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Abstract

Vitamin B1 (thiamin) is considered to be the oldest vitamin and in 1936 R.R. Williams and colleagues determined its chemical structure and were able to synthesize this vitamin. Vitamin B1 influences pro-apoptotic proteins, mitochondrial membrane potential, cytochrome C release, protein kinases, p38-MAPK, suppresses oxidative stress-induced NF-kappaB and has anti-inflammatory properties. Deficiency of vitamin B1 may cause beriberi, dysfunction of the nervous system, neuroinflammation, T cell infiltration, chemokine CCL2 activation, over expression of proinflammatory cytokines, such as IL-1, TNF, IL-6, and arachidonic acid products, and induces expression of CD40 by the microglia and CD40L by astrocytes which provoke the death of neurons. Here we report the relationship between vitamin B complex and immunity.
... Vitamin B6 is a crucial component in many metabolic pathways, with cardiovascular, neuroprotective, and anti-inflammatory properties (Spinas et al. 2015;Pisoschi et al. 2022). Vitamin B6 (pyridoxine) has therapeutic benefits in reducing the negative impacts of lead exposure, functioning as an antioxidant, promoting embryo weight gain and growth, strengthening the immune system, among other positive properties. ...
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Background Heavy metals like lead (Pb) have been used by humans for a very long time, but throughout the industrial revolution, their use expanded, increasing exposure to the metal. Lead, however, has no biological purpose in the human body and is hazardous when it gets into soft tissues and organs. Lead is still used in a variety of industries, including battery manufacturing and car maintenance, despite efforts to limit its usage. Objective This study investigates the teratogenic and morphometric effects of lead on chick embryos and the potential ameliorative effects of vitamin B6. Methods Two hundred fertilized eggs from the golden black chicken were divided into four groups: control, lead acetate, vitamin B6, and lead + vitamin B6. Results On the 14th day, embryos were analyzed. Significant reductions in body weight and size were observed in the lead‐exposed group (33.93 ± 1.27 g) compared to the control (41.12 ± 0.97 g). Pronounced deformities included rudimentary beaks, protruding eyes, tridactyl limbs, hydrocephaly, and neck deformities. Appendicular deformities like phocomelia, amelia, and abnormal phalanges growth were also noted. Vitamin B6 demonstrated therapeutic benefits, significantly improving mean embryo weight in the Lead + Vitamin B6 group (42.37 ± 0.99 g). The lead‐exposed group showed a reduction in maxilla length (3.61 ± 1.30 mm) compared to the Lead + Vitamin B6 group (7.57 ± 0.79 mm). This group also showed reduced severity of muscular dystrophy and bone thinning, with signs of recovery in beak and bone sizes. Conclusions The study highlights vitamin B6's beneficial impact in mitigating lead's toxic effects on chick embryonic development.
... For example, vitamin B2, or riboflavin, is crucial for cellular energy metabolism (Spinas et al., 2015). Studies have suggested that both UV light and vitamin B2 can help reduce the levels of MERS-CoV in the body (Bashandy et al., 2018). ...
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Amidst the relentless battle against Coronaviridae, vaccines stand as our beacon of hope, illuminating a path towards an eventual triumph over the pandemic. Through tireless collaboration and scientific ingenuity, researchers have forged ahead, developing a diverse array of vaccines to combat COVID-19 and its variants. Yet, alongside these remarkable achievements, formidable challenges persist. Vaccine hesitancy, fueled by misinformation and cultural complexities, threatens to impede progress, underscoring the need for comprehensive strategies to foster trust and understanding. Moreover, the imperative of global cooperation looms large, demanding equitable vaccine distribution to ensure that no community is left behind in our shared pursuit of health and resilience. As we navigate these uncharted waters, let us draw inspiration from the resilience and compassion that define our collective humanity, forging ahead with determination and unity to overcome this unprecedented crisis.
... One of the metabolites produced by probiotics, vitamin B, is essential for regulating inflammation and the immune system. For instance, vitamins B1 and B3 inhibit the production of pro-inflammatory cytokines in stimulated alveolar macrophages by inactivating the oxidative stress-induced NF-κB cascade (Spinas et al., 2015). Furthermore, vitamin B6 allevi-ates oxidative stress and inflammation in the skin and decreases the pathogenic infiltration of immune cells (Martínez-Navarro et al., 2020). ...
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This study investigated the anti-inflammatory effects of cell-free supernatant of Lactococcus lactis IDCC 2301 on lipopolysaccharide (LPS)-induced RAW 264.7 macrophages. Expression of inflammatory mediators and cytokines, and the production of nitric oxide (NO) and prostaglandin E 2 (PGE 2 ) were qualitatively analysed. The expression of signal transductors in inflammatory cascades was quantified by western blot. Treatment with cell-free supernatant of L. lactis IDCC 2301 significantly decreased the mRNA expression levels of tumour necrosis factor (TNF-α) and interleukins including IL-1β and IL-6. The levels of inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX-2) were also remarkably reduced in LPS-induced macrophages after the treatment. Furthermore, L. lactis IDCC 2301 reduced the levels of both dephosphorylated and phosphorylated forms of nuclear factor-kappa B (NF-κB), IκB-α, extracellular signal-regulated kinases (ERK), c-Jun amino-terminal kinases (JNK), and p38 in LPS-induced RAW 264.7 cells. Therefore, L. lactis IDCC 2301 shows anti-inflammatory activity by suppressing the NF-κB and mitogen-activated protein kinase (MAPK) signaling pathways.
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Recent insights into the influence of nutrition on immune system components have driven the development of dietary strategies targeting the prevention and management of major metabolic-inflammatory diseases. This review summarizes the bidirectional relationship between nutrition and immunocompetence, beginning with an overview of immune system components and their functions. It examines the effects of nutritional status, dietary patterns, and food bioactives on systemic inflammation, immune cell populations, and lymphoid tissues, as well as their associations with infectious and chronic disease pathogenesis. The mechanisms by which key nutrients influence immune constituents are delineated, focusing on vitamins A, D, E, C, and B, as well as minerals including zinc, iron, and selenium. Also highlighted are the immunomodulatory effects of polyunsaturated fatty acids as well as bioactive phenolic compounds and probiotics, given their expanding relevance. Each section addresses the implications of nutritional and nutraceutical interventions involving these nutrients within the broader context of major infectious, metabolic, and inflammatory diseases. This review further underscores that, while targeted nutrient supplementation can effectively restore immune function to optimal levels, caution is necessary in certain cases, as it may increase morbidity in specific diseases. In other instances, dietary counseling should be integrated to ensure that therapeutic goals are achieved safely and effectively.
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Background Viral respiratory infections (VRIs) continue to be among the most common illnesses and are known to be one of the main reasons of medical consultations worldwide. COVID-19 remains a major public concern and a threat to global health. The current focus lies on the pivotal role of the human host's immunologic response in combating viral threats. This critical review aims to examine the current evidence on the potential benefit of nutritional supplements in the prevention and treatment of COVID-19 and viral respiratory infections (VRIs). Methods The study was performed in the Google-Scholar and PubMed databases with a main emphasis on publications between January 2000 and September 2023. Consequently, a total of 202 articles were included in this literature review, distributed as follows: 62 meta-analyses and systematic reviews, 20 randomized clinical trials, 11 clinical trials, 28 observational cohorts and 81 others. Of these, 44 % were published between 2020 and 2023. Results The research indicates that Vitamin C may have a mitigating effect on VRIs, whereas a deficiency in Vitamin D might heighten susceptibility to COVID-19. Understanding the roles of Vitamins A, B, and E is hampered by limited data availability. Zinc supplementation and probiotics emerge as potential preventive measures for both COVID-19 and VRIs, with selenium and magnesium demonstrating promising results in treating VRIs. The recommendation for omega-3 fatty acid supplementation for COVID-19 treatment awaits further evidence. Conclusion Currently, there is insufficient clinical evidence to definitively establish the efficacy of vitamin, mineral, probiotic and/or omega-3 supplementation for combating COVID-19 and VRIs.
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Background Nineteen non-antibacterials were examined to show that their consumption for treatment of other diseases may inhibit Helicobacter pylori. Four antibiotics were used for comparison. Materials and methods Agar dilution method was used to examine the susceptibility of 20 H. pylori isolates to 4 antibiotics; metronidazole (MTZ), clarithromycin (CLR), amoxicillin (AMX), tetracycline (TET) and 19 non-antibacterials; proton pump inhibitors (PPIs), H2-blockers, bismuth subsalicylate (BSS), antifungals, statins, acetaminophen (ACE), aspirin (ASA), B-vitamins (B-Vits; Vit B1, Vit B6 and Vit Bcomplex) and vitamin C (Vit C). Blood agar plates were prepared with different concentrations of drugs and spot-inoculated with bacterial suspensions. Plates were incubated at 37 °C under microaerobic conditions and examined after 3–5 days. The isolate #20 that was mucoid and resistant to 19 drugs, including MTZ and SMV was tested against combined MTZ (8 μg/mL) and SMV (100 μg/mL). Results were analyzed statistically. Results Minimum inhibitory concentrations (MICs, μg/mL) of drugs and the frequency of susceptible H. pylori were determined as MTZ (8, 80%), CLR (2, 90%), AMX (1, 100%), TET (0.5, 70%), PPIs (8–128, 80%), H2-blockers (2000–8000, 75–80%), BSS (15, 85%), antifungals (64–256, 30–80%), statins (100–250, 35–90%), ACE (40, 75%), ASA (800, 75%), B-Vits (5000–20000, 80–100%) and Vit C (2048, 85%). Susceptibility of H. pylori isolates to 16 out of 19 non-antimicrobials (75–100%) was almost similar to those of antibiotics (70–100%) (P-value >0.05). The highest susceptibility rate (100%) belonged to Vit B1, Vit B6 and AMX. Out of 20 H. pylori isolates, 17 (85%) were susceptible to ≥13 non-antimicrobials and 3 (15%) were susceptible to < 13 (P-value <0.05). Mucoid H. pylori showed susceptibility to combination of MTZ and SMV. Conclusions Most of non-antibacterials inhibited H. pylori isolates, similar to antibiotics but their MICs exceeded those of antibiotics and their plasma concentrations. At low plasma concentration, non-antimicrobials may act as weak antibacterials, antibiotic adjuvants and immunostimulators.
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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a highly pathogenic and transmissible coronavirus, has resulted in a pandemic named coronavirus disease 2019 (COVID-19). It has taken over the world in no time causing nearly 5 million deaths and almost 500 million people being affected as of June 2022 causing an extensive burden on healthcare facilities globally. Though the disease onset is via respiratory tract, but it affects almost all organs of the body and due to induction of mutations in the virus, combating with the disease is extremely difficult. The major damage associated with disease is driven through inflammatory pathways in tissues with accompanying cytokine storm mediated mainly by macrophages. Building a strong immune system requires maintenance of a healthy diet along with keeping vitamin and coenzyme deficiencies away. The review focuses on the importance of the vitamins for maintaining a good immune system to reduce the susceptibility to SARS-CoV-2 infection, to fight the infection efficiently, and to reduce the impact of the disease. Vitamins play an essential role in modulating the immune responses to infection via altering the signaling pathways, which can act as potential weapons against the disease. Various water- and fat-soluble vitamins like vitamin B, C, D, and E have crucial roles in mediating primary interferon response, improving innate as well as adaptive functions of immunity and antioxidant properties. The current understanding about the supplementation of various vitamins as an adjunct therapeutic strategy to fight COVID-19 disease has also been discussed.
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Gut microbiota plays a crucial role in providing colonization resistance against multi-drug resistant organisms including carbapenem-resistant Klebsiella pneumoniae (CRKP). However, the impact of different carbapenems on intestinal colonization resistance against CRKP remains poorly understood. In this study, we aimed to investigate the effects of three commonly used carbapenems (meropenem, imipenem, and ertapenem) administered at single-day doses, which are typically employed in emergency departments for managing infected patients, on CRKP gut colonization. We conducted experiments in mice by intravenously administering each carbapenem using human-simulated one-day regimens. The composition of the gut microbiota was analyzed using 16S rRNA amplicon sequencing before and after carbapenem administration. Our results revealed that all three carbapenems, when administered at a single-day dose significantly altered the abundance and diversity of the gut microbiota, leading to compromised colonization resistance against CRKP. Notably, the ertapenem and imipenem groups showed an increase in Allobaculum , Bifidobacterium , Enterobacteriaceae , while the meropenem and imipenem groups exhibited a decrease in Ruminococcaceae , S24-7, and Akkermania . Additionally, the Shannon index exhibited a negative correlation with both the number of days of CRKP colonization CFUs and the duration of bacteria shedding. Furthermore, the count of CRKP in mice after ertapenem administration on the first day and the duration of CRKP shedding were significantly lower compared to meropenem and imipenem. Predictive metabolic pathway analysis demonstrated that the three carbapenems similarly affected a range of metabolic pathways of gut microflora, including carbohydrate metabolism and vitamin B. Our findings emphasize that ertapenem, with its relatively narrow spectrum, minimizes perturbations of the gut microbiota and has a relatively less impact on gut colonization resistance against CRKP. IMPORTANCE The intestinal colonization of carbapenem-resistant Klebsiella pneumoniae (CRKP) is an important source of clinical infection. Our research showed that even single-day dose use of carbapenems caused CRKP colonization and continuous bacterial shedding, which reminds clinical doctors to prescribe carbapenems cautiously. Whenever possible, ertapenem should be the preferred choice over other carbapenems especially when the identified or highly suspected pathogens can be effectively targeted by ertapenem.
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Thiamine, also known as vitamin B1, is an essential nutrient that plays a crucial role in energy metabolism and overall health. It is a water-soluble vitamin that plays an important role in the conversion of carbohydrates into energy in the body. Thiamine is essential for the proper functioning of the nervous system, heart and muscles. Thiamine deficiency is a life-threatening disease that leads to various disorders and lesions in the nerves and brain, at least in vertebrates. Several thiamine precursors with higher bioavailability have been developed to compensate for thiamine deficiency, including benfotiamine. Benfotiamine is more bioavailable and has higher tissue penetration than thiamine. Studies have shown its antioxidant and anti-inflammatory potential in activated immune and glial cells. It also improves complications observed in type 2 diabetes and has beneficial effects in mouse models of neurodegenerative disease. Benfotiamine represents an off-the-shelf agent used to support nerve health, promote healthy aging and support glucose metabolism. Accordingly, the present review aimed to provide an overview of the neuroprotective effects of thiamine/benfotiamine in the context of inflammation and oxidative stress.
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Micronutrient deficiencies are a well-established fact in obesity. However, few studies exist on the relationship between micronutrient intake and mental health. In this study, we investigated the associations between daily intakes of vitamins and minerals and scoring items that measure mental health in people living with central obesity. One hundred males and females with central obesity and metabolic abnormalities were included in the study. Demographic, clinical, anthropometric, and biochemical data were collected. Mental health statuses were assessed with validated questionnaires, and daily micronutrient intakes were assessed with food diaries and Nutritionist ProTM software v7.9. The mental component score (MCS-12) positively correlated with vitamin A (Rho = 0.249, p = 0.038), vitamin C (Rho = 0.293, p = 0.014), riboflavin (Rho = 0.264, p = 0.026), and folate (Rho = 0.238, p = 0.046). Rosenberg Self-Esteem Scale (RSES) correlated with sodium (Rho = 0.269, p = 0.026), and the Center for Epidemiologic Studies Depression Scale Revised (CESD-R) correlated with chromium (Rho = 0.313, p = 0.009). In the regression analysis, after potential confounders were adjusted for, only riboflavin was positively associated with the MCS-12 log (beta ± SD = 0.047 ± 0.023, p = 0.044). Our study provides evidence of the link between dietary riboflavin and mental health in people with obesity, and it highlights the importance of monitoring both nutritional status and mental health when managing obesity.
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Multiple sclerosis (MS) is a complex multifactorial disease that results from the interplay between environmental factors and a susceptible genetic background. Experimental autoimmune encephalomyelitis (EAE) has been widely used to investigate the mechanisms underlying MS pathogenesis. Chemokines, such as CCL2, are involved in the development of EAE. We have previously shown that thiamine deficiency (TD) induced CCL2 in neurons. We hypothesized that TD may affect the pathogenesis of EAE. In this study, EAE was induced in C57BL/6J mice by the injection of myelin oligodendroglial glycoprotein (MOG) peptides 35-55 with or without TD. TD aggravated the development of EAE, which was indicated by clinical scores and pathologic alterations in the spinal cord. TD also accelerated the development of EAE in an adoptive transfer EAE model. TD caused microglial activation and a drastic increase (up 140%) in leukocyte infiltration in the spinal cord of the EAE mice; specifically, TD increased Th1 and Th17 cells. TD upregulated the expression of CCL2 and its receptor CCR2 in the spinal cord of EAE mice. Cells in peripheral lymph node and spleen isolated from MOG-primed TD mice showed much stronger proliferative responses to MOG. CCL2 stimulated the proliferation and migration of T lymphocytes in vitro. Our results suggested that TD exacerbated the development of EAE through activating CCL2 and inducing pathologic inflammation.
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Incomplete β-oxidation of fatty acids in mitochondria is a feature of insulin resistance and type 2 diabetes mellitus (T2DM). Previous studies revealed that plasma concentrations of medium- and long-chain acylcarnitines (by-products of incomplete β-oxidation) are elevated in type 2 diabetes and insulin resistance. In a previous study, we reported that mixed D, L isomers of C12- or C14-carnitine induced an NFκB-luciferase reporter gene in RAW 264.7 cells suggesting potential activation of proinflammatory pathways. Here, we determined whether the physiologically relevant L-acylcarnitines activate classical pro-inflammatory signaling pathways and if these outcomes involve pattern recognition receptor (PRR)-associated pathways. Acylcarnitines induced the expression of COX-2 in a chain length dependent manner in RAW 264.7 cells. L-C14 carnitine (5-25μM), used as a representative acylcarnitine, stimulated the expression and secretion of pro-inflammatory cytokines in a dose-dependent manner. Furthermore, L-C14 carnitine induced phosphorylation of JNK and ERK, common downstream components of many pro-inflammatory signaling pathways including PRRs. Knockdown of MyD88, a key co-factor in PRR signaling and inflammation, blunted the pro-inflammatory effects of acylcarnitine. While these results point to potential involvement of PRRs, L-C14 carnitine promoted IL-8 secretion from human epithelial cells (HCT-116) lacking TLR2 and TLR4, and did not activate reporter constructs in TLR-overexpression cell models. Thus, acylcarnitines have the potential to activate inflammation, but the specific molecular and tissue target(s) involved remain to be identified.
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Virtual Histology Intravascular Ultrasound (VH-IVUS) may be used to detect early signs of unstable coronary artery disease. Monocyte Chemoattractant Protein-1 (MCP-1) is linked with coronary atherosclerosis and plaque instability and could potentially be modified by folic acid treatment. In a randomized, prospective study, 102 patients with stable angina pectoris (SAP) received percutaneous coronary intervention and established medical treatment as well as either homocysteine-lowering folic acid/vitamin B12 (±B6) or placebo (±B6) for 1 year before VH-IVUS was performed. The presence of VH-Thin-Cap Fibroatheroma (VH-TCFA) in non-intervened coronary vessels was registered and serum levels of MCP-1 were measured. The patients were subsequently followed for incident myocardial infarction (MI). Patients treated with folic acid/vitamin B12 had a geometric mean (SD) MCP-1 level of 79.95 (1.49) versus 86.00 (1.43) pg/mL for patients receiving placebo (p-value 0.34). VH-TCFA lesions were present in 7.8% of patients and did not differ between intervention arms (p-value 0.47). Serum levels of MCP-1 were 1.46 (95% CI 1.12 to 1.92) times higher in patients with VH-TCFA lesions than in those without (p-value 0.005). Afterwards, patients were followed for median 2.1 years and 3.8% experienced a myocardial infarction (MI), which in post-hoc Cox regression analyses was independently predicted by both MCP-1 (P-value 0.006) and VH-TCFA (p-value 0.01). In patients with SAP receiving established medical treatment, folic acid supplementation is not associated with either presence of VH-TCFA or levels of MCP-1. MCP-1 is however associated with VH-TCFA, a finding corroborated by increased risk for future MI. ClinicalTrials.gov Identifier: NCT00354081.
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Several emerging lines of evidence support an anti-inflammatory role for nicotinic acid (niacin); however, its role in the regulation of leukocyte migration in response to inflammatory stimuli has not been elucidated until now. Herein, we have examined the effect of nicotinic acid on neutrophil recruitment in experimentally induced inflammation. We demonstrated that nicotinic acid treatment inhibited interleukin (IL)-8-induced, leukotriene (LT)B4-induced, and carrageenan-induced neutrophil migration into the pleural cavity of BALB/c mice and reduced neutrophil rolling and adherence in a mouse cremaster muscle preparation. Surprisingly, nicotinic acid treatment increased the level of the neutrophil chemoattractant KC in response to carrageenan. These results suggest that nicotinic acid plays an important role in the regulation of inflammation due to its ability to inhibit the actions of the neutrophil chemoattractants IL-8 and LTB4. Further inhibition of chemoattractants leads to impairment of leukocyte rolling and adherence to the vascular endothelium in the microcirculation of inflamed tissues.
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Background In vitro, vitamin B12 acts as a natural inhibitor of hepatitis C virus (HCV) replication. Objective To assess the effect of vitamin B12 on virological response in patients with chronic HCV hepatitis naïve to antiviral therapy. Methods Ninety-four patients with chronic HCV hepatitis were randomly assigned to receive pegylated interferon α plus ribavirin (standard-of-care; SOC) or SOC plus vitamin B12 (SOC+B12). Viral response—namely, undetectable serum HCV-RNA, was evaluated 4 weeks after starting treatment (rapid viral response), 12 weeks after starting treatment (complete early viral response) and 24 or 48 weeks after starting treatment (end-of-treatment viral response) and 24 weeks after completing treatment (sustained viral response (SVR)). Genotyping for the interleukin (IL)-28B polymorphism was performed a posteriori in a subset (42/64) of HCV genotype 1 carriers. Results Overall, rapid viral response did not differ between the two groups, whereas the rates of complete early viral response (p=0.03), end-of-treatment viral response (p=0.03) and SVR (p=0.001) were significantly higher in SOC+B12 patients than in SOC patients. In SOC+B12 patients, the SVR rate was also significantly higher in carriers of a difficult-to-treat genotype (p=0.002) and in patients with a high baseline viral load (p=0.002). Distribution of genotype IL-28B did not differ between the two groups. At multivariate analysis, only easy-to-treat HCV genotypes (OR=9.00; 95% CI 2.5 to 37.5; p=0.001) and vitamin B12 supplementation (OR=6.9; 95% CI 2.0 to 23.6; p=0.002) were independently associated with SVR. Conclusion Vitamin B12 supplementation significantly improves SVR rates in HCV-infected patients naïve to antiviral therapy.
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Liver is a vital organ for the detoxification of toxic substances present in the body and hepatic injury is associated with excessive exposure to toxicants. The present study was designed to evaluate the possible hepatoprotective effects of riboflavin against carbon tetrachloride (CCl4) induced hepatic injury in rats. Rats were divided into six groups. Hepatotoxicity was induced by the administration of a single intraperitoneal dose of CCl4 in experimental rats. Riboflavin was administered at 30 and 100mg/kg by oral gavage to test its protective effect on hepatic injury biochemically and histopathologically in the blood/liver and liver respectively. The administration of CCl4 resulted in marked alteration in serum hepatic enzymes (like AST, ALT and ALP), oxidant parameters (like GSH and MDA) and pro-inflammatory cytokine TNF-α release from blood leukocytes indicative of hepatic injury. Changes in serum hepatic enzymes, oxidant parameters and TNF-α production induced by CCl4 were reversed by riboflavin treatment in a dose dependent manner. Treatment with standard drug, silymarin also reversed CCl4 induced changes in biomarkers of liver function, oxidant parameters and inflammation. The biochemical observations were paralleled by histopathological findings in rat liver both in the case of CCl4 and treatment groups. In conclusion, riboflavin produced a protective effect against CCl4-induced liver damage. Our study suggests that riboflavin may be used as a hepato-protective agent against toxic effects caused by CCl4 and other chemical agents in the liver.
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Hereditary folate malabsorption (HFM) is a rare autosomal recessive disorder. Severe folate deficiency in HFM can result in immunodeficiency. We describe a female infant with HFM who acquired severe Pneumocystis pneumonia. The objective of the present study was to elucidate her immunological phenotype and to examine the time course of immune recovery following parenteral folate therapy. The patient demonstrated a combined immunodeficiency with an impaired T cell proliferation response, pan-hypogammaglobulinemia, and an imbalanced pro-inflammatory cytokine profile. She had a normal white blood cell count, normal lymphocyte subsets, and normal complement levels. Two novel mutations were identified within the SLC46A1 gene to produce a compound heterozygote. We confirmed full recovery of her immunological and neurophysiological status with parenteral folate replacement. The time course of recovery of her immunological profile varied widely, however. HFM should be recognized as a unique form of immunodeficiency.
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It is known that cobalamin (Cbl) deficiency damages myelin by increasing tumor necrosis factor (TNF)-α and decreasing epidermal growth factor (EGF) levels in rat central nervous system (CNS), and affects the peripheral nervous system (PNS) morphologically and functionally. It is also known that some polyneuropathies not due to Cbl deficiency are connected with increased TNF-α levels, and that various cytokines (including TNF-α) and growth factors regulate the in vitro synthesis of normal prions (PrP(C)s). Given that there is extensive evidence that PrP(C)s play a key role in the maintenance of CNS and PNS myelin, we investigated whether the PrP(C) octapeptide repeat (OR) region is involved in the pathogenesis of rat Cbl-deficient (Cbl-D) polyneuropathy. After intracerebroventricularly administering antibodies (Abs) against the OR-region (OR-Abs) to Cbl-D rats to prevent myelin damage and maximum nerve conduction velocity (MNCV) abnormalities, and PrP(C)s to otherwise normal rats to reproduce PNS Cbl-D-like lesions, we measured PrP(C) levels and MNCV of the sciatic and tibial nerves. PrP(C) and TNF-α levels were increased in sciatic and tibial nerves of Cbl-D and saline-treated rats, and the OR-Abs normalized the myelin ultrastructure, TNF-α levels, and MNCV values of the sciatic and tibial nerves of Cbl-D rats. The same peripheral nerves of the otherwise normal PrP(C)-treated rats showed typical Cbl-D myelin lesions, significantly increased TNF-α levels, and significantly decreased MNCV values. These findings demonstrate that Cbl deficiency induces excess PrP(C)s and thereby excess OR regions, which seem to be responsible for the PNS myelin damage, as has recently been found in the case of CNS myelin damage (Scalabrino et al., 2012). Furthermore, excess TNF-α is also involved in the pathogenesis of Cbl-D polyneuropathy. In conclusion, we have extended the list of prion diseases by adding one caused by excess PrP(C)s and the polyneuropathies related to excess TNF-α.
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  The influence of riboflavin (vitamin B(2) ) upon growth, invasion, and migration in non-small cell lung cancer cell lines was evaluated. Riboflavin at 1, 10, 25, 50, 100, 200, or 400 μmol/L was added into A549, H3255, or Calu-6 cells. The effects of this compound upon level and/or expression of reactive oxygen species (ROS), inflammatory cytokines, intercellular adhesion molecule (ICAM)-1, fibronectin, matrix metalloproteinase (MMP)-9, MMP-2, focal adhesion kinase (FAK), nuclear factor kappa B (NF-κB), and mitogen-activated protein kinase (MAPK) were examined. Results showed that riboflavin at test doses did not affect the level of ROS and glutathione. Riboflavin at 200 and 400 μmol/L significantly enhanced cell growth in test lung cancer cell lines, and at 400 μmol/L significantly increased the release of interleukin-6, tumor necrosis factor-alpha, and vascular endothelial growth factor. This agent at 200 and 400 μmol/L also upregulated protein production of ICAM-1, fibronectin, MMP-9, MMP-2, NF-κB p50, p-p38 MAPK, and FAK; and at 400 μmol/L enhanced invasion and migration in test cell lines. These findings suggested that riboflavin at high doses might promote lung cancer progression.