Preventive Effect of Vitamin C on Dextran Sulfate Sodium (DSS)-Induced Colitis via the Regulation of IL-22 and IL-6 Production in Gulo(−/−) Mice

Reactive oxygen species (ROS), which are exceptionally high in IBD lesions, are known to cause abnormal immune responses to inflammatory reactions in inflammatory bowel diseases (IBD) through damage to the intestinal mucosal linings. Moreover, they are theorized to be an agent of IBD development. Vitamin C is widely known to be an effective antioxidant for its ability to regulate inflammatory responses through its ROS scavenging effect. Therefore, we examined vitamin C’s influence on the development and progression of IBD in Gulo(−/−) mice, which cannot synthesize vitamin C like humans due to a defect in the expression of L-gulono-γ–lactone oxidase, an essential enzyme for vitamin C production. First, we found extensive oxidative stress and an inflammation increase in the colon of vitamin C-insufficient Gulo(−/−) mice. We also found decreased IL-22 production and NKp46(+) cell recruitment and the impaired activation of the p38MAPK pathway. Additionally, comparing vitamin C-insufficient Gulo(−/−) mice to vitamin C-sufficient Gulo(−/−) mice and wild-type mice, the insufficient group faced a decrease in mucin-1 expression, accompanied by an increase in IL-6 production, followed by the activation of the STAT3 and Akt pathways. The results suggest that vitamin C insufficiency induces severe colitis, meaning vitamin C could also take on a preventative role by regulating the production of cytokines and the induction of inflammation.     

Vitamin C and Heart Health: A Review Based on Findings from Epidemiologic Studies

Vitamin C is a powerful dietary antioxidant that has received considerable attention in the literature related to its possible role in heart health. Although classical vitamin C deficiency, marked by scurvy, is rare in most parts of the world, some research has shown variable heart disease risks depending on plasma vitamin C concentration, even within the normal range. Furthermore, other studies have suggested possible heart-related benefits to vitamin C taken in doses beyond the minimal amounts required to prevent classically defined deficiency. The objective of this review is to systematically review the findings of existing epidemiologic research on vitamin C and its potential role in cardiovascular disease (CVD). It is well established that vitamin C inhibits oxidation of LDL-protein, thereby reducing atherosclerosis, but the cardiovascular outcomes related to this action and other actions of vitamin C are not fully understood. Randomized controlled trials as well as observational cohort studies have investigated this topic with varying results. Vitamin C has been linked in some work to improvements in lipid profiles, arterial stiffness, and endothelial function. However, other studies have failed to confirm these results, and observational cohort studies are varied in their findings on the vitamin’s effect on CVD risk and mortality. Overall, current research suggests that vitamin C deficiency is associated with a higher risk of mortality from CVD and that vitamin C may slightly improve endothelial function and lipid profiles in some groups, especially those with low plasma vitamin C levels. However, the current literature provides little support for the widespread use of vitamin C supplementation to reduce CVD risk or mortality.     

Vitamin D Analogs Regulate the Vitamin D System and Cell Viability in Ovarian Cancer Cells

Background: Ovarian cancer (OC) is one of the most lethal cancers in women. The active form of vitamin D₃, 1,25-dihydroxyvitamin D₃ (1,25D₃, calcitriol) has anticancer activity in several cancers, including ovarian cancer, but the required pharmacological doses may cause hypercalcemia. We hypothesized that newly developed, low calcemic, vitamin D analogs (an1,25Ds) may be used as anticancer agents instead of calcitriol in ovarian cancer cells. Methods: We used two patient-derived high-grade serous ovarian cancer (HGSOC) cell lines with low (13781) and high (14433) mRNA expression levels of the gene encoding 1,25-dihydroxyvitamin D₃ 24-hydroxylase CYP24A1, one of the main target genes of calcitriol. We tested the effect of calcitriol and four structurally related series of an1,25Ds (PRI-1906, PRI-1907, PRI-5201, PRI-5202) on cell number, viability, the expression of CYP24A1, and the vitamin D receptor (VDR). Results: CYP24A1 mRNA expression increased in a concentration-dependent manner after treatment with all compounds. In both cell lines, after 4 h, PRI-5202 was the most potent analog (in 13781 cells: EC₅₀ = 2.98 ± 1.10 nmol/L, in 14433 cells: EC₅₀ = 0.92 ± 0.20 nmol/L), while PRI-1907 was the least active one (in 13781 cells: EC₅₀ = n/d, in 14433 cells: EC₅₀ = n/d). This difference among the analogs disappeared after 5 days of treatment. The 13781 cells were more sensitive to the an1,25Ds compared with 14433 cells. The an1,25Ds increased nuclear VDR levels and reduced cell viability, but only in the 13781 cell line. Conclusions: The an1,25Ds had different potencies in the HGSOC cell lines and their efficacy in increasing CYP24A1 expression was cell line- and chemical structure-dependent. Therefore, choosing sensitive cancer cell lines and further optimization of the analogs’ structure might lead to new treatment options against ovarian cancer.     

Vitamin C Suppresses Pancreatic Carcinogenesis through the Inhibition of Both Glucose Metabolism and Wnt Signaling

Cumulative studies have indicated that high-dose vitamin C has antitumor effects against a variety of cancers. However, the molecular mechanisms underlying these inhibitory effects against tumorigenesis and metastasis, particularly in relation to pancreatic cancer, are unclear. Here, we report that vitamin C at high concentrations impairs the growth and survival of pancreatic ductal adenocarcinoma (PDAC) cells by inhibiting glucose metabolism. Vitamin C was also found to trigger apoptosis in a caspase-independent manner. We further demonstrate that it suppresses the invasion and metastasis of PDAC cells by inhibiting the Wnt/β-catenin-mediated epithelial-mesenchymal transition (EMT). Taken together, our results suggest that vitamin C has therapeutic effects against pancreatic cancer.     

Vitamin D-Related Genes and Thyroid Cancer—A Systematic Review

Vitamin D, formerly known for its role in calcium-phosphorus homeostasis, was shown to exert a broad influence on immunity and on differentiation and proliferation processes in the last few years. In the field of endocrinology, there is proof of the potential role of vitamin D and vitamin D-related genes in the pathogenesis of thyroid cancer—the most prevalent endocrine malignancy. Therefore, the study aimed to systematically review the publications on the association between vitamin D-related gene variants (polymorphisms, mutations, etc.) and thyroid cancer. PubMed, EMBASE, Scopus, and Web of Science electronic databases were searched for relevant studies. A total of ten studies were found that met the inclusion criteria. Six vitamin D-related genes were analyzed (VDR—vitamin D receptor, CYP2R1—cytochrome P450 family 2 subfamily R member 1, CYP24A1—cytochrome P450 family 24 subfamily A member 1, CYP27B1—cytochrome P450 family 27 subfamily B member 1, DHCR7—7-dehydrocholesterol reductase and CUBN—cubilin). Moreover, a meta-analysis was conducted to summarize the data from the studies on VDR polymorphisms (rs2228570/FokI, rs1544410/BsmI, rs7975232/ApaI and rs731236/TaqI). Some associations between thyroid cancer risk (VDR, CYP24A1, DHCR7) or the clinical course of the disease (VDR) and vitamin D-related gene polymorphisms were described in the literature. However, these results seem inconclusive and need validation. A meta-analysis of the five studies of common VDR polymorphisms did not confirm their association with increased susceptibility to differentiated thyroid cancer. Further efforts are necessary to improve our understanding of thyroid cancer pathogenesis and implement targeted therapies for refractory cases.     

Enjoy Carefully: The Multifaceted Role of Vitamin E in Neuro-Nutrition

Vitamin E is often associated with health benefits, such as antioxidant, anti-inflammatory and cholesterol-lowering effects. These properties make its supplementation a suitable therapeutic approach in neurodegenerative disorders, for example, Alzheimer’s or Parkinson’s disease. However, trials evaluating the effects of vitamin E supplementation are inconsistent. In randomized controlled trials, the observed associations often cannot be substantiated. This could be due to the wide variety of study designs regarding the dosage and duration of vitamin E supplementation. Furthermore, genetic variants can influence vitamin E uptake and/or metabolism, thereby distorting its overall effect. Recent studies also show adverse effects of vitamin E supplementation regarding Alzheimer’s disease due to the increased synthesis of amyloid β. These diverse effects may underline the inhomogeneous outcomes associated with its supplementation and argue for a more thoughtful usage of vitamin E. Specifically, the genetic and nutritional profile should be taken into consideration to identify suitable candidates who will benefit from supplementation. In this review, we will provide an overview of the current knowledge of vitamin E supplementation in neurodegenerative disease and give an outlook on individualized, sustainable neuro-nutrition, with a focus on vitamin E supplementation.     

Parkinson’s Disease Etiology: Insights and Associations with Phosphate Toxicity

The present paper investigated the association of Parkinson’s disease etiology with phosphate toxicity, a pathophysiological condition in which dysregulated phosphate metabolism causes excessive inorganic phosphate sequestration in body tissue that damages organ systems. Excessive phosphate is proposed to reduce Complex I function of the mitochondrial electron transport chain in Parkinson’s disease and is linked to opening of the mitochondrial permeability transition pore, resulting in increased reactive oxygen species, inflammation, DNA damage, mitochondrial membrane depolarization, and ATP depletion causing cell death. Parkinson’s disease is associated with α-synuclein and Lewy body dementia, a secondary tauopathy related to hyperphosphorylation of tau protein, and tauopathy is among several pathophysiological pathways shared between Parkinson’s disease and diabetes. Excessive phosphate is also associated with ectopic calcification, bone mineral disorders, and low levels of serum vitamin D in patients with Parkinson’s disease. Sarcopenia and cancer in Parkinson’s disease patients are also associated with phosphate toxicity. Additionally, Parkinson’s disease benefits are related to low dietary phosphate intake. More studies are needed to investigate the potential mediating role of phosphate toxicity in the etiology of Parkinson’s disease.     

The Role of Vitamin D in Supporting Health in the COVID-19 Era

The genomic activity of vitamin D is associated with metabolic effects, and the hormone has a strong impact on several physiological functions and, therefore, on health. Among its renowned functions, vitamin D is an immunomodulator and a molecule with an anti-inflammatory effect, and, recently, it has been much studied in relation to its response against viral infections, especially against COVID-19. This review aims to take stock of the correlation studies between vitamin D deficiency and increased risks of severe COVID-19 disease and, similarly, between vitamin D deficiency and acute respiratory distress syndrome. Based on this evidence, supplementation with vitamin D has been tested in clinical trials, and the results are discussed. Finally, this study includes a biochemical analysis on the effects of vitamin D in the body’s defense mechanisms against viral infection. In particular, the antioxidant and anti-inflammatory functions are considered in relation to energy metabolism, and the potential, beneficial effect of vitamin D in COVID-19 is described, with discussion of its influence on different biochemical pathways. The proposed, broader view of vitamin D activity could support a better-integrated approach in supplementation strategies against severe COVID-19, which could be valuable in a near future of living with an infection becoming endemic.     

Effects of Hypocalcemic Vitamin D Analogs in the Expression of DNA Damage Induced in Minilungs from hESCs: Implications for Lung Fibrosis

In our previous work, we evaluated the therapeutic effects of 1α,25-Dihydroxyvitamin D₃, the biologically active form of vitamin D, in the context of bleomycin-induced lung fibrosis. Contrary to the expected, vitamin D supplementation increased the DNA damage expression and cellular senescence in alveolar epithelial type II cells and aggravated the overall lung pathology induced in mice by bleomycin. These effects were probably due to an alteration in the cellular DNA double-strand breaks’ repair capability. In the present work, we have evaluated the effects of two hypocalcemic vitamin D analogs (calcipotriol and paricalcitol) in the expression of DNA damage in the context of minilungs derived from human embryonic stem cells and in the cell line A549.     

Interaction between Metformin,Folate and Vitamin B12 and the Potential Impact on Fetal Growth and Long-Term Metabolic Health in Diabetic Pregnancies

Metformin is the first-line treatment for many people with type 2 diabetes mellitus (T2DM) and gestational diabetes mellitus (GDM) to maintain glycaemic control. Recent evidence suggests metformin can cross the placenta during pregnancy, thereby exposing the fetus to high concentrations of metformin and potentially restricting placental and fetal growth. Offspring exposed to metformin during gestation are at increased risk of being born small for gestational age (SGA) and show signs of ‘catch up’ growth and obesity during childhood which increases their risk of future cardiometabolic diseases. The mechanisms by which metformin impacts on the fetal growth and long-term health of the offspring remain to be established. Metformin is associated with maternal vitamin B₁₂ deficiency and antifolate like activity. Vitamin B₁₂ and folate balance is vital for one carbon metabolism, which is essential for DNA methylation and purine/pyrimidine synthesis of nucleic acids. Folate:vitamin B₁₂ imbalance induced by metformin may lead to genomic instability and aberrant gene expression, thus promoting fetal programming. Mitochondrial aerobic respiration may also be affected, thereby inhibiting placental and fetal growth, and suppressing mammalian target of rapamycin (mTOR) activity for cellular nutrient transport. Vitamin supplementation, before or during metformin treatment in pregnancy, could be a promising strategy to improve maternal vitamin B₁₂ and folate levels and reduce the incidence of SGA births and childhood obesity. Heterogeneous diagnostic and screening criteria for GDM and the transient nature of nutrient biomarkers have led to inconsistencies in clinical study designs to investigate the effects of metformin on folate:vitamin B₁₂ balance and child development. As rates of diabetes in pregnancy continue to escalate, more women are likely to be prescribed metformin; thus, it is of paramount importance to improve our understanding of metformin’s transgenerational effects to develop prophylactic strategies for the prevention of adverse fetal outcomes.     

Micro-RNAs in Response to Active Forms of Vitamin D3 in Human Leukemia and Lymphoma Cells

Non-coding micro-RNA (miRNAs) regulate the protein expression responsible for cell growth and proliferation. miRNAs also play a role in a cancer cells’ response to drug treatment. Knowing that leukemia and lymphoma cells show different responses to active forms of vitamin D₃, we decided to investigate the role of selected miRNA molecules and regulated proteins, analyzing if there is a correlation between the selected miRNAs and regulated proteins in response to two active forms of vitamin D₃, calcitriol and tacalcitol. A total of nine human cell lines were analyzed: five leukemias: MV-4-1, Thp-1, HL-60, K562, and KG-1; and four lymphomas: Raji, Daudi, Jurkat, and U2932. We selected five miRNA molecules—miR-27b, miR-32, miR-125b, miR-181a, and miR-181b—and the proteins regulated by these molecules, namely, CYP24A1, Bak1, Bim, p21, p27, p53, and NF-kB. The results showed that the level of selected miRNAs correlates with the level of proteins, especially p27, Bak1, NFκB, and CYP24A1, and miR-27b and miR-125b could be responsible for the anticancer activity of active forms of vitamin D₃ in human leukemia and lymphoma.     

活性炭对维生素B3和维生素C吸附与缓释行为研究

研究活性炭吸附维生素B3和维生素C以及在模拟体内环境中的释放过程。探讨了活性炭孔结构对吸附维生素如和维生素C的影响,并对活性炭缓释维生素B3过程进行了数学模拟,初步探讨了吸附和释放机制。实验所用活性炭对维生素B3有较强吸附能力,吸附量达到了94．9mg／g,对维生素C的吸附量仅38．5mg/g。采用活性炭对维生素磁有良好的缓释性能,其整个释放过程符合药物体外释放一级动力学模型为Q=38.25—36．90e^-0.04924t。所用活性炭适于作为缓释维生素B3的载体,而由于维生素C的不稳定性,不适宜使用活性炭缓释。     

活性炭对维生素B_3和维生素C吸附与缓释行为研究

研究活性炭吸附维生素B3和维生素C以及在模拟体内环境中的释放过程。探讨了活性炭孔结构对吸附维生素B3和维生素C的影响,并对活性炭缓释维生素B3过程进行了数学模拟,初步探讨了吸附和释放机制。实验所用活性炭对维生素B3有较强吸附能力,吸附量达到了94.9 mg/g,对维生素C的吸附量仅38.5 mg/g。采用活性炭对维生素B3有良好的缓释性能,其整个释放过程符合药物体外释放一级动力学模型为Q=38.25-36.90 e-0.049 24t。所用活性炭适于作为缓释维生素B3的载体,而由于维生素C的不稳定性,不适宜使用活性炭缓释。     

Blocking Muscarinic Receptor 3 Attenuates Tumor Growth and Decreases Immunosuppressive and Cholinergic Markers in an Orthotopic Mouse Model of Colorectal Cancer

Tumor cells have evolved to express immunosuppressive molecules allowing their evasion from the host’s immune system. These molecules include programmed death ligands 1 and 2 (PD-L1 and PD-L2). Cancer cells can also produce acetylcholine (ACh), which plays a role in tumor development. Moreover, tumor innervation can stimulate vascularization leading to tumor growth and metastasis. The effects of atropine and muscarinic receptor 3 (M3R) blocker, 1,1-dimethyl-4-diphenylacetoxypiperidinium iodide (4-DAMP), on cancer growth and spread were evaluated in vitro using murine colon cancer cell line, CT-26, and in vivo in an orthotopic mouse model of colorectal cancer. In the in vitro model, atropine and 4-DAMP significantly inhibited CT-26 cell proliferation in a dose dependent manner and induced apoptosis. Atropine attenuated immunosuppressive markers and M3R via inhibition of EGFR/AKT/ERK signaling pathways. However, 4-DAMP showed no effect on the expression of PD-L1, PD-L2, and choline acetyltransferase (ChAT) on CT-26 cells but attenuated M3R by suppressing the phosphorylation of AKT and ERK. Blocking of M3R in vivo decreased tumor growth and expression of immunosuppressive, cholinergic, and angiogenic markers through inhibition of AKT and ERK, leading to an improved immune response against cancer. The expression of immunosuppressive and cholinergic markers may hold potential in determining prognosis and treatment regimens for colorectal cancer patients. This study’s results demonstrate that blocking M3R has pronounced antitumor effects via several mechanisms, including inhibition of immunosuppressive molecules, enhancement of antitumor immune response, and suppression of tumor angiogenesis via suppression of the AKT/ERK signaling pathway. These findings suggest a crosstalk between the cholinergic and immune systems during cancer development. In addition, the cholinergic system influences cancer evasion from the host’s immunity.     

Role of Cannabidiol for Improvement of the Quality of Life in Cancer Patients: Potential and Challenges

There is currently a growing interest in the use of cannabidiol (CBD) to alleviate the symptoms caused by cancer, including pain, sleep disruption, and anxiety. CBD is often self-administered as an over-the-counter supplement, and patients have reported benefits from its use. However, despite the progress made, the mechanisms underlying CBD’s anti-cancer activity remain divergent and unclear. Herein, we provide a comprehensive review of molecular mechanisms to determine convergent anti-cancer actions of CBD from pre-clinical and clinical studies. In vitro studies have begun to elucidate the molecular targets of CBD and provide evidence of CBD’s anti-tumor properties in cell and mouse models of cancer. Furthermore, several clinical trials have been completed testing CBD’s efficacy in treating cancer-related pain. However, most use a mixture of CBD and the psychoactive, tetrahydrocannabinol (THC), and/or use variable dosing that is not consistent between individual patients. Despite these limitations, significant reductions in pain and opioid use have been reported in cancer patients using CBD or CBD+THC. Additionally, significant improvements in quality-of-life measures and patients’ overall satisfaction with their treatment have been reported. Thus, there is growing evidence suggesting that CBD might be useful to improve the overall quality of life of cancer patients by both alleviating cancer symptoms and by synergizing with cancer therapies to improve their efficacy. However, many questions remain unanswered regarding the use of CBD in cancer treatment, including the optimal dose, effective combinations with other drugs, and which biomarkers/clinical presentation of symptoms may guide its use.     

Solid Tumors and Kinase Inhibition: Management and Therapy Efficacy Evolution

The increasing numbers of cancer cases worldwide and the exceedingly high mortality rates of some tumor subtypes raise the question about if the current protocols for cancer management are effective and what has been done to improve upon oncologic patients’ prognoses. The traditional chemo-immunotherapy options for cancer treatment focus on the use of cytotoxic agents that are able to overcome neoplastic clones’ survival mechanisms and induce apoptosis, as well as on the ability to capacitate the host’s immune system to hinder the continuous growth of malignant cells. The need to avert the highly toxic profiles of conventional chemo-immunotherapy and to overcome the emerging cases of tumor multidrug resistance has fueled a growing interest in the field of precision medicine and targeted molecular therapies in the last couple of decades, although relatively new alternatives in oncologic practices, the increased specificity, and the positive clinical outcomes achieved through targeted molecular therapies have already consolidated them as promising prospects for the future of cancer management. In recent years, the development and application of targeted drugs as tyrosine kinase inhibitors have enabled cancer treatment to enter the era of specificity. In addition, the combined use of targeted therapy, immunotherapy, and traditional chemotherapy has innovated the standard treatment for many malignancies, bringing new light to patients with recurrent tumors. This article comprises a series of clinical trials that, in the past 5 years, utilized kinase inhibitors (KIs) as a monotherapy or in combination with other cytotoxic agents to treat patients afflicted with solid tumors. The results, with varying degrees of efficacy, are reported.     

In Silico and In Vitro Studies of Benzothiazole-Isothioureas Derivatives as a Multitarget Compound for Alzheimer’s Disease

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder. Inhibiting acetylcholinesterase (AChE), amyloid beta (Aβ_1-42) aggregation and avoiding the oxidative stress could prevent the progression of AD. Benzothiazole groups have shown neuroprotective activity whereas isothioureas groups act as AChE inhibitors and antioxidants. Therefore, 22 benzothiazole-isothiourea derivatives (3a–v) were evaluated by docking simulations as inhibitors of AChE and Aβ_1-42 aggregation. In silico studies showed that 3f, 3r and 3t had a delta G (ΔG) value better than curcumin and galantamine on Aβ_1-42 and AChE, respectively. The physicochemical and pharmacokinetics predictions showed that only 3t does not violate Lipinski’s rule of five, though it has moderated cytotoxicity activity. Then, 3f, 3r and 3t were synthetized and chemically characterized for their in vitro evaluation including their antioxidant activity and their cytotoxicity in PC12 cells. 3r was able to inhibit AChE, avoid Aβ_1-42 aggregation and exhibit antioxidant activity; nevertheless, it showed cytotoxic against PC12 cells. Compound 3t showed the best anti-Aβ_1-42 aggregation and inhibitory AChE activity and, despite that predictor, showed that it could be cytotoxic; in vitro with PC12 cell was negative. Therefore, 3t could be employed as a scaffold to develop new molecules with multitarget activity for AD and, due to physicochemical and pharmacokinetics predictions, it could be administered in vivo using liposomes due to is not able to cross the BBB.