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Journal of Leukocyte Biology Mar 2020Dysregulation of neutrophil activation causes disease in humans. Neither global inhibition of neutrophil functions nor neutrophil depletion provides safe and/or... (Review)
Review
Dysregulation of neutrophil activation causes disease in humans. Neither global inhibition of neutrophil functions nor neutrophil depletion provides safe and/or effective therapeutic approaches. The role of neutrophil granule exocytosis in multiple steps leading to recruitment and cell injury led each of our laboratories to develop molecular inhibitors that interfere with specific molecular regulators of secretion. This review summarizes neutrophil granule formation and contents, the role granule cargo plays in neutrophil functional responses and neutrophil-mediated diseases, and the mechanisms of granule release that provide the rationale for development of our exocytosis inhibitors. We present evidence for the inhibition of granule exocytosis in vitro and in vivo by those inhibitors and summarize animal data indicating that inhibition of neutrophil exocytosis is a viable therapeutic strategy.
Topics: Animals; Cytoplasmic Granules; Disease; Exocytosis; Humans; Molecular Targeted Therapy; Neutrophils; SNARE Proteins
PubMed: 31990103
DOI: 10.1002/JLB.3RI0120-645R -
Cellular and Molecular Life Sciences :... Apr 2021Extracellular NAD represents a key signaling molecule in different physiological and pathological conditions. It exerts such function both directly, through the... (Review)
Review
Extracellular NAD represents a key signaling molecule in different physiological and pathological conditions. It exerts such function both directly, through the activation of specific purinergic receptors, or indirectly, serving as substrate of ectoenzymes, such as CD73, nucleotide pyrophosphatase/phosphodiesterase 1, CD38 and its paralog CD157, and ecto ADP ribosyltransferases. By hydrolyzing NAD, these enzymes dictate extracellular NAD availability, thus regulating its direct signaling role. In addition, they can generate from NAD smaller signaling molecules, like the immunomodulator adenosine, or they can use NAD to ADP-ribosylate various extracellular proteins and membrane receptors, with significant impact on the control of immunity, inflammatory response, tumorigenesis, and other diseases. Besides, they release from NAD several pyridine metabolites that can be taken up by the cell for the intracellular regeneration of NAD itself. The extracellular environment also hosts nicotinamide phosphoribosyltransferase and nicotinic acid phosphoribosyltransferase, which inside the cell catalyze key reactions in NAD salvaging pathways. The extracellular forms of these enzymes behave as cytokines, with pro-inflammatory functions. This review summarizes the current knowledge on the extracellular NAD metabolome and describes the major biochemical properties of the enzymes involved in extracellular NAD metabolism, focusing on the contribution of their catalytic activities to the biological function. By uncovering the controversies and gaps in their characterization, further research directions are suggested, also to better exploit the great potential of these enzymes as therapeutic targets in various human diseases.
Topics: ADP Ribose Transferases; Animals; Disease; Humans; Metabolome; NAD; Pentosyltransferases; Pyrophosphatases; Signal Transduction
PubMed: 33755743
DOI: 10.1007/s00018-020-03742-1 -
International Journal of Molecular... Jul 2020The inflammasome is a large intracellular protein complex that activates inflammatory caspase-1 and induces the maturation of interleukin (IL)-1β and IL-18. Mitophagy... (Review)
Review
The inflammasome is a large intracellular protein complex that activates inflammatory caspase-1 and induces the maturation of interleukin (IL)-1β and IL-18. Mitophagy plays an essential role in the maintenance of mitochondrial homeostasis during stress. Previous studies have indicated compelling evidence of the crosstalk between inflammasome and mitophagy. Mitophagy regulation of the inflammasome, or vice versa, is crucial for various biological functions, such as controlling inflammation and metabolism, immune and anti-tumor responses, and pyroptotic cell death. Uncontrolled regulation of the inflammasome often results in pathological inflammation and pyroptosis, and causes a variety of human diseases, including metabolic and inflammatory diseases, infection, and cancer. Here, we discuss how improved understanding of the interactions between inflammasome and mitophagy can lead to novel therapies against various disease pathologies, and how the inflammasome-mitophagy connection is currently being targeted pharmacologically by diverse agents and small molecules. A deeper understanding of the inflammasome-mitophagy connection will provide new insights into human health and disease through the balance between mitochondrial clearance and pathology.
Topics: Animals; Caspase 1; Disease; Humans; Immunity; Inflammasomes; Inflammation; Interleukin-1beta; Mitochondria; Mitophagy; NLR Family, Pyrin Domain-Containing 3 Protein; Pyroptosis
PubMed: 32630319
DOI: 10.3390/ijms21134714 -
Journal of Cancer Research and... Apr 2023A biomarker is a measurable indicator used to distinguish precisely/objectively either normal biological state/pathological condition/response to a specific therapeutic... (Review)
Review
A biomarker is a measurable indicator used to distinguish precisely/objectively either normal biological state/pathological condition/response to a specific therapeutic intervention. The use of novel molecular biomarkers within evidence-based medicine may improve the diagnosis/treatment of disease, improve health outcomes, and reduce the disease's socio-economic impact. Presently cancer biomarkers are the backbone of therapy, with greater efficacy and better survival rates. Cancer biomarkers are extensively used to treat cancer and monitor the disease's progress, drug response, relapses, and drug resistance. The highest percent of all biomarkers explored are in the domain of cancer. Extensive research using various methods/tissues is carried out for identifying biomarkers for early detection, which has been mostly unsuccessful. The quantitative/qualitative detection of various biomarkers in different tissues should ideally be done in accordance with qualification rules laid down by the Early Detection Research Network (EDRN), Program for the Assessment of Clinical Cancer Tests (PACCT), and National Academy of Clinical Biochemistry. Many biomarkers are presently under investigation, but lacunae lie in the biomarker's sensitivity and specificity. An ideal biomarker should be quantifiable, reliable, of considerable high/low expression, correlate with the outcome progression, cost-effective, and consistent across gender and ethnic groups. Further, we also highlight that these biomarkers' application remains questionable in childhood malignancies due to the lack of reference values in the pediatric population. The development of a cancer biomarker stands very challenging due to its complexity and sensitivity/resistance to the therapy. In past decades, the cross-talks between molecular pathways have been targeted to study the nature of cancer. To generate sensitive and specific biomarkers representing the pathogenesis of specific cancer, predicting the treatment responses and outcomes would necessitate inclusion of multiple biomarkers.
Topics: Child; Humans; Biomarkers, Tumor; Neoplasms; Biomarkers; Cost-Effectiveness Analysis
PubMed: 37147979
DOI: 10.4103/jcrt.jcrt_384_22 -
Cephalalgia : An International Journal... Oct 2021Photophobia is one of the most common symptoms in migraine, and the underlying mechanism is uncertain. The discovery of the intrinsically-photosensitive retinal ganglion... (Review)
Review
Photophobia is one of the most common symptoms in migraine, and the underlying mechanism is uncertain. The discovery of the intrinsically-photosensitive retinal ganglion cells which signal the intensity of light on the retina has led to discussion of their role in the pathogenesis of photophobia. In the current review, we discuss the relationship between pain and discomfort leading to light aversion (traditional photophobia) and discomfort from flicker, patterns, and colour that are also common in migraine and cannot be explained solely by the activity of intrinsically-photosensitive retinal ganglion cells. We argue that, at least in migraine, a cortical mechanism provides a parsimonious explanation for discomfort from all forms of visual stimulation, and that the traditional definition of photophobia as pain in response to light may be too restrictive. Future investigation that directly compares the retinal and cortical contributions to photophobia in migraine with that in other conditions may offer better specificity in identifying biomarkers and possible mechanisms to target for treatment.
Topics: Humans; Migraine Disorders; Photic Stimulation; Photophobia; Retinal Ganglion Cells; Syndrome
PubMed: 33990148
DOI: 10.1177/03331024211014633 -
Cells Oct 2021Fibroblasts are the major cell population in the connective tissue of most organs, where they are essential for their structural integrity. They are best known for their... (Review)
Review
Fibroblasts are the major cell population in the connective tissue of most organs, where they are essential for their structural integrity. They are best known for their role in remodelling the extracellular matrix, however more recently they have been recognised as a functionally highly diverse cell population that constantly responds and adapts to their environment. Biological memory is the process of a sustained altered cellular state and functions in response to a transient or persistent environmental stimulus. While it is well established that fibroblasts retain a memory of their anatomical location, how other environmental stimuli influence fibroblast behaviour and function is less clear. The ability of fibroblasts to respond and memorise different environmental stimuli is essential for tissue development and homeostasis and may become dysregulated in chronic disease conditions such as fibrosis and cancer. Here we summarise the four emerging key areas of fibroblast adaptation: positional, mechanical, inflammatory, and metabolic memory and highlight the underlying mechanisms and their implications in tissue homeostasis and disease.
Topics: Disease; Embryonic Development; Fibroblasts; Homeostasis; Humans; Inflammation; Models, Biological
PubMed: 34831065
DOI: 10.3390/cells10112840 -
Cells Jul 2020Activation and subsequent differentiation of T cells following antigenic stimulation are triggered by highly coordinated signaling events that lead to instilling cells... (Review)
Review
Activation and subsequent differentiation of T cells following antigenic stimulation are triggered by highly coordinated signaling events that lead to instilling cells with a discrete metabolic and transcriptional feature. Compelling studies indicate that intracellular nicotinamide adenine dinucleotide (NAD) levels have profound influence on diverse signaling and metabolic pathways of T cells, and hence dictate their functional fate. CD38, a major mammalian NAD glycohydrolase (NADase), expresses on T cells following activation and appears to be an essential modulator of intracellular NAD levels. The enzymatic activity of CD38 in the process of generating the second messenger cADPR utilizes intracellular NAD and thus limits its availability to different NAD consuming enzymes (PARP, ART, and sirtuins) inside the cells. The present review discusses how the CD38-NAD axis affects T cell activation and differentiation through interfering with their signaling and metabolic processes. We also describe the pivotal role of the CD38-NAD axis in influencing the chromatin remodeling and rewiring T cell response. Overall, this review emphasizes the crucial contribution of the CD38NAD axis in altering T cell response in various pathophysiological conditions.
Topics: ADP-ribosyl Cyclase 1; Animals; Disease; Health; Humans; NAD; Signal Transduction; T-Lymphocytes
PubMed: 32709019
DOI: 10.3390/cells9071716 -
Biochemia Medica Feb 2024YKL-40 or Chitinase-3-Like Protein 1 (CHI3L1) is a highly conserved glycoprotein that binds heparin and chitin in a non-enzymatic manner. It is a member of the chitinase... (Review)
Review
YKL-40 or Chitinase-3-Like Protein 1 (CHI3L1) is a highly conserved glycoprotein that binds heparin and chitin in a non-enzymatic manner. It is a member of the chitinase protein family 18, subfamily A, and unlike true chitinases, YKL-40 is a chitinase-like protein without enzymatic activity for chitin. Although its accurate function is yet unknown, the pattern of its expression in the normal and disease states suggests its possible engagement in apoptosis, inflammation and remodeling or degradation of the extracellular matrix. During an inflammatory response, YKL-40 is involved in a complicated interaction between host and bacteria, both promoting and attenuating immune response and potentially being served as an autoantigen in a vicious circle of autoimmunity. Based on its pathophysiology and mechanism of action, the aim of this review was to summarize research on the growing role of YKL-40 as a persuasive biomarker for inflammatory diseases' early diagnosis, prediction and follow-up ( cardiovascular, gastrointestinal, endocrinological, immunological, musculoskeletal, neurological, respiratory, urinary, infectious) with detailed structural and functional background of YKL-40.
Topics: Chitinase-3-Like Protein 1; Inflammation; Biomarkers; Disease; Research; Humans; Animals; Early Diagnosis
PubMed: 38125621
DOI: 10.11613/BM.2024.010502 -
Cyborg and Bionic Systems (Washington,... 2022The rapid development of medical micromotors draws a beautiful blueprint for the noninvasive or minimally invasive diagnosis and therapy. By combining stimuli-sensitive... (Review)
Review
The rapid development of medical micromotors draws a beautiful blueprint for the noninvasive or minimally invasive diagnosis and therapy. By combining stimuli-sensitive hydrogel materials, micromotors are bestowed with new characteristics such as stimuli-responsive shape transformation/morphing, excellent biocompatibility and biodegradability, and drug loading ability. Actuated by chemical fuels or external fields (e.g., magnetic field, ultrasound, light, and electric field), hydrogel-based stimuli-responsive (HBSR) micromotors can be utilized to load therapeutic agents into the hydrogel networks or directly grip the target cargos (e.g., drug-loaded particles, cells, and thrombus), transport them to sites of interest (e.g., tumor area and diseased tissues), and unload the cargos or execute a specific task (e.g., cell capture, targeted sampling, and removal of blood clots) in response to a stimulus (e.g., change of temperature, pH, ion strength, and chemicals) in the physiological environment. The high flexibility, adaptive capacity, and shape morphing property enable the HBSR micromotors to complete specific medical tasks in complex physiological scenarios, especially in confined, hard-to-reach tissues, and vessels of the body. Herein, this review summarizes the current progress in hydrogel-based medical micromotors with stimuli responsiveness. The thermo-responsive, photothermal-responsive, magnetocaloric-responsive, pH-responsive, ionic-strength-responsive, and chemoresponsive micromotors are discussed in detail. Finally, current challenges and future perspectives for the development of HBSR micromotors in the biomedical field are discussed.
PubMed: 36285306
DOI: 10.34133/2022/9852853 -
International Journal of Molecular... Sep 2020Stimulus-responsive drug delivery systems generally aim to release the active pharmaceutical ingredient (API) in response to specific conditions and have recently been... (Review)
Review
Stimulus-responsive drug delivery systems generally aim to release the active pharmaceutical ingredient (API) in response to specific conditions and have recently been explored for disease treatments. These approaches can also be extended to molecular imaging to report on disease diagnosis and management. The stimuli used for activation are based on differences between the environment of the diseased or targeted sites, and normal tissues. Endogenous stimuli include pH, redox reactions, enzymatic activity, temperature and others. Exogenous site-specific stimuli include the use of magnetic fields, light, ultrasound and others. These endogenous or exogenous stimuli lead to structural changes or cleavage of the cargo carrier, leading to release of the API. A wide variety of stimulus-responsive systems have been developed-responsive to both a single stimulus or multiple stimuli-and represent a theranostic tool for disease treatment. In this review, stimuli commonly used in the development of theranostic nanoplatforms are enumerated. An emphasis on chemical structure and property relationships is provided, aiming to focus on insights for the design of stimulus-responsive delivery systems. Several examples of theranostic applications of these stimulus-responsive nanomedicines are discussed.
Topics: Drug Delivery Systems; Humans; Nanomedicine; Nanoparticles; Neoplasms; Polymers
PubMed: 32887466
DOI: 10.3390/ijms21176380