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Background: Cerebrotendinous xanthomatosis (CTX) is a rare lipid storage disease, caused by deficiency of sterol-27-hydroxylase. Xanthomatous lesions in numerous tissues, and an elevation of cholestanol levels, characterize the disease. Its natural course is progressive neurologic deterioration, leading to premature death. Chronic treatment with oral chenodeoxycholic acid (CDCA) reduces cholestanol levels. Occurrence of premature atherosclerosis has been described in CTX in an unknown mechanism.Aim: The aim of the current work was to evaluate the potential metabolic abnormalities and preclinical vascular changes in Israeli CTX patients.Methods: Ten subjects with CTX were studied. Features of the metabolic syndrome were evaluated, and carotid intima media thickness (cIMT) was measured in the common carotid arteries.Results: All patients were diagnosed with CTX, and all received treatment with CDCA, which resulted in normalization of their plasma cholestanol levels. At the conclusion of the follow up, risk factors for CVD and features of MS were present in all the patients and in three patients, cIMT was higher compared to control subjects.Conclusion: Cardiovascular risk factors and premature vascular changes exist in young CTX patients and proper assessment should be implemented with preventive measures to reduce the risk of atherosclerotic cardiovascular disease in CTX patients.

For patients with advanced non-small-cell lung cancer (NSCLC), dual immune checkpoint blockade (ICB) with CTLA4 inhibitors and PD-1 or PD-L1 inhibitors (hereafter, PD-(L)1 inhibitors) is associated with higher rates of anti-tumour activity and immune-related toxicities, when compared with treatment with PD-(L)1 inhibitors alone. However, there are currently no validated biomarkers to identify which patients will benefit from dual ICB1,2. Here we show that patients with NSCLC who have mutations in the STK11 and/or KEAP1 tumour suppressor genes derived clinical benefit from dual ICB with the PD-L1 inhibitor durvalumab and the CTLA4 inhibitor tremelimumab, but not from durvalumab alone, when added to chemotherapy in the randomized phase III POSEIDON trial3. Unbiased genetic screens identified loss of both of these tumour suppressor genes as independent drivers of resistance to PD-(L)1 inhibition, and showed that loss of Keap1 was the strongest genomic predictor of dual ICB efficacy-a finding that was confirmed in several mouse models of Kras-driven NSCLC. In both mouse models and patients, KEAP1 and STK11 alterations were associated with an adverse tumour microenvironment, which was characterized by a preponderance of suppressive myeloid cells and the depletion of CD8+ cytotoxic T cells, but relative sparing of CD4+ effector subsets. Dual ICB potently engaged CD4+ effector cells and reprogrammed the tumour myeloid cell compartment towards inducible nitric oxide synthase (iNOS)-expressing tumoricidal phenotypes that-together with CD4+ and CD8+ T cells-contributed to anti-tumour efficacy. These data support the use of chemo-immunotherapy with dual ICB to mitigate resistance to PD-(L)1 inhibition in patients with NSCLC who have STK11 and/or KEAP1 alterations.

Carotenoids are common and diverse organic compounds with various functional roles in animals. Except for certain aphids, mites, and gall midges, all animals only acquire necessary carotenoids through their diet. The house fly (Musca domestica) is a cosmopolitan pest insect that populates diverse habitats. Its larvae feed on organic substrates that may vary in carotenoid composition according to their specific content. We hypothesized that the carotenoid composition in the adult house fly’s body would reflect the carotenoid composition in the larval feed. House fly larvae were reared on diets that differed in carotenoid composition. HPLC analysis of the emerging adult flies indicate that the carotenoid composition of adult house flies is related, but not identical, to the carotenoid composition in its natal substrate. These findings may be developed to help identify potential sources of house fly infestations. Also, it is recommended that rearing substrates of house fly larvae, used for animal feed, should be carefully considered.

Given the health benefits of carotenoids, it is crucial to evaluate their levels in patients undergoing malabsorptive procedures like one anastomosis gastric bypass (OAGB). This study aimed to assess serum carotenoid levels before and 6 months following OAGB. Prospectively collected data from patients who underwent primary OAGB were analyzed. Data included anthropometrics, dietary intake assessments, and biochemical tests. Serum samples were analyzed for lipid profile and serum carotenoids, including lutein, zeaxanthin, α-carotene, β-carotene, phytofluene, ζ-carotene, and lycopene. Data from 27 patients (median age 47.0 years and 55.6% female) were available before and 6 months post-OAGB. The median pre-surgical BMI was 39.5 kg/m2, and the median excess weight loss at 6 months post-surgery was 63.9%. Significant decreases in all carotenoid levels were observed over time (p < 0.001 for all). A median relative decline of 65.1% in absolute total carotenoid levels and 12.7% in total cholesterol levels were found. No associations were observed between changes in clinical outcomes and carotenoid levels during the study period. This study reveals significant decreases in carotenoid levels within the first 6 months following OAGB. Nutritional intervention studies are needed to explore how incorporating carotenoid-rich foods affects post-surgery carotenoid levels and clinical outcomes. [ABSTRACT FROM AUTHOR]

Simple Summary: Carotenoids are organic compounds with various important functions in animals. Most animals obtain their carotenoids only from their food. House flies are common pests with a worldwide distribution. Their larvae feed on organic matter that may vary substantially in its carotenoid composition. This study examines if the carotenoid composition in the body of adult house flies is related to the composition in the larval feed. House fly larvae were reared on diets that differed in carotenoid composition. HPLC analysis of the emerging adult flies indicates that the carotenoid composition in adult house flies was similar, but not identical, to the composition in the larval feed. These results suggest that carotenoid composition in adult flies may be used to estimate the composition in their natal habitat and therefore may be used to identify potential sources of house fly infestations. Also, the feed of house fly larvae, used for animal feed, should be carefully considered. Carotenoids are common and diverse organic compounds with various functional roles in animals. Except for certain aphids, mites, and gall midges, all animals only acquire necessary carotenoids through their diet. The house fly (Musca domestica) is a cosmopolitan pest insect that populates diverse habitats. Its larvae feed on organic substrates that may vary in carotenoid composition according to their specific content. We hypothesized that the carotenoid composition in the adult house fly's body would reflect the carotenoid composition in the larval feed. House fly larvae were reared on diets that differed in carotenoid composition. HPLC analysis of the emerging adult flies indicate that the carotenoid composition of adult house flies is related, but not identical, to the carotenoid composition in its natal substrate. These findings may be developed to help identify potential sources of house fly infestations. Also, it is recommended that rearing substrates of house fly larvae, used for animal feed, should be carefully considered. [ABSTRACT FROM AUTHOR]

Vitamin A and provitamin A carotenoids are involved in the regulation of adipose tissue metabolism and inflammation. We examined the effect of dietary supplementation using all-trans and 9-cis β-carotene-rich Dunaliella bardawil alga as the sole source of vitamin A on obesity-associated comorbidities and adipose tissue dysfunction in a diet-induced obesity mouse model. Three-week-old male mice (C57BL/6) were randomly allocated into two groups and fed a high-fat, vitamin A-deficient diet supplemented with either vitamin A (HFD) or β-carotene (BC) (HFD-BC). Vitamin A levels in the liver, WATs, and BAT of the HFD-BC group were 1.5–2.4-fold higher than of the HFD group. BC concentrations were 5–6-fold greater in BAT compared to WAT in the HFD-BC group. The eWAT mRNA levels of the Mcp-1 and Cd68 were 1.6- and 2.1-fold lower, respectively, and the plasma cholesterol and triglyceride concentrations were 30% and 28% lower in the HFD-BC group compared with the HFD group. Dietary BC can be the exclusive vitamin A source in mice fed a high-fat diet, as shown by the vitamin A concentration in the plasma and tissues. Feeding BC rather than vitamin A reduces adipose tissue macrophage recruitment markers and plasma lipid concentrations.

Objective While extensive research revealed that interleukin (IL)-1β contributes to insulin resistance (IR) development, the role of IL-1α in obesity and IR was scarcely studied. Using control, whole body IL-1α knockout (KO) or myeloid-cell-specific IL-1α-deficient mice, we tested the hypothesis that IL-1α deficiency would protect against high-fat diet (HFD)-induced obesity and its metabolic consequences.Research design and methods To induce obesity and IR, control and IL-1α KO mice were given either chow or HFD for 16 weeks. Glucose tolerance test was performed at 10 and 15 weeks, representing early and progressive stages of glucose intolerance, respectively. Liver and epididymal white adipose tissue (eWAT) samples were analyzed for general morphology and adipocyte size. Plasma levels of adiponectin, insulin, total cholesterol and triglyceride (TG), lipoprotein profile as well as hepatic lipids were analyzed. Expression of lipid and inflammation-related genes in liver and eWAT was analyzed. Primary mouse hepatocytes isolated from control mice were treated either with dimethyl sulfoxide (DMSO) (control) or 20 ng/mL recombinant IL-1α for 24 hours and subjected to gene expression analysis.Results Although total body weight gain was similar, IL-1α KO mice showed reduced adiposity and were completely protected from HFD-induced glucose intolerance. In addition, plasma total cholesterol and TG levels were lower and HFD-induced accumulation of liver TGs was completely inhibited in IL-1α KO compared with control mice. Expression of stearoyl-CoA desaturase1 (SCD1), fatty acid synthase (FASN), elongation of long-chain fatty acids family member 6 (ELOVL6), acetyl-CoA carboxylase (ACC), key enzymes that promote de-novo lipogenesis, was lower in livers of IL-1α KO mice. Treatment with recombinant IL-1α elevated the expression of ELOVL6 and FASN in mouse primary hepatocytes. Finally, mice with myeloid-cell-specific deletion of IL-1α did not show reduced adiposity and improved glucose tolerance.Conclusions We demonstrate a novel role of IL-1α in promoting adiposity, obesity-induced glucose intolerance and liver TG accumulation and suggest that IL-1α blockade could be used for treatment of obesity and its metabolic consequences.