Modulation of inflammatory signaling by vitamin E metabolites and its therapeutic implications.

Naturally occurring vitamin E is a lipophilic plant-derived molecule corresponding to the 2 R forms of alpha-tocopherol. A series of natural analogs or tocochromanols are present in nature, including β-, γ- and δ-tocopherol (βT, γT, δT), the corresponding tocotrienols (αTE, βTE, γTE, δTE) and tocomonoenols. Differences between these analogs as lipophilic antioxidants and modulators of molecular processes suggest specific therapeutic properties against various disorders associated with acute and chronic inflammation.

Protective effect of alpha-tocopherol on lipogenesis and oxysterol production in hypercholesterolemia-induced nonalcoholic steatohepatitis.

Despite limited number of studies, oxysterols are known to contribute to the progression of nonalcoholic steatohepatitis (NASH) by affecting lipid/cholesterol metabolism and elevating proinflammatory and profibrotic processes. Accordingly, we used a high cholesterol-mediated in vivo NASH model and aimed to determine alterations in fatty acid content and oxysterol levels together with their effects on cholesterol/lipid metabolism during the progression of the disease. We further investigated the beneficial role of α-tocopherol.

Impact of Seipin in cholesterol mediated lipid droplet maturation; status of endoplasmic reticulum stress and lipophagy.

The global prevalence of nonalcoholic fatty liver disease (NAFLD) defined by the increased number of lipid droplets (LDs) in hepatocytes, have risen continuously in parallel with the obesity. LDs and related proteins are known to affect cellular metabolism and signaling. Seipin, one of the most important LD-related proteins, plays a critical role in LD biogenesis.

Vitamin E discussion forum position paper on the revision of the nomenclature of vitamin E.

This position paper opens a discussion forum of this Journal dedicated to a scientific debate on Vitamin E nomenclature. With this article we provide the scientific and medical communities with what we consider relevant information in favor of revising the nomenclature of vitamin E. To our knowledge, only RRR-α-tocopherol has been medically used to protect against a deficiency disease in humans, and therefore, it would be appropriate to restrict the term vitamin to this molecule.

Protective effects of an electrophilic metabolite of docosahexaenoic acid on UVB-induced oxidative cell death, dermatitis, and carcinogenesis.

Docosahexaenoic acid (DHA), a representative omega-3 (ω-3) polyunsaturated fatty acids, undergoes metabolism to produce biologically active electrophilic species. 17-Oxo-DHA is one such reactive metabolite generated from DHA by cyclooxygenase-2 and dehydrogenase in activated macrophages. The present study was aimed to investigate the effects of 17-oxo-DHA on ultraviolet B (UVB)-induced oxidative stress, inflammation, and carcinogenesis in mouse skin.

Cholesterol accumulation in hepatocytes mediates IRE1/p38 branch of endoplasmic reticulum stress to promote nonalcoholic steatohepatitis.

Non-alcoholic fatty liver disease (NAFLD), based on the elevating obesity incidence, is one of the major health issue worldwide. Transition from NAFLD to non-alcoholic steatohepatitis (NASH) is driven by increased apoptosis and is relevant to higher morbidity rates. In regard to limited understanding on cholesterol mediated hepatocyte alterations in NALFD/NASH transition, we investigated endoplasmic reticulum (ER) stress and related apoptosis.

Endoplasmic Reticulum Stress and miRNA Impairment in Aging and Age-Related Diseases.

Aging is a physiological process defined by decreased cellular and tissue functions. Reduced capacity of protein degradation is one of the important hallmarks of aging that may lead to misfolded protein accumulation and progressive loss of function in organ systems. Recognition of unfolded/misfolded protein aggregates endoplasmic reticulum (ER) stress sensors activates an adaptive mechanism, the unfolded protein response (UPR).

Deficiency of SREBP1c modulates autophagy mediated lipid droplet catabolism during oleic acid induced steatosis.

Objective: Increased fatty acid and triglyceride synthesis in liver, majorly modulated by Sterol Regulator Elementing Binding Protein 1c (SREBP1c), is one of the main features of non-alcoholic fatty liver disease (NAFLD). In the present study, we aimed to identify the relation between SREBP1c and autophagy mediated lipid droplet (LD) catabolism in oleic acid (OA) induced lipid accumulation.

Methods: Increased LD formation and SREBP1c induction were identified in hepatocytes (AML12 cells) following the OA administration.

High cholesterol diet activates ER stress mediated apoptosis in testes tissue: Role of α-tocopherol.

The seminiferous tubules where spermatogenesis occurs are enveloped and protected by the Sertoli cells to support germ cells undergoing meiosis to produce haploid gametes. Clearly, induction of apoptosis in seminiferous tubules leads to abnormalities in spermatogenesis and male infertility. Studies demonstrated that increased hyperlipidemia impairs male infertility and spermatogenesis by enhancing seminiferous tubules apoptosis.

alpha-Tocopherol supplementation reduces inflammation and apoptosis in high cholesterol mediated nonalcoholic steatohepatitis.

Inflammation and apoptosis signaling are crucial steps in the progression from nonalcoholic fatty liver disease (NAFLD) to nonalcoholic steatohepatitis (NASH). Alpha-tocopherol, the most active form of vitamin E, is an important modulator of signaling mechanisms, but its involvement to cholesterol-induced NASH pathogenesis remains poorly defined. Herein we have reported a novel effect of α-tocopherol in the transition from hepatic steatosis to NASH.

High-throughput profiling reveals perturbation of endoplasmic reticulum stress-related genes in atherosclerosis induced by high-cholesterol diet and the protective role of vitamin E.

Formation of atherosclerotic plaques, called atherogenesis, is a complex process affected by genetic and environmental factors. It was proposed that endoplasmic reticulum (ER) stress is an important factor in the pathogenesis of atherosclerosis and that vitamin E affects atherosclerotic plaque formation via its antioxidant properties. Here, we investigated ER stress-related molecular mechanisms in high-cholesterol diet (HCD, 2%)-induced atherosclerosis model and the role of vitamin E supplementation in it, beyond its antioxidant properties.

HSP70 Inhibition Leads to the Activation of Proteasomal System under Mild Hyperthermia Conditions in Young and Senescent Fibroblasts.

Aging has been characterized with the accumulation of oxidized proteins, as a consequence of progressive decline in proteostasis capacity. Among others, proteasomal system is an efficient protein turnover complex to avoid aggregation of oxidized proteins. Heat shock protein 70 (HSP70) is another critical player that is involved in some key processes including the correct folding of misfolded proteins and targeting aggregated proteins to the proteasome for rapid degradation.

Cholesterol induced autophagy via IRE1/JNK pathway promotes autophagic cell death in heart tissue.

Background: Cardiovascular diseases (CVDs), with highest mortality and morbidity rates, are the major cause of death in the world. Due to the limited information on heart tissue changes, mediated by hypercholesterolemia, we planned to investigate molecular mechanisms of endoplasmic reticulum (ER) stress and related cell death in high cholesterol fed rabbit model and possible beneficial effects of α-tocopherol.

Methods: Molecular changes in rabbit heart tissue and cultured cardiomyocytes (H9c2 cells) were measured by western blotting, qRT-PCR, immunflouresence and flow cytometry experiments.

Vitamin E: Regulatory role in the cardiovascular system.

Cardiovascular disease (CVD) is one of the major causes of morbidity and mortality, all around the world. Vitamin E is an important nutrient influencing key cellular and molecular mechanisms as well as gene expression regulation centrally involved in the prevention of CVD. Cell culture and animal studies have focused on the identification of vitamin E regulated signaling pathways and involvement on inflammation, lipid homeostasis, and atherosclerotic plaque stability.

High Cholesterol Diet-Induced Changes in Oxysterol and Scavenger Receptor Levels in Heart Tissue.

Involvement of high cholesterol and oxidative stress in cardiovascular diseases is well studied, as it can be hypothesized that various products originated from lipid peroxidation, such as oxysterols, or affected protein expression might lead to cardiomyocyte damage followed by the pathological modifications. Although oxidation of excessive cholesterol to oxysterols in elevated stress conditions is identified by a number of studies, the role of a high cholesterol diet in regulating fatty acid and oxysterol accumulation, together with scavenger receptor mRNA levels, in the heart remains little investigated. Our study provides a detailed analysis of the changes in fatty acid, oxysterol, and scavenger receptor profiles and its relation with histological alterations in the heart tissue.

Antitumor and antimetastatic effects of walnut oil in esophageal adenocarcinoma cells.

Background: Walnuts contain many components including specific fatty acids, which could be active against cancer. Even though the anticarcinogenic effect of some of the individual fatty acids in walnut oil has been described, the effect of walnut oil itself on esophageal cancer cells hasn't yet been investigated.

Objective: We aimed to investigate whether walnut oil affects tumor growth and metastatic potential in esophageal cancer cells.

CD36 expression in peripheral blood mononuclear cells reflects the onset of atherosclerosis.

Together with complex genetic and environmental factors, increased serum cholesterol and ox-LDL levels are considered as major triggering factors of atherosclerosis. Mononuclear cell infiltration to the arterial wall and uptake of ox-LDL, which is facilitated by CD36 receptor through an uncontrolled manner, play a key role in foam cell formation followed by atherogenesis development. The aim of this study was to analyze if CD36 expression in peripheral blood mononuclear cells reflect its aortic tissue level in hypercholesterolemia.

Impact of high cholesterol and endoplasmic reticulum stress on metabolic diseases: An updated mini-review.

Endoplasmic reticulum (ER) is the major site of protein folding and calcium storage. Beside the role of ER in protein homeostasis, it controls the cholesterol production and lipid-membrane biosynthesis as well as surviving and cell death signaling mechanisms in the cell. It is well-documented that elevated plasma cholesterol induces adverse effects in cardiovascular diseases (CVDs), liver disorders, such as non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatosis hepatitis (NASH), and metabolic diseases which are associated with oxidative and ER stress.

Proteasome inhibitors in cancer therapy: Treatment regimen and peripheral neuropathy as a side effect.

Proteasomal system plays an important role in protein turnover, which is essential for homeostasis of cells. Besides degradation of oxidized proteins, it is involved in the regulation of many different signaling pathways. These pathways include mainly cell differentiation, proliferation, apoptosis, transcriptional activation and angiogenesis.

Vitamin E: Emerging aspects and new directions.

The discovery of vitamin E will have its 100th anniversary in 2022, but we still have more questions than answers regarding the biological functions and the essentiality of vitamin E for human health. Discovered as a factor essential for rat fertility and soon after characterized for its properties of fat-soluble antioxidant, vitamin E was identified to have signaling and gene regulation effects in the 1980s. In the same years the cytochrome P-450 dependent metabolism of vitamin E was characterized and a first series of studies on short-chain carboxyethyl metabolites in the 1990s paved the way to the hypothesis of a biological role for this metabolism alternative to vitamin E catabolism.

Endoplasmic reticulum stress related molecular mechanisms in nonalcoholic steatohepatitis.

Nonalcoholic steatohepatitis (NASH) is considered to be a common health problem since the incidence of nonalcoholic fatty liver disease (NAFLD) has increased in recent years. Disturbed hepatic cholesterol homeostasis and free cholesterol accumulation in liver results in increased oxidative stress leading to the endoplasmic reticulum (ER) stress. Activated ER stress maintains protein homeostasis however, delayed or inadequate ER stress responses may induce fat accumulation, insulin resistance, inflammation, apoptosis, and autophagy, all of which increase with age and play crucial roles in the pathogenesis of NASH.

Effect of a hypercholesterolemia as a starting factor on spinal degeneration in rabbits and role of Vitamin E (α-tocopherol).

Background: To identify the role of the hypercholesterolemia as a starting factor in discovertebral degeneration that ultimately causes lower back pain, and investigate the role of Vitamin E in this process.

Methods: The rabbits (n = 32) were divided into two broad experimental groups: A control group, and a hypercholesterolemia group, namely cholesterol, and cholesterol plus Vitamin E groups and they were fed sequentially for 4 or 8 weeks. Serum cholesterol and Vitamin E (α-tocopherol) levels were determined; vascular tissue was prepared for histopathological analyses and vertebra was decalcified for the study.

Nrf2 silencing to inhibit proteolytic defense induced by hyperthermia in HT22 cells.

Nrf2 pathway has been known to be protective against cancer progression however recent studies have revealed that the antioxidant activity of Nrf2 contributes to chemotherapy resistance. For many years, hyperthermia has been used as an additional therapy to increase the efficiency of chemotherapy and radiotherapy. Besides the positive effects of hyperthermia during treatment procedure, thermotolerance has been found to develop against heat treatment.

Heat shock proteins and proteasomal degradation in normal and tumor cells.

Proteasomal degradation of oxidized proteins is a crucial mechanism to prevent the accumulation of cellular damage. The removal of the damage is generally a required process for healthy organisms to keep the integrity while in cancer cells the situation may be different. In normal conditions, cancer cells have higher proteasome activity compared to normal cells.

The effect of resveratrol on signal transduction pathways and the role of pro-apoptotic Bax protein on apoptosis in HCT- 116 colon carcinoma cell lines.

Colon carcinoma is the third among the cancer related deaths. The role of pro-apoptotic Bax protein on the resveratrol related apoptosis, mitochondrial membrane potential and signal pathways has not been identified in colon carcinoma cells. In this direction, HCT-116 bax positive and HCT-116 negative cell lines were utilized to detect the apoptotic effect and I?B, MEK1 and STAT 3 signal transduction pathways of resveratrol.