Current Drug Targets - Volume 20, Issue 12, 2019

Background: Phosphoinositide 3-kinase (PI3Ks) is a member of intracellular lipid kinases and involved in the regulation of cellular proliferation, differentiation and survival. Overexpression of the PI3K/Akt/mTOR signalling has been reported in various forms of cancers, especially in colorectal cancers (CRC). Due to their significant roles in the initiation and progression events of colorectal cancer, they are recognized as a striking therapeutic target. Objective: The present review is aimed to provide a detailed outline on the role of PI3K/Akt/mTOR pathway in the initiation and progression events of colorectal cancers as well as its function in drug resistance. Further, the role of PI3K/Akt/mTOR inhibitors alone and in combination with other chemotherapeutic drugs, in alleviating colorectal cancer is also discussed. The review contains preclinical and clinical evidence as well as patent literature of the pathway inhibitors which are natural and synthetic in origin. Methods: The data were obtained from PubMed/Medline databases, Scopus and Google patent literature. Results: PI3K/Akt/mTOR signalling is an important event in colorectal carcinogenesis. In addition, it plays significant roles in acquiring drug resistance as well as metastatic initiation events of CRCs. Several small molecules of natural and synthetic origin have been found to be potent inhibitors of CRCs by effectively downregulating the pathway. Data from various clinical studies also support these pathway inhibitors and several among them are patented. Conclusion: Inhibitors of the PI3K/mTOR pathway have been successful for the treatment of primary and metastatic colorectal cancers, rendering the pathway as a promising clinical cancer therapeutic target.

Cancer is the second leading cause of morbidity and mortality worldwide. Although chemotherapy and radiotherapy enhance the survival rate of cancerous patients but they have several acute toxic effects. Therefore, there is a need to search for new anticancer agents having better efficacy and lesser side effects. In this regard, herbal treatment is found to be a safe method for treating and preventing cancer. Here, an attempt has been made to screen some less explored medicinal plants like Ammania baccifera, Asclepias curassavica, Azadarichta indica, Butea monosperma, Croton tiglium, Hedera nepalensis, Jatropha curcas, Momordica charantia, Moringa oleifera, Psidium guajava, etc. having potent anticancer activity with minimum cytotoxic value (IC50 >3μM) and lesser or negligible toxicity. They are rich in active phytochemicals with a wide range of drug targets. In this study, these medicinal plants were evaluated for dose-dependent cytotoxicological studies via in vitro MTT assay and in vivo tumor models along with some more plants which are reported to have IC50 value in the range of 0.019-0.528 mg/ml. The findings indicate that these plants inhibit tumor growth by their antiproliferative, pro-apoptotic, anti-metastatic and anti-angiogenic molecular targets. They are widely used because of their easy availability, affordable price and having no or sometimes minimal side effects. This review provides a baseline for the discovery of anticancer drugs from medicinal plants having minimum cytotoxic value with minimal side effects and establishment of their analogues for the welfare of mankind.

Medical chronobiology deals with the way body’s rhythm influences a person’s health and disease states. To match body rhythms, deliberate alteration of drug concentration is done to optimize therapeutic outcomes and minimize size effects and this approach is known as Chronotherapeutics. In general the concept of homeostasis has been the base for the treatment of diseases. Little importance has been given in understanding biologic rhythms and their underlying mechanisms. Designing of cardiovascular drug is done to achieve a constant or near-constant effect throughout the 24-hour with the prescribed dose. However in many cases, medication requirement during night and day time are not the same. Body rhythms may have profound effect on the treatment outcomes. It is a wrongful approach to assume that a drug dosed in the morning or evening will have the same antihypertensive effect. The vast literature record of circadian variations in Blood Pressure (BP), heart rate, hormone secretion, and platelet aggregation are examples of the impact of chronobiology. In this study we analyze the effect of circadian pattern of blood pressure on action of various antihypertensives and investigate the perspective of chronotherapeutics- whether it is a fruitful approach and rationalize its utility in the treatment of hypertension.

Nanotechnology has emerged as one of the leading research areas involving nanoscale manipulation of atoms and molecules. During the past decade, the growth of nanotechnology has been one of the most important developments that have taken place in the biomedical field. The new generation nanomaterials like Quantum dots are gaining much importance. Also, there is a growing interest in the development of nano-theranostics platforms in medical diagnostics, biomedical imaging, drug delivery, etc. Quantum dots are also known as nanoscale semiconductor crystals, with unique electronic and optical properties. Recently, silicon quantum dots are being studied extensively due to their less-toxic, inert nature and ease of surface modification. The silicon quantum dots (2-10nm) are comparatively stable, having optical properties of silicon nanocrystals. This review focuses on silicon quantum dots and their various biomedical applications like drug delivery regenerative medicine and tissue engineering. Also, the processes involved in their modification for various biomedical applications along with future aspects are discussed.

Metabolic Syndrome (MetS) involves a cluster of five conditions, i.e. obesity, hyperglycaemia, hypertension, hypertriglyceridemia and low High-Density Lipoprotein (HDL) cholesterol. All components of MetS share an underlying chronic inflammatory aetiology, manifested by increased levels of pro-inflammatory cytokines. The pathogenic role of inflammation in the development of MetS suggested that toll-like receptor (TLR) activation may trigger MetS. This review summarises the supporting evidence on the interactions between MetS and TLR activation, bridged by the elevation of TLR ligands during MetS. The regulatory circuits mediated by TLR activation, which modulates signal propagation, leading to the state of chronic inflammation, are also discussed. Taken together, TLR activation could be the molecular basis in the development of MetS-induced inflammation.

Intense research interests have been observed in establishing PPAR gamma as a therapeutic target for diabetes. However, PPARγ is also emerging as an important therapeutic target for varied disease states other than type 2 diabetes like neurodegenerative disorders, cancer, spinal cord injury, asthma, and cardiovascular problems. Furthermore, glitazones, the synthetic thiazolidinediones, also known as insulin sensitizers, are the largely studied PPARγ agonists and the only ones approved for the treatment of type 2 diabetes. However, they are loaded with side effects like fluid retention, obesity, hepatic failure, bone fractures, and cardiac failure; which restrict their clinical application. Medicinal plants used traditionally are the sources of bioactive compounds to be used for the development of successful drugs and many structurally diverse natural molecules are already established as PPARγ agonists. These natural partial agonists when compared to full agonist synthetic thiazolidinediones led to weaker PPARγ activation with lesser side effects but are not thoroughly investigated. Their thorough characterization and elucidation of mechanistic activity might prove beneficial for counteracting diseases by modulating PPARγ activity through dietary changes. We aim to review the therapeutic significance of PPARγ for ailments other than diabetes and highlight natural molecules with potential PPARγ agonistic activity.

Background: Human African Trypanosomiasis (HAT), also known as sleeping sickness is one of the 20 neglected tropical diseases listed by the World Health Organization, which lead to death if left untreated. This disease is caused by Trypanosoma brucei gambiense, which is the chronic form of the disease present in western and central Africa, and by T. brucei rhodesiense, which is the acute form of the disease located in eastern and southern Africa. Many reports have highlighted the effectiveness of flavonoid-based compounds against T. brucei. Objective: The present review summarizes the current standings and perspectives for the use of flavonoids as lead compounds for the potential treatment of HAT. Methods: A literature search was conducted for naturally occurring and synthetic anti-T brucei flavonoids by referencing textbooks and scientific databases (SciFinder, PubMed, Science Direct, Wiley, ACS, SciELO, Google Scholar, Springer, among others) from their inception until February 2019. Results: Flavonoids isolated from different parts of plants and species were reported to exhibit moderate to high in vitro antitrypanosomal activity against T. brucei. In addition, synthetic flavonoids revealed anti-T. brucei activity. Molecular interactions of bioactive flavonoids with T. brucei protein targets showed promising results. Conclusion: According to in vitro anti-T brucei studies, there is evidence that flavonoids might be lead compounds for the potential treatment of HAT. However, toxicological studies, as well as the mechanism of action of the in vitro active flavonoids are needed to support their use as potential leads for the treatment of HAT.