scholarly journals Molecular and Cellular Heterogeneity in Rheumatoid Arthritis: Mechanisms and Clinical Implications

2021 ◽  
Vol 12 ◽  
Author(s):  
Jianan Zhao ◽  
Shicheng Guo ◽  
Steven J. Schrodi ◽  
Dongyi He
Keyword(s):  
Rheumatoid Arthritis ◽  
Molecular Mechanisms ◽  
Clinical Care ◽  
Treatment Options ◽  
Cellular Heterogeneity ◽  
Clinical Effects ◽  
Cytokine Inhibitors ◽  
Monocyte Cell ◽  
Inflammatory Drugs

Rheumatoid arthritis is an autoimmune disease that exhibits significant clinical heterogeneity. There are various treatments for rheumatoid arthritis, including disease-modifying anti-rheumatic drugs (DMARDs), glucocorticoids, non-steroidal anti-inflammatory drugs (NSAIDs), and inflammatory cytokine inhibitors (ICI), typically associated with differentiated clinical effects and characteristics. Personalized responsiveness is observed to the standard treatment due to the pathophysiological heterogeneity in rheumatoid arthritis, resulting in an overall poor prognosis. Understanding the role of individual variation in cellular and molecular mechanisms related to rheumatoid arthritis will considerably improve clinical care and patient outcomes. In this review, we discuss the source of pathophysiological heterogeneity derived from genetic, molecular, and cellular heterogeneity and their possible impact on precision medicine and personalized treatment of rheumatoid arthritis. We provide emphasized description of the heterogeneity derived from mast cells, monocyte cell, macrophage fibroblast-like synoviocytes and, interactions within immune cells and with inflammatory cytokines, as well as the potential as a new therapeutic target to develop a novel treatment approach. Finally, we summarize the latest clinical trials of treatment options for rheumatoid arthritis and provide a suggestive framework for implementing preclinical and clinical experimental results into clinical practice.

scholarly journals Cellular and mitochondrial mechanisms of atrial fibrillation

2020 ◽  
Vol 115 (6) ◽  
Author(s):  
Fleur E. Mason ◽  
Julius Ryan D. Pronto ◽  
Khaled Alhussini ◽  
Christoph Maack ◽  
Niels Voigt
Keyword(s):  
Atrial Fibrillation ◽  
Nicotinamide Adenine Dinucleotide ◽  
Molecular Mechanisms ◽  
Treatment Options ◽  
Specific Treatment ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Nicotinamide Adenine ◽  
Mitochondrial Activity ◽  
Atp Production

AbstractThe molecular mechanisms underlying atrial fibrillation (AF), the most common form of arrhythmia, are poorly understood and therefore target-specific treatment options remain an unmet clinical need. Excitation–contraction coupling in cardiac myocytes requires high amounts of adenosine triphosphate (ATP), which is replenished by oxidative phosphorylation in mitochondria. Calcium (Ca2+) is a key regulator of mitochondrial function by stimulating the Krebs cycle, which produces nicotinamide adenine dinucleotide for ATP production at the electron transport chain and nicotinamide adenine dinucleotide phosphate for the elimination of reactive oxygen species (ROS). While it is now well established that mitochondrial dysfunction plays an important role in the pathophysiology of heart failure, this has been less investigated in atrial myocytes in AF. Considering the high prevalence of AF, investigating the role of mitochondria in this disease may guide the path towards new therapeutic targets. In this review, we discuss the importance of mitochondrial Ca2+ handling in regulating ATP production and mitochondrial ROS emission and how alterations, particularly in these aspects of mitochondrial activity, may play a role in AF. In addition to describing research advances, we highlight areas in which further studies are required to elucidate the role of mitochondria in AF.

scholarly journals Circadian Rhythms, the Mesolimbic Dopaminergic Circuit, and Drug Addiction

2007 ◽  
Vol 7 ◽  
pp. 194-202 ◽  
Author(s):  
Colleen A. McClung
Keyword(s):  
Circadian Rhythms ◽  
Drug Addiction ◽  
Molecular Mechanisms ◽  
Dopaminergic System ◽  
Treatment Options ◽  
Drug Induced ◽  
Circadian Genes ◽  
Dopaminergic Transmission ◽  
Central Pacemaker

Drug addiction is a devastating disease that affects millions of individuals worldwide. Through better understanding of the genetic variations that create a vulnerability for addiction and the molecular mechanisms that underlie the progression of addiction, better treatment options can be created for those that suffer from this condition. Recent studies point to a link between abnormal or disrupted circadian rhythms and the development of addiction. In addition, studies suggest a role for specific genes that make up the molecular clock in the regulation of drug sensitivity, sensitization, and reward. The influence of circadian genes and rhythms on drug-induced behaviors may be mediated through the mesolimbic dopaminergic system. This system has long been implicated in the development of addiction, and recent evidence supports a regulatory role for the brain's central pacemaker and circadian gene expression in the regulation of dopaminergic transmission. This review highlights the association between circadian genes and drug addiction, and the possible role of the mesolimbic dopaminergic system in this association.

scholarly journals Natural Compounds in Sex Hormone-Dependent Cancers: The Role of Triterpenes as Therapeutic Agents

2021 ◽  
Vol 11 ◽  
Author(s):  
Codruţa Şoica ◽  
Mirela Voicu ◽  
Roxana Ghiulai ◽  
Cristina Dehelean ◽  
Roxana Racoviceanu ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Therapeutic Potential ◽  
Treatment Options ◽  
Active Role ◽  
Structural Features ◽  
Sex Hormone ◽  
Ongoing Research ◽  
New Treatment ◽  
Highly Correlated

Sex hormone-dependent cancers currently contribute to the high number of cancer-related deaths worldwide. The study and elucidation of the molecular mechanisms underlying the progression of these tumors was a double-edged sword, leading to the expansion and development of new treatment options, with the cost of triggering more aggressive, therapy resistant relapses. The interaction of androgen, estrogen and progesterone hormones with specific receptors (AR, ER, PR) has emerged as a key player in the development and progression of breast, ovarian, prostate and endometrium cancers. Sex hormone-dependent cancers share a common and rather unique carcinogenesis mechanism involving the active role of endogenous and exogenous sex hormones to maintain high mitotic rates and increased cell proliferation thus increasing the probability of aberrant gene occurrence and accumulation highly correlated with abnormal cell division and the occurrence of malignant phenotypes. Cancer related hormone therapy has evolved, currently being associated with the blockade of other signaling pathways often associated with carcinogenesis and tumor progression in cancers, with promising results. However, despite the established developments, there are still several shortcomings to be addressed. Triterpenes are natural occurring secondary metabolites biosynthesized by various pathways starting from squalene cyclization. Due to their versatile therapeutic potential, including the extensively researched antiproliferative effect, these compounds are most definitely a cornerstone in the research and development of new natural/semisynthetic anticancer therapies. The present work thoroughly describes the ongoing research related to the antitumor activity of triterpenes in sex hormone-dependent cancers. Also, the current review highlights both the biological activity of various triterpenoid compounds and their featured mechanisms of action correlated with important chemical structural features.

scholarly journals The Emerging Role of Glucagon-like Peptide-1 Receptor Agonists for the Management of NAFLD

2021 ◽  
Author(s):  
Chandani Patel Chavez ◽  
Kenneth Cusi ◽  
Sushma Kadiyala
Keyword(s):  
Evidence Synthesis ◽  
Clinical Care ◽  
Treatment Options ◽  
Critical Role ◽  
Risk Groups ◽  
The United States ◽  
Multidisciplinary Teams ◽  
Consensus Statements ◽  
Meta Analyses

Abstract Context The burden of cirrhosis from NAFLD is reaching epidemic proportions in the United States. This calls for greater awareness among endocrinologists, who often see but may miss the diagnosis in adults with obesity or type 2 diabetes mellitus (T2D) who are at the highest risk. At the same time, recent studies suggest that GLP-1RAs are beneficial versus steatohepatitis (NASH) in this population. This minireview aims to assist endocrinologists to recognize the condition and recent work on the role of GLP-1RAs in NAFLD/NASH. Evidence acquisition Evidence from observational studies, randomized controlled trials, and meta-analyses. Evidence Synthesis Endocrinologists should lead multidisciplinary teams to implement recent consensus statements on NAFLD that call for screening and treatment of clinically significant fibrosis to prevent cirrhosis, especially in the high-risk groups (i.e., people with obesity, prediabetes or T2D). With no FDA-approved agents, weight loss is central to their successful management, with pharmacological treatment options limited today to vitamin E (in people without T2D) and diabetes medications that reverse steatohepatitis, such as pioglitazone or GLP-1RA. Recently the benefit of GLP-1RAs in NAFLD, suggested from earlier trials, has been confirmed in adults with biopsy-proven NASH. In 2021, the FDA also approved semaglutide for obesity management. Conclusion A paradigm change is developing between the endocrinologist’s greater awareness about their critical role to curve the epidemic of NAFLD and new clinical care pathways that include a broader use of GLP-1RAs in the management of these complex patients.

scholarly journals Role of Enzymes in Causing Neurological Disorders

2021 ◽  
Vol 12 (1) ◽  
pp. 466-476
Author(s):  
Vysakh Visweswaran ◽  
Roshni PR
Keyword(s):  
Neurological Disorders ◽  
Drug Targets ◽  
Molecular Mechanisms ◽  
Neurological Diseases ◽  
Treatment Options ◽  
Direct Result ◽  
Permanent Disability ◽  
Genetic Abnormalities ◽  
Underlying Pathology

Diseases of the nervous system are always associated with poor prognosis and limited treatment options. The fragile nature of the neurons and their inability to replicate means that neurological disorders are associated with a permanent disability. Pharmacotherapy of neurological diseases requires understanding the molecular mechanisms involved in the disease pathology. In most of the cases a faulty cellular biochemical pathway is involved, resulting from a defective enzyme. This article focusses on role of enzymes in various neurological disorders. To review pertinent literature and summarise the role of enzymes in the underlying pathology of various neurological disorders. A comprehensive literature search was conducted using PubMed, SCOPUS, J-GATE and Google Scholar and relevant papers were collected using the keywords enzymes, Alzheimer's disease, redox, thiamine, depression, neurotransmitters, epileptogenesis. The literature review highlighted the role of enzymes in major neurological disorders and their potential to be used as drug targets and biomarkers. Identifying defective enzymes gives us new molecular targets to focus on for developing more effective pharmacotherapeutic options. They can be also considered as potential biomarkers. An abnormal enzyme is most often a direct result of an underlying genetic abnormality. Identifying and screening for these genetic abnormalities can be used in early identification and prevention of disease in individuals who have a genetic predisposition. The modern advances in genetic engineering shows a lot of promise in correcting these abnormalities and development of revolutionary cures although ethical concerns remain. 

scholarly journals Emerging roles of the Hedgehog signalling pathway in inflammatory bowel disease

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Zhuo Xie ◽  
Mudan Zhang ◽  
Gaoshi Zhou ◽  
Lihui Lin ◽  
Jing Han ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Bowel Disease ◽  
Molecular Mechanisms ◽  
Treatment Options ◽  
Critical Role ◽  
Signalling Pathway ◽  
Hedgehog Signalling Pathway ◽  
Inflammatory Bowel ◽  
Effective Drugs

AbstractThe Hedgehog (Hh) signalling pathway plays a critical role in the growth and patterning during embryonic development and maintenance of adult tissue homeostasis. Emerging data indicate that Hh signalling is implicated in the pathogenesis of inflammatory bowel disease (IBD). Current therapeutic treatments for IBD require optimisation, and novel effective drugs are warranted. Targeting the Hh signalling pathway may pave the way for successful IBD treatment. In this review, we introduce the molecular mechanisms underlying the Hh signalling pathway and its role in maintaining intestinal homeostasis. Then, we present interactions between the Hh signalling and other pathways involved in IBD and colitis-associated colorectal cancer (CAC), such as the Wnt and nuclear factor-kappa B (NF-κB) pathways. Furthermore, we summarise the latest research on Hh signalling associated with the occurrence and progression of IBD and CAC. Finally, we discuss the future directions for research on the role of Hh signalling in IBD pathogenesis and provide viewpoints on novel treatment options for IBD by targeting Hh signalling. An in-depth understanding of the complex role of Hh signalling in IBD pathogenesis will contribute to the development of new effective therapies for IBD patients.

scholarly journals Systems Biology and Kidney Disease

2020 ◽  
Vol 15 (5) ◽  
pp. 695-703 ◽  
Author(s):  
Jennifer A. Schaub ◽  
Habib Hamidi ◽  
Lalita Subramanian ◽  
Matthias Kretzler
Keyword(s):  
Systems Biology ◽  
Molecular Mechanisms ◽  
Kidney Diseases ◽  
Clinical Care ◽  
Treatment Options ◽  
Cell Types ◽  
Current State ◽  
Health And Disease ◽  
National Databases ◽  
Different Cell Types

The kidney is a complex organ responsible for maintaining multiple aspects of homeostasis in the human body. The combination of distinct, yet interrelated, molecular functions across different cell types make the delineation of factors associated with loss or decline in kidney function challenging. Consequently, there has been a paucity of new diagnostic markers and treatment options becoming available to clinicians and patients in managing kidney diseases. A systems biology approach to understanding the kidney leverages recent advances in computational technology and methods to integrate diverse sets of data. It has the potential to unravel the interplay of multiple genes, proteins, and molecular mechanisms that drive key functions in kidney health and disease. The emergence of large, detailed, multilevel biologic and clinical data from national databases, cohort studies, and trials now provide the critical pieces needed for meaningful application of systems biology approaches in nephrology. The purpose of this review is to provide an overview of the current state in the evolution of the field. Recent successes of systems biology to identify targeted therapies linked to mechanistic biomarkers in the kidney are described to emphasize the relevance to clinical care and the outlook for improving outcomes for patients with kidney diseases.

Defining the role of glucocorticoids in inflammation

2018 ◽  
Vol 132 (14) ◽  
pp. 1529-1543 ◽  
Author(s):  
Simona Ronchetti ◽  
Graziella Migliorati ◽  
Stefano Bruscoli ◽  
Carlo Riccardi
Keyword(s):  
Clinical Practice ◽  
Side Effects ◽  
Adverse Effects ◽  
Molecular Mechanisms ◽  
Molecular Targets ◽  
Great Promise ◽  
Body Of Knowledge ◽  
Inflammatory Drugs ◽  
Anti Inflammatory

An established body of knowledge and clinical practice has argued in favor of the use of glucocorticoids in various chronic inflammatory and autoimmune diseases. However, the very well-known adverse effects associated with their treatment hampers continuation of therapy with glucocorticoids. Analyses of the molecular mechanisms underlying the actions of glucocorticoids have led to the discovery of several mediators that add complexity and diversity to the puzzling world of these hormones and anti-inflammatory drugs. Such mediators hold great promise as alternative pharmacologic tools to be used as anti-inflammatory drugs with the same properties as glucocorticoids, but avoiding their metabolic side effects. This review summarizes findings about the molecular targets and mediators of glucocorticoid function.

scholarly journals TNS1- ALK Fusion in a Recurrent, Metastatic Uterine Mesenchymal Tumor Originally Diagnosed as Leiomyosarcoma

2019 ◽  
Vol 48 (1) ◽  
pp. 116
Author(s):  
Jessica Lee ◽  
Arun Singh ◽  
Siraj M. Ali ◽  
Douglas I. Lin ◽  
Samuel J. Klempner
Keyword(s):  
Clinical Care ◽  
Treatment Options ◽  
Standard Of Care ◽  
Genomic Profiling ◽  
Curative Intent ◽  
Case Identification ◽  
Complementary Role ◽  
Comprehensive Genomic Profiling ◽  
Standard Of Care Treatment

<p><strong>Objective.</strong> We report a female patient diagnosed with a leiomyosarcoma and who harbored a druggable target as identified by comprehensive genomic profiling in the course of clinical care.</p><p><strong>Case Report.</strong> The patient progressed five years after curative intent surgery and adjuvant treatment. After failure of multiple lines of chemotherapy,she was enrolled in a trial of an ALK inhibitor based on comprehensive genomic profiling (CGP) identifying an TNS1-ALK fusion.</p><p><strong>Conclusion. </strong>In this case, identification of the ALK kinase fusion permitted enrollment in a matched mechanism driven clinical trial after exhausting standard of care treatment options. CGP raises the possibility of uterine inflammatory myofibroblastic tumor as an alternative diagnosisto leiomyosarcoma, highlighting the complementary role of CGP beyond immunohistochemical analyses.</p>

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