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International Journal of Molecular... Dec 2021The retina is an exquisite target for defects of oxidative phosphorylation (OXPHOS) associated with mitochondrial impairment. Retinal involvement occurs in two ways,... (Review)
Review
The retina is an exquisite target for defects of oxidative phosphorylation (OXPHOS) associated with mitochondrial impairment. Retinal involvement occurs in two ways, retinal dystrophy (retinitis pigmentosa) and subacute or chronic optic atrophy, which are the most common clinical entities. Both can present as isolated or virtually exclusive conditions, or as part of more complex, frequently multisystem syndromes. In most cases, mutations of mtDNA have been found in association with mitochondrial retinopathy. The main genetic abnormalities of mtDNA include mutations associated with neurogenic muscle weakness, ataxia and retinitis pigmentosa (NARP) sometimes with earlier onset and increased severity (maternally inherited Leigh syndrome, MILS), single large-scale deletions determining Kearns-Sayre syndrome (KSS, of which retinal dystrophy is a cardinal symptom), and mutations, particularly in mtDNA-encoded ND genes, associated with Leber hereditary optic neuropathy (LHON). However, mutations in nuclear genes can also cause mitochondrial retinopathy, including autosomal recessive phenocopies of LHON, and slowly progressive optic atrophy caused by dominant or, more rarely, recessive, mutations in the fusion/mitochondrial shaping protein OPA1, encoded by a nuclear gene on chromosome 3q29.
Topics: Animals; DNA, Mitochondrial; Humans; Mitochondria; Mitochondrial Diseases; Optic Atrophy, Hereditary, Leber; Retinal Diseases
PubMed: 35008635
DOI: 10.3390/ijms23010210 -
Cell Communication and Signaling : CCS Apr 2020The dynamic interactions of cancer cells with their microenvironment consisting of stromal cells (cellular part) and extracellular matrix (ECM) components (non-cellular)... (Review)
Review
The dynamic interactions of cancer cells with their microenvironment consisting of stromal cells (cellular part) and extracellular matrix (ECM) components (non-cellular) is essential to stimulate the heterogeneity of cancer cell, clonal evolution and to increase the multidrug resistance ending in cancer cell progression and metastasis. The reciprocal cell-cell/ECM interaction and tumor cell hijacking of non-malignant cells force stromal cells to lose their function and acquire new phenotypes that promote development and invasion of tumor cells. Understanding the underlying cellular and molecular mechanisms governing these interactions can be used as a novel strategy to indirectly disrupt cancer cell interplay and contribute to the development of efficient and safe therapeutic strategies to fight cancer. Furthermore, the tumor-derived circulating materials can also be used as cancer diagnostic tools to precisely predict and monitor the outcome of therapy. This review evaluates such potentials in various advanced cancer models, with a focus on 3D systems as well as lab-on-chip devices. Video abstract.
Topics: Animals; Carcinogenesis; Cell Communication; Extracellular Matrix; Humans; Neoplasms; Stromal Cells; Tumor Microenvironment
PubMed: 32264958
DOI: 10.1186/s12964-020-0530-4 -
International Journal of Molecular... Dec 2020Copper is one of the most abundant basic transition metals in the human body. It takes part in oxygen metabolism, collagen synthesis, and skin pigmentation, maintaining... (Review)
Review
Copper is one of the most abundant basic transition metals in the human body. It takes part in oxygen metabolism, collagen synthesis, and skin pigmentation, maintaining the integrity of blood vessels, as well as in iron homeostasis, antioxidant defense, and neurotransmitter synthesis. It may also be involved in cell signaling and may participate in modulation of membrane receptor-ligand interactions, control of kinase and related phosphatase functions, as well as many cellular pathways. Its role is also important in controlling gene expression in the nucleus. In the nervous system in particular, copper is involved in myelination, and by modulating synaptic activity as well as excitotoxic cell death and signaling cascades induced by neurotrophic factors, copper is important for various neuronal functions. Current data suggest that both excess copper levels and copper deficiency can be harmful, and careful homeostatic control is important. This knowledge opens up an important new area for potential therapeutic interventions based on copper supplementation or removal in neurodegenerative diseases including Wilson's disease (WD), Menkes disease (MD), Alzheimer's disease (AD), Parkinson's disease (PD), and others. However, much remains to be discovered, in particular, how to regulate copper homeostasis to prevent neurodegeneration, when to chelate copper, and when to supplement it.
Topics: Animals; Astrocytes; Biological Transport; Biomarkers; Brain; Copper; Disease Management; Disease Susceptibility; Hepatolenticular Degeneration; Homeostasis; Humans; Metabolic Networks and Pathways; Neurodegenerative Diseases; Neurons; Organ Specificity
PubMed: 33291628
DOI: 10.3390/ijms21239259 -
Cold Spring Harbor Perspectives in... Mar 2013During the past century, few proteins have matched erythropoietin (Epo) in capturing the imagination of physiologists, molecular biologists, and, more recently,... (Review)
Review
During the past century, few proteins have matched erythropoietin (Epo) in capturing the imagination of physiologists, molecular biologists, and, more recently, physicians and patients. Its appeal rests on its commanding role as the premier erythroid cytokine, the elegant mechanism underlying the regulation of its gene, and its remarkable impact as a therapeutic agent, arguably the most successful drug spawned by the revolution in recombinant DNA technology. This concise review will begin with a synopsis of the colorful history of this protein, culminating in its purification and molecular cloning. It then covers in more detail the contemporary understanding of Epo's physiology as well as its structure and interaction with its receptor. A major part of this article focuses on the regulation of the Epo gene and the discovery of HIF, a transcription factor that plays a cardinal role in molecular adaptation to hypoxia. In the concluding section, a synopsis of Epo's role in disorders of red blood cell production will be followed by an assessment of the remarkable impact of Epo therapy in the treatment of anemias, as well as concerns that provide a strong impetus for the development of even safer and more effective treatment.
Topics: Anemia; Cell Hypoxia; Erythropoietin; Gene Expression Regulation; Hematopoiesis; History, 19th Century; History, 20th Century; Humans; Hypoxia-Inducible Factor 1; Kidney Failure, Chronic; Receptors, Erythropoietin; Recombinant Proteins; Transcription Factors
PubMed: 23457296
DOI: 10.1101/cshperspect.a011619 -
Nature Medicine Oct 2023Precision medicine is part of the logical evolution of contemporary evidence-based medicine that seeks to reduce errors and optimize outcomes when making medical... (Review)
Review
Precision medicine is part of the logical evolution of contemporary evidence-based medicine that seeks to reduce errors and optimize outcomes when making medical decisions and health recommendations. Diabetes affects hundreds of millions of people worldwide, many of whom will develop life-threatening complications and die prematurely. Precision medicine can potentially address this enormous problem by accounting for heterogeneity in the etiology, clinical presentation and pathogenesis of common forms of diabetes and risks of complications. This second international consensus report on precision diabetes medicine summarizes the findings from a systematic evidence review across the key pillars of precision medicine (prevention, diagnosis, treatment, prognosis) in four recognized forms of diabetes (monogenic, gestational, type 1, type 2). These reviews address key questions about the translation of precision medicine research into practice. Although not complete, owing to the vast literature on this topic, they revealed opportunities for the immediate or near-term clinical implementation of precision diabetes medicine; furthermore, we expose important gaps in knowledge, focusing on the need to obtain new clinically relevant evidence. Gaps include the need for common standards for clinical readiness, including consideration of cost-effectiveness, health equity, predictive accuracy, liability and accessibility. Key milestones are outlined for the broad clinical implementation of precision diabetes medicine.
Topics: Humans; Precision Medicine; Consensus; Diabetes Mellitus; Evidence-Based Medicine
PubMed: 37794253
DOI: 10.1038/s41591-023-02502-5 -
The Journal of Allergy and Clinical... Mar 2022Microbial interventions against allergic asthma have robust epidemiologic underpinnings and the potential to recalibrate disease-inducing immune responses. Oral...
BACKGROUND
Microbial interventions against allergic asthma have robust epidemiologic underpinnings and the potential to recalibrate disease-inducing immune responses. Oral administration of OM-85, a standardized lysate of human airways bacteria, is widely used empirically to prevent respiratory infections and a clinical trial is testing its ability to prevent asthma in high-risk children. We previously showed that intranasal administration of microbial products from farm environments abrogates experimental allergic asthma.
OBJECTIVES
We sought to investigate whether direct administration of OM-85 to the airway compartment protects against experimental allergic asthma; and to identify protective cellular and molecular mechanisms activated through this natural route.
METHODS
Different strains of mice sensitized and challenged with ovalbumin or Alternaria received OM-85 intranasally, and cardinal cellular and molecular asthma phenotypes were measured. Airway transfer experiments assessed whether OM-85-treated dendritic cells protect allergen-sensitized, OM-85-naive mice against asthma.
RESULTS
Airway OM-85 administration suppressed allergic asthma in all models acting on multiple innate and adaptive immune targets: the airway epithelium/IL-33/ILC2 axis, lung allergen-induced type 2 responses, and dendritic cells whose Myd88/Trif-dependent tolerogenic reprogramming was sufficient to transfer OM-85-induced asthma protection.
CONCLUSIONS
We provide the first demonstration that administering a standardized bacterial lysate to the airway compartment protects from experimental allergic asthma by engaging multiple immune pathways. Because protection required a cumulative dose 27- to 46-fold lower than the one reportedly active through the oral route, the efficacy of intranasal OM-85 administration may reflect its direct access to the airway mucosal networks controlling the initiation and development of allergic asthma.
Topics: Allergens; Animals; Asthma; Cell Extracts; Dendritic Cells; Disease Models, Animal; Epithelium; Humans; Immunity, Innate; Interleukin-33; Lung; Lymphocytes; Mice; Mice, Inbred BALB C; Ovalbumin
PubMed: 34560105
DOI: 10.1016/j.jaci.2021.09.013 -
Life (Basel, Switzerland) Jun 2021Inhibitors of 3-hydroxy-3methylgultaryl-coenzyme A reductase (statins) are one of the main groups of drugs used in preventing and treating cardiovascular diseases... (Review)
Review
Inhibitors of 3-hydroxy-3methylgultaryl-coenzyme A reductase (statins) are one of the main groups of drugs used in preventing and treating cardiovascular diseases worldwide. They are widely available, cheap, and well-tolerated. Based on statins' pleiotropic properties, including improvement of endothelial dysfunction, antioxidant properties, atherosclerotic plaque stabilization, and inhibition of inflammatory responses, it can be hypothesized that the use of statins, at least as an adjuvant in antiviral therapy, may be justified. All these effects might be especially beneficial in patients with COVID-19, suffering from endothelial dysfunction, microvascular and macrovascular thrombosis, and cytokine storm. Here, we review the recent data regarding the pathophysiology of SARS-CoV-2 activity in host cells, proposed COVID-19 therapy, the pleiotropic activity of statins, and statins in clinical trials in respiratory infections. According to the guidelines of the European and American Cardiac Societies, in patients with cardiovascular disease or high cardiovascular risk with concomitant COVID-19 it is recommended to continue statin treatment. However, the initiation of statin therapy de novo in COVID-19 treatment should only be done as part of a clinical trial.
PubMed: 34208435
DOI: 10.3390/life11060565 -
Progress in Neurobiology Mar 2019Parkinson's disease (PD) is the second-most common progressive neurodegenerative disorder. Although the clinical diagnosis of PD is still based on its cardinal motor... (Review)
Review
Parkinson's disease (PD) is the second-most common progressive neurodegenerative disorder. Although the clinical diagnosis of PD is still based on its cardinal motor dysfunctions, several non-motor symptoms (NMS) have been established as integral part of the disease. Unlike motor disorders, development of therapies against NMS are still challenging and remain a critical unmet clinical need. During the last decade, several studies have characterised the molecular, physiological and behavioural alterations of the circadian system in PD patients. As a consequence, and given the ubiquitous nature of circadian rhythms in the entire organism, the biological clock has emerged as a potential therapeutic target to ease suffering from both motor and NMS in PD patients. Here we discuss the emerging field of using bright light, physical exercise and melatonin as chronotherapeutic tools to alleviate motor disorders, sleep/wake alterations, anxiety and depression in PD patients. We also highlight the potential of these readily available therapies to improve the general quality of life and wellbeing of PD patients. Finally, we provide specific data- and mechanisms-driven recommendations that might help improve the therapeutic benefit of light and physical exercise in PD patients.
Topics: Chronotherapy; Exercise Therapy; Humans; Parkinson Disease; Phototherapy
PubMed: 30658126
DOI: 10.1016/j.pneurobio.2019.01.002 -
Cellular and Molecular Life Sciences :... Mar 2022Under physiological conditions, hematopoietic stem and progenitor cells (HSPCs) in the bone marrow niches are responsible for the highly regulated and interconnected... (Review)
Review
Under physiological conditions, hematopoietic stem and progenitor cells (HSPCs) in the bone marrow niches are responsible for the highly regulated and interconnected hematopoiesis process. At the same time, they must recognize potential threats and respond promptly to protect the host. A wide spectrum of microbial agents/products and the consequences of infection-induced mediators (e.g. cytokines, chemokines, and growth factors) can have prominent impact on HSPCs. While COVID-19 starts as a respiratory tract infection, it is considered a systemic disease which profoundly alters the hematopoietic system. Lymphopenia, neutrophilia, thrombocytopenia, and stress erythropoiesis are the hallmark of SARS-CoV-2 infection. Moreover, thrombocytopenia and blood hypercoagulability are common among COVID-19 patients with severe disease. Notably, the invasion of erythroid precursors and progenitors by SARS-CoV-2 is a cardinal feature of COVID-19 disease which may in part explain the mechanism underlying hypoxia. These pieces of evidence support the notion of skewed steady-state hematopoiesis to stress hematopoiesis following SARS-CoV-2 infection. The functional consequences of these alterations depend on the magnitude of the effect, which launches a unique hematopoietic response that is associated with increased myeloid at the expense of decreased lymphoid cells. This article reviews some of the key pathways including the infectious and inflammatory processes that control hematopoiesis, followed by a comprehensive review that summarizes the latest evidence and discusses how SARS-CoV-2 infection impacts hematopoiesis.
Topics: COVID-19; Chemokines; Cytokines; Hematopoiesis; Hematopoietic Stem Cells; Humans; SARS-CoV-2; Thrombocytopenia
PubMed: 35284964
DOI: 10.1007/s00018-022-04220-6