Pharmacology & Therapeutics最新文献

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by three core impairments: impaired communication, impaired reciprocal social interaction, and restricted, repetitive, and stereotypical behavior patterns. Spectrum refers to the heterogeneity of presentation, severity of symptoms, and medical comorbidities associated with ASD. Among the most common underlying medical conditions are attention-deficit/hyperactivity disorder (ADHD), anxiety, depression, epilepsy, digestive disorders, metabolic disorders, and immune disorders. At present, in the absence of an objective and accurate diagnosis of ASD, such as a blood test, pharmacological management remains a challenge. There are no approved medications to treat the core symptoms of the disorder and behavioral interventions are typically used as first line treatment. Additionally, psychotropic drugs with different mechanisms of action have been approved to reduce associated symptoms and comorbidities, including aripiprazole, risperidone, and haloperidol for irritability and aggression, methylphenidate, atomoxetine, clonidine, and guanfacine for ADHD, and melatonin for sleep disturbances. The purpose of this review is to emphasize that it is imperative to develop objective, personalized diagnostic kits in order to tailor and individualize treatment strategies, as well as to describe the current pharmacological management options available in clinical practice and new prospects that may be helpful in managing ASD's core symptoms.

The pathogenesis of pulmonary fibrosis, including idiopathic pulmonary fibrosis (IPF) and other forms of interstitial lung disease, involves a complex interplay of various factors including host genetics, environmental pollutants, infection, aberrant repair and dysregulated immune responses. Highly variable clinical outcomes of some ILDs, in particular IPF, have made it difficult to identify the precise mechanisms involved in disease pathogenesis and thus the development of a specific cure or treatment to halt and reverse the decline in patient health. With the advent of in-depth molecular diagnostics, it is becoming evident that the pathogenesis of IPF is unlikely to be the same for all patients and therefore will likely require different treatment approaches. Chronic inflammation is a cardinal feature of IPF and is driven by both innate and adaptive immune responses. Inflammatory cells and activated fibroblasts secrete various pro-inflammatory cytokines and chemokines that perpetuate the inflammatory response and contribute to the recruitment and activation of more immune cells and fibroblasts. The balance between pro-inflammatory and regulatory immune cell subsets, as well as the interactions between immune cell types and resident cells within the lung microenvironment, ultimately determines the extent of fibrosis and the potential for resolution. This review examines the role of the innate and adaptive immune responses in pulmonary fibrosis, with an emphasis on IPF. The role of different immune cell types is discussed as well as novel anti-inflammatory and immunotherapy approaches currently in clinical trial or in preclinical development.

Biological responsiveness refers to the capacity of living organisms to adapt to changes in both their internal and external environments through physiological and behavioral mechanisms. One of the prominent aspects of aging is the decline in this responsiveness, which can lead to a deterioration in the processes required for maintenance, survival, and growth. The vital link between physiological responsiveness and the essential life processes lies within the signaling systems. To devise effective strategies for controlling the aging process, a comprehensive reevaluation of this connecting loop is imperative.

This review aims to explore the impact of aging on signaling systems responsible for responsiveness and introduce a novel perspective on intervening in the aging process by restoring the compromised responsiveness. These innovative mechanistic approaches for modulating altered responsiveness hold the potential to illuminate the development of action plans aimed at controlling the aging process and treating age-related disorders.

Upon heterodimerizing with other nuclear receptors, retinoid X receptors (RXR) act as ligand-dependent transcription factors, regulating transcription of critical signaling pathways that impact numerous hallmarks of cancer. By controlling both inflammation and immune responses, ligands that activate RXR can modulate the tumor microenvironment. Several small molecule agonists of these essential receptors have been synthesized. Historically, RXR agonists were tested for inhibition of growth in cancer cells, but more recent drug discovery programs screen new molecules for inhibition of inflammation or activation of immune cells. Bexarotene is the first successful example of an effective therapeutic that molecularly targets RXR; this drug was approved to treat cutaneous T cell lymphoma and is still used as a standard of care treatment for this disease. No additional RXR agonists have yet achieved FDA approval, but several promising novel compounds are being developed. In this review, we provide an overview of the multiple mechanisms by which RXR signaling regulates inflammation and tumor immunity. We also discuss the potential of RXR-dependent immune cell modulation for the treatment or prevention of cancer and concomitant challenges and opportunities.

During carcinogenesis, neoplastic cells accumulate mutations in genes important for cellular homeostasis, producing defective proteins. Viral infections occur when viral capsid proteins bind to the host cell receptor, allowing the virus to enter the cells. In both cases, proteins play important roles in cancer development and viral infection, so these targets can be exploited to develop alternative treatments. mRNA display technology is a very powerful tool for the development of peptides capable of acting on specific targets in neoplastic cells or on viral capsid proteins. mRNA display technology allows the selection and evolution of peptides with desired functional properties from libraries of many nucleic acid variants. Among other advantages of this technology, the use of flexizymes allows the production of peptides with unnatural amino acid residues, which can enhance the activity of these molecules. From target immobilization, peptides with greater specificity for the targets of interest are generated during the selection rounds. Herein, we will explore the use of mRNA display technology for the development of active peptides after successive rounds of selection, using proteins present in neoplastic cells and viral particles as targets.

Boron has become a crucial weapon in anticancer research due to its significant intervention in cell proliferation. Being an excellent bio-isosteric replacement of carbon, it has modulated the anticancer efficacy of various molecules in the development pipeline. It has elicited promising results through interactions with various therapeutic targets such as HIF-1α, steroid sulfatase, arginase, proteasome, etc. Since boron liberates alpha particles, it has a wide-scale application in Boron Neutron Capture therapy (BNCT), a radiotherapy that demonstrates selectivity towards cancer cells due to high boron uptake capacity. Significant advances in the medicinal chemistry of boronated compounds, such as boronated sugars, natural/unnatural amino acids, boronated DNA binders, etc., have been reported over the past few years as BNCT agents. In addition, boronated nanoparticles have assisted the field of bio-nano medicines by their usage in radiotherapy. This review exclusively focuses on the medicinal chemistry aspects, radiotherapeutic, and chemotherapeutic aspects of boron in cancer therapeutics. Emphasis is also given on the mechanism of action along with advantages over conventional therapies.

Epigenetic regulation is a process that takes place through adaptive cellular pathways influenced by environmental factors and metabolic changes to modulate gene activity with heritable phenotypic variations without altering the DNA sequences of many target genes. Epigenetic regulation can be facilitated by diverse mechanisms: many different types of post-translational modifications (PTMs) of histone and non-histone nuclear proteins, DNA methylation, altered levels of noncoding RNAs, incorporation of histone variants, nucleosomal positioning, chromatin remodeling, etc. These factors modulate chromatin structure and stability with or without the involvement of metabolic products, depending on the cellular context of target cells or environmental stimuli, such as intake of alcohol (ethanol) or Western-style high-fat diets. Alterations of epigenetics have been actively studied, since they are frequently associated with multiple disease states. Consequently, explorations of epigenetic regulation have recently shed light on the pathogenesis and progression of alcohol-associated disorders. In this review, we highlight the roles of various types of PTMs, including less-characterized modifications of nuclear histone and non-histone proteins, in the epigenetic regulation of alcohol-associated liver disease (ALD) and other disorders. We also describe challenges in characterizing specific PTMs and suggest future opportunities for basic and translational research to prevent or treat ALD and many other disease states.

Chronic pain is a frequent, distressing and poorly understood health problem. Plasticity of synaptic transmission in the nociceptive pathways after inflammation or injury is assumed to be an important cellular basis for chronic, pathological pain. Glutamate serves as the main excitatory neurotransmitter at key synapses in the somatosensory nociceptive pathways, in which it acts on both ionotropic and metabotropic glutamate receptors. Although conventionally postsynaptic, compelling anatomical and physiological evidence demonstrates the presence of presynaptic glutamate receptors in the nociceptive pathways. Presynaptic glutamate receptors play crucial roles in nociceptive synaptic transmission and plasticity. They modulate presynaptic neurotransmitter release and synaptic plasticity, which in turn regulates pain sensitization. In this review, we summarize the latest understanding of the expression of presynaptic glutamate receptors in the nociceptive pathways, and how they contribute to nociceptive information processing and pain hypersensitivity associated with inflammation / injury. We uncover the cellular and molecular mechanisms of presynaptic glutamate receptors in shaping synaptic transmission and plasticity to mediate pain chronicity, which may provide therapeutic approaches for treatment of chronic pain.

Copper is an essential trace element that is required for the activity of many enzymes and cellular processes, including energy homeostasis and neurotransmitter biosynthesis; however, excess copper accumulation results in significant cellular toxicity. The liver is the major organ for maintaining copper homeostasis. Inactivating mutations of the copper-transporting P-type ATPase, ATP7B, result in Wilson's disease, an autosomal recessive disorder that requires life-long medicinal therapy or liver transplantation. Current treatment protocols are limited to either sequestration of copper via chelation or reduction of copper absorption in the gut (zinc therapy). The goal of these strategies is to reduce free copper, redox stress, and cellular toxicity. Several lines of evidence in Wilson's disease animal models and patients have revealed altered hepatic metabolism and impaired hepatic nuclear receptor activity. Nuclear receptors are transcription factors that coordinate hepatic metabolism in normal and diseased livers, and several hepatic nuclear receptors have decreased activity in Wilson's disease and Atp7b^−/− models. In this review, we summarize the basic physiology that underlies Wilson's disease pathology, Wilson's disease animal models, and the possibility of targeting nuclear receptor activity in Wilson's disease patients.

Severe hypertriglyceridemia (sHTG), defined as a triglyceride (TG) concentration ≥ 500 mg/dL (≥ 5.7 mmol/L) is an important risk factor for acute pancreatitis. Although lifestyle, some medications, and certain conditions such as diabetes may lead to HTG, sHTG results from a combination of major and minor genetic defects in proteins that regulate TG lipolysis. Familial chylomicronemia syndrome (FCS) is a rare disorder caused by complete loss of function in lipoprotein lipase (LPL) or LPL activating proteins due to two homozygous recessive traits or compound heterozygous traits. Multifactorial chylomicronemia syndrome (MCS) and sHTG are due to the accumulation of rare heterozygous variants and polygenic defects that predispose individuals to sHTG phenotypes. Until recently, treatment of sHTG focused on lifestyle interventions, control of secondary factors, and nonselective pharmacotherapies that had modest TG-lowering efficacy and no corresponding reductions in atherosclerotic cardiovascular disease events. Genetic discoveries have allowed for the development of novel pathway-specific therapeutics targeting LPL modulating proteins. New targets directed towards inhibition of apolipoprotein C-III (apoC-III), angiopoietin-like protein 3 (ANGPTL3), angiopoietin-like protein 4 (ANGPTL4), and fibroblast growth factor-21 (FGF21) offer far more efficacy in treating the various phenotypes of sHTG and opportunities to reduce the risk of acute pancreatitis and atherosclerotic cardiovascular disease events.