scholarly journals Rubella Virus Infected Macrophages and Neutrophils Define Patterns of Granulomatous Inflammation in Inborn and Acquired Errors of Immunity

2021 ◽  
Vol 12 ◽  
Author(s):  
Ludmila Perelygina ◽  
Raeesa Faisthalab ◽  
Emily Abernathy ◽  
Min-hsin Chen ◽  
LiJuan Hao ◽  
...  
Keyword(s):  
Rubella Virus ◽  
Molecular Mechanisms ◽  
Hematopoietic Cell Transplantation ◽  
Case Series ◽  
Granulomatous Inflammation ◽  
Immunohistochemical Analysis ◽  
Cell Types ◽  
Therapeutic Interventions ◽  
Inborn Errors ◽  
Histological Data

Rubella virus (RuV) has recently been found in association with granulomatous inflammation of the skin and several internal organs in patients with inborn errors of immunity (IEI). The cellular tropism and molecular mechanisms of RuV persistence and pathogenesis in select immunocompromised hosts are not clear. We provide clinical, immunological, virological, and histological data on a cohort of 28 patients with a broad spectrum of IEI and RuV-associated granulomas in skin and nine extracutaneous tissues to further delineate this relationship. Combined immunodeficiency was the most frequent diagnosis (67.8%) among patients. Patients with previously undocumented conditions, i.e., humoral immunodeficiencies, a secondary immunodeficiency, and a defect of innate immunity were identified as being susceptible to RuV-associated granulomas. Hematopoietic cell transplantation was the most successful treatment in this case series resulting in granuloma resolution; steroids, and TNF-α and IL-1R inhibitors were moderately effective. In addition to M2 macrophages, neutrophils were identified by immunohistochemical analysis as a novel cell type infected with RuV. Four patterns of RuV-associated granulomatous inflammation were classified based on the structural organization of granulomas and identity and location of cell types harboring RuV antigen. Identification of conditions that increase susceptibility to RuV-associated granulomas combined with structural characterization of the granulomas may lead to a better understanding of the pathogenesis of RuV-associated granulomas and discover new targets for therapeutic interventions.

scholarly journals Molecular Alterations in Sporadic and SOD1-ALS Immortalized Lymphocytes: Towards a Personalized Therapy

2021 ◽  
Vol 22 (6) ◽  
pp. 3007
Author(s):  
Isabel Lastres-Becker ◽  
Gracia Porras ◽  
Marina Arribas-Blázquez ◽  
Inés Maestro ◽  
Daniel Borrego-Hernández ◽  
...  
Keyword(s):  
Motor Neurons ◽  
Molecular Mechanisms ◽  
Cell Types ◽  
Therapeutic Interventions ◽  
Autophagic Flux ◽  
Metabolic Disturbances ◽  
Molecular Alterations ◽  
Healthy Donors ◽  
Inflammatory Profile ◽  
Als Patients

Amyotrophic lateral sclerosis (ALS) is a fatal neurological condition where motor neurons (MNs) degenerate. Most of the ALS cases are sporadic (sALS), whereas 10% are hereditarily transmitted (fALS), among which mutations are found in the gene that codes for the enzyme superoxide dismutase 1 (SOD1). A central question in ALS field is whether causative mutations display selective alterations not found in sALS patients, or they converge on shared molecular pathways. To identify specific and common mechanisms for designing appropriate therapeutic interventions, we focused on the SOD1-mutated (SOD1-ALS) versus sALS patients. Since ALS pathology involves different cell types other than MNs, we generated lymphoblastoid cell lines (LCLs) from sALS and SOD1-ALS patients and healthy donors and investigated whether they show changes in oxidative stress, mitochondrial dysfunction, metabolic disturbances, the antioxidant NRF2 pathway, inflammatory profile, and autophagic flux. Both oxidative phosphorylation and glycolysis appear to be upregulated in lymphoblasts from sALS and SOD1-ALS. Our results indicate significant differences in NRF2/ARE pathway between sALS and SOD1-ALS lymphoblasts. Furthermore, levels of inflammatory cytokines and autophagic flux discriminate between sALS and SOD1-ALS lymphoblasts. Overall, different molecular mechanisms are involved in sALS and SOD1-ALS patients and thus, personalized medicine should be developed for each case.

scholarly journals Cellular and Molecular Mechanisms of Kidney Injury in 2,8-Dihydroxyadenine Nephropathy

2020 ◽  
Vol 31 (4) ◽  
pp. 799-816 ◽  
Author(s):  
Barbara Mara Klinkhammer ◽  
Sonja Djudjaj ◽  
Uta Kunter ◽  
Runolfur Palsson ◽  
Vidar Orn Edvardsson ◽  
...  
Keyword(s):  
Clinical Relevance ◽  
Molecular Mechanisms ◽  
Granulomatous Inflammation ◽  
Kidney Injury ◽  
Rare Condition ◽  
Therapeutic Interventions ◽  
Renal Tubules ◽  
Rodent Models ◽  
Adenine Phosphoribosyltransferase ◽  
Reparative Process

BackgroundHereditary deficiency of adenine phosphoribosyltransferase causes 2,8-dihydroxyadenine (2,8-DHA) nephropathy, a rare condition characterized by formation of 2,8-DHA crystals within renal tubules. Clinical relevance of rodent models of 2,8-DHA crystal nephropathy induced by excessive adenine intake is unknown.MethodsUsing animal models and patient kidney biopsies, we assessed the pathogenic sequelae of 2,8-DHA crystal-induced kidney damage. We also used knockout mice to investigate the role of TNF receptors 1 and 2 (TNFR1 and TNFR2), CD44, or alpha2-HS glycoprotein (AHSG), all of which are involved in the pathogenesis of other types of crystal-induced nephropathies.ResultsAdenine-enriched diet in mice induced 2,8-DHA nephropathy, leading to progressive kidney disease, characterized by crystal deposits, tubular injury, inflammation, and fibrosis. Kidney injury depended on crystal size. The smallest crystals were endocytosed by tubular epithelial cells. Crystals of variable size were excreted in urine. Large crystals obstructed whole tubules. Medium-sized crystals induced a particular reparative process that we term extratubulation. In this process, tubular cells, in coordination with macrophages, overgrew and translocated crystals into the interstitium, restoring the tubular luminal patency; this was followed by degradation of interstitial crystals by granulomatous inflammation. Patients with adenine phosphoribosyltransferase deficiency showed similar histopathological findings regarding crystal morphology, crystal clearance, and renal injury. In mice, deletion of Tnfr1 significantly reduced tubular CD44 and annexin two expression, as well as inflammation, thereby ameliorating the disease course. In contrast, genetic deletion of Tnfr2, Cd44, or Ahsg had no effect on the manifestations of 2,8-DHA nephropathy.ConclusionsRodent models of the cellular and molecular mechanisms of 2,8-DHA nephropathy and crystal clearance have clinical relevance and offer insight into potential future targets for therapeutic interventions.

scholarly journals The Rise of Retinal Organoids for Vision Research

2020 ◽  
Vol 21 (22) ◽  
pp. 8484 ◽  
Author(s):  
Kritika Sharma ◽  
Tim U. Krohne ◽  
Volker Busskamp
Keyword(s):  
Molecular Mechanisms ◽  
Cell Types ◽  
Therapeutic Interventions ◽  
Retinal Cell ◽  
Retinal Diseases ◽  
Organ Systems ◽  
Cell Sources ◽  
Retinal Degenerative Diseases

Retinal degenerative diseases lead to irreversible blindness. Decades of research into the cellular and molecular mechanisms of retinal diseases, using either animal models or human cell-derived 2D systems, facilitated the development of several therapeutic interventions. Recently, human stem cell-derived 3D retinal organoids have been developed. These self-organizing 3D organ systems have shown to recapitulate the in vivo human retinogenesis resulting in morphological and functionally similar retinal cell types in vitro. In less than a decade, retinal organoids have assisted in modeling several retinal diseases that were rather difficult to mimic in rodent models. Retinal organoids are also considered as a photoreceptor source for cell transplantation therapies to counteract blindness. Here, we highlight the development and field’s improvements of retinal organoids and discuss their application aspects as human disease models, pharmaceutical testbeds, and cell sources for transplantations.

Wound healing and local neuroendocrine regulation in the injured liver

2008 ◽  
Vol 10 ◽  
Author(s):  
Mohammad R. Ebrahimkhani ◽  
Ahmed M. Elsharkawy ◽  
Derek A. Mann
Keyword(s):  
Wound Healing ◽  
Molecular Mechanisms ◽  
Cell Types ◽  
Neuroendocrine System ◽  
Therapeutic Interventions ◽  
Antifibrotic Therapy ◽  
Complex Process ◽  
Wound Healing Response ◽  
Fibrotic Scar ◽  
Different Cell Types

The hepatic wound-healing response is a complex process involving many different cell types and factors. It leads to the formation of excessive matrix and a fibrotic scar, which ultimately disrupts proper functioning of the liver and establishes cirrhosis. Activated hepatic myofibroblasts, which are derived from cells such as hepatic stellate cells (HSCs), play a key role in this process. Upon chronic liver injury, there is an upregulation in the local neuroendocrine system and it has recently been demonstrated that activated HSCs express specific receptors and respond to different components of this system. Neuroendocrine factors and their receptors participate in a complex network that modulates liver inflammation and wound healing, and controls the development and progression of liver fibrosis. The first part of this review provides an overview of the molecular mechanisms governing hepatic wound healing. In the second section, we explore important components of the hepatic neuroendocrine system and their recently highlighted roles in HSC biology and hepatic fibrogenesis. We discuss the therapeutic interventions that are being developed for use in antifibrotic therapy.

scholarly journals Exosomes are the Driving Force in Preparing the Soil for the Metastatic Seeds: Lessons from the Prostate Cancer

Cells ◽  
2020 ◽  
Vol 9 (3) ◽  
pp. 564 ◽  
Author(s):  
Saber H. Saber ◽  
Hamdy E. A. Ali ◽  
Rofaida Gaballa ◽  
Mohamed Gaballah ◽  
Hamed I. Ali ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Molecular Mechanisms ◽  
Cancer Metastasis ◽  
Membrane Vesicles ◽  
Cell Types ◽  
Bioactive Molecules ◽  
Therapeutic Interventions ◽  
Target Cells ◽  
Molecular Signatures ◽  
Cellular Processes

Exosomes are nano-membrane vesicles that various cell types secrete during physiological and pathophysiological conditions. By shuttling bioactive molecules such as nucleic acids, proteins, and lipids to target cells, exosomes serve as key regulators for multiple cellular processes, including cancer metastasis. Recently, microvesicles have emerged as a challenge in the treatment of prostate cancer (PCa), encountered either when the number of vesicles increases or when the vesicles move into circulation, potentially with an ability to induce drug resistance, angiogenesis, and metastasis. Notably, the exosomal cargo can induce the desmoplastic response of PCa-associated cells in a tumor microenvironment (TME) to promote PCa metastasis. However, the crosstalk between PCa-derived exosomes and the TME remains only partially understood. In this review, we provide new insights into the metabolic and molecular signatures of PCa-associated exosomes in reprogramming the TME, and the subsequent promotion of aggressive phenotypes of PCa cells. Elucidating the molecular mechanisms of TME reprogramming by exosomes draws more practical and universal conclusions for the development of new therapeutic interventions when considering TME in the treatment of PCa patients.

INVESTIGATING CRMP4 FUNCTION IN NERVE REGENERATION

2008 ◽  
Vol 31 (4) ◽  
pp. 18
Author(s):  
S Ong Tone ◽  
Y Z Alabed ◽  
A Di Polo ◽  
A E Fournier
Keyword(s):  
Optic Nerve ◽  
Neurite Outgrowth ◽  
Nerve Regeneration ◽  
Nerve Injury ◽  
Molecular Mechanisms ◽  
Ganglion Cells ◽  
Cell Types ◽  
Therapeutic Interventions ◽  
Growth State

Background: The failure of CNS neurons to spontaneously regenerate following injury can be partially attributed to the expression of neurite outgrowth inhibitory myelin associated inhibitors (MAIs). MAIs signal through a tripartite receptor complex to activate the cytosolic protein RhoA and influence cytoskeletal dynamics. RhoA antagonists promote neuronal survival and regeneration in animal models of nerve injury. However, RhoA's potential as a therapeutic target may be limited by its widespread roles in multiple cellular processes and cell types. In an attempt to discover more specific therapeutic targets to promote nerve regeneration, our lab identified the cytosolic phosphoprotein CRMP4b (Collapsin Response Mediator Protein 4b) as a protein that functionally interacts with RhoA to mediate neurite outgrowth inhibition. Blockade of the RhoA-CRMP4b interaction with a competitive peptide (C4RIP) attenuates myelin-dependent neurite outgrowth inhibition. Methods: We are currently investigating the in vivo roles of CRMP4in regeneration in an optic nerve injury model by developing a readily deliverable version of C4RIP. Results: Preliminary results suggest that overexpression of C4RIP in retinal ganglion cells by adeno-associated virus does not promote regeneration. However, studies investigating the ability of C4RIP to promote nerve regeneration into the optic nerve following stimulation of neurons into anactive growth state are currently in progress. Conclusion: Elucidating the role of CRMP4 in nerve regeneration may provide insight into the molecular mechanisms following nervous system injury and lead to the development of more specific therapeutic interventions. Reference: Alabed YZ, Pool M, Ong Tone S, Fournier AE.Identification of CRMP4 as a convergent regulator of axon outgrowth inhibition. J Neurosci 2007;27:1702-11.

Inflammageing in the cardiovascular system: mechanisms, emerging targets, and novel therapeutic strategies

2020 ◽  
Vol 134 (17) ◽  
pp. 2243-2262
Author(s):  
Danlin Liu ◽  
Gavin Richardson ◽  
Fehmi M. Benli ◽  
Catherine Park ◽  
João V. de Souza ◽  
...  
Keyword(s):  
Cardiovascular Diseases ◽  
Cardiovascular System ◽  
Nlrp3 Inflammasome ◽  
Molecular Mechanisms ◽  
Molecular Targets ◽  
Therapeutic Interventions ◽  
Low Grade ◽  
Cardiovascular Research ◽  
Inflammatory Processes ◽  
Ach Receptors

Abstract In the elderly population, pathological inflammation has been associated with ageing-associated diseases. The term ‘inflammageing’, which was used for the first time by Franceschi and co-workers in 2000, is associated with the chronic, low-grade, subclinical inflammatory processes coupled to biological ageing. The source of these inflammatory processes is debated. The senescence-associated secretory phenotype (SASP) has been proposed as the main origin of inflammageing. The SASP is characterised by the release of inflammatory cytokines, elevated activation of the NLRP3 inflammasome, altered regulation of acetylcholine (ACh) nicotinic receptors, and abnormal NAD+ metabolism. Therefore, SASP may be ‘druggable’ by small molecule therapeutics targeting those emerging molecular targets. It has been shown that inflammageing is a hallmark of various cardiovascular diseases, including atherosclerosis, hypertension, and adverse cardiac remodelling. Therefore, the pathomechanism involving SASP activation via the NLRP3 inflammasome; modulation of NLRP3 via α7 nicotinic ACh receptors; and modulation by senolytics targeting other proteins have gained a lot of interest within cardiovascular research and drug development communities. In this review, which offers a unique view from both clinical and preclinical target-based drug discovery perspectives, we have focused on cardiovascular inflammageing and its molecular mechanisms. We have outlined the mechanistic links between inflammageing, SASP, interleukin (IL)-1β, NLRP3 inflammasome, nicotinic ACh receptors, and molecular targets of senolytic drugs in the context of cardiovascular diseases. We have addressed the ‘druggability’ of NLRP3 and nicotinic α7 receptors by small molecules, as these proteins represent novel and exciting targets for therapeutic interventions targeting inflammageing in the cardiovascular system and beyond.

Acute hepatic porphyrias for the neurologist: current concepts and perspectives

2021 ◽  
Author(s):  
Paulo Victor Sgobbi de Souza ◽  
Bruno de Mattos Lombardi Badia ◽  
Igor Braga Farias ◽  
Eduardo Augusto Gonçalves ◽  
Wladimir Bocca Vieira de Rezende Pinto ◽  
...  
Keyword(s):  
Central Nervous System Involvement ◽  
Therapeutic Interventions ◽  
Inborn Errors ◽  
Intravenous Glucose ◽  
Inherited Metabolic Disorders ◽  
Life Threatening ◽  
Acute Porphyrias ◽  
Diagnostic Work ◽  
Atypical Presentations ◽  
Interfering Rna

ABSTRACT Background: Acute hepatic porphyrias represent an expanding group of complex inherited metabolic disorders due to inborn errors of metabolism involving heme biosynthesis. Objective: We aimed to review the main clinical and therapeutic aspects associated with acute hepatic porphyrias. Methods: The authors provided a wide non-systematic review of current concepts and recently acquired knowledge about acute hepatic porphyrias. Results: Acute neurovisceral attacks are the most common and life-threatening presentation of this group and are often considered the main clinical manifestation by clinicians during differential diagnosis and the start of proper diagnostic work-up for acute porphyrias. However, atypical presentations with central nervous system involvement, neuropsychiatric disturbances, and some subtypes with photosensitivity usually make the definite diagnosis difficult and late. Early therapeutic interventions are essential during emergency treatment and intercritical periods to avoid recurrent severe presentations. The availability of new disease-modifying therapeutic proposals based on small interfering RNA (siRNA)-based therapies, complementary to the classic intravenous glucose infusion and hemin-based treatments, emphasizes the importance of early diagnosis and genetic counseling of patients. Conclusions: This review article highlights the main biochemical, pathophysiological, clinical, and therapeutic aspects of acute hepatic porphyrias in clinical practice.

Pediatric Visual Snow Syndrome (VSS): A Case Series

2019 ◽  
pp. 249-254
Author(s):  
Kenneth J. Ciuffreda ◽  
MH Esther Han ◽  
Barry Tannen
Keyword(s):  
Visual Field ◽  
Case Series ◽  
Therapeutic Interventions ◽  
Visual Condition ◽  
Visual Phenomena ◽  
Entire Visual Field ◽  
The Individual ◽  
Vision Therapy ◽  
Abnormal Visual

Visual snow syndrome (VSS) is a relatively rare, unusual, and disturbing abnormal visual condition. The individual perceives “visual snow” (VS) throughout the entire visual field, as well as other abnormal visual phenomena (e.g., photopsia). Only relatively recently has treatment been proposed (e.g., chromatic filters) in adults with VSS, but rarely in the pediatric VSS population (i.e., medications). In this paper, we present three well-documented cases of VSS in children, including their successful neuro-optometric therapeutic interventions (i.e., chromatic filters and saccadic-based vision therapy)

Wnt/beta-catenin and PI3K/Akt/mTOR Signaling Pathways in Glioblastoma: Two Main Targets for Drug Design: A Review

2020 ◽  
Vol 26 (15) ◽  
pp. 1729-1741 ◽  
Author(s):  
Seyed H. Shahcheraghi ◽  
Venant Tchokonte-Nana ◽  
Marzieh Lotfi ◽  
Malihe Lotfi ◽  
Ahmad Ghorbani ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Molecular Mechanisms ◽  
Cellular Proliferation ◽  
Chemotherapy Resistance ◽  
Wnt Signaling Pathway ◽  
Therapeutic Interventions ◽  
Beta Catenin ◽  
Clinical Prognosis ◽  
Invasion And Migration ◽  
And Migration

: Glioblastoma (GBM) is the most common and malignant astrocytic glioma, accounting for about 90% of all brain tumors with poor prognosis. Despite recent advances in understanding molecular mechanisms of oncogenesis and the improved neuroimaging technologies, surgery, and adjuvant treatments, the clinical prognosis of patients with GBM remains persistently unfavorable. The signaling pathways and the regulation of growth factors of glioblastoma cells are very abnormal. The various signaling pathways have been suggested to be involved in cellular proliferation, invasion, and glioma metastasis. The Wnt signaling pathway with its pleiotropic functions in neurogenesis and stem cell proliferation is implicated in various human cancers, including glioma. In addition, the PI3K/Akt/mTOR pathway is closely related to growth, metabolism, survival, angiogenesis, autophagy, and chemotherapy resistance of GBM. Understanding the mechanisms of GBM’s invasion, represented by invasion and migration, is an important tool in designing effective therapeutic interventions. This review will investigate two main signaling pathways in GBM: PI3K/Akt/mTOR and Wnt/beta-catenin signaling pathways.

Sign in / Sign up

Export Citation Format

Share Document