Cytokine & Growth Factor Reviews最新文献

Myeloid-derived suppressor cells (MDSCs) are important components of the tumor microenvironment (TME), which drive the tumor immune escape by inducing immunosuppression. The expansion and function of MDSCs are tightly associated with signaling pathways induced by molecules from tumor cells, stromal cells, and activated immune cells in the TME. Although these pathways have been well-characterized, the understanding of the epigenetic regulators involved is incomplete. Since histone modifications are the most studied epigenetic changes in MDSCs, we summarize current knowledge on the role of histone modifications in MDSCs within this review. We first discuss the influence of the TME on histone modifications in MDSCs, with an emphasis on histone modifications and modifiers that direct MDSC differentiation and function. Furthermore, we highlight current epigenetic interventions that can reverse MDSC-induced immunosuppression by modulating histone modifications and discuss future research directions to fully appreciate the role of histone modifications in MDSCs.

The Nucleotide-binding domain leucine-rich repeat and pyrin domain containing receptor 3 (NLRP3), a member of the nucleotide-binding oligomerization domain (NOD) like receptors (NLRs) family, plays an important role in the innate immune response against pathogen invasions. NLRP3 inflammasome consisting of NLRP3 protein, the adapter protein apoptosis-associated speck-like protein containing a caspase recruitment domain (CARD) (ASC), and the effector protein pro-caspase-1, is central to this process. Upon activation, NLRP3 inflammasome initiates the release of inflammatory cytokines and triggers a form of cell death known as pyroptosis. Dysregulation or inappropriate activation of NLRP3 has been implicated in various human diseases, including type 2 diabetes, colitis, depression, and gout. Consequently, understanding the mechanism underlying NLRP3 inflammasome activation is critical for the development of therapeutic drugs. In the pursuit of potential therapeutic agents, peptides present several advantages over small molecules. They offer higher selectivity, increased potency, reduced toxicity, and fewer off-target effects. The advancements in molecular biology have expanded the opportunities for applying peptides in medicine, unlocking their vast medical potential. This review begins by providing a comprehensive summary of recent research progress regarding the mechanisms governing NLRP3 inflammasome activation. Subsequently, we offer an overview of current peptide inhibitors capable of modulating the NLRP3 inflammasome activation pathway.

Stroke is one of the devastating clinical conditions that causes death and permanent disability. Its occurrence causes the reduction of oxygen and glucose supply, resulting in events such as inflammatory response, oxidative stress, and apoptosis in the brain. Microglia are brain-resident immune cells in the central nervous system (CNS) that exert diverse roles and respond to pathological process after an ischemic insult. The discovery of fibroblast growth factors (FGFs) in mammals, resulted to the findings that they can treat experimental models of stroke in animals effectively. FGFs function as homeostatic factors that control cells and hormones involved in metabolism, and they also regulate the secretion of proinflammatory (M1) and anti-inflammatory (M2) cytokines after stroke. In this review, we outline current evidence of microglia activation in experimental models of stroke focusing on its ability to exacerbate damage or repair tissue. Also, our review sheds light on the pharmacological actions of FGFs on multiple targets to regulate microglial modulation and highlighted their theoretical molecular mechanisms to provide possible therapeutic targets, as well as their limitations for the treatment of stroke.

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The cyclic GMP-AMP synthase (cGAS) is a widely recognized pattern recognition receptor responsible for detecting pathogenic DNA in the cytosol and inducing the production of type I interferon (IFN) to combat infections. The recently discovered nuclear localization of cGAS has changed the old dogma, illuminated a captivating dimension of innate immunity, and sparked many fundamental questions beyond the field of immunology. This review explores cGAS nuclear localization models, activation mechanisms, and biological significance. This expansion challenges the conventional understanding of cGAS and opens new avenues for scientific exploration, promising insights into cellular surveillance and potentially unveiling new therapeutic targets for immune disorders.

CD14 is a co-receptor of Toll-like receptor (TLR)− 4, with a critical role in innate immune responses. CD14 recognizes bacterial lipopolysaccharides, pathogen-, and damage-associated molecular patterns, thereby facilitating inflammatory immune responses. In addition to its well-established association with TLR4, CD14 is also implicated in TLR4-independent signaling, which leads to the apoptotic death of differentiated dendritic cells and activation of the noncanonical inflammasome pathway. CD14 also has a role beyond that of the immune responses. It contributes to tissue homeostasis by promoting the clearance of various apoptotic cells via recognizing externalized phosphatidylinositol phosphates. CD14 also has context-dependent roles, particularly in barrier tissues that include the skin and gastrointestinal tract. For example, CD14⁺ dendritic cells in the skin can induce immunostimulatory or immunosuppressive responses. In the gastrointestinal system, CD14 is involved in producing inflammatory cytokines in inflammatory bowel disease and maintaining of intestinal integrity. This review focuses on the multifaceted roles of CD14 in innate immunity and its potential regulatory functions in barrier tissues characterized by rapid cell renewal. By providing insights into the diverse functions of CD14, this review offers potential therapeutic implications for this versatile molecule in immune modulation and tissue homeostasis.

Myocardial infarction with nonobstructive coronary arteries (MINOCA) remains a puzzling clinical entity. It is characterized by clinical evidence of myocardial infarction (MI) with normal or near-normal coronary arteries in angiography. Given the complex etiology including multiple possible scenarios with varied pathogenetic mechanisms, profound investigation of the plausible biomarkers of MINOCA may bring further pathophysiological insights and novel diagnostic opportunities. Cytokines have a great diagnostic potential and are used as biomarkers for many diseases. An unusual trio of visfatin, placental growth factor (PlGF) and fractalkine (CX3CL1) can directly promote vascular dysfunction, inflammation and angiogenesis through the activation of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling. They are redundant in physiological processes and become overexpressed in the pathomechanisms underlying MINOCA. The knowledge about their concentration might serve as a valuable diagnostic and/or therapeutic tool for assessing vascular endothelial function. Here we analyze the current knowledge on visfatin, PlGF and CX3CL1 in the context of MINOCA and present the novel clinical implications of their combined expression as predictors or indicators of this condition.

NOD-like receptor thermal protein domain-associated protein 3 (NLRP3) receptor serves as the central node of immune sensing in the innate immune system, and plays an important role in the initiation and progression of chronic diseases. Cryo-electron microscopy (cryo-EM) has provided insights into the conformation of various oligomers within the NLRP3 activation pathway, significantly advancing our understanding of the mechanisms underlying NLRP3 inflammasome activation. Despite the extensive network of protein-protein interactions (PPIs) involved in the assembly and activation of NLRP3 inflammasome, the utilization of protein-protein interactions has been relatively overlooked in the development of NLRP3 inhibitors. This review focuses on summarizing PPIs within the NLRP3 inflammasome activation pathway and small molecule inhibitors capable of interfering with PPIs to counteract the NLRP3 overactivation. Small molecule NLRP3 inhibitors have been gained significant attention owing to their remarkable efficacy, excellent safety profiles, and unique mechanisms of action.

Progranulin (PGRN), encoded by the GRN gene in humans, was originally isolated as a secreted growth factor that implicates in a multitude of processes ranging from regulation of tumorigenesis, inflammation to neural proliferation. Compelling evidence indicating that GRN mutation can lead to various common neuronal degenerative diseases and rare lysosomal storage diseases. These findings have unveiled a critical role for PGRN as a lysosomal protein in maintaining lysosomal function. The phenotypic spectrum of PGRN imbalance has expanded to encompass a broad spectrum of diseases, including autoimmune diseases, metabolic, musculoskeletal and cardiovascular diseases. These diseases collectively referred to as Progranulinopathy- a term encompasses the wide spectrum of disorders influenced by PGRN imbalance. Unlike its known extracellular function as a growth factor-like molecule associated with multiple membrane receptors, PGRN also serves as an intracellular co-chaperone engaged in the folding and traffic of its associated proteins, particularly the lysosomal hydrolases. This chaperone activity is required for PGRN to exert its diverse functions across a broad range of diseases, encompassing both the central nervous system and peripheral systems. In this comprehensive review, we present an update of the emerging role of PGRN in Progranulinopathy, with special focus on elucidating the intricate interplay between PGRN and a diverse array of proteins at various levels, ranging from extracellular fluids and intracellular components, as well as various pathophysiological processes involved. This review seeks to offer a comprehensive grasp of PGRN's diverse functions, aiming to unveil intricate mechanisms behind Progranulinopathy and open doors for future research endeavors.

Extracellular vesicles (EVs) are messengers that carry information in the form of proteins, lipids, and nucleic acids and are not only essential for intercellular communication but also play a critical role in the progression of various pathologies, including ovarian cancer. There has been recent substantial research characterising EV cargo, specifically, the lipid profile of EVs. Lipids are involved in formation and cargo sorting of EVs, their release and cellular uptake. Numerous lipidomic studies demonstrated the enrichment of specific classes of lipids in EVs derived from cancer cells suggesting that the EV associated lipids can potentially be employed as minimally invasive biomarkers for early diagnosis of various malignancies, including ovarian cancer. In this review, we aim to provide a general overview of the heterogeneity of EV, biogenesis, their lipid content, and function in cancer progression focussing on ovarian cancer.

There is a complex interaction between pro-tumoural and anti-tumoural networks in the tumour microenvironment (TME). Throughout tumourigenesis, communication between malignant cells and various cells of the TME contributes to metabolic reprogramming. Tumour Dysregulation of metabolic pathways offer an evolutional advantage in the TME and enhance the tumour progression, invasiveness, and metastasis. Therefore, understanding these interactions within the TME is crucial for the development of innovative cancer treatments. Extracellular vesicles (EVs) serve as carriers of various materials that include microRNAs, proteins, and lipids that play a vital role in the communication between tumour cells and non-tumour cells. EVs are actively involved in the metabolic reprogramming process. This review summarized recent findings regarding the involvement of EVs in the metabolic reprogramming of various cells in the TME of gastrointestinal cancers. Additionally, we highlight identified microRNAs involved in the reprogramming process in this group of cancers and explained the abnormal tumour metabolism targeted by exosomal cargos as well as the novel potential therapeutic approaches.