Caffeine affects the neurobehavioral impact of sodium benzoate in adolescent rats.

The continuous high intake of caffeinated products may harm CNS. Sodium benzoate (SB), broadly used for food preservation, may also have an impact. The current research studied the influence of caffeine and two doses of SB during adolescence period on behavior and brain alterations. Adolescent rats (90-120 gm) were exposed to vehicle, SB 100 and 400 mg/kg, p.o, caffeine (30 mg/kg, i.p), SB 100 or 400 + caffeine for 28 days. Locomotor performances were assessed by the open field, learning and memory were considered with novel object and y-maze, while anxiety was evaluated by light and dark as well as successive allays tests. The results showed that the motor activity of adolescent rats increased with each single treatment. Recognition memory was improved by SB100 and its combination with caffeine while working memory was reduced by SB (100 or 400) combination with caffeine compared with caffeine group. The anxiolytic effect of caffeine was reduced by SB co-treatment in either dose. Concerning biochemical study in the frontal cortex and hippocampus, oxidative biomarkers as well as Cholinesterase content were elevated due to SB400 + caffeine. Dopamine content was almost elevated by all treatments in both regions while GABA content was increased in the frontal cortex only. The obtained results pointed to histopathological changes as a result of brain oxidative stress and undesirable working memory consequences due to caffeine administration with SB, mostly the large dose. The outcomes propose new recommendations to evade the consolidation between processed nourishment and caffeinated beverages during adolescence.

Long-term abuse of caffeine sodium benzoate induces endothelial cells injury and leads to coagulation dysfunction.

Our hospital admitted a patient who had difficulty in coagulation even after blood replacement, and the patient had abused caffeine sodium benzoate (CSB) for more than 20 years. Hence, we aimed to explore whether CSB may cause dysfunction in vascular endothelial cells and its possible mechanism. Low, medium, and high concentrations of serum of long-term CSB intake patients were used to treat HUVECs, with LPS as the positive control. MTT and CCK8 were performed to verify CSB's damaging effect on HUVECs. The expression of ET-1, ICAM-1, VCAM-1, and E-selectin were measured by ELISA. TUNEL assay and Matrigel tube formation assay were carried out to detect apoptosis and angiogenesis of HUVECs. Flow cytometry was applied to analyze cell cycles and expression of CD11b, PDGF, and ICAM-1. Expression of PDGF-BB and PCNA were examined by western blot. The activation of MAPK signaling pathway was detected by qRT-PCR and western blot. Intracellular Ca2+ density was detected by fluorescent probes. CCK8 assay showed high concentration of CSB inhibited cell viability. Cell proliferation and angiogenesis were inhibited by CSB. ET-1, ICAM-1, VCAM-1, and E-selectin upregulated in CSB groups. CSB enhanced apoptosis of HUVECs. CD11b, ICAM-1 increased and PDGF reduced in CSB groups. The expression level and phosphorylation level of MEK, ERK, JUN, and p38 in MAPK pathway elevated in CSB groups. The expression of PCNA and PDGF-BB was suppressed by CSB. Intracellular Ca2+ intensity was increased by CSB. Abuse of CSB injured HUVECs and caused coagulation disorders.

Molecular docking study of frequently used food additives for selected targets depending on the chromosomal abnormalities they cause.

Food additives (FAs) (flavor enhancers, sweeteners, etc.) protect foods during storage and transportation, making them attractive to consumers. Today, while the desire to access natural foods is increasing, the chemicals added to foods have started to be questioned. In this respect, genotoxicity tests have gained importance. Studies show that some food additives may have genotoxic risks. Previous studies carried out in our laboratory also revealed genotoxic effects of Monopotassium glutamate (MPG), Monosodium glutamate (MSG), Magnesium diglutamate (MDG) as flavor enhancers; Potassium benzoate (PB), Potassium sorbate (PS), Sodium benzoate (SB), Sodium sorbate (SS) as preservatives; Acesulfame potassium (ACE-K), Xylitol (XYL) as sweeteners. In this study, we determined the interactions of these food additives with ATM and p53 proteins, which are activated in the cell due to genotoxic effects, and with DNA by employing the molecular docking method for the first time. Among the food additives, SB (-4.307) for ATM, XYL (-4.629) for p53, and XYL (-4.927) for DNA showed the highest affinity. Therefore, flexible docking (IFD) scores were determined for SB, XYL, and MDG from flavor enhancers. The potential binding modes of the food additives to target molecules' possible inhibition mechanisms were determined by molecular docking. Thus, new information was obtained to show how these additives cause chromosomal abnormalities.

Prospective Effect of Nano-Selenium Particles on Thyroid Dysfunction and Oxidative Stress Induced by Sodium Benzoate in Male Albino Rats.

<b>Background and Objective:</b> The negative effects of preservatives, such as sodium benzoate, have received increasing global attention. The objective of the study was to investigate the potential protective effects of nano-selenium (nano-Se) on thyroid functions, oxidative stress and inflammatory cytokine responses of albino rats. <b>Materials and Methods:</b> Thirty-five male rats were divided into five groups, 7 rats in each: GI: A control group, GII: Corn oil, GIII: Nano-selenium, GIV: Sodium benzoate, GV: Selenium nanoparticles followed with sodium benzoate. At the end of study, sera were separated from all rats for estimation of MDA, GSH, GSH-PX, glucose, interleukin-1ß, TSH, T3, FT3, T4 and FT4. All data were statistically analyzed using Analysis of Variance (ANOVA). <b>Results:</b> Sodium benzoate treatment showed opposite effects as it decreased levels of T3, FT3, F4, FT4, GSH and GSH-PX. On the contrary, it increased serum levels of TSH, MDA, NO, glucose and IL-1β when compared to the control group. Whereas, nano-selenium promoted a significant increase in levels of thyroid hormones T3, T4 and FT4, upgrading GSH and GSH-PX. While it reduced TSH, MDA, NO, glucose and IL-1β levels when compared to the sodium benzoate group. <b>Conclusion:</b> Nano-selenium treatment as a protector showed the ability to reduce lipid peroxidation and restore glutathione peroxidase activity, thus, selenium complex at nano-level can reduce oxidative stress and damage of thyroid hormones caused by sodium benzoate administration.

Elucidating the Mechanisms of Sodium Benzoate in Alzheimer Disease: Insights from Quantitative Proteomics Analysis of Serum Samples.

BACKGROUND: N-methyl-D-aspartate receptors (NMDARs) are crucial components of brain function involved in memory and neurotransmission. Sodium benzoate is a promising NMDAR enhancer and has been proven to be a novel, safe, and efficient therapy for patients with Alzheimer disease (AD). However, in addition to the role of sodium benzoate as an NMDA enhancer, other mechanisms of sodium benzoate in treating AD are still unclear. To elucidate the potential mechanisms of sodium benzoate in Alzheimer disease, this study employed label-free quantitative proteomics to analyze serum samples from AD cohorts with and without sodium benzoate treatment. METHODS: The serum proteins from each patient were separated into 24 fractions using an immobilized pH gradient, digested with trypsin, and then subjected to nanoLC‒MS/MS to analyze the proteome of all patients. The nanoLC‒MS/MS data were obtained with a label-free quantitative proteomic approach. Proteins with fold changes were analyzed with STRING and Cytoscape to find key protein networks/processes and hub proteins. RESULTS: Our analysis identified 861 and 927 protein groups in the benzoate treatment cohort and the placebo cohort, respectively. The results demonstrated that sodium benzoate had the most significant effect on the complement and coagulation cascade pathways, amyloidosis disease, immune responses, and lipid metabolic processes. Moreover, Transthyretin, Fibrinogen alpha chain, Haptoglobin, Apolipoprotein B-100, Fibrinogen beta chain, Apolipoprotein E, and Alpha-1-acid glycoprotein 1 were identified as hub proteins in the protein‒protein interaction networks. CONCLUSIONS: These findings suggest that sodium benzoate may exert its influence on important pathways associated with AD, thus contributing to the improvement in the pathogenesis of the disease.

Adjunctive transcranial direct current stimulation (tDCS) plus sodium benzoate for the treatment of early-phase Alzheimer's disease: A randomized, double-blind, placebo-controlled trial.

Previous studies found that an NMDA receptor (NMDAR) enhancer, sodium benzoate, improved cognitive function of patients with early-phase Alzheimer's disease (AD). Transcranial direct current stimulation (tDCS) induces NMDAR-dependent synaptic plasticity and strengthens cognitive function of AD patients. This study aimed to evaluate efficacy and safety of tDCS plus benzoate in early-phase dementia. In this 24-week randomized, double-blind, placebo-controlled trial, 97 patients with early-phase AD received 10-session tDCS during the first 2 weeks. They then took benzoate or placebo for 24 weeks. We assessed the patients using Alzheimer's disease assessment scale - cognitive subscale (ADAS-cog), Clinician's Interview-Based Impression of Change plus Caregiver Input, Mini Mental Status Examination, Alzheimer's disease Cooperative Study scale for ADL in MCI, and a battery of additional cognitive tests. Forty-seven patients received sodium benzoate, and the other 50 placebo. The two treatment groups didn't differ significantly in ADAS-cog or other measures. Addition of benzoate to tDCS didn't get extra benefit or side effect in this study. For more thoroughly studying the potential of combining tDCS with benzoate in the AD treatment, future research should use other study designs, such as longer-term benzoate treatment, adding benzoate in the middle of tDCS trial sessions, or administering benzoate then tDCS.

Comparative effects of benzoic acid and sodium benzoate in diets for nursery pigs on growth performance and acidification of digesta and urine.

The objective of this study was to evaluate the comparative effects of benzoic acid and sodium benzoate in feeds on digesta pH, urinary pH, and growth performance for nursery pigs. A total of 432 pigs (6.9 ±â€…0.9 kg BW) were assigned to eight treatments (6 pigs per pen, replication = 9) in a randomized complete block design with initial body weight (BW) as a block and fed for 41 d in three phases (7/17/17 d, respectively). Treatments were 1) a basal diet (NC), 2) NC + 0.25% bacitracin methylene disalicylate (antibiotic; bacitracin: 250 g/t feed; PC), 3) NC + 0.25% benzoic acid, 4) NC + 0.35% benzoic acid, 5) NC + 0.50% benzoic acid, 6) NC + 0.30% sodium benzoate, 7) NC + 0.40% sodium benzoate, and 8) NC + 0.60% sodium benzoate. Growth performance and fecal scores were measured for each phase. One gilt representing the median BW of each pen was euthanized to collect digesta from the stomach, proximal jejunum, distal jejunum, and cecum, and urine. The PC tended to improve average daily gain (ADG) in phase 1 (P = 0.052) and phase 2 (P = 0.093) as well as average daily feed intake (ADFI) in phase 2 (P = 0.052). Overall, increasing supplemental benzoic acid tended to have a quadratic effect on ADG (P = 0.094), but no difference in ADFI was observed. Increasing supplemental sodium benzoate showed a quadratic effect (P < 0.05) on ADG and linearly increased (P < 0.05) ADFI. Urinary pH linearly decreased (P < 0.05) with increasing supplemental benzoic acid, but was not affected by supplemental sodium benzoate. Increasing supplemental benzoic acid or sodium benzoate linearly increased (P < 0.05) benzoic acid content in digesta of the stomach. Increasing supplemental benzoic acid or sodium benzoate also linearly increased (P < 0.05) urinary hippuric acid. However, the PC did not decrease urinary pH or increase urinary benzoic acid and hippuric acid. With slope-ratio assay using ADG and urinary hippuric acid as dependent variables and benzoic acid intake as an independent variable, the relative bioavailability of benzoic acid compared to sodium benzoate was not different. In conclusion, supplementation of benzoic acid and sodium benzoate could improve the growth performance of nursery pigs. The relative bioavailability of sodium benzoate to benzoic acid of nursery pigs did not differ based on BW gain and urinary hippuric acid.

Newly weaned pigs are exposed to various challenges during the postweaning period, resulting in retarded growth performance. Dietary antibiotics have been used to reduce the negative impacts of weaning stress. However, use of antibiotics in feeds has been phased out in response to concerns associated with microbial resistance. In this study, dietary benzoic acid was supplemented to promote growth performance and increase urinary hippuric acid of nursery pigs. The sodium benzoate may show similar effects with benzoic acid on growth performance and urinary hippuric acid, as sodium benzoate can be highly converted to benzoic acid via the action of gastric acid in stomach. Thus, this study aimed to investigate the effects of increasing benzoic acid and sodium benzoate supplementation on growth performance and acidification of digesta and urine, and to investigate the comparative effects of benzoic acid and sodium benzoate supplemented in diets for nursery pigs. Dietary benzoic acid and sodium benzoate improved body weight gain and increased urinary hippuric acid of nursery pigs. Both sodium benzoate and benzoic acid had similar effects when fed to nursery pigs for their body weight gain and metabolism. Benzoic acid, however, had a stronger effect acidifying urine compared with sodium benzoate.

Determination of D-serine and D-alanine Tissue Levels in the Prefrontal Cortex and Hippocampus of Rats After a Single Dose of Sodium Benzoate, a D-Amino Acid Oxidase Inhibitor, with Potential Antipsychotic and Antidepressant Properties.

The effects of the N-methyl-D-aspartate receptor activators D-serine, D-alanine, and sarcosine against schizophrenia and depression are promising. Nevertheless, high doses of D-serine and sarcosine are associated with undesirable nephrotoxicity or worsened prostatic cancer. Thus, alternatives are needed. DAAO inhibition can increase D-serine as well as D-alanine and protect against D-serine-induced nephrotoxicity. Although several DAAO inhibitors improve the symptoms of schizophrenia and depression, they can increase the plasma levels but not brain levels of D-serine. The mechanism of action of DAAO inhibitors remains unclear. We investigated the effects of the DAAO inhibitor sodium benzoate on the prefrontal cortex and hippocampal level of D-alanine as known another substrate with antipsychotic and antidepressant properties and other NMDAR-related amino acids, such as, L-alanine, D-serine, L-serine, D-glutamate, L-glutamate, and glycine levels. Our results indicate that sodium benzoate exerts antipsychotic and antidepressant-like effects without changing the D-serine levels in the brain prefrontal cortex (PFC) and hippocampus. Moreover, D-alanine levels in the PFC and hippocampus did not change. Despite these negative findings regarding the effects of D-amino acids in the PFC and hippocampus, sodium benzoate exhibited antipsychotic and antidepressant-like effects. Thus, the therapeutic effects of sodium benzoate are independent of D-serine or D-alanine levels. In conclusion, sodium benzoate may be effective among patients with schizophrenia or depression; however, the mechanisms of actions remain to be elucidated.

Zinc supplement reverses short-term memory deficit in sodium benzoate-induced neurotoxicity in male Wistar rats by enhancing anti-oxidative capacity via Nrf 2 up-regulation.

Sodium benzoate (SB) is a commonly-used food preservative, with a controversial report to its neurological benefit and toxicity. Zinc (Zn) is a trace element that plays a crucial role in memory, inflammation and oxidative stress. This study was to investigate the effect of SB on rat cognition and memory and the possible modulatory effect of Zn supplement. Twenty four male Wistar rats were divided into four groups of six animals each. Animals in groups 1-4 were treated with normal saline 1 ml/kg, SB 200 mg/kg, zinc sulphate 10 ml/kg and SB 200 mg/kg + zinc sulphate 10 ml/kg/day daily respectively for three weeks. After treatment, the animals were subjected to different behavioural tests, and then sacrificed. Their blood samples were collected for catalase(CAT), superoxide dismutase(SOD) and interleukin-1B(IL-1B) assay. Brain samples were also collected for nuclear factor-erythroid-related factor 2(Nrf2), and acetylcholinesterase (AchE) mRNA gene expression. The serum levels of CAT and SOD were (p < 0.0001; p < 0.0001) reduced in the SB only-treated group compared to the other groups. Nrf2 gene expression was totally shut down in the SB only-treated group but, up-regulated in the Zn-treated groups (p < 0.0001). The serum level of IL-1B was higher in the SB only-treated group compared to the other groups. SB-treated group spent longer time in the close arm (p = <0.0001), shorter time in the open arm (p = <0.0001) and had higher anxiety index (p = 0.0045) than the Zn-treated groups. Conclusively, Zinc improves memory deficit, has anxiolytic, anti-oxidant and anti-inflammatory properties.

Protective role of the dandelion extract against the blood-liver axis, cell membranes, and anemia disorder in sodium benzoate-exposed rats.

Sodium benzoate (SB) as an additive in various food products prevents the growth of microbes. Although SB is considered safe, many studies have reported adverse effects. The aim of this study was to investigate the effect of dandelion extract on cell damage and hematological and biochemical disorders induced by SB in male albino rats. Different doses of SB (200 and 600 mg/kg) and ethanolic dandelion root extract (D) (40 mg/kg) were used in a 2-week treatment of rats. Rat mortality and a higher frequency of behavioral alterations such as apathy, anxiety, and aggression have been reported at a higher dose of SB. Changes in urine pH, proteinuria, nitrituria, and bilirubinemia caused by SB were regulated by adding dandelion extract. Analysis of specific serum and urine parameters, as well as microscopic analysis of hepatocytes, showed liver and kidney failure. Anemia associated with hemolytic disorder due to erythrocyte impaired the presence of acanthocytes, and decreased values of erythrocyte blood count, hemoglobin concentration, average red blood cell size, hemoglobin amount per red blood cell, and mean corpuscular hemoglobin concentration were caused by SB treatment. As a dietary supplement, dandelion extract can be useful in the prevention of SB-induced liver and kidney injury, and also a remedy against induced anemia, neutropenia, thrombocytopenia, hyperproteinemia, hyperglycemia, and reduction of inflammatory responses.

Prevention of microbes-induced spoilage in sodium chloride-free cucumber fermentations employing preservatives.

This study evaluated preservatives to stabilize sodium chloride (NaCl)-free-cucumber fermentations. The brining of air-purged laboratory cucumber fermentations with 100.0 mM calcium chloride (CaCl2 ) and 25.0 mM acetic acid resulted in immediate rises in pH, the chemical reduction of the medium, and malodors. Supplementation with 3.0 mM sodium benzoate or 3.0 mM potassium sorbate enabled a decline in pH, a continuous oxidative state of the medium, and delayed rising pH spoilage. However, lactic and acetic acids eventually disappeared in fermentations supplemented with preservatives. The amount of preservatives needed to suppress growth of brined-cucumber-spoilage microbes was determined in Fermented Cucumber Juice Medium (FCJM). Supplementation of FCJM with 10.0 mM sodium benzoate was inhibitory for the spoilage yeasts, Issatchenkia occidentalis and Pichia manshurica, and the lactobacilli, Lentilactobacillus buchneri and Lentilactobacillus parafarraginis, but not of Zygosaccharomyces globiformis. Potassium sorbate inhibited the spoilage yeasts at 15.0 mM in FCJM but not the lactobacilli. Supplementation of FCJM with 20.0 mM fumaric acid had a bactericidal effect on the spoilage-associated lactobacilli. As expected, NaCl-free-commercial cucumber fermentations brined with 100 mM CaCl2 , no acetic acid, and 6 mM potassium sorbate resulted in complete fermentations, but supported rising pH, microbially induced spoilage during long-term storage. Post-fermentation supplementation with 12 mM sodium benzoate, 10 mM fumaric acid, a combination of the two, or 10 mM fumaric acid and 2 mM AITC prevented microbial activity during long-term bulk storage. PRACTICAL APPLICATION: Several preservative-based strategies for stabilizing NaCl-free cucumber fermentation in a commercial production setting were developed, enabling the implementation of a processing technology that reduces wastewater volumes and environmental impact.

Sodium benzoate and sodium bisulfate as preservatives in apple juice and alternative sanitizers for washing cherry tomatoes.

Unpasteurized apple ciders and fresh produce have been linked to multistate outbreaks due to contamination by foodborne pathogens. Organic acids such as benzoic acid are effective antimicrobials, and acidified sodium benzoate (NaB) has been reported to be effective in reducing pathogens inoculated on cherry tomatoes and preventing cross-contamination. Sodium bisulfate (SBS) is a powerful acidulant but has not been studied in combination with NaB. The objective of the present study was to characterize the antibacterial activity of SBS and its combination with NaB in tryptic soy broth (TSB) and apple juice, as well as washing cherry tomatoes. The minimum inhibitory concentration and minimum bactericidal concentration of SBS were all 0.5% w/v (corresponding to TSB medium pH of 4.30) and 1.0% w/v (corresponding to TSB medium pH of 2.88), respectively, for Escherichia coli O157:H7 ATCC 43895, Salmonella Enteritidis ATCC 13076, and Listeria monocytogenes Scott A. In TSB, the triple combination of 1.0% w/v SBS, 0.1% w/v NaB, and 0.02% w/v oregano oil (OO) showed the faster inactivation rate of the three bacteria than treatments with one or two antimicrobials; the activity of double combinations followed the order of 0.1% w/v NaB +1.0% w/v SBS > 0.1% w/v NaB +0.5% w/v SBS + 0.02% w/v OO > 0.1% w/v NaB +0.5% w/v SBS. pH was a critical factor in the activity of antimicrobial combinations in TSB, and L. monocytogenes was more resistant than Gram-negative E. coli O157:H7 and S. Enteritis. In apple juice added with 0.05% w/v NaB, 0.25% w/v SBS, and 0.01% w/v OO alone or in combinations, 5 log CFU/mL or greater reductions in 72 h were observed for E. coli O157:H7 and S. Enteritidis in double and triple combinations, while only the triple combination and the SBS-OO combination resulted in the same effect for L. monocytogenes. For cherry tomatoes inoculated with 6.8 log CFU/g E. coli O157:H7, complete decontamination (>6 log CFU/g) was achieved after soaking for 1 min in solutions containing 0.5-1.5% w/v SBS and 0.1% w/v NaB or 1.5% w/v SBS alone, and no pathogens were detected in all wash solutions containing 0.5-1.5% w/v SBS with and without NaB. The lower pH of wash solutions with a higher amount of SBS was a dominant factor in decontamination and prevention of cross-contamination. The present study showed the potential of SBS and its combination with NaB to enhance the safety of apple juice and cherry tomatoes.

Anti-adhesion and anti-biofilm activity of slightly acidic electrolyzed water combined with sodium benzoate against Streptococcus mutans: A novel ecofriendly oral sanitizer to prevent cariogenesis.

Streptococcus mutans (S. mutans) can promote the establishment of high acidic biofilms and therefore have contribution to the development of dental caries. Alleviating the acidic environment and/or disrupting the structure of S. mutans biofilm are effective approaches against dental caries, rather than killing the microorganisms. The anti-biofilm effect of slightly acidic electrolyzed water (SAEW) is entirely based on the hypochlorous acid and ROS generation. In this study, sodium benzoate (NaB) acts as a pH adjuster and enhances SAEW's anti-biofilm activity. The results showed that the SAEW combined with NaB (SAEW + NaB) is highly effective in controlling biofilm. The adhesive strength of biofilm was significantly reduced by SAEW, and NaB was found to have a synergy effect with SAEW. Biofilm treated by SAEW + NaB was entirely removed by 60 s of ultrasonic wave, whereas the untreated biofilm can only be removed to a lesser extent. Atomic force microscope (AFM) analysis revealed that SAEW and NaB reduced the height of S. mutans biofilm. The metabolites derived from biofilm positively changed during the periodic 1-min treat, the production of lactic acid was hindered by the treatment. Altogether, these findings suggested a novel therapeutic intervention against S. mutans biofilm by targeting the cariogenic action.

Sodium benzoate induces neurobehavioral deficits and brain oxido-inflammatory stress in male Wistar rats: Ameliorative role of ascorbic acid.

BACKGROUND: Sodium benzoate (SB) is a widely used food preservative. However, excessive intake of a high dose of SB poses a risk of neurotoxicity. Ascorbic acid (AA) is a naturally occurring antioxidant found in fruits with reported neuroprotective properties. The present study investigated the neurobehavioral and biochemical alterations in SB-treated rats and the ameliorative effect of AA in rats. METHODS: Forty-two male Wistar rats were divided into six groups (n = 7). Group 1 (vehicle, 10 ml/kg), Groups 2-4 rats SB (150, 300, and 600 mg/kg), Group 5 AA (100 mg/kg) and Group 6 (SB 600 mg/kg + AA 100 mg/kg). Treatment was daily administered for 28 days by oral route. Anxiogenic behavior, locomotor, and exploratory activities were evaluated in the open field monitored with a camera, and memory performance in Y-maze. Brain oxidative stress, inflammatory, apoptosis, and cholinergic markers were determined. The cortico-hippocampal tissues were examined histologically. RESULTS: SB-treated rats showed significant anxiogenic-like behavior and impairment in locomotor, exploratory, and memory performance. This was reversed in SB (600 mg/kg)-treated rats coadministered with AA. SB-treated rats showed a decrease in antioxidant enzyme activities, increase malondialdehyde (MDA), nitrite, tumor necrosis factor-alpha, caspase-3, and acetylcholinesterase activity in the striatum, hippocampus, frontal cortex, and cerebellum. These biochemical changes were reversed in AA-treated rats. Reduced cortico-hippocampal neuronal cell count and the pyknotic index were found in SB-treated rats, which was also reversed in AA-treated rats. CONCLUSION: Conclusively, sodium-benzoate-induced neurobehavioral deficits and brain biochemical changes were ameliorated by ascorbic acid probably via antioxidant, anti-inflammatory, and apoptotic mechanisms.

Beyond Dopamine Receptor Antagonism: New Targets for Schizophrenia Treatment and Prevention.

Treatment of schizophrenia (SCZ) historically relies on the use of antipsychotic drugs to treat psychosis, with all of the currently available antipsychotics acting through the antagonism of dopamine D2 receptors. Although antipsychotics reduce psychotic symptoms in many patients, they induce numerous undesirable effects and are not effective against negative and cognitive symptoms. These highlight the need to develop new drugs to treat SCZ. An advanced understanding of the circuitry of SCZ has pointed to pathological origins in the excitation/inhibition balance in regions such as the hippocampus, and restoring function in this region, particularly as a means to compensate for parvalbumin (PV) interneuron loss and resultant hippocampal hyperactivity, may be a more efficacious approach to relieve a broad range of SCZ symptoms. Other targets, such as cholinergic receptors and the trace amine-associated receptor 1 (TAAR1), have also shown some promise for the treatment of SCZ. Importantly, assessing efficacy of novel compounds must take into consideration treatment history of the patient, as preclinical studies suggest prior antipsychotic treatment may interfere with the efficacy of these novel agents. However, while novel therapeutic targets may be more effective in treating SCZ, a more effective approach would be to prevent the transition to SCZ in susceptible individuals. A focus on stress, which has been shown to be a predisposing factor in risk for SCZ, is a possible avenue that has shown promise in preclinical studies. Therefore, therapeutic approaches based on our current understanding of the circuitry of SCZ and its etiology are likely to enable development of more effective therapeutic interventions for this complex disorder.

Alleviation of Huntington pathology in mice by oral administration of food additive glyceryl tribenzoate.

Huntington's disease (HD) is a neurodegenerative disorder characterized by accumulation of mutant huntingtin protein and significant loss of neurons in striatum and cortex. Along with motor difficulties, the HD patients also manifest anxiety and loss of cognition. Unfortunately, the clinically approved drugs only offer symptomatic relief and are not free from side effects. This study underlines the importance of glyceryl tribenzoate (GTB), an FDA-approved food flavoring ingredient, in alleviating HD pathology in transgenic N171-82Q mouse model. Oral administration of GTB significantly reduced mutant huntingtin level in striatum, motor cortex as well as hippocampus and increased the integrity of viable neurons. Furthermore, we found the presence of sodium benzoate (NaB), a FDA-approved drug for urea cycle disorders and glycine encephalopathy, in the brain of GTB-fed HD mice. Accordingly, NaB administration also markedly decreased huntingtin level in striatum and cortex. Glial activation is found to coincide with neuronal death in affected regions of HD brains. Interestingly, both GTB and NaB treatment suppressed activation of glial cells and inflammation in the brain. Finally, neuroprotective effect of GTB and NaB resulted in improved motor performance of HD mice. Collectively, these results suggest that GTB and NaB may be repurposed for HD.

Sodium Benzoate, a Metabolite of Cinnamon and a Food Additive, Improves Cognitive Functions in Mice after Controlled Cortical Impact Injury.

Traumatic brain injury (TBI) is a major health concern, sometimes leading to long-term neurological disability, especially in children, young adults and war veterans. Although research investigators and clinicians have applied different treatment strategies or neurosurgical procedures to solve this health issue, we are still in need of an effective therapy to halt the pathogenesis of brain injury. Earlier, we reported that sodium benzoate (NaB), a metabolite of cinnamon and a Food and Drug Administration-approved drug against urea cycle disorders and glycine encephalopathy, protects neurons in animal models of Parkinson's disease and Alzheimer's disease. This study was undertaken to examine the therapeutic efficacy of NaB in a controlled cortical impact (CCI)-induced preclinical mouse model of TBI. Oral treatment with NaB, but not sodium formate (NaFO), was found to decrease the activation of microglia and astrocytes and to inhibit the expression of inducible nitric oxide synthase (iNOS) in the hippocampus and cortex of CCI-insulted mice. Further, administration of NaB also reduced the vascular damage and decreased the size of the lesion cavity in the brain of CCI-induced mice. Importantly, NaB-treated mice showed significant improvements in memory and locomotor functions as well as displaying a substantial reduction in depression-like behaviors. These results delineate a novel neuroprotective property of NaB, highlighting its possible therapeutic importance in TBI.

Histone benzoylation serves as an epigenetic mark for DPF and YEATS family proteins.

Histone modifications and their functional readout serve as an important mechanism for gene regulation. Lysine benzoylation (Kbz) on histones is a recently identified acylation mark associated with active transcription. However, it remains to be explored whether putative readers exist to recognize this epigenetic mark. Here, our systematic binding studies demonstrated that the DPF and YEATS, but not the Bromodomain family members, are readers for histone Kbz. Co-crystal structural analyses revealed a 'hydrophobic encapsulation' and a 'tip-sensor' mechanism for Kbz readout by DPF and YEATS, respectively. Moreover, the DPF and YEATS family members display subtle yet unique features to create somewhat flexible engagements of different acylation marks. For instance, YEATS2 but not the other YEATS proteins exhibits best preference for Kbz than lysine acetylation and crotonylation due to its wider 'tip-sensor' pocket. The levels of histone benzoylation in cultured cells or in mice are upregulated upon sodium benzoate treatment, highlighting its dynamic regulation. In summary, our work identifies the first readers for histone Kbz and reveals the molecular basis underlying Kbz recognition, thus paving the way for further functional dissections of histone benzoylation.

Effect of ethanolic extract from Morus alba L. leaves on the quality and sensory aspects of chilled pork under retail conditions.

The aim of this study was to investigate the performance of ethanolic extract from Morus alba L. leaves (MLEE) in preserving chilled pork under retail conditions. The four treatments were 5 mg/mL sodium benzoate solution (SB), 1 mg/mL MLEE solution (high-concentration MLEE; HM), 0.5 mg/mL MLEE solution (low-concentration MLEE; LM), and 0 mg/mL MLEE solution (C). The quality characteristics, pH, thiobarbituric acid reactive substances values, metmyoglobin, total volatile basic nitrogen, and number of microbes of MLEE-treated chilled pork stored at 4 °C for 9 days were consistent with those obtained by the SB treatment and lower than those obtained by the C treatment. Sensory analyses showed that treatment of pork with MLEE did not have a negative impact on its sensory characteristics. MLEE can extend the shelf life of chilled pork from 3 days to 6 days (9 days) in first-class (second-class) fresh meat. Results suggest that MLEE could be a candidate resource in the preservation of chilled pork.

Cancer proteome and metabolite changes linked to SHMT2.

Serine hydroxymethyltransferase 2 (SHMT2) converts serine plus tetrahydrofolate (THF) into glycine plus methylene-THF and is upregulated at the protein level in lung and other cancers. In order to better understand the role of SHMT2 in cancer a model system of HeLa cells engineered for inducible over-expression or knock-down of SHMT2 was characterized for cell proliferation and changes in metabolites and proteome as a function of SHMT2. Ectopic over-expression of SHMT2 increased cell proliferation in vitro and tumor growth in vivo. Knockdown of SHMT2 expression in vitro caused a state of glycine auxotrophy and accumulation of phosphoribosylaminoimidazolecarboxamide (AICAR), an intermediate of folate/1-carbon-pathway-dependent de novo purine nucleotide synthesis. Decreased glycine in the HeLa cell-based xenograft tumors with knocked down SHMT2 was potentiated by administration of the anti-hyperglycinemia agent benzoate. However, tumor growth was not affected by SHMT2 knockdown with or without benzoate treatment. Benzoate inhibited cell proliferation in vitro, but this was independent of SHMT2 modulation. The abundance of proteins of mitochondrial respiration complexes 1 and 3 was inversely correlated with SHMT2 levels. Proximity biotinylation in vivo (BioID) identified 48 mostly mitochondrial proteins associated with SHMT2 including the mitochondrial enzymes Acyl-CoA thioesterase (ACOT2) and glutamate dehydrogenase (GLUD1) along with more than 20 proteins from mitochondrial respiration complexes 1 and 3. These data provide insights into possible mechanisms through which elevated SHMT2 in cancers may be linked to changes in metabolism and mitochondrial function.