Aqueous extract of Polygala japonica Houtt. ameliorated nonalcoholic steatohepatitis in mice through restoring the gut microbiota disorders and affecting the metabolites in feces and liver.

BACKGROUND: Polygala japonica Houtt. (PJ) has been demonstrated with several biological potentials such as lipid-lowering and anti-inflammatory effects. However, the effects and mechanisms of PJ on nonalcoholic steatohepatitis (NASH) remain unclear. PURPOSE: The aim of this study was to evaluate the effects of PJ on NASH and illustrate the mechanism based on modulating gut microbiota and host metabolism. MATERIALS AND METHODS: NASH mouse model was induced using methionine and choline deficient (MCD) diet and orally treated with PJ. The therapeutic, anti-inflammatory, and anti-oxidative effects of PJ on mice with NASH were firstly assessed. Then, the gut microbiota of mice was analyzed using 16S rRNA sequencing to assess the changes. Finally, the effects of PJ on the metabolites in liver and feces were explored by untargeted metabolomics. RESULTS: The results indicated that PJ could improve hepatic steatosis, liver injury, inflammatory response, and oxidative stress in NASH mice. PJ treatment also affected the diversity of gut microbiota and changed the relative abundances of Faecalibaculum. Lactobacillus, Muribaculaceae, Dubosiella, Akkermansia, Lachnospiraceae_NK4A136_group, and Turicibacter in NASH mice. In addition, PJ treatment modulated 59 metabolites both in liver and feces. Metabolites involved in histidine, and tryptophan metabolism pathways were identified as the key metabolites according to the correlation analysis between differential gut microbiota and metabolites. CONCLUSION: Our study demonstrated the therapeutic, anti-inflammatory and anti-oxidative potentials of PJ on NASH. The mechanisms of PJ treatment were related to the improvement of gut microbiota dysbiosis and the regulation of histidine and tryptophan metabolism.

NMR-based metabolomic analysis for the effects of moxibustion on imiquimod-induced psoriatic mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Moxibustion is a traditional medical intervention of traditional Chinese medicine. It refers to the direct or indirect application of ignited moxa wool made of mugwort leaves to acupuncture points or other specific parts of the body for either treating or preventing diseases. Moxibustion has been proven to be effective in treating skin lesions of psoriasis. AIM OF THE STUDY: This study was performed to elucidate molecular mechanisms underlying the effects of moxibustion treatment on imiquimod-induced psoriatic mice. MATERIALS AND METHODS: We established an imiquimod (IMQ)-induced psoriatic mice (Model) and assessed the effects of moxibustion (Moxi) treatment on skin lesions of psoriatic mice by the PASI scores and expressions of inflammation-related factors relative to normal control mice (NC). We then performed nuclear magnetic resonance (NMR)-based metabolomic analysis on the skin tissues of the NC, Model and Moxi-treated mice to address metabolic differences among the three groups. RESULTS: Moxi mice showed reduced PASI scores and decreased expressions of the pro-inflammatory cytokines IL-8, IL-17A and IL-23 relative to Model mice. Compared with the Model group, the NC and Moxi groups shared 9 characteristic metabolites and 4 significantly altered metabolic pathways except for taurine and hypotaurine metabolism uniquely identified in the NC group. To a certain extent, moxibustion treatment improved metabolic disorders of skin lesions of psoriatic mice by decreasing glucose, valine, asparagine, aspartate and alanine-mediated cell proliferation and synthesis of scaffold proteins, alleviating histidine-mediated hyperproliferation of blood vessels, and promoting triacylglycerol decomposition. CONCLUSIONS: This study reveals the molecular mechanisms underlying the effects of moxibustion treatment on the skin lesions of psoriasis, potentially improving the clinical efficacy of moxibustion.

Regulation of Nucleotide Metabolism with Nutrient-Sensing Nanodrugs for Cancer Therapy.

The continual growth of tumor cells requires considerable nutrient consumption. Methotrexate (MTX) is used to treat certain types of cancer by blocking the DNA and RNA productions through interfering one-carbon metabolism and de novo purine and pyrimidine synthesis. However, treatment of MTX may cause many serious adverse effects, which hamper its clinical application. Herein, the authors synthesize ferrous ions, histidine, and MTX assembled nanoparticles (FHM) to deliver MTX at tumor site and enhance the sensitivity of tumor cells to MTX with histidine catabolism. Furthermore, fasting-mimicking diet (FMD) is applied to intervene in the one-carbon metabolism and enhance the cytotoxicity of MTX. Meanwhile, FMD treatment can significantly augment the cellular uptake and tumor accumulation of FHM nanoparticles. Due to the triple inhibitions of the one-carbon metabolism, the proliferation of tumor cells is strongly disturbed, as which is highly replying on DNA and RNA production. Taken together, a 95% lower dose of MTX adopted in combined therapy significantly inhibits the growth of two types of murine tumors without evident systemic toxicity. This strategy may provide a promising nucleotide metabolism-based nanomedicine for cancer therapy.

The Role of Diet Modification in Atopic Dermatitis: Navigating the Complexity.

Diet has long been understood to have an intricate association with atopic dermatitis, although much remains unelucidated. Skin barrier dysfunction with dysbiosis and consequent impairment of immune tolerance likely underly the pathogenesis of coincident atopic dermatitis and food allergy. There is a wide range of possible skin reactions to food, complicating the diagnosis and understanding of food allergies. Many patients, parents, and providers incorrectly suspect diet as causative of atopic dermatitis symptoms and many have tried elimination diets. This frequently leads to inaccurate labeling of food allergies, contributing to a dangerous spiral of inappropriate testing, referrals, and dietary changes, while neglecting established atopic dermatitis treatment essentials. Alternatively, certain dietary supplements or the introduction of certain foods may be beneficial for atopic dermatitis management or prevention. Greater consensus on the role of diet among providers of patients with atopic dermatitis is strongly encouraged to improve the management of atopic dermatitis.

Potential Benefits and Pitfalls of Histidine Supplementation for Cancer Therapy Enhancement.

Dietary supplementation of the amino acid histidine has demonstrable benefits in various clinical conditions. Recent work in a pediatric leukemia mouse model exposed a surprising potential application of histidine supplementation for cancer therapy enhancement. These findings demand a deeper reassessment of the physiological effects and potential drawbacks of histidine supplementation. As pertinent to this question, we discuss the safety of high doses of histidine and its relevant metabolic fates in the human body. We refrain from recommendations or final conclusions because comprehensive preclinical evidence for safety and efficacy of histidine supplementation is still lacking. However, we emphasize the incentive to study the safety of histidine supplementation and its potential to improve the clinical outcome of pediatric blood cancers through a simple dietary supplementation. The need for comprehensive preclinical testing of histidine supplementation in healthy and tumor-bearing mice is fundamental, and we hope that this review will facilitate such studies.

l-Histidine Supplementation in Adults and Young Children with Atopic Dermatitis (Eczema).

Atopic dermatitis (AD) is an incurable, inflammatory skin condition that is prevalent (∼20%) in young children. There is an unmet clinical need, particularly in children, for safe interventions that target the etiology of the disease. Deficiencies in the skin barrier protein, filaggrin (FLG) have been identified as major predisposing factors in AD. In mammals, l-histidine is rapidly incorporated into epidermal FLG and subsequent FLG proteolysis releases l-histidine as an important natural moisturizing factor (NMF). It has therefore been hypothesized that l-histidine supplementation would be a safe approach to augment both FLG and the NMF, enhance skin barrier function, and reduce AD severity. In a clinical pilot study, adult subjects (n = 24) with AD took either a placebo or 4 g oral l-histidine daily for 8 wk. Unlike the placebo, l-histidine reduced AD (34% reduction in SCORing Atopic Dermatitis scores; P < 0.003) after 4 wk. Nine and 8 adverse events (AEs), and 1 and 0 severe AEs were recorded in the l-histidine or placebo groups, respectively, with no AE being causally related to l-histidine ingestion. A survey of adults (n = 98) taking 4 g l-histidine daily reiterated a lack of causal AEs and also reported a 33% reduction in topical corticosteroid use. A placebo-controlled, clinical pilot study conducted in young children with AD (n = 49; mean age 3.5 y) taking 0.8 g l-histidine daily, showed that eczema area and severity index scores were reduced by 49% (P < 0.02) at 12 wk, whereas a placebo had no effect. The children taking l-histidine had 50 minor AEs (compared with 39 on placebo), with 78% considered as "not," 18% "unlikely," and 4% "possibly" related to l-histidine ingestion. These studies indicate that at the levels reported, oral l-histidine supplementation is well tolerated and has potential as a safe intervention for long-term use in the management of AD in all age groups.

Benefits and Adverse Effects of Histidine Supplementation.

Histidine is a nutritionally essential amino acid with many recognized benefits to human health, while circulating concentrations of histidine decline in pathologic conditions [e.g., chronic obstructive pulmonary disease (COPD) and chronic kidney disease (CKD)]. The purpose of this review is to examine the existing literature regarding the benefits of histidine intake, the adverse effects of excess histidine, and the upper tolerance level for histidine. Supplementation with doses of 4.0-4.5 g histidine/d and increased dietary histidine intake are associated with decreased BMI, adiposity, markers of glucose homeostasis (e.g., HOMA-IR, fasting blood glucose, 2-h postprandial blood glucose), proinflammatory cytokines, and oxidative stress. It is unclear from the limited number of studies in humans whether the improvements in glucoregulatory markers, inflammation, and oxidative stress are due to reduced BMI and adiposity, increased carnosine (a metabolic product of histidine with antioxidant effects), or both. Histidine intake also improves cognitive function (e.g., reduces appetite, anxiety, and stress responses and improves sleep) potentially through the metabolism of histidine to histamine; however, this relation is ambiguous in humans. At high intakes of histidine (>24 g/d), studies report adverse effects of histidine such as decreased serum zinc and cognitive impairment. There is limited research on the effects of histidine intake at doses between 4.5 and 24 g/d, and thus, a tolerable upper level has not been established. Determining tolerance to histidine supplementation has been limited by small sample sizes and, more important, a lack of a clear biomarker for histidine supplementation. The U-shaped curve of circulating zinc concentrations with histidine supplementation could be exploited as a relevant biomarker for supplemental histidine tolerance. Histidine is an important amino acid and may be necessary as a supplement in some populations; however, gaps in knowledge, which this review highlights, need to be addressed scientifically.

Selenoneine Ameliorates Hepatocellular Injury and Hepatic Steatosis in a Mouse Model of NAFLD.

Selenoneine is a novel organic selenium compound markedly found in the blood, muscles, and other tissues of fish. This study aimed to determine whether selenoneine attenuates hepatocellular injury and hepatic steatosis in a mouse model of non-alcoholic fatty liver disease (NAFLD). Mice lacking farnesoid X receptor (FXR) were used as a model for fatty liver disease, because they exhibited hepatomegaly, hepatic steatosis, and hepatic inflammation. Fxr-null mice were fed a 0.3 mg Se/kg selenoneine-containing diet for four months. Significant decreases in the levels of hepatomegaly, hepatic damage-associated diagnostic markers, hepatic triglycerides, and total bile acids were found in Fxr-null mice fed with a selenoneine-rich diet. Hepatic and blood clot total selenium concentrations were 1.7 and 1.9 times higher in the selenoneine group than in the control group. A marked accumulation of selenoneine was found in the liver and blood clot of the selenoneine group. The expression levels of oxidative stress-related genes (heme oxygenase 1 (Hmox1), glutathione S-transferase alpha 1 (Gsta1), and Gsta2), fatty acid synthetic genes (stearoyl CoA desaturase 1(Scd1) and acetyl-CoA carboxylase 1 (Acc1)), and selenoprotein (glutathione peroxidase 1 (Gpx1) and selenoprotein P (Selenop)) were significantly decreased in the selenoneine group. These results suggest that selenoneine attenuates hepatic steatosis and hepatocellular injury in an NAFLD mouse model.

Carnosine and histidine-containing dipeptides improve dyslipidemia: a systematic review and meta-analysis of randomized controlled trials.

CONTEXT: Cardiovascular disease is a major public health problem and represents a significant burden of disease globally. Lifestyle interventions have their limitations and an intervention that will effectively address cardiovascular risk factors to help reduce this growing burden of disease is required. OBJECTIVE: Carnosine and other histidine-containing dipeptides (HCDs) have exerted positive effects on cardiovascular risk factors and diseases in animal and human studies. The authors conducted a systematic review and meta-analysis examining the effects of HCDs on cardiovascular outcomes in line with the PRISMA guidelines. DATA SOURCES: The Medline, Medline in process, Embase, Cumulative Index of Nursing and Allied Health, and All EBM databases were searched from inception until January 25, 2019, for randomized controlled trials (RCTs) examining the effects of HCDs on cardiovascular outcomes, compared with placebo or controls. DATA EXTRACTION: Basic characteristics of the study and populations, interventions, and study results were extracted. The grading of recommendations assessment, development, and evaluation approach was used to assess the quality of evidence for each outcome. DATA ANALYSIS: A total of 21 studies were included. Of these, 18 were pooled for meta-analysis (n = 913). In low risk of bias studies, HCD-supplemented groups had lower total cholesterol (n = 6 RCTs; n = 401; weighted mean difference [WMD], -0.32 mmol/L [95%CI, -0.57 to -0.07], P = 0.01) and triglyceride levels (n = 6 RCTs; n = 401; WMD, -0.14 mmol/L [95%CI, -0.20 to -0.08], P < 0.001) compared with controls. In studies using carnosine, triglycerides levels were also lower in the intervention group vs controls (n = 5 RCTS; n = 309; P < 0.001). There were no significant differences in blood pressure, heart rate, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol (HDL-C) or the total cholesterol to HDL-C ratio between groups. CONCLUSIONS: Carnosine and other HCDs may have a role in improving lipid profiles. Larger studies with sufficient follow-up are necessary to confirm these findings and explore the use of HCDs in the prevention of cardiovascular diseases. SYSTEMIC REVIEW REGISTRATION: PROSPERO registration no.: CRD42017075354.

Histidine in Health and Disease: Metabolism, Physiological Importance, and Use as a Supplement.

L-histidine (HIS) is an essential amino acid with unique roles in proton buffering, metal ion chelation, scavenging of reactive oxygen and nitrogen species, erythropoiesis, and the histaminergic system. Several HIS-rich proteins (e.g., haemoproteins, HIS-rich glycoproteins, histatins, HIS-rich calcium-binding protein, and filaggrin), HIS-containing dipeptides (particularly carnosine), and methyl- and sulphur-containing derivatives of HIS (3-methylhistidine, 1-methylhistidine, and ergothioneine) have specific functions. The unique chemical properties and physiological functions are the basis of the theoretical rationale to suggest HIS supplementation in a wide range of conditions. Several decades of experience have confirmed the effectiveness of HIS as a component of solutions used for organ preservation and myocardial protection in cardiac surgery. Further studies are needed to elucidate the effects of HIS supplementation on neurological disorders, atopic dermatitis, metabolic syndrome, diabetes, uraemic anaemia, ulcers, inflammatory bowel diseases, malignancies, and muscle performance during strenuous exercise. Signs of toxicity, mutagenic activity, and allergic reactions or peptic ulcers have not been reported, although HIS is a histamine precursor. Of concern should be findings of hepatic enlargement and increases in ammonia and glutamine and of decrease in branched-chain amino acids (valine, leucine, and isoleucine) in blood plasma indicating that HIS supplementation is inappropriate in patients with liver disease.

A Truncating De Novo Point Mutation in a Young Infant with Severe Menkes Disease.

Menkes disease is a rare neurodegenerative disorder caused by mutations in ATP7A gene. Deficiency in copper-dependent enzymes results in the unique kinky hair appearance, neurodegeneration, developmental delay, seizures, failure to thrive and other connective tissue or organ abnormalities. Other than biochemical tests, DNA-based diagnosis is now playing an important role. More than two hundred mutations in ATP7A gene were identified. Early copper supplementation can help improve neurological symptoms, but not non-neurological problems. Further molecular studies are needed to identify additional mutation types and to understand the mechanism of pathogenesis. This may help in discovering the possible treatment measures to cure the disease. We present a case with the clinical features and biochemical findings, abnormal brain magnetic resonance imaging as well as the effects of treatment with copper-histidine. Direct sequencing of ATP7A gene revealed a de novo point mutation which resulted in an early stop codon with truncated protein.

Dietary interventions that reduce mTOR activity rescue autistic-like behavioral deficits in mice.

Enhanced mammalian target of rapamycin (mTOR) signaling in the brain has been implicated in the pathogenesis of autism spectrum disorder (ASD). Inhibition of the mTOR pathway improves behavior and neuropathology in mouse models of ASD containing mTOR-associated single gene mutations. The current study demonstrated that the amino acids histidine, lysine, threonine inhibited mTOR signaling and IgE-mediated mast cell activation, while the amino acids leucine, isoleucine, valine had no effect on mTOR signaling in BMMCs. Based on these results, we designed an mTOR-targeting amino acid diet (Active 1 diet) and assessed the effects of dietary interventions with the amino acid diet or a multi-nutrient supplementation diet (Active 2 diet) on autistic-like behavior and mTOR signaling in food allergic mice and in inbred BTBR T+Itpr3tf/J mice. Cow's milk allergic (CMA) or BTBR male mice were fed a Control, Active 1, or Active 2 diet for 7 consecutive weeks. CMA mice showed reduced social interaction and increased self-grooming behavior. Both diets reversed behavioral impairments and inhibited the mTOR activity in the prefrontal cortex and amygdala of CMA mice. In BTBR mice, only Active 1 diet reduced repetitive self-grooming behavior and attenuated the mTOR activity in the prefrontal and somatosensory cortices. The current results suggest that activated mTOR signaling pathway in the brain may be a convergent pathway in the pathogenesis of ASD bridging genetic background and environmental triggers (food allergy) and that mTOR over-activation could serve as a potential therapeutic target for the treatment of ASD.

Anti-diabetic potential of chromium histidinate in diabetic retinopathy rats.

BACKGROUND: Chromium (Cr) is commonly used as a complementary medicine for diabetes mellitus. Several studies suggest that Cr intakes may improve glucose metabolism and decrease oxidative stress. Therefore, we aimed to assess the effects of chromium histidinate (CrHis) supplementation using a range of reliable biomarkers of oxidative damage and histopathological changes in rats with diabetic retinopathy. METHODS: Diabetes was induced with streptozotocin [(STZ), 55 mg/kg] by intraperitoneal injection in male Long-Evans rats. Three weeks after STZ injection, rats were divided into four groups, namely, untreated normal controls, normal rats receiving CrHis (110 µg/kg/day); untreated diabetics and diabetics treated with CrHis (110 µg/kg/day) orally for 12 weeks. RESULTS: In the untreated diabetic group, levels of serum glucose, glycosylated haemoglobin (HbA1c), total cholesterol (TC) and retina malondialdehyde (MDA) were significantly increased, while expressions of retina insulin, and glucose transporter 1 (GLUT 1) and glucose transporter 3 (GLUT3) and level of serum insulin were decreased. CrHis supplementation was found to reduce the levels of glucose, HbA1c, total cholesterol and MDA and to improve the GLUT1, GLUT3 and insulin expressions in STZ-induced diabetic rats. CrHis prevents the changes in the expressions of GLUT1, GLUT3 and insulin and the level of MDA in the retina tissue, confirming the protective effect of CrHis supplementation against the retinopathy caused by STZ. Histopathologic findings suggest that the CrHis-treated diabetic group had normal retinal tissue appearance compared with the untreated diabetic group. CONCLUSIONS: These results verify that CrHis has critical beneficial effects against retinal complications. Although detailed studies are required for the evaluation of the exact mechanism of the ameliorative effects of CrHis against diabetic complications, these preliminary experimental findings demonstrate that CrHis exhibits antidiabetic effects in a rat model of diabetic retinopathy by regulating the glucose metabolism and suppressing retinal tissue damage.

Histidine supplementation alleviates inflammation in the adipose tissue of high-fat diet-induced obese rats via the NF-κB- and PPARγ-involved pathways.

Obesity is considered to be accompanied by a chronic low-grade inflammatory state that contributes to the occurrence of many chronic diseases. Our previous study has demonstrated that histidine supplementation significantly ameliorates inflammation and oxidative stress in obese women. However, the in vivo potential mechanisms are not known. The present study was conducted to investigate the mechanisms underlying the effects of histidine on inflammation in a high-fat diet (HFD)-induced female obese rat model. An obese model was established in female Sprague-Dawley rats by HFD feeding for 8 weeks and followed by histidine supplementation for another 4 weeks. The results revealed that HFD-increased body weight and HFD-lowered serum histidine concentrations were significantly reversed by histidine supplementation (P< 0·05). In addition, the serum concentrations of TNF-α, IL-6, C-reactive protein (CRP) and malondialdehyde were significantly reduced and those of superoxide dismutase (SOD) were significantly increased by histidine supplementation when compared with those in obese rats (P< 0·05). Correspondingly, the mRNA expressions of TNF-α, IL-6 and CRP in the adipose tissue were significantly down-regulated and that of CuZnSOD was significantly up-regulated by histidine supplementation (P< 0·05). Histidine supplementation significantly reduced the HFD-induced translocation of NF-κB p65 into the nucleus (P= 0·032) by reducing the phosphorylation of the inhibitor of κBα in the adipose tissue. The results also revealed that the expression of adiponectin was markedly increased both in the serum and in the adipose tissue after histidine supplementation, accompanied by the activation of PPARγ (P= 0·021). These findings indicate that histidine is an effective candidate for ameliorating inflammation and oxidative stress in obese individuals via the NF-κB- and PPARγ-involved pathways.

Bis (histidine) with N2 vehicle: an important skeleton for MR/chelation therapy.

Bis (histidine) ethylenediamine tetraacetic acid, EDTA-bis (amide) analog, has been synthesized starting from with EDTA bis-anhydride and protected histidine and evaluated in vitro as an important agent for MR and chelation therapy. The kinetic inertness of compound was analyzed by the exchange reactions with the essential metals of human body. The stability and protonation constants of the complexes formed between the ligand and M(3+) and M(2+) have been determined by pH potentiometry and spectrophotometry at 25 °C and constant ionic strength maintained with 0.10 m KCl. The in vivo stability and metabolite profile were confirmed in plasma and serum.

Histidine supplementation improves insulin resistance through suppressed inflammation in obese women with the metabolic syndrome: a randomised controlled trial.

AIMS/HYPOTHESIS: Increased inflammation and oxidative stress are associated with insulin resistance (IR) and metabolic disorders. Serum histidine levels are lower and are negatively associated with inflammation and oxidative stress in obese women. The objective of this study was to evaluate the efficacy of histidine supplementation on IR, inflammation, oxidative stress and metabolic disorders in obese women with the metabolic syndrome (MetS). METHODS: A total of 100 obese women aged 33-51 years with BMI ≥ 28 kg/m² and diagnosed with MetS were included following a health examination in the community hospital in this randomised, double-blinded, placebo-controlled trial. Participants were allocated to interventions by an investigator using sequentially numbered sealed envelopes and received 4 g/day histidine (n = 50) or identical placebo (n = 50) for 12 weeks. Participants then attended the same clinic every 2 weeks for scheduled interviews and to count tablets returned. Serum histidine, HOMA-IR, BMI, waist circumference, fat mass, serum NEFA, and variables connected to inflammation and oxidative stress were measured at baseline and 12 weeks. Participants, examining physicians and investigators assessing the outcomes were blinded to group assignment. In addition, the inflammatory mechanisms of histidine were also explored in adipocytes. RESULTS: At 12 weeks, a total of 92 participants completed this trail. Compared with the placebo group (n = 47), histidine supplementation significantly decreased HOMA-IR (-1.09 [95% CI -1.49, -0.68]), BMI (-0.86 kg/m² [95% CI -1.55, -0.17]), waist circumference (-2.86 cm [95% CI -3.86, -1.86]), fat mass (-2.71 kg [95% CI -3.69, -1.73]), serum NEFA (-173.26 µmol/l [95% CI -208.57, -137.94]), serum inflammatory cytokines (TNF-α, -3.96 pg/ml [95% CI -5.29, -2.62]; IL-6, -2.15 pg/ml [95% CI -2.52, -1.78]), oxidative stress (superoxide dismutase, 17.84 U/ml [95% CI 15.03, 20.65]; glutathione peroxidase, 13.71 nmol/ml [95% CI 9.65, 17.78]) and increased serum histidine and adiponectin by 18.23 µmol/l [95% CI 11.74, 24.71] and 2.02 ng/ml [95% CI 0.60, 3.44] in histidine supplementation group (n = 45), respectively. There were significant correlations between changes in serum histidine and changes of IR and its risk factors. No side effects were observed during the intervention. In vitro study indicated that histidine suppresses IL6 and TNF mRNA expression and nuclear factor kappa-B (NF-κB) protein production in palmitic acid-induced adipocytes in a dose-dependent manner, and these changes were diminished by an inhibitor of NF-κB. CONCLUSIONS/INTERPRETATION: Histidine supplementation could improve IR, reduce BMI, fat mass and NEFA and suppress inflammation and oxidative stress in obese women with MetS; histidine could improve IR through suppressed pro-inflammatory cytokine expression, possibly by the NF-κB pathway, in adipocytes.

The effects of chromium picolinate and chromium histidinate administration on NF-κB and Nrf2/HO-1 pathway in the brain of diabetic rats.

The objective of this experiment was to investigate the effects of supplemental chromium picolinate (CrPic) and chromium histidinate (CrHis) on nuclear factor-kappa B (NF-κB p65) and nuclear factor (erythroid-derived 2)-like 2 (Nrf2) signaling pathway in diabetic rat brain. Nondiabetic (n = 45) and diabetic (n = 45) male Wistar rats were either not supplemented or supplemented with CrPic or CrHis via drinking water to consume 8 µg elemental chromium (Cr) per day for 12 weeks. Diabetes was induced by streptozotocin injection (40 mg/kg i.p., for 2 weeks) and maintained by high-fat feeding (40 %). Diabetes was associated with increases in cerebral NF-κB and 4-hydroxynonenal (4-HNE) protein adducts and decreased in cerebral nuclear factor of kappa light polypeptide gene enhancer in B cells inhibitor, alpha (IκBα) and Nrf2 levels. Both Cr chelates were effective to decrease levels of NF-κB and 4-HNE protein adducts and to increase levels of IκBα and Nrf2 in the brain of diabetic rats. However, responses of these increases and decreases were more notable when Cr was supplemented as CrHis than as CrPic. In conclusion, Cr may play a protective role in cerebral antioxidant defense system in diabetic subjects via the Nrf2 pathway by reducing inflammation through NF-κB p65 inhibition. Histidinate form of Cr was superior to picolinate form of Cr in reducing NF-κB expression and increasing Nrf2 expression in the brain of diabetic rats.

New lipoic acid derivative drug sodium zinc dihydrolipoylhistidinate prevents cardiac dysfunction in an isolated perfused rat heart model.

OBJECTIVE: Myocardial ischemia/reperfusion injury is a life-limiting condition. Reactive oxygen species are released upon reperfusion, resulting in damage to myocardial cells. Accordingly, antioxidant drugs have been shown to protect the myocardium against ischemia/reperfusion injury. The purpose of the present study was to determine the cardioprotective effects of the new lipoic acid-derivative drug sodium zinc dihydrolipoylhistidinate in a global ischemia isolated perfused rat heart model. DESIGN: Animals were randomly divided into five groups: 1) normal group, 2) control ischemia/reperfusion group, 3) high-dose sodium zinc dihydrolipoylhistidinate (1 ng/mL) plus ischemia/reperfusion group, 4) medium-dose sodium zinc dihydrolipoylhistidinate (0.1 ng/mL) plus ischemia/reperfusion group, or 5) low-dose sodium zinc dihydrolipoylhistidinate (0.01 ng/mL) plus ischemia/reperfusion group. SETTING: University medical center research laboratory. SUBJECTS: Male Sprague-Dawley rats weighing 250-300 g. MEASUREMENTS AND MAIN RESULTS: Hearts underwent ischemia/reperfusion after isolation with or without sodium zinc dihydrolipoylhistidinate treatment. We then conducted cardiac histopathology and transmission electron microscopy analyses and assessed cardiac function. In addition, we examined the effects of sodium zinc dihydrolipoylhistidinate on ischemia/reperfusion-induced mitochondrial dysfunction. We found that cardiac dysfunction and mitochondrial damage were significantly reduced after reperfusion by sodium zinc dihydrolipoylhistidinate treatment. However, only rats treated with high-dose sodium zinc dihydrolipoylhistidinate showed improved cardiac function. Furthermore, treatment with sodium zinc dihydrolipoylhistidinate significantly improved mitochondrial function in vitro. CONCLUSIONS: These findings suggest that sodium zinc dihydrolipoylhistidinate attenuates ischemia/reperfusion-induced myocardial dysfunction in rats. Furthermore, sodium zinc dihydrolipoylhistidinate exerted cardioprotective effects via preservation of mitochondrial function. Taken together, our results strongly support the potential therapeutic role of sodium zinc dihydrolipoylhistidinate in the treatment of ischemia/reperfusion injury.

Beneficial effects of histidine and carnosine on ethanol-induced chronic liver injury.

Alleviative effects of histidine and carnosine in mice against ethanol-induced oxidative and inflammatory was examined. After chronic alcoholic liver injury was induced, histidine and carnosine at 0.5, 1, 2g/L were added to the drinking water for 3 weeks. Results showed that the post-intake of histidine or carnosine markedly decreased alanine aminotransferase and aspartate aminotransferase activities (P<0.05). Ethanol treatment increased malondialdehyde (MDA) level, decreased glutathione (GSH) content and catalase and glutathione peroxidase (GPX) activities, and increased cytochrome P450 2E1 (CYP2E1) activity in liver (P<0.05). The post-intake of histidine and carnosine significantly decreased MDA formations, increased GSH content, enhanced catalase and GPX activities, and suppressed CYP2E1 activity (P<0.05), in which the effects on catalase and CYP2E1 activities were dose-dependent (P<0.05). Ethanol treatment elevated hepatic levels of c-reactive protein (CRP), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) (P<0.05), the post-intake of histidine and carnosine significantly and dose-dependently diminished the release of CRP, IL-6, and TNF-alpha (P<0.05). Ethanol treatment caused down-regulation in both catalase and GPX mRNA expression, and up-regulated both IL-6 and TNF-alpha mRNA expression (P<0.05). Histidine and carnosine post-treatments significantly and dose-dependently upregulated catalase mRNA, and down-regulated mRNA expression of IL-6 and TNF-alpha (P<0.05). Based on the observed anti-oxidative and anti-inflammatory effects, the supplement of histidine or carnosine might be helpful for the treatment of chronic alcoholic liver injury.