The Long Pentraxin PTX3 as a New Biomarker and Pharmacological Target in Age-Related Macular Degeneration and Diabetic Retinopathy

Age related macular degeneration (AMD) and diabetic retinopathy (DR) are multifactorial, neurodegenerative and inflammatory diseases of the eye primarily involving cellular and molecular components of the outer and inner blood-retina barriers (BRB), respectively. Largely contributed by genetic factors, particularly polymorphisms in complement genes, AMD is a paradigm of retinal immune dysregulation. DR, a major complication of diabetes mellitus, typically presents with increased vascular permeability and occlusion of the retinal vasculature that leads, in the proliferative form of the disease, to neovascularization, a pathogenic trait shared with advanced AMD. In spite of distinct etiology and clinical manifestations, both pathologies share common drivers, such as chronic inflammation, either of immune (in AMD) or metabolic (in DR) origin, which initiates and propagates degeneration of the neural retina, yet the underlying mechanisms are still unclear. As a soluble pattern recognition molecule with complement regulatory functions and a marker of vascular damage, long pentraxin 3 (PTX3) is emerging as a novel player in ocular homeostasis and a potential pharmacological target in neurodegenerative disorders of the retina. Physiologically present in the human eye and induced in inflammatory conditions, this protein is strategically positioned at the BRB interface, where it acts as a “molecular trap” for complement, and modulates inflammation both in homeostatic and pathological conditions. Here, we discuss current viewpoints on PTX3 and retinal diseases, with a focus on AMD and DR, the roles therein proposed for this pentraxin, and their implications for the development of new therapeutic strategies.

Lipid droplets associated perilipins protein insights into finding a therapeutic target approach to cure non-alcoholic fatty liver disease (NAFLD)

Background Non-alcoholic fatty liver disease (NAFLD) is now the most common form of chronic liver disease in the world, and it’s linked to a slew of other risk factors including diabetes, obesity, dysbiosis and inflammatory bowel disease. More than 30 years ago, a patient was diagnosed with fatty liver with excessive fat accumulation in hepatocytes, a disorder known as hepatosteatosis. There will be no promising therapeutic medicines available from 1980 to 2021 which can reverse the fatty liver to normal liver state. In this review, we highlighted on lipid droplet associated protein which play a major role in accumulation of fat in liver cells and how these cellular pathway could be a promising therapeutic approach to treat the fatty liver disease. Main body Over the last few decades, Western countries follow a high-fat diet and change their lifestyle pattern due to certain metabolic disorders prevalence rate is very high all over the world. NAFLD is a major health issue and burden globally nowadays. Researchers are trying to find out the potential therapeutic target to combat the disease. The exact pathophysiology of the disease is still unclear. In the present decades. There is no Food and Drug Administration approved drugs are available to reverse the chronic condition of the disease. Based on literature survey, lipid droplets and their associated protein like perilipins play an eminent role in body fat regulation. In this review, we explain all types of perilipins such as perilipin1-5 (PLIN1-5) and their role in the pathogenesis of fatty liver which will be helpful to find the novel pharmacological target to treat the fatty liver. Conclusion In this review, majorly focussed on how fat is get deposited into hepatocytes follow the cellular signalling involved during lipid droplet biogenesis and leads to NAFLD. However, up to date still there mechanism of action is unclear. In this review, we hypothesized that lipid droplets associated proteins like perilipins could be better pharmacological target to reverse the chronic stage of fatty liver disease and how these lipid droplets associated proteins hide a clue to maintain the normal lipid homeostasis in the human body.

Unexpected scaffold rearrangement product of pirenzepine found in commercial samples

Pharmacovigilance aims at a better understanding of the molecular events triggered by medications to prevent adverse effects, which despite significant advances in our analytical repertoire plague the use of drugs until today. In this study, we find that clinically prescribed and commercially available pirenzepine may not be the correct compound. Pirenzepine can undergo an unexpected scaffold rearrangement from the pharmaceutical active ingredient (API) to a previously uncharacterized benzimidazole. The rearrangement occurs under highly acidic conditions, which were believed to favour the dihydrochloride formation of pirenzepine. The rearranged products of pirenzepine and the structurally related telenzepine have significantly decreased affinity for the muscarinic acetylcholine receptor, the pharmacological target of these compounds. Fortunately, in situ rearrangement after oral application is no safety issue, as we show that reaction kinetics in gastric acid prevent rearrangement. The research community should consider appropriate measures to perform reliable receiving inspections in the commercial supply of well described and frequently used chemicals, in particular if experiments yield unexpected results.

Alternative RAS in Various Hypoxic Conditions: From Myocardial Infarction to COVID-19

Alternative branches of the classical renin–angiotensin–aldosterone system (RAS) represent an important cascade in which angiotensin 2 (AngII) undergoes cleavage via the action of the angiotensin-converting enzyme 2 (ACE2) with subsequent production of Ang(1-7) and other related metabolites eliciting its effects via Mas receptor activation. Generally, this branch of the RAS system is described as its non-canonical alternative arm with counterbalancing actions to the classical RAS, conveying vasodilation, anti-inflammatory, anti-remodeling and anti-proliferative effects. The implication of this branch was proposed for many different diseases, ranging from acute cardiovascular conditions, through chronic respiratory diseases to cancer, nonetheless, hypoxia is one of the most prominent common factors discussed in conjugation with the changes in the activity of alternative RAS branches. The aim of this review is to bring complex insights into the mechanisms behind the various forms of hypoxic insults on the activity of alternative RAS branches based on the different duration of stimuli and causes (acute vs. intermittent vs. chronic), localization and tissue (heart vs. vessels vs. lungs) and clinical relevance of studied phenomenon (experimental vs. clinical condition). Moreover, we provide novel insights into the future strategies utilizing the alternative RAS as a diagnostic tool as well as a promising pharmacological target in serious hypoxia-associated cardiovascular and cardiopulmonary diseases.

TFEB Dependent Autophagy-Lysosomal Pathway: An Emerging Pharmacological Target in Sepsis

Sepsis is a life-threatening syndrome induced by aberrant host response towards infection. The autophagy-lysosomal pathway (ALP) plays a fundamental role in maintaining cellular homeostasis and conferring organ protection. However, this pathway is often impaired in sepsis, resulting in dysregulated host response and organ dysfunction. Transcription factor EB (TFEB) is a master modulator of the ALP. TFEB promotes both autophagy and lysosomal biogenesis via transcriptional regulation of target genes bearing the coordinated lysosomal expression and regulation (CLEAR) motif. Recently, increasing evidences have linked TFEB and the TFEB dependent ALP with pathogenetic mechanisms and therapeutic implications in sepsis. Therefore, this review describes the existed knowledge about the mechanisms of TFEB activation in regulating the ALP and the evidences of their protection against sepsis, such as immune modulation and organ protection. In addition, TFEB activators with diversified pharmacological targets are summarized, along with recent advances of their potential therapeutic applications in treating sepsis.