Targeting epidermal growth factor receptor and its downstream signaling pathways by natural products: A mechanistic insight.

The epidermal growth factor receptor (EGFR) is a transmembrane receptor tyrosine kinase (RTK) that maintains normal tissues and cell signaling pathways. EGFR is overactivated and overexpressed in many malignancies, including breast, lung, pancreatic, and kidney. Further, the EGFR gene mutations and protein overexpression activate downstream signaling pathways in cancerous cells, stimulating the growth, survival, resistance to apoptosis, and progression of tumors. Anti-EGFR therapy is the potential approach for treating malignancies and has demonstrated clinical success in treating specific cancers. The recent report suggests most of the clinically used EGFR tyrosine kinase inhibitors developed resistance to the cancer cells. This perspective provides a brief overview of EGFR and its implications in cancer. We have summarized natural products-derived anticancer compounds with the mechanistic basis of tumor inhibition via the EGFR pathway. We propose that developing natural lead molecules into new anticancer agents has a bright future after clinical investigation.

Fluorescent Turn-On Anthracene-Based Aluminum(III) Sensor for a Therapeutic Study in Alzheimer's Disease Model of Drosophila.

A new anthracene-based probe (E)-N'-(1-(anthracen-9-yl)ethylidene)-2-hydroxybenzohydrazide (AHB) has been efficiently synthesized and characterized by various spectroscopic methods. It exhibits extremely selective and sensitive fluorometric sensing of Al3+ ions with a large enhancement in the fluorescent intensity due to the restricted photoinduced electron transfer (PET) mechanism with a chelation-enhanced fluorescence (CHEF) effect. The AHB-Al3+ complex shows a remarkably low limit of detection at 0.498 nM. The binding mechanism has been proposed based on Job's plot, 1H NMR titration, Fourier transform infrared (FT-IR), high-resolution mass spectrometry (HRMS), and density functional theory (DFT) studies. The chemosensor is reusable and reversible in the presence of ctDNA. The practical usability of the fluorosensor has been established by a test strip kit. Further, the therapeutic potential of AHB against Al3+ ion-induced tau protein toxicity has been tested in the eye of Alzheimer's disease (AD) model of Drosophila via metal chelation therapy. AHB shows great therapeutic potential with 53.3% rescue in the eye phenotype. The in vivo interaction study of AHB with Al3+ in the gut tissue of Drosophila confirms its sensing efficiency in the biological environment. A detailed comparison table included evaluates the effectiveness of AHB.

Epigenetics in NAFLD/NASH: Targets and therapy.

Recently non-alcoholic fatty liver disease (NAFLD) has grabbed considerable scientific attention, owing to its rapid increase in prevalence worldwide and growing burden on end-stage liver diseases. Metabolic syndrome including obesity, diabetes, and hypertension poses a grave risk to NAFLD etiology and progression. With no drugs available, the mainstay of NAFLD management remains lifestyle changes with exercise and dietary modifications. Nonselective drugs such as metformin, thiazolidinediones (TZDs), ursodeoxycholic acid (UDCA), silymarin, etc., are also being used to target the interrelated pathways for treating NAFLD. Considering the enormous disease burden and the unmet need for drugs, fresh insights into pathogenesis and drug discovery are required. The emergence of the field of epigenetics offers a convincing explanation for the basis of lifestyle, environmental, and other risk factors to influence NAFLD pathogenesis. Therefore, understanding these epigenetic modifications to target the primary cause of the disease might prove a rational strategy to prevent the disease and develop novel therapeutic interventions. Apart from describing the role of epigenetics in the pathogenesis of NAFLD as in other reviews, this review additionally provides an elaborate discussion on exploiting the high plasticity of epigenetic modifications in response to environmental cues, for developing novel therapeutics for NAFLD. Besides, this extensive review provides evidence for epigenetic mechanisms utilized by several potential drugs for NAFLD.

Ethnopharmacological and Phytopharmaceutical Evaluation of Prosopis cineraria: An Overview and Future Prospects.

BACKGROUND: Prosopis cineraria (L.) Druce ('khejri') is an important tree that occurs worldwide in arid regions. It has been mentioned in the Indian Ayurvedic system of medicines as having several clinical properties. Different parts of this plant are used in India, Pakistan, Bangladesh, the United Arab Emirates, Saudi Arabia and Iran for treating various ailments such as leprosy, leucoderma, dysentery, asthma, bronchitis, piles, jaundice and muscular tremors. Since all parts of the tree are useful, it is called 'Kalp Taru' or 'Wonder Tree' in India. Phytochemical studies of P. cineraria have underlined the presence of various classes of phytochemicals, such as flavone derivatives (prosogerin A, B, C, D and E), alkaloids (spicigerine and prosophylline), tannins (gallic acid), steroids (stigmasterol, campesterol and sitosterol, etc.), fatty acids and amino acids, etc., that have been obtained from different parts of the plant. METHODS: We undertook a comprehensive, critical and systematic literature survey on ethnomedicinal, phytochemical and pharmacological aspects of P. cineraria. Efforts were made to establish/corroborate the scientific reasons of ethnomedicinal use with the help of published modern studies. RESULTS: Based on in-depth analysis of more than 200 studies, we were able to corroborate a large number of facts pertaining to uses of different parts of this plant for treating various maladies. Further, it yielded several new insights on phyto-pharmacological aspects of P. cineraria. CONCLUSION: Results of this study are useful for commercialization of the products derived from phytochemicals of P. cineraria.

The Geometry of Plasticity-Induced Sensitization in Isoinhibitory Rate Motifs.

A well-known phenomenon in sensory perception is desensitization, wherein behavioral responses to persistent stimuli become attenuated over time. In this letter, our focus is on studying mechanisms through which desensitization may be mediated at the network level and, specifically, how sensitivity changes arise as a function of long-term plasticity. Our principal object of study is a generic isoinhibitory motif: a small excitatory-inhibitory network with recurrent inhibition. Such a motif is of interest due to its overrepresentation in laminar sensory network architectures. Here, we introduce a sensitivity analysis derived from control theory in which we characterize the fixed-energy reachable set of the motif. This set describes the regions of the phase-space that are more easily (in terms of stimulus energy) accessed, thus providing a holistic assessment of sensitivity. We specifically focus on how the geometry of this set changes due to repetitive application of a persistent stimulus. We find that for certain motif dynamics, this geometry contracts along the stimulus orientation while expanding in orthogonal directions. In other words, the motif not only desensitizes to the persistent input, but heightens its responsiveness (sensitizes) to those that are orthogonal. We develop a perturbation analysis that links this sensitization to both plasticity-induced changes in synaptic weights and the intrinsic dynamics of the network, highlighting that the effect is not purely due to weight-dependent disinhibition. Instead, this effect depends on the relative neuronal time constants and the consequent stimulus-induced drift that arises in the motif phase-space. For tightly distributed (but random) parameter ranges, sensitization is quite generic and manifests in larger recurrent E-I networks within which the motif is embedded.