Macrophage classical M1 activation via TLR4 triggers a variety of responses to achieve the elimination of foreign pathogens.  During this process, there is also an increase in lipid droplets which contain large quantities of triacylglycerol (TAG) and phospholipid (PL).  The functional consequences of this increment in lipid mass are poorly understood.  Here we studied the contribution of glycerolipid synthesis to lipid accumulation, focusing specifically on the first and rate-limiting enzyme of the pathway: glycerol-3-phosphate acyltransferase (GPAT).  Using bone marrow derived macrophages (BMDM) treated with Kdo2-lipid A (KLA), we showed that glycerolipid synthesis is induced during macrophage activation.  GPAT4 protein level and GPAT3/GPAT4 enzymatic activity increase during this process, and these two isoforms were required for the accumulation of cell TAG and PL.  The phagocytic capacity of 
Gpat3-/-
 and
 Gpat4-/-BMDM was impaired. Additionally, inhibiting fatty acid β-oxidation reduced phagocytosis only partially, suggesting that lipid accumulation is not necessary for the energy requirements for phagocytosis.  Finally, 
Gpat4-/-
 BMDM expressed and released more pro-inflammatory cytokines and chemokines after macrophage activation, suggesting a role for GPAT4 in suppressing inflammatory responses.  Together these results provide evidence that glycerolipid synthesis directed by GPAT4 is important for the attenuation of the inflammatory response in activated macrophages.

Glycerol-3-phosphate acyltransferases 3 and 4 direct glycerolipid synthesis and affect functionality in activated macrophages.

Head and neck squamous cell carcinoma (HNSCC) describes a heterogeneous group of human neoplasms of the head and neck with high rates of morbidity and mortality, constituting about 3% of all cancers and ~1.5% of all cancer deaths. HNSCC constituted the seventh most prevalent human malignancy and the most common human cancer in the world in 2020, according to multi-population observations conducted by the GLOBOCAN group. Since approximately 60–70% of patients present with stage III/IV neoplastic disease, HNSCC is still one of the leading causes of death in cancer patients worldwide, with an overall survival rate that is too low, not exceeding 40–60% of these patients. Despite the application of newer surgical techniques and the implementation of modern combined oncological treatment, the disease often follows a fatal course due to frequent nodal metastases and local neoplastic recurrences. The role of micronutrients in the initiation, development, and progression of HNSCC has been the subject of considerable research. Of particular interest has been vitamin D, the pleiotropic biologically active fat-soluble family of secosteroids (vitamin-D-like steroids), which constitutes a key regulator of bone, calcium, and phosphate homeostasis, as well as carcinogenesis and the further development of various neoplasms. Considerable evidence suggests that vitamin D plays a key role in cellular proliferation, angiogenesis, immunity, and cellular metabolism. A number of basic science, clinical, and epidemiological studies indicate that vitamin D has multidirectional biological effects and influences anti-cancer intracellular mechanisms and cancer risk, and that vitamin D dietary supplements have various prophylactic benefits. In the 20th century, it was reported that vitamin D may play various roles in the protection and regulation of normal cellular phenotypes and in cancer prevention and adjunctive therapy in various human neoplasms, including HNSCC, by regulating a number of intracellular mechanisms, including control of tumour cell expansion and differentiation, apoptosis, intercellular interactions, angio- and lymphogenesis, immune function, and tumour invasion. These regulatory properties mainly occur indirectly via epigenetic and transcriptional changes regulating the function of transcription factors, chromatin modifiers, non-coding RNA (ncRNAs), and microRNAs (miRs) through protein-protein interactions and signalling pathways. In this way, calcitriol enhances intercellular communication in cancer biology, restores the connection with the extracellular matrix, and promotes the epithelial phenotype; it thus counteracts the tumour-associated detachment from the extracellular matrix and inhibits the formation of metastases. Furthermore, the confirmation that the vitamin D receptor (VDR) is present in many human tissues confirmed the physiopathological significance of vitamin D in various human tumours. Recent studies indicate quantitative associations between exposure to vitamin D and the incidence of HNC, i.e., cancer risk assessment included circulating calcidiol plasma/serum concentrations, vitamin D intake, the presence of the VDR gene polymorphism, and genes involved in the vitamin D metabolism pathway. Moreover, the chemopreventive efficacy of vitamin D in precancerous lesions of the head and neck and their role as predictors of mortality, survival, and recurrence of head and neck cancer are also widely discussed. As such, it may be considered a promising potential anti-cancer agent for developing innovative methods of targeted therapy. The proposed review discusses in detail the mechanisms regulating the relationship between vitamin D and HNSCC. It also provides an overview of the current literature, including key opinion-forming systematic reviews as well as epidemiological, prospective, longitudinal, cross-sectional, and interventional studies based on in vitro and animal models of HNSCC, all of which are accessible via the PubMed/Medline/EMBASE/Cochrane Library databases. This article presents the data in line with increasing clinical credibility.

/pdf/role-of-vitamin-d-in-head-and-neck-cancer-immune-function-q8ppwndt.pdf

Role of Vitamin D in Head and Neck Cancer—Immune Function, Anti-Tumour Effect, and Its Impact on Patient Prognosis

Individuals with serious mental disorders (SMD) may have a higher risk of vitamin D (VIT-D) deficiency. They also experience higher mortality because of coronavirus disease 2019 (COVID-19) infection. Therefore, we have conducted a comprehensive review to examine the significance of VIT-D for public health and public mental health during the ongoing COVID-19 pandemic. This review had three specific aims, from a global perspective to (a) create a profile of VIT-D and review the epidemiology of VIT-D deficiency, (b) explore VIT-D deficiency as risk factor for SMD and COVID-19 infections and (c) examine the effectiveness of VIT-D supplementation for both conditions. We found that, in terms of SMD, the evidence from laboratory and observational studies points towards some association between VIT-D deficiency and depression or schizophrenia. Mendelian randomisation studies, however, suggest no, or reverse, causality. The evidence from intervention studies is conflicting. Concerning COVID-19 infection, on proof of principle, VIT-D could provide a plausible defence against the infection itself and against an adverse clinical course. But data from observational studies and the first preliminary intervention studies remain conflicting, with stronger evidence that VIT-D may mitigate the clinical course of COVID-19 infection rather than the risk of infection in the first place. From a public health and public mental health point of view, based on the currently limited knowledge, for individuals with SMD, the benefits of VIT-D optimisation through supplementation seem to outweigh the risks. VIT-D supplementation, however, should not substitute for vaccination or medical care for COVID-19 infection.

https://journals.sagepub.com/doi/pdf/10.1177/20451253211027699

Vitamin D in the time of the coronavirus (COVID-19) pandemic – a clinical review from a public health and public mental health perspective

Correlation between serum 25(OH)D and cognitive impairment in Parkinson's disease

The single‐stranded RNA virus, SARS‐CoV‐2, causing the COVID‐19 pandemic, has severely impacted daily life globally. It has been suggested to supplement the general population with vitamin D to reduce the impact of COVID‐19. Nevertheless, no clear consensus can be found as to whether vitamin D affects COVID‐19 disease burden. Some studies found that vitamin D levels and/or vitamin D supplementation alleviated COVID‐19 disease severity and mortality. Contrarily, other studies found no such effects of vitamin D. To understand this lack of consensus, it is relevant to investigate molecular studies of the vitamin D receptor (VDR), as such studies might explain apparent controversies. We have investigated recent studies of how transcriptional regulation by the VDR affects the immune response against SARS‐CoV‐2. One study found that cells from severe COVID‐19 patients displayed a dysregulated vitamin D response. Contrarily, another study observed a normal immune response towards SARS‐CoV‐2 in a patient with a non‐functional VDR. These observations indicate that hypovitaminosis D is not a prerequisite for an efficient immune response against SARS‐CoV‐2 and therefore not a driving factor for developing severe COVID‐19. However, should a patient develop severe COVID‐19, vitamin D seems to be beneficial potentially by dampening the cytokine storm.

https://onlinelibrary.wiley.com/doi/pdfdirect/10.1111/bcpt.13872

Vitamin D and SARS‐CoV‐2

Vitamin D inhibits palmitate-induced macrophage pro-inflammatory cytokine production by targeting the MAPK pathway

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Vitamin D inhibits palmitate-induced macrophage pro-inflammatory cytokine production by targeting the MAPK pathway