Hypoxia is a major hallmark of the tumor microenvironment that is strictly associated with rapid cancer progression and induction of metastasis. Hypoxia inhibits disulfide bond formation and impairs protein folding in the Endoplasmic Reticulum (ER). The stress in the ER induces the activation of Unfolded Protein Response (UPR) pathways via the induction of protein kinase RNA-like endoplasmic reticulum kinase (PERK). As a result, the level of phosphorylated Eukaryotic Initiation Factor 2 alpha (eIF2α) is markedly elevated, resulting in the promotion of a pro-adaptive signaling pathway by the inhibition of global protein synthesis and selective translation of Activating Transcription Factor 4 (ATF4). On the contrary, during conditions of prolonged ER stress, pro-adaptive responses fail and apoptotic cell death ensues. Interestingly, similar to the activity of the mitochondria, the ER may also directly activate the apoptotic pathway through ER stress-mediated leakage of calcium into the cytoplasm that leads to the activation of death effectors. Apoptotic cell death also ensues by ATF4-CHOP- mediated induction of several pro-apoptotic genes and suppression of the synthesis of anti-apoptotic Bcl-2 proteins. Advancing molecular insight into the transition of tumor cells from adaptation to apoptosis under hypoxia-induced ER stress may provide answers on how to overcome the limitations of current anti-tumor therapies. Targeting components of the UPR pathways may provide more effective elimination of tumor cells and as a result, contribute to the development of more promising anti-tumor therapeutic agents.

Lutein and zeaxanthin belong to the xanthophyll family of carotenoids, which are pigments produced by plants. Structurally, they are very similar, differing only slightly in the arrangement of atoms. Key sources of these carotenoids include kale, savoy cabbage, spinach, broccoli, peas, parsley, corn, and egg yolks. The recommended daily intake of lutein is approximately 10.0 mg and that of zeaxanthin is 2 mg. Lutein intake in adults varies, with average intakes being 1–2 mg/day. Due to the lack of synthesis of consumption of these compounds in humans, these substances are extremely important for the proper functioning of certain organs of the body (eye, skin, heart, intestines). Eating a lot of dark leafy vegetables and some fruits can help to prevent our bodies from developing diseases. The protective effects of carotenoids are mainly related to their defense against oxidative stress and their ability to scavenge free radicals. Lutein and zeaxanthin are the only dietary carotenoids that accumulate in the retina, specifically the macula, and are called macular pigments. These carotenoids are concentrated by the action of specific binding proteins such as StARD3, which binds lutein, and GSTP1, which binds zeaxanthin and its dietary metabolite, mesozeaxanthin. It has been shown that supportive therapy with lutein and zeaxanthin can have a beneficial effect in delaying the progression of eye diseases such as age-related macular degeneration (AMD) and cataracts. This article presents the current state of knowledge on the role of lutein and zeaxanthin, especially from human studies targeting their metabolism and bioavailability, with recommendations to consume xanthophyll-rich foods.

Thiamine (thiamin, B1) is a vitamin necessary for proper cell function. It exists in a free form as a thiamine, or as a mono-, di- or triphosphate. Thiamine plays a special role in the body as a coenzyme necessary for the metabolism of carbohydrates, fats and proteins. In addition, it participates in the cellular respiration and oxidation of fatty acids: in malnourished people, high doses of glucose result in acute thiamine deficiency. It also participates in energy production in the mitochondria and protein synthesis. In addition, it is also needed to ensure the proper functioning of the central and peripheral nervous system, where it is involved in neurotransmitter synthesis. Its deficiency leads to mitochondrial dysfunction, lactate and pyruvate accumulation, and consequently to focal thalamic degeneration, manifested as Wernicke’s encephalopathy or Wernicke–Korsakoff syndrome. It can also lead to severe or even fatal neurologic and cardiovascular complications, including heart failure, neuropathy leading to ataxia and paralysis, confusion, or delirium. The most common risk factor for thiamine deficiency is alcohol abuse. This paper presents current knowledge of the biological functions of thiamine, its antioxidant properties, and the effects of its deficiency in the body.

Inositol-requiring enzyme type 1 (IRE1) is a serine/threonine kinase acting as one of three branches of the Unfolded Protein Response (UPR) signaling pathway, which is activated upon endoplasmic reticulum (ER) stress conditions. It is known to be capable of inducing both pro-survival and pro-apoptotic cellular responses, which are strictly related to numerous human pathologies. Among others, IRE1 activity has been confirmed to be increased in cancer, neurodegeneration, inflammatory and metabolic disorders, which are associated with an accumulation of misfolded proteins within ER lumen and the resulting ER stress conditions. Emerging evidence suggests that genetic or pharmacological modulation of IRE1 may have a significant impact on cell viability, and thus may be a promising step forward towards development of novel therapeutic strategies. In this review, we extensively describe the structural analysis of IRE1 molecule, the molecular dynamics associated with IRE1 activation, and interconnection between it and the other branches of the UPR with regard to its potential use as a therapeutic target. Detailed knowledge of the molecular characteristics of the IRE1 protein and its activation may allow the design of specific kinase or RNase modulators that may act as drug candidates.

Cancer constitutes a grave problem nowadays in view of the fact that it has become one of the main causes of death worldwide. Poor clinical prognosis is presumably due to cancer cells metabolism as tumor microenvironment is affected by oxidative stress. This event triggers adequate cellular response and thereby creates appropriate conditions for further cancer progression. Endoplasmic reticulum (ER) stress occurs when the balance between an ability of the ER to fold and transfer proteins and the degradation of the misfolded ones become distorted. Since ER is an organelle relatively sensitive to oxidative damage, aforementioned conditions swiftly cause the activation of the unfolded protein response (UPR) signaling pathway. The output of the UPR, depending on numerous factors, may vary and switch between the pro-survival and the pro-apoptotic branch, and hence it displays opposing effects in deciding the fate of the cancer cell. The role of UPR-related proteins in tumorigenesis, such as binding the immunoglobulin protein (BiP) and inositol-requiring enzyme-1α (IRE1α), activating transcription factor 6 (ATF6) or the protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK), has already been specifically described so far. Nevertheless, due to the paradoxical outcomes of the UPR activation as well as gaps in current knowledge, it still needs to be further investigated. Herein we would like to elicit the actual link between neoplastic diseases and the UPR signaling pathway, considering its major branches and discussing its potential use in the development of a novel, anti-cancer, targeted therapy.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) responsible for coronavirus disease 2019 (COVID-19) was discovered in December 2019 in Wuhan, China. Since that time, the virus has spread around the world, which resulted in an announcement of the World Health Organization (WHO), dated in March 2020, that COVID-19 was a worldwide pandemic, and since then, the world has been struggling with this disease. SARS-CoV-2, similar to other RNA viruses, continually mutates, and new variants are appearing. Among large numbers of detected SARS-CoV-2 variants, only an insignificant amount of them are able to pose a risk to public health, as they are more contagious and cause more severe conditions. The emerged variants were classified by the Centers for Disease Control and Prevention (CDC) in collaboration with SARS-CoV-2 Interagency Group (SIG) according to strictly defined pattern. Variants were classified as variants of concern, variants of interest, and variants of high consequence. In the last few months, three variants of concern (B.1.1.7, B.1.351, and P.1) and four variants of interests (B.1.526, B.1.525, B.1.427/B.1.429, and P.2) were distinguished and are essential for close monitoring. This analysis summarizes the principal information concerning SARS-CoV-2 variants, such as their infectivity, severity, mutations, and immune susceptibility.