Vitamin D3: an ever green molecule.

Vitamin D3 is a key regulator of vertebrates homeostasis. It is synthesized from the precursor 7-dehydrocholesterol upon UVB exposure in the skin and then hydrolyzed in the liver in position 25, to be finally converted into its active form, 1,25-dihydroxyvitamin D (1,25(OH)2D or calcitriol), in the kidneys. The biological activity of this molecule depends on its binding to the nuclear receptor VDR, which binds VDRE once complexed with RXR-alpha. Despite being present in different types of food, the best way to assume it at physiological levels remains the exposure to UVB radiation at certain hours of the day and at particular angles of the Earth's crust. There is plenty of evidence that altered levels of vitamin D3 are associated with pathological conditions, such as osteoporosis, cancer, immunological and infectious diseases. In this review, we discuss vitamin D3 metabolism, its role in several diseases and the link between vitamin D3 and immune cells

Bortezomib modulates CHIT1 and YKL40 in monocyte-derived osteoclast and in myeloma cells

Osteolytic bone disease is a common manifestation of multiple myeloma (MM) that leads to progressive skeleton destruction and is the most severe cause of morbidity in MM patients.It results from increased osteolytic activity and decrease osteoblastic function. Activation of mammalian chitinases CHIT1 and YKL40 is associated with osteoclast (OCs) differentiation and bone digestion. In the current study, we investigated the effect of two Bortezomib’s concentration (BO) (2.5 nM and 5nM) on osteoclastogenesis by analyzing regulation of chitinase expression. OCs exposition to BO was able to inhibit the expression of different OCs markers such as RANK, CTSK, TRAP and MMP9. In addition BO-treatment reduced CHIT1 enzymatic activity and both CHIT1 and YKL40 mRNA expression levels and cytoplasmatic and secreted protein. Moreover, immunofluorescence evaluation of mature OCs showed that BO was able to translocate YKL40 into the nucleus, while CHIT1 remained into the cytoplasm. Since MM cell lines such as U266, SKM-M1 and MM1 showed high levels of CHIT1 activity, we analyzed bone resorption ability of U266 using dentin disc assay resorption pits. Silencing chitinase proteins in U266 cell line with specific siRNAs, resulted in pits number reduction on dentine discs. In conclusion, we showed that BO decreases osteoclastogenesis and reduces bone resorption in OCs and U266 cell line by modulating the chitinases CHIT1 and YKL40. These results indicate that chitinases may be a therapeutic target for bone disease in MM patients

Expression and localization of CHI3L1 in monocyte derived dendritic cells

Chitinase-3-like-1 protein (CHI3L1) also called YKL-40, is a 40 kDa mammalian glycoprotein which is a heparin, chitin and collagen binding member of the mammalian chitinase-like proteins. Biological activities of CHI3L1 embrace regulation of cell proliferation, adhesion, angiogenesis, migration and activation. CHI3L1 is produced by variety of cells, including neutrophils, monocytes/macrophages, osteoclasts and Kupffer cells [1]. CHI3L1 secretion is induced by interferon (INF)-g and interleukin (IL)-6 and is an acute phase reactant associated with disease severity and mortality in a variety of infectious [2]. In this study, we have examined the expression and localization of CHI3L1 during the differentiation and maturation of monocyte derived dendritic cells by real time RT-PCR, Western Blot, Confocal Immunofluorescence, and Immunocytochemical assays. Potential nuclear localization signal (NLS) was determinated using the open source software cNLS Mapper and Chimera. Peripheral blood monocytes were differentiated toward immature DCs (iDC) and mature DCs (mDCs) through a combination of factors and cytokines. Our result showed, for the first time, that CHI3L1 is expressed during the process of differentiation and maturation of DCs in time dependent manner. Furthermore, CHI3L1 is evenly distributed in cytoplasm and in the nucleus of both the iDCs and mDCs. In conclusion, the discovery of CHI3L1 expression in DCs has opened new dilemma for designing DC-based cancer immunotherapeutic. In fact, on the light of these results one can’t exclude that as well as activated Tumor-associated macrophages (TAMs) also DCs infiltration could to be a significant unfavorable prognostic factor for cancer patients

Chitotriosidase expression in monocyte-derived dendritic cells

Chitotriosidase (CHIT1) belongs to 18 glycosyl-hydrolase family, an ancient gene family that is widely expressed from prokaryotes to eukaryotes [1]. CHIT1 is a very critical enzyme to regulate the susceptibility to infection of organisms containing chitin as structural components. Conversely, during the development of acute/chronic inflammatory disorders, the enzymatic activity of CHIT1 increases significantly. The CHIT1 is expressed in activated macrophages as well in different lines monocyte-derived such as Kupffer cells and osteoclasts [2]. So far, it is unknown whether CHIT1 is expressed in other cells involved in the immune response such as monocyte-derived DCs. In this study we have investigated whether CHIT1 is produced in monocyte-derived DCs (moDCs) and the differential expression of CHIT1 during the different stage of moDCs differentiation. The presence of CHIT1 were examined by real time RT-PCR, Western Blot and Confocal Immunofluorescence, in Immature Dendritic cells (iDCs), generated from human monocytes by stimulation with granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-4 (IL-4) and in mature Dendritic cells (mDCs), obtained by using lipopolysaccharide (LPS) and interferon-gamma (IFN-g). We observed that CHIT1 was expressed during the DCs differentiation and maturation process in time dependent manner. The maturation of DCs showed a significantly increased expression of CHIT1 mRNA and protein. Furthermore, the CHIT1 was evenly distributed in cytoplasm both in iDCs and in mDCs. The enzymatic activity confirmed that CHIT1 could play a role in moDCs function. Taken together, our data confirm the crucial role of CHIT1 in primary immune responses and indicate that could be correlated with the immunogenicity of DCs

Influence of Resveratrol on the Immune Response

Resveratrol is the most well-known polyphenolic stilbenoid, present in grapes, mulberries, peanuts, rhubarb, and in several other plants. Resveratrol can play a beneficial role in the prevention and in the progression of chronic diseases related to inflammation such as diabetes, obesity, cardiovascular diseases, neurodegeneration, and cancers among other conditions. Moreover, resveratrol regulates immunity by interfering with immune cell regulation, proinflammatory cytokines’ synthesis, and gene expression. At the molecular level, it targets sirtuin, adenosine monophosphate kinase, nuclear factor-κB, inflammatory cytokines, anti-oxidant enzymes along with cellular processes such as gluconeogenesis, lipid metabolism, mitochondrial biogenesis, angiogenesis, and apoptosis. Resveratrol can suppress the toll-like receptor (TLR) and pro-inflammatory genes’ expression. The antioxidant activity of resveratrol and the ability to inhibit enzymes involved in the production of eicosanoids contribute to its anti-inflammation properties. The effects of this biologically active compound on the immune system are associated with widespread health benefits for different autoimmune and chronic inflammatory diseases. This review offers a systematic understanding of how resveratrol targets multiple inflammatory components and exerts immune-regulatory effects on immune cells

Vitamin D3 as Potential Treatment Adjuncts for COVID-19

Severe acute respiratory syndrome coronavirus type (SARS-CoV2, also known as COVID-19), which is the latest pandemic infectious disease, constitutes a serious risk to human health. SARS-CoV2 infection causes immune activation and systemic hyperinflammation which can lead to respiratory distress syndrome (ARDS). ARDS victims are characterized by a significant increase in IL-6 and IL-1. Macrophage activation, associated with the “cytokine storm”, promotes the dysregulation of the innate immunity. So far, without vaccines or specific therapy, all efforts to design drugs or clinical trials are worthwhile. Vitamin D and its receptor vitamin D receptor (VDR) exert a critical role in infections due to their remarkable impact on both innate and adaptive immune responses and on the suppression of the inflammatory process. The protective properties of vitamin D supplementation have been supported by numerous observational studies and by meta-analysis of clinical trials for prevention of viral acute respiratory infection. In this review, we compare the mechanisms of the host immune response to SARS-CoV2 infection and the immunomodulatory actions that vitamin D exerts in order to consider the preventive effect of vitamin D supplementation on SARS-CoV2 viral infection

Autoimmunity in the elderly: Implications for cancer

Immunosenescence is the aging process involving the immune system competencies. These changes imply a reduced level of immunosurveillance against cancer onset and the occurrence of autoimmune phenomena. The clinical presentation of autoimmune diseases in the elderly is characterized in most cases by atypical features, insidious presentation and poor specificity of laboratory parameters. The role of autoimmune reactivity in the elderly either as a consequence of or as a risk factor for cancer development has aroused great interest among clinicians and researchers, as well as the influence of a chronic inflammatory state as a predisposing factor for autoimmunity and cancer occurrence. Particularly, we have investigated the pathogenetic effect of two cell subsets, Treg cells and Th17 lymphocytes, involved in the control mechanisms both of autoimmune reactions and cancer onset, as the possible future approach to treat cancer in older adults

Lipoprotein(a) in Cardiovascular Diseases

Lipoprotein(a) (Lp(a)) is an LDL-like molecule consisting of an apolipoprotein B-100 (apo(B-100)) particle attached by a disulphide bridge to apo(a). Many observations have pointed out that Lp(a) levels may be a risk factor for cardiovascular diseases. Lp(a) inhibits the activation of transforming growth factor (TGF) and contributes to the growth of arterial atherosclerotic lesions by promoting the proliferation of vascular smooth muscle cells and the migration of smooth muscle cells to endothelial cells. Moreover Lp(a) inhibits plasminogen binding to the surfaces of endothelial cells and decreases the activity of �brin-dependent tissue-type plasminogen activator. Lp(a) may act as a proin�ammatory mediator that augments the lesion formation in atherosclerotic plaques. Elevated serum Lp(a) is an independent predictor of coronary artery disease and myocardial infarction. Furthermore, Lp(a) levels should be a marker of restenosis aer percutaneous transluminal coronary angioplasty, saphenous vein bypass gra atherosclerosis, and accelerated coronary atherosclerosis of cardiac transplantation. Finally, the possibility that Lp(a) may be a risk factor for ischemic stroke has been assessed in several studies. Recent �ndings suggest that Lp(a)-lowering therapy might be bene�cial in patients with high Lp(a) levels. A future therapeutic approach could include apheresis in high-risk patients in order to reduce major coronary events

Options for Topical Treatment of Oxidative Eye Diseases with a Special Focus on Retinopathies

Antioxidants, usually administered orally through the systemic route, are known to counteract the harmful effects of oxidative stress on retinal cells. The formulation of these antioxidants as eye drops might offer a new option in the treatment of oxidative retinopathies. In this review, we will focus on the use of some of the most potent antioxidants in treating retinal neuropathies. Melatonin, known for its neuroprotective qualities, may mitigate oxidative damage in the retina. N-acetyl-cysteine (NAC), a precursor to glutathione, enhances the endogenous antioxidant defense system, potentially reducing retinal oxidative stress. Idebenone, a synthetic analogue of coenzyme Q10, and edaravone, a free radical scavenger, contribute to cellular protection against oxidative injury. Epigallocatechin-3-gallate (EGCG), a polyphenol found in green tea, possesses anti-inflammatory and antioxidant effects that could be beneficial in cases of retinopathy. Formulating these antioxidants as eye drops presents a localized and targeted delivery method, ensuring effective concentrations reach the retina. This approach might minimize systemic side effects and enhance therapeutic efficacy. In this paper, we also introduce a relatively new strategy: the alkylation of two antioxidants, namely, edaravone and EGCG, to improve their insertion into the lipid bilayer of liposomes or even directly into cellular membranes, facilitating their crossing of epithelial barriers and targeting the posterior segment of the eye. The synergistic action of these antioxidants may offer a multifaceted defense against oxidative damage, holding potential for the treatment and management of oxidative retinopathies. Further research and clinical trials will be necessary to validate the safety and efficacy of these formulations, but the prospect of antioxidant-based eye drops represents a promising avenue for future ocular therapies

Lipoprotein(a) in Cardiovascular Diseases

Lipoprotein(a) (Lp(a)) is an LDL-like molecule consisting of an apolipoprotein B-100 (apo(B-100)) particle attached by a disulphide bridge to apo(a). Many observations have pointed out that Lp(a) levels may be a risk factor for cardiovascular diseases. Lp(a) inhibits the activation of transforming growth factor (TGF) and contributes to the growth of arterial atherosclerotic lesions by promoting the proliferation of vascular smooth muscle cells and the migration of smooth muscle cells to endothelial cells. Moreover Lp(a) inhibits plasminogen binding to the surfaces of endothelial cells and decreases the activity of fibrin-dependent tissue-type plasminogen activator. Lp(a) may act as a proinflammatory mediator that augments the lesion formation in atherosclerotic plaques. Elevated serum Lp(a) is an independent predictor of coronary artery disease and myocardial infarction. Furthermore, Lp(a) levels should be a marker of restenosis after percutaneous transluminal coronary angioplasty, saphenous vein bypass graft atherosclerosis, and accelerated coronary atherosclerosis of cardiac transplantation. Finally, the possibility that Lp(a) may be a risk factor for ischemic stroke has been assessed in several studies. Recent findings suggest that Lp(a)-lowering therapy might be beneficial in patients with high Lp(a) levels. A future therapeutic approach could include apheresis in high-risk patients in order to reduce major coronary events