Rheumatoid arthritis (RA) is a chronic inflammatory joint disease that can lead to clinical manifestations of systemic diseases. Its leading features include chronic synovial inflammation and ...degeneration of the bones and joints. In the past decades, multiple susceptibilities for rheumatoid arthritis have been identified along with the development of a remarkable variety of drugs for its treatment; which include analgesics, glucocorticoids, nonsteroidal anti-inflammatory medications (NSAIDs), disease-modifying anti-rheumatic drugs (DMARDs), and biologic response modifiers (bDMARDs). Despite the existence of many clinical treatment options, the prognosis of some patients remains poor due to complex mechanism of the disease. Programmed cell death (PCD) has been extensively studied and ascertained to be one of the essential pathological mechanisms of RA. Its dysregulation in various associated cell types contributes to the development of RA. In this review, we summarize the role of apoptosis, cell death-associated neutrophil extracellular trap formation, necroptosis, pyroptosis, and autophagy in the pathophysiology of RA to provide a theoretical reference and insightful direction to the discovery and development of novel therapeutic targets for RA.
Influenza A Virus (IAV) replications start from the deposition of inhaled virus-laden droplets on the epithelial cells in the pulmonary tracts. In order to understand the local deposition patterns ...and within-host dynamics of infectious aerosols, accurate information of high-resolution imaging capabilities, as well as real-time flow cytometry analysis, are required for tracking infected cells, virus agents, and immune system responses. However, clinical and animal studies are in deficit to meet the above-mentioned demands, due to their limited operational flexibility and imaging resolution. Therefore, this study developed an experimentally validated multiscale numerical model, i.e., the Computational Fluid-Particle Dynamics (CFPD) plus Host Cell Dynamics (HCD) model, to predict the transport and deposition of the low-strain IAV-laden droplets, as well as the resultant regional immune system responses. The hygroscopic growth and shrinkage of IAV-laden droplets were also accurately modeled. The subject-specific respiratory system was discretized using polyhedron-core meshes. By recreating both mouth and nasal breathing scenarios, simulations of isotonic IAV-laden droplets with three different compositions were achieved. It is the first time that parametric analysis has been performed to investigate how different exposure conditions can influence the IAV aerodynamics in the lung and the subsequent immune system responses. Numerical results show a higher viral accretion followed by a faster immune system response in the supraglottic region when IAV-laden droplets with the higher NaCl concentration were inhaled. Consequently, more severe symptoms and longer recovery are expected at the pharynx. Furthermore, local deposition patterns of IAV-laden droplets and post-deposition infection dynamics provide direct quantitative evidence to enhance the fundamental understanding of the underlying mechanisms for upper airway and lower airway infections.
•A multiscale model to predict pulmonary IAV-laden droplet dynamics with hygroscopic growth.•An integrated in-host dynamics model to predict after-infection response.•Polyhedral-core mesh employment with enhanced computational efficiency.•Realistic transient mouth and nose breathing patterns.
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.
Most currently recommended therapies for metabolic dysfunction-associated fatty liver disease (MAFLD) involve diet control and exercise therapy. We searched PubMed and compiled the most recent ...research into possible forms of programmed cell death in MAFLD, including apoptosis, necroptosis, autophagy, pyroptosis and ferroptosis. Here, we summarize the state of knowledge on the signaling mechanisms for each type and, based on their characteristics, discuss how they might be relevant in MAFLD-related pathological mechanisms. Although significant challenges exist in the translation of fundamental science into clinical therapy, this review should provide a theoretical basis for innovative MAFLD clinical treatment plans that target programmed cell death.
Rheumatoid arthritis (RA) is an autoimmune disease that severely affects patients' physical and mental health, leading to chronic synovitis and destruction of bone joints. Although various available ...clinical treatment options exist, patients respond with varying efficacies due to multiple factors, and there is an urgent need to discover new treatment options to improve clinical outcomes. Cuproptosis is a newly characterized form of cell death. Copper causes cuproptosis by binding to lipid-acylated components of the tricarboxylic acid cycle, leading to protein aggregation, loss of iron-sulfur cluster proteins, and eventually proteotoxic stress. Targeting copper cytotoxicity and cuproptosis are considered potential options for treating oncological diseases. The synovial hypoxic environment and the presence of excessive glycolysis in multiple cells appear to act as inhibitors of cuproptosis, which can lead to excessive survival and proliferation of multiple immune cells, such as fibroblast-like synoviocytes, effector T cells, and macrophages, further mediating inflammation and bone destruction in RA. Therefore, in this study, we attempted to elaborate and summarize the linkage of cuproptosis and key genes regulating cuproptosis to the pathological mechanisms of RA and their effects on a variety of immune cells. This study aimed to provide a theoretical basis and support for translating preclinical and experimental results of RA to clinical protocols.
Osteoarthritis (OA) is a common joint disorder characterized by the degeneration of cartilage and inflammation, affecting millions worldwide. The disease’s complex pathogenesis involves various cell ...types, such as chondrocytes, synovial cells, osteoblasts, and immune cells, contributing to the intricate interplay of factors leading to tissue degradation and pain. RNA interference (RNAi) therapy, particularly through the use of small interfering RNA (siRNA), emerges as a promising avenue for OA treatment due to its capacity for specific gene silencing. siRNA molecules can modulate post-transcriptional gene expression, targeting key pathways involved in cellular proliferation, apoptosis, senescence, autophagy, biomolecule secretion, inflammation, and bone remodeling. This review delves into the mechanisms by which siRNA targets various cell populations within the OA milieu, offering a comprehensive overview of the potential therapeutic benefits and challenges in clinical application. By summarizing the current advancements in siRNA delivery systems and therapeutic targets, we provide a solid theoretical foundation for the future development of novel siRNA-based strategies for OA diagnosis and treatment, paving the way for innovative and more effective approaches to managing this debilitating disease.
In the past decade, G protein-coupled receptors have emerged as drug targets, and their physiological and pathological effects have been extensively studied. Among these receptors, GPR119 is ...expressed in multiple organs, including the liver. It can be activated by a variety of endogenous and exogenous ligands. After GPR119 is activated, the cell secretes a variety of incretins, including glucagon-like peptide-1 and glucagon-like peptide-2, which may attenuate the metabolic dysfunction associated with fatty liver disease, including improving glucose and lipid metabolism, inhibiting inflammation, reducing appetite, and regulating the intestinal microbial system. GPR119 has been a potential therapeutic target for diabetes mellitus type 2 for many years, but its role in metabolic dysfunction associated fatty liver disease deserves further attention. In this review, we discuss relevant research and current progress in the physiology and pharmacology of the GPR119/incretin axis and speculate on the potential therapeutic role of this axis in metabolic dysfunction associated with fatty liver disease, which provides guidance for transforming experimental research into clinical applications.
Ion mobility spectrometry (IMS) which acts as a rapid analysis technique is widely used in the field detection of illicit drugs and explosives. Due to limited separation abilities of the pint-sized ...IMS challenges and problems still exist regarding high false positive and false negative responses due to the interference of the matrix. In addition, the gas-phase ion chemistry and special phenomena in the IMS spectra, such one substance showing two peaks, were not identified unambiguously. In order to explain or resolve these questions, in this paper, an ion mobility spectrometry was coupled to a mass spectrometry (IMS-MS). A commercial IMS is embedded in a custom-built ion chamber shell was attached to the mass spectrometer. The faraday plate of IMS was fabricated with a hole for the ions to passing through to the mass spectrometer. The ion transmission efficiency of IMS-MS was optimized by optimizing the various parameters, especially the distance between the faraday plate and the cone of mass spectrum. This design keeps the integrity of the two original instruments and the mass spectrometry still works with multimode ionization source (i.e., IMS-MS, ESI-MS, APCI-MS modes). The illicit drugs and explosive samples were analyzed by the IMS-MS with 63Ni source. The results showed that the IMS-MS is of high sensitivity. The ionization mechanism of the illicit drug and explosive samples with 63Ni source were systematically studied. In addition, the interferent which interfered the detection of cocaine was identified as dibutyl phthalate (DBP) by this platform. The reason why the acetone solution of amphetamine showed two peaks was explained.
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•The IMS and MS were integrated together without any destruction of MS hardware.•The gas-phase ion chemistry of 12 illicit drugs and 9 explosives have been studied by IMS-MS.•The reasons of amphetamine solution with acetone as solvent showing two peaks in IMS was explicated.•The interference which interfere cocaine detection was proved to be DBP by IMS-MS.
Cement is a primary component of concrete and is consumed extensively for construction and transportation infrastructures worldwide. Cement is largely produced and consumed locally but has global ...impact in terms of both energy consumption and greenhouse gas emissions. China is both the largest producer of cement and the biggest emitter of CO2 emissions in the world. It has been widely recognized that uncertainties of China׳s CO2 emissions were poorly quantified and clear discrepancies can be identified among different sources. These discrepancies arise from many uncertainties, including system boundary and statistical standards, availability of production data (especially for the clinker and cement outputs), and emission factors. We argue that the emission factors (EFs, either default values or adjusted ones) are the most important here and highlight the importance of clearly defining the CO2 accounting and reporting boundaries for determining the emission factors. We therefore developed a factory-level measurement for different types of clinker and cement production, primarily using onsite surveys and sampling, with the objective of distinguishing process-, combustion- and electricity-related emission factors on a factory level. It is a bottom-up CO2 emission inventory for China using the uniform formula and calculators and the first time factory-level sampling method (BFSM) based on three tiers of production lines, provincial and national integrations. Our results indicate that China׳s carbon emissions from cement production might be overestimated in the previous estimates because they overlooked the technology transition from the wet process to the dry process, differences in lime content and clinker-to-cement ratios, raw materials and fuels substitutions, and usages of blend additives.
•CO2 emission factors are critical for estimating the emissions from China׳s cement production.•The importance of clearly defining the CO2 accounting and reporting boundaries and determining of emission factors is discussed.•A large amount of onsite factory-level samples are collected and measured.•Four different types of cement production cases in China are compared.•Discrepancies of CO2 emission factors between measured data and two widely used public data are analyzed.
The increasing prevalence of metabolic syndrome has become a serious public health problem. Certain bacteria-derived metabolites play a key role in maintaining human health by regulating the host ...metabolism. Recent evidence shows that indole-3-propionic acid content can be used to predict the occurrence and development of metabolic diseases. Supplementing indole-3-propionic acid can effectively improve metabolic disorders and is considered a promising metabolite. Therefore, this article systematically reviews the latest research on indole-3-propionic acid and elaborates its source of metabolism and its association with metabolic diseases. Indole-3-propionic acid can improve blood glucose and increase insulin sensitivity, inhibit liver lipid synthesis and inflammatory factors, correct intestinal microbial disorders, maintain the intestinal barrier, and suppress the intestinal immune response. The study of the mechanism of the metabolic benefits of indole-3-propionic acid is expected to be a potential compound for treating metabolic syndrome.
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