Biochemical Actions Research Articles

Effect of concomitant treatment of curcumin and melatonin on cisplatin-induced nephrotoxicity in rats

Cisplatin (CP) is a potent anticancer drug used to treat solid tumors. Its use, however, is dose-limited by its nephrotoxicity. We aimed to compare the effect of melatonin and curcumin given singly, with that of a combination of these two agents on CP-induced nephrotoxicity in rats. CP (6 mg/kg, given once intraperitoneally) induced nephrotoxicity as evidenced by several significant adverse physiological, biochemical and histopathological actions that included a reduction in body weight, increased urine production, and significant alterations in some conventional and novel renal damage indices in plasma, urine and kidneys. CP also elevated several pro-inflammatory cytokines and caused renal oxidative/nitrosative stress. Supplementation with either curcumin (200 mg/kg) or melatonin (10 mg /kg) given singly by oral gavage for eight consecutive days prior to CP injection and four days thereafter, significantly mitigated the adverse renal effects of CP, by attenuating the pro-inflammatory and apoptotic mediators and improving antioxidant competence in renal tissues of CP- treated rats. When curcumin and melatonin were given together, the ameliorative effect was augmented in some of the measured indices e.g. tumor necrosis factor alpha, cystatin C, uric acid, phosphorus in plasma and, urine creatinine and creatinine clearance. Renal platinum concertation was reduced more with curcumin than that with melatonin, while the reduction was maximized when both melatonin and curcumin were given. Pending further pharmacological and toxicological studies, a combination of these two agents is likely to be mor effective in mitigating the adverse renal effects of CP administered to cancer patients.

Clinical Evidence for Targeting NAD Therapeutically.

Nicotinamide adenine dinucleotide (NAD) pharmacology is a promising class of treatments for age-related conditions that are likely to have a favorable side effect profile for human use, given the widespread use of the NAD precursor vitamin B3 supplements. However, despite several decades of active investigation and numerous possible biochemical mechanisms of action suggested, only a small number of randomized and adequately powered clinical trials of NAD upregulation as a therapeutic strategy have taken place. We conducted a systematic review of the literature, following the PRISMA guidelines, in an attempt to determine whether or not the human clinical trials performed to date support the potential benefits of NAD supplementation in a range of skin, metabolic and age-related conditions. In addition, we sought medical indications that have yielded the most promising results in the limited studies to date. We conclude that promising, yet still speculative, results have been reported for the treatment of psoriasis and enhancement of skeletal muscle activity. However, further trials are required to determine the optimal method of raising NAD levels, identifying the target conditions, and comparisons to the present standard of care for these conditions. Lastly, pharmacological methods that increase NAD levels should also be directly compared to physiological means of raising NAD levels, such as exercise programs and dietary interventions that are tailored to older individuals, and which may be more effective.

Biochemical and physical actions of hyaluronic acid delivered by intradermal jet injection route.

Administration of exogenous hyaluronic acid (HA) by liquid jet injection is considered as a beneficial therapy for dermatology conditions. This paper reviews variety of the factors which would optimize the clinical output of hyaluronic acid in this treatment modality. A pneumatically accelerated jet penetrates the epidermis and spherically spreads micro-droplets of HA in the dermis without significant damage to the tissue and blood vessels. Kinetic energy of the jet activates two parallel mechanisms of action-mechanical and biological-which act synergistically to initiate and augment the regenerative effect. Jet-induced micro-trauma stimulates collagen synthesis and tissue repair without inflammation. Aside from the biophysical stimulation of dermal fibroblast, the biomolecular properties of exogenous HA provide excellent clinical results for skin atrophy, remodeling of dermal scarring, and reverse formation of fibrotic tissue. The effect is mediated by HA-specific cell receptors and depends on molecular weight and the rheological properties of HA polymer. Skin mechanical properties play a key role in predicting HA dispersion patterns. Tolerability and safety of the treatment approach are determined by the jet's physical impact on the tissue and/or by the safety profile of the injected material. Although pneumatic jet delivery of a hyaluronic acid has a limited use in clinical practice, this treatment approach has a strong potential for extended implementation in esthetic dermatology. The synergistic mechanism has significant advantages of predictable and rapid clinical outcomes with a low discomfort. Additional well-designed investigations are required for establishing a scientific foundation and guidelines for this treatment modality.

Immunogenic necroptosis in the anti-tumor photodynamic action of BAM-SiPc, a silicon(IV) phthalocyanine-based photosensitizer.

Photodynamic therapy (PDT) is an anti-tumor modality which employs three individually non-toxic substances, including photosensitizer, light and oxygen, to produce a toxic effect. Besides causing damage to blood vessels that supply oxygen and nutrients to the tumor and killing the tumor by a direct cytotoxic effect, PDT has also been known to trigger an anti-tumor immune response. For instance, our previous study showed that PDT with BAM-SiPc, a silicon(IV) phthalocyanine based-photosensitizer, can not only eradicate the mouse CT26 tumor cells in a Balb/c mouse model, but also protect the mice against further re-challenge of the tumor cells through an immunomodulatory mechanism. To understand more about the immune effect, the biochemical actions of BAM-SiPc-PDT on CT26 cells were studied in the in vitro system. It was confirmed that the PDT treatment could induce immunogenic necroptosis in the tumor cells. Upon treatment, different damage-associated molecular patterns were exposed onto the cell surface or released from the cells. Among them, calreticulin was found to translocate to the cell membrane through a pathway similar to that in chemotherapy. The activation of immune response was also demonstrated by an increase in the expression of different chemokines.

Quercetin Caused Redox Homeostasis Imbalance and Activated the Kynurenine Pathway

The search for new and better antimicrobial therapy is a continuous effort. Quercetin is a polyphenol with promising antimicrobial properties. However, the understanding of its antimicrobial mechanism is limited. In this study, we investigated the biochemical mechanistic action of quercetin as an antibacterial compound. Isolates of Bacillus subtilis, Pseudomonas aeruginosa, Escherichia coli, Klebsiella pneumonia, and Staphylococcus aureus were initially exposed to quercetin for antibacterial evaluation. Subsequently, S. aureus (Gram-positive) and E. coli (Gram-negative) cells were exposed to quercetin with or without ascorbic acid, and cells were harvested for selected biochemical assays. These assays included redox homeostasis (lipid peroxidation, total thiol, total antioxidant capacity), nitric oxide, and kynurenine concentration as well as DNA fragmentation. The results revealed that quercetin caused lipid peroxidation in the bacterial isolates. Lipid peroxidation may indicate ensuing oxidative stress resulting from quercetin treatment. Furthermore, tryptophan degradation to kynurenine was activated by quercetin in S. aureus but not in E. coli, suggesting that local L-tryptophan concentration might become limiting for bacterial growth. These findings, considered together, may indicate that quercetin restricts bacterial growth by promoting oxidative cellular stress, as well as by reducing the local L-tryptophan availability by activating the kynurenine pathway, thus contributing to our understanding of the molecular mechanism of the antimicrobial action of quercetin.

Lithium influences whole-organism metabolic rate in Drosophila subobscura.

Lithium is widely used to treat bipolar disorder. However, the efficacy and vulnerability as to its side effects are known to differ. Although the specific biochemical mechanism of action is still elusive, lithium may influence mitochondrial function, and consequently, metabolism. Lithium exposure in this study was conducted on a unique set of mito-nuclear introgression lines of Drosophila subobscura to disentangle the independent effects of mitochondrial DNA (mtDNA) against a common nuclear DNA background. The study addressed three issues: (a) whether lithium has a dose-dependent effect on whole-organism metabolic rate, (b) whether mtDNA haplotypes show divergent metabolic efficiency measured by metabolic rate to lithium exposure and (c) whether lithium influences the whole-organism metabolic rate across sexes. The results confirm that lithium influenced the whole-organism metabolic rate, showing a subtle balance between efficacy and adverse effects within a narrow dose range. In addition, lithium exposure was found to influence metabolism differently based on mtDNA haplotypes and sex. This preliminary research may have a range of biological implications for the role of mitochondrial variability in psychiatric disease and treatment by contributing to the understanding and predicting of the lithium treatment response and risk for toxic side effects.

Binuclear 3,3′,5,5′-tetramethyl-1H,H-4,4′-bipyrazole Ruthenium(II) complexes: Synthesis, characterization and biological studies

Organometallic Ru(II) arene complexes have emerged as potential alternative to platinum anti-tumor drugs due to their stability in solution and in the solid state, significant biological activity and reduced toxicity and hydrophobicity of their ancillary arene groups. We report here a series of Ru(II)-arene dinuclear complexes prepared from 3,3′,5,5′-tetramethyl-1H,H-4,4′-bipyrazole and [(η6-arene)RuCl2] dimers. The new compounds were spectroscopically (FT-IR, 1H, 13C, ESI-MS) and structurally characterized. These complexes were found to adopt the piano stool coordination geometry around the Ru(II) ions, with the bipyrazole ligand bridging two metal centers through its pyridinic nitrogen. Their in vitro cytotoxicity was paralleled in human epithelial normal, cancerous and cisplatin-resistant cancerous cells. Ultimately, two possible mechanisms of drug biochemical action underlying the observed effects (DNA targeting and proteasome inhibitory abilities) were explored.

Microglia mediated neuroinflammation - signaling regulation and therapeutic considerations with special reference to some natural compounds.

Neuroinflammation plays a central role in multiple neurodegenerative diseases and neurological disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), cerebral ischemic injury etc. In this connection, microglia, the key players in the central nervous system, mediate the inflammatory response process. In brain injuries, activated microglia can clear the cellular debris and invading pathogens and release neurotrophic factors; however, prolonged microglia activation may cause neuronal death through excessive release of inflammatory mediators. Therefore, it is of paramount importance to understand the underlying molecular mechanisms of microglia activation to design an effective therapeutic strategy to alleviate neuronal injury. Recent studies have shown that some natural compounds and herbal extracts possess anti-inflammatory properties that may suppress microglial activation and ameliorate neuroinflammation and hence are neuroprotective. In this review, we will update some of the common signaling pathways that regulate microglia activation. Among the various signaling pathways, the Notch-1, mitogen-activated protein kinases (MAPKs), and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) have been reported to exacerbate microglia mediated neuroinflammation that is implicated in different neuropathological diseases. The search for natural compounds or agents, specifically those derived from natural herbal extracts such as Gastrodin, scutellarin, RG1 etc. has been the focus of many of our recent studies because they have been found to regulate microglia activation. The pharmacological effects of these agents and their potential mechanisms for regulating microglia activation are systematically reviewed here for a fuller understanding of their biochemical action and therapeutic potential for treatment of microglia mediated neuropathological diseases.

Role of Curcumin and (-)-Epigallocatechin-3-O-Gallate in Bladder Cancer Treatment: A Review.

The incidence of bladder cancer (BC) is increasing, and although current therapeutic approaches are effective in many cases, recurrence of BC is common. Therefore, it seems necessary to search not only for novel therapeutic approaches, but also for new therapeutic agents. Natural polyphenols, such as curcumin (CUR) and epigallocatechin gallate (EGCG), possess remarkable antitumor activity. Their biochemical mechanisms of action include regulation of signaling pathways, modeling of proteins involved in apoptosis and cell cycle inhibition, angiogenesis, and the proliferation, migration and adhesion of tumor cells. Both compounds also present antioxidant, anti-inflammatory, antibacterial and antiviral properties. CUR has been considered a promising candidate for the treatment of cystic fibrosis, Alzheimer’s disease or malaria, whereas EGCG can play a supportive role in the treatment of obesity, metabolic and neurodegenerative diseases. The review summarizes the latest research on the role of CUR and EGCG in the treatment of BC. In particular, the effects of CUR and EGCG, and their prospects for use in BC therapy, their inhibition of cancer development and their prevention of multidrug resistance, are described. The literature’s data indicate the possibility of achieving the effect of synergism of both polyphenols in BC therapy, which has been observed so far in the treatment of ovarian, breast and prostate cancer.

MicroRNA-148b-3p and MicroRNA-25-3p Are Overexpressed in Fetuses with Late-Onset Fetal Growth Restriction

Objective: It was the aim of this study to describe a micro­RNA (miRNA) profile characteristic of late-onset fetal growth restriction (FGR) and to investigate the pathways involved in their biochemical action. Methods: In this prospective study, 25 fetuses (16 normal and 9 with FGR [estimated fetal weight <10th centile plus cerebroplacental ratio <0.6765 multiples of the median]) were evaluated with Doppler ultrasound after 36 weeks. Afterwards, for every fetus, plasma from umbilical vein blood was collected at birth, miRNA was extracted, and full miRNA sequencing was performed. Subsequently, comparisons were done in order to obtain those miRNAs that were differentially expressed. Results: The FGR fetuses expressed upregulation of two miRNAs: miR-25-3p and, especially, miR-148b-3p, a miRNA directly involved in Schwann cell migration, neuronal plasticity, and energy metabolism (p = 0.0072, p = 0.0013). Conclusions: FGR fetuses express a different miRNA profile, which includes overexpression of miR-25-3p and miR-148b-3p. This information might improve our understanding of the pathophysiological processes involved in late-onset FGR. Future validation and feasibility studies will be required to propose miRNAs as a valid tool in the diagnosis and management of FGR.

Amine-modified kaolinite clay preserved thyroid function and renal oxidative balance after sub-acute exposure in rats.

Kaolinite clay is an abundant natural resource in Nigeria with several industrial applications. Incidentally, the wide-scale use of kaolinite clay is hampered by its small surface area. The objective of this study was to assess the effects of amine-modified clay on electrolyte, thyroid, and kidney function markers. Modification of kaolinite clay with an amine functional group was achieved using surface grafting technique. Characterization with a scanning electron microscope and Brunauer-Emmett Teller surface area analyzer confirmed this modification. However, there is sparse information on the effect of amine-modified kaolinite clay on electrolyte homeostasis, thyroid, and renal function. Rats were administered amine-modified kaolinite clay at the doses of 1, 2, and 5mg/kg body weight. After 14days of repeated-dose treatment, there were no significant changes in levels of albumin, uric acid, triiodothyronine, thyroxine, ratio of triiodothyronine to thyroxine, and relative kidney organ weight. Furthermore, there were no changes in the concentration of potassium, although amine-modified kaolinite clay significantly decreased sodium, calcium, and total cholesterol levels. Amine-modified kaolinite clay, at all treatment doses, also preserved the renal histoarchitecture and oxidative balance in rats. This study reports on the effect of amine-modified kaolinite clay on renal markers and thyroid function, and further deepens our understanding of their biochemical action. This baseline data may boost the prospect of using amine-modified kaolinite clay in the treatment of contaminated water.

Effects of anti-wrinkle and skin-whitening fermented black ginseng on human subjects and underlying mechanism of action

ABSTRACT The aim of this study was to determine the effects of anti-wrinkle and skin-whitening of fermented black ginseng (FBG) in human subjects and to examine underlying biochemical mechanisms of action. A clinical study was performed to evaluate efficacy and safety using a 1% FBG cream formulation. Twenty-three subjects were recruited and instructed to apply control or FBG creams each on half of their face twice daily for 8 weeks. After 8 weeks, FBG cream significantly reduced the appearance of eye wrinkles compared to prior to exposure and control cream. Skin color was significantly brightened using FBG cream in comparison with a control cream. To determine the mechanism of actions involved in anti-wrinkle and skin-whitening effects various concentrations of FBG were applied to human fibroblast CCD-986sk and mouse melanoma B16F1 cells. Collagen synthesis in CCD-986sk cells was improved significantly at 1, 3, 10, or 30 µg/ml of FBG. At 30 µg/ml, FBG significantly inhibited (73%) collagenase, and matrix metalloproteinase-1 (MMP-1) compared to control. Tyrosinase activity and DOPA (3,4-dihydroxy-L-phenylalanine) oxidation were significantly decreased at all tested concentrations. Melanin production in B16F1 cells was concentration-dependently reduced from 15% to 60% by all concentrations of FBG. These results suggested that a 1% FBG cream exerted anti-wrinkle and skin-whitening effects.

Effects of anti-wrinkle and skin-whitening fermented black ginseng on human subjects and underlying mechanism of action

ABSTRACT The aim of this study was to determine the effects of anti-wrinkle and skin-whitening of fermented black ginseng (FBG) in human subjects and to examine underlying biochemical mechanisms of action. A clinical study was performed to evaluate efficacy and safety using a 1% FBG cream formulation. Twenty-three subjects were recruited and instructed to apply control or FBG creams each on half of their face twice daily for 8 weeks. After 8 weeks FBG cream significantly reduced appearance of eye wrinkles compared to prior to exposure and control cream. Skin color was significantly brightened using FBG cream in comparison with control cream. To determine the mechanism of actions involved in anti-wrinkle and skin-whitening effects various concentrations of FBG were applied to human fibroblast CCD-986sk and mouse melanoma B16F1 cells. Collagen synthesis in CCD-986sk cells was improved significantly at 1, 3, 10, or 30 µg/ml of FBG. At 30 µg/ml, FBG significantly inhibited (73%) collagenase, and matrix metalloproteinase-1 (MMP-1) compared to control. Tyrosinase activity and DOPA (3,4-dihydroxy-L-phenylalanine) oxidation were significantly decreased at all tested concentrations. Melanin production in B16F1 cells was concentration-dependently reduced 15% to 60% by all concentrations of FBG. These results suggested that a 1% FBG cream exerted anti-wrinkle and skin-whitening effects.

Myristica fragrans essential oil nanoemulsion as novel green preservative against fungal and aflatoxin contamination of food commodities with emphasis on biochemical mode of action and molecular docking of major components

The study reports the antifungal and antiaflatoxigenic mechanism of action of chitosan fabricated Myristica fragrans essential oil nanoemulsion (Nm-MFEO) against an aflatoxigenic strain of Aspergillus flavus (AF LHP R14). Significant inhibition in ergosterol biosynthesis by Nm-MFEO indicated plasma membrane as potential target site of antifungal action. Moreover, Nm-MFEO caused dose dependent inhibition of methylglyoxal (aflatoxin inducer) biosynthesis suggesting novel antiaflatoxigenic mechanism of action. Significant impairment in enzymatic (superoxide dismutase and catalase) and non-enzymatic (oxidized and reduced glutathione and ratio of oxidized and reduced glutathione) anti-oxidative defense molecules in AF LHP R14 cells after treatment with Nm-MFEO suggested biochemical mechanism of action. Nm-MFEO exhibited promising antioxidant activity as determined through DPPH˙ and ABTS˙+ assay with IC50 value 1.20, 0.157 μL/mL, respectively and higher phenolic content (11.87 μg/mg gallic acid). Further, the in silico molecular docking of major components of MFEO viz. myristicin, elemicin and thujanol with aflatoxin producing regulatory genes Ver 1 and Omt A depicted important molecular site of interaction supporting the applicability of MFEO nanoemulsion as plant based green food preservative. The present study is the first report on the effect of chitosan fabricated MFEO nanoemulsion resulting in the inhibition of methylglyoxal, thereby suggesting its future exploitation for the development of aflatoxin resistant food crop varieties through green transgenics.

Saturation Transfer Difference in Characterization of Glycosaminoglycan-Protein Interactions

Novel methods in nuclear magnetic resonance (NMR) spectroscopy have recently been developed to investigate the binding properties of intermolecular complexes endowed with biomedical functions. Among these methods is the saturation transfer difference (STD), which enables the mapping of specific binding motifs of functional ligands. STD can efficiently uncover the specific and preferential binding sites of these ligands in their intermolecular complexes. This is particularly useful in the case of glycosaminoglycans (GAGs), a group of sulfated polysaccharides that play pivotal roles in various biological and pathological processes. The activity of GAGs is ultimately mediated through molecular interactions with key functional proteins, namely, GAG-binding proteins (GBPs). The quality of the GAG-GBP interactions depends on sulfation patterns, oligosaccharide length, and the composing monosaccharides of GAGs. Through STD NMR, information about the atoms of the GAG ligands involved in the complexes is provided. Here we highlight the latest achievements of the literature using STD NMR on GAG oligosaccharide-GBP complexes. Interestingly, most of the GBPs studied so far by STD NMR belong to one of the three major classes: coagulation factors, growth factors, or chemokine/cytokines. Unveiling the structural requirements of GAG ligands in bindings with their protein partners is a crucial step to understand the biochemical and medical actions of GAGs. This process is also a requirement in GAG-based drug discovery and development.

Propofol Attenuates Hypoxia-Induced Inflammation in BV2 Microglia by Inhibiting Oxidative Stress and NF-κB/Hif-1α Signaling.

Hypoxia-induced neuroinflammation typically causes neurological damage and can occur during stroke, neonatal hypoxic-ischemic encephalopathy, and other diseases. Propofol is widely used as an intravenous anesthetic. Studies have shown that propofol has antineuroinflammatory effect. However, the underlying mechanism remains to be fully elucidated. Thus, we aimed to investigate the beneficial effects of propofol against hypoxia-induced neuroinflammation and elucidated its potential cellular and biochemical mechanisms of action. In this study, we chose cobalt chloride (CoCl2) to establish a hypoxic model. We found that propofol decreased hypoxia-induced proinflammatory cytokines (TNFα, IL-1β, and IL-6) in BV2 microglia, significantly suppressed the excessive production of reactive oxygen species, and increased the total antioxidant capacity and superoxide dismutase activity. Furthermore, propofol attenuated the hypoxia-induced decrease in mitochondrial membrane potential andy 2 strongly inhibited protein expression of nuclear factor-kappa B (NF-κB) subunit p65 and hypoxia inducible factor-1α (Hif-1α) in hypoxic BV2 cells. To investigate the role of NF-κB p65, specific small interfering RNA (siRNA) against NF-κB p65 were transfected into BV2 cells, followed by exposure to hypoxia for 24 h. Hypoxia-induced Hif-1α production was downregulated after NF-κB p65 silencing. Further, propofol suppressed Hif-1α expression by inhibiting the upregulation of NF-κB p65 after exposure to hypoxia in BV2 microglia. In summary, propofol attenuates hypoxia-induced neuroinflammation, at least in part by inhibiting oxidative stress and NF-κB/Hif-1α signaling.

Antibacterial activity and biocompatibility of curcumin/TiO2 nanotube array system on Ti6Al4V bone implants

ABSTRACT The present study addresses the issue of infection on and around titanium orthopaedic implants by modifying the Ti6Al4V implant surface with titania nanotubes via electrochemical anodisation followed by coating with a bioactive compound, curcumin. This natural phytochemical compound was used as coating material to enhance the hydrophobicity of the surface to limit initial bacterial adhesion and further to induce bacterial cell death by its biochemical action. Titanium nanotubes were coated with curcumin by direct dropping method. The study of antimicrobial activity indicates that curcumin coated nanotubular surface (TNTC) showed up to 43% and 38% reduction of E. coli and S. aureus population, respectively, within 24 h. Simultaneously, the in-vitro cellular experiments suggested that TNTC supported cell adhesion, proliferation and osteoblastic differentiation of mesenchymal stem cells. Thus, it was demonstrated that curcumin can serve as an effective material for coating bone plates to enhance the antimicrobial property while retaining its biocompatibility.

A Review of Resistance Mechanisms of Synthetic Insecticides and Botanicals, Phytochemicals, and Essential Oils as Alternative Larvicidal Agents Against Mosquitoes.

Mosquitoes are a serious threat to the society, acting as vector to several dreadful diseases. Mosquito management programes profoundly depend on the routine of chemical insecticides that subsequently lead to the expansion of resistance midst the vectors, along with other problems such as environmental pollution, bio magnification, and adversely affecting the quality of public and animal health, worldwide. The worldwide risk of insect vector transmitted diseases, with their associated illness and mortality, emphasizes the need for effective mosquitocides. Hence there is an immediate necessity to develop new eco-friendly pesticides. As a result, numerous investigators have worked on the development of eco-friendly effective mosquitocidal compounds of plant origin. These products have a cumulative advantage of being cost-effective, environmentally benign, biodegradable, and safe to non-target organisms. This review aims at describing the current state of research on behavioral, physiological, and biochemical effects of plant derived compounds with larvicidal effects on mosquitoes. The mode of physiological and biochemical action of known compounds derived from various plant families as well as the potential of plant secondary metabolites, plant extracts, and also the essential oils (EO), as mosquitocidal agents are discussed. This review clearly indicates that the application of vegetal-based compounds as mosquito control proxies can serve as alternative biocontrol methods in mosquito management programes.

Vitamins and Minerals for Energy, Fatigue and Cognition: A Narrative Review of the Biochemical and Clinical Evidence.

Vitamins and minerals are essential to humans as they play essential roles in a variety of basic metabolic pathways that support fundamental cellular functions. In particular, their involvement in energy-yielding metabolism, DNA synthesis, oxygen transport, and neuronal functions makes them critical for brain and muscular function. These, in turn, translate into effects on cognitive and psychological processes, including mental and physical fatigue. This review is focused on B vitamins (B1, B2, B3, B5, B6, B8, B9 and B12), vitamin C, iron, magnesium and zinc, which have recognized roles in these outcomes. It summarizes the biochemical bases and actions of these micronutrients at both the molecular and cellular levels and connects them with cognitive and psychological symptoms, as well as manifestations of fatigue that may occur when status or supplies of these micronutrients are not adequate.

BAX inhibitor-1: between stress and survival.

Cellular gatekeepers are essential to maintain order within a cell and anticipate signals of stress to promote survival. BCL2 associated X, apoptosis regulator (BAX) inhibitor-1 (BI-1), also named transmembrane BAX inhibitor motif containing-6, is a highly conserved endoplasmic reticulum (ER) transmembrane protein. Originally identified as an inhibitor of BAX-induced apoptosis, its pro-survival properties have been expanded to include functions targeted against ER stress, calcium imbalance, reactive oxygen species accumulation, and metabolic dysregulation. Nevertheless, the structural biology and biochemical mechanism of action of BI-1 are still under debate. BI-1 has been implicated in several diseases, including chronic liver disease, diabetes, ischemia/reperfusion injury, neurodegeneration, and cancer. While most studies have demonstrated a beneficial role for BI-1 in the ubiquitous maintenance of cellular homeostasis, its expression in cancer cells seems most often to contribute to tumorigenesis and metastasis. Here, we summarize what is known about BI-1 and encourage future studies on BI-1's contribution to cellular life and death decisions to advocate its potential as a target for drug development and other therapeutic strategies.