Lack of gut microbiome recovery with spinal cord injury rehabilitation.

Spinal cord injury (SCI) is a devastating event that significantly changes daily function and quality of life and is linked to bowel and bladder dysfunction and frequent antibiotic treatment. We aimed to study the composition of the gut microbiome in individuals with SCI during the initial sub-acute rehabilitation process and during the chronic phase of the injury. This study included 100 fecal samples from 63 participants (Median age 40 years, 94% males): 13 cases with SCI in the sub-acute phase with 50 longitudinal samples, 18 cases with chronic SCI, and 32 age and gender-matched controls. We show, using complementary methods, that the time from the injury was a dominant factor linked with gut microbiome composition. Surprisingly, we demonstrated a lack of gut microbial recovery during rehabilitation during the sub-acute phase, with further deviation from the non-SCI control group in the chronic ambulatory SCI group. To generalize the results, we were able to show significant similarity of the signal when comparing to a previous cohort with SCI, to subjects from the American Gut Project who reported low physical activity, and to subjects from another population-based cohort who reported less normal stool consistency. Restoration of the microbiome composition may be another desirable measure for SCI recovery in the future, but further research is needed to test whether such restoration is associated with improved neurological outcomes and quality of life.

Effects of high oleic acid peanuts on mice's liver and adipose tissue metabolic parameters and gut microbiota composition.

This study aimed to investigate the effects of two types of peanuts, regular Hanoch (HN) and a new high-oleic cultivar., Hanoch-Oleic (HO), on metabolic parameters and gut microbiota composition. Male C57BL/6 mice were fed with a normal diet (ND) or ND supplemented with HN (NDh) or HO (NDo). Following 18 weeks of diet regimen, the NDo group exhibited reduced body weight and peri-gonadal adipose-to-body weight ratio, paralleled to lesser food consumption. Although blood levels of total cholesterol, HDL-cholesterol, free fatty acids, and liver enzyme levels did not differ between groups, decreased insulin sensitivity was found in the NDh group. Within adipose tissue, the expression of lipolytic and lipogenic enzymes was higher, while those related to lipid oxidation were lower in the NDh group compared to the NDo group. Additionally, HO peanuts consumption promoted the establishment of a healthy microbiota, with an enhanced abundance of Bifidobacterium, Lactobacillus, and Coprococcus genera. In conclusion, the inclusion of the HO peanut cultivar., rather than the conventional peanut cultivar., in a balanced diet was related to better metabolic outcomes and was linked to a favorable microbiota profile.

Chiliadenus iphionoides Reduces Body Weight and Improves Parameters Related to Hepatic Lipid and Glucose Metabolism in a High-Fat-Diet-Induced Mice Model of NAFLD.

Non-alcoholic fatty liver disease (NAFLD) has become an epidemic with increasing prevalence. Limited treatment options and poor adherence emphasize the urgent need for novel therapies for the treatment and/or prevention of NAFLD. Bioactive natural compounds found in medicinal plants are promising as novel therapeutic agents for NAFLD. Chiliadenus iphionoides, a medicinal plant with several health-promoting properties, is an encouraging candidate. The current study aimed to elucidate the metabolic effects of C. iphionoides consumption in a high-fat-diet (HFD)-induced model of NAFLD. Male C57BL/6J mice (n = 40, 7-8-week-old) were fed a HFD (60% fat) with/without 0.5 or 2.5 gr C. iphionoides for fifteen weeks. Diet supplementation with C. iphionoides significantly ameliorated HFD-induced weight gain. Likewise, liver and adipose tissue weights were profoundly lower in the C. iphionoides-fed groups. Reduced liver steatosis in those groups was corroborated by histology, plasma liver enzyme levels, and lipid profile, indicating improved liver function and lipid metabolism in addition to enhanced insulin sensitivity. The addition of C. iphionoides to an obesogeneic diet can beneficially alleviate metabolic alterations and may be a practicable strategy for the management of NAFLD.

Metabolic and Microbiome Alterations Following the Enrichment of a High-Fat Diet With High Oleic Acid Peanuts Versus the Traditional Peanuts Cultivar in Mice.

A new Israeli-developed peanut cultivar, "Hanoch-Oleic" (HO), uniquely contains enlarged oleic acid contents and was designed to confer additional beneficial effects over the traditional cultivar, "Hanoch" (HN). This work elucidates metabolic changes and microbiota adaptations elicited by HO addition to a high-fat diet (HFD). Male C57BL/6 mice were fed for 18 weeks with a normal diet or a HFD with/without the addition of HN (HFDh) or HO (HFDo). Body-weight did not differ between HFD-fed mice groups, while liver and adipose weight were elevated in the HFDh and HFD groups, respectively. Insulin-sensitivity (IS) was also decreased in these groups, though to a much greater extent in the traditional peanuts-fed group. Modifications in lipids metabolism were evident by the addition of peanuts to a HFD. Liver inflammation seems to return to normal only in HFDh. Peanuts promoted an increase in α-diversity, with HFDo exhibiting changes in the abundance of microbiota that is primarily associated with ameliorated gut health and barrier capacity. In conclusion, the HO cultivar appears to be metabolically superior to the traditional peanut cultivar and was associated with an improved inflammatory state and microbial profile. Nevertheless, IS-negative effects reinforced by peanuts addition, predominantly NH, need to be comprehensively defined.

Cannabis Extract Effects on Metabolic Parameters and Gut Microbiota Composition in a Mice Model of NAFLD and Obesity.

Nonalcoholic fatty liver disease (NAFLD) is a major cause of chronic liver abnormalities and has been linked with metabolic syndrome hallmarks. Unfortunately, current treatments are limited. This work aimed to elucidate the effects of three cannabis extracts on metabolic alteration and gut microbiota composition in a mouse model of NAFLD and obesity. Male mice were fed with a high-fat diet (HFD) for 12 weeks. Following the establishment of obesity, the HFD-fed group was subdivided into HFD or HFD that was supplemented with one of three cannabis extracts (CN1, CN2, and CN6) for additional 8 weeks. Metabolic parameters together with intestinal microbiota composition were evaluated. Except for several minor changes in gene expression, no profound metabolic effect was found due to cannabis extracts addition. Nevertheless, marked changes were observed in gut microbiota diversity and composition, with CN1 and CN6 exhibiting microbial abundance patterns that are associated with more beneficial outcomes. Taken together, specific cannabis extracts' addition to an HFD results in more favorable modifications in gut microbiota. Although no marked metabolic effect was disclosed, longer treatments duration and/or higher extracts concentrations may be needed. More research is required to ascertain this conjecture and to establish the influence of various cannabis extracts on host health in general and NAFLD in particular.

THC and CBD affect metabolic syndrome parameters including microbiome in mice fed high fat-cholesterol diet.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is associated with metabolic syndrome, which often includes obesity, diabetes, and dyslipidemia. Several studies in mice and humans have implicated the involvement of the gut microbiome in NAFLD. While cannabis and its phytocannabinoids may potentially be beneficial for treating metabolic disorders such as NAFLD, their effects on liver diseases and gut microbiota profile have yet to be addressed. In this study, we evaluated the therapeutic effects of the two major cannabinoids, delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), on NAFLD progression. METHODS: NAFLD was induced by feeding mice a high fat-cholesterol diet (HFCD) for 6 weeks. During this period, the individual cannabinoids, THC or CBD, were added to the experimental diets at a concentration of 2.5 or 2.39 mg/kg. Profile of lipids, liver enzymes, glucose tolerance, and gene expression related to carbohydrate lipids metabolism and liver inflammation was analyzed. The effect of THC or CBD on microbiota composition in the gut was evaluated. RESULTS: While not alleviating hepatic steatosis, THC or CBD treatment influenced a number of parameters in the HFCD mouse model. CBD increased food intake, improved glucose tolerance, reduced some of the inflammatory response including TNFa and iNOS, and partially mitigated the microbiome dysbiosis observed in the HFCD fed mice. THC produced a much weaker response, only slightly reducing inflammatory-related gene expression and microbiome dysbiosis. CONCLUSIONS: The results of this study indicate the potential therapeutic effects of individual phytocannabinoids are different from the effects of the cannabis plant possessing a mixture of compounds. While CBD may help ameliorate symptoms of NAFLD, THC alone may not be as effective. This disparity can putatively be explained based on changes in the gut microbiota.

Broccoli Florets Supplementation Improves Insulin Sensitivity and Alters Gut Microbiome Population-A Steatosis Mice Model Induced by High-Fat Diet.

Nonalcoholic fatty liver disease (NAFLD) is linked to obesity, type 2 diabetes, hyperlipidemia, and gut dysbiosis. Gut microbiota profoundly affects the host energy homeostasis, which, in turn, is affected by a high-fat diet (HFD) through the liver-gut axis, among others. Broccoli contains beneficial bioactive compounds and may protect against several diseases. This study aimed to determine the effects of broccoli supplementation to an HFD on metabolic parameters and gut microbiome in mice. Male (7-8 weeks old) C57BL/J6 mice were divided into four groups: normal diet (ND), high-fat diet (HFD), high-fat diet+10% broccoli florets (HFD + F), and high-fat diet + 10% broccoli stalks (HFD + S). Liver histology and serum biochemical factors were evaluated. Alterations in protein and gene expression of the key players in lipid and carbohydrate metabolism as well as in gut microbiota alterations were also investigated. Broccoli florets addition to the HFD significantly reduced serum insulin levels, HOMA-IR index, and upregulated adiponectin receptor expression. Conversely, no significant difference was found in the group supplemented with broccoli stalks. Both broccoli stalks and florets did not affect fat accumulation, carbohydrate, or lipid metabolism-related parameters. Modifications in diversity and in microbial structure of proteobacteria strains, Akermansia muciniphila and Mucispirillum schaedleri were observed in the broccoli-supplemented HFD-fed mice. The present study suggests that dietary broccoli alters parameters related to insulin sensitivity and modulates the intestinal environment. More studies are needed to confirm the results of this study and to investigate the mechanisms underlying these beneficial effects.

Dietary broccoli improves markers associated with glucose and lipid metabolism through modulation of gut microbiota in mice.

OBJECTIVE: Broccoli is a "functional food" that contains bioactive compounds and phytochemicals that have beneficial health-promoting effects. This study aimed at investigating the effects of broccoli consumption on lipid and glucose metabolism and gut microbiota. METHODS: Male C57BL/6J mice (7-8 wk old) were fed ad libitum with a normal diet supplemented with or without 10% (w/w) broccoli florets or broccoli stalks. Oral glucose tolerance tests were performed at week 15. After 17 wk, blood and tissues were collected. Serum parameters, histology, gene and protein expression, and intestinal microbiota composition were evaluated. RESULTS: Stalk supplementation led to reductions in fasting glucose levels, serum insulin, and the homeostasis model assessment-insulin resistance (HOMA-IR) index. Liver enzymes improved in both experimental groups, and broccoli florets decreased total triacylglycerols. The stalks group had elevated fatty acid oxidation-related genes and proteins (AMPK, PPARα, and CPT1). Diverse microbiota populations were observed in both broccoli groups. Broccoli stalks were found to be richer in Akkermansia muciniphila, while broccoli florets reduced Mucispirillum schaedleri abundance and increased bacterial richness. CONCLUSIONS: Long-term whole broccoli supplementation decreased inflammation, improved lipid parameters and insulin sensitivity, and altered the gut microbiome in mice. Our data provide new information regarding the potential benefits of broccoli stalks in metabolic parameters.

High oleic peanuts improve parameters leading to fatty liver development and change the microbiota in mice intestine.

BACKGROUND: Oleic-acid consumption can possibly prevent or delay metabolic diseases. In Israel, a Virginia-type peanut cultivar with a high content of oleic acid has been developed. OBJECTIVE: This study examined the effect of consuming high oleic peanuts (D7) on the development of fatty liver compared to the standard HN strain. DESIGN: The two peanut cultivars were added to normal diet (ND) and high-fat (HF) mouse diet. Male C57BL/6 mice were fed for 8 and 10 weeks on a 4% D7, 4% HN, or control diet. At the end of the experiments, blood and tissues were collected. Triglyceride, lipid levels, histology, and protein expression were examined. The diets' effects on intestinal microbiota were also evaluated. RESULTS: Both D7 and HFD7 led to a reduction in plasma triglycerides. Lipids, triglycerides, and free fatty acids in the liver were low in diets containing D7. Additionally, CD36 expression decreased in the D7 group. Consumption of D7 led to higher Prevotella levels, and consumption of ND that contained HN or D7 led to a lower Firmicutes/Bacteroidetes ratio. CONCLUSION: These findings suggest that consumption of peanuts high in oleic acid (D7) may have the potential to delay primary fatty liver symptoms.

Effect of dietary oils from various sources on carbohydrate and fat metabolism in mice.

BACKGROUND: Dietary oils differ in their fatty acid composition and the presence of additional microcomponents (antioxidants, etc.). These differences are thought to invoke different biochemical pathways, thus affecting fats and carbohydrates metabolism differently. Olive oil (OO) and soybean oil (SO) are common vegetable oils in the local cuisine. Peanuts oils of local varieties are viewed as potential sources of dietary vegetable oils, especially in the food industry. OBJECTIVE: We examined the effect of four different dietary vegetable oils on carbohydrate and lipid metabolism in mice. The selected oils were OO, high in oleic acid, extracted from cultivated high oleic acid peanut (C-PO), regular peanut oil (PO), and SO. DESIGN: In this study, 32 male C57BL/6J mice were randomly divided into four groups (n = 8 in each group) and were fed with four different diets enriched with 4% (w/w) dietary vegetable oils (OO, C-PO, PO, or SO). After 10 weeks, the mice were sacrificed. Western blot was used to examine proteins such as phospho-AMP-activated protein kinase (p-AMPK), ace-tyl-CoA carboxylase (ACC), cluster of differentiation 36 (CD36), and Sirtuin 1 (SIRT1), whereas real-time polymerase chain reaction (PCR) was used to examine the expression of sterol regulatory element-binding protein-1c (SREBP-1C), fatty acid synthase (FAS), glucose-6-phosphatase (G6Pase), and CD36 transcripts. RESULTS: In mice-fed SO, lipid accumulation was predominately in adipose tissue, accompanied a tendency decrease in insulin sensitivity. Mice-fed OO had lower plasma triglycerides (TG) and increased hepatic CD36 gene expression. The C-PO group presented lower messenger RNA (mRNA) levels in the liver for all examined genes: SREBP-1c, FAS, G6Pase, and CD36. There were no significant differences in weight gain, plasma cholesterol and high-density lipoprotein (HDL) cholesterol levels, hepatic ACC, SIRT1, AMPK, and CD36 protein levels or in liver function among the diets. DISCUSSION: It seems that as long as fat is consumed in moderation, oil types may play a lesser role in the metabolism of healthy individuals. CONCLUSION: This finding has the potential to increase flexibility in choosing oil types for consumption.

Cannabis Extracts Affected Metabolic Syndrome Parameters in Mice Fed High-Fat/Cholesterol Diet.

Introduction: Nonalcoholic fatty liver disease (NAFLD) is associated with metabolic syndrome, which often includes obesity, diabetes, and dyslipidemia. Several studies in mice and humans have implicated the involvement of the gut microbiome in NAFLD. While cannabis may potentially be beneficial for treating metabolic disorders such as NAFLD, the effects of cannabis on liver diseases and gut microbiota profile are yet to be addressed. In this study, we evaluated the therapeutic effects of cannabis strains with different cannabinoid profiles on NAFLD progression. Materials and Methods: NAFLD was induced by feeding mice a high-fat/cholesterol diet (HFCD) for 6 weeks. During this period, cannabis extracts were administrated orally at a concentration of 5 mg/kg every 3 days. Profile of lipids, liver enzymes, glucose tolerance, and gene expression related to carbohydrate lipid metabolism and liver inflammation were analyzed. The effect of cannabis strains on microbiota composition in the gut was evaluated. Results: A cannabidiol (CBD)-rich extract produced an increase in inflammatory related gene expression and a less diverse microbiota profile, associated with increased fasting glucose levels in HFCD-fed mice. In contrast, mice receiving a tetrahydrocannabinol (THC)-rich extract exhibited moderate weight gain, improved glucose response curves, and a decrease in liver enzymes. Conclusions: The results of this study indicate that the administration of cannabis containing elevated levels of THC may help ameliorate symptoms of NAFLD, whereas administration of CBD-rich cannabis extracts may cause a proinflammatory effect in the liver, linked with an unfavorable change in the microbiota profile. Our preliminary data suggest that these effects are mediated by mechanisms other than increased expression of the endocannabinoid receptors cannabinoid receptor 1 (CB1) and CB2.

Utilization of a Deep Learning Algorithm for Microscope-Based Fatty Vacuole Quantification in a Fatty Liver Model in Mice.

Quantification of fatty vacuoles in the liver, with differentiation from lumina of liver blood vessels and bile ducts, is an example where the traditional semiquantitative pathology assessment can be enhanced with artificial intelligence (AI) algorithms. Using glass slides of mice liver as a model for nonalcoholic fatty liver disease, a deep learning AI algorithm was developed. This algorithm uses a segmentation framework for vacuole quantification and can be deployed to analyze live histopathology fields during the microscope-based pathology assessment. We compared the manual semiquantitative microscope-based assessment with the quantitative output of the deep learning algorithm. The deep learning algorithm was able to recognize and quantify the percent of fatty vacuoles, exhibiting a strong and significant correlation (r = 0.87, P < .001) between the semiquantitative and quantitative assessment methods. The use of deep learning algorithms for difficult quantifications within the microscope-based pathology assessment can help improve outputs of toxicologic pathology workflows.

Cholesterol Induces Nrf-2- and HIF-1α-Dependent Hepatocyte Proliferation and Liver Regeneration to Ameliorate Bile Acid Toxicity in Mouse Models of NASH and Fibrosis.

Nonalcoholic steatohepatitis (NASH) is currently one of the most common liver diseases worldwide. The toxic effects of lipids and bile acids contribute to NASH. The regenerative pathway in response to damage to the liver includes activation of the inflammatory process and priming of hepatocytes to proliferate to restore tissue homeostasis. However, the effects of cholesterol on bile acid toxicity, inflammation, and fibrosis remain unknown. We have used two mouse models of bile acid toxicity to induce liver inflammation and fibrosis. A three-week study was conducted using wild-type mice receiving an atherogenic diet (1% (w/w) cholesterol and 0.5% (w/w) cholic acid) and its separate constituents. Mdr2-/- mice were fed a high-cholesterol-enriched diet or standard AIN-93 diet for 6 weeks. We measured serum transaminase levels to assess liver tissue necrosis and fibrosis; iNOS, SAA1, SAA2, and F4/80 levels to determine liver inflammation; PCNA and HGF levels to evaluate proliferative response; and Nrf-2, HIF-1α, and downstream gene expression to establish protective responses. In both studies, high bile acid levels increased serum transaminases and liver fibrosis, whereas cholesterol supplementation attenuated these effects. Cholesterol supplementation activated survival and the robustness of HIF-1α and Nrf-2 gene expression in hepatocytes, induced liver inflammation and hepatocyte proliferation, and inhibited stellate cell hyperplasia and fibrosis. In conclusion, our data show for the first time that cholesterol intake protects against bile acid liver toxicity. The balance between hepatic cholesterol and bile acid levels may be of prognostic value in liver disease progression and trajectory.

The effect of a low-carbohydrate high-fat diet and ethnicity on daily glucose profile in type 2 diabetes determined by continuous glucose monitoring.

BACKGROUND AND AIMS: Nutrition is an integral part of type 2 diabetes (T2DM) treatment, but the optimal macronutrient composition is still debated and previous studies have not addressed the role of ethnicity in dietary response. The current study aims were to compare the effect of short-term glycemic response to low-carbohydrate high-fat (LC-HF) diet vs. high-carbohydrate low-fat (HC-LF) diet using continuous glucose monitoring (CGM) and to evaluate the response of individuals with T2DM of Yemenite (Y-DM) and non-Yemenite origin (NY-DM). METHODS: Twenty T2DM males, ten Y-DM and ten NY-DM underwent meal tolerance test and indexes of insulin resistance and secretion were calculated. Subsequently, patients were connected to CGM to assess daily glycemic control and glucose variability in response to isocaloric HC-LF or LC-HF diet, receiving each diet for 2 days by providing prepared meals. Daily glucose levels, area under the glucose curve (G-AUC) and parameters of glucose variability [standard deviation (SD), mean amplitude of glycemic excursions (MAGE) and mean absolute glucose (MAG)] were evaluated. RESULTS: The LC-HF resulted in a significantly lower G-AUC (p < 0.001) and in lower variability parameters (p < 0.001) vs. the HC-LF diet. However, Y-DM showed less reduction in glucose variability indices upon diet-switching vs. NY-DM; MAGE decreased, respectively, by 69% vs. 89%, p = 0.043 and MAG by 34% vs. 45%, p = 0.007 in Y-DM compared to NY-DM. CONCLUSIONS: These results suggest that LC-HF diet is effective in reducing glycemic fluctuation in T2DM and that ethnicity may have a role in the response to dietary regime.

Galactomannan More than Pectin Exacerbates Liver Injury in Mice Fed with High-Fat, High-Cholesterol Diet.

SCOPE: Galactomannan and citrus pectin are considered 'super fibers' known for altering gut microbiota composition and improving glucose and lipid metabolism. The study aims to investigate the fiber's effect on a nonalcoholic steatohepatitis (NASH) model. METHODS AND RESULTS: Two feeding experiments are carried out using groups of 7-8 week-old male C57BL/6J mice. The diets used are based on a high cholesterol/cholate diet (HCD), such as a nutritional NASH model. Mice are fed a diet with or without 15% fiber-citrus pectin (HCD-CP) or galactomannan (HCD-G) together with the HCD (first experiment), which commenced 3 weeks prior to the HCD (second experiment). Liver damage is evaluated by histological and biochemical parameters. Galactomannan leads to lesser weight gain and improved glucose tolerance, but increased liver damage. This is shown by elevated levels of liver enzymes compared to that with HCD alone. Fibers induce higher steatosis, as evaluated by liver histology. This intriguing result is linked to various changes in the gut microbiota, such as elevated Proteobacteria levels in the galactomannan group, which are correlated with disturbed metabolism and dysbiosis. CONCLUSIONS: In a NASH mouse model, galactomannan increases liver damage but improves glucose metabolism. Changes in the microbiota composition may answer this enigmatic observation.

Fenugreek galactomannan and citrus pectin improve several parameters associated with glucose metabolism and modulate gut microbiota in mice.

OBJECTIVE: Galactomannans derived from fenugreek confer known health benefits; however, there is little information regarding health benefits of citrus pectin (CP) and its association with gut microbiome metabolites. The aim of this study was to examine links between galactomannan and CP consumption, microbiota development, and glucose metabolism. DESIGN: Male C57 BL/6 J mice ages 7 to 8 wk were fed ad libitum with a normal diet or one supplemented with 15% of either galactomannan or CP. At 3 wk, an oral glucose tolerance test was performed. Animals were sacrificed at 4 wk and relevant organs were harvested. RESULTS: Fiber enrichment led to reductions in weight gain, fasting glucose levels, and total serum cholesterol (P < 0.05). Compared with mice fed the normal diet, microbiota populations were altered in both fiber groups and were found to be richer in Bacteroidetes rather than Firmicutes (P < 0.05). The modification was significantly greater in galactomannan-fed than in CP-fed mice (P < 0.0001). Also, enhanced levels of the short-chain fatty acid (SCFA) propionate were found in the cecal contents of CP-fed animals (P < 0.05). Protein expression levels of monocarboxylate transporter 1, which may promote transport of SCFA, were measured in the large intestines after fiber consumption. Enhanced adenosine monophosphate-activated protein kinase (AMPK) activation was observed in livers of galactomannan-fed mice (P < 0.05). CONCLUSION: Consumption of diets containing soluble fibers, as used in this study, resulted in gut microbiota comprising a healthier flora, and led to positive effects on weight, glycemic control, and liver ß oxidation via AMPK.

Non-alcoholic fatty liver disease, to struggle with the strangle: Oxygen availability in fatty livers.

Nonalcoholic fatty liver diseases (NAFLD) is one of the most common chronic liver disease in Western countries. Oxygen is a central component of the cellular microenvironment, which participate in the regulation of cell survival, differentiation, functions and energy metabolism. Accordingly, sufficient oxygen supply is an important factor for tissue durability, mainly in highly metabolic tissues, such as the liver. Accumulating evidence from the past few decades provides strong support for the existence of interruptions in oxygen availability in fatty livers. This outcome may be the consequence of both, impaired systemic microcirculation and cellular membrane modifications which occur under steatotic conditions. This review summarizes current knowledge regarding the main factors which can affect oxygen supply in fatty liver.

Prolonged feeding with green tea polyphenols exacerbates cholesterol-induced fatty liver disease in mice.

SCOPE: This study investigated the potential deleterious impact of dietary supplementation with green tea extract (GTE) on the progression of fatty liver disease, in a mouse model of cholesterol-induced steatohepatitis that represents chronic liver injury. METHODS AND RESULTS: Male C57BL mice (n = 32, 8-wk-old) were fed for 6 wk with one of the following diets: normal control diet (ND, Con), Con + 1% w/w polyphenols from GTE (Con + GTE); high cholesterol diet, Con + 1% cholesterol + 0.5% cholate w/w (HCD); HCD + 1% green tea polyphenols w/w (HCD + GTE). Hepatic steatosis, oxidative, and inflammatory markers and bile acid synthesis pathways were measured. HCD supplementation resulted in hepatic steatosis and liver damage. In animals supplemented with the HCD + GTE an exacerbated hepatic steatosis, oxidative stress, and inflammatory response were observed compared to HCD supplemented animals. HCD + GTE supplementation elevated blood levels of liver enzymes and serum bile acids compared HCD-treated animals. HCD + GTE supplementation altered bile acid synthesis in the cholesterol clearance pathway, inducing a shift from the classically regulated CYP7A1 pathway to the alternative acidic pathway. CONCLUSION: Prolonged GTE supplementation dramatically increased hepatic oxidative stress, inflammation and liver injury, and altered the bile acid synthesis pathway in mice fed a HCD.

Early beta-cell dysfunction characterizes males with type 2 diabetes of Yemenite origin.

AIMS: The aim of the current study was to characterize ß-cell function, insulin sensitivity and line of inheritance in patients with recent-onset type 2 diabetes of Yemenite and non-Yemenite Jewish origin. METHODS: A cohort study including 121 GAD negative diabetic patients, 59 of Yemenite and 62 of non-Yemenite origin, treated by diet ± oral antihyperglycemic monotherapy who underwent 180-min meal tolerance test (MMT). Based on MMT, indexes of insulin resistance and secretion were calculated. RESULTS: There were no significant differences in age, sex, diabetes duration, BMI, HbA1c and lipid profile. A significant difference was found in family history of diabetes: 63 % of patients of Yemenite origin had maternal inheritance versus 35 % in the non-Yemenite origin (p < 0.001). Both indexes of ß-cell function, the insulinogenic and the disposition indexes were significantly lower in patients of Yemenite origin compared with non-Yemenite origin (0.66 ± 0.4 vs. 0.93 ± 0.8, p = 0.04; 2.3 ± 1.8 vs. 3.3 ± 3.3, p = 0.04, respectively) with no difference in insulin sensitivity. When females and males were analyzed separately, the difference in maternal inheritance remained significant in both, but the difference in ß-cell function indexes was observed only in males (p = 0.03, p = 0.01, respectively). CONCLUSIONS: Males with recent-onset diabetes of Yemenite origin have a significant reduction of ß-cell function and reduced ability to compensate for insulin resistance compared with diabetic males of non-Yemenite origin. Both males and females of Yemenite origin have a significantly higher maternal inheritance of diabetes. These data suggest different underlying mechanisms leading to early loss of ß-cell in diabetic males of Yemenite origin.

Glabridin, an isoflavan from licorice root, upregulates paraoxonase 2 expression under hyperglycemia and protects it from oxidation.

SCOPE: Hyperglycemia is associated with oxidative stress, which accelerates cardiovascular complications. This study investigates the potential of glabridin to regulate paraoxonase 2 (PON2) levels, in vivo, and explores the glabridin protective effect on PON2 through tryptophan-fluorescence quenching and mass spectrometry. METHODS AND RESULTS: Adult mouse offspring of saturated fatty acids fed mothers, which developed hyperglycemia after exposure to a high fat diet in their adult life, had lower levels of heart PON2 mRNA and protein expression than did the control mice (64 and 26%, respectively). Glabridin supplementation significantly upregulated PON2 mRNA and protein expression in the liver (2.1-fold and 2.6-fold, respectively) and heart (2.5-fold and 1.6-fold, respectively) in these mice. In vitro studies demonstrated that the fluorescence quenching of PON2 by glabridin was a result of the formation of a glabridin-PON2 interaction. The binding constant (7.61 × 10(5) M(-1) ) and the ΔG (-33.55kJ/mol) indicated that this interaction was driven by a hydrophobic force, which confers protection against CuSO4 -induced PON2 oxidation. CONCLUSION: Such results indicate that glabridin preserves the anti-atherogenic abilities of PON2 by maintaining its levels, in vivo. The glabridin-PON2 interaction may be the mechanism by which glabridin protects PON2 from oxidation, thus contributing to the protection of PON2 activity in hyperglycemia.