Myocardial and metabolic dysfunction in type 2 diabetic rats: impact of ghrelin

Diabetes mellitus (DM) is commonly associated with metabolic and cardiac dysfunctions. The aim of this study was to examine the effect of ghrelin on metabolic and cardiac dysfunctions in a type-2 diabetes mellitus (T2DM) rat model. For this, 48 male adult Sprague-Dawley rats were divided equally into 4 groups: Group I, fed normal chow, served as normal control group; Groups II-IV, were fed a high-fat diet for 2?weeks followed by injection of streptozotocin (STZ) (35?mg/kg body mass) to create a model of T2DM; Group II, were not treated; Group III, were treated with the vehicle (saline); Group IV, were treated with ghrelin (40?μg/kg body mass) twice daily for 10 days. The untreated diabetic rats showed a significant increase in serum fasting blood glucose, insulin homeostasis model assessment (HOMA) index, triglycerides (TGs), low-density lipoprotein cholesterol (LDL-C), total serum cholesterol (TC), and body mass, with a decrease in high-density lipoprotein cholesterol (HDL-C) (p?< 0.05). Hearts isolated from diabetic rats showed a significant increase in myocardial fat content, a significant decrease in GLUT4, and an increase in acyl-CoA oxidase enzyme mRNA (p?< 0.05). Ghrelin administration for 10?days caused a significant improvement in lipid profile, HOMA index, and body mass, and significantly corrected the myocardial mass, significantly reduced the fat content of the myocardium, significantly increased GLUT4, and decreased acyl CoA oxidase mRNA (p?< 0.05). Thus, ghrelin improves both the metabolic functions and the disturbed energy metabolism in the cardiac muscle of obese diabetic rats.     

Kinetics of rebounding of lymphoid and myeloid cells in mouse peripheral blood, spleen and bone marrow after treatment with cyclophosphamide

Recently, we showed that post cyclophosphamide (CTX) microenvironment benefits the function of transferred T cells. Analysis of the kinetics of cellular recovery after CTX treatment showed that a single 4 mg/mouse CTX treatment decreased the absolute number of leukocytes in the peripheral blood (PBL) at days 3-15, and in the spleen and bone marrow (BM) at days 3-6. The absolute numbers of CD11c(+)CD11b(-) and CD11c(+)CD11b(+) dendritic cells (DCs), CD11b(+) and Ly6G(+) myeloid cells, T and B cells, CD4(+)CD25(+) T regulatory (T(reg)) cells, and NK1.1(+) cells also decreased. The cell numbers returned to control levels during the recovery phase. The absolute numbers of B cells remained low for 3 weeks. The numbers of DCs increased in PBL and spleen at day 9 but returned to control levels at day 15. These data indicate that CTX alters the cellular microenvironment in kinetics that might be precisely targeted to benefit the host.     

Mutations in RIPK4 cause the autosomal-recessive form of popliteal pterygium syndrome

The autosomal-recessive form of popliteal pterygium syndrome, also known as Bartsocas-Papas syndrome, is a rare, but frequently lethal disorder characterized by marked popliteal pterygium associated with multiple congenital malformations. Using Affymetrix 250K SNP array genotyping and homozygosity mapping, we mapped this malformation syndrome to chromosomal region 21q22.3. Direct sequencing of RIPK4 (receptor-interacting serine/threonine kinase protein 4) showed a homozygous transversion (c.362T>A) that causes substitution of a conserved isoleucine with asparagine at amino acid position 121 (p.Ile121Asn) in the serine/threonine kinase domain of the protein. Additional pathogenic mutations-a homozygous transition (c.551C>T) that leads to a missense substitution (p.Thr184Ile) at a conserved position and a homozygous one base-pair insertion mutation (c.777_778insA) predicted to lead to a premature stop codon (p.Arg260ThrfsX14) within the kinase domain-were observed in two families. Molecular modeling of the kinase domain showed that both the Ile121 and Thr184 positions are critical for the protein's stability and kinase activity. Luciferase reporter assays also demonstrated that these mutations are critical for the catalytic activity of RIPK4. RIPK4 mediates activation of the nuclear factor-κB (NF-κB) signaling pathway and is required for keratinocyte differentiation and craniofacial and limb development. The phenotype of Ripk4(-/-) mice is consistent with the human phenotype presented herein. Additionally, the spectrum of malformations observed in the presented families is similar, but less severe than the conserved helix-loop-helix ubiquitous kinase (CHUK)-deficient human fetus phenotype; known as Cocoon syndrome; this similarity indicates that RIPK4 and CHUK might function via closely related pathways to promote keratinocyte differentiation and epithelial growth.     

HCV infection among Saudi population: high prevalence of genotype 4 and increased viral clearance rate

HCV is a major etiological agent of liver disease with a high rate of chronic evolution. The virus possesses 6 genotypes with many subtypes. The rate of spontaneous clearance among HCV infected individuals denotes a genetic determinant factor. The current study was designed in order to estimate the rate of HCV infection and ratio of virus clearance among a group of infected patients in Saudi Arabia from 2008 to 2011. It was additionally designed to determine the genotypes of the HCV in persistently infected patients. HCV seroprevalence was conducted on a total of 15,323 individuals. Seropositive individuals were tested by Cobas AmpliPrep/Cobas TaqMan HCV assay to determine the ratio of persistently infected patients to those who showed spontaneous viral clearance. HCV genotyping on random samples from persistently infected patients were conducted based on the differences in the 5'untranslated region (5'UTR). Anti-HCV antibodies were detected in 7.3% of the totally examined sera. A high percentage of the HCV infected individuals experienced virus clearance (48.4%). HCV genotyping revealed the presence of genotypes 1 and 4, the latter represented 97.6% of the tested strains. Evidences of the widespread of the HCV genotype 4 and a high rate of HCV virus clearance were found in Saudi Arabia.     

NODULE ROOT and COCHLEATA Maintain Nodule Development and Are Legume Orthologs of Arabidopsis BLADE-ON-PETIOLE Genes

During their symbiotic interaction with rhizobia, legume plants develop symbiosis-specific organs on their roots, called nodules, that house nitrogen-fixing bacteria. The molecular mechanisms governing the identity and maintenance of these organs are unknown. Using Medicago truncatula nodule root (noot) mutants and pea (Pisum sativum) cochleata (coch) mutants, which are characterized by the abnormal development of roots from the nodule, we identified the NOOT and COCH genes as being necessary for the robust maintenance of nodule identity throughout the nodule developmental program. NOOT and COCH are Arabidopsis thaliana BLADE-ON-PETIOLE orthologs, and we have shown that their functions in leaf and flower development are conserved in M. truncatula and pea. The identification of these two genes defines a clade in the BTB/POZ-ankyrin domain proteins that shares conserved functions in eudicot organ development and suggests that NOOT and COCH were recruited to repress root identity in the legume symbiotic organ.     

Alternating Magnetic Field Induced Membrane Permeability in Erythromycin Magneto-Liposomes A Potential Solution to Antibiotic Resistance

Biophysics - Antibiotic resistance is a serious problem facing the world; it is increasing every year due to over or misuse of antibiotics that led to developing new mechanisms of drug resistance...     

Synthesis and evaluation of novel spiro derivatives for pyrrolopyrimidines as anti-hyperglycemia promising compounds

Pyrrolopyrimidin-4-ylidene-malononitriles IIa–d were prepared as important intermediates for preparation of a new series of spiro-pyrrolopyrimidines. These intermediates undergo cyclisation via reaction with acetylacetone, guanidine hydrochloride or hydrazine hydrate. Elemental and spectroscopic evidences for the structures of these compounds are presented. The final compounds have been monitored for in vivo anti-hyperglycemic activity, compared with Amaryl as standard drug. Among 12 tested compounds, both spiro (pyrano IIIb and pyrazlo Va) derivatives exhibit promising anti-hyperglycemic activity.     

Synthesis,antitumour activities and molecular docking of thiocarboxylic acid ester-based NSAID scaffolds: COX-2 inhibition and mechanistic studies

A new series of NSAID thioesters were synthesized and evaluated for their in vitro antitumor effects against a panel of four human tumor cell lines, namely: HepG2, MCF-7, HCT-116 and Caco-2, using the MTT assay. Compared to the reference drugs 5-FU, afatinib and celecoxib, compounds 2b, 3b, 6a, 7a, 7b and 8a showed potent broad-spectrum antitumor activity against the selected tumour cell lines. Accordingly, these compounds were selected for mechanistic studies about COX inhibition and kinase assays. In vitro COX-1/COX-2 enzyme inhibition assay results indicated that compounds 2b, 3b, 6a, 7a, 7b, 8a and 8?b selectively inhibited the COX-2 enzyme (IC₅₀?=?～0.20–0.69?μM), with SI values of (>72.5–250) compared with celecoxib (IC₅₀?=?0.16?μM, COX-2 SI:?>?312.5); however, all the tested compounds did not inhibit the COX-1 enzyme (IC₅₀?>?50?μM). On the other hand, EGFR, HER2, HER4 and cSrc kinase inhibition assays were evaluated at a 10?μM concentration. The selected candidates displayed limited activities against the various tested kinases; the compounds 2a, 3b, 6a, 7a, 7b and 8a showed no activity to weak activity (% inhibition?=?～0–10%). The molecular docking study revealed the importance of the thioester moiety for the interaction of the drugs with the amino acids in the active sites of COX-2. The aforementioned results indicated that thioester based on NSAID scaffolds derivatives may serve as new antitumor compounds.