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Ferroptosis, characterized by glutamate overload, glutathione depletion, and cysteine/cystine deprivation during iron- and oxidative-damage-dependent cell death, is a particular mode of regulated cell death. It is expected to effectively treat cancer through its tumor-suppressor function, as mitochondria are the intracellular energy factory and a binding site of reactive oxygen species production, closely related to ferroptosis. This review summarizes relevant research on the mechanisms of ferroptosis, highlights mitochondria's role in it, and collects and classifies the inducers of ferroptosis. A deeper understanding of the relationship between ferroptosis and mitochondrial function may provide new strategies for tumor treatment and drug development based on ferroptosis. [ABSTRACT FROM AUTHOR]

This review explored the role of mitochondria in retinal ganglion cells (RGCs), which are essential for visual processing. Mitochondrial dysfunction is a key factor in the pathogenesis of various vision-related disorders, including glaucoma, hereditary optic neuropathy, and age-related macular degeneration. This review highlighted the critical role of mitochondria in RGCs, which provide metabolic support, regulate cellular health, and respond to cellular stress while also producing reactive oxygen species (ROS) that can damage cellular components. Maintaining mitochondrial function is essential for meeting RGCs' high metabolic demands and ensuring redox homeostasis, which is crucial for their proper function and visual health. Oxidative stress, exacerbated by factors like elevated intraocular pressure and environmental factors, contributes to diseases such as glaucoma and age-related vision loss by triggering cellular damage pathways. Strategies targeting mitochondrial function or bolstering antioxidant defenses include mitochondrial-based therapies, gene therapies, and mitochondrial transplantation. These advances can offer potential strategies for addressing mitochondrial dysfunction in the retina, with implications that extend beyond ocular diseases. [ABSTRACT FROM AUTHOR]

Royal jelly (RJ) is a highly nutritious natural product with great potential for use in medicine, cosmetics, and as a health-promoting food. This bee product is a mixture of important compounds, such as proteins, vitamins, lipids, minerals, hormones, neurotransmitters, flavonoids, and polyphenols, that underlie the remarkable biological and therapeutic activities of RJ. Various bioactive molecules like 10-hydroxy-2-decenoic acid (10-HDA), antibacterial protein, apisin, the major royal jelly proteins, and specific peptides such as apisimin, royalisin, royalactin, apidaecin, defensin-1, and jelleins are characteristic ingredients of RJ. RJ shows numerous physiological and pharmacological properties, including vasodilatory, hypotensive, antihypercholesterolaemic, antidiabetic, immunomodulatory, anti-inflammatory, antioxidant, anti-aging, neuroprotective, antimicrobial, estrogenic, anti-allergic, anti-osteoporotic, and anti-tumor effects. Moreover, RJ may reduce menopause symptoms and improve the health of the reproductive system, liver, and kidneys, and promote wound healing. This article provides an overview of the molecular mechanisms underlying the beneficial effects of RJ in various diseases, aging, and aging-related complications, with special emphasis on the bioactive components of RJ and their health-promoting properties. The data presented should be an incentive for future clinical studies that hopefully will advance our knowledge about the therapeutic potential of RJ and facilitate the development of novel RJ-based therapeutic opportunities for improving human health and well-being. [ABSTRACT FROM AUTHOR]

Hypertrophic cardiomyopathy (HCM) is a heart condition characterized by cellular and metabolic dysfunction, with mitochondrial dysfunction playing a crucial role. Although the direct relationship between genetic mutations and mitochondrial dysfunction remains unclear, targeting mitochondrial dysfunction presents promising opportunities for treatment, as there are currently no effective treatments available for HCM. This review adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Extension for Scoping Reviews guidelines. Searches were conducted in databases such as PubMed, Embase, and Scopus up to September 2023 using "MESH terms". Bibliographic references from pertinent articles were also included. Hypertrophic cardiomyopathy (HCM) is influenced by ionic homeostasis, cardiac tissue remodeling, metabolic balance, genetic mutations, reactive oxygen species regulation, and mitochondrial dysfunction. The latter is a common factor regardless of the cause and is linked to intracellular calcium handling, energetic and oxidative stress, and HCM-induced hypertrophy. Hypertrophic cardiomyopathy treatments focus on symptom management and complication prevention. Targeted therapeutic approaches, such as improving mitochondrial bioenergetics, are being explored. This includes coenzyme Q and elamipretide therapies and metabolic strategies like therapeutic ketosis. Understanding the biomolecular, genetic, and mitochondrial mechanisms underlying HCM is crucial for developing new therapeutic modalities. [ABSTRACT FROM AUTHOR]

Cysteine and its derivatives, including H2S, can influence bacterial virulence and sensitivity to antibiotics. In minimal sulfate media, H2S is generated under stress to prevent excess cysteine and, together with incorporation into glutathione and export into the medium, is a mechanism of cysteine homeostasis. Here, we studied the features of cysteine homeostasis in LB medium, where the main source of sulfur is cystine, whose import can create excess cysteine inside cells. We used mutants in the mechanisms of cysteine homeostasis and a set of microbiological and biochemical methods, including the real-time monitoring of sulfide and oxygen, the determination of cysteine and glutathione (GSH), and the expression of the Fur, OxyR, and SOS regulons genes. During normal growth, the parental strain generated H2S when switching respiration to another substrate. The mutations affected the onset time, the intensity and duration of H2S production, cysteine and glutathione levels, bacterial growth and respiration rates, and the induction of defense systems. Exposure to chloramphenicol and high doses of ciprofloxacin increased cysteine content and GSH synthesis. A high inverse relationship between log CFU/mL and bacterial growth rate before ciprofloxacin addition was revealed. The study points to the important role of maintaining cysteine homeostasis during normal growth and antibiotic exposure in LB medium. [ABSTRACT FROM AUTHOR]

In this study, serum metabolic profiling of patients diagnosed with papillary thyroid carcinoma (PTC) and benign thyroid pathologies (BT) aimed to identify specific biomarkers and altered pathways when compared with healthy controls (C). The blood was collected after a histological confirmation from PTC (n = 24) and BT patients (n = 31) in parallel with healthy controls (n = 81). The untargeted metabolomics protocol was applied by UHPLC-QTOF-ESI+-MS analysis and the statistical analysis was performed using the MetaboAnalyst 5.0 platform. The partial least squares-discrimination analysis, including VIP values, random forest graphs, and heatmaps (p < 0.05), was complemented with biomarker analysis (with AUROC ranking) and pathway analysis, suggesting a model for abnormal metabolic pathways in PTC and BT based on 166 identified metabolites. There were 11 classes of putative biomarkers selected that were involved in altered metabolic pathways, e.g., polar molecules (amino acids and glycolysis metabolites, purines and pyrimidines, and selenium complexes) and lipids including free fatty acids, bile acids, acylated carnitines, corticosteroids, prostaglandins, and phospholipids. Specific biomarkers of discrimination were identified in each class of metabolites and upregulated or downregulated comparative to controls, PTC group, and BT group. The lipidomic window was revealed to be more relevant for finding biomarkers related to thyroid carcinoma or benign thyroid nodules, since our study reflected a stronger involvement of lipids and selenium-related molecules in metabolic discrimination. [ABSTRACT FROM AUTHOR]

The respiratory barrier, a thin epithelial barrier that separates the interior of the human body from the environment, is easily damaged by toxicants, and chronic respiratory diseases are common. It also allows the permeation of drugs for topical treatment. Animal experimentation is used to train medical technicians, evaluate toxicants, and develop inhaled formulations. Species differences in the architecture of the respiratory tract explain why some species are better at predicting human toxicity than others. Some species are useful as disease models. This review describes the anatomical differences between the human and mammalian lungs and lists the characteristics of currently used mammalian models for the most relevant chronic respiratory diseases (asthma, chronic obstructive pulmonary disease, cystic fibrosis, pulmonary hypertension, pulmonary fibrosis, and tuberculosis). The generation of animal models is not easy because they do not develop these diseases spontaneously. Mouse models are common, but other species are more appropriate for some diseases. Zebrafish and fruit flies can help study immunological aspects. It is expected that combinations of in silico, in vitro, and in vivo (mammalian and invertebrate) models will be used in the future for drug development. [ABSTRACT FROM AUTHOR]

Cystinosis is a low-prevalence lysosomal storage disease. The pathomechanism involves abnormal functioning of the cystinosine lysosomal cystine transporter (CTNS), causing intraliposomal accumulation of the amino acid cysteine disulfide, which crystallizes and deposits in several parts of the body. The most common ophthalmic complication of cystinosis is the deposition of "gold dust" cystine crystals on the cornea, which already occurs in infancy and leads to severe photosensitivity and dry eyes as it gradually progresses with age. In the specific treatment of cystinosis, preparations containing cysteamine (CYA) are used. The availability of commercialized eyedrops for the targeted treatment is scarce, and only Cystadrops® are commercially available with strong limitations. Thus, magistral CYA-containing compounded eyedrops (CYA-CED) could have a key role in patient care; however, a rationally designed comprehensive study on the commercialized and magistral products is still missing. This work aims to build up a comprehensive study about commercialized and magistral CYA eye drops, involving pharmacokinetic and physicochemical characterization (applying mucoadhesivity, rheology test, investigation of drug release, and parallel artificial membrane permeability assays), as well as ex vivo tests, well supported by statistical analysis. [ABSTRACT FROM AUTHOR]

Biologics address a range of unmet clinical needs, but the occurrence of biologics-induced liver injury remains a major challenge. Development of cimaglermin alfa (GGF2) was terminated due to transient elevations in serum aminotransferases and total bilirubin. Tocilizumab has been reported to induce transient aminotransferase elevations, requiring frequent monitoring. To evaluate the clinical risk of biologics-induced liver injury, a novel quantitative systems toxicology modeling platform, BIOLOGXsym™, representing relevant liver biochemistry and the mechanistic effects of biologics on liver pathophysiology, was developed in conjunction with clinically relevant data from a human biomimetic liver microphysiology system. Phenotypic and mechanistic toxicity data and metabolomics analysis from the Liver Acinus Microphysiology System showed that tocilizumab and GGF2 increased high mobility group box 1, indicating hepatic injury and stress. Tocilizumab exposure was associated with increased oxidative stress and extracellular/tissue remodeling, and GGF2 decreased bile acid secretion. BIOLOGXsym simulations, leveraging the in vivo exposure predicted by physiologically-based pharmacokinetic modeling and mechanistic toxicity data from the Liver Acinus Microphysiology System, reproduced the clinically observed liver signals of tocilizumab and GGF2, demonstrating that mechanistic toxicity data from microphysiology systems can be successfully integrated into a quantitative systems toxicology model to identify liabilities of biologics-induced liver injury and provide mechanistic insights into observed liver safety signals. [ABSTRACT FROM AUTHOR]

The reaction of the 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonate) free radical (ABTS●) with proteins (bovine serum albumin, blood plasma, egg white, erythrocyte membranes, and Bacto Peptone) leads not only to a reduction of ABTS● but also to the appearance of a purple color (absorption maximum at 550–560 nm). The aim of this study was to characterize the formation and explain the nature of the product responsible for the appearance of this color. The purple color co-precipitated with protein, and was diminished by reducing agents. A similar color was generated by tyrosine upon reaction with ABTS●. The most feasible explanation for the color formation is the addiction of ABTS● to proteins' tyrosine residues. The product formation was decreased by nitration of the bovine serum albumin (BSA) tyrosine residues. The formation of the purple product of tyrosine was optimal at pH 6.5. A decrease in pH induced a bathochromic shift of the spectra of the product. The product was not a free radical, as demonstrated by electrom paramagnetic resonance (EPR) spectroscopy. Another byproduct of the reaction of ABTS● with tyrosine and proteins was dityrosine. These byproducts can contribute to the non-stoichiometry of the antioxidant assays with ABTS●. The formation of the purple ABTS adduct may be a useful index of radical addition reactions of protein tyrosine residues. [ABSTRACT FROM AUTHOR]

The metabolism and intercellular transfer of glutathione or its precursors may play an important role in cellular defense against oxidative stress, a common hallmark of neurodegeneration. In the 1990s, several studies in the Neurobiology field led to the widely accepted notion that astrocytes produce large amounts of glutathione that serve to feed neurons with precursors for glutathione synthesis. This assumption has important implications for health and disease since a reduction in this supply from astrocytes could compromise the capacity of neurons to cope with oxidative stress. However, at first glance, this shuttling would imply a large energy expenditure to get to the same point in a nearby cell. Thus, are there additional underlying reasons for this expensive mechanism? Are neurons unable to import and/or synthesize the three non-essential amino acids that are the glutathione building blocks? The rather oxidizing extracellular environment favors the presence of cysteine (Cys) as cystine (Cis), less favorable for neuronal import. Therefore, it has also been proposed that astrocytic GSH efflux could induce a change in the redox status of the extracellular space nearby the neurons, locally lowering the Cis/Cys ratio. This astrocytic glutathione release would also increase their demand for precursors, stimulating Cis uptake, which these cells can import, further impacting the local decline of the Cis/Cys ratio, in turn, contributing to a more reduced extracellular environment and subsequently favoring neuronal Cys import. Here, we revisit the experimental evidence that led to the accepted hypothesis of astrocytes acting as suppliers of neuronal glutathione precursors, considering recent data from the Human Protein Atlas. In addition, we highlight some potential drawbacks of this hypothesis, mainly supported by heterogeneous cellular models. Finally, we outline additional and more cost-efficient possibilities by which astrocytes could support neuronal glutathione levels, including its shuttling in extracellular vesicles. [ABSTRACT FROM AUTHOR]

Sulfur-containing amino acids methionine (Met), cysteine (Cys) and taurine (Tau) are common dietary constituents with important cellular roles. Met restriction is already known to exert in vivo anticancer activity. However, since Met is a precursor of Cys and Cys produces Tau, the role of Cys and Tau in the anticancer activity of Met-restricted diets is poorly understood. In this work, we screened the in vivo anticancer activity of several Met-deficient artificial diets supplemented with Cys, Tau or both. Diet B1 (6% casein, 2.5% leucine, 0.2% Cys and 1% lipids) and diet B2B (6% casein, 5% glutamine, 2.5% leucine, 0.2% Tau and 1% lipids) showed the highest activity and were selected for further studies. Both diets induced marked anticancer activity in two animal models of metastatic colon cancer, which were established by injecting CT26.WT murine colon cancer cells in the tail vein or peritoneum of immunocompetent BALB/cAnNRj mice. Diets B1 and B2B also increased survival of mice with disseminated ovarian cancer (intraperitoneal ID8 Tp53−/− cells in C57BL/6JRj mice) and renal cell carcinoma (intraperitoneal Renca cells in BALB/cAnNRj mice). The high activity of diet B1 in mice with metastatic colon cancer may be useful in colon cancer therapy. [ABSTRACT FROM AUTHOR]

The renin-angiotensin system (RAS) is one of the main regulatory systems of cardiovascular homeostasis. It is mainly composed of angiotensin-converting enzyme (ACE) and angiotensin II receptors AT1 and AT2. ACE and AT1 are targets of choice for the treatment of hypertension, whereas the AT2 receptor is still not exploited due to the lack of knowledge of its physiological properties. Peptide toxins from venoms display multiple biological functions associated with varied chemical and structural properties. If Brazilian viper toxins have been described to inhibit ACE, no animal toxin is known to act on AT1/AT2 receptors. We screened a library of toxins on angiotensin II receptors with a radioligand competition binding assay. Functional characterization of the selected toxin was conducted by measuring second messenger production, G-protein activation and β-arrestin 2 recruitment using bioluminescence resonance energy transfer (BRET) based biosensors. We identified one original toxin, A-CTX-cMila, which is a 7-residues cyclic peptide from Conus miliaris with no homology sequence with known angiotensin peptides nor identified toxins, displaying a 100-fold selectivity for AT1 over AT2. This toxin shows a competitive antagonism mode of action on AT1, blocking Gαq, Gαi3, GαoA, β-arrestin 2 pathways and ERK1/2 activation. These results describe the first animal toxin active on angiotensin II receptors. [ABSTRACT FROM AUTHOR]

The most frequent alterations in plasma amino acid concentrations in type 1 and type 2 diabetes are decreased L-serine and increased branched-chain amino acid (BCAA; valine, leucine, and isoleucine) levels. The likely cause of L-serine deficiency is decreased synthesis of 3-phosphoglycerate, the main endogenous precursor of L-serine, due to impaired glycolysis. The BCAA levels increase due to decreased supply of pyruvate and oxaloacetate from glycolysis, enhanced supply of NADH + H+ from beta-oxidation, and subsequent decrease in the flux through the citric acid cycle in muscles. These alterations decrease the supply of α-ketoglutarate for BCAA transamination and the activity of branched-chain keto acid dehydrogenase, the rate-limiting enzyme in BCAA catabolism. L-serine deficiency contributes to decreased synthesis of phospholipids and increased synthesis of deoxysphinganines, which play a role in diabetic neuropathy, impaired homocysteine disposal, and glycine deficiency. Enhanced BCAA levels contribute to increased levels of aromatic amino acids (phenylalanine, tyrosine, and tryptophan), insulin resistance, and accumulation of various metabolites, whose influence on diabetes progression is not clear. It is concluded that amino acid concentrations should be monitored in patients with diabetes, and systematic investigation is needed to examine the effects of L-serine and glycine supplementation on diabetes progression when these amino acids are decreased. [ABSTRACT FROM AUTHOR]

Like in many other pathologies, oxidative stress is involved in the development of neurodegenerative disorders. Human serum albumin (HSA) is the main protein in different body fluids including cerebrospinal fluid (CSF). By its redox state in terms of cysteine-34, albumin serves as marker for oxidative burden. We aimed to evaluate the redox state of HSA in patients with multiple sclerosis in serum and CSF in comparison to controls to identify possible correlations with disease activity and severity. Samples were stored at −70 °C until analysis by HPLC for the determination of albumin redox state in terms of the fractions of human mercaptalbumin (HMA), human nonmercaptalbumin1 (HNA1), and human nonmercaptalbumin2 (HNA2). Albumin in CSF showed significantly higher fractions of the reduced form HMA and decreased HNA1 and HNA2. There was no difference between albumin redox states in serum of patients and controls. In CSF of patients HNA2 showed a trend to higher fractions compared to controls. Albumin redox state in serum was associated with physical disability in remission while albumin redox state in CSF was related to disease activity. Thus, albumin redox state in serum and CSF of patients in relation to disease condition merits further investigation. [ABSTRACT FROM AUTHOR]

Medically assisted reproduction, now considered a routine, successful treatment for infertility worldwide, has produced at least 8 million live births. However, a growing body of evidence is pointing toward an increased incidence of epigenetic/imprinting disorders in the offspring, raising concern that the techniques involved may have an impact on crucial stages of early embryo and fetal development highly vulnerable to epigenetic influence. In this paper, the key role of methylation processes in epigenesis, namely the essential biochemical/metabolic pathways involving folates and one-carbon cycles necessary for correct DNA/histone methylation, is discussed. Furthermore, potential contributors to epigenetics dysregulation during the three phases of assisted reproduction: preparation for and controlled ovarian hyperstimulation (COH); methylation processes during the preimplantation embryo culture stages; the effects of unmetabolized folic acid (UMFA) during embryogenesis on imprinting methyl "tags", are described. Advances in technology have opened a window into developmental processes that were previously inaccessible to research: it is now clear that ART procedures have the potential to influence DNA methylation in embryonic and fetal life, with an impact on health and disease risk in future generations. Critical re-evaluation of protocols and procedures is now an urgent priority, with a focus on interventions targeted toward improving ART procedures, with special attention to in vitro culture protocols and the effects of excessive folic acid intake. [ABSTRACT FROM AUTHOR]

Ferroptosis, characterized by glutamate overload, glutathione depletion, and cysteine/cystine deprivation during iron- and oxidative-damage-dependent cell death, is a particular mode of regulated cell death. It is expected to effectively treat cancer through its tumor-suppressor function, as mitochondria are the intracellular energy factory and a binding site of reactive oxygen species production, closely related to ferroptosis. This review summarizes relevant research on the mechanisms of ferroptosis, highlights mitochondria’s role in it, and collects and classifies the inducers of ferroptosis. A deeper understanding of the relationship between ferroptosis and mitochondrial function may provide new strategies for tumor treatment and drug development based on ferroptosis.

We studied the kinetics of the reaction of N-acetyl-l-cysteine (NAC or RSH) with cupric ions at an equimolar ratio of the reactants in aqueous acid solution (pH 1.4–2) using UV/Vis absorption and circular dichroism (CD) spectroscopies. Cu2+ showed a strong catalytic effect on the 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonate) radical (ABTSr) consumption and autoxidation of NAC. Difference spectra revealed the formation of intermediates with absorption maxima at 233 and 302 nm (ε302/Cu > 8 × 103 M−1 cm−1) and two positive Cotton effects centered at 284 and 302 nm. These intermediates accumulate during the first, O2-independent, phase of the NAC autoxidation. The autocatalytic production of another chiral intermediate, characterized by two positive Cotton effects at 280 and 333 nm and an intense negative one at 305 nm, was observed in the second reaction phase. The intermediates are rapidly oxidized by added ABTSr; otherwise, they are stable for hours in the reaction solution, undergoing a slow pH- and O2-dependent photosensitive decay. The kinetic and spectral data are consistent with proposed structures of the intermediates as disulfide-bridged dicopper(I) complexes of types cis-/trans-CuI2(RS)2(RSSR) and CuI2(RSSR)2. The electronic transitions observed in the UV/Vis and CD spectra are tentatively attributed to Cu(I) → disulfide charge transfer with an interaction of the transition dipole moments (exciton coupling). The catalytic activity of the intermediates as potential O2 activators via Cu(II) peroxo-complexes is discussed. A mechanism for autocatalytic oxidation of Cu(I)–thiolates promoted by a growing electronically coupled –[CuI2(RSSR)]n– polymer is suggested. The obtained results are in line with other reported observations regarding copper-catalyzed autoxidation of thiols and provide new insight into these complicated, not yet fully understood systems. The proposed hypotheses point to the importance of the Cu(I)–disulfide interaction, which may have a profound impact on biological systems. [ABSTRACT FROM AUTHOR]

Chirality is a universal phenomenon, embracing the space–time domains of non-organic and organic nature. The biological time arrow, evident in the aging of proteins and organisms, should be linked to the prevalent biomolecular chirality. This hypothesis drives our exploration of protein aging, in relation to the biological aging of an organism. Recent advances in the chirality discrimination methods and theoretical considerations of the non-equilibrium thermodynamics clarify the fundamental issues, concerning the biphasic, alternative, and stepwise changes in the conformational entropy associated with protein folding. Living cells represent open, non-equilibrium, self-organizing, and dissipative systems. The non-equilibrium thermodynamics of cell biology are determined by utilizing the energy stored, transferred, and released, via adenosine triphosphate (ATP). At the protein level, the synthesis of a homochiral polypeptide chain of L-amino acids (L-AAs) represents the first state in the evolution of the dynamic non-equilibrium state of the system. At the next step the non-equilibrium state of a protein-centric system is supported and amended by a broad set of posttranslational modifications (PTMs). The enzymatic phosphorylation, being the most abundant and ATP-driven form of PTMs, illustrates the principal significance of the energy-coupling, in maintaining and reshaping the system. However, the physiological functions of phosphorylation are under the permanent risk of being compromised by spontaneous racemization. Therefore, the major distinct steps in protein-centric aging include the biosynthesis of a polypeptide chain, protein folding assisted by the system of PTMs, and age-dependent spontaneous protein racemization and degradation. To the best of our knowledge, we are the first to pay attention to the biphasic, alternative, and stepwise changes in the conformational entropy of protein folding. The broader view on protein folding, including the impact of spontaneous racemization, will help in the goal-oriented experimental design in the field of chiral proteomics. [ABSTRACT FROM AUTHOR]

Cystine-knot miniproteins (CKMPs) are an intriguing group of cysteine-rich molecules that combine the characteristics of proteins and peptides. Typically, CKMPs are fewer than 50 residues in length and share a characteristic knotted scaffold characterized by the presence of three intramolecular disulfide bonds that form the singular knotted structure. The knot scaffold confers on these proteins remarkable chemical, thermal, and proteolytic stability. Recently, CKMPs have emerged as a novel class of natural molecules with interesting pharmacological properties. In the present work, a novel cystine-knot metallocarboxypeptidase inhibitor (chuPCI) was isolated from tubers of Solanum tuberosum, subsp. andigenum cv. Churqueña. Our results demonstrated that chuPCI is a member of the A/B-type family of metallocarboxypeptidases inhibitors. chuPCI was expressed and characterized by a combination of biochemical and mass spectrometric techniques. Direct comparison of the MALDI-TOF mass spectra for the native and recombinant molecules allowed us to confirm the presence of four different forms of chuPCI in the tubers. The majority of such forms have a molecular weight of 4309 Da and contain a cyclized Gln in the N-terminus. The other three forms are derived from N-terminal and/or C-terminal proteolytic cleavages. Taken together, our results contribute to increase the current repertoire of natural CKMPs. [ABSTRACT FROM AUTHOR]

Central among the fetotoxic responses to in utero ethanol (E) exposure is redox-shift related glutathione (GSH) loss and apoptosis. Previously, we reported that despite an E-generated Nrf2 upregulation, fetal neurons still succumb. In this study, we investigate if the compromised GSH results from an impaired inward transport of cysteine (Cys), a precursor of GSH in association with dysregulated excitatory amino acid carrier1 (EAAC1), a cysteine transporter. In utero binge model involves administration of isocaloric dextrose or 20% E (3.5 g/kg)/ by gavage at 12 h intervals to pregnant Sprague Dawley (SD) rats, starting gestation day (gd) 17 with a final dose on gd19, 2 h prior to sacrifice. Primary cerebral cortical neurons (PCNs) from embryonic day 16-17 fetal SD rats were the in vitro model. E reduced both PCN and cerebral cortical GSH and Cys up to 50% and the abridged GSH could be blocked by administration of N-acetylcysteine. E reduced EAAC1 protein expression in utero and in PCNs (p < 0.05). This was accompanied by a 60-70% decrease in neuron surface expression of EAAC1 along with significant reductions of EAAC1/Slc1a1 mRNA (p < 0.05). In PCNs, EAAC1 knockdown significantly decreased GSH but not oxidized glutathione (GSSG) illustrating that while not the sole provider of Cys, EAAC1 plays an important role in neuron GSH homeostasis. These studies strongly support the concept that in both E exposed intact fetal brain and cultured PCNs a mechanism underlying E impairment of GSH homeostasis is reduction of import of external Cys which is mediated by perturbations of EAAC1 expression/function. [ABSTRACT FROM AUTHOR]

Multifunctional polymer nanoconjugates containing multiple components show great promise in cancer therapy, but in most cases complete analysis of each component is difficult. Polymalic acid (PMLA) based nanoconjugates have demonstrated successful brain and breast cancer treatment. They consist of multiple components including targeting antibodies, Morpholino antisense oligonucleotides (AONs), and endosome escape moieties. The component analysis of PMLA nanoconjugates is extremely difficult using conventional spectrometry and HPLC method. Taking advantage of the nature of polyester of PMLA, which can be cleaved by ammonium hydroxide, we describe a method to analyze the content of antibody and AON within nanoconjugates simultaneously using SEC-HPLC by selectively cleaving the PMLA backbone. The selected cleavage conditions only degrade PMLA without affecting the integrity and biological activity of the antibody. Although the amount of antibody could also be determined using the bicinchoninic acid (BCA) method, our selective cleavage method gives more reliable results and is more powerful. Our approach provides a new direction for the component analysis of polymer nanoconjugates and nanoparticles. [ABSTRACT FROM AUTHOR]

A high-level of sexual sterility is of importance for the sterile insect technique (SIT). However, the use of high-dose-intensity gamma radiation to induce sterility has negative impacts not only on reproductive cells but also on somatic cells. In this study, we investigated the metabolite differences in somatic tissues between non-irradiated, 20-Gy-irradiated, and 40-Gy-irradiated male Monochamus alternatus, an important vector of the pathogenic nematode, Bursaphelenchus xylophilus, which kills Asian pines. The results showed that metabolite levels changed moderately in the 20-Gy samples but were markedly altered in the 40-Gy samples compared with the non-irradiated samples. Twenty-six and 53 metabolites were disturbed by 20-Gy and 40-Gy radiation, respectively. Thirty-six metabolites were found to be markedly altered in the 40-Gy samples but were not changed significantly in the 20-Gy samples. The comprehensive metabolomic disorders induced by 40-Gy radiation dysregulated six metabolic pathways involved in the life process. The findings presented in this manuscript will contribute to our knowledge of the characteristic metabolic changes associated with gamma-radiation-induced damage to somatic cells and will allow for better exploration of the SIT for the control of this target pest. [ABSTRACT FROM AUTHOR]

Thiols (sulfhydryl groups) are effective antioxidants that can preserve the correct structure of proteins, and can protect cells and tissues from damage induced by oxidative stress. Abnormal levels of thiols have been measured in the blood of patients with moderate-to-severe chronic kidney disease (CKD) compared to healthy subjects, as well as in end-stage renal disease (ESRD) patients on haemodialysis or peritoneal dialysis. The levels of protein thiols (a measure of the endogenous antioxidant capacity inversely related to protein oxidation) and S-thiolated proteins (mixed disulphides of protein thiols and low molecular mass thiols), and the protein thiolation index (the molar ratio of the S-thiolated proteins to free protein thiols in plasma) have been investigated in the plasma or red blood cells of CKD and ESRD patients as possible biomarkers of oxidative stress. This type of minimally invasive analysis provides valuable information on the redox status of the less-easily accessible tissues and organs, and of the whole organism. This review provides an overview of reversible modifications in protein thiols in the setting of CKD and renal replacement therapy. The evidence suggests that protein thiols, S-thiolated proteins, and the protein thiolation index are promising biomarkers of reversible oxidative stress that could be included in the routine monitoring of CKD and ESRD patients. [ABSTRACT FROM AUTHOR]

Reactive oxygen species (ROS) can be both beneficial and deleterious. Under normal physiological conditions, ROS production is tightly regulated, and ROS participate in both pathogen defense and cellular signaling. However, insufficient ROS detoxification or ROS overproduction generates oxidative stress, resulting in cellular damage. Oxidative stress has been linked to various inflammatory diseases. Inflammation is an essential response in the protection against injurious insults and thus important at the onset of wound healing. However, hampered resolution of inflammation can result in a chronic, exaggerated response with additional tissue damage. In the pathogenesis of several inflammatory skin conditions, e.g., sunburn and psoriasis, inflammatory-mediated tissue damage is central. The prolonged release of excess ROS in the skin can aggravate inflammatory injury and promote chronic inflammation. The cellular redox balance is therefore tightly regulated by several (enzymatic) antioxidants and pro-oxidants; however, in case of chronic inflammation, the antioxidant system may be depleted, and prolonged oxidative stress occurs. Due to the central role of ROS in inflammatory pathologies, restoring the redox balance forms an innovative therapeutic target in the development of new strategies for treating inflammatory skin conditions. Nevertheless, the clinical use of antioxidant-related therapies is still in its infancy. [ABSTRACT FROM AUTHOR]

Physiological and ecological constraints that cause the slow growth and depleted production of crops have raised a major concern in the agriculture industry as they represent a possible threat of short food supply in the future. The key feature that regulates the stress signaling pathway is always related to the reactive oxygen species (ROS). The accumulation of ROS in plant cells would leave traces of biomarkers at the genome, proteome, and metabolome levels, which could be identified with the recent technological breakthrough coupled with improved performance of bioinformatics. This review highlights the recent breakthrough in molecular strategies (comprising transcriptomics, proteomics, and metabolomics) in identifying oxidative stress biomarkers and the arising opportunities and obstacles observed in research on biomarkers in rice. The major issue in incorporating bioinformatics to validate the biomarkers from different omic platforms for the use of rice-breeding programs is also discussed. The development of powerful techniques for identification of oxidative stress-related biomarkers and the integration of data from different disciplines shed light on the oxidative response pathways in plants. [ABSTRACT FROM AUTHOR]

Abiotic stress poses major problems to agriculture and increasing efforts are being made to understand plant stress response and tolerance mechanisms and to develop new tools that underpin successful agriculture. However, the molecular mechanisms of plant stress tolerance are not fully understood, and the data available is incomplete and sometimes contradictory. Here, we review the significance of protein and non-protein thiol compounds in relation to plant tolerance of abiotic stress. First, the roles of the amino acids cysteine and methionine, are discussed, followed by an extensive discussion of the low-molecular-weight tripeptide, thiol glutathione, which plays a central part in plant stress response and oxidative signalling and of glutathione-related enzymes, including those involved in the biosynthesis of non-protein thiol compounds. Special attention is given to the glutathione redox state, to phytochelatins and to the role of glutathione in the regulation of the cell cycle. The protein thiol section focuses on glutaredoxins and thioredoxins, proteins with oxidoreductase activity, which are involved in protein glutathionylation. The review concludes with a brief overview of and future perspectives for the involvement of plant thiols in abiotic stress tolerance. [ABSTRACT FROM AUTHOR]

The effects of lipoic acid (LA) on the antioxidant status of broilers were investigated. Birds (1 day old) were randomly assigned to four groups and fed corn-soybean diets supplemented with 0, 100, 200, 300 mg/kg LA, respectively. The feeding program included a starter diet from 1 to 21 days of age and a grower diet from 22 to 42 days of age. Serum, liver and muscle samples were collected at 42 days of age. For antioxidant enzymes, superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activity in serum, liver and breast muscle significantly increased in chickens fed with LA. The concentration of malondiadehyde (MDA), an indicator of lipid peroxidation, was significantly lower in serum, liver and leg muscle in birds that received LA than in the control group. Treatments with LA significantly increased glutathione (GSH) content in liver and increased α-tocopherol content in leg muscle as compared to the control. These results indicate that dietary supplementation with 300 mg/kg LA may enhance antioxidant capability and depress oxidative stress in broilers. [ABSTRACT FROM AUTHOR]

Two varieties of foxtail millet protein concentrates (white and yellow) were characterized for in vitro trypsin digestibility, functional and physicochemical properties. Millet protein concentrate was easily digested by trypsin in vitro. Essential amino acids were above the amounts recommended by the Food Agricultural Organization/World Health Organization (FAO/WHO/UNU) for humans. Yellow millet protein concentrate (YMPC) possessed the highest differential scanning calorimetry result (peak temperature of 88.98 °C, delta H = 0.01 J/g), white millet protein concentrate (WMPC) had the lowest (peak temperature 84.06 °C, delta H = 0.10 J/g). The millet protein concentrates had molecular sizes around 14.4 and 97.4 kDa. They have U-shape solubility curves. Waterbinding capacity was in the range of 5.0 and 7.0 g/g, while oil absorption capacity ranged between 4.8 and 5.9 g/g. WMPC had higher bulk density (0.22 g/mL) and emulsifying capacity than YMPC and Soy Protein Concentrate (SPC). Foam capacity and foam stability ranged from 137 to 73 g/mL for WMPC, from 124 to 61 g/mL SPC and from 124 to 46 g/mL for YMPC. Millet protein concentrates are potential functional food ingredients. [ABSTRACT FROM AUTHOR]

Extracellular glutathione (GSH) and oxidized glutathione (GSSG) can modulate the function of the extracellular calcium sensing receptor (CaSR). The CaSR has a binding pocket in the extracellular domain of CaSR large enough to bind either GSH or GSSG, as well as the naturally occurring oxidized derivative L-cysteine glutathione disulfide (CySSG) and the compound cysteinyl glutathione (CysGSH). Modeling the binding energies (ΔG) of CySSG and CysGSH to CaSR reveals that both cysteine derivatives may have greater affinities for CaSR than either GSH or GSSG. GSH, CySSG, and GSSG are found in circulation in mammals and, among the three, CySSG is more affected by HIV/AIDs and aging than either GSH or GSSG. The beta-carbon linkage of cysteine in CysGSH may model a new class of calcimimetics, exemplified by etelcalcetide. Circulating glutathionergic compounds, particularly CySSG, may mediate calcium-regulatory responses via receptor-binding to CaSR in a variety of organs, including parathyroids, kidneys, and bones. Receptor-mediated actions of glutathionergics may thus complement their roles in redox regulation and detoxification. The glutathionergic binding site(s) on CaSR are suggested to be a target for development of drugs that can be used in treating kidney and other diseases whose mechanisms involve CaSR dysregulation. [ABSTRACT FROM AUTHOR]

Methionine restriction (MetR) is an efficient method of amino acid restriction (AR) in cells and organisms that induces low energy metabolism (LEM) similar to caloric restriction (CR). The implementation of MetR as a therapy for cancer or other diseases is not simple since the elimination of a single amino acid in the diet is difficult. However, the in vivo turnover rate of cysteine is usually higher than the rate of intake through food. For this reason, every cell can enzymatically synthesize cysteine from methionine, which enables the use of specific enzymatic inhibitors. In this work, we analysed the potential of cysteine restriction (CysR) in the murine cell line L929. This study determined metabolic fingerprints using mass spectrometry (LC/MS). The profiles were compared with profiles created in an earlier work under MetR. The study was supplemented by proliferation studies using D-amino acid analogues and inhibitors of intracellular cysteine synthesis. CysR showed a proliferation inhibition potential comparable to that of MetR. However, the metabolic footprints differed significantly and showed that CysR does not induce classic LEM at the metabolic level. Nevertheless, CysR offers great potential as an alternative for decisive interventions in general and tumour metabolism at the metabolic level. [ABSTRACT FROM AUTHOR]

The bacterial flagellum is a complex and dynamic nanomachine that propels bacteria through liquids. It consists of a basal body, a hook, and a long filament. The flagellar filament is composed of thousands of copies of the protein flagellin (FliC) arranged helically and ending with a filament cap composed of an oligomer of the protein FliD. The overall structure of the filament core is preserved across bacterial species, while the outer domains exhibit high variability, and in some cases are even completely absent. Flagellar assembly is a complex and energetically costly process triggered by environmental stimuli and, accordingly, highly regulated on transcriptional, translational and post-translational levels. Apart from its role in locomotion, the filament is critically important in several other aspects of bacterial survival, reproduction and pathogenicity, such as adhesion to surfaces, secretion of virulence factors and formation of biofilms. Additionally, due to its ability to provoke potent immune responses, flagellins have a role as adjuvants in vaccine development. In this review, we summarize the latest knowledge on the structure of flagellins, capping proteins and filaments, as well as their regulation and role during the colonization and infection of the host. [ABSTRACT FROM AUTHOR]

Ferroptosis is a type of cell death that was described less than a decade ago. It is caused by the excess of free intracellular iron that leads to lipid (hydro) peroxidation. Iron is essential as a redox metal in several physiological functions. The brain is one of the organs known to be affected by iron homeostatic balance disruption. Since the 1960s, increased concentration of iron in the central nervous system has been associated with oxidative stress, oxidation of proteins and lipids, and cell death. Here, we review the main mechanisms involved in the process of ferroptosis such as lipid peroxidation, glutathione peroxidase 4 enzyme activity, and iron metabolism. Moreover, the association of ferroptosis with the pathophysiology of some neurodegenerative diseases, namely Alzheimer's, Parkinson's, and Huntington's diseases, has also been addressed. [ABSTRACT FROM AUTHOR]

Various environmental stresses singly or in combination generate excess amounts of reactive oxygen species (ROS), leading to oxidative stress and impaired redox homeostasis. Generation of ROS is the obvious outcome of abiotic stresses and is gaining importance not only for their ubiquitous generation and subsequent damaging effects in plants but also for their diversified roles in signaling cascade, affecting other biomolecules, hormones concerning growth, development, or regulation of stress tolerance. Therefore, a good balance between ROS generation and the antioxidant defense system protects photosynthetic machinery, maintains membrane integrity, and prevents damage to nucleic acids and proteins. Notably, the antioxidant defense system not only scavenges ROS but also regulates the ROS titer for signaling. A glut of studies have been executed over the last few decades to discover the pattern of ROS generation and ROS scavenging. Reports suggested a sharp threshold level of ROS for being beneficial or toxic, depending on the plant species, their growth stages, types of abiotic stresses, stress intensity, and duration. Approaches towards enhancing the antioxidant defense in plants is one of the vital areas of research for plant biologists. Therefore, in this review, we accumulated and discussed the physicochemical basis of ROS production, cellular compartment-specific ROS generation pathways, and their possible distressing effects. Moreover, the function of the antioxidant defense system for detoxification and homeostasis of ROS for maximizing defense is also discussed in light of the latest research endeavors and experimental evidence. [ABSTRACT FROM AUTHOR]

The evolution of an aquatic lifestyle from land dwelling venomous elapids is a radical ecological modification, bringing about many evolutionary changes from morphology to diet. Diet is an important ecological facet which can play a key role in regulating functional traits such as venom composition and prey-specific targeting of venom. In addition to predating upon novel prey (e.g., fish, fish eggs and invertebrates), the venoms of aquatic elapids also face the challenge of increased prey-escape potential in the aquatic environment. Thus, despite the independent radiation into an aquatic niche on four separate occasions, the venoms of aquatic elapids are evolving under convergent selection pressures. Utilising a biolayer interferometry binding assay, this study set out to elucidate whether crude venoms from representative aquatic elapids were target-specific to the orthosteric site of postsynaptic nicotinic acetylcholine receptor mimotopes of fish compared to other terrestrial prey types. Representatives of the four aquatic lineages were: aquatic coral snakes representative was Micrurus surinamensis;, sea kraits representative was Laticauda colubrina; sea snakes representatives were two Aipysurus spp. and eight Hydrophis spp; and water cobras representative was Naja annulata. No prey-specific differences in crude venom binding were observed from any species tested, except for Aipysurus laevis, which showed slight evidence of prey-potency differences. For Hydrophis caerulescens, H. peronii, H. schistosus and M. surinamensis, there was a lack of binding to the orthosteric site of any target lineage. Subsequent testing on the in vitro chick-biventer cervicis muscle preparation suggested that, while the venoms of these species bound postsynaptically, they bound to allosteric sites rather than orthosteric. Allosteric binding is potentially a weaker but faster-acting form of neurotoxicity and we hypothesise that the switch to allosteric binding is likely due to selection pressures related to prey-escape potential. This research has potentially opened up the possibility of a new functional class of toxins which have never been assessed previously while shedding light on the selection pressures shaping venom evolution. [ABSTRACT FROM AUTHOR]

Ultrashort cationic lipopeptides (USCLs) are considered to be a promising class of antimicrobials with high activity against a broad-spectrum of microorganisms. However, the majority of these compounds are characterized by significant toxicity toward human cells, which hinders their potential application. To overcome those limitations, several approaches have been advanced. One of these is disulfide cyclization that has been shown to improve drug-like characteristics of peptides. In this article the effect of disulfide cyclization of the polar head of N-palmitoylated USCLs on in vitro biological activity has been studied. Lipopeptides used in this study consisted of three or four basic amino acids (lysine and arginine) and cystine in a cyclic peptide. In general, disulfide cyclization of the lipopeptides resulted in peptides with reduced cytotoxicity. Disulfide-cyclized USCLs exhibited improved selectivity between Candida sp., Gram-positive strains and normal cells in contrast to their linear counterparts. Interactions between selected USCLs and membranes were studied by molecular dynamics simulations using a coarse-grained force field. Moreover, membrane permeabilization properties and kinetics were examined. Fluorescence and transmission electron microscopy revealed damage to Candida cell membrane and organelles. Concluding, USCLs are strong membrane disruptors and disulfide cyclization of polar head can have a beneficial effect on its in vitro selectivity between Candida sp. and normal human cells. [ABSTRACT FROM AUTHOR]

Amino acids are indispensable for the growth of cancer cells. This includes essential amino acids, the carbon skeleton of which cannot be synthesized, and conditionally essential amino acids, for which the metabolic demands exceed the capacity to synthesize them. Moreover, amino acids are important signaling molecules regulating metabolic pathways, protein translation, autophagy, defense against reactive oxygen species, and many other functions. Blocking uptake of amino acids into cancer cells is therefore a viable strategy to reduce growth. A number of studies have used genome-wide silencing or knock-out approaches, which cover all known amino acid transporters in a large variety of cancer cell lines. In this review, these studies are interrogated together with other databases to identify vulnerabilities with regard to amino acid transport. Several themes emerge, such as synthetic lethality, reduced redundancy, and selective vulnerability, which can be exploited to stop cancer cell growth. [ABSTRACT FROM AUTHOR]

Besides their primary involvement in the recycling and degradation of proteins in endo-lysosomal compartments and also in specialized biological functions, cysteine cathepsins are pivotal proteolytic contributors of various deleterious diseases. While the molecular mechanisms of regulation via their natural inhibitors have been exhaustively studied, less is currently known about how their enzymatic activity is modulated during the redox imbalance associated with oxidative stress and their exposure resistance to oxidants. More specifically, there is only patchy information on the regulation of lung cysteine cathepsins, while the respiratory system is directly exposed to countless exogenous oxidants contained in dust, tobacco, combustion fumes, and industrial or domestic particles. Papain-like enzymes (clan CA, family C1, subfamily C1A) encompass a conserved catalytic thiolate-imidazolium pair (Cys25-His159) in their active site. Although the sulfhydryl group (with a low acidic pKa) is a potent nucleophile highly susceptible to chemical modifications, some cysteine cathepsins reveal an unanticipated resistance to oxidative stress. Besides an introductory chapter and peculiar attention to lung cysteine cathepsins, the purpose of this review is to afford a concise update of the current knowledge on molecular mechanisms associated with the regulation of cysteine cathepsins by redox balance and by oxidants (e.g., Michael acceptors, reactive oxygen, and nitrogen species). [ABSTRACT FROM AUTHOR]

The glucagon receptor (GCGR) is a G-protein-coupled receptor (GPCR) that mediates the activity of glucagon. Disruption of GCGR results in many metabolic alterations, including increased glucose tolerance, decreased adiposity, hypoglycemia, and pancreatic α-cell hyperplasia. To better understand the global transcriptomic changes resulting from GCGR deficiency, we performed whole-organism RNA sequencing analysis in wild type and gcgr-deficient zebrafish. We found that the expression of 1645 genes changes more than two-fold among mutants. Most of these genes are related to metabolism of carbohydrates, lipids, and amino acids. Genes related to fatty acid β-oxidation, amino acid catabolism, and ureagenesis are often downregulated. Among gcrgr-deficient zebrafish, we experimentally confirmed increases in lipid accumulation in the liver and whole-body glucose uptake, as well as a modest decrease in total amino acid content. These results provide new information about the global metabolic network that GCGR signaling regulates in addition to a better understanding of the receptor's physiological functions. [ABSTRACT FROM AUTHOR]

Oxidative stress plays a pivotal role in the pathogenesis of cardiovascular diseases (CVD). Postmenopausal women have an increased risk of developing CVD due to decreased estrogen availability, which is accompanied by increased oxidative stress. Serum free thiols (R-SH) provide a robust and powerful read-out of systemic oxidative stress. In this study, we aimed to establish serum levels of free thiols and explore associations between free thiols and demographic, clinical, and biochemical parameters related to obesity and the risk for developing CVD in both pre- and postmenopausal women. Serum free thiols were measured in a cohort consisting of healthy pre- (n = 223) and postmenopausal (n = 118) Omani women. Postmenopausal women had significantly lower levels of serum free thiols as compared to premenopausal women (762.9 ± 85.3 vs. 780 ± 80.9 μM, age-adjusted p < 0.001). Women′s age was positively associated with serum free thiol levels in premenopausal women (β = 0.36, p = 0.002), whereas an inverse association was observed in postmenopausal women (β = −0.29, p = 0.002). Homocysteine levels were significantly inversely associated with serum free thiol levels in both pre- (β = −0.19, p = 0.005) and postmenopausal (β = −0.20, p = 0.032) women, independent from known cardiovascular risk factors. In this study, we show that postmenopausal women are affected by increased systemic oxidative stress, which independently associates with homocysteine levels. [ABSTRACT FROM AUTHOR]

The house dust mite (HDM) Dermatophagoides pteronyssinus is an important risk factor for asthma and rhinitis. Allergen specific immunotherapy that is based on recombinant proteins has been proposed for the safer and more efficient treatment of allergic diseases. The aim of this study was to design and obtain a hybrid protein (DPx4) containing antigenic regions of allergens Der p 1, Der p 2, Der p 7, and Der p 10 from this mite. DPx4 was produced in Escherichia coli and its folding was determined by circular dichroism. Non-denaturing dot-blot, ELISA, basophil activation test, dot blot with monoclonal antibodies, ELISA inhibition, and cysteine protease activity assays were performed. Mice that were immunized with DPx4 were also analyzed. We found that DPx4 had no cysteine protease activity and it showed significantly lower IgE reactivity than Der p 1, Der p 2, and D. pteronyssinus extract. DPx4 induced lower basophil activation than Der p 2 and the allergen extract. Immunized mice produced IgG antibodies that inhibited the binding of allergic patient's IgE to the allergen extract and induced comparatively higher levels of IL-10 than the extract in peripheral blood mononuclear cells (PBMC) culture. These results suggest that DPx4 has immunological properties that are useful for the development of a mite allergy vaccine. [ABSTRACT FROM AUTHOR]

Heme oxygenase (HO)-1 is known to metabolize heme into biliverdin/bilirubin, carbon monoxide, and ferrous iron, and it has been suggested to demonstrate cytoprotective effects against various stress-related conditions. HO-1 is commonly regarded as a survival molecule, exerting an important role in cancer progression and its inhibition is considered beneficial in a number of cancers. However, increasing studies have shown a dark side of HO-1, in which HO-1 acts as a critical mediator in ferroptosis induction and plays a causative factor for the progression of several diseases. Ferroptosis is a newly identified iron- and lipid peroxidation-dependent cell death. The critical role of HO-1 in heme metabolism makes it an important candidate to mediate protective or detrimental effects via ferroptosis induction. This review summarizes the current understanding on the regulatory mechanisms of HO-1 in ferroptosis. The amount of cellular iron and reactive oxygen species (ROS) is the determinative momentum for the role of HO-1, in which excessive cellular iron and ROS tend to enforce HO-1 from a protective role to a perpetrator. Despite the dark side that is related to cell death, there is a prospective application of HO-1 to mediate ferroptosis for cancer therapy as a chemotherapeutic strategy against tumors. [ABSTRACT FROM AUTHOR]

Energy production is the main task of the cancer cell metabolism because the costs of duplicating are enormous. Although energy is derived in cells by dismantling the carbon-to-carbon bonds of any macronutrient, cancer nutritional needs for energetic purposes have been studied primarily as being dependent on glycolysis. Since the end of the last century, the awareness of the dependence of cancer metabolism on amino acids not only for protein synthesis but also to match energy needs has grown. The roles of specific amino acids such as glutamine, glycine and serine have been explored in different experimental conditions and reviewed. Moreover, epidemiological evidence has revealed that some amino acids used as a supplement for therapeutic reasons, particularly the branched-chain ones, may reduce the incidence of liver cancer and a specific molecular mechanism has been proposed as functional to their protective action. By contrast and puzzling clinicians, the metabolomic signature of some pathologies connected to an increased risk of cancer, such as prolonged hyperinsulinemia in insulin-resistant patients, is identified by elevated plasma levels of the same branched-chain amino acids. Most recently, certain formulations of amino acids, deeply different from the amino acid compositions normally present in foods, have shown the power to master cancer cells epigenetically, slowing growth or driving cancer cells to apoptotic death, while being both beneficial for normal cell function and the animal's health and lifespan. In this review, we will analyze and try to disentangle some of the many knots dealing with the complexities of amino acid biology and links to cancer metabolism. [ABSTRACT FROM AUTHOR]

Earlier, we reported that gestational ethanol (E) can dysregulate neuron glutathione (GSH) homeostasis partially via impairing the EAAC1-mediated inward transport of Cysteine (Cys) and this can affect fetal brain development. In this study, we investigated if there is a role for the transulfuration pathway (TSP), a critical bio-synthetic point to supply Cys in E-induced dysregulation of GSH homeostasis. These studies utilized an in utero E binge model where the pregnant Sprague–Dawley (SD) rat dams received five doses of E at 3.5 g/kg by gastric intubation beginning embryonic day (ED) 17 until ED19 separated by 12 h. The postnatal day 7 (PN7) alcohol model employed an oral dosing of 4 g/kg body weight split into 2 feedings at 2 h interval and an iso-caloric and iso-volumic equivalent maltose-dextrin milk solution served as controls. The in vitro model consisted of cerebral cortical neuron cultures from embryonic day (ED) 16–17 fetus from SD rats and differentiated neurons from ED18 rat cerebral cortical neuroblasts. E concentrations were 4 mg/mL. E induced an accumulation of cystathionine in primary cortical neurons (PCNs), 2nd trimester equivalent in utero binge, and 3rd trimester equivalent PN7 model suggesting that breakdown of cystathionine, a required process for Cys supply is impaired. This was associated with a significant reduction in cystathionine γ-lyase (CSE) protein expression in PCN (p < 0.05) and in fetal cerebral cortex in utero (53%, p < 0.05) without a change in the expression of cystathionine β-synthase (CBS). Concomitantly, E decreased Cse mRNA expression in PCNs (by 32% within 6 h of exposure, p < 0.05) and in fetal brain (33%, p < 0.05). In parallel, knock down of CSE in differentiated rat cortical neuroblasts exaggerated the E-induced ROS, GSH loss with a pronounced caspase-3 activation and cell death. These studies illustrate the importance of TSP in CSE-related maintenance of GSH and the downstream events via Cys synthesis in neurons and fetal brain. [ABSTRACT FROM AUTHOR]