PMID: 

Biosci Microbiota Food Health. 2020 ;39(2):39-44. Epub 2019 Nov 29. PMID: 32328399

Abstract Title: 

OLL2712 induces IL-10 production by intestinal dendritic cells.

Abstract: 

Recently many researchers have revealed that certain lactic acid bacteria (LAB) have beneficial effects on the immune system. Understanding the mechanisms of how certain LAB induce immunomodulatory functions is important for the development of food ingredients that improve our health.OLL2712 has been shown to induce production of interleukin (IL)-10, an anti-inflammatory cytokine, by murine-induced dendritic cells (DCs) and peritoneal macrophages. However, it is probable that-induced DCs have different properties compared with intestinal DCs, and the effects of the LAB on intestinal DCs are not fully understood. In this report, we investigated whetherOLL2712 had efficacy for inducing intestinal DCs to produce IL-10and whether oral administration of the bacteria induced the same effect. Co-culture ofOLL2712 with purified DCs from the mesenteric lymph node (MLN) or Peyer's patch (PP) elevated IL-10 mRNA expression and protein production by both kinds of DCs. Addition of the LAB enhanced IL-10 production by T cells during antigen-specific responses in co-culture of MLN or PP DCs and T cells. Oral administration ofOLL2712 for 6 days increased IL-10 gene expression in MLN DCs, and upregulated IL-10 gene expression in PP DCs was observed 12 hr after oral administration of the LAB. Our results suggested thatOLL2712 could modulate immune responses by enhancing IL-10 production from intestinal DCs.

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PMID: 

Med Hypotheses. 2020 May 6 ;142:109815. Epub 2020 May 6. PMID: 32408070

Abstract Title: 

Does zinc supplementation enhance the clinical efficacy of chloroquine/hydroxychloroquine to win today's battle against COVID-19?

Abstract: 

Currently, drug repurposing is an alternative to novel drug development for the treatment of COVID-19 patients. The antimalarial drug chloroquine (CQ) and its metabolite hydroxychloroquine (HCQ) are currently being tested in several clinical studies as potential candidates to limit SARS-CoV-2-mediated morbidity and mortality. CQ and HCQ (CQ/HCQ) inhibit pH-dependent steps of SARS-CoV-2 replication by increasing pH in intracellular vesicles and interfere with virus particle delivery into host cells. Besides direct antiviral effects, CQ/HCQ specifically target extracellular zinc to intracellular lysosomes where it interferes with RNA-dependent RNA polymerase activity and coronavirus replication. As zinc deficiency frequently occurs in elderly patients and in those with cardiovascular disease, chronic pulmonary disease, or diabetes, we hypothesize that CQ/HCQ plus zinc supplementation may be more effective in reducing COVID-19 morbidity and mortality than CQ or HCQ in monotherapy. Therefore, CQ/HCQ in combination with zinc should be considered as additional study arm for COVID-19 clinical trials.

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PMID: 

Free Radic Biol Med. 2020 May 13. Epub 2020 May 13. PMID: 32416241

Abstract Title: 

Zinc and the modulation of Nrf2 in human neuroblastoma cells.

Abstract: 

Zinc plays a key role in the modulation of neuronal redox homeostasis. A decreased zinc availability is associated with neuronal NADPH oxidase and nitric oxide synthase activation, deregulation of redox signaling, and impaired glutathione synthesis. The present work tested the hypothesis that zinc is necessary in the neuronal defense response against dopamine (DA)-induced oxidative stress, in particular through heme oxygenase-1 (HO-1) upregulation. DA showed higher cytotoxicity when zinc availability was low. Human IMR-32 neuroblastoma cells responded to high DA concentrations (100 μM) by upregulating HO-1. This upregulation involved Nrf2 translocation to the nucleus, degradation of the Bach-1 repressor, and Nrf2-DNA binding, but it was independent of ERK1/2 activation. DA-mediated induction of HO-1 expression was dependent on the concentration of zinc in the medium. IMR-32 cells incubated in zinc deficient medium showed an impaired response to DA, with lower HO-1 mRNA and protein levels than control DA-challenged cells. This altered HO-1 upregulation was reversed by zinc supplementation. In the presence of DA, Nrf2 nuclear translocation and Bach-1 degradation werelower in zinc deficient cells. The mechanisms involved include: i) impaired Nrf2-tubulin interactions and ii) alterations in the proteasome-mediated degradation of Bach-1 secondary to a decreased ubiquitylation. Results suggest that zinc is crucial in the neuronal response to DA-induced oxidative stress in part through its role in the modulation of the Nrf2-and Bach-1-driven upregulation of HO-1 expression.

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PMID: 

Poult Sci. 2020 Jan ;99(1):441-453. Epub 2019 Dec 30. PMID: 32416829

Abstract Title: 

Dietary zinc source impacts intestinal morphology and oxidative stress in young broilers.

Abstract: 

Zinc is an essential nutritional trace element for all forms of life as it plays an important role in numerous biological processes. In poultry, zinc is provided by in-feed supplementation, mainly as zinc oxide or zinc sulfate. Alternatively zinc can be supplemented as organic sources, which are characterized by using an organic ligand that may be an amino acid, peptide, or protein to bind zinc and have a higher bioavailability than inorganic zinc sources. There are limited number of studies directly comparing the effects of inorganic vs. organic zinc sources on performance and intestinal health in broilers. Therefore, a digestibility and a performance study were conducted to evaluate and compare the effect of an amino acid-complexed zinc source vs. an inorganic zinc source on intestinal health. The experiment consisted of 2 treatments: either a zinc amino acid complex or zinc sulfate was added to a wheat-rye based diet at 60 ppm Zn, with 10 replicates (34 broilers per pen) per treatment. Effects on performance, intestinal morphology, microbiota composition, and oxidative stress were measured. Supplementing zinc amino acid complexes improved the zinc digestibility coefficient as compared to supplementation with zinc sulfate. Broilers supplemented with zinc amino acid complexes had a significantly lower feed conversion ratio in the starter phase compared to birds supplemented with zinc sulfateA significantly higher villus length was observed in broilers supplemented with zinc amino acid complexes at days 10 and 28. Supplementation with zinc amino acid complexes resulted in a decreased abundance of several genera belonging to the phylum of Proteobacteria. Plasma malondialdehyde levels and glutathione peroxidase activity showed an improved oxidative status in broilers supplemented with zinc amino acid complexes. In conclusion, zinc supplied in feed as amino acid complex is more readily absorbed, potentially conferring a protective effect on villus epithelial cells in the starter phase.

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PMID: 

Cochrane Database Syst Rev. 2020 04 8 ;4:CD010205. Epub 2020 Apr 8. PMID: 32266964

Abstract Title: 

Zinc supplementation for the promotion of growth and prevention of infections in infants less than six months of age.

Abstract: 

BACKGROUND: Zinc is a vital micronutrient for humans and is essential for protein synthesis, cell growth, and differentiation. Severe zinc deficiency can lead to slower physical, cognitive and sexual growth, cause skin disorders, decrease immunity, increase incidence of acute illnesses in infants and children and contribute to childhood stunting. By estimation, 17.3% of the world population is at risk of inadequate zinc intake. Such nutritional impairment increases the risk of diarrhoea and pneumonia by 20%, as well as leads to a global loss of more than 16 million disability-adjusted life years in children less than five years of age. Not only does zinc deficiency affect lives, it adds to the considerable financial burden on depleted resources in countries that are most affected. By preventing or curing this deficiency, we can improve childhood mortality, morbidity and growth.OBJECTIVES: To assess the effectiveness of zinc supplementation for the promotion of growth, reduction in mortality, and the prevention of infections in infants less than six months of age.SEARCH METHODS: We used the standard search strategy of the Cochrane Neonatal Group to search the Cochrane Central Register of Controlled Trials (CENTRAL 2018, Issue 4), MEDLINE via PubMed (1966 to 18 May 2018), Embase (1980 to 18 May 2018), and CINAHL (1982 to 18 May 2018). We also searched clinical trials databases, conference proceedings, and the reference lists of retrieved articles for randomised controlled trials and quasi-randomised trials. An updated search from 1 January 2018 to 29 January 2020 was run in the following databases: CENTRAL via CRS Web, MEDLINE via Ovid, and CINAHL via EBSCOhost.SELECTION CRITERIA: All randomised controlled (individual and cluster randomised) and quasi-randomised trials of zinc supplementation in healthy, term infants, less than six months of age comparing infant mortality, incidence of diarrhoea or respiratory illnesses, growth and/or serum zinc levels were eligible.DATA COLLECTION AND ANALYSIS: Two review authors screened search results (title and abstracts) and relevant full texts. Studies fulfilling prespecified inclusion criteria were included with any disagreements resolved by consensus. Extraction and analysis were then conducted. We used the GRADE approach to assess the quality of evidence as indicated by certainty in effect estimates.MAIN RESULTS: Eight studies (with 85,629 infants) were included and five studies were meta-analysed, out of which four studies compared zinc with placebo, and one compared zinc plus riboflavin versus riboflavin. Certain growth outcomes after six months of intervention (Weight for Age Z-scores (WAZ) (standardised mean difference) (SMD) 0.16, 95% CI 0.03 to 0.29; three studies, n = 955; fixed-effect; heterogeneity Chi² P = 0.96); I² = 0%); change in WAZ (SMD 0.16, 95% CI 0.07 to 0.25; one study, n = 386; fixed-effect); (Weight-for-Length Z-score (WLZ) (SMD 0.15, 95% CI 0.02 to 0.28; three studies, n = 955; fixed-effect; heterogeneity: Chi² P = 0.81); I² = 0%); (change in WLZ (SMD 0.17, 95% CI 0.06 to 0.28; one study, n = 386; fixed-effect)) were positively affected by zinc supplementation compared to placebo. A single study reported no difference in the incidence of diarrhoea and lower respiratory tract infection with zinc supplementation. Zinc had no effect on mortality in children younger than 12 months. When zinc plus riboflavin was compared to riboflavin only, significant improvement was observed in the incidence of wasting at 24 months (risk ratio (RR) 0.59, 95% CI 0.37 to 0.96; one study, n = 296; fixed-effect), but significant worsening of incidence of stunting was present at 21 months (RR1.53, 95% CI 1.09 to 2.16; one study, n = 298; fixed-effect).AUTHORS' CONCLUSIONS: There was a significant positive impact of zinc supplementation on WAZ and WLZ after six months of intervention in infants compared to placebo. When a combined supplement of zinc and riboflavin was compared to riboflavin, there was a significant reduction in wasting at 24 months, but stunting at 21 months was negatively affected. Although included trials were of good-to-moderate quality, evidence that could be meta-analysed was based on a few studies which affected the overall quality of results. Regardless, there is a need for strong trials conducted in infants younger than six months before a strong recommendation can be made supporting zinc supplementation in this age group.

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PMID: 

Brief Bioinform. 2020 May 11. Epub 2020 May 11. PMID: 32393985

Abstract Title: 

Therapeutic targets and signaling mechanisms of vitamin C activity against sepsis: a bioinformatics study.

Abstract: 

Sepsis is a life-threatening complication of pneumonia, including coronavirus disease-2019 (COVID-19)-induced pneumonia. Evidence of the benefits of vitamin C (VC) for the treatment of sepsis is accumulating. However, data revealing the targets and molecular mechanisms of VC action against sepsis are limited. In this report, a bioinformatics analysis of network pharmacology was conducted to demonstrate screening targets, biological functions, and the signaling pathways of VC action against sepsis. As shown in network assays, 63 primary causal targets for the VC action against sepsis were identified from the data, and four optimal core targets for the VC action against sepsis were identified. These core targets were epidermal growth factor receptor (EGFR), mitogen-activated protein kinase-1 (MAPK1), proto-oncogene c (JUN), and signal transducer and activator of transcription-3 (STAT3). In addition, all biological processes (including a top 20) and signaling pathways (including a top 20) potentially involved in the VC action against sepsis were identified. The hub genes potentially involved in the VC action against sepsis and interlaced networks from the Kyoto Encyclopedia of Genes and Genomes Mapper assays were highlighted. Considering all the bioinformatic findings, we conclude that VC antisepsis effects are mechanistically and pharmacologically implicated with suppression of immune dysfunction-related and inflammation-associated functional processes and other signaling pathways. These primary predictive biotargets may potentially be used to treat sepsis in future clinical practice.

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PMID: 

Biomed Res Int. 2016 ;2016:1934518. Epub 2016 Dec 13. PMID: 28070504

Abstract Title: 

Sunlight Effects on Immune System: Is There Something Else in addition to UV-Induced Immunosuppression?

Abstract: 

Sunlight, composed of different types of radiation, including ultraviolet wavelengths, is an essential source of light and warmth for life on earth but has strong negative effects on human health, such as promoting the malignant transformation of skin cells and suppressing the ability of the human immune system to efficiently detect and attack malignant cells. UV-induced immunosuppression has been extensively studied since it was first described by Dr. Kripke and Dr. Fisher in the late 1970s. However, skin exposure to sunlight has not only this and other unfavorable effects, for example, mutagenesis and carcinogenesis, but also a positive one: the induction of Vitamin D synthesis, which performs several roles within the immune system in addition to favoring bone homeostasis. The impact of low levels of UV exposure on the immune system has not been fully reported yet, but it bears interesting differences with the suppressive effect of high levels of UV radiation, as shown by some recent studies. The aim of this article is to put some ideas in perspective and pose some questions within the field of photoimmunology based on established and new information, which may lead to new experimental approaches and, eventually, to a better understanding of the effects of sunlight on the human immune system.

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PMID: 

Photochem Photobiol Sci. 2020 May 19. Epub 2020 May 19. PMID: 32428049

Abstract Title: 

Photoprotection conferred by low level summer sunlight exposures against pro-inflammatory UVR insult.

Abstract: 

Tanning (melanisation and epidermal thickening) is a photoprotective response to solar UVR exposure, but it's unclear to what degree low-level exposures induce this in light-skin individuals, or whether this modifies the histological inflammatory response to UVR. Objectives were to examine if, in light-skin people, a simulated summer's casual sunlight exposures induces (i) melanogenesis, (ii) epidermal thickening and (iii) demonstrable protection against both clinical (erythema) and histological (neutrophil infiltration) impacts of higher-level, pro-inflammatory UVR challenge. A UVR intervention study was designed to simulate a summer's brief sunlight exposures (95% UVA, 5% UVB) as can provide sufficient vitamin D. Ten healthy adults of phototype II, median 47 years (range 30-59 years), 2 male/8 female, received 1.3 SED 3× weekly for 6 weeks, and were subsequently challenged with 2× personal MED of UVB on small areas of UVR-exposed and UVR-protected buttock skin. Skin erythema and pigmentation were measured spectrophotometrically. Punch biopsies were taken from (i) unexposed skin (ii) skin following the ×18 low-level UVR exposures and (iii) skin at 24 h following the 2 × MED challenge, with skin sections evaluated for epidermal thickness, and for neutrophil infiltration by immunohistochemistry. The 6-weeks' UVR exposures significantly increased skin pigmentation, skin lightness (L*) reducing from 69.37 (SD2.8) to 65.52 (2.33) at course-end (p

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PMID: 

Adv Exp Med Biol. 2017 ;996:155-168. PMID: 29124698

Abstract Title: 

Role of Vitamin D in Rheumatoid Arthritis.

Abstract: 

Vitamin D is a fat soluble hormone, with a well described role in bone health and calcium/phosphate metabolism. Recent evidences have related vitamin D to other physiological functions and pathological conditions. Specifically, vitamin D has widely proven activities on immune system and evidences suggest that it may be implicated in the pathogenesis of rheumatoid arthritis (RA). The relationship between vitamin D and RA is complex, also because a deficitary vitamin D status, which is very common in RA patients, can contribute to the increased risk of osteoporosis typical of RA. In this chapter, will be described and discussed the main aspects of the relationship between RA and vitamin D.

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PMID: 

Int J Mol Sci. 2020 May 15 ;21(10). Epub 2020 May 15. PMID: 32429317

Abstract Title: 

Ellagic Acid Controls Cell Proliferation and Induces Apoptosis in Breast Cancer Cells via Inhibition of Cyclin-Dependent Kinase 6.

Abstract: 

Cyclin-Dependent Kinase 6 (CDK6) plays an important role in cancer progression, and thus, it is considered as an attractive drug target in anticancer therapeutics. This study presents an evaluation of dietary phytochemicals, capsaicin, tocopherol, rosmarinic acid, ursolic acid, ellagic acid (EA), limonene, caffeic acid, and ferulic acid for their potential to inhibit the activity of CDK6. Molecular docking and fluorescence binding studies revealed appreciable binding affinities of these compounds to the CDK6. Among them, EA shows the highest binding affinity for CDK6, and thus a molecular dynamics simulation study of 200 ns was performed to get deeper insights into the binding mechanism and stability of the CDK6-EA complex. Fluorescence binding studies revealed that EA binds to the CDK6 with a binding constant of= 10Mand subsequently inhibits its enzyme activity with an ICvalue of 3.053µM. Analysis of thermodynamic parameters of CDK6-EA complex formation suggested a hydrophobic interaction driven process. The treatment of EA decreases the colonization of cancer cells and induces apoptosis. Moreover, the expression of CDK6 has been downregulated in EA-treated human breast cancer cell lines. In conclusion, this study establishes EA as a potent CDK6 inhibitor that can be further evaluated in CDK6 directed anticancer therapies.

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