1H NMR metabolomics insights into comparative diabesity in male and female zebrafish and the antidiabetic activity of DL-limonene.

Zebrafish have been utilized for many years as a model animal for pharmacological studies on diabetes and obesity. High-fat diet (HFD), streptozotocin and alloxan injection, and glucose immersion have all been used to induce diabetes and obesity in zebrafish. Currently, studies commonly used both male and female zebrafish, which may influence the outcomes since male and female zebrafish are biologically different. This study was designed to investigate the difference between the metabolites of male and female diabetic zebrafish, using limonene - a natural product which has shown several promising results in vitro and in vivo in treating diabetes and obesity-and provide new insights into how endogenous metabolites change following limonene treatment. Using HFD-fed male and female zebrafish, we were able to develop an animal model of T2D and identify several endogenous metabolites that might be used as diagnostic biomarkers for diabetes. The endogenous metabolites in males and females were different, even though both genders had high blood glucose levels and a high BMI. Treatment with limonene prevented high blood glucose levels and improved in diabesity zebrafish by limonene, through reversal of the metabolic changes caused by HFD in both genders. In addition, limonene was able to reverse the elevated expression of AKT during HFD.

The functions of Ca2+/calmodulin-dependent protein kinase II (CaMKII) in diabetes progression.

The increase in blood glucose causes a myriad of pathways and molecular components to malfunction, leading to diabetes. Diabetes affects each organ differently by activating distinct pathways. It has an impact on the liver, pancreas, kidney (nephropathy), eyes (retinopathy), and nervous system (neuropathy). Understanding the effects of diabetes on each organ is the first step in developing a sustained treatment for the disease. Among the many cellular molecules impacted by diabetes is Ca2+/calmodulin-dependent protein kinase II (CaMKII), a complex Ca2+/calmodulin-activated serine/threonine-protein kinase. When intracellular [Ca2+] rises, it binds to calmodulin (CaM) to produce Ca2+/CaM, which activates CaMKIIs. This factor is involved in the pancreas, liver, heart, muscles, and various organs. Thus, Understanding CaMKII action in each organ is critical for gaining a complete picture of diabetic complications. Therefore, this review covers CaMKII's functions in many organs and how it affects and has been affected by diabetes.

Metabolomics based biomarker identification of anti-diabetes and anti-obesity properties of Malaysian herbs.

BACKGROUND: Today, obesity affects over one-third of the global population and is hugely considered the Industrial Revolution's side effect. This multi-factorial disease is continuously spreading across developing countries, including the Middle East and Southeast Asia region, where Malaysia and Darussalam Brunei are the most affected. The sedentary lifestyle and availability of surplus foods have dramatically increased the number of individuals with type 2 diabetes in these countries. Thus, an adequate medical strategy must be developed urgently to address and remedy these diseases. Natural sources have been attracting attention, especially in Malaysia, where most land areas are under plant cover. Metabolomics, as a prophylactic technique, has been used extensively in Malaysia to investigate the potential use and benefits of herbs to combat obesity and diabetes. AIM OF REVIEW: This review aims to explain the application of the metabolomics approach in the study of anti-diabetes and anti-obesity activity of Malaysian herbs to identify the stand-up point for future advancement in using these herbs as a primary source for drug exploration. KEY SCIENTIFIC CONCEPTS OF REVIEW: This review provides an overview of using metabolomics technique in studying the anti-diabetes and anti-obesity activity of Malaysian herbs. Specific emphasis is given to the changed metabolites in both in vivo and in vitro treatment of Malaysia herbs that might be future drugs for treating diabetes and obesity.

AgRP/NPY and POMC neurons in the arcuate nucleus and their potential role in treatment of obesity.

Obesity is a major health crisis affecting over a third of the global population. This multifactorial disease is regulated via interoceptive neural circuits in the brain, whose alteration results in excessive body weight. Certain central neuronal populations in the brain are recognised as crucial nodes in energy homeostasis; in particular, the hypothalamic arcuate nucleus (ARC) region contains two peptide microcircuits that control energy balance with antagonistic functions: agouti-related peptide/neuropeptide-Y (AgRP/NPY) signals hunger and stimulates food intake; and pro-opiomelanocortin (POMC) signals satiety and reduces food intake. These neuronal peptides levels react to energy status and integrate signals from peripheral ghrelin, leptin, and insulin to regulate feeding and energy expenditure. To manage obesity comprehensively, it is crucial to understand cellular and molecular mechanisms of information processing in ARC neurons, since these regulate energy homeostasis. Importantly, a specific strategy focusing on ARC circuits needs to be devised to assist in treating obese patients and maintaining weight loss with minimal or no side effects. The aim of this review is to elucidate the recent developments in the study of AgRP-, NPY- and POMC-producing neurons, specific to their role in controlling metabolism. The impact of ghrelin, leptin, and insulin signalling via action of these neurons is also surveyed, since they also impact energy balance through this route. Lastly, we present key proteins, targeted genes, compounds, drugs, and therapies that actively work via these neurons and could potentially be used as therapeutic targets for treating obesity conditions.

The molecular mechanism of vgf in appetite, lipids, and insulin regulation.

Obesity is an indication of an imbalance between energy expenditure and food intake. It is a complicated disease of epidemic proportions as it involves many factors and organs. Sedentary lifestyles and overeating have caused a substantial rise in people with obesity and type 2 diabetes. Thus, the discovery of successful and sustainable therapies for these chronic illnesses is critical. However, the mechanisms of obesity and diabetes and the crosstalk between these diseases are still ambiguous. Numerous studies are being done to study these mechanisms, with updates made frequently. VGF peptide and its derivatives are anticipated to have a role in the development of obesity and diabetes. However, contradictory studies have produced conflicting findings on the function of VGF. Therefore, in this review, we attempt to clarify and explain the role of VGF peptides in the brain, pancreas, and adipose tissue in the development of obesity.

CREB nuclear transcription activity as a targeting factor in the treatment of diabetes and diabetes complications.

Diabetes mellitus is a metabolic disorder diagnosed by elevated blood glucose levels and a defect in insulin production. Blood glucose, an energy source in the body, is regenerated by two fundamental processes: glycolysis and gluconeogenesis. These two processes are the main mechanisms used by humans and many other animals to maintain blood glucose levels, thereby avoiding hypoglycaemia. The released insulin from pancreatic ß-cells activates glycolysis. However, the glucagon released from the pancreatic α-cells activates gluconeogenesis in the liver, leading to pyruvate conversion to glucose-6-phosphate by different enzymes such as fructose 1,6-bisphosphatase and glucose 6-phosphatase. These enzymes' expression is controlled by the glucagon/ cyclic adenosine 3',5'-monophosphate (cAMP)/ proteinkinase A (PKA) pathway. This pathway phosphorylates cAMP-response element-binding protein (CREB) in the nucleus to bind it to these enzyme promoters and activate their expression. During fasting, this process is activated to supply the body with glucose; however, it is overactivated in diabetes. Thus, the inhibition of this process by blocking the expression of the enzymes via CREB is an alternative strategy for the treatment of diabetes. This review was designed to investigate the association between CREB activity and the treatment of diabetes and diabetes complications. The phosphorylation of CREB is a crucial step in regulating the gene expression of the enzymes of gluconeogenesis. Many studies have proven that CREB is over-activated by glucagon and many other factors contributing to the elevation of fasting glucose levels in people with diabetes. The physiological function of CREB should be regarded in developing a therapeutic strategy for the treatment of diabetes mellitus and its complications. However, the accessible laboratory findings for CREB activity of the previous research still not strong enough for continuing to the clinical trial yet.

FoxO1 signaling as a therapeutic target for type 2 diabetes and obesity.

Glucose production and the consumption of high levels of carbohydrate increase the chance of insulin resistance, especially in cases of obesity. Therefore, maintaining a balanced glucose homeostasis might form a strategy to prevent or cure diabetes and obesity. The activation and inhibition of glucose production is complicated due to the presence of many interfering pathways. These pathways can be viewed at the downstream level because they activate certain transcription factors, which include the Forkhead-O1 (FoxO1). This has been identified as a significant agent in the pancreas, liver, and adipose tissue, which is significant in the regulation of lipids and glucose. The objective of this review is to discuss the intersecting portrayal of FoxO1 and its parallel cross-talk which highlights obesity-induced insulin susceptibility in the discovery of a targeted remedy. The review also analyses current progress and provides a blueprint on therapeutics, small molecules, and extracts/phytochemicals which are explored at the pre-clinical level.

Iron regulated outer membrane proteins (IROMPs) as potential targets against carbapenem-resistant Acinetobacter spp. isolated from a Medical Centre in Malaysia.

BACKGROUND & OBJECTIVES: Carbapenem-resistant Acinetobacter spp. have gained increasing significance as opportunistic pathogens in hospitalized patients. Carbapenem resistance is often associated with the loss and/or decrease in outer membrane proteins (OMP) and overexpression of multidrug efflux systems. However, carbapenem-hydrolysing beta-lactamases of Ambler Class B (metallo-enzymes) and Ambler Class D (oxacillinases) have also been detected in Acinetobacter spp. In this study we have investigated the role of the iron regulated outer membrane protein (IROMPs) and the loss of a 29-kDa OMP in carbapenem resistance of Acinetobacter calcoaceticus. METHODS: Carbapenem resistant clinical isolates (n=39) of Acinetobacter baumannii / calcoaceticus were used. Identification of Acinetobacter spp. at species level was done by amplified ribosomal DNA restriction analysis (ARDRA). MIC was evaluated using agar dilution method according to CLSI standards. Presence of outer membrane proteins were determined by SDS-PAGE. A representative strain of A. calcoaceticus, S26 with the loss of 29-kDa OMP was selected for further analysis as strain S26 had unique resistance mechanism, that is, the presence of IMP-4 metallo-beta-lactamases. IROMPs were expressed under iron deficit conditions. Bands corresponding to IROMPs were excised from SDS-PAGE and used to immunize rabbits for the production of polyclonal antibodies. The antibodies raised against IROMPs were detected by an in-house ELISA and then used for bactericidal activity against carbapenem resistant A. baumannii / calcoaceticus. RESULTS: All isolates were resistant to all antibiotics including imipenem and meropenem and had loss of a 29-kDa OMP. The polyclonal antibodies showed bactericidal effect against the organism tested and it specifically killed the bacteria grown in iron deficit medium. INTERPRETATION & CONCLUSIONS: In this study, a 29-kDa OMP has been identified to be the major outer membrane protein in A. baumannii / calcoaceticus and loss of this porin and overexpression of IROMPs have contributed to carbapenem resistance. Polyclonal antibodies raised against IROMPs may have a role in antimicrobial therapy in these isolates.

Detection and characterization of class 1 integrons among carbapenem-resistant isolates of Acinetobacter spp. in Malaysia.

BACKGROUND AND PURPOSE: To detect and characterize class 1 integrons among carbapenem-resistant strains of Acinetobacter spp. at University Malaya Medical Centre (UMMC), Kuala Lumpur, Malaysia. METHODS: Thirty nine carbapenem-resistant Acinetobacter strains were obtained from UMMC from August 2003 to March 2004 and analyzed for the presence of bla(IMP) genes and class 1 integrons. RESULTS: Class 1 integrons were detected in 31 of 39 strains. Two Acinetobacter calcoaceticus strains harbored an integron-borne bla(IMP-4) metallo-beta-lactamase, 1 of which was located on a 36-kb plasmid. Two different amplified products were found in the 31 isolates with 3 restriction pattern profiles 1, 2, and 3. Correlation was observed between carriage of class 1 integrons and genomic relatedness among these isolates, indicating that particular mechanisms of carbapenem resistance could have been acquired by genotypically distinct clinical isolates of Acinetobacter spp. CONCLUSION: Although class 1 integrons are widely disseminated among clinical isolates of Acinetobacter spp. they do not play a major role in the spread of carbapenem resistance.