whose origin is enigmatic, having an impact on later stage of life drastically due to irreparable damage of cognition, characterised by the presence of neurotoxic amyloid-beta (Aβ) plaques and hyper phosphorylated Tau protein as fibrillary tangles. Existing therapeutic regimen mainly focuses on symptomatic relief by targeting neurotransmitters that are secondary to AD pathology. Plant derived licensed drugs, Galantamine and Huperzine-A were studied extensively due to their AChE inhibitory action for mild to moderate cases of AD. Although many studies have proved the efficacy of AChEIs as a preferable symptom reliever, they cannot offer long term protection. The future generation drugs of AD is expected to alter various factors that underlie the disease course with a symptomatic benefit promise. As AD involves complex pathology, it is essential to consider several molecular divergent factors apart from the events that result in the production of toxic plaques and neurofibrillary tangles. Even though several herbals have shown neuroprotective actions, we have mentioned about the phytoconstituents that have been tested experimentally against different Alzheimer’s pathology models. These phytoconstituents need to be considered by the researchers for further drug development process to make them viable clinically, which is currently a lacuna.

Bacterial infections have always been an unrestrained challenge to the medical community due to the rise of multi-drug tolerant and resistant strains. Pioneering work on Escherichia coli polyphosphate kinase (PPK) by Arthur Kornberg has generated great interest in this polyphosphate (PolyP) synthesizing enzyme. PPK has wide distribution among pathogens and is involved in promoting pathogenesis, stress management and susceptibility to antibiotics. Further, the absence of a PPK orthologue in humans makes it a potential drug target. This review covers the functional and structural aspects of polyphosphate kinases in bacterial pathogens. A description of molecules being designed against PPKs has been provided, challenges associated with PPK inhibitor design are highlighted and the strategies to enable development of efficient drug against this enzyme have also been discussed.

Background and Objectives: It is generally accepted that inflammatory cells found in the tumor microenvironment are involved in the neoplastic process, promoting cell proliferation, survival, and migration. Therefore, administering anti-inflammatory medication in cancer therapy seems to be justified. A potential pathway associated with the aforementioned issue is cyclooxygenase-2 inhibition, particularly as the overexpression of this enzyme has been proven to occur in cancer tissues and is also associated with a poor prognosis in several types of human malignancies. Celecoxib, a COX-2 selective inhibitor, has been utilized for over 20 years, particularly as an anti-inflammatory, analgesic and antipyretic medication. However, to date, its antineoplastic properties have not been sufficiently investigated. In recent years, the number of research studies on the antineoplastic effects of celecoxib has increased considerably. The vast majority of publications refers to preclinical studies attempting to elucidate its mechanisms of action. Clinical trials concerning celecoxib have focused primarily on the treatment of cancers of the colon, breast, lung, prostate, stomach, head and neck, as well as premalignant lesions such as familial adenoma polyposis. In this review article authors attempt to summarise the latest research which has elucidated celecoxib use in the treatment and prevention of cancer. Conclusion: Both preclinical and clinical studies have demonstrated promising results of the role of celecoxib in the treatment and prevention of cancer – the best outcome was observed in colon, breast, prostate and head and neck cancers. However, more clinical trials providing real evidence-based clinical advances of celecoxib use are needed.

Alzheimer's, a degenerative cause of the brain cells, is called as a progressive neurodegenerative disease and appears to have a heterogeneous etiology with main emphasis on amyloid-cascade and hyperphosphorylated tau-cascade hypotheses, that are directly linked with macromolecules called enzymes such as β- & γ-secretases, colinesterases, transglutaminases, and glycogen synthase kinase (GSK-3), cyclin-dependent kinase (cdk-5), microtubule affinity-regulating kinase (MARK). The catalytic activity of the above enzymes is the result of cognitive deficits, memory impairment and synaptic dysfunction and loss, and ultimately neuronal death. However, some other enzymes also lead to these dysfunctional events when reduced to their normal activities and levels in the brain, such as α- secretase, protein kinase C, phosphatases etc; metabolized to neurotransmitters, enzymes like monoamine oxidase (MAO), catechol-O-methyltransferase (COMT) etc. or these abnormalities can occur when enzymes act by other mechanisms such as phosphodiesterase reduces brain nucleotides (cGMP and cAMP) levels, phospholipase A2: PLA2 is associated with reactive oxygen species (ROS) production etc. On therapeutic fronts, several significant clinical trials are underway by targeting different enzymes for development of new therapeutics to treat Alzheimer's, such as inhibitors for β-secretase, GSK-3, MAO, phosphodiesterase, PLA2, cholinesterases etc, modulators of α- & γ-secretase activities and activators for protein kinase C, sirtuins etc. The last decades have perceived an increasing focus on findings and search for new putative and novel enzymatic targets for Alzheimer's. Here, we review the functions, pathological roles, and worth of almost all the Alzheimer's associated enzymes that address to therapeutic strategies and preventive approaches for treatment of Alzheimer's.

The Receptor for Advanced Glycation End Products (RAGE) is an important cell surface receptor, which belongs to the IgG super family and is now considered as a pattern recognition receptor. Because of its relevance in many human clinical settings, it is now pursued as a very attractive therapeutic target. However, particular features of this receptor such as a wide repertoire of ligands with different binding domains, the existence of many RAGE variants as well as the presence of cytoplasmatic adaptors leading a diverse signaling, are important limitations in the search for successful pharmacological approaches to inhibit RAGE signaling. Therefore, the present review aimed to display the most promising approaches to inhibit RAGE signaling, and provide an up to date review of progress in this area.

While polyphenols may have important effects on pluripotential stem cells that make them noteworthy as potential antineoplastic agents, their action on stem cells may portend other health benefits, such as treatments for cardiovascular and neurocognitive disorders. Resveratrol, the beststudied polyphenol, has been found to enable stem cells to differentiate into cardiomyocytes, neurons, osteocytes, and pancreatic beta cells, as well as facilitating augmentation of stem cell populations and protecting them from toxic injury. Curcumin protects mesenchymal stem cells from toxicity, and prevents them from facilitating chondrocytic hypertrophy. Quercetin enabled osteocytic and pancreatic beta cell differentiation, and protected neuronal stem cells from injury. Epigallocatechin gallate prevented damage to osteocyte precursors and averted differentiation into undesirable adipocytes. Genistein facilitated osteogenesis while preventing adipogenesis. Several other polyphenols, daidzein, caffeic and chlorogenic acid, kaempferol, and piceatannol, protect stems cells from reactive oxygen species and foster stem cells differentiation away from adipocytic and toward osteocytic lineages. Further research should better elucidate the pharmacokinetic profiles of each polyphenol, explore novel delivery systems, and expand investigation beyond rodent models to additional species.

Autophagy is a process the primary role of which is to clear up damaged cellular components such as long-lived proteins and organelles, thus participating in the conservation of different cells. Osteoporosis associated with aging is characterized by consistent changes in bone metabolism with suppression of bone formation as well as increased bone resorption. In advanced age, not only bone mass but also bone strength decrease in both sexes, resulting in an increased incidence of fractures. Clinical and animal experiments reveal that age-related bone loss is associated with many factors such as accumulation of autophagy, increased levels of reactive oxygen species, sex hormone deficiency, and high levels of endogenous glucocorticoids. Available basic and clinical studies indicate that age-associated factors can regulate autophagy. Those factors play important roles in bone remodeling and contribute to decreased bone mass and bone strength with aging. In this review, we summarize the mechanisms involved in bone metabolism related to aging and autophagy, supplying a theory for therapeutic targets to rescue bone mass and bone strength in older people.