Diets that boost ketone production are increasingly used for treating several neurological disorders. Elevation in ketones in most cases is considered favorable, as they provide energy and are efficient in fueling the body’s energy needs. Despite all the benefits from ketones, the above normal elevation in the concentration of ketones in the circulation tend to illicit various pathological complications by activating injurious pathways leading to cellular damage. Recent literature demonstrates a plausible link between elevated levels of circulating ketones and oxidative stress, linking hyperketonemia to innumerable morbid conditions. Ketone bodies are produced by the oxidation of fatty acids in the liver as a source of alternative energy that generally occurs in glucose limiting conditions. Regulation of ketogenesis and ketolysis plays an important role in dictating ketone concentrations in the blood. Hyperketonemia is a condition with elevated blood levels of acetoacetate (AA), 3-β-hydroxybutyrate (BHB), and acetone. Several physiological and pathological triggers, such as fasting, ketogenic diet, and diabetes cause an accumulation and elevation of circulating ketones. Complications of the brain, kidney, liver, and microvasculature were found to be elevated in diabetic patients who had elevated ketones compared to those diabetics with normal ketone levels. This review summarizes the mechanisms by which hyperketonemia and ketoacidosis cause an increase in redox imbalance and thereby increasing the risk of morbidity and mortality in patients.

Aims: 25-Hydroxyvitamin D [25(OH)VD] deficiency/inadequacy is a major public health issue affecting more than 1 billion people worldwide. A convincing association exists between low levels of circulating 25(OH)VD and the poor health outcomes associated with chronic diseases. However, high supraphysiological doses of VD are needed to achieve the required 25(OH)VD levels in the blood, because many subjects respond poorly to supplementation.Results: This study reports a link between 25(OH)VD deficiency and a reduction in glutathione (GSH) in obese adolescents. The improvement in GSH status that results from cosupplementation with VD and l-cysteine (LC; a GSH precursor) significantly reduced oxidative stress in a mouse model of 25(OH)VD deficiency. It also positively upregulated VD regulatory genes (VDBP/VD-25-hydroxylase/VDR) in the liver and glucose metabolism genes (PGC-1α/VDR/GLUT-4) in muscle, boosted 25(OH)VD, and reduced inflammation and insulin resistance (IR) levels in the blood compared with supplementation with VD alone. In vitro GSH deficiency caused increased oxidative stress and downregulation of VDBP/VD-25-hydroxylase/VDR and upregulation of CYP24a1 in hepatocytes and downregulation of PGC-1α/VDR/GLUT-4 in myotubes. This study demonstrates that improvement in the GSH status exerts beneficial effects on the blood levels of 25(OH)VD, as well as on the inflammation and IR in a VD-deficient mouse model. Thus, the VD supplements widely consumed by the public are unlikely to be successful unless the GSH status is also corrected.Innovation: These studies demonstrate a previously undiscovered mechanism by which GSH status positively upregulates the bioavailability of 25(OH)VD.Conclusion: Supplementation with a combination of VD and LC or GSH precursor, rather than supplementation with VD alone, is beneficial and helps achieve more successful VD supplementation.

Background/Aims: The incidence of developing microvascular dysfunction is significantly higher in type 1 diabetic (T1D) patients. Hyperketonemia (acetoacetate, β-hydroxybutyrate) is frequently found along with hyperglycemia in T1D. Whether hyperketonemia per se contributes to the excess oxidative stress and cellular injury observed in T1D is not known. Methods: HUVEC were treated with ketones in the presence or absence of high glucose for 24 h. NOX4 siRNA was used to specifically knockdown NOX4 expression in HUVEC. Results: Ketones alone or in combination with high glucose treatment cause a significant increase in oxidative stress, ICAM-1, and monocyte adhesivity to HUVEC. Using an antisense approach, we show that ketone induced increases in ROS, ICAM-1 expression, and monocyte adhesion in endothelial cells were prevented in NOX4 knockdown cells. Conclusion: This study reports that elevated levels of ketones upregulate NOX, contributing to increased oxidative stress, ICAM-1 levels, and cellular dysfunction. This provides a novel biochemical mechanism that elucidates the role of hyperketonemia in the excess cellular injury in T1D. New drugs targeting inhibition of NOX seems promising in preventing higher risk of complications associated with T1D.

Platelets are cytoplasmic fragments generated by megakaryocytes in the bone marrow and do not possess a nucleus. They contribute to the "Circulome" consisting of all circulating cells, factors and macromolecules such as cfDNA. Their primary function is to recognize vascular lesions and initiate thrombus formation that ceases bleeding. This distinctive characteristic of platelets also contributes to cancer and its progression. The ability of platelets to recognize and interact with other cells and neighboring platelets enables them to interact with tumor cells in the circulation. Receptor recognition and factor mediated crosstalk between tumor cells and platelets stimulate platelet activation, release of factors, and aggregation that promotes tumor cell survival and cancer progression. This review describes platelet: (i) contributions to the "Circulome" (ii) their importance as diagnostic tools in predicting cancer risk and (iii) therapies targeting platelet activation in inhibiting tumor progression and metastasis.

Background There is a significantly higher incidence of cardiovascular disease (CVD) among type 1 diabetic (T1D) patients than among non-diabetic subjects. T1D is associated with hyperketonemia, a condition with elevated blood levels of ketones, in addition to hyperglycemia. The biochemical mechanism by which vitamin D (VD) may reduce the risk of CVD is not known. This study examines whether VD can be beneficial in reducing hyperketonemia (acetoacetate, AA) induced oxidative stress in endothelial cells. Methods HUVEC were pretreated with 1,25(OH)2D3, and later exposed to the ketone body acetoacetate. Results The increases in ROS production, ICAM-1 expression, MCP-1 secretion, and monocyte adhesion in HUVEC treated with AA were significantly reduced following treatment with 1,25(OH)2D3. Interestingly, an increase in glutathione (GSH) levels was also observed with 1,25(OH)2D3 in ketone treated cells. The effects of 1,25(OH)2D3 on GSH, ROS, and monocyte-endothelial adhesion were prevented in GCLC knockdown HUVEC. This suggests that 1,25(OH)2D3 inhibits ROS, MCP-1, ICAM-1, and adherence of monocytes mediated by the upregulation of GCLC and GSH. Conclusion This study provides evidence for the biochemical mechanism through which VD supplementation may reduce the excess monocyte adhesion to endothelium and inflammation associated with T1D.

ScopeVitamin D binding protein (VDBP) status has an effect on and can potentially improve the status of 25(OH) vitamin D and increase the metabolic actions of 25(OH) vitamin D under physiological and pathological conditions. Diabetes is associated with lower levels of glutathione (GSH) and 25(OH) vitamin D. This study examined the hypothesis that upregulation of GSH will also upregulate blood levels of VDBP and 25(OH) vitamin D in type 2 diabetic rats.Methods and resultsL‐cysteine (LC) supplementation was used to upregulate GSH status in a FL83B hepatocyte cell culture model and in vivo using Zucker diabetic fatty (ZDF) rats. Results show that LC supplementation upregulates both protein and mRNA expression of VDBP and vitamin D receptor (VDR) and GSH status in hepatocytes exposed to high glucose, and that GSH deficiency, induced by glutamate cysteine ligase knockdown, resulted in the downregulation of GSH, VDBP, and VDR and an increase in oxidative stress levels in hepatocytes. In vivo, LC supplementation increased GSH and protein and mRNA expression of VDBP and vitamin D 25‐hydroxylase (CYP2R1) in the liver, and simultaneously resulted in elevated blood levels of LC and GSH, as well as increases in VDBP and 25(OH) vitamin D levels, and decreased inflammatory biomarkers in ZDF rats compared with those in placebo‐supplemented ZDF rats consuming a similar diet.ConclusionLC supplementation may provide a novel approach by which to raise blood levels of VDBP and 25(OH) vitamin D in type 2 diabetes.

The role of platelets in cancer progression has been well recognized in the field of cancer biology. Emerging studies are elaborating further the additional roles and added extent that platelets play in promoting tumorigenesis. Platelets release factors that support tumor growth and also form heterotypic aggregates with tumor cells, which can provide an immune-evasive advantage. Their most critical role may be the inhibition of immune cell function that can negatively impact the body’s ability in preventing tumor establishment and growth. This review summarizes the importance of platelets in tumor progression, therapeutic response, survival, and finally the notion of immunotherapy modulation being likely to benefit from the inclusion of platelet inhibitors.

The consensus molecular subtypes (CMS) in colorectal cancer (CRC) represent distinct molecular subcategories of disease as reflected by comprehensive molecular profiling. The four CMS subtypes represent unique biology. CMS1 represents high immune infiltration. CMS2 demonstrates upregulation of canonical pathways such as WNT signaling. Widespread metabolic changes are seen in CMS3. CMS4 represents a mesenchymal phenotype with hallmark features including complement activation, matrix remodeling, angiogenesis, epithelial-mesechymal transition (EMT), integrin upregulation and stromal infiltration. In contrast to this new paradigm, a number of observations regarding CRC remain disconnected. Cancers are associated with thrombocytosis. Venous thromboembolic events are more likely in malignancy and may signify worse prognosis. Aspirin, an anti-platelet agent, has been linked in large observational studies to decrease incidence of adenocarcinoma and less advanced presentations of cancer, in particular CRC. Inflammatory bowel disease is a risk factor for CRC. Gross markers to recognize the immunothrombotic link such as the platelet to lymphocyte ratio are associated with poorer outcomes in many cancers. Platelets are increasingly recognized for their dual roles in coordinating the immune response in addition to hemostasis. Here, we explore how these different but related observations coalesce. Platelets, as first responders to pathogens and injury, form the link between hemostasis and immunity. We outline how platelets contribute to tumorigenesis and how some disconnected ideas may be linked through inflammation. CMS4 through its shared mechanisms has predicted platelet activation as a hallmark feature. We demonstrate a platelet gene expression signature that predicts platelet presence within CMS4 tumors.