Co-administration of etomoxir and RU-486 mitigates insulin resistance in hepatic and muscular tissues of STZ-induced diabetic rats.

Insulin resistance is a condition of central importance in a cluster of clinical disorders including diabetes mellitus, hypertension, dyslipidemia, central obesity and coronary heart disease. Despite its association with numerous health problems, the mechanism responsible for the development of this phenomenon remains to be established. A novel theory has proposed that insulin resistance in diabetes stems, at least in part, from enhanced free fatty acid (FFA) oxidation and/or excessive production of glucocorticoids (GCs). Several key predictions of this premise were subjected to experimental testing using streptozotocin (STZ)-treated rats as a model for insulin-dependent diabetes mellitus and euglycemic-hyperinsulinemic clamp technique for the in vivo measurement of insulin actions. Euglycemic clamp studies with an insulin infusion index of 5 mU/kg/min were used to measure endogenous glucose production (EGP), glucose infusion rate (GIR), glucose disposal rate (GDR) and skeletal muscle glucose utilization index (GUI). Post-absorptive basal EGP and plasma levels of glucose and free fatty acids (FFA) were elevated in the STZ diabetic rats compared to their corresponding control values. In contrast, hypoinsulinemia was evident in these animals. Steady-state GIR and GDR during euglycemic-hyperinsulinemic clamp were markedly decreased in the STZ diabetic rats. Similarly, insulin-mediated suppression of EGP and plasma FFA concentration was also impaired in these animals. GUI, a measure of 2-deoxyglucose (2-DG) uptake, was increased in response to insulin in the order of white gastrocnemus (WG), red gastrocnemus (RG), extensor digitorum longus and soleus muscles. This parallels the percentage of red fibers in these muscles. Diabetes interferes with insulin's ability to increase 2-DG uptake in all of the above muscles with the exception of WG. Nullification of the associated hyperlipidemic and hypercortisolemic states of diabetes with etomoxir (hyperlipidemic) and the glucocorticoid receptor blocker RU-486 (hypercortisolemic) ameliorated the diabetes-related impairment of the in vivo insulin action. Overall these results together with those garnered from the literature support the notion that hypercortisolemia and the enhancement of FFA oxidation are involved, at least in part, in the development of hepatic and skeletal muscle insulin resistance in poorly controlled type I diabetes.     

Middle Holocene vegetation and human impact in central Sudan: charcoal from the neolithic site at Kadero

Charcoal recovered from middens and graves in the neolithic site of Kadero, north of Khartoum, Sudan was analysed. The site lies within the semi-desert vegetation zone at present. During the occupation period (5960-5030 uncal B.P.), a scrub and thorn savanna grew around the site. It is further suggested that the vegetation during the neolithic period at Kadero was already under strong human impact through controlled fires, felling and grazing.     

Photoprotective effects of some quinoxaline 1,4-dioxides in hairless mice

2-benzoyl-3-phenylquinoxaline 1,4-dioxide (BPQ) and other substituted quinoxaline 1,4-dioxides (QdO) were tested for their ability to inhibit the stimulations of ornithine decarboxylase (ODC) enzyme activity and DNA synthesis, two biochemical markers linked to skin tumour promotion by ultraviolet B (UVB) radiation. Topical application of BPQ on the dorsal skin of hairless mice was found to inhibit in a dose-dependent manner UVB-induced ODC activity and DNA synthesis. When applied 20 min before UVB radiation, a dose of 17 mg BPQ applied in 0.4 ml of vehicle inhibited UVB-induced ODC activity and DNA synthesis by 95% and 85%, respectively. This inhibitory effect is dependent on the time of administration of BPQ relative to UVB radiation, with a generally greater inhibition observed when this compound is applied before rather than after UVB treatment. The inhibitory abilities of the other QdO on the ODC and DNA responses induced by UVB radiation greatly varied and appear to be dependent on the structure of the compounds and their metabolic activation in the skin following irradiation. The remarkable effectiveness of BPQ against the ODC and DNA markers of UVB promotion is also observed following multiple applications of this agent. These results suggest that QdO, in particular BPQ and certain derivatives of it, may be useful in protecting the skin against UVB-induced skin damage.     

HSP27 modulates agonist-induced association of translocated RhoA and PKC-alpha in muscle cells of the colon.

The recruitment of signal transduction molecules to the membrane is crucial for the efficient coupling of extracellular signals and contractile response. The trafficking is dynamic. We have investigated a possible cross talk between agonist-induced association of translocated RhoA and translocated protein kinase C-alpha (PKC-alpha) and a role for heat shock protein 27 (HSP27) in mediating this interaction. Immunoprecipitation with HSP27 monoclonal antibody followed by immunoblotting with either RhoA antibody or PKC-alpha antibody indicated that acetylcholine induced associations of HSP27-RhoA and HSP27-PKC-alpha in the membrane fraction but not in the cytosolic fraction. Immunoprecipitation with anti-RhoA monoclonal antibody followed by immunoblotting with PKC-alpha antibody indicated that acetylcholine induced a significant complexing of RhoA-PKC-alpha in the membrane fraction but not in the cytosolic fraction. In summary, the data indicate that agonist-induced contraction is associated with 1) association of translocated RhoA with HSP27 on the membrane, 2) association of translocated PKC-alpha with HSP27 on the membrane, and 3) association of PKC-alpha with RhoA on the membrane. The data suggest an important role for HSP27 in modulating a multiprotein complex that includes translocated RhoA and PKC-alpha.     

Synthesis and anti-H5N1 virus activity of triazole- and oxadiazole-pyrimidine hybrids and their nucleoside analogs

Abstract

New 1,2,3-triazole glycosides and 1,2,4-thioglycosides incorporating a substituted pyrimidinedione ring system were synthesized via click dipolar cycloaddition and heterocyclization of hydrazine-1-carbodithioate derivatives, respectively. The sugar hydrazine derivatives linked aminodimethyluracil were also prepared. In addition, the oxadiazoline substituted with acyclic sugar moieties linked to the pyrimidinedione as acyclic nucleoside analogs were synthesized. The antiviral activity of the synthesized compounds against avian influenza H5N1 virus was investigated and compounds 18, 13 and 19 showed good activities against the virus strains.     

A comparison of subcutaneous and intraperitoneal oxytetracycline injection methods for control of infectious disease in the rat

After receiving once daily intraperitoneal (i.p.) or subcutaneous (s.c.) injections of oxytetracycline (15 mg/100 g bodyweight) for 7 days, laboratory rats had significantly different oxytetracycline serum levels depending on the method of injection. Regardless of injection method, the biological half-life of the antibiotic was 4.25 h and serum antibiotic levels never fell below therapeutic levels for certain rat pathogens during 24 h post-injection. Severe peritonitis and cellulitis were found in rats whether injected s.c. or i.p. and some animals lost bodyweight. It appeared that either injection method would be an effective treatment for certain infectious diseases of laboratory rats but tissue damage, probably from oxytetracycline's acidity, made both methods unattractive.     

Suppression of experimental autoimmune encephalomyelitis by the oral administration of myelin basic protein

The oral administration of myelin basic protein (MBP) to Lewis rats prior to an encephalitogenic challenge resulted in total inhibition or a significant delay in the onset of experimental autoimmune encephalomyelitis (EAE). In vitro lymphocyte proliferative responses to MBP were significantly decreased in MBP-fed rats when compared with vehicle-fed controls. Suppression of EAE and in vitro proliferative responses to MBP were observed to be antigen specific, since oral feeding of a control protein exerted no suppressive effect. Moreover, the specificity of MBP-induced oral tolerance was shown to be species specific, since feeding guinea pig MBP (GPMBP) or human MBP (HuMBP) induced protection only against a GPMBP or HuMBP challenge, respectively. Conversely, Lewis rats could not be orally tolerized to the self antigen rat MBP.