Carbon Chemist

Tag: Compound

  • Is there an association between vitamin D, immunocompetence, and aging?

    Is there an association between vitamin D, immunocompetence, and aging?

    [ad_1]

    In a recent review published in the journal Nutrients, researchers explored the role of an individual’s immunocompetence in the responsiveness to vitamin D.

    They discussed the modulation of immunocompetence via the epigenetic programming function of the vitamin D receptor (VDR) and its ligand and highlighted the impact of aging on immunocompetence.

    Study: Vitamin D and Aging: Central Role of Immunocompetence. Image Credit: Iryna Imago/Shutterstock.comStudy: Vitamin D and Aging: Central Role of Immunocompetence. Image Credit: Iryna Imago/Shutterstock.com

    Background

    Vitamin D plays a crucial role in bone health by regulating calcium homeostasis and preventing conditions like rickets and osteomalacia. However, its influence on immunity extends beyond this function.

    Vitamin D deficiency, linked to modern lifestyle factors like limited sun exposure, affects the endogenous production of active vitamin D metabolites.

    The inactive vitamin D3 is converted to active 1,25(OH)2D3 in the liver and kidneys, which acts as a hormone and affects various tissues. Notably, various cells, including those of the innate immune system, can produce 1,25(OH)2D3 locally, contributing to auto- and paracrine effects. This compound acts as a ligand of high affinity for VDR, regulating the expression of numerous genes.

    The vitamin D status, indicated by serum 25(OH)D3 levels, categorizes individuals into deficient, insufficient, or sufficient groups. Vitamin D responsiveness varies among people due to genetic and epigenetic factors influencing molecular responses.

    Low responders, constituting about 25% of the population, may have increased susceptibility to diseases related to compromised immunity. The VDR-based modulation of immunocompetence may contribute to aging and reduce the risk of age-related diseases.

    The present review offers insights into the immunomodulatory functions of vitamin D and its impact on various health aspects beyond bone metabolism.

    Vitamin D signaling

    VDR binds specifically to genomic DNA, recognizing the motif RGKTSA. In complex with retinoid X receptor (RXR), VDR preferentially binds to direct repeat sequences in the euchromatin. Various “pioneer factors” facilitate VDR in opening chromatin, which is crucial for efficient binding.

    Chromatin accessibility and VDR binding can be assessed using next-generation sequencing technologies, including ChIP-seq (chromatin immunoprecipitation sequencing) and ATAC-seq (assay for transposase-accessible chromatin using sequencing), especially in peripheral blood mononuclear cells.

    Genomic regions of vitamin D target genes demonstrate changes in chromatin accessibility and VDR binding after vitamin D3 supplementation.

    Enhancers and transcription start site regions, even at a considerable linear distance, can interact via DNA looping within the same topologically associating domain, influencing gene expression.

    VDR’s genomic actions involve protein-protein interactions with the Mediator complex and RNA polymerase II, influencing transcription. Vitamin D also exerts epigenomic effects, altering DNA methylation, histone modifications, and chromatin organization, dynamically shaping the cell’s epigenetic landscape.

    These genomic and epigenomic effects contribute to vitamin D’s modulatory role in hematopoiesis and immunocompetence, affecting human immune cells both in vitro and in vivo.

    Epigenetic programming of immune cells

    Throughout embryogenesis and adult cellular differentiation, stem and progenitor cells undergo epigenetic programming, determining the function of terminally differentiated cells. 1,25(OH)2D3 plays a crucial role in this process, influencing hematopoiesis and the differentiation of immune cells.

    Hematopoietic stem cells (HSCs) differentiate into various blood and immune cell types, and 1,25(OH)2D3 regulates embryonic HSC numbers.

    Various transcription factors influenced by vitamin D drive the differentiation of myeloid progenitor cells into granulocytes and monocytes. Vitamin D is also the differentiation of monocytes into dendritic cells and macrophages.

    Epigenetic programming by vitamin D contributes to innate immune cell adaptation, modulating responses to infections, inflammation, and diseases.

    Variability in vitamin D status and response index among individuals affects the epigenetic programming of monocytes and derived cells, emphasizing the potential of optimized vitamin D3 supplementation for supporting proper immune cell epigenetics and overall immunocompetence. However, further research is needed to validate this concept fully.

    Decline in immunocompetence during aging

    Aging involves accumulating molecular damage, resulting in cellular dysfunction and weakened organs. Immunocompetence, crucial for appropriate immune responses, declines with age, leading to increased susceptibility to infections and diseases.

    The thymus atrophies, diminishing the production of T-cells, and “inflammaging” ensues. However, interindividual differences exist, and some individuals may display relatively higher immunocompetence.

    Lower immunocompetence correlates with accelerated aging and heightened disease risks. Vitamin D sufficiency may protect against cancers by preserving immunocompetence.

    Adequate vitamin D levels could stabilize immune resilience, safeguard against diseases, and contribute to healthy aging by mitigating various hallmarks of aging, including inflammation and cellular stress.

    Conclusion

    In conclusion, the active form of vitamin D plays a crucial role in modulating the epigenome of immune cells, particularly in monocytes.

    The observed associations between vitamin D deficiency, increased disease risk, and accelerated aging may be attributed to diminished immunocompetence.

    Considering individual responsiveness, a precautionary daily vitamin D3 dose of 1 µg (40 IU)/kg body mass is suggested, exceeding general recommendations but staying within safe limits to strengthen immunocompetence. The researchers emphasize personalized vitamin D supplementation to safeguard against prevalent diseases and promote healthy aging.

    [ad_2]

    Source link

  • Researchers discover new class of compound that targets cancer stem cells

    Researchers discover new class of compound that targets cancer stem cells

    [ad_1]

    Many cancer therapies, in addition to producing numerous side effects, fail to achieve complete tumour remission, partly due to the presence of cancer stem cells, which are difficult to eradicate. These cells can self-renew and play a key role in tumor recurrence and metastasis processes, so there is significant interest in developing therapies that target this subset of tumour cells. 

    A collaboration between chemists from the Center for Research in Biological Chemistry and Molecular Materials (CiQUS), led by Prof. JL Mascareñas, and cell biologists from the CSIC (Instituto de Investigaciones Biomédicas Sols-Morreale, IIBM CSIC-UAM, Madrid), led by Dr. Bruno Sainz, has led to the discovery of a new class of compound that targets cancer stem cells and reduces their potential to generate tumors. For some years, Prof. Mascareñas’ laboratory has been conducting basic research on certain molecules based on metal complexes that can interact very selectively with DNA. These findings have allowed Dr. Sainz’s group to conduct extensive studies with mice implanted with patients’ tumors, demonstrating a powerful antitumor effect of these complexes. The scientists have demonstrated anticancer effects in pancreatic, colorectal, and osteosarcoma tumors, with low secondary toxicity, and studies on other types of cancer are currently underway. 

    Cancer stem cells rely on mitochondrial respiration to survive and evade the immune system’s defenses, which represents a metabolic Achilles’ heel. Mechanistic studies carried out this time suggest that the new compound, called Ru1, promotes a decrease in the expression of genes necessary for this respiration, the main energy source for these cells, causing them to lose their cancerous potential. Dr. Sainz’s group has also demonstrated that combined therapies with other antitumor agents are possible, resulting in additive effects. 

    The preliminary results of the scientific work, which also includes contributions from the USC’s ACUIGEN group, have just been published in a leading cancer research journal. All these studies have been made possible thanks to the support of different entities, including the Ignicia program (Xunta de Galicia), the Spanish Association Against Cancer, or the CaixaImpulse program (“la Caixa” Foundation), and the project is currently in an advanced stage for its transfer and preclinical valorization. 

    Source:

    Center for Research in Biological Chemistry and Molecular Materials (CiQUS)

    Journal reference:

    Alcalá, S., et al. (2024). Targeting cancer stem cell OXPHOS with tailored ruthenium complexes as a new anti-cancer strategy. Journal of Experimental & Clinical Cancer Research. doi.org/10.1186/s13046-023-02931-7.

    [ad_2]

    Source link