Long-lasting partnership between insulin resistance and endothelial dysfunction: role of metabolic memory

Background and Purpose

The persistence of deleterious effects of hyperglycaemia even after glucose normalization is referred to as ‘metabolic memory’. However, similar persistent effects of the metabolic consequences of a high fat diet (HFD) have not been described.

Experimental Approach

Rats were given a normal pellet diet (NPD) or a HFD for 3 months. The animals from the HFD group were then returned to the NPD to observe the long-term effects of insulin resistance. Endothelial dysfunction was assessed by carbachol-mediated vasorelaxation and eNOS phosphorylation.

Key Results

As expected, HFD consumption resulted in insulin resistance and endothelial dysfunction. Phosphorylation of eNOS at S1177 was decreased in HFD rats, compared with that in the NPD group. Rats on 3 months of HFD showed glucose intolerance and impaired insulin sensitivity and were then switched back to NPD (REV group). Levels of cholesterol and triglyceride, and adiposity returned to normal in REV rats. However, endothelium-dependent vascular responses to carbachol which were impaired in HFD rats, continued to be impaired in REV rats. Similarly, decreased eNOS phosphorylation after HFD was not improved after 1 or 6 months of REV.

Conclusions and Implications

Our data indicate that returning to NPD did not improve the insulin sensitivity or the endothelial dysfunction induced by HFD. Although some biochemical parameters responsible for insulin resistance and endothelial dysfunction were normalized, molecular and vascular abnormalities, involving NO, persisted for several months, highlighting the long-lasting effects of metabolic memory.     

Synthesis, anticancer, and molecular docking studies of pyranone derivatives

A series of novel Pyran scaffolds of Thiazolidin-4-one [RA-3(a–d)] and Piperazine [BR (1–4)] were synthesized as potent bi-heterocyclic molecules. All the newly synthesized compounds were confirmed by spectral studies. These synthesized compounds were screened for in vivo anticancer activity. Compounds RA-3a, RA-3c, and BR-3 displayed the highest anticancer activity against Ehrlich Ascites Carcinoma cells and docking study of all the synthesized title compounds was carried out using Molegro Virtual Docker on GABARAPL1 (GABA_A receptor-associated protein-1 cancer receptor). These studies revealed the importance of Pyranone, Thiazolidnones, and Piperazine nucleus for their anticancer activity.     

Antioxidant Activity and Cytotoxicity of the Traditional Indonesian Medicine Tahongai (Kleinhovia hospita L.) Extract

We investigated the leaves of Kleinhovia hospita, a plant which has been traditionally used in Indonesia as phytotherapy to cure liver disease, to describe antioxidant materials from plant sources. K. hospita leaves were extracted with methanol and further partitioned into n-hexane, diethyl ether, and ethyl acetate. The antioxidant activity of each fraction and the residue was assessed using a 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging method and their cytotoxicity on HepG2 liver cancer cells was determined by a MTT assay. The K. hospita leaf methanol extract showed strong antioxidant activity (96%) compared with vitamin C (98%) by the DPPH method and the measured activity from the subsequent extracts of the methanol extract were 48.9% for n-hexane, 74.0% for diethyl ether, 84.3% for ethyl acetate, and 77.1% for the residue. The MTT assay showed the cytotoxicity of the methanol extract on HepG2 cells at 14%, 76%, and 80% at concentrations of 50μg/mL, 87.5μg/mL, and 125μg/mL, respectively. Leaf extracts of the medicinal plant K. hospita showed potent antioxidant activity and moderate cytotoxicity on HepG2 liver cancer cells.     

Biological activity of the essential oil of Kadsura longipedunculata (Schisandraceae) and its major components

Objectives The aim was to determine the chemical composition of the essential oil of Kadsura longipedunculata and the biological activity of the oil and its major components. Methods The essential oil from stem bark of Kadsura longipedunculata was analysed by capillary gas chromatography (GLC/FID) and gas chromatography–mass spectrometry (GLC/MS). The ability of the oil to reduce diphenylpicrylhydrazine (DPPH^?) was used to evaluate the antioxidant activity. Inhibition of both lipoxygenase and prostaglandin E₂ was used to assess the anti‐inflammatory activity. Antimicrobial activity was studied in vitro against a range of bacteria and fungi using diffusion and microdilution methods. Inhibition of trypanosome proliferation was assessed using resazurin as vital stain. The in‐vitro cytotoxicity of the essential oil on six human cancer cell lines (HepG2, MIA PaCa‐2, HeLa, HL‐60, MDA‐MB‐231 and SW‐480) was examined using the MTT assay. Key findings Fifty compounds, representing 97.63% of total oil, were identified. δ‐Cadinene (21.79%), camphene (7.27%), borneol (6.05%), cubenol (5.12%) and δ‐cadinol (5.11%) were found to be the major components of the oil. The oil exerted a good antimicrobial activity against all Gram‐positive bacteria tested, including methicillin‐resistant Staphylococcus aureus and vancomycin‐resistant Enterococcus faecalis. Streptococcus pyogenes and S. agalactiae were the most sensitive bacteria with a minimal inhibitory concentration (MIC) of 60 µg/ml oil. The essential oil showed a moderate fungicidal activity against yeasts, but it did not show any activity against Gram‐negative bacteria. The essential oil showed a good trypanocidal activity in Trypanosoma b. brucei with an IC50 value of 50.52 ± 0.029 µg/ml. Radical scavenging activity had an IC50 value of 3.06 ± 0.79 mg/ml. 5‐Lipoxygenase inhibition (IC50 = 38.58 µg/ml) and prostaglandin E₂ production inhibition (28.82% at 25 µg/ml) accounted for anti‐inflammatory activity of the oil. The oil exhibited some degree of cytotoxic activity against MIA PaCa‐2, HepG‐2 and SW‐480 cell lines with IC50 values of 133.53, 136.96 and 136.62 µg/ml, respectively. The oil increased caspase 3/7 activity (an indicator of apoptosis) 2.5–4 fold in MIA Paca‐2 cells. Camphene and borneol did not show antioxidant activity. However, both compounds exhibited some degree of antimicrobial, trypanocidal, anti‐inflammatory and cytotoxic activity. Conclusions This investigation provided evidence for, and confirmed the efficacy of, K. longipedunculata, a traditionally used Chinese medicinal plant for the treatment of inflammation and infection.     

Natural Killer/T-cell Neoplasms: Analysis of Incidence,Patient Characteristics,and Survival Outcomes in the United States

Background

Limited data are available regarding the incidence, survival patterns, and long-term outcomes of natural killer (NK)/T-cell neoplasms in the United States.

Rupture of the intra-articular portion of the long head of the biceps associated with a symptomatic os acromiale

We report the case of a 45-year-old male who presented with a 5-year history of shoulder pain following an injury. Clinical and radiological investigations revealed a ruptured long head of the biceps and a meso-os acromiale. We performed an arthroscopic resection of the intra-articular stump of the long head of the biceps, followed by internal fixation of the mobile os acromiale using a tension band technique. Rupture of the long head of the biceps associated with a symptomatic os acromiale has not been previously described. This case reinforces the importance of routine shoulder arthroscopy in the treatment of symptomatic os acromiale.     

THE HISTOGENESIS OF BASEMENT MEMBRANES

A parietal yolk sac carcinoma of the mouse that secretes large quantities of basement membrane-like material has been used to study the formation of basement membranes. Suitably characterized fluorescein-labeled antibodies against this material stained basement membranes of epithelial structures and vessels, as well as reticulin. When absorbed with reticulin and vascular basement membranes of the spleen until these structures no longer fluoresced, the antibody still stained the basement membrane-like material of the tumor, its normal embryonic counterpart (Reichert's membrane), and the basement membranes at the bases of epithelial cells. The observation made previously that parietal yolk sac cells secreted, in the absence of connective tissue and reticulin, the basement membrane (Reichert's membrane) upon which they rested has been confirmed through the localization of ferritin-labeled antibody to the endoplasmic reticulin of the secreting cells. Since a basement membrane proven to be an epithelial secretion is antigenically similar to basement membranes at the bases of all epithelial cells studied but antigenically different from connective tissue elements, it is postulated that the basement membranes at the bases of epithelial cells in general are an epithelial secretion, and are not a condensation of ground substance as is commonly believed.     

Living through a volcanic eruption: Understanding the experience of survivors as a phenomenological existential phenomenon

Mount Merapi in Indonesia is the most active volcano in the world with its 4–6‐year eruption cycle. The mountain and surrounding areas are populated by hundreds of thousands of people who live near the volcano despite the danger posed to their wellbeing. The aim of this study was to explore the lived experience of people who survived the most recent eruption of Mount Merapi, which took place in 2010. Investigators conducted interviews with 20 participants to generate textual data that were coded and themed. Three themes linked to the phenomenological existential experience (temporality and relationality) of living through a volcanic eruption emerged from the data. These themes were: connectivity, disconnection and reconnection. Results indicate that the close relationship individuals have with Mount Merapi and others in their neighbourhood outweighs the risk of living in the shadow of an active volcano. This is the first study to analyze the phenomenological existential elements of living through a volcanic eruption.     

A Noninvasive Clinical Scoring Model Predicts Risk of Nonalcoholic Steatohepatitis in Morbidly Obese Patients

Background  

A simple model to predict nonalcoholic steatohepatitis (NASH) in patients with nonalcoholic fatty liver disease is desirable to optimize the selection of patients for liver biopsy. We investigated a large group of morbidly obese patients to derive a scoring system based on simple clinical and laboratory variables.     

Monogenic diabetes secondary to congenital lipodystrophy in a 14-year-old Yemeni girl

A 14-year-old female from Yemen presented with intense abdominal pain and headache. She was born at term to distant cousins, developmentally delayed and significantly dysmorphic. Four years ago, she was diagnosed with diabetes mellitus and undiagnosed hepatic, cardiac, genetic, neurologic, endocrine, musculoskeletal, and gastrointestinal disorders. No therapy was prescribed. Admission laboratory data showed blood glucose = 391 mg/dl, hemoglobin A1c= 12.2%, C-peptide = 3.5 ng/ml, insulin = 6.8 uIU/ml, triglyceride =385 mg/dl, and serum leptin <0.5 ng/ml, (1.1-27.5). Chromosome analysis (46, XX) was normal and serology for Glutamic acid Decarboxylase (GAD), hepatitis and HIV were negative. Clinical examination and laboratory data suggested congenital generalized lipodystrophy (CGL, type BSCL-2). This case illustrates that CGL should be in the differential diagnosis for non-obese patients with diabetes and insulin resistance.