Structural and Mechanistic Insights of CRAC Channel as a Drug Target in Autoimmune Disorder.
Current drug targets. 2020;(1):55-75
BACKGROUND Calcium (Ca2+) ion is a major intracellular signaling messenger, controlling a diverse array of cellular functions like gene expression, secretion, cell growth, proliferation, and apoptosis. The major mechanism controlling this Ca2+ homeostasis is store-operated Ca2+ release-activated Ca2+ (CRAC) channels. CRAC channels are integral membrane protein majorly constituted via two proteins, the stromal interaction molecule (STIM) and ORAI. Following Ca2+ depletion in the Endoplasmic reticulum (ER) store, STIM1 interacts with ORAI1 and leads to the opening of the CRAC channel gate and consequently allows the influx of Ca2+ ions. A plethora of studies report that aberrant CRAC channel activity due to Loss- or gain-of-function mutations in ORAI1 and STIM1 disturbs this Ca2+ homeostasis and causes several autoimmune disorders. Hence, it clearly indicates that the therapeutic target of CRAC channels provides the space for a new approach to treat autoimmune disorders. OBJECTIVE This review aims to provide the key structural and mechanical insights of STIM1, ORAI1 and other molecular modulators involved in CRAC channel regulation. RESULTS AND CONCLUSION Understanding the structure and function of the protein is the foremost step towards improving the effective target specificity by limiting their potential side effects. Herein, the review mainly focusses on the structural underpinnings of the CRAC channel gating mechanism along with its biophysical properties that would provide the solid foundation to aid the development of novel targeted drugs for an autoimmune disorder. Finally, the immune deficiencies caused due to mutations in CRAC channel and currently used pharmacological blockers with their limitation are briefly summarized.
Integrative Metabolomics to Identify Molecular Signatures of Responses to Vaccines and Infections.
Approaches to the identification of metabolites have progressed from early biochemical pathway evaluation to modern high-dimensional metabolomics, a powerful tool to identify and characterize biomarkers of health and disease. In addition to its relevance to classic metabolic diseases, metabolomics has been key to the emergence of immunometabolism, an important area of study, as leukocytes generate and are impacted by key metabolites important to innate and adaptive immunity. Herein, we discuss the metabolomic signatures and pathways perturbed by the activation of the human immune system during infection and vaccination. For example, infection induces changes in lipid (e.g., free fatty acids, sphingolipids, and lysophosphatidylcholines) and amino acid pathways (e.g., tryptophan, serine, and threonine), while vaccination can trigger changes in carbohydrate and bile acid pathways. Amino acid, carbohydrate, lipid, and nucleotide metabolism is relevant to immunity and is perturbed by both infections and vaccinations. Metabolomics holds substantial promise to provide fresh insight into the molecular mechanisms underlying the host immune response. Its integration with other systems biology platforms will enhance studies of human health and disease.
Effectiveness and safety of intermittent preventive treatment for malaria using either dihydroartemisinin-piperaquine or artesunate-amodiaquine in reducing malaria related morbidities and improving cognitive ability in school-aged children in Tanzania: A study protocol for a controlled randomised trial.
Contemporary clinical trials communications. 2020;:100546
BACKGROUND In high transmission settings, up to 70% of school-aged children harbour malaria parasites without showing any clinical symptoms. Thus, epidemiologically, school aged children act as a substantial reservoir for malaria transmission. Asymptomatic Plasmodium infections induce inflammation leading to iron deficiency anaemia. Consequently, anaemia retards child growth, predisposes children to other diseases and reduces cognitive potential that could lead to poor academic performance. School aged children become increasingly more vulnerable as compared to those aged less than five years due to delayed acquisition of protective immunity. None of the existing Intermittent Preventive Treatment (IPT) strategies is targeting school-aged children. Here, we describe the study protocol of a clinical trial conducted in north-eastern Tanzania to expand the IPT by assessing the effectiveness and safety of two antimalarial drugs, Dihydroartemisinin-Piperaquine (DP) and Artesunate-Amodiaquine (ASAQ) in preventing malaria related morbidities in school-aged children (IPTsc) living in a high endemic area. METHODS/DESIGN The trial is a phase IIIb, individual randomized, open label, controlled trial enrolling school children aged 5-15 years, who receive either DP or ASAQ or control (no drug), using a "balanced block design" with the "standard of care" arm as reference. The interventional treatments are given three times a year for the first year. A second non-interventional year will assess possible rebound effects. Sample size was estimated to 1602 school children (534 per group) from selected primary schools in an area with high malaria endemicity. Thick and thin blood smears (to measure malaria parasitaemia using microscope) were obtained prior to treatment at baseline, and will be obtained again at month 12 and 20 from all participants. Haemoglobin concentration using a haemoglobinometer (HemoCue AB, Sweden) will be measured four monthly. Finger-prick blood (dried bloodspot-DBS) prepared on Whatman 3 M filter paper, will be used for sub-microscopic malaria parasite detection usingPCR, detect markers of drug resistance (using next generation sequencing (NGS) technology), and malaria serological assays (using enzyme-linked immunosorbent assay, ELISA). To determine the benefit of IPTsc on cognitive and psychomotor ability test of everyday attention for children (TEA-Ch) and a '20 m Shuttle run' respectively, will be conducted at baseline, month 12 and 20. The primary endpoints are change in mean haemoglobin from baseline concentration and reduction in clinical malaria incidence at month 12 and 20 of follow up. Mixed design methods are used to assess the acceptability, cost-effectiveness and feasibility of IPTsc as part of a more comprehensive school children health package. Statistical analysis will be in the form of multilevel modelling, owing to repeated measurements and clustering effect of participants. DISCUSSION Malaria intervention using IPTsc strategy may be integrated in the existing national school health programme. However, there is limited systematic evidence to assess the effectiveness and operational feasibility of this approach. School-aged children are easily accessible in most endemic malaria settings. The evidence from this study will guide the implementation of the strategy to provide complementary approach to reduce malaria related morbidity, anaemia and contribute to the overall burden reduction. TRIAL REGISTRATION Clinicaltrials.gov: NCT03640403, registered on Aug 21, 2018, prospectively registered.Url https://www.clinicaltrials.gov/ct2/show/NCT03640403?term=NCT03640403&rank=1.
Nutraceuticals-Based Immunotherapeutic Concepts and Opportunities for the Mitigation of Cellular Senescence and Aging: A Narrative Review.
Ageing research reviews. 2020;:101141
The role of increased tissue senescent cell (SC) burden in driving the process of ageing and associated disorders is rapidly gaining attention. Amongst various plausible factors, impairment in immune functions is emerging as a critical regulator of known age-associated accumulation of SC. Immune cells dysfunctions with age are multi-faceted and are uniquely attributed to the independent processes of immunosenescence and cellular senescence which may collectively impair immune system mediated clearance of SC. Moreover, being functionally and phenotypically heterogenic, immune cells are also liable to be affected by senescence microenvironment in other tissues. Therefore, strategies aimed at improving immunosenescence and cellular senescence in immune cells can have pleiotropic effects on ageing physiology including the accumulation of SC. In this regard, nutraceutical's immunomodulatory attributes are well documented which may have implications in developing nutrition-oriented immunotherapeutic approaches against SC. In particular, the three diverse sources of bioactive ingredients, viz., phytochemicals, probiotic bacteria and omega-3-fatty acids have shown promising anti-immunosenescence and anti-cellular senescence potential in immune cells influencing aging and immunity in ways beyond modest stimulation of immune responses. The present narrative review describes the preventive and therapeutic attributes of phytochemicals such as polyphenols, probiotic microbes and omega-3-fatty acids in influencing the emerging nexus of immunosenescence, cellular senescence and SC during aging. Outstanding questions and nutraceuticals-based pro-longevity and niche research areas have been deliberated. Further research using integrative approaches is recommended for developing nutrition-based holistic immunotherapeutic strategies for 'healthy ageing'.
Probiotics in the prevention and treatment of atopic dermatitis.
Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology. 2020;:43-45
The use of probiotic supplements might change the composition of the intestinal flora of children, subsequently modulating the immune system's reactivity. The effects of probiotic administration for the prevention/treatment of allergic diseases and atopic dermatitis, in particular, are still so controversial that no definitive recommendation can be made at this stage. Differences in strain specificity, timing, and length of administration all contribute to diversifying the conclusions of this review.
Phytochemical Profiles and their Anti-inflammatory Responses Against Influenza from Traditional Chinese Medicine or Herbs.
Mini reviews in medicinal chemistry. 2020;(20):2153-2164
Traditional Chinese medicine (TCM) or herbs are widely used in the prevention and treatment of viral infectious diseases. However, the underlying mechanisms of TCMs remain largely obscure due to complicated material basis and multi-target therapeutics. TCMs have been reported to display anti-influenza activity associated with immunoregulatory mechanisms by enhancing host antiinfluenza immune responses. Previous studies have helped us understand the direct harm caused by the virus itself. In this review, we have tried to summarize recent progress in TCM-based anti-influenza research on the indirect harmful immune responses caused by influenza viruses. In particular, the phytochemicals from TCMs responsible for molecular mechanisms of action belonging to different classes, including phenolic compounds, flavonoids, alkaloids and polysaccharides, have been identified and demonstrated. In addition, this review focuses on the pharmacological mechanism, e.g., inflammatory responses and the interferon (IFN) signaling pathway, which can provide a theoretical basis and approaches for TCM based anti-influenza treatment.
IKAROS Family Zinc Finger 1-Associated Diseases in Primary Immunodeficiency Patients.
Immunology and allergy clinics of North America. 2020;(3):461-470
Ikaros zinc finger 1 (IKZF1 or Ikaros) is a hematopoietic zinc finger DNA-binding transcription factor that acts as a critical regulator of lymphocyte and myeloid differentiation. Loss-of-function germline heterozygous mutations in IKZF1 affecting DNA-binding were described as causative of 2 distinct primary immunodeficiency (PID)/inborn error of immunity diseases. Mutations acting by haploinsufficiency present with a common variable immune deficiency-like phenotype mainly characterized by increased susceptibility to infections. Mutations acting in a dominant negative fashion present with a combined immunodeficiency phenotype with high prevalence of Pneumocystis jirovecii pneumonia. Pathophysiology and manifestations of IKAROS-associated diseases in patients with PID are reviewed here.
Gastrointestinal Disorders and the Nervous System.
Continuum (Minneapolis, Minn.). 2020;(3):577-590
PURPOSE OF REVIEW This article describes the neurologic sequelae of various nutritional micronutrient deficiencies, celiac disease, inflammatory bowel disease, and liver disease. Where relevant, appropriate treatments for these conditions are also discussed. The developing field of the microbiome and nervous system interaction is also outlined. RECENT FINDINGS Pathology in the gastrointestinal system can affect the nervous system when it causes micronutrient deficiency, when immune responses created by the gastrointestinal system affect the nervous system, when toxins caused by gastrointestinal organ failure harm the nervous system, and when treatments aimed at a gastrointestinal medical condition cause damage to the nervous system as a side effect. SUMMARY This article addresses familiar concepts and new developments in the treatment and understanding of diseases that affect the gut and nervous system simultaneously.
Local Responses and Systemic Induced Resistance Mediated by Ectomycorrhizal Fungi.
Frontiers in plant science. 2020;:590063
Ectomycorrhizal fungi (EMF) grow as saprotrophs in soil and interact with plants, forming mutualistic associations with roots of many economically and ecologically important forest tree genera. EMF ensheath the root tips and produce an extensive extramatrical mycelium for nutrient uptake from the soil. In contrast to other mycorrhizal fungal symbioses, EMF do not invade plant cells but form an interface for nutrient exchange adjacent to the cortex cells. The interaction of roots and EMF affects host stress resistance but uncovering the underlying molecular mechanisms is an emerging topic. Here, we focused on local and systemic effects of EMF modulating defenses against insects or pathogens in aboveground tissues in comparison with arbuscular mycorrhizal induced systemic resistance. Molecular studies indicate a role of chitin in defense activation by EMF in local tissues and an immune response that is induced by yet unknown signals in aboveground tissues. Volatile organic compounds may be involved in long-distance communication between below- and aboveground tissues, in addition to metabolite signals in the xylem or phloem. In leaves of EMF-colonized plants, jasmonate signaling is involved in transcriptional re-wiring, leading to metabolic shifts in the secondary and nitrogen-based defense metabolism but cross talk with salicylate-related signaling is likely. Ectomycorrhizal-induced plant immunity shares commonalities with systemic acquired resistance and induced systemic resistance. We highlight novel developments and provide a guide to future research directions in EMF-induced resistance.
Beyond Neuronal Heat Sensing: Diversity of TRPV1 Heat-Capsaicin Receptor-Channel Functions.
Frontiers in cellular neuroscience. 2020;:612480
Transient receptor potential vanilloid 1 (TRPV1) is a calcium-permeable ion channel best known for its ability to be gated by the pungent constituent of red chili pepper, capsaicin, and related chemicals from the group of vanilloids as well as by noxious heat. As such, it is mostly expressed in sensory neurons to act as a detector of painful stimuli produced by pungent chemicals and high temperatures. Its activation is also sensitized by the numerous endogenous inflammatory mediators and second messengers, making it an important determinant of nociceptive signaling. Except for such signaling, though, neuronal TRPV1 activation may influence various organ functions by promoting the release of bioactive neuropeptides from sensory fiber innervation organs. However, TRPV1 is also found outside the sensory nervous system in which its activation and function is not that straightforward. Thus, TRPV1 expression is detected in skeletal muscle; in some types of smooth muscle; in epithelial and immune cells; and in adipocytes, where it can be activated by the combination of dietary vanilloids, endovanilloids, and pro-inflammatory factors while the intracellular calcium signaling that this initiates can regulate processes as diverse as muscle constriction, cell differentiation, and carcinogenesis. The purpose of the present review is to provide a clear-cut distinction between neurogenic TRPV1 effects in various tissues consequent to its activation in sensory nerve endings and non-neurogenic TRPV1 effects due to its expression in cell types other than sensory neurons.