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Impaired nicotinamide adenine dinucleotide (NAD+ ) metabolism in diabetes and diabetic tissues: Implications for nicotinamide-related compound treatment.
Fan, L, Cacicedo, JM, Ido, Y
Journal of diabetes investigation. 2020;(6):1403-1419
Abstract
One of the biochemical abnormalities found in diabetic tissues is a decrease in the cytosolic oxidized to reduced forms of the nicotinamide adenine dinucleotide ratio (NAD+ /NADH also known as pseudohypoxia) caused by oxidation of excessive substrates (glucose through the polyol pathway, free fatty acids and lactate). Subsequently, a decline in NAD+ levels as a result of the activation of poly adenine nucleotide diphosphate-ribose polymerase (mainly in type 1 diabetes) or the inhibition of adenine nucleotide monophosphate-activated protein kinase (in type 2 diabetes). Thus, replenishment of NAD+ levels by nicotinamide-related compounds could be beneficial. However, these compounds also increase nicotinamide catabolites that cause oxidative stress. This is particularly troublesome for patients with diabetes, because they have impaired nicotinamide salvage pathway reactions at the level of nicotinamide phosphoribosyl transferase and phosphoribosyl pyrophosphate, which occurs by the following mechanisms. First, phosphoribosyl pyrophosphate synthesis from pentose phosphate pathway is compromised by a decrease in plasma thiamine and transketolase activity. Second, nicotinamide phosphoribosyl transferase expression is decreased because of reduced adenosine monophosphate-activated protein kinase activity, which occurs in type 2 diabetes. The adenosine monophosphate-activated protein kinase inhibition is caused by an activation of protein kinase C and D1 as a result of enhanced diacylglycerol synthesis caused by pseudohypoxia and increased fatty acids levels. In this regard, nicotinamide-related compounds should be given with caution to treat diabetes. To minimize the risk and maximize the benefit, nicotinamide-related compounds should be taken with insulin sensitizers (for type 2 diabetes), polyphenols, benfotiamine, acetyl-L-carnitine and aldose reductase inhibitors. The efficacy of these regimens can be monitored by measuring serum NAD+ and urinary nicotinamide catabolites.
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2.
Cytokine storm in aged people with CoV-2: possible role of vitamins as therapy or preventive strategy.
Fiorino, S, Gallo, C, Zippi, M, Sabbatani, S, Manfredi, R, Moretti, R, Fogacci, E, Maggioli, C, Travasoni Loffredo, F, Giampieri, E, et al
Aging clinical and experimental research. 2020;(10):2115-2131
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Abstract
BACKGROUND In December 2019, a novel human-infecting coronavirus, SARS-CoV-2, had emerged. The WHO has classified the epidemic as a "public health emergency of international concern". A dramatic situation has unfolded with thousands of deaths, occurring mainly in the aged and very ill people. Epidemiological studies suggest that immune system function is impaired in elderly individuals and these subjects often present a deficiency in fat-soluble and hydrosoluble vitamins. METHODS We searched for reviews describing the characteristics of autoimmune diseases and the available therapeutic protocols for their treatment. We set them as a paradigm with the purpose to uncover common pathogenetic mechanisms between these pathological conditions and SARS-CoV-2 infection. Furthermore, we searched for studies describing the possible efficacy of vitamins A, D, E, and C in improving the immune system function. RESULTS SARS-CoV-2 infection induces strong immune system dysfunction characterized by the development of an intense proinflammatory response in the host, and the development of a life-threatening condition defined as cytokine release syndrome (CRS). This leads to acute respiratory syndrome (ARDS), mainly in aged people. High mortality and lethality rates have been observed in elderly subjects with CoV-2-related infection. CONCLUSIONS Vitamins may shift the proinflammatory Th17-mediated immune response arising in autoimmune diseases towards a T-cell regulatory phenotype. This review discusses the possible activity of vitamins A, D, E, and C in restoring normal antiviral immune system function and the potential therapeutic role of these micronutrients as part of a therapeutic strategy against SARS-CoV-2 infection.
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Graves' disease: Clinical manifestations, immune pathogenesis (cytokines and chemokines) and therapy.
Antonelli, A, Fallahi, P, Elia, G, Ragusa, F, Paparo, SR, Ruffilli, I, Patrizio, A, Gonnella, D, Giusti, C, Virili, C, et al
Best practice & research. Clinical endocrinology & metabolism. 2020;(1):101388
Abstract
Graves' disease (GD) is characterized by thyrotoxicosis, caused by the presence of circulating thyroid stimulating antibodies (TSAb), that are determinant also in the pathogenesis of its extrathyroidal manifestations [Graves' ophthalmopathy (GO), pretibial myxedema]. T helper (Th)1 immune response prevails in the immune-pathogenesis of GD and GO, during the active phase, when Th1 chemokines, and their (C-X-C)R3 receptor, play a key role. In GD, the existing treatments are not ideal for hyperthyroidism (long-term remission with anti-thyroid-drugs only in 50% of patients; while radioiodine and surgery cause hypothyroidism). In GD, antigen-specific therapy has been recently published, with the induction of T cell tolerance via an immunization by TSH-R peptides. In GO, rituximab and drugs targeting cytokines have been evaluated. Furthermore, teprotumumab (a human monoclonal anti-IGF-1R blocking antibody) showed to be very effective in GO patients. Further researches are necessary to identify novel effective therapies targeting GD, or GO.
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Does intestinal dysbiosis contribute to an aberrant inflammatory response to severe acute respiratory syndrome coronavirus 2 in frail patients?
Terruzzi, I, Senesi, P
Nutrition (Burbank, Los Angeles County, Calif.). 2020;:110996
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Abstract
In a few months, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has become the main health problem worldwide. Epidemiologic studies revealed that populations have different vulnerabilities to SARS-CoV-2. Severe outcomes of the coronavirus disease 2019 (COVID-19) with an increased risk of death are observed in patients with metabolic syndrome, as well as diabetic and heart conditions (frail population). Excessive proinflammatory cytokine storm could be the main cause of increased vulnerability in this frail population. In patients with diabetes and/or heart disease, a low inflammatory state is often associated with gut dysbiosis. The increase amount of microbial metabolites (i.e., trimethylamine N-oxide and lipopolysaccharide), which generate an inflammatory microenvironment, is probably associated with an improved risk of severe illness from COVID-19. Nutritional interventions aimed at restoring the gut microbial balance could represent preventive strategies to protect the frail population from COVID-19. This narrative review presents the possible molecular mechanisms by which intestinal dysbiosis that enhances the inflammatory state could promote the spread of SARS-CoV-2 infection. Some nutritional strategies to counteract inflammation in frail patients are also analyzed.
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Cytokines and Growth Factors as Predictors of Response to Medical Treatment in Diabetic Macular Edema.
Torres-Costa, S, Alves Valente, MC, Falcão-Reis, F, Falcão, M
The Journal of pharmacology and experimental therapeutics. 2020;(3):445-452
Abstract
Diabetic macular edema (DME) is the most common cause of visual loss in patients with diabetes. Antivascular endothelial growth factors (anti-VEGF) agents are first-line therapy for DME. Nevertheless, up to 60% of patients (depending on the anti-VEGF drug used) have an inadequate response to anti-VEGF treatment. Several cytokines are increased in aqueous humor of patients with DME. Differences in response to treatment may be related to baseline cytokine levels. Intravitreal corticosteroids may be used as an alternative to anti-VEGF agents. Steroids have a different pharmacological profile and act on different pathophysiologic mechanisms. Their effect on aqueous humor cytokines is different from the effect of anti-VEGF therapy. This review highlights the major cytokines involved in DME and evaluates whether baseline cytokine levels could be predictors of response to treatment in DME. SIGNIFICANCE STATEMENT Antivascular endothelial growth factor (anti-VEGF) agents are efficient as diabetic macular edema (DME) treatment. However, in some cases, DME fails to respond to anti-VEGF intravitreal injections. Changes in cytokine levels after treatment supported the idea that other cytokines than VEGF are implicated in DME pathogenesis and could be predictors of response to anti-VEGF treatment or corticosteroids allowing targeted and individualized therapy guided by cytokine levels.
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Human Breast Milk: Bioactive Components, from Stem Cells to Health Outcomes.
Bardanzellu, F, Peroni, DG, Fanos, V
Current nutrition reports. 2020;(1):1-13
Abstract
PURPOSE OF REVIEW Breast milk (BM) is a peculiar fluid owing unique properties and resulting the ideal food during early neonatal period. As widely known, it can improve the outcome of both neonate and lactating mother, influencing their whole life. BM is characterized by several beneficial components; among these, a great role is played by BM own and specific microbiome, deeply investigated in many studies. Moreover, the use of metabolomics in BM analysis allowed a better characterization of its metabolic pathways that vary according to lactation stage and neonatal gestational age. The aim of this review is to describe growth factors, cytokines, immunity mediators, and stem cells (SCs) contained in BM and investigate their functions and effects on neonatal outcome, especially focusing on immuno- and neurodevelopment. RECENT FINDINGS We evaluated recent and updated literature on this field. The article that we analyzed to write this review have been found in MEDLINE using breast milk-derived stem cells, biofactors, growth factors, breastfeeding-related outcomes, neurodevelopment, and neonatal immunological system as keywords. Discovering and characterizing BM components could result very useful to clarify the pathophysiology of their influence on neonatal growth and even to improve artificial formulations' composition. Moreover, since SCs abilities and their involvement in the development of several diseases, they could help to discover specific targets for new therapies. It could be useful to characterize BM-derived SC markers, properties, and variations during lactation stages, to understand their potential role in therapeutic applications, since they could be noninvasively isolated from BM. More studies will help to describe more in detail the characteristics of mother-to-child communication through breastfeeding and its potential role in the next future.
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Bacterial Natural Compounds with Anti-Inflammatory and Immunomodulatory Properties (Mini Review).
Jenab, A, Roghanian, R, Emtiazi, G
Drug design, development and therapy. 2020;:3787-3801
Abstract
Inflammation is part of the body's complex biological response to harmful stimuli such as damaged cells, pathogens, or irritants. It is a protective response involving blood cells, immune cells, and molecular mediators. The inflammation not only can eliminate the primary cause of cell injury but also clears out necrotic cells, tissue damaged from the original insults and inflammatory process. Furthermore, it can initiate tissue repair. Pro-inflammatory cytokines are produced predominantly by activated macrophages and are involved in the up-regulation of inflammatory reactions. They are involved in further regulating inflammatory reactions. There is ample evidence that some pro-inflammatory cytokines, such as interleukin 1β (IL-1β), IL-6, and tumor necrosis factor-α (TNF-α), are involved in the pathological pain process. Some of the natural compounds promote cytokines production and inhibit inflammatory responses. The natural compounds which are produced from microorganisms such as omega-3 fatty acid, cyclic peptide, antimicrobial peptide, oligosaccharides, and polysaccharides can reduce inflammation and could be easily incorporated into the diet without any adverse effects. For example, SCFA (short-chain fatty acids), peptide bacteriocin, and polycyclic peptide bacteriocin (nisin) could be used in the treatment of atherosclerosis, orthopedic postoperative infections, and mycobacterium tuberculosis infection, respectively. Also, fatty acids (saturated and unsaturated fatty acids) can be introduced as anti-inflammatory drugs. This review article summarizes bacterial natural compounds with modulating effects on cytokines that are surveyed which may have potential anti-inflammatory drug-like activity.
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Pathophysiology and Pathology of Acute Kidney Injury in Patients With COVID-19.
Ng, JH, Bijol, V, Sparks, MA, Sise, ME, Izzedine, H, Jhaveri, KD
Advances in chronic kidney disease. 2020;(5):365-376
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Abstract
Acute kidney injury (AKI) is common among hospitalized patients with Coronavirus Infectious Disease 2019 (COVID-19), with the occurrence of AKI ranging from 0.5% to 80%. The variability in the occurrence of AKI has been attributed to the difference in geographic locations, race/ethnicity, and severity of illness. AKI among hospitalized patients is associated with increased length of stay and in-hospital deaths. Even patients with AKI who survive to hospital discharge are at risk of developing chronic kidney disease or end-stage kidney disease. An improved knowledge of the pathophysiology of AKI in COVID-19 is crucial to mitigate and manage AKI and to improve the survival of patients who developed AKI during COVID-19. The goal of this article is to provide our current understanding of the etiology and the pathophysiology of AKI in the setting of COVID-19.
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Osteocyte-Mediated Translation of Mechanical Stimuli to Cellular Signaling and Its Role in Bone and Non-bone-Related Clinical Complications.
Yan, Y, Wang, L, Ge, L, Pathak, JL
Current osteoporosis reports. 2020;(1):67-80
Abstract
PURPOSE OF REVIEW Osteocytes comprise > 95% of the cellular component in bone tissue and produce a wide range of cytokines and cellular signaling molecules in response to mechanical stimuli. In this review, we aimed to summarize the molecular mechanisms involved in the osteocyte-mediated translation of mechanical stimuli to cellular signaling, and discuss their role in skeletal (bone) diseases and extra-skeletal (non-bone) clinical complications. RECENT FINDINGS Two decades before, osteocytes were assumed as a dormant cells buried in bone matrix. In recent years, emerging evidences have shown that osteocytes are pivotal not only for bone homeostasis but also for vital organ functions such as muscle, kidney, and heart. Osteocyte mechanotransduction regulates osteoblast and osteoclast function and maintains bone homeostasis. Mechanical stimuli modulate the release of osteocyte-derived cytokines, signaling molecules, and extracellular cellular vesicles that regulate not only the surrounding bone cell function and bone homeostasis but also the distant organ function in a paracrine and endocrine fashion. Mechanical loading and unloading modulate the osteocytic release of NO, PGE2, and ATPs that regulates multiple cellular signaling such as Wnt/β-catenin, RANKL/OPG, BMPs, PTH, IGF1, VEGF, sclerostin, and others. Therefore, the in-depth study of the molecular mechanism of osteocyte mechanotransduction could unravel therapeutic targets for various bone and non-bone-related clinical complications such as osteoporosis, sarcopenia, and cancer metastasis to bone.
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The incretin system in healthy humans: The role of GIP and GLP-1.
Holst, JJ
Metabolism: clinical and experimental. 2019;:46-55
Abstract
The incretin effect, the amplification of insulin secretion occurring when glucose is taken in orally as compared to infused intravenously, is one of the factors that help the body to tolerate carbohydrate/glucose ingestion. These include 1) amount and type of carbohydrates; 2) gastric emptying rate; 3) digestion and absorption of the carbohydrates; 4) secretion and effect of the incretin hormones; 5) disposition of absorbed nutrients/glucose. The incretin effect can also be viewed as the fraction of the ingested glucose load handled via gastrointestinal mechanisms (including the incretin effect); it is calculated by comparison of the amount of glucose required to copy, by intravenous infusion, the oral load. Typically, for 75 g of oral glucose, about 25 g are required. This means that the GastroIntestinal Glucose Disposal (GIGD) is 66%. Both the GIGD and the incretin effect depend on the amount of glucose ingested: for higher doses the GIGD may amount to 80%, which shows that this effect is a major contributor to glucose tolerance. The main mechanism behind it is stimulation of insulin secretion by a proportional secretion of the insulinotropic hormones GIP and GLP-1. Recently it has become possible to estimate their contributions in healthy humans using specific and potent receptor antagonists. Both hormones act to improve glucose tolerance (i.e. the antagonists impair tolerance) and their effects are additive. GIP seems to be quantitatively the most important, particularly regarding insulin secretion, whereas the action of GLP-1 is mainly displayed via inhibition of glucagon secretion.