Improved Energy Metabolism Research Articles

613-P: Preventive Effect of Sulforaphane on Type 2 Diabetes-Induced Diabetic Cardiomyopathy via AMPK-Mediated Activation of Glucose/Lipid Metabolism and Nrf2 Function

Dyslipidemia has been shown to play a crucial role in the development of diabetic cardiomyopathy (DCM) in type 2 diabetes (T2D). AMP-activated protein kinase (AMPK), particularly α2 isoform can improve energy metabolism in cardiomyopathy. Sulforaphane (SFN), a natural isothiocyanate in vegetables, is important in cardiac protection from diabetes. We investigated whether SFN can protect heart from T2D damage, which is mediated by AMPKα2 via improving energy metabolism and activating Nrf2-mediated anti-oxidative pathways. AMPKα2 knockout (AMPKα2-KO) mice and their wild type (WT, C57BL/6J) mice were fed high-fat diet (HFD) for 3 months to induce insulin resistance, and then intraperitoneal injection of streptozotocin to induce hyperglycemia as T2D model. Age-matched mice were fed with normal diet (ND) without streptozotocin as control. T2D and control mice were treated with or without SFN for 3 months (3m) and then stop SFN treatment, remained feeding either ND or HFD for additional three months (6m). Echocardiography were performed before sacrifice both in 3m and 6m group. SFN treatment improved cardiac remodeling and dysfunction induced by T2D both in 3m and 6m group. The cardiac pathogenic changes induced by T2D, including fibrosis, lipotoxicity, inflammation, oxidative stress/damage along with suppression of AMPK signaling pathways was prevented by SFN in WT diabetic mice, as evidenced by down-regulating FN, TGF-β PAI-1, TNF-α, SCD-1and up-regulating CPT1-B, PPARα, Nrf2. The cardiac protection by SFN for 3 months from T2D could last till 6 months. AMPKα2-KO mice are also susceptible to T2D-induced cardiomyopathy; however, the protective effect of SFN on the heart from diabetes was lost in diabetic AMPKα2-KO mice. These results suggest that SFN treatment can attenuate cardiac damage induced by T2D both in the 3m and 6m group, and AMPKα2 plays the pivotal role in the SNF-mediated cardiac protection. Disclosure Y. Sun: None. L. Cai: None. Z. Li: None. Funding American Diabetes Association (1-18-IBS-082 to L.C.)

Improving Energy Metabolism of Deproteinized Extract of Calf Blood Through Regulation of Hmgcs2, Cpt1a, Angptl4, Cyp8b1, and Ehhadh Genes in Mice

Herein, we described the physicochemical properties of deproteinized extract of calf blood(DECB) and established a hypoxia model treated with or without DECB to detect the sugar, lactic acid, protein, and ATP contents of mice and then identified and analyzed the differentially expressed genes between two groups using mRNA expression chip. According to the results of the airtight hypoxia experiment, mice in the model+DECB group had a significantly prolonged time of hypoxia tolerance compared with the model group. The biochemical test indicated that DECB could significantly increase the level of sugar, ATP and proteins and reduce the amount of lactic acid in mice. It also revealed that Hmgcs2, Cpt1a, Angptl4, Cyp8b1, and Ehhadh genes were involved in mice energy metabolism, and were closely associated with metabolic signaling pathway. These results suggest that DECB might be a potential drug to treat metabolic diseases. Among the genes with differential expression under hypoxia, Angptl4, Cyp8b1, and Ehhadh were critical factors for sugar metabolism. Hmgcs2 provided energy directly, and Cptla regulated cellular inflammatory responses, promoting energy metabolism.

Aspalathin, a natural product with the potential to reverse hepatic insulin resistance by improving energy metabolism and mitochondrial respiration.

Aspalathin is a rooibos flavonoid with established blood glucose lowering properties, however, its efficacy to moderate complications associated with hepatic insulin resistance is unknown. To study such effects, C3A liver cells exposed to palmitate were used as a model of hepatic insulin resistance. These hepatocytes displayed impaired substrate metabolism, including reduced glucose transport and free fatty acid uptake. These defects included impaired insulin signaling, evident through reduced phosphatidylinositol-4,5-bisphosphate 3-kinase/ protein kinase B (PI3K/AKT) protein expression, and mitochondrial dysfunction, depicted by a lower mitochondrial respiration rate. Aspalathin was able to ameliorate these defects by correcting altered substrate metabolism, improving insulin signaling and mitochondrial bioenergetics. Activation of 5ʹ-adenosine monophosphate-activated protein kinase (AMPK) may be a plausible mechanism by which aspalathin increases hepatic energy expenditure. Overall, these results encourage further studies assessing the potential use of aspalathin as a nutraceutical to improve hepatocellular energy expenditure, and reverse metabolic disease-associated complications.

Effect of Acetyl-L-carnitine Used for Protection of Neonatal Hypoxic-Ischemic Brain Injury on Acute Kidney Changes in Male and Female Rats.

Neonatal hypoxia-ischemia (HI) is a common cause of brain injury in infants. Acute kidney injury frequently occurs after birth asphyxia and is associated with adverse outcome. Treatment with acetyl-L-carnitine (ALCAR) after HI protects brain and improves outcome. Rat pups underwent carotid ligation and 75min hypoxia on postnatal day 7 to determine effects of HI on kidney which is understudied in this model. HI + ALCAR pups were treated at 0, 4 and 24h after HI. The organic cation/carnitine transporter 2 (OCTN2), transports ALCAR and functions to reabsorb carnitine and acylcarnitines from urine. At 24h after injury OCTN2 levels were significantly decreased in kidney from HI pups, 0.80 ± 0.04 (mean± SEM,p < 0.01), compared to sham controls 1.03 ± 0.04, and HI + ALCAR pups 1.11 ± 0.06. The effect of HI on the level of pyruvate dehydrogenase (PDH) was determined since kidney has high energy requirements. At 24h after HI, kidney PDH/β-actin ratios were significantly lower in HI pups, 0.98 ± 0.05 (mean ± SEM,p < 0.05), compared to sham controls 1.16 ± 0.06, and HI + ALCAR pups 1.24 ± 0.03, p < 0.01. Treatment of pups with ALCAR after HI prevented the decrease in renal OCTN2 and PDH levels at 24h after injury. Protection of PDH and OCTN2 after HI would improve energy metabolism in kidney, maintain tissue carnitine levels and overall carnitine homeostasis which is essential for neonatal health.

Effect of Aerobic Exercise on Serum Metabolites in Mice with Hepatocellular Carcinoma After Surgery.

BackgroundModern medicine has suggested exercise therapy is one of the main treatments for postoperative rehabilitation of tumors. It can influence the recovery of cancer patients by changing the body’s material metabolism and energy metabolism. However, studies on metabolic changes of exercise therapy on hepatocellular carcinoma (HCC) patients after surgery are limited. The aim of this study was to explore the effect of aerobic exercise on mice after orthotopic HCC surgery by serum metabolomics test and explore the related mechanism.Material/MethodsA total of 60 C57Bl/6 mice were used to establish an orthotopic xenograft model of H22 mouse hepatoma cells. Mice were randomly divided into 6 groups and it was found that the metabolic products of the early postoperative exercise group and sedentary group mainly included L-tryptophan, citric acid, and other energy-related metabolites.ResultsEnergy metabolites, such as succinic acid of the high-intensity exercise group were increased after surgery, whereas phospholipid metabolites, including phosphatidylethanolamine (18: 0/0: 0), were decreased. In the moderate-intensity exercise group, the change tendency was consistent, and the level of various metabolites decreased.ConclusionsThus, it is likely that aerobic exercise reduced the degree of postoperative stress responses and improved energy metabolism in mice. The underlying mechanism involves improving the tricarboxylic acid cycle, intervening in energy metabolism, reorganization caused by the tumor, reducing the abnormal increase of phospholipase activity caused by the stress of liver cancer, reducing the level of hemolytic phospholipids, thereby inhibiting mitochondrial pathway-initiated apoptosis.

Systematic Review of Basic Research on Alzheimer's Disease with Shen Zhi Ling Oral Liquid.

Objective The present report systematically reviewed the basic research of Shen Zhi Ling oral liquid (Tiao Xin preparation) treatment on Alzheimer's disease (AD). Methods CNKI, Wanfang, and VIP were searched, and the literature was selected according to inclusion and exclusion criteria. Data were extracted, and descriptive analysis was used. Results Twenty-four articles were included, all of which were published as “Tiao Xin preparation.” There were seven types of AD models involved. The mechanism of action of Shen Zhi Ling oral liquid in the treatment of AD primarily included suppression of Aβ deposition and tau hyperphosphorylation, regulation of multiple neurotransmitters, improvement in energy metabolism, and promotion of the expression of autophagy-related and learning-memory-associated proteins. Conclusions AD is a complex disease caused by multiple factors. Shen Zhi Ling oral liquid exhibited multiple and multitarget effects and great potential for treating AD. The continuous development of molecular biology and related disciplines will further elucidate the mechanism of Shen Zhi Ling oral liquid intervention in AD.

Determination of berberine-upregulated endogenous short-chain fatty acids through derivatization by 2-bromoacetophenone.

Short-chain fatty acids (SCFAs) are a major group of endogenous metabolites generated by the gut microbiota and have been reported to play an important role in physical health, such as improving energy metabolism. Here, using 2-bromoacetophenone as the derivatization reagent (BP, 10mg/mL, 40°C for 20min), a sensitive liquid chromatography-tandem mass spectrometric method was established for the quantitative determination of seven short-chain fatty acids in plasma and feces. The analyses were performed on a C18 column in positive multiple reaction monitoring mode. Specificity, linearity, accuracy, precision, recovery, and stability were observed within the quantitative limits of biological sample analysis. The established method has largely improved the sensitivity by 200- to 2000-fold than that in gas chromatography (GC). Especially for butyrate, the lower quantitative limit of 1ng/mL, 1600-fold higher in sensitivity than that of GC (1.6μg/mL), ensured the accurate determination of its low level in blood or feces (88 ± 29ng/mL in blood, 176 ± 18μg/g in feces). Then, the validated method was applied for therapeutic studies of berberine in hyperlipidemia hamsters in vivo and screening of 13 compounds (including five metabolites of berberine and eight typical isoquinoline alkaloids) in vitro. After berberine treatment (oral, 200mg/kg, 2weeks) to hyperlipidemia hamsters, the levels of butyrate were significantly upregulated in blood (77 ± 10ng/mL vs. 117 ± 13ng/mL, *P < 0.05) and feces (132 ± 11μg/g vs. 547 ± 57μg/g, ***P < 0.001), which further verified butyrate as an active endogenous metabolite in coordination with berberine to lower the blood lipids. Additionally, the berberine metabolites (M1, M2, M3), as well as two isoquinoline alkaloids (tetrandrine and dauricine), could also obviously induce the production of SCFAs (butyrate, etc.) in gut microbiota. In total, we have successfully established a new derivative LC-MS/MS method for the targeted quantitative determination of seven SCFAs in biological samples. Graphical abstract.

Maternal nicotinamide supplementation during the perinatal period modifies the small intestine morphology and antioxidative status of offspring kids

Nicotinamide (NAM) was evidenced to have the capacity to improve energy metabolism and attenuate oxidative stress during the perinatal period. As there is an association between maternal nutrition and the developmental outcomes of offspring, the aim was to investigate the effect of maternal NAM supplementation on small intestine morphology and some antioxidative parameters of offspring kids. Fifteen multiparous does were paired and allocated into 3 treatments: control (C), postpartum (P, supplemented post-kidding), and entire-perinatal (EP, supplemented from d -21 to 28 around kidding). NAM was drenched to does at 5 g/d and at 0700 h every day. After kidding, the kids were named LC, LP, and LEP, respectively, and fed milk from their mothers until d 28 of life. For the offspring kids, BW and ADG were not affected. The villus height in the duodenum was higher in LP than in LC, and that in the ileum was higher in LEP. The ratio of villus height to crypt depth of intestine was increased in LEP. The serum IgG was tended to elevate by maternal NAM supplementation, and the total antioxidant capacity was decreased in both LP and LEP. The does supplemented with NAM had an improved antioxidative status, and lower level of milk IL-1β was found in EP. The MDA of the mammary tissue was also decreased by NAM. Moreover, the milk metabolomics profile showed that glycerol was decreased while citramalic acid and sucrose were elevated with NAM supplementation. Glycerolipid metabolism, galactose metabolism, and starch and sucrose metabolism were enriched. Thus, these data indicated that maternal NAM supplementation improved the small intestinal development of offspring kids partially by affecting the antioxidative status and milk metabolites of the does. This knowledge further suggested that the development of a nutritional strategy from prepartum period and milk feeding in early life are important for offspring kids.

A novel traditional Chinese medicine ameliorates fatigue-induced cardiac hypertrophy and dysfunction via regulation of energy metabolism.

Prolonged exercise and exercise training can adversely affect cardiac function in some individuals. QiShenYiQi Pills (QSYQ), which are a compound Chinese medicine, have been previously shown to improve pressure overload-induced cardiac hypertrophy. We hypothesized that QSYQ can ameliorate as well the fatigue-induced cardiac hypertrophy. This study was to test this hypothesis and underlying mechanism with a focus on its role in energy regulation. Male Sprague-Dawley rats were used to establish exercise adaptation and fatigue model on a motorized rodent treadmill. Echocardiographic analysis and heart function test were performed to assess heart systolic function. Food-intake weight/body weight and heart weight/body weight were assessed, and hematoxylin and eosin staining and immunofluorescence staining of myocardium sections were performed. ATP synthase expression and activity and ATP, ADP, and AMP levels were assessed using Western blot and ELISA. Expression of proteins related to energy metabolism and IGF-1R signaling was determined using Western blot. QSYQ attenuated the food-intake weight/body weight decrease, improved myocardial structure and heart function, and restored the expression and distribution of myocardial connexin 43 after fatigue, concomitant with an increased ATP production and a restoration of metabolism-related protein expression. QSYQ upgraded the expression of IGF-1R, P-AMPK/AMPK, peroxisome proliferator-activated receptor-γ coactivator-1α, nuclear respiratory factor-1, P-phosphatidylinositol 3-kinase (PI3K)/PI3K, and P-Akt/Akt thereby attenuated the dysregulation of IGF-1R signaling after fatigue. QSYQ relieved fatigue-induced cardiac hypertrophy and enhanced heart function, which is correlated with its potential to improve energy metabolism by regulating IGF-1R signaling. NEW & NOTEWORTHY Prolonged exercise may impact some people leading to pathological cardiac hypertrophy. This study using an animal model of fatigue-induced cardiac hypertrophy provides evidence showing the potential of QiShenYiQi Pills, a novel traditional Chinese medicine, to prevent the cardiac adaptive hypertrophy from development to pathological hypertrophy and demonstrates that this effect is correlated with its capacity for regulating energy metabolism through interacting with insulin-like growth factor-1 receptor.

Association between skeletal muscle mass and serum concentrations of lipoprotein lipase, GPIHBP1, and hepatic triglyceride lipase in young Japanese men

BackgroundTwo important regulators for circulating lipid metabolisms are lipoprotein lipase (LPL) and hepatic triglyceride lipase (HTGL). In relation to this, glycosylphosphatidylinositol anchored high-density lipoprotein binding protein 1 (GPIHBP1) has been shown to have a vital role in LPL lipolytic processing. However, the relationships between skeletal muscle mass and lipid metabolism, including LPL, GPIHBP1, and HTGL, remain to be elucidated. Demonstration of these relationships may lead to clarification of the metabolic dysfunctions caused by sarcopenia. In this study, these relationships were investigated in young Japanese men who had no age-related factors; participants included wrestling athletes with abundant skeletal muscle.MethodsA total of 111 young Japanese men who were not taking medications were enrolled; 70 wrestling athletes and 41 control students were included. The participants’ body compositions, serum concentrations of lipoprotein, LPL, GPIHBP1 and HTGL and thyroid function test results were determined under conditions of no extreme dietary restrictions and exercises.ResultsCompared with the control participants, wrestling athletes had significantly higher skeletal muscle index (SMI) (p < 0.001), higher serum concentrations of LPL (p < 0.001) and GPIHBP1 (p < 0.001), and lower fat mass index (p = 0.024). Kruskal–Wallis tests with Bonferroni multiple comparison tests showed that serum LPL and GPIHBP1 concentrations were significantly higher in the participants with higher SMI. Spearman’s correlation analyses showed that SMI was positively correlated with LPL (ρ = 0.341, p < 0.001) and GPIHBP1 (ρ = 0.309, p = 0.001) concentration. The serum concentrations of LPL and GPIHBP1 were also inversely correlated with serum concentrations of triglyceride (LPL, ρ = − 0.198, p = 0.037; GPIHBP1, ρ = − 0.249, p = 0.008). Serum HTGL concentration was positively correlated with serum concentrations of total cholesterol (ρ = 0.308, p = 0.001), low-density lipoprotein-cholesterol (ρ = 0.336, p < 0.001), and free 3,5,3′-triiodothyronine (ρ = 0.260, p = 0.006), but not with SMI.ConclusionsThe results suggest that increased skeletal muscle mass leads to improvements in energy metabolism by promoting triglyceride-rich lipoprotein hydrolysis through the increase in circulating LPL and GPIHBP1.

Interval running training improves age-related skeletal muscle wasting and bone loss: Experiments with ovariectomized rats.

What is the central question of this study? What is the effect and mechanism of interval running training on age-related muscle wasting and bone loss in an ovariectomized rat model? What is the main finding and its importance? Interval running training improved muscle growth and osteogenic differentiation by enhancing the expression of bone morphogenic proteins and sirtuins in ageing-induced ovariectomized rats. Therefore, the repetition of low and high intensities within a single exercise bout, such as interval running training, may be recommended as a practical intervention to prevent skeletal muscle wasting and bone loss in the elderly. Effective prophylactic strategies are needed for the suppression of age-related muscle wasting and bone loss after menopause. Exercise training is attractive due to its potential for improving energy metabolism, as well as age-related muscle wasting and bone loss. In particular, interval running (IR) training involves a repetition of low and high intensities within a single exercise bout. Therefore, this study elucidated the effect of interval training on muscle and bone health, as well as anti-ageing, in ovariectomized (OVX) rats. The anti-ageing effect of IR on muscle and bone was tested using western blotting and micro-computed tomography analysis, tartrate-resistant acid phosphatase and immunohistochemical staining. IR significantly inhibited the expression of inflammatory molecules, and improved antioxidant activity via down-regulation of mitogen-activated protein kinases (MAPKs) in the ageing-induced OVX rats skeletal muscle. IR compared with continuous running (CR) improved muscle mass and growth in OVX rats by the promotion of muscle growth-related factors including MyoD, myogenin, phospho-mechanistic target of rapamycin (p-mTOR), sirtuins (SIRTs), and bone morphogenic proteins (BMPs). IR also effectively recovered OVX-induced bone loss via the down-regulation of bone resorption and osteoclast formation in receptor activator of nuclear factor κB ligand (RANKL)-treated bone marrowmacrophages (BMMs). In particular, IR led to high expression of SIRT1 and 6, which promoted osteogenic differentiation and bone formation via modulating the BMP signalling pathway compared with CR training. The in vivo effect of IR was confirmed by immunohistochemical staining with the improvement of bone formation molecules such as BMPs and SIRTs. These results suggested that IR training affected myogenic and osteogenic formation. So, IR training may be considered for prevention of muscle wasting and bone loss for the elderly.

Oxaloacetate Protects Rat Liver From Experimental Warm Ischemia/Reperfusion Injury by Improving Cellular Energy Metabolism

Liver ischemia/reperfusion injury (IRI) is an important cause of liver damage especially early after liver transplantation, following liver resection, and in other clinical situations. Using rat experimental models, we identified oxaloacetate (OAA) as a key metabolite able to protect hepatocytes from hypoxia and IRI. In vitro screening of metabolic intermediates beneficial for hepatocyte survival under hypoxia was performed by measures of cell death and injury. In vivo, the effect of OAA was evaluated using the left portal vein ligation (LPVL) model of liver ischemia and a model of warm IRI. Liver injury was evaluated in vivo by serum transaminase levels, liver histology, and liver weight (edema). Levels and activity of caspase 3 were also measured. In vitro, the addition of OAA to hepatocytes kept in a hypoxic environment significantly improved cell viability (P < 0.01), decreased cell injury (P < 0.01), and improved energy metabolism (P < 0.01). Administration of OAA significantly reduced the extent of liver injury in the LPVL model with lower levels of alanine aminotransferase (ALT; P < 0.01), aspartate aminotransferase (AST; P < 0.01), and reduced liver necrosis (P < 0.05). When tested in a warm IRI model, OAA significantly decreased ALT (P < 0.001) and AST levels (P < 0.001), prevented liver edema (P < 0.001), significantly decreased caspase 3 expression (P < 0.01), as well as histological signs of cellular vesiculation and vacuolation (P < 0.05). This was associated with higher adenosine triphosphate (P < 0.05) and energy charge levels (P < 0.01). In conclusion, OAA can significantly improve survival of ischemic hepatocytes. The hepatoprotective effect of OAA was associated with increased levels of liver bioenergetics both in vitro and in vivo. These results suggest that it is possible to support mitochondrial activity despite the presence of ischemia and that OAA can effectively reduce ischemia-induced injury in the liver.

Omega 3 rich diet modulates energy metabolism via GPR120-Nrf2 crosstalk in a novel antioxidant mouse model

With obesity rates reaching epidemic proportions, more studies concentrated on reducing the risk and treating this epidemic are vital. Redox stress is an important metabolic regulator involved in the pathophysiology of cardiovascular disease, Type 2 diabetes, and obesity. Oxygen and nitrogen-derived free radicals alter glucose and lipid homeostasis in key metabolic tissues, leading to increases in risk of developing metabolic syndrome. Oxidants derived from dietary fat differ in their metabolic regulation, with numerous studies showing benefits from a high omega 3 rich diet compared to the frequently consumed “western diet” rich in saturated fat. Omega 3 (OM3) fatty acids improve lipid profile, lower inflammation, and ameliorate insulin resistance, possibly through maintaining redox homeostasis. This study is based on the hypothesis that altering endogenous antioxidant production and/or increasing OM3 rich diet consumption will improve energy metabolism and maintain insulin sensitivity. We tested the comparative metabolic effects of a diet rich in saturated fat (HFD) and an omega 3-enriched diet (OM3) in the newly developed ‘stress-less’ mice model that overexpresses the endogenous antioxidant catalase. Eight weeks of dietary intervention showed that mice overexpressing endogenous catalase compared to their wild-type controls when fed an OM3 enriched diet, in contrast to HFD, activated GPR120-Nrf2 cross-talk to maintain balanced energy metabolism, normal circadian rhythm, and insulin sensitivity. These findings suggest that redox regulation of GPR120/FFAR4 might be an important target in reducing risk of metabolic syndrome and associated diseases.

Olfactory receptor 43 reduces hepatic lipid accumulation and adiposity in mice

Olfactory receptors are primarily expressed in nasal olfactory epithelium, but these receptors are also ectopically expressed in diverse tissues. In this study, we investigated the biological functions of Olfr43, a mouse homolog of human OR1A1, in cultured hepatocytes and mice to assess its functionality in lipid metabolism. Olfr43 was expressed in mouse hepatocytes, and Olfr43 activation by a known ligand, (−)-carvone, stimulated cAMP response element-binding protein (CREB) activity. In ligand-receptor binding studies using site-directed mutagenesis, (−)-carvone binding required two residues, M257 and Y258, in Olfr43. In the mouse study, oral administration of (−)-carvone for 5 weeks in high-fat diet-fed mice improved energy metabolism, including reductions in hepatic steatosis and adiposity, and improved glucose and insulin tolerance. In mouse livers and cultured mouse hepatocytes, Olfr43 activation simulated the CREB-hairy and enhancer of split 1 (HES1)-peroxisome proliferator-activated receptor (PPAR)-γ signaling axis, leading to a reduction in hepatic triglyceride accumulation in the mouse liver. Thus, long-term administration of (−)-carvone reduces hepatic steatosis. The knockdown of Olfr43 gene expression in cultured hepatocytes negated these effects of (−)-carvone. In conclusion, an ectopic olfactory receptor, hepatic Olfr43, regulates energy metabolism via the CREB-HES1-PPARγ signaling axis.

Butyrate stimulates hepatic gluconeogenesis in mouse primary hepatocytes.

Butyrate is a major short-chain fatty acid (SCFA) produced by microbial fermentation of dietary fiber in the gastrointestinal tract. Butyrate is also a well-known broad-spectrum histone deacetylase (HDAC) inhibitor. Butyrate has been reported to improve energy metabolism in rodents, which is associated with its beneficial effects on skeletal muscle, brown fat tissue and pancreatic β-cells. The present study investigated the direct effect of butyrate on hepatic gluconeogenesis in mouse primary hepatocytes and the underlying mechanism. Isolated mouse primary hepatocytes were incubated with sodium butyrate, other HDAC inhibitors and other SCFAs. Hepatic glucose production was measured and gluconeogenic gene expression was detected by polymerase chain reaction analysis. The phosphorylation of cyclic adenosine monophosphate (cAMP) response element binding protein (CREB) was assessed by western blot analysis. The results revealed that sodium butyrate dose-dependently increased hepatic glucose production and gluconeogenic gene expression in isolated mouse primary hepatocytes. Trichostatin A, a potent broad-spectrum HDAC inhibitor, had the opposite effect. Similar to sodium butyrate, propionate, which is another SCFA, promoted hepatic glucose production and gluconeogenic gene expression in the presence or absence of gluconeogenic substrates, which were further enhanced by cAMP. Furthermore, sodium butyrate also increased the accumulation of intracellular ATP and induced the phosphorylation of CREB in mouse hepatocytes. In conclusion, the present study suggested that butyrate stimulates hepatic gluconeogenesis and induces gluconeogenic gene expression as a substrate and cAMP/CREB signaling activator.

Small Molecule Oligopeptides Isolated from Walnut (Juglans regia L.) and Their Anti-Fatigue Effects in Mice

Walnut (Juglans regia L.) is unique for its extensive biological activities and pharmaceutical properties. There are few studies on walnut oligopeptides (WOPs), which are small molecule peptides extracted from walnuts. This study aimed to evaluate the anti-fatigue effects of WOPs on ICR mice and explore the possible underlying mechanism. Mice were randomly divided into four experimental sets and each set of mice were then randomly divided into four groups. The vehicle group was administered distilled water, and the three WOP intervention groups were orally administered WOP solution at a dose of 110, 220, and 440 mg/kg of body weight, respectively. After 30 days of WOP intervention, the anti-fatigue activity of WOPs were evaluated using the weight-loaded swimming test and by measuring the change of biochemical parameters, glycogen storage and energy metabolism enzymes, anti-oxidative capacity and mitochondrial function. It was observed that WOPs could significantly prolong the swimming time, decrease the accumulation of lactate dehydrogenase (LDH), creatine kinase (CK), blood urea nitrogen (BUN) and blood lactic acid (BLA), and increased the glycogen storage of liver and gastrocnemius muscle. WOPs also markedly inhibited fatigue induced oxidative stress by increasing the activity of superoxide dismutase (SOD), glutathione peroxidase (GPX) and decreasing the content malondialdehyde (MDA). Notably, WOPs improved the activity of pyruvate kinase (PK), succinate dehydrogenase (SDH), Na+-K+-ATPase, and enhanced the mRNA expression of mitochondrial biogenesis factors and mitochondrial DNA content in skeletal muscles of mice. These results suggest that WOPs have beneficial anti-fatigue effects, which may be attributed to their positive effects on increasing glycogen storage, improving energy metabolism, inhibiting oxidative stress, enhancing mitochondrial function in skeletal muscle, and ameliorating the cell damage and the muscular injury.

Metabolic Therapy in hypertensive encephalopathy: emphasis on comorbidity of pathology

The development of primary and repeated disorders of cerebral circulation, vascular dementia, transient ischemic attacks, which are a consequence of the development of acute pathology in patients with hypertensive encephalopathy, lead to a state of persistent disability and disability. Today, the emphasis of treatment is placed on the important role of oxygen deficiency, which leads to the restriction of aerobic energy production due to disturbances in the energy-synthesizing function of the mitochondrial respiratory chain, depletion of endogenous antioxidant stores and activation of lipid peroxidation of cell membranes, leading to death of brain cells. By 2018, a large evidence base for the effectiveness of the use of metabolic therapy in neurology, which takes into account an important factor of the impact of comorbidity of the pathology. The effectiveness of antioxidant therapy in acute and chronic cerebrovascular diseases is confirmed by the fact that the antioxidant improves energy metabolism in the cell, and as a metabolite of the tricarboxylic acid cycle (succinate, which provides pronounced antioxidant and antihypoxic properties) has a positive effect on the main links of pathogenesis of diseases associated with processes freely Radical oxidation. It is proved that the preparation of Mexicor reduces the manifestation of oxidative stress, inhibits free radical peroxide oxidation of lipids, improves cellular energy metabolism, activates the energy-synthesizing functions of mitochondria, enhances compensatory activation of aerobic glycolysis and reduces the degree of inhibition of oxidative processes in the Krebs cycle. The drug Mexocor has a wide spectrum of pharmacological action, which allows it to be used successfully in acute and chronic cerebrovascular diseases, accompanied by vascular comorbidity.

Danshensu for Myocardial Ischemic Injury: Preclinical Evidence and Novel Methodology of Quality Assessment Tool.

Background: Danshensu (DSS) possesses unique bioactivity on the cardiovascular system. However, there is a lack of systematical summary of DSS for acute myocardial ischemia injury and no quality assessment tool for the systematical review of cell experiments. Here, we aimed to assess the preclinical evidences and possible mechanisms of DSS for myocardial ischemia injury, and to develop a quality assessment tool for the systematical review of cell experiments.Methods: Thirty-two studies with 473 animals and 134 cells were identified by searching seven databases. All data analysis was performed using RevMan 5.3. CAMARADES 10-item checklist was used to assess the methodological quality of animal experiments. A new 10-item checklist was first developed to assess the methodological quality of cell studies.Results: The score of study quality ranged from 3 to 7 points in animal studies, while the cell studies scored 3–6 points. Meta-analysis showed that DSS had significant effects on reducing myocardial infarct (MI) size in vivo, and increasing cell viability and reducing apoptosis rate in vitro compared with controls (P < 0.01). The possible mechanisms of DSS for MI are improving circulation, antioxidant, anti-apoptosis, anti-inflammatory, promoting angiogenesis, anti-excessive autophagy, anti-calcium overload, and improving energy metabolism.Conclusions: DSS could exert cardioprotective effect on myocardial ischemia injury, and thus is a probable candidate for further clinical trials andtreatment of AMI. In addition, the newly devloped 10-item checklist for assessing methodological quality of cell study that recommened to use the sysmatic review of cell studies.

Failure to sense energy depletion may be a novel therapeutic target in chronic kidney disease

The kidneys consume a large amount of energy to regulate volume status and blood pressure and to excrete uremic toxins. The identification of factors that cause energy mismatch in the setting of chronic kidney disease (CKD) and the development of interventions aimed at improving this mismatch are key research imperatives. Although the critical cellular energy sensor 5'-adenosine monophosphate (AMP)-activated protein kinase (AMPK) is known to be inactivated in CKD, the mechanism of AMPK dysregulation is unknown. In a mouse model of CKD, metabolome analysis confirmed a decrease in AMPK activation in the kidneys despite a high AMP: ATP ratio, suggesting that AMPK did not sense energy depletion. Similar AMPK inactivation was found in heart and skeletal muscle in CKD mice. Several uremic factors were shown to inactivate AMPK invitro and in exvivo preparations of kidney tissue. The specific AMPK activator A-769662, which bypasses the AMP sensing mechanism, ameliorated fibrosis and improved energy status in the kidneys of CKD mice, whereas an AMP analog did not. We further demonstrated that a low-protein diet activated AMPK independent of the AMP sensing mechanism, leading to improvement in energy metabolism and kidney fibrosis. These results suggest that a failure to sense AMP is the key mechanism underlying the vicious cycle of energy depletion and CKD progression and direct AMPK activation may be a novel therapeutic approach in CKD.

Effect of Ischemic Preconditioning on the Recovery of Cardiac Autonomic Control From Repeated Sprint Exercise.

Repeated sprint exercise (RSE) acutely impairs post-exercise heart rate (HR) recovery (HRR) and time-domain heart rate variability (i. e., RMSSD), likely in part, due to lactic acidosis-induced reduction of cardiac vagal reactivation. In contrast, ischemic preconditioning (IPC) mediates cardiac vagal activation and augments energy metabolism efficiency during prolonged ischemia followed by reperfusion. Therefore, we investigated whether IPC could improve recovery of cardiac autonomic control from RSE partially via improved energy metabolism responses to RSE. Fifteen men team-sport practitioners (mean ± SD: 25 ± 5 years) were randomly exposed to IPC in the legs (3 × 5 min at 220 mmHg) or control (CT; 3 × 5 min at 20 mmHg) 48 h, 24 h, and 35 min before performing 3 sets of 6 shuttle running sprints (15 + 15 m with 180° change of direction and 20 s of active recovery). Sets 1 and 2 were followed by 180 s and set 3 by 360 s of inactive recovery. Short-term HRR was analyzed after all sets via linear regression of HR decay within the first 30 s of recovery (T30) and delta from peak HR to 60 s of recovery (HRR60s). Long-term HRR was analyzed throughout recovery from set 3 via first-order exponential regression of HR decay. Moreover, RMSSD was calculated using 30-s data segments throughout recovery from set 3. Energy metabolism responses were inferred via peak pulmonary oxygen uptake (peak), peak carbon dioxide output (peak), peak respiratory exchange ratio (RERpeak), first-order exponential regression of decay within 360 s of recovery and blood lactate concentration ([Lac-]). IPC did not change T30, but increased HRR60s after all sets (condition main effect: P = 0.03; partial eta square (η2p) = 0.27, i.e., large effect size). IPC did not change long-term HRR and RMSSD throughout recovery, nor did IPC change any energy metabolism parameter. In conclusion, IPC accelerated to some extent the short-term recovery, but did not change the long-term recovery of cardiac autonomic control from RSE, and such accelerator effect was not accompanied by any IPC effect on surrogates of energy metabolism responses to RSE.