Skinnerscarborough6082

The complex computations of the brain require a constant supply of blood flow to meet its immense metabolic needs. Perturbations in blood supply, even in the smallest vascular networks, can have a profound effect on neuronal function and cognition. Type 1 diabetes is a prevalent and insidious metabolic disorder that progressively and heterogeneously disrupts vascular signalling and function in the brain. As a result, it is associated with an array of adverse vascular changes such as impaired regulation of vascular tone, pathological neovascularization and vasoregression, capillary plugging and blood brain barrier disruption. In this review, we highlight the link between microvascular dysfunction and cognitive impairment that is commonly associated with type 1 diabetes, with the aim of synthesizing current knowledge in this field.Gulf War Illness (GWI) is a chronic multisymptomatic disorder that afflicts over 1/3rd of the 1991 GW veterans. It spans multiple bodily systems and presents itself as a syndrome exhibiting diverse symptoms including fatigue, depression, mood, and memory and concentration deficits, musculoskeletal pain and gastrointestinal distress in GW veterans. The etiology of GWI is complex and many factors, including chemical, physiological, and environmental stressors present in the GW arena, have been implicated for its development. It has been over 30 years since the end of the GW but, GWI has been persistent in suffering veterans who are also dealing with paucity of effective treatments. The multifactorial aspect of GWI along with genetic heterogeneity and lack of available data surrounding war-time exposures have proved to be challenging in developing pre-clinical models of GWI. Despite this, over a dozen GWI animal models exist in the literature. In this article, following a brief discussion of GW history, GWI defibit biological complexity reflective of the clinical presentation in GWI, animal models have been critical for identifying molecular underpinnings of GWI and evaluating treatment strategies for GWI.Glioma is one of the most common and lethal brain tumors. Surgical resection followed by radiotherapy plus chemotherapy is the current standard of care for patients with glioma. The existence of resistance to genotoxic therapy, as well as the nature of tumor heterogeneity greatly limits the efficacy of glioma therapy. DNA damage repair pathways play essential roles in many aspects of glioma biology such as cancer progression, therapy resistance, and tumor relapse. O6-methylguanine-DNA methyltransferase (MGMT) repairs the cytotoxic DNA lesion generated by temozolomide (TMZ), considered as the main mechanism of drug resistance. In addition, mismatch repair, base excision repair, and homologous recombination DNA repair also play pivotal roles in treatment resistance as well. Furthermore, cellular mechanisms, such as cancer stem cells, evasion from apoptosis, and metabolic reprogramming, also contribute to TMZ resistance in gliomas. Investigations over the past two decades have revealed comprehensive mechanisms of glioma therapy resistance, which has led to the development of novel therapeutic strategies and targeting molecules.The gabapentinoid drugs, gabapentin and pregabalin, are first-line treatments for neuropathic pain. The epidemics of chronic pain and opioid misuse have given rise to the widespread use of non-opioid drugs such as the gabapentinoids for treatment. Unfortunately, the widespread use of gabapentinoid drugs has resulted in reports of misuse and abuse. Here we summarize the clinical reports of gabapentinoid abuse in different patient populations to help inform clinical practice of chronic pain management.Psoriasis, psoriatic arthritis, and axial spondyloarthritis are systemic inflammatory diseases, each commonly manifesting as a spectrum of symptoms, complications, and comorbidities that arise differently in individual patients. Drugs targeting inflammatory cytokines common to the pathogenesis of each of these conditions have been developed, although their specific actions in the different tissues involved are variable. For a drug to be effective, it must be efficiently delivered to and locally bioactive in disease-relevant tissues. Detailed clinical data shed light on the therapeutic effects of individual biologics on specific domains or clinical manifestations of disease and assist in guiding treatment decisions. Pharmacologic, molecular, and functional properties of drugs strongly impact their observed safety and efficacy, and an understanding of these properties provides complementary insight. Secukinumab, a fully human monoclonal IgG1/κ antibody selectively targeting interleukin (IL)-17A, has been in clinical use for >6 years in the treatment of moderate to severe psoriasis, psoriatic arthritis, and both radiographic (also known as ankylosing spondylitis) and nonradiographic axial spondyloarthritis. In this review, we discuss pharmacokinetic and pharmacodynamic data for secukinumab to introduce clinicians to the pharmacological properties of this widely used drug. Understanding how these properties affect the observed clinical efficacy, safety, and tolerability of this drug in the treatment of IL-17A-mediated systemic inflammatory diseases is important for all physicians treating these conditions.Fibrosis is defined by excessive formation and accumulation of extracellular matrix proteins, produced by myofibroblasts, that supersedes normal wound healing responses to injury and results in progressive architectural remodelling. Fibrosis is often detected in advanced disease stages when an organ is already severely damaged and can no longer function properly. Therefore, there is an urgent need for reliable and easily detectable markers to identify and monitor fibrosis onset and progression as early as possible; this will greatly facilitate the development of novel therapeutic strategies. Osteoprotegerin (OPG), a well-known regulator of bone extracellular matrix and most studied for its role in regulating bone mass, is expressed in various organs and functions as a decoy for receptor activator of nuclear factor kappa-B ligand (RANKL) and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Recently, OPG has been linked to fibrosis and fibrogenesis, and has been included in a panel of markers to diagnose liver fibrosis. Multiple studies now suggest that OPG may be a general biomarker suitable for detection of fibrosis and/or monitoring the impact of fibrosis treatment. This review summarizes our current understanding of the role of OPG in fibrosis and will discuss its potential as a biomarker and/or novel therapeutic target for fibrosis.The accuracy in predicting in vivo hepatic clearance of drugs from in vitro data (often termed as in vitro-to-in vivo extrapolation, IVIVE) has improved in part by applying the extended-clearance concept that considers the interplay between hepatic metabolism and uptake/efflux processes. However, the IVIVE-based prediction performs poorly in predicting the hepatic uptake clearance of highly albumin-bound anionic drugs. Their hepatic uptake clearances tend to be much higher than expected based on the free-drug theory. Such observation can be attributable to a phenomenon called albumin-mediated hepatic uptake, for which various models have been thus far proposed. Our group has been applying a facilitated-dissociation model, which assumes the enhanced dissociation of the drug-albumin complex upon interaction with the cell surface. By considering the albumin-mediated hepatic uptake (using the facilitated-dissociation model or alternative kinetic models), a number of investigations demonstrated the improvement in the prediction accuracy for the hepatic clearance of highly protein-bound anionic drugs that are substrates for hepatic uptake transporters. This review summarizes the reported kinetic analyses of the albumin-mediated hepatic uptake of highly albumin-bound drugs concerning the IVIVE and the clinical and physiological relevance.Antibody-drug conjugates (ADCs) are cancer therapeutic agents comprised of an antibody, a linker and a small-molecule payload. ADCs use the specificity of the antibody to target the toxic payload to tumor cells. After intravenous administration, ADCs enter circulation, distribute to tumor tissues and bind to the tumor surface antigen. The antigen then undergoes endocytosis to internalize the ADC into tumor cells, where it is transported to lysosomes to release the payload. The released toxic payloads can induce apoptosis through DNA damage or microtubule inhibition and can kill surrounding cancer cells through the bystander effect. The first ADC drug was approved by the United States Food and Drug Administration (FDA) in 2000, but the following decade saw no new approved ADC drugs. see more From 2011 to 2018, four ADC drugs were approved, while in 2019 and 2020 five more ADCs entered the market. This demonstrates an increasing trend for the clinical development of ADCs. This review summarizes the recent clinical research, with a specific focus on how the in vivo processing of ADCs influences their design. We aim to provide comprehensive information about current ADCs to facilitate future development.Cell death and the clearance of apoptotic cells are tightly regulated by various signaling molecules in order to maintain physiological tissue function and homeostasis. The phagocytic removal of apoptotic cells is known as the process of efferocytosis, and abnormal efferocytosis is linked to various health complications and diseases, such as cardiovascular disease, inflammatory diseases, and autoimmune diseases. During efferocytosis, phagocytic cells and/or apoptotic cells release signals, such as "find me" and "eat me" signals, to stimulate the phagocytic engulfment of apoptotic cells. Primary phagocytic cells are macrophages and dendritic cells; however, more recently, other neighboring cell types have also been shown to exhibit phagocytic character, including endothelial cells and fibroblasts, although they are comparatively slower in clearing dead cells. In this review, we focus on macrophage efferocytosis of vascular cells, such as endothelial cells, smooth muscle cells, fibroblasts, and pericytes, and its relation to the progression and development of cardiovascular disease. We also highlight the role of efferocytosis-related molecules and their contribution to the maintenance of vascular homeostasis.Initially adopted as a mucolytic about 60 years ago, the cysteine prodrug N-acetylcysteine (NAC) is the standard of care to treat paracetamol intoxication, and is included on the World Health Organization's list of essential medicines. Additionally, NAC increasingly became the epitome of an "antioxidant". Arguably, it is the most widely used "antioxidant" in experimental cell and animal biology, as well as clinical studies. Most investigators use and test NAC with the idea that it prevents or attenuates oxidative stress. Conventionally, it is assumed that NAC acts as (i) a reductant of disulfide bonds, (ii) a scavenger of reactive oxygen species and/or (iii) a precursor for glutathione biosynthesis. While these mechanisms may apply under specific circumstances, they cannot be generalized to explain the effects of NAC in a majority of settings and situations. In most cases the mechanism of action has remained unclear and untested. In this review, we discuss the validity of conventional assumptions and the scope of a newly discovered mechanism of action, namely the conversion of NAC into hydrogen sulfide and sulfane sulfur species.