The time course of pathogenesis of fructose mediated hepatic insulin resistance (HepIR) is not well-delineated and we chronicle it here from post-weaning to adulthood stages. Weaned rats were provided for either 4 or 8 weeks, i.e., upto adolescence or adulthood, chow + drinking water, chow + fructose, 15% or chow + fructose, 15% + hydroalcoholic extract of leaves of Aegle marmelos (AM-HM, 500 mg/kg/d, po) and assessed for feed intake, fructose intake, body weight, fasting blood sugar, oral glucose tolerance test, HOMA-IR, insulin tolerance test and lipid profile. Activities of enzymes (glucose-6-phosphatase, hexokinase, phosphofructokinase, aldehyde dehydrogenase), hormones (leptin, ghrelin, insulin), insulin signaling molecules (Akt-PI3k, AMPK, JNK) hallmarks of inflammation (TNF-α), angiogenesis (VEGF), hypoxia (HIF-1), lipogenesis (mTOR) and regulatory nuclear transcription factors of de novo lipogenesis and hepatic insulin resistance gene (SREBP-1, FoxO1) that together govern the hepatic fructose metabolism, were also studied. The effect of fructose-rich environment on metabolic milieu of hepatocytes was confirmed using (human hepatocellular carcinoma) HepG2 cells. Using in vitro model, fructose uptake and glucose output from isolated murine hepatocytes were measured to establish the HepIR under fructose environment and delineate the effect of AM-HM. The leaves from the plant Aegle marmelos (L) Correa were extracted, fractionated and validated for rutin content using LC-MS/MS. The rutin content of extract was quantified and correlated with oral pharmacokinetic parameters in rat. The outcomes of the study suggest that the molecular and metabolic markers of fructose induced HepIR in developing and adult rats are distinct. Further, AM-HM exerts a multi-pronged attack by raising insulin secretion, augmenting insulin action, improving downstream signaling of insulin, reducing overall requirement of insulin and modulating hepatic expression of glucose transporter (Glut2). The butanol fraction of AM-HM holds promise for future development.
Fructose consumption is responsible for the onset of insulin resistance (IR), and metabolic syndrome. It possesses no functional utility in body and its detrimental effects on hepatic metabolic milieu are beyond those produced by glucose. The need of the hour is to identify fructose-induced IR as an unique pathological state to be managed differentially. The effect of aqueous leaf extract of Aegle marmelos (AM) on hepatic markers of insulin resistance using HepG2 cells cultured in either fructose or glucose-rich environment is investigated. Human hepatocellular carcinoma cells (HepG2) were grown under standard conditions in either-DMEM without glucose (NC), DMEM with high glucose 25 mM (Glu), DMEM-glucose+0.55 mM fructose (FC1), DMEM-glucose+1 mM fructose (FC2) or DMEM-glucose+1 mM fructose+0.1 µM insulin (FC3). The cells were treated with either AM, rutin, quercetin, metformin or pioglitazone and assessed for levels of hexokinase, phosphofructokinase (PFK), aldehyde dehydrogenase, phosphatidylinositol kinase (PI3K), signal transducer and activator of transcription-3 (STAT-3), mitochondrial target of rapamycin (mTOR), hypoxia-induced factor (HIF-1α), vascular endothelial growth factor (VEGF) and tumour necrosis factor (TNF-α). Summarily, when results from fructose- and glucose-rich environment were compared, then (1) IR was more pronounced in former; (2) AM performed better in former; (3) metformin and pioglitazone were equivocal in either; (4) rutin and quercetin showed deviant effects from AM; and lastly (5) effects of rutin were closer to AM than quercetin. We hypothesize that AM ameliorates fructose-induced IR through a mechanism which is distinct from standard drugs and not shared by individual phytoconstituents in toto.
Purpose Fructose is highly lipogenic, and its unhindered ingestion by children and adolescents is understood to induce hypertriglyceridemia and non-alcoholic fatty liver disease (ped-NAFLD) that is till date managed symptomatically or surgically. The aim of the present study was to investigate the potential of hydroethanolic extract of leaves of Guava (PG-HM) to suppress the alterations in the hepatic molecular signals due to unrestricted fructose (15%) drinking by growing rats. Methods Weaned rats (4 weeks old) in control groups had ad libitum access to fructose drinking solution (15%) for four (4FDR) or eight (8FDR) weeks, ie, till puberty or early adulthood, respectively, while treatment groups (4PGR, 8PGR) additionally received PG-HM (500 mg/kg, po). Results The PG-HM suppressed ped-NAFLD through hepatic signalling pathways of 1) leptin-insulin (Akt/FOX-O1/SREBP-1c), 2) hypoxia-inflammation (HIF-1ɑ/VEGF, TNF-ɑ), 3) mitochondrial function (complexes I–V), 4) oxidative stress (MDA, GSH, SOD) and 5) glycolysis/gluconeogenesis/ de novo lipogenesis (hexokinase, phosphofructokinase, ketohexokinase, aldehyde dehydrogenase). Parri passu , the insulin sensitizing effect of PG-HM and its ethyl acetate fraction (PG-EA) was elucidated using HepG2 cells grown in media enhanced with fructose. Further, in murine hepatocytes cultured in fructose-rich media, PG-HM (35 µg mL-1) outperformed Pioglitazone (15 µM) and Metformin (5 mM), to suppress hepatic insulin resistance. Conclusion This study established that hydroethanolic extract of leaves of Guava (PG-HM) has potential to suppress hepatic metabolic alteration for the management of the pediatric NAFLD.
The objective of this case study was to highlight the role played by our regional laboratory in identifying N. gonorrhoeae bacteraemia infection in an otherwise unsuspecting patient who presented to Emergency department with fever. Using blood culture technique with BACTEC 9240, plate culture, catalase test, oxidase test and Gram's stain, preliminary diagnosis was made at the regional laboratory. Blood culture became positive on day 3 and Gram's stain from culture day 4 identified intracellular Gram-negative diplococci. The blood picture showed neutrophilia and a raised CRP indicating an underlying bacterial infection. This helped the physicians in starting prompt treatment with Ceftriaxone 500 mg and Azithromycin 1 g. The culture plates and blood culture bottles were then sent to the referral laboratory where confirmatory diagnosis was made using MALDI TOF (Matrix Assisted Laser Desorption Ionisation-Time of Flight), that gave a reading of 2.2 and a VITEK 2 system that gave a 99% probability. The timely detection of Neisseria by the regional laboratory helped the local health authorities to isolate the patient and treat him promptly, thereby preventing the spread of this infection to other parts of his body.
To develop hydroethanolic extract of leaves of Psidium guajava L. (Myrtaceae), identify novel target and lead compound for pediatric non alcoholic fatty liver disease (ped-NAFLD). Hydroethanolic extract (PG-HM) and sequential fractions of locally collected leaves of P.guajava were prepared and standardized for quercetin content using LC-MS/MS. The effect of PG-HM on markers of ped-NAFLD in weaned rats with unrestricted access to liquid fructose (15%) till puberty and early adulthood, was evaluated. The PG-HM was investigated using 1) HepG2 cells grown in fructose containing medium for intercellular signalling, 2) isolated murine hepatocytes for mitochondrial effects, 3) jejunum isolated from fructose drinking rats for effect on ex vivo fructose transport, 4) molecular dynamics for in silico binding of quercetin with GLUT5, 5) normal rats for oral pharmacokinetics. The quercetin content in PG-HM was 3630.66 ± 17.61 ng ml-1 and the Cmax and Tmax were 140.527 ± 5.718 ng ml-1 and 0.75 ± 0.079 h, respectively. The PG-HM mitigated ped-NAFLD through hepatic signalling pathways of 1) leptin-insulin (Akt/FOX-O1/SREBP-1c), 2) hypoxia-inflammation (HIF-1ɑ/VEGF, TNF-ɑ), 3) mitochondrial function (complexes I-V), 4) oxidative stress (MDA, GSH, SOD) and 5) glycolysis/gluconeogenesis/de novo lipogenesis (hexokinase, phosphofructokinase, ketohexokinase, aldehyde dehydrogenase). For the first time, the PG-HM is reported to reduce and delay the fructose transport across jejunum that may be implicated to the binding of quercetin with GLUT5. For prevention and treatment of ped-NAFLD, the PG-HM, GLUT5 and quercetin are evidenced as dietary supplement, drug target and lead compound, respectively.
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