Article

Bombax ceiba Linn. leaf extract rich in phenolic compounds to mitigate non-alcoholic fatty liver-related complications in experimental model

Authors:
  • national research center
To read the full-text of this research, you can request a copy directly from the authors.

Abstract

Objectives: Obesity, diabetes mellitus, insulin resistance (IR), and hypertriglyceridemia are common features observed in non-alcoholic fatty liver diseases (NAFLD). There is a critical medical necessity to find novel therapeutics that can halt the development of NAFLD. Methods: Bombax ceiba Linn. leaf extract was prepared and its phytochemical profile was determined. Standard and high carbohydrate high-fat diets (HCHF) were prepared. Rats were fed HCHF for 18 weeks to induce a non-alcoholic fatty liver (NAFL) model. Forty male rats were divided into control, B. ceiba Linn. leaf extract, NAFL, prophylactic, and treated groups. Serum fasting blood sugar (FBS), insulin, insulin resistance (HOMA-IR), cholesterol, high-density lipoprotein (HDL), triglycerides (TG), low density lipoprotein (LDL), alanine aminotransferase (ALT), aspartate aminotransferase (AST), intelectin-1 (ITLN1), p38 MAP kinase (MAPK), peroxisome proliferator-activated receptor alpha (PPAR-α), and interleukin-6 (IL-6) were evaluated. Results: Data obtained showed that HCHF-induced NAFL resulting in a significant increase in FBS, serum insulin, HOMA-IR, cholesterol, LDL, TG, ALT, AST, and IL-6 and a significant decrease in serum levels of HDL, ITLN1, p38 MAP kinase, and PPAR-α compared to the control group. The analysis of B. ceiba Linn. leaf extract showed high content of phenol compounds which may cause a significant decrease in the levels of FBS, insulin, HOMA-IR values, lipid profile, and levels of IL-6 while a significant increase in serum levels of LDL, ITLN1, p38 MAP kinase, and PPAR-α compared to the NAFL group. Conclusions: B. ceiba Linn. Leaf extract is a highly protective and promising therapeutic agent against inflammation and oxidative stress in the NAFLD model induced by HCHF.

No full-text available

Request Full-text Paper PDF

To read the full-text of this research,
you can request a copy directly from the authors.

... To reduce the adverse effects associated with present therapies and increase patient compliance, novel therapeutic techniques, such as the employing of all-natural compounds possessing anti-inflammatory qualities, must be developed [7][8][9]. ...
Article
Full-text available
Background It is necessary to develop advanced therapies utilizing natural ingredients with anti-inflammatory qualities in order to lessen the negative effects of chemotherapeutics. Results The bioactive N1-(5-methyl-5H-indolo[2,3-b]quinolin-11-yl)benzene-1,4-diamine hydrochloride (NIQBD) was synthesized. After that, soluble starch nanoparticles (StNPs) was used as a carrier for the synthesized NIQBD with different concentrations (50 mg, 100 mg, and 200 mg). The obtained StNPs loaded with different concentrations of NIQBD were coded as StNPs-1, StNPs-2, and StNPs-3. It was observed that, StNPs-1, StNPs-2, and StNPs-3 exhibited an average size of 246, 300, and 328 nm, respectively. Additionally, they also formed with homogeneity particles as depicted from polydispersity index values (PDI). The PDI values of StNPs-1, StNPs-2, and StNPs-3 are 0.298, 0.177, and 0.262, respectively. In vivo investigation of the potential properties of the different concentrations of StNPs loaded with NIQBD against MTX-induced inflammation in the lung and liver showed a statistically substantial increase in levels of reduced glutathione (GSH) accompanied by a significant decrease in levels of oxidants such as malondialdehyde (MDA), nitric oxide (NO), advanced oxidation protein product (AOPP), matrix metalloproteinase 9/Gelatinase B (MMP-9), and levels of inflammatory mediators including interleukin 1-beta (IL-1β), nuclear factor kappa-B (NF-κB) in both lung and liver tissues, and a significant decrease in levels of plasma homocysteine (Hcy) compared to the MTX-induced inflammation group. The highly significant results were obtained by treatment with a concentration of 200 mg/mL. Histopathological examination supported these results, where treatment showed minimal inflammatory infiltration and congestion in lung tissue, a mildly congested central vein, and mild activation of Kupffer cells in liver tissues. Conclusion Combining the treatment of MTX with natural antioxidant supplements may help reducing the associated oxidation and inflammation.
Article
Full-text available
Moringa oleifera (MO) known as the miracle tree is a famous nutritional source in many countries. In this study, the neuroprotective activity of MO seeds was investigated. Fractions of the 70% ethanol seed extract of MO were injected at a dose of 250 mg kg⁻¹ day⁻¹ to albino rats for 15 days, after-which induction of dementia was done using 100 mg/kg AlCl3 over 30 days. Results revealed that all fractions ameliorated the effects of AlCl3 where methylene chloride and ethyl acetate fractions, containing the major bioactive compound niazimicin (NZ), showed the best activities. Biological investigations proved NZ to be a highly potent neuroprotective drug lead as a first report, by causing a decrease in the levels of malondialdehyde, cholinesterase, nitric oxide (NO) and amyloid β by 47%, 34%, 53% and 59%, respectively, and increasing glutathione levels by 54%. Molecular docking studies suggested NZ neuroprotective effects to be mediated by inhibition of caspase-3 and inducible nitric oxide synthase enzymes. Practical applications The current findings present the neuroprotective effect of Moringa oleifera seeds consumed as a food supplement and in daily diet. In addition, niazimicin is a promising lead for the development of novel agents against Alzheimer’s disease as seen by the reported results.
Article
Full-text available
Our previous studies have shown that chlorogenic acid (CGA) could significantly improve acute and chronic liver injury through antioxidant and anti-inflammatory activities. However, its effect on non-alcoholic fatty liver disease (NAFLD) are not entirely clear. This study aims to explore the effect of CGA on NAFLD induced by high-fat diet (HFD) and whether it regulates the gut microbiota and Glucagon-like peptide-1 (GLP-1). NAFLD mice were established by HFD and treated with or without CGA. Serum transaminase, fasting blood glucose (FBG), blood lipids, insulin, GLP-1 and lipopolysaccharide (LPS) were detected. Liver histology was evaluated with Hematoxylin-eosin staining. Toll like receptor 4 (TLR4) signaling pathway was analyzed with western blot and inflammatory cytokines were detected with real-time PCR. The content of gut microbiota were determined with real-time PCR of the bacterial 16S rRNA gene. Expressions of intestine tight junctional protein were examined with immunohistochemistry. CGA could alleviate HFD-induced hepatic steatosis and inflammation, reduce serum transaminase, FBG and blood lipids, increase insulin sensitivity. CGA also could reverse HFD-induced activation of TLR4 signaling pathway and expression of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in liver. Meanwhile, CGA increased the content of Bifidobacterium and reduced the content of Escherichia coli in feces. Furthermore, CGA could increase the expression of tight junction proteins Occludin and zonula occludens-1 (ZO-1) in intestinal tissue. Moreover, CGA could the level of LPS and increased the level of GLP-1 in portal vein. These results indicated that CGA protected against HFD-induced hepatic steatosis and inflammation probably through its anti-inflammatory effects associated with regulation of gut microbiota and an increase of GLP-1 secretion and thus could be used as a potential drug for prevention and treatment of NAFLD.
Article
Full-text available
Alzheimer's disease (AD) is an irreversible neurodegenerative disorder manifested by cognitive deterioration where the available treatments failed to delay its progression. The objective of this study was to investigate the neuroprotective activity in an aluminum chloride (AlCl3)‐induced AD in vivo model and phytochemical profile of the traditional Egyptian herb Mentha longifolia (Ml). Male albino rats were injected with Ml fractions and essential oil for 15 days followed by AlCl3 for 30 days. Oxidative stress and neuroinflammatory markers were measured namely: malondialdehyde (MDA), reduced glutathione (GSH), nitric oxide (NO), and nuclear factor‐κB (NF‐κB). Furthermore, cholinesterase activity was tested and analysis of brain neurotransmitters using HPLC was performed. Results showed that methylene chloride and ethyl acetate fractions were able to reverse the AlCl3 mediated MDA increase, GSH decrease and exhibited anticholinesterase activity. EaFr reversed the increased levels of NF‐κB and NO. Ml fractions and oil counteracted the AlCl3 effect on brain neurotransmitters. Forty metabolites were tentatively characterized in the bioactive fractions using UPLC‐PDA‐ESI‐MS. 5,6,4′‐trihydroxy‐3′,7,8‐trimethoxy flavone was isolated from Ml as a first report, in addition to 5,6‐dihydroxy‐3′,4′,7,8‐tetramethoxy flavone and rosmarinic acid. These findings suggest that Ml is a promising nutraceutical and source of lead compounds halting AD progression. Practical applications The results presented in this paper unravels the neuroprotective effect of Mentha longifolia fractions and oil by acting as anti‐inflammatory, antioxidant agents, and regulating the levels of neurotransmitters. This provides basic knowledge for the development of Ml as a source of lead compounds and a promising food supplement protective against Alzheimer's disease.
Article
Full-text available
Nonalcoholic fatty liver disease (NAFLD) is one of the most common causes of chronic liver disease, sometimes ranges from simple steatosis to nonalcoholic steatohepatitis (NASH). Various hits including excessive hepatic steatosis, oxidative stress, apoptosis, and inflammation, contribute to NASH development. Gallic acid (GA), a natural polyphenol, was reported to exert a protective effect on hepatic steatosis in animal models, but the precise molecular mechanisms remain unclear. Here, we examined the effect of GA on hepatic lipid accumulation, apoptosis, and inflammatory response caused by hepatocyte–macrophage crosstalk. We demonstrated that GA attenuated palmitic acid (PA)-induced fat accumulation via the activation of AMP-activated protein kinase (AMPK) in HepG2 cells. GA also ameliorated cell viability and suppressed apoptosis-related gene expression and caspase 3/7 activity induced by PA and H2O2. In a co-culture of lipid-laden Hepa 1-6 hepatocytes and RAW 264 macrophages, GA reduced inflammatory mediator expression and induced antioxidant enzyme expression. These results indicate that GA suppresses hepatic lipid accumulation, apoptosis, and inflammation caused by the interaction between hepatocytes and macrophages. The potential effects of GA observed in our study could be effective in preventing NASH and its complications.
Article
Full-text available
Chronic excessive alcohol consumption could induce serious liver injury. In this study, therapeutic effect of aqueous methanol extract of Bombax ceiba L. flowers (BCE)(Family: Bombacaceae)was investigated against hepatic steatosis. This study included seven groups, and the research period was eight weeks. The first group served as control. The six remaining groups were divided into two categories, three groups in each. The first category was fed fat diet. The second category was fed fat diet and orally administrated ethanol, which was given in graduate doses from 2 g/kg/d to 6 g/kg/d. Then, one group from each category was orally treated with the standard drug fluvastatin (2 mg/Kg/d). Another group was orally treated with BCE (200 mg/kg/d). The third group left untreated. The results revealed that BCE significantly decrease both the body and liver weight. The treatment with BCE extract also ameliorates the effect of alcohol induced increase of liver enzyme activities. In addition, the extract was significantly increased hepatic liver antioxidants and decreased malondialdehyde (MDA)level. Also, serum lipid profiles: triglycerides (TG), total cholesterol (TC)and low density lipoprotein (LDL)were significantly decreased after BCE treatment. Histopathological study showed fatty changes induced by alcohol which were improved by BCE treatment. These data suggest that the BCE has anti-inflammatory, anti-oxidant and anti-steatosis potential properties against alcohol induced liver damage. This may be due to the presence of flavonoids and other phenol compounds.
Article
Full-text available
The liver is not only involved in metabolism and detoxification, but also participate in innate immune function and thus exposed to frequent target Thus, they are the frequent target of physical injury. Interestingly, liver has the unique ability to regenerate and completely recoup from most acute, non iterative situation. However, multiple conditions, including viral hepatitis, non alcoholic fatty liver disease, long term alcohol abuse and chronic use of medications can cause persistent injury in which regenerative capacity eventually becomes dysfunctional resulting in hepatic scaring and cirrhosis. Despite the recent therapeutic advances and significant development of modern medicine, hepatic diseases remain a health problem worldwide. Thus, the search for the new therapeutic agents to treat liver disease is still in demand. Many synthetic drugs have been demonstrated to be strong radical scavengers, but they are also carcinogenic and cause liver damage. Present day various hepatic problems are encountered with number of synthetic and plant based drugs. Nexavar (sorafenib) is a chemotherapeutic medication used to treat advanced renal cell carcinoma associated with several side effects. There are a few effective varieties of herbal preparation like Liv-52, silymarin and Stronger neomin phages (SNMC) against hepatic complications. Plants are the huge repository of bioactive secondary metabolites viz; phenol, flavonoid, alkaloid etc. In this review we will try to present exclusive study on phenolics with its mode of action mitigating liver associated complications. And also its future prospects as new drug lead.
Article
Full-text available
Metabolic syndrome (MetS) is defined as multiple risk factors including abdominal obesity, dyslipidaemia, abnormal glycae-mia, and elevated blood pressure. The incidence of MetS and pathophysiological mechanisms underlying its development are still not fully understood. It is thought that the occurrence of MetS arises from the complex relationship between genetic and environmental factors. The aim of the study was to overview and summarise current knowledge regarding genetic determinants of MetS. Also analysed were the relationship between polymorphisms of the genes encoding selected adipokines (vaspin, chemerin, omentin) and the risk of MetS, as well as other metabolic disorders. The precise determination of MetS genotype is difficult because metabolic syndrome occurrence is a combination of multiple risk factors. A thorough understanding of pathomechanisms of MetS, involving selected adipokines, may in the future allow the use of these adipokines as potential biomarkers of metabolic disorder risk. Streszczenie Zespół metaboliczny (MetS) definiowany jest jako nagromadzenie czynników ryzyka, takich jak otyłość brzuszna, dyslipi-demia, nieprawidłowa glikemia i podwyższone ciśnienie tętnicze. Przyczyny występowania MetS oraz mechanizmy patofi-zjologiczne leżące u podłoża jego rozwoju nadal nie zostały do końca poznane. Uważa się, że zespół ten wynika ze złożonej zależności pomiędzy czynnikami genetycznymi i środowiskowymi. Celem pracy był przegląd dotychczasowych badań nad genetycznymi uwarunkowaniami MetS oraz analiza powiązań między polimorfizmami genów kodujących wybrane adipo-kiny (waspinę, chemerynę, omentynę) a ryzykiem występowania MetS i innych chorób metabolicznych. Określenie geno-typu charakterystycznego dla MetS jest trudne ze względu na współwystępowanie wielu czynników ryzyka. Zrozumienie patomechanizmu powstawania MetS, w tym udziału wybranych adipokin, może w przyszłości pozwolić na opracowanie biomarkerów chorób metabolicznych.
Article
Full-text available
Over the last decade, the understanding of the association between insulin resistance (IR) and non-alcoholic fatty liver disease (NAFLD) has dramatically evolved. There is clear understanding that carriers of some common genetic variants, i.e., the patatin-like phospholipase domain-containing 3 (PNPLA3) or the transmembrane 6 superfamily member 2 (TM6SF2) are at risk of developing severe forms of NAFLD even in the presence of reduced or absent IR. In contrast, there are obese patients with "metabolic" (non-genetically driven) NAFLD who present severe IR. Owing to the epidemic obesity and the high prevalence of these genetic variants in the general population, the number of pediatric cases with combination of genetic and metabolic NAFLD is expected to be very high. Gut dysbiosis, excessive dietary intake of saturated fats/fructose-enriched foods and exposure to some chemicals contribute all to both IR and NAFLD, adding further complexity to the understanding of their relationship. Once NAFLD is established, IR can accelerate the progression to the more severe form of liver derangement that is the non-alcoholic steatohepatitis.
Article
Full-text available
Non-alcoholic fatty liver disease (NAFLD) encompasses the simple steatosis to more progressive steatosis with associated hepatitis, fibrosis, cirrhosis, and in some cases hepatocellular carcinoma. NAFLD is a growing epidemic, not only in the United States, but worldwide in part due to obesity and insulin resistance leading to liver accumulation of triglycerides and free fatty acids. Numerous risk factors for the development of NAFLD have been espoused with most having some form of metabolic derangement or insulin resistance at the core of its pathophysiology. NAFLD patients are at increased risk of liver-related as well as cardiovascular mortality, and NAFLD is rapidly becoming the leading indication for liver transplantation. Liver biopsy remains the gold standard for definitive diagnosis, but the development of noninvasive advanced imaging, biochemical and genetic tests will no doubt provide future clinicians with a great deal of information and opportunity for enhanced understanding of the pathogenesis and targeted treatment. As it currently stands several medications/ supplements are being used in the treatment of NAFLD; however, none seem to be the "magic bullet" in curtailing this growing problem yet. In this review we summarized the current knowledge of NAFLD epidemiology, risk factors, diagnosis, pathogenesis, pathologic changes, natural history, and treatment in order to aid in further understanding this disease and better managing NAFLD patients.
Article
Full-text available
Bombax ceiba Linn belongs to the family of Bombacaceae and is an important medicinal plant. In Bangladesh, Bombax ceiba Linn is locally known as “Shimul tree”. The whole part of the plant used as traditional folk medicine for the treatment of antidysentric, anti diahorreal and antipyretic effects. The present communication attempts to evaluate fatty acid analysis by GC-MS spectrophotometer, total protein content by Kjeldahl method and to quantify some active constituents i.e. alkaloid, saponin and flavonoid. The fatty acid compositions of the petroleum ether extract of leaves and seeds of Bombax ceiba grown in Bangaladesh were determined by gas chromatography- mass spectrophotometer. 8 compounds were identified from leaves and 13 compounds were identified from the seeds. For both cases Palmitic acid showed higher value. The findings from present study showed the protein content for seeds have higher value (18.89%) than leaves of Bombax ceiba . The present investigation showed that both leaves and seeds of Bombax ceiba contain phytochemicals such as flavanoids, alakaloids and saponins in appreciable quantities. The flavonoid content of leaves was 5.97% and for the case of seeds (5.72%), the alkaloid content for leaves was (9.73%) and for seeds (31.44), the saponin content for the case of leaves (13.90%) and for the case of seeds was (43.58%).
Article
Full-text available
Nonalcoholic fatty liver disease (NAFLD) is an obesity-associated disease and dysregulation of adipokines has an important role in its development. Omentin-1 (ITLN1 protein) and resistin are two adipokine secreted from adipose tissue. Single nucleotide polymorphisms in the adipokine genes may affect expression and activity of the adipokine, and thus play a contributory role in NAFLD pathogenesis. The aim of the present study was to investigate the association between omentin-1 rs2274907 (326A/T) and resistin rs1862513 (-420 C/G) polymorphisms and risk of NAFLD in Iranian patients. This case-control study was done on 282 subjects included 94 patients with NAFLD and 188 healthy peoples. The genotypes were determined using PCR-RFLP method. The frequency of omentin-1 AT genotype in patients with NAFLD was significantly different from that in the control (OR=2.3, 95% CI: 1.3-3.8, P=0.003). A significant association was observed between NAFLD and the GG genotype regarding resistin rs1862513 polymorphism (OR=2.3, 95% CI: 1.1-4.8, P=0.03). In conclusion, Omentin-1 rs2274907 and resistin rs1862513 polymorphisms might be a candidate genetic factor for susceptibility to NAFLD.
Article
Full-text available
Aim: The flowers of Bombax ceiba are traditionally used as home remedy in the treatment of jaundice and spleen enlargement. The present work investigated the effect of aqueous extract of flowers of Bombax ceiba (BCAE) on experimentally induced hepatotoxicity in rats to substantiate its traditional use as hepatoprotective agent. Methods: Hepatotoxicity was induced in rats by carbon tetrachloride (CCl4) treatment; at the same time vehicle or BCAE (250 or 500 mg/kg) or silymarin (25 mg/kg) were administered daily orally for seven days. Hepatotoxicity was assessed by estimating the activities of marker enzymes and by histological studies. The antioxidant effect of BCAE was assessed by measuring amount of antioxidant phytochemicals (total phenolics and flavonoids), and DPPH free radical scavenging assay of the extract. Results: BCAE treatment significantly prevented the CCl4-induced elevations in levels of glutamate oxaloacatate transaminase, glutamic pyruvic transaminase, alkaline phosphatase, bilirubin, and triglycerides, and decreased the total protein levels. Treatment with BCAE attenuated the CCl4-induced cytotoxic damage to liver. BCAE exhibited presence of antioxidant phytochemicals and showed scavanging action on DPPH radicals. The hepatoprotective effect of BCAE was comparable to that of the standard antioxidant hepatoprotective agent, silymarin. These findings indicated that BCAE showed hepatoprotective effect against CCl4-induced hepatotoxicity and exhibited in vitro antioxidant effects. Conclusion: Bombax ceiba flowers exhibited hepatoprotective effect which may be attributed to antioxidant potential. This study also validated their traditional medicinal use in liver disorders.
Article
Full-text available
Bombax ceiba Linn., commonly called as Semal, is used in various gastro-intestinal disturbances. It contains Lupeol which inhibits PTP-1B, adipogenesis, TG synthesis and accumulation of lipids in adipocytes and adipokines whereas the flavonoids isolated from B.ceiba has FAS inhibitory activity. The present study was aimed to investigate ameliorative potential of Bombax ceiba to experimental obesity in Wistar rats, and its possible mechanism of action. Male Wistar albino rats weighing 180-220 g were employed in present study. Experimental obesity was induced by feeding high fat diet for 10 weeks. Methanolic extract of B.ceiba extract 100, 200 and 400 mg/kg and Gemfibrozil 50 mg/kg as standard drug were given orally from 7th to 10th week. Induction with HFD for 10 weeks caused significant (p < 0.05) increase in% body wt, BMI, LEE indices; serum glucose, triglyceride, LDL, VLDL, cholesterol, free fatty acid, ALT, AST; tissue TBARS, nitrate/nitrite levels; different fat pads and relative liver weight; and significant decrease in food intake (g and kcal), serum HDL and tissue glutathione levels in HFD control rats. Treatment with B.ceiba extract and Gemfibrozil significantly attenuated these HFD induced changes, as compared to HFD control. The effect of B.ceiba 200 and 400 mg/kg was more pronounced in comparison to Gemfibrozil. On the basis of results obtained, it may be concluded that the methanolic extract of stem bark of Bombax ceiba has significant ameliorative potential against HFD induced obesity in rats, possibly through modulation of FAS and PTP-1B signaling due to the presence of flavonoids and lupeol.
Article
Full-text available
Prolonged deprivation of food induces dramatic changes in mammalian metabolism, including the release of large amounts of fatty acids from the adipose tissue, followed by their oxidation in the liver. The nuclear receptor known as peroxisome proliferator-activated receptor α (PPARα) was found to play a role in regulating mitochondrial and peroxisomal fatty acid oxidation, suggesting that PPARα may be involved in the transcriptional response to fasting. To investigate this possibility, PPARα-null mice were subjected to a high fat diet or to fasting, and their responses were compared with those of wild- type mice. PPARα-null mice chronically fed a high fat diet showed a massive accumulation of lipid in their livers. A similar phenotype was noted in PPARα-null mice fasted for 24 hours, who also displayed severe hypoglycemia, hypoketonemia, hypothermia, and elevated plasma free fatty acid levels, indicat- ing a dramatic inhibition of fatty acid uptake and oxidation. It is shown that to accommodate the increased requirement for hepatic fatty acid oxidation, PPARα mRNA is induced during fasting in wild- type mice. The data indicate that PPARα plays a pivotal role in the management of energy stores during fasting. By modulating gene expression, PPARα stimulates hepatic fatty acid oxidation to supply sub- strates that can be metabolized by other tissues.
Article
Full-text available
Interleukin-6 (IL-6) is a pleiotropic cytokine which is expressed in many inflammatory cells in response to different types of stimuli, regulating a number of biological processes. The IL-6 gene is polymorphic in both the 5' and 3' flanking regions and more than 150 single nucleotide polymorphisms have been identified so far. Genetic polymorphisms of IL-6 may affect the outcomes of several diseases, where the presence of high levels of circulating IL-6 have been correlated to the stage and/or the progression of the disease itself. The -174 G/C polymorphism is a frequent polymorphism, that is located in the upstream regulatory region of the IL-6 gene and affects IL-6 production. However, the data in the literature on the genetic association between the -174 G/C polymorphism and some specific liver diseases characterized by different etiologies are still controversial. In particular, most of the studies are quite unanimous in describing a correlation between the presence of the high-producer genotype and a worse evolution of the chronic liver disease. This is valid for patients with hepatitis C virus (HCV)-related chronic hepatitis and liver cirrhosis and hepatocellular carcinoma (HCC) whatever the etiology. Studies in hepatitis B virus-related chronic liver diseases are not conclusive, while specific populations like non alcoholic fatty liver disease/non-alcoholic steatohepatitis, autoimmune and human immunodeficiency virus/HCV co-infected patients show a higher prevalence of the low-producer genotype, probably due to the complexity of these clinical pictures. In this direction, a systematic revision of these data should shed more light on the role of this polymorphism in chronic liver diseases and HCC.
Article
Full-text available
Omentin is an adipocytokine that is abundantly expressed in visceral fat tissue. We investigated the association of omentin with the number of metabolic risk factors. The study population comprised 201 Japanese men who underwent annual health checkups. Plasma omentin levels were determined by enzyme-linked immunosorbent assay. We divided the subjects into 4 groups according to omentin levels. A reduction of plasma omentin levels significantly correlated with an increase in the mean number of metabolic risk factors such as increased waist circumference, dyslipidemia, high blood pressure and glucose intolerance. Circulating omentin levels negatively correlated with the multiplicity of metabolic risk factors, suggesting that omentin acts as a biomarker of metabolic disorders.
Article
Full-text available
Dual-specificity MAP kinase phosphatases (MKPs) provide a complex negative regulatory network that acts to shape the duration, magnitude and spatiotemporal profile of MAP kinase activities in response to both physiological and pathological stimuli. Individual MKPs may exhibit either exquisite specificity towards a single mitogen-activated protein kinase (MAPK) isoform or be able to regulate multiple MAPK pathways in a single cell or tissue. They can act as negative feedback regulators of MAPK activity, but can also provide mechanisms of crosstalk between distinct MAPK pathways and between MAPK signalling and other intracellular signalling modules. In this review, we explore the current state of knowledge with respect to the regulation of MKP expression levels and activities, the mechanisms by which individual MKPs recognize and interact with different MAPK isoforms and their role in the spatiotemporal regulation of MAPK signalling.
Article
Full-text available
The worldwide prevalence of obesity and related metabolic disorders is rising rapidly, increasing the burden on our healthcare system. Obesity is often accompanied by excess fat storage in tissues other than adipose tissue, including liver and skeletal muscle, which may lead to local insulin resistance and may stimulate inflammation, as in steatohepatitis. In addition, obesity changes the morphology and composition of adipose tissue, leading to changes in protein production and secretion. Some of these secreted proteins, including several proinflammatory mediators, may be produced by macrophages resident in the adipose tissue. The changes in inflammatory status of adipose tissue and liver with obesity feed a growing recognition that obesity represents a state of chronic low-level inflammation. Various molecular mechanisms have been implicated in obesity-induced inflammation, some of which are modulated by the peroxisome proliferator-activated receptors (PPARs). PPARs are ligand-activated transcription factors involved in the regulation of numerous biological processes, including lipid and glucose metabolism, and overall energy homeostasis. Importantly, PPARs also modulate the inflammatory response, which makes them an interesting therapeutic target to mitigate obesity-induced inflammation and its consequences. This review will address the role of PPARs in obesity-induced inflammation specifically in adipose tissue, liver, and the vascular wall.
Article
Full-text available
Nonalcoholic fatty liver disease (NAFLD) has become increasingly recognized as the most common cause of abnormal liver enzymes in the last few decades and is among the most common forms of chronic liver disease in the Western world and across the globe. With the growing epidemic of obesity and diabetes, NAFLD is estimated to affect about one-quarter of the US population. Although most patients with NAFLD have nonprogressive bland steatosis, a minority of patients develop the histological subtype of nonalcoholic steatohepatitis (NASH), which may progress to cirrhosis, hepatocellular carcinoma, and liver-related death. This is especially true when NASH patients have type 2 diabetes. Treatment of NAFLD should therefore be directed towards patients with established NASH. Sustained weight loss seems to improve insulin resistance and associated NASH. In fact, weight loss with bariatric surgery leads to biochemical and histological improvement in morbidly obese patients with NASH. Several pharmacologic agents have been studied in an effort to improve insulin resistance and pro-inflammatory mediators potentially responsible for the development and progression of NASH. While some studies have shown initial promise, none has established long-term efficacy using randomized clinical trials. This paper briefly reviews the epidemiology, natural history, and pathophysiology of NAFLD and NASH and then focuses on the clinical trials of various therapeutic modalities for NAFLD. These include weight loss agents, bariatric surgery, insulin-sensitizing agents, lipid-lowering agents, antioxidants, probiotics, anti-tumor necrosis factor agents, cytoprotective and other novel agents.
Article
Full-text available
Some studies have pointed to a role of TNF-alpha in pathogenesis of non alcoholic fatty liver disease (NAFLD). The aim of our study was to investigate the influence of G308A polymorphism TNF alpha gene on the histological changes, insulin resistance and TNF-alpha levels in overweight patients. A population of 66 patients with NAFLD was recruited in a cross sectional study. A biochemical analysis of serum was measured. Genotype of TNF alpha gene G308A was studied. Fifteen patients (22.7%) had the genotype G308A (mutant type group) and 51 patients (77.3%) G308G (wild type group). Patients with mutant type group presented more moderate-severe portal inflammation (86.7%) in liver biopsy compared to patient with wild genotype (19.7%). Mutant type group had more moderate-severe fibrosis (73.3%) than wild type group (51.3%). The multivariate analysis adjusted by age, sex, BMI and genotype with the dependent variable (fibrosis) showed that HOMA remained in the model, with an increase of the probability to develop fibrosis of 1.78 (CI95%:1.06-3.2) and develop moderate-severe inflammation of 1.45 (CI95%:1.02-2.1) with each increase of one unit on HOMA levels. In conclusion, Patients with mutant genotype have more frequently moderate-severe portal inflammation and fibrosis than wild type genotype.
Article
Full-text available
The mitogen-activated protein (MAP) kinase phosphatase (MKP) family plays an important function in regulating the pro-inflammatory cytokines by deactivating MAP kinases. MKP-1 is essential for the dephosphorylation of p38 MAP kinase that regulates expression of IL-6, TNF-alpha, and IL-1 beta. We hypothesized that MKP-1 regulates inflammatory bone loss in experimental periodontitis. Wild-type and Mkp-1(-/-) mice received A. actinomycetemcomitans LPS injection in the palatal region or PBS control 3 times/wk for 30 days. Mice were killed, and maxillae were assessed by microcomputed tomography, histological analysis, and TRAP staining for measurement of bone loss, extent of inflammation, and degree of osteoclastogenesis. Results indicated that, in LPS-injected Mkp-1(-/-) mice, significantly greater bone loss occurred with more inflammatory infiltrate and a significant increase in osteoclastogenesis compared with Mkp-1(-/-) control sites or either wild-type group. Analysis of these data indicates that MKP-1 plays a key role in the regulation of inflammatory bone loss.
Article
Full-text available
The p38(MAPK) protein kinases affect a variety of intracellular responses, with well-recognized roles in inflammation, cell-cycle regulation, cell death, development, differentiation, senescence and tumorigenesis. In this review, we examine the regulatory and effector components of this pathway, focusing on their emerging roles in biological processes involved in different pathologies. We summarize how this pathway has been exploited for the development of therapeutics and discuss the potential obstacles of targeting this promiscuous protein kinase pathway for the treatment of different diseases. Furthermore, we discuss how the p38(MAPK) pathway might be best exploited for the development of more effective therapeutics with minimal side effects in a range of specific disease settings.
Article
Caffeic acid (CA) is derived from many plants and may have the ability to reduce hepatic lipid accumulation. The gut microbiota produces lipopolysaccharides and further influences hepatic lipid metabolism, and thus plays an important role in the development of nonalcoholic fatty liver disease (NAFLD). However, whether the beneficial effects of CA are associated with the gut microbiota remains unclear. The present study aimed to investigate the benefits of experimental treatment with CA on the gut microbiota and metabolic functions in a mouse model of NAFLD. In this study, C57BL/6J mice received a high-fat diet (HFD) for 8 weeks and were then fed a HFD supplemented with or without CA for another 8 weeks. HFD induced obesity and increased accumulation of intrahepatic lipids, serum biochemical parameters and gene expression related to lipid metabolism. Microbiota composition was determined via 16S rRNA sequencing, and analysis revealed that HFD led to dysbiosis, accompanied by endotoxemia and low-grade inflammation. CA reverted the imbalance in the gut microbiota and related lipopolysaccharide-mediated inflammation, thus inhibiting deregulation of lipid metabolism-related gene expression. Our results support the possibility that CA can be used as a therapeutic approach for obesity-associated NAFLD via its anti-inflammatory and prebiotic integrative response.
Article
Objective To evaluate the influence of irisin on the experimental paradigm of non-alcoholic fatty liver (NAFL) as a part of MetS cluster. Methods Forty male albino rats were divided into four groups; normal control, standard diet + irisin, high carbohydrate and fat diet (HCHF), and HCHF + irisin. After the experimental period, levels of fasting blood sugar (FBS), insulin, lipid profile, kidney functions, salusin-alpha (Sal-α), adropin, and retinol-binding protein-4 (RBP-4) were evaluated. Peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1α) expression in skeletal muscle was evaluated by quantitative real-time PCR. Aorta, liver, pancreas, and skeletal muscle tissue samples were prepared for histopathological examination. Results Rats administrated HCHF showed elevated levels of FBS, lipid profile, kidney functions, RBP-4, and upregulation of PGC-1α expression along with a decline in levels of insulin, Sal-α, and adropin while administration of irisin significantly attenuated these levels. Conclusions Irisin as based therapy could emerge as a new line of treatment against MetS and its related diseases.
Article
Background and Objective: Yogurt is a distinctive vesicle for active compounds and the widest-spread fermented dairy product. This study aimed to explore the ameliorative role of emulsified yogurt fortified with Ashwagandha Ethanolic Extract (AEE) and probiotic bacteria against Aluminium Chloride (AlCl3)-induced toxicity in rats. Materials and Methods: Yogurt was evaluated chemically, microbiologically and sensory as well as biologically using experimental animals. Results: Results revealed that fortified yogurt with either AEE, probiotics, or their mixture did not disturb the main chemical composition of yogurt. Yogurt antioxidants and phenolic content increased by adding AEE, alone or in the presence of probiotics; however, it decreased after 15 days of storage but remained higher in the mixture-treated yogurt. Furthermore, all the physicochemical and sensory properties were significantly improved with the addition of AEE, separately or combined with probiotics bacteria. The biological study showed oral administration of rats with the emulsions of yogurt fortified with AEE and probiotic bacteria, alone or in combination, together with Aluminium chloride succeeded to decline AlCl3induced toxicities; this was evidenced by the significant reduction in serum tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL1β), alanine aminotransferase (ALAT), aspartate aminotransferase (ASAT), urea, creatinine, cholesterol, triglycerides and low dense lipoproteincholesterol (LDL-c) values. Also, reduced glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT) were markedly increased in liver, kidney and brain tissues coupled with a sharp reduction in the malondialdehyde (MDA) and nitric oxide (NO). The neurochemical markers, dopamine, serotonin and acetylcholinesterase (ACh-ase) were also favorably improved. Conclusion: It could conclude that AEE and probiotics succeeded to improve physicochemical, microbiological, sensory qualities as well as health benefits as they restored AlCl3induced hepato-renal-neuro deteriorations; they are promising-supplement for the protection against toxicities.
Article
The therapeutic potential of green tea as a rich source of antioxidants and anti‐inflammatory compounds has been investigated by several studies. The present study aimed to systematically review and analyze randomized clinical trials (RCTs) assessing the effects of green tea, catechin, and other forms of green tea supplementation on levels of liver enzymes. PubMed, SCOPUS, EMBASE, and Cochrane databases were searched until February 2019. All RCTs investigating the effect of green tea or its catechin on liver enzymes including alanine transaminase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and bilirubin were included. A total of 15 RCTs were included. The overall effect of green tea on liver enzymes was nonsignificant (ALT [Standardized mean difference (SMD)= −0.17, CI −0.42 to 0.08, p = .19], AST [SMD = −0.07, CI −0.43 to 0.29, p = .69], and ALP [SMD = −0.17, CI −0.45 to 0.1, p = .22]). However, subgroup analyses showed that green tea reduced the levels of liver enzymes in participants with nonalcoholic fatty liver disease (NAFLD) but in healthy subjects, a small significant increase in liver enzymes was observed. In conclusion, the results of this study suggest that the effect of green tea on liver enzymes is dependent on the health status of individuals. While a moderate reducing effect was observed in patients with NAFLD, in healthy subjects, a small increasing effect was found.
Article
Ethnopharmacological relevance: various extracts of Moringa oleifera Lam. leaves, were reported to possess antiobesity effect in experimental animals models, yet its active doses and mechanism of action are still unclear. Materials and methods: The metabolic profiling of 70% ethanol extract of M. oleifera (MO) leaves was performed using HPLC-MS/MS analysis. The antiobesity activity of MO was tested in high fat diet induced obesity in rats at 200 and 400 mg/kg body weight orally for 1 month. Total cholesterol (TC), high density lipoproteins (HDL-C), low density lipoprotein-cholesterol (LDL-C), triglycerides (TGs), insulin resistance, insulin sensitivity, and adipose tissue index were monitored. In addition, fatty acid synthase (FAS) and HMG-CoA reductase mRNA from liver tissue, Peroxisome Proliferator-Activated Receptor alpha (PPARα) and Melanocortin-4 receptor (MC4R) RNA from adipose tissue were quantified using qRT-PCR. MO hard gelatin capsules (400 mg/capsule) were formulated and standardized using HPLC-RP analysis and tested on fifteen female participants, aged 45-55 with a BMI of 29-34 kg/m2. Results: Thirteen metabolites were tentatively identified using HPLC-MS/MS analysis including flavonols, flavones and a phenolic acid. MO 400 showed a prominent effect on reducing the rats' final weights, % weight increase and adiposity index (P < 0.05). Glucose, insulin and HOMA-IR were significantly reduced and R-QUICKI was significantly increased by MO 400 (P < 0.001). Mean tissue level of leptin and vaspin were significantly reduced, adiponectin, omentin and GLUT-4 expression were increased significantly by MO 400 (P < 0.01). MO 400 significantly suppressed FAS and HMG-CoA reductase and increased mRNA expression of MC4R and PPAR-α (P < 0.01). Eight weeks administration of MO hard gelatin capsules to obese patients showed significant reduction of the average BMI, TC and LDL compared to the baseline values (p < 0.05). Conclusion: Our results presented a scientific evidence for the traditional use of M. oleifera leaves as antiobesity herbal medicine.
Article
Previous studies in humans have indicated that de novo lipogenesis contributes considerably to redundant lipid storage and steatosis in the liver of patients with nonalcoholic fatty liver disease (NAFLD), and...
Article
The mitogen-activated protein kinases (MAPKs) participate in a multitude of processes that control hepatic metabolism. The liver regulates glucose and lipid metabolism, and under pathophysiological conditions such as obesity, type 2 diabetes mellitus (T2DM), and non-alcoholic fatty liver disease (NAFLD) these processes become dysfunctional. Stress responses activate the hepatic MAPKs, and this is thought to impair insulin action and lipid metabolism. The MAPKs also activate the MAPK phosphatases (MKPs) which oppose their actions. How the MAPK/MKP balance is controlled in liver metabolism and how perturbations in these activities contribute to metabolic disease remains unclear. Discussion of recent insights into the MAPK/MKP signaling role in hepatic metabolic function and disease will be the focus of this review.
Article
NAFLD is closely linked with hepatic insulin resistance. Accumulation of hepatic diacylglycerol activates PKC-ε, impairing insulin receptor activation and insulin-stimulated glycogen synthesis. Peripheral insulin resistance indirectly influences hepatic glucose and lipid metabolism by increasing flux of substrates that promote lipogenesis (glucose and fatty acids) and gluconeogenesis (glycerol and fatty acid-derived acetyl-CoA, an allosteric activator of pyruvate carboxylase). Weight loss with diet or bariatric surgery effectively treats NAFLD, but drugs specifically approved for NAFLD are not available. Some new pharmacological strategies act broadly to alter energy balance or influence pathways that contribute to NAFLD (e.g., agonists for PPAR γ, PPAR α/δ, FXR and analogs for FGF-21, and GLP-1). Others specifically inhibit key enzymes involved in lipid synthesis (e.g., mitochondrial pyruvate carrier, acetyl-CoA carboxylase, stearoyl-CoA desaturase, and monoacyl- and diacyl-glycerol transferases). Finally, a novel class of liver-targeted mitochondrial uncoupling agents increases hepatocellular energy expenditure, reversing the metabolic and hepatic complications of NAFLD.
Article
Nonalcoholic fatty liver disease (NAFLD) encompasses a range of liver pathology ranging from simple steatosis to varying degrees of inflammation, hepatocyte injury and fibrosis. Without intervention it can progress to end-stage liver disease and hepatocellular carcinoma. Given its close association with obesity, the prevalence of NAFLD has increased dramatically worldwide. Currently, there are no FDA-approved medications for the treatment of NAFLD and although lifestyle modifications with appropriate diet and exercise have been shown to be beneficial, this has been difficult to achieve and sustain for the majority of patients. As such, the search for effective therapeutic agents is an active area of research. Peroxisome proliferator-activated receptors (PPARs) belong to a class of nuclear receptors. Because of their key role in the transcriptional regulation of glucose and lipid metabolism, PPAR ligands have been investigated as possible therapeutic agents for NAFLD. Here we review the current evidence from preclinical and clinical studies investigating the therapeutic potential of PPAR ligands for the treatment of this spectrum of liver disorders.
Article
Nonalcoholic fatty liver disease (NAFLD) has a wide spectrum of liver damage with a worldwide prevalence of almost 20%. AMP-activated protein kinase α1 (AMPKα1) is an energy sensor that plays a key role in regulating lipid metabolism of the liver. This study explores the role of AMPKα1 overexpression in a steatotic hepatocyte model. The results displayed that the AMPKα1 overexpression suppressed lipid accumulation in the cytoplasm, decreased triglyceride levels, maintained the survival of steatotic hepatocyte model with decreased cell apoptosis and increased survival rate. Besides, AMPKα1 overexpression promoted the expression of lipid catabolism-related genes, reduced the level of anabolism-related genes, alleviated the inflammatory response by reducing pro-inflammatory cytokines and increasing anti-inflammatory cytokines. Moreover, AMPKα1 overexpression could inhibit the activation of p38 mitogen-activated protein kinase (p38MAPK). Finally, Anisomycin, a frequently-used activator of p38MAPK, reversed the inhibitory effect of pc-AMPKα1 on the expression of p-p38MAPK, suggesting that AMPKα1 overexpression alleviates inflammatory response through the inactivation of p38MAPK. These results indicated that AMPKα1 may serve as a novel target for treatment of NAFLD.
Article
Obesity is a new global pandemic, with growing incidence and prevalence. This disease is associated with increased risk of several pathologies, including diabetes, cardiovascular diseases, and cancer. The mechanisms underlying obesity-associated metabolic changes are the focus of efforts to identify new therapies. Stress-activated protein kinases (SAPK), including cJun N-terminal kinases (JNKs) and p38, are required for cellular responses to metabolic stress and therefore might contribute to the pathogenesis of obesity. Tissue-specific knockout models support a cell-type-specific role for JNK isoforms, in particular JNK1, highlighting its importance in cell homeostasis and organ crosstalk. However, more efforts are needed to elucidate the specific roles of other JNK isoforms and p38 family members in metabolism and obesity. This review provides an overview of the role of SAPKs in the regulation of metabolism.
Article
Type 2 diabetes currently affects more than a third of a billion people worldwide and is the leading cause of end-stage renal disease, nontraumatic loss of limb, and blindness in working adults, with estimated annual worldwide health care costs exceeding half a trillion dollars. 1 Furthermore, the worldwide prevalence of type 2 diabetes is projected to increase by more than 75% during the next two decades, with the largest increases occurring in Asia and the Indian subcontinent. 1 Although impaired beta-cell function is ultimately responsible for the progression from normoglycemia to hyperglycemia, insulin resistance predates beta-cell dysfunction and plays a major role in the pathogenesis of type 2 diabetes. 2,3 After carbohydrate ingestion, glucose is deposited primarily in muscle and the liver as glycogen, and alterations in insulin responsiveness in these organs result in fasting and postprandial hyperglycemia. 4,5.
Article
Most clinical laboratories directly measure serum triglyceride, total cholesterol, and high- density lipoprotein cholesterol. They indirectly calculate low-density lipoprotein cholesterol value using the Friedewald equation. Although high serum triglyceride (>400 mg/dL or 4.52 mmol/L) devaluates low-density lipoprotein cholesterol calculation by using this formula, effects of low serum triglyceride (<100 mg/dL or 1.13 mmol/L) on its accuracy is less defined.Two hundred thirty serum samples were assayed during a one-year period. In 115 samples, the triglyceride level was below 100 mg/dL and in 115 samples from age- and sex-matched patients the triglyceride level was 150 - 350 mg/dL (1.69 - 3.95 mmol/L). In both groups total cholesterol was above 250 mg/dL (6.46 mmol/L). On each sample, total cholesterol, high-density lipoprotein cholesterol, and triglyceride were directly measured in duplicate and low-density lipoprotein cholesterol measured directly and calculated with Friedewald equation as well. Statistical analysis showed that when triglyceride is <100 mg/dL, calculated low- density lipoprotein cholesterol is significantly overestimated (average :12.17 mg/dL or 0.31 mmol/L), where as when triglyceride is between 150 and 300 mg/dL no significant difference between calculated and measured low-density lipoprotein cholesterol is observed. In patients with low serum triglyceride and undesirably high total cholesterol levels, Friedewald equation may overestimate low-density lipoprotein cholesterol concentration and it should be either directly assayed or be calculated by a modified Friedewald equation. Using linear regression modeling, we propose a modified equation.
Article
The adiponectin polymorphism has been implicated in susceptibility to non-alcoholic fatty liver disease (NAFLD), but the results remain inconclusive. The aim of this meta-analysis is to investigate the association between adiponectin polymorphisms and NAFLD risk. All eligible case-control studies published up to September 2013 were identified by searching PubMed, Web of Science and CNKI. Effect sizes of odds ratio (OR) and 95% confidence interval (95% CI) were calculated by using a fixed- or random-effect model. A total of ten case-control studies were included, of those, there were nine studies (1223 cases and 1580 controls) for +45T>G polymorphism, seven studies (876 cases and 989 controls) for +276G>T polymorphism and three studies (299 cases and 383 controls) for -11337C>G polymorphism. Overall, a significantly increased risk was found for +45T>G and -11377C>G polymorphism (+45T>G: OR=1.45, 95%CI: 1.06-2.00 for recessive model, OR=1.48, 95%CI: 1.07-2.06 for GG vs TT; -11377C>G: OR=1.52, 95%CI: 1.10-2.09 for dominant model, OR=3.88, 95%CI: 1.29-11.68 for GG vs CC), while for +276G>T polymorphism, we found a significantly decreased risk between them (OR=0.65, 95%CI: 0.45-0.94 for recessive model, OR=0.58, 95%CI: 0.40-0.84 for TT vs GG). In subgroup analysis by ethnicity, significant association was detected among Asians for +276G>T polymorphism, but not for +45T>G polymorphism. Besides, none of the three adiponectin polymorphisms was associated with the serum adiponectin levels. This meta-analysis suggests that adiponectin +45T>G and -11377C>G polymorphisms might be a risk factor for NAFLD, while +276G>T polymorphism may be a protective factor for NAFLD among Asians.
Article
The definition of nonalcoholic fatty liver disease has evolved in recent years. Today, it is considered a nonspecific term encompassing several clinicopathologic entities (steatosis alone, steatonecrosis, steatohepatitis and histologic alcoholiclike hepatitis) that are similar to alcoholic liver disease. Studies of nonalcoholic fatty liver disease have come to conflicting conclusions about the course of the disease. It can be argued that the disparate results are largely the result of nonuniform definitions. When histologic features such as hepatocyte ballooning, necrosis, and Mallory hyaline are seen, nonalcoholic fatty liver disease has been shown to be associated with an aggressive outcome. Steatosis alone, in contrast, appears to be benign. The current understanding of nonalcoholic fatty liver disease, the limited treatments available, and two theories of the pathogenesis of the disease are also reviewed here.
Article
Fatty acid synthase (FAS) had been found overexpress and hyperactive in most cancers. Pharmacological inhibitors of FAS activity preferentially repress cancer cell proliferation and induce cancer cell apoptosis without affecting nonmalignant fibroblasts. These made FAS an excellent drug target for cancer therapy. The activity of FAS in 11 different kinds of cancer cells, including esophageal carcinoma (EC109, EC8712, H5E973), gastric carcinoma (N87, BGC823), lung carcinoma (A549, 95-D), hepatoma (HepG2), uterine cervix cancer (HeLa) and leukaemia (K562, U937) were compared using spectrophotometric method. We selected the cell line with the highest FAS activity as cell model to study the inhibitory effect of the flavonoids extracts on FAS. Four plants including Canavium album Raeuseh leaves, Bombax ceiba Linn, Brassica albograbra Bailey, and Citrus reticulata Blanco were selected for extracting flavonoids. The results showed significantly different FAS activity among different cancer cells. The FAS activity is the lowest in gastric cancer cell N87 (15.91 ± 3.61 U/mg protein) and the highest in lung cancer cell A549 (127.36 ± 10.14 U/mg protein). The cancer cell A549 was used as cell model to test the inhibitory effort of flavonoids extracts on FAS. Results showed that the flavonoids extracts of Citrus reticulata Blanco and Canavium album Raeuseh leaves have higher inhibitory effect on FAS activity compared with the universally used FAS inhibitor C75 and both extracts inhibit cancer cell proliferation when added to cultured cancer cells. These studies provided a good cell model for testing the inhibitory effect on FAS activity and suggested that Citrus reticulata Blanco rind and Canavium album Raeuseh leaves are good biomaterials for separating and purifying natural flavonoids FAS inhibitors and exploring their inhibitory mechanisms.
Article
Received: 26-Apr-2011; Revised: 29-May-2011; Accepted: 28-Jun-2010; Online first: 28-Aug-2011 Copyright: © 2011 Hussein J. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Abstract Background: Diabetes mellitus is a metabolic disease characterized by chronic hyperglycemia resulting from defects in insulin secretion, almost always with a major contribution from insulin resistance which may be affected by cell membrane fatty acids and phospholipids fractions.
Article
Non-alcoholic fatty liver disease (NAFLD) is the most common liver pathology characterized by fat accumulation in a context of metabolic syndrome or insulin resistance. It can be associated with obesity, diabetes, hyperinsulinemia, dyslipidemia as well as hypertension. NAFLD consists of a large spectrum of hepatic lesions including benign steatosis, non-alcoholic steatohepatitis (NASH), cirrhosis or hepatocellular carcinoma. Upon chronic stress, NASH would occur via at least "two-hits" process involving modulation of a high number of genes and proteins. Firstly, the accumulation of fat, either due to the increased inflow of free fatty acids or de novo lipogenesis, leads to steatosis. Secondly, when adaptive mechanisms for stress tolerance are overwhelmed, lipotoxicity and chronic inflammation trigger major hepatic damages, mainly via oxidative and inflammatory stress, lipid peroxidation and cell death. As a consequence, all these processes concur to favor steatohepatitis, fibrosis and cancer. Recently, the elucidation of physiopathological signaling cascades controlling NAFLD and NASH benefited from large-scale studies, namely the omics, such as transcriptomics, genomics, proteomics, and lipidomics. The advent of lipidomics would allow shedding light upon the respective roles of triglyceride and fatty acid metabolites in the lipotoxic liver injury hypothesis for the pathogenesis of NASH. In this review, the contribution of the omics to the understanding of the molecular basis of NASH is discussed that could offer perspectives for novel biomarkers discovery.
Article
Emerging evidence suggests that the lack of PPARα enhances hepatic steatosis and inflammation in Ppara-null mice when fed a high-fat diet (HFD). Thus, the aim of this study was to determine whether Ppara-null mice are more susceptible to nonalcoholic steatohepatitis (NASH) than their wild-type (WT) counterparts following short-term feeding with a HFD. Age-matched male WT and Ppara-null mice were randomly assigned to consume ad libitum a standard Lieber-DeCarli liquid diet (STD) (35% energy from fat) or a HFD (71% energy from fat) for 3 wk. Liver histology, plasma transaminase levels, and indicators of oxidative/nitrosative stress and inflammatory cytokines were evaluated in all groups. Levels of lobular inflammation and the NASH activity score were greater in HFD-exposed Ppara-null mice than in the other 3 groups. Biochemical analysis revealed elevated levels of ethanol-inducible cytochrome P450 2E1 and TNFα accompanied by increased levels of malondialdehyde as well as oxidized and nitrated proteins in Ppara-null mice. Elevated oxidative stress and inflammation were associated with activation of c-Jun-N-terminal kinase and p38 kinase, resulting in increased hepatocyte apoptosis in Ppara-null mice fed a HFD. These results, with increased steatosis, oxidative stress, and inflammation observed in Ppara-null mice fed a HFD, demonstrate that inhibition of PPARα functions may increase susceptibility to high fat-induced NASH.
Article
Growing evidence indicates that the innate immune system and oxidative stress caused by gut-derived endotoxins play a key role in alcoholic liver disease (ALD). Intracellular mechanisms associated with endotoxin-induced signaling play a crucial role in the initiation and progression of ALD. It is now widely accepted that activation of the innate immune system and increased release of pro-inflammatory cytokines and other mediators play an important role in the development of ALD. Accumulating evidence suggests that alcohol-mediated upregulation of CYP2E1 expression may initiate lipid peroxidation via reactive oxygen species. Non-alcoholic steatohepatitis (NASH) is a liver disease characterized by histopathological features similar to those observed in ALD, but in the absence of significant alcohol consumption. Initial efforts to clarify the mechanisms that promote the progression from steatosis to steatohepatitis somewhat artificially divided disease mechanisms into "first and second hits." This model considered the development of steatosis to be the "first hit," increasing the sensitivity of the liver to the putative "second hit," leading to hepatocyte injury, inflammation, and oxidative stress. We have emphasized the important role of gut-derived bacterial toxins, the innate immune system, and oxidative stress in the common pathogenic mechanism in ALD and NASH progression.
Article
Mitogen-activated protein kinase (MAPK) signalling occurs in response to almost any change in the extracellular or intracellular milieu that affects the metabolism of the cell, organ or the entire organism. MAPK-dependent signal transduction is required for physiological metabolic adaptation, but inappropriate MAPK signalling contributes to the development of several interdependent pathological traits, collectively known as metabolic syndrome. Metabolic syndrome leads to life-threatening clinical consequences, such as type 2 diabetes. This Review provides an overview of the MAPK-signalling mechanisms that underly basic cellular metabolism, discussing their link to disease.
Article
The novel adipokines omentin, chemerin, and adipsin are associated with insulin resistance and the components of the metabolic syndrome. We assayed circulating levels of these molecules and examined their association with clinical, biochemical, and histological phenotypes in patients with nonalcoholic fatty liver disease (NAFLD). Serum levels of omentin, chemerin, and adipsin were assayed by enzyme-linked immunosorbent assay in 99 patients with biopsy-proven NAFLD and 75 control subjects. We analyzed associations between adipokines and the characteristics of patients with NAFLD using multivariable linear regression models. Adipsin levels did not differ between patients and controls, whereas both omentin and chemerin levels were significantly higher in patients with biopsy-proven NAFLD than in controls (both p values <0.001). Serum omentin levels were significantly associated with C-reactive protein (r = 0.29, p < 0.01) and the degree of hepatocyte ballooning (r = 0.27, p < 0.01), whereas chemerin showed a modest association with liver fibrosis (r = 0.22, p = 0.04). After stepwise linear regression analysis adjusting for potential confounders, serum omentin levels retained their independent significance as a predictor of hepatocyte ballooning in patients with NAFLD (β = 1.42; t = 2.79, p < 0.01). Our results suggest that serum omentin levels are raised in patients with NAFLD regardless of potential confounders and represent an independent predictor of hepatocyte ballooning.
Article
Obesity induces an insulin-resistant state in adipose tissue, liver, and muscle and is a strong risk factor for the development of type 2 diabetes mellitus. Insulin resistance in the setting of obesity results from a combination of altered functions of insulin target cells and the accumulation of macrophages that secrete proinflammatory mediators. At the molecular level, insulin resistance is promoted by a transition in macrophage polarization from an alternative M2 activation state maintained by STAT6 and PPARs to a classical M1 activation state driven by NF-kappaB, AP1, and other signal-dependent transcription factors that play crucial roles in innate immunity. Strategies focused on inhibiting the inflammation/insulin resistance axis that otherwise preserve essential innate immune functions may hold promise for therapeutic intervention.
Article
To assay the levels of serum omentin-1 in subjects with different levels of glucose regulation and to analyze the relationship between serum omentin-1 levels and body mass index (BMI), glycoslated hemoglobin (HbA1c), plasma glucose, insulin resistance index (HOMA-IR), TNF-alpha and IL-6 levels. Forty-six patients with impaired glucose regulation (IGR), 55 patients with newly diagnosed and untreated type 2 diabetes mellitus (T2DM), and 50 subjects with normal glucose tolerance (NGT) were enrolled in this study. The levels of serum omentin-1 and plasma glucose at fasting and at 2h after glucose load and fasting serum levels of TNF-alpha, IL-6, insulin, and HbA1c were measured. HOMA-IR was calculated. The levels of serum omentin-1 were lower in the IGR and T2DM groups than in the NGT group. Within groups, omentin-1 levels were no significant difference before and after glucose load. The level of serum omentin-1 was negatively correlated to BMI, HOMA-IR, fasting insulin, TNF-alpha, IL-6, plasma glucose. HOMA-IR and BMI were independent related factors that influenced the levels of serum omentin-1. Serum omentin-1 levels were decreased in impaired glucose regulation subjects. Lack of omentin-1 may contribute to the development of insulin resistance and T2DM.
Article
The aim of this study was to investigate the development of non-alcoholic fatty liver disease (NAFLD) in response to a high-fat diet in rats and to test the hypothesis that dietary coenzyme Q monomethyl ether (CoQme) has antisteatogenic effects. Rats were fed a standard low-fat diet (control) for 18 wk or a diet containing 35% fat (57% metabolizable energy) for 10 wk, then divided into three groups for the following 8 wk. One group was given CoQ9me (30mg/kg body weight per day in 0.3mL olive oil: high fat+CoQ9me), the second olive oil (0.3mL/d) only (high fat + olive oil), and the third group received no supplements (high fat). Insulin levels and the activity of alanine aminotransferase in the plasma were significantly increased in all high-fat diet groups, and the homeostasis model assessment of insulin resistance indicated insulin resistance. Triacylglycerol concentrations in whole plasma and in very low-density lipoprotein and low-density lipoprotein fractions were also raised. Liver histology showed lipid accumulation in animals fed the high-fat diets, and liver triacylglycerol levels were increased (2.5- to 3-fold) in all high-fat diet groups. These effects were not changed by the administration of CoQ9me. Rats fed a diet with 57% energy from fat showed insulin resistance, hypertriglyceridemia, increased very low-density lipoprotein production, hepatic steatosis, and liver damage, and thus provide a good model for the early stages of NAFLD. Dietary CoQ9me, however, did not ameliorate the damaging effects of the high-fat diet.