Lutein prevented cardiac and renal injury in STZ-induced hyperglycemic rats due to potential amelioration of altered activities in polyol pathway and oxidative stress markers.

In the present study, we appraise the anti-inflammatory efficacy of lutein oxidative degradation derivatives mediated through UV-irradiation over lutein in counteracting the inflammation induced by lipopolysaccharide (LPS) in rats (n = 5 per group). UV-irradiated lutein fragments were identified as anhydrolutein (B, C40H54O), 2,6,6-trimethylcyclohexa-1,4-dienylium (M1, C9H13), (2E,4E,6E,8E)-9-(4-hydroxy-2,6,6-trimethylcyclohex-1-1en-1-yl)-3,7-dimethylnona-2,4,6,8-tetraen-1-ylium (M2, C20H29O), 4-[(1E,3E,5E,7E)-3,7,-dimethyldeca-1,3,5,7-tetraen-1-yl]-3,5,5-methylcyclohex-3-en-1-ol (M3, C21H30O) and zeaxanthin (M4, C40H56O) and its isomers as 13'-Z zeaxanthin, 13'-Z lutein, all-trans zeaxanthin, and 9-Z lutein. Induction of inflammation by LPS significantly increased the production of nitrites (3.3 fold in the serum and 2.6 fold in the liver), prostaglandin E2 (26 fold in the serum), and pro-inflammatory cytokines like tumor necrosis factor-α (6.6 fold in the serum), and interleukin-6 (4.8 fold in the serum). Oxidative derivatives of lutein, especially M1, M2 and M3, ameliorated acute inflammation in rats by inhibiting the production of nitrites, malondialdehyde (MDA), PGE2, TNF-α, and IL-6 cytokines more efficiently than lutein in rats. The anti-inflammatory mechanism of derivatives might be related to the decrease of inflammatory cytokines and the increase of antioxidant enzymes (superoxide dismutase, catalase, glutathione peroxidase, glutathione S transferase, glutathione reductase), which would result in the reduction of iNOS, COX-2 and MDA and subsequently inflammatory responses.

Intestinal and pancreatic α-amylase and α-glucosidase inhibitors offer an approach to lower the levels of post-prandial hyperglycemia through the control of dietary starch breakdown in digestion. This study hypothesized that lactucaxanthin (Lxn) in lettuce (Lactuca sativa) inhibits the activity of α-amylase and α-glucosidase. In this study, the interaction of Lxn with α-amylase and α-glucosidase in silico and its inhibitory effect on these enzymes were studied using in vitro and STZ-induced diabetic rat models. Lxn was isolated from lettuce with 96% purity confirmed by HPLC and LCMS. The in silico analysis showed that Lxn has a lower binding energy (-6.05 and -6.34 kcal mol) with α-amylase and α-glucosidase compared to their synthetic inhibitors, acarbose (-0.21 kcal mol) and miglitol (-2.78 kcal mol), respectively. In vitro α-amylase and α-glucosidase inhibition assays revealed that Lxn had IC values of 435.5 μg mL and 1.84 mg mL, but acarbose has values of 2.5 and 16.19 μg mL. The in vivo results showed an increased activity for α-amylase and α-glucosidase in the intestine (4.7 and 1.30 fold, p < 0.05) and pancreas (1.3 and 1.48 fold, p < 0.05) of STZ induced diabetic rats compared to normal rats. Whereas the activity decreased (p < 0.05) in the Lxn fed diabetic rats, except for the intestinal α-glucosidase activity (1.69 ± 0.12 PNP per min per mg protein). This was confirmed by the low blood glucose level (239.4 ± 18.2 mg dL) in diabetic rats fed Lxn compared to the diabetic group (572.2 ± 30.5 mg dL, p < 0.05). Lxn significantly inhibited (p < 0.05) the activity of α-amylase and α-glucosidase and could be of medical and nutritional relevance in the treatment of diabetes.

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Nemaline Myopathy (NM) is a disorder of skeletal muscles caused by mutations in sarcomere proteins and characterized by accumulation of microscopic rod or threadlike structures (nemaline bodies) in skeletal muscles. Patients diagnosed with both NM and infantile cardiomyopathy are very rare. A male infant presented, within the first few hours of life, with severe dilated cardiomyopathy, biventricular dysfunction and left ventricular noncompaction. A muscle biopsy on the 8th day of life from the

Molecular effects of sterol-enriched wheat bran oil (eWBA) on lipid metabolism, inflammatory markers, and liver proteome associated with nonalcoholic/metabolic-related fatty liver disease (MAFLD) are not completely known. In this study, dietary eWBA intervention was used to investigate its effect in ameliorating liver injury in high fat diet (HFC)-fed C57BL/6 mice. Specifically, we examined eWBA's effects on (i) differentially expressed hepatic factors which regulate carbohydrate and lipid homeostasis markers, such as sterol regulatory element-binding protein-2 (SREBP-2), peroxisome proliferator-activated receptors-γ (PPARγ), pro-protein convertase subtilisin/kexin type-9 (PCSK9), low-density lipoprotein receptor (LDL-R), and apolipoprotein-E (APO-E) factors, and (ii) levels of two cytokines, tumor necrosis factor (TNF-α) and transforming growth factor beta (TGF-β). Liver of HFC-fed mice exhibited characteristic features of MAFLD, such as increased liver injury serum markers (SGOT, SGPT), liver lipids, and PCSK9 protein. Mice fed eWBA-supplemented HFC exhibited amelioration of serum cholesterol, triglycerides, SGOT, and SGPT levels as well as a reduction in liver lipids and PCSK9 and SREBP-2 proteins. Pro-inflammatory and profibrogenic cytokines in the liver of the groups fed with eWBA -supplemented HFC were normalized with respect to the group without eWBA. To conclude, eWBA reduces the expression of SREBP-2, APO-E, and PCSK9 in the liver which down regulates various signal molecules thereby ameliorates liver injury in a mouse model of MAFLD. Down-regulated FAS and ZNF-236 of liver proteins with eWBA intervention could be the initial markers for steatosis.

No abstract

Malignant peripheral nerve sheath tumors (MPNSTs) are chemotherapy resistant sarcomas that are a leading cause of death in neurofibromatosis type 1 (NF1). Although NF1-related MPNSTs derive from neural crest cell origin, they also exhibit intratumoral heterogeneity. TP53 mutations are associated with significantly decreased survival in MPNSTs, however the mechanisms underlying TP53-mediated therapy responses are unclear in the context of NF1-deficiency. We evaluated the role of two commonly altered genes, MET and TP53, in kinome reprograming and cellular differentiation in preclinical MPNST mouse models. We previously showed that MET amplification occurs early in human MPNST progression and that Trp53 loss abrogated MET-addiction resulting in MET inhibitor resistance. Here we demonstrate a novel mechanism of therapy resistance whereby p53 alters MET stability, localization, and downstream signaling leading to kinome reprogramming and lineage plasticity. Trp53 loss also resulted in a shift from RAS/ERK to AKT signaling and enhanced sensitivity to MEK and mTOR inhibition. In response to MET, MEK and mTOR inhibition, we observed broad and heterogeneous activation of key differentiation genes in Trp53-deficient lines suggesting Trp53 loss also impacts lineage plasticity in MPNSTs. These results demonstrate the mechanisms by which p53 loss alters MET dependency and therapy resistance in MPNSTS through kinome reprogramming and phenotypic flexibility.