(-)-Adrenaline elicits positive inotropic, lusitropic, and biochemical effects through β2-adrenoceptors in human atrial myocardium from nonfailing and failing hearts, consistent with Gs coupling but not with Gi coupling

Activation of either coexisting β₁- or β₂-adrenoceptors with noradrenaline or adrenaline, respectively, causes maximum increases of contractility of human atrial myocardium. Previous biochemical work with the β₂-selective agonist zinterol is consistent with activation of the cascade β₂-adrenoceptors→Gsα-protein→adenylyl cyclase→cAMP→protein kinase (PKA)→phosphorylation of phospholamban, troponin I, and C-protein→hastened relaxation of human atria from nonfailing hearts. However, in feline and rodent myocardium, catecholamines and zinterol usually do not hasten relaxation through activation of β₂-adrenoceptors, presumably because of coupling of the receptors to Gi protein. It is unknown whether the endogenously occurring β₂-adrenoceptor agonist adrenaline acts through the above cascade in human atrium and whether its mode of action could be changed in heart failure. We assessed the effects of (-)-adrenaline, mediated through β₂-adrenoceptors (in the presence of CGP 20712A 300 nM to block β₁-adrenoceptors), on contractility and relaxation of right atrial trabecula obtained from nonfailing and failing human hearts. Cyclic AMP levels were measured as well as phosphorylation of phospholamban, troponin I, and protein C with Western blots and the back-phosphorylation procedure. For comparison, β₁-adrenoceptor-mediated effects of (-)-noradrenaline were investigated in the presence of ICI 118,551 (50 nM to block β₂-adrenoceptors). The positive inotropic effects of both (-)-noradrenaline and (-)-adrenaline were accompanied by reductions in time to peak force and time to reach 50% relaxation. (-)-Adrenaline caused similar positive inotropic and lusitropic effects in atrial trabeculae from failing hearts. However, the inotropic potency, but not the lusitropic potency, of (-)-noradrenaline was reduced fourfold in atrial trabeculae from heart failure patients. Both (-)-adrenaline and (-)-noradrenaline enhanced cyclic AMP levels and produced phosphorylation of phospholamban, troponin I, and C-protein to a similar extent in atrial trabeculae from nonfailing hearts. The hastening of relaxation caused by (-)-adrenaline together with the PKA-catalyzed phosphorylation of the three proteins involved in relaxation, indicate coupling of β₂-adrenoceptors to Gs protein. The phosphorylation of phospholamban at serine16 and threonine17 evoked by (-)-adrenaline through β₂-adrenoceptors and by (-)-noradrenaline through β₁-adrenoceptors was not different in atria from nonfailing and failing hearts. Activation of β₂-adrenoceptors caused an increase in phosphorylase a activity in atrium from failing hearts further emphasizing the presence of the β₂-adrenoceptor–Gsα-protein pathway in human heart. The positive inotropic and lusitropic potencies of (-)-adrenaline were conserved across Arg16Gly- and Gln27Glu-β₂-adrenoceptor polymorphisms in the right atrium from patients undergoing coronary artery bypass surgery, chronically treated with β₁-selective blockers. The persistent relaxant and biochemical effects of (-)-adrenaline through β₂-adrenoceptors and of (-)-noradrenaline through β₁-adrenoceptors in heart failure are inconsistent with an important role of coupling of β₂-adrenoceptors with Giα-protein in human atrial myocardium.     

Anti-diarrhoeal and ulcer-protective effects of violacein isolated from Chromobacterium violaceum in Wistar rats

Violacein was isolated from Chromobacterium violaceum , a soil Gram-negative bacterium collected from the forest water body soil sample from Kolli Hills of Tamil Nadu, India. In the present study the anti-diarrhoeal and ulcer-protective properties of violacein were investigated in Wistar rats using castor oil, magnesium sulphate and ethanol. The intestinal transit in rats was significantly ( P  < 0.001) reduced and gastric emptying was delayed; 40 mg/kg of violacein elicited a greater anti-motility activity than 0.1 mg/kg of atropine. Violacein exhibited ulcer-protective properties against ethanol-induced ulceration in rats with maximal anti-ulcer activity at 40 mg/kg. Violacein also exerted significant anti-enteropooling effects, causing a dose-related inhibitory effect on castor oil-induced enteropooling in rats. A profound anti-diarrhoeal activity was observed when violacein was tested in diarrhoeic rats. The frequencies of defaecation as well as the wetness of the faecal droppings were significantly reduced. Furthermore, violacein (40 mg/kg) produced 87.84% inhibition of castor oil-induced diarrhoea in rats. The results suggested that violacein can be used for the treatment of diarrhoeal and ulcer-related diseases.     

Adriamycin induced spermatogenesis defect is due to the reduction in epididymal adipose tissue mass: a possible hypothesis

Adriamycin is an anthracycline antibiotic used as anticancer drug since past few decades. Though effective against cancer, it is cardiotoxic, nephrotoxic, hepatotoxic and also toxic for reproductive system. Although a number of potential toxic mechanisms have been identified following exposure to adriamycin, the major pathogenic mechanism appears to be the generation of toxic reactive oxygen species (ROS). Animals treated with adriamycin have shown a decrease in total sperm count. This implies that adriamycin impairs the process of spermatogenesis. Epididymal white adipose tissue (EWAT) is necessary for normal spermatogenesis, and decrease in the EWAT causes disturbance in spermatogenesis. Factor X is an unknown molecule synthesized by EWAT that plays crucial role in spermatogenesis. Adriamycin inhibits Kruppel-like factor 4 (KLF-4) and thus downregulates the adipogenesis process needed to maintain the EWAT mass. Apart form adipocytes, KLF-4 and peroxisome proliferator-activated receptor gamma (PPAR-γ) are also found in spermatogonium and testis, implying its vital role in spermatogenesis. Adriamycin treatment inhibits KLF-4 and thus PPAR-γ in EWAT and spermatogonium. Reduction of EWAT might cause a decrease in Factor X level. Declining of Factor X level, KLF-4 and PPAR-γ together will lead to disturbance in spermatogenesis process.     

A novel herbal formulation against dengue vector mosquitoes <Emphasis Type="Italic">Aedes aegypti</Emphasis> and <Emphasis Type="Italic">Aedes albopictus</Emphasis>

The objective of this study was to develop a herbal formulation to control dengue vector mosquitoes. PONNEEM, a novel herbal formulation prepared using the oils of neem (Azadirachta indica), karanj (Pongamia glabra) and their extracts, was tested for larvicidal, ovicidal and oviposition deterrent activities against Aedes aegypti and Aedes albopictus at 1, 0.5, 0.3 and 0.1 ppm concentrations. Cent percent larvicidal and ovicidal activities were observed at 0.1 ppm in the two mosquito species under laboratory and sunlight-exposed conditions up to 12 months from the date of manufacture. Oviposition deterrent activity of 69.97% and 71.05% was observed at 1 ppm concentration of PONNEEM against A. aegypti and A. albopictus, respectively. Reduction in enzyme levels for α-esterase was 0.089 ± 0.008 and 0.099 ± 0.140 μg napthol produced/min/mg larval protein; for β-esterase, it was 0.004 ± 0.009 and 0.001 ± 0.028 μg napthol produced/min/mg larval protein; for glutathione S-transferase, it was 10.4814 ± 0.23 and 11.4811 ± 0.21 μmol/min/mg larval protein and for total protein, it was 0.177 ± 0.010 and 0.008 ± 0.005 mg/individual larva in treated groups of A. aegypti and A. albopictus, respectively. The nontarget organisms such as Gambusia affinis and Diplonychus indicus were not affected. No mortality was observed in control. PONNEEM can be used effectively for the management of human vector mosquitoes.     

Larvicidal activity of pectolinaringenin from Clerodendrum phlomidis L. against Culex quinquefasciatus Say and Aedes aegypti L. (Diptera: Culicidae)

Larvicidal activity of 12 fractions and a compound of chloroform extract of Clerodendrum phlomidis L. (Lamiaceae) was assayed for their toxicity against the early fourth-instar larvae of the filarial vector Culex quinquefasciatus Say and dengue vector Aedes aegypti L. The fractions were tested at 100-, 50-, 25- and 12.5-ppm concentrations. The compound pectolinaringenin was tested at 5-, 2.5-, 1.0- and 0.5-ppm concentrations. Among the different fractions, fraction 5 recorded the lowest LC(50) and LC(90) values of 5.02, 61.63?ppm and 32.86, 73.62?ppm against C. quinquefasciatus and A. aegypti, respectively. The compound pectolinaringenin showed the lowest LC(50) and LC(90) values of 0.62, 2.87?ppm and 0.79, 5.31?ppm against C. quinquefasciatus and A. aegypti, respectively. This is the first report on the mosquito larvicidal activity of the isolated compound pectolinaringenin from C. phlomidis. The results of this study show that the chloroform extract of C. phlomidis can be used as a potent source and pectolinaringenin as a new natural mosquito larvicidal agent.     

Hypolipidemic activity of <Emphasis Type="Italic">Symplocos cochinchinensis</Emphasis> S. Moore leaves in hyperlipidemic rats

The hypolipidemic activity of Symplocos cochinchinensis S. Moore leaves was studied in Triton WR-1339- and high fat diet-induced hyperlipidemic rats. In Triton WR-1339-induced hyperlipidemic rats, the hexane extract (250 and 500 mg/kg) exerted a significant (P < 0.01) lipid-lowering effect compared to ethyl acetate and methanol extracts, as assessed by the reversal of the plasma levels of total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C). In high fat diet-fed hyperlipidemic rats, the hexane extract (250 and 500 mg/kg) caused the lowering of lipid levels in the plasma and liver. The hypolipidemic activity of S. cochinchinensis leaves was compared with fenofibrate, a known lipid-lowering drug, in both models.     

Antidiabetic and antioxidant activities of Toddalia asiatica (L.) Lam. leaves in Streptozotocin induced diabetic rats

Ethnopharmacological relevance

The leaves of Toddalia asiatica (L.) Lam. have been utilized traditionally for the cure of diabetes.

Aim of the study

The present study was aimed to assess the antidiabetic and antioxidant effects of T. asiatica leaves in Streptozotocin (STZ) induced diabetic rats.

Materials and methods

The phytochemical screening, total phenolic content, HPLC analysis, acute toxicity study and oral glucose tolerance test were carried out. Glucose lowering effect of the hexane, ethyl acetate and methanol extracts of T. asiatica leaves was studied in STZ-induced diabetic rats. The antidiabetic and antioxidant activities were studied for the ethyl acetate extract. The effects of extracts on blood glucose, body weight, plasma insulin, total protein, liver glycogen, plasma enzymes (SGOT, SGPT and ALP) and activities of SOD, CAT and GPx were analyzed.

Results

T. asiatica leaves ethyl acetate extract (TALEe) showed highly significant blood glucose lowering effect. Phytochemical evaluation of TALEe showed the presence of alkaloids, terpenoids, cumarins, flavonoids and phenolic compounds. The total phenolic content of TALEe was 126 mg of gallic acid equivalents/g extract. HPLC analysis revealed the presence of flindersine and ulopterol. Acute toxicity study of TALEe revealed no death or toxicity. The oral glucose tolerance test showed lowered area under curve (AUC_glucose) values in TALEe treated rats. After treatment with TALEe (250 and 500 mg/kg) for 28 days there was a significant decrease in blood glucose, plasma enzymes (SGOT, SGPT and ALP) and significant increase in body weight, total protein, serum insulin and liver glycogen levels in treated diabetic rats. The activities of antioxidant enzymes SOD, CAT and GPx were reversed to near normal in treated diabetic rats. Histopathology of pancreas in TALEe treated groups showed regeneration of β-cells.

Conclusion

The results of the experiments showed that TALEe exerted significant antidiabetic and antioxidant effects in STZ-induced diabetic rats justifying its traditional use.     

The role of ECMO in COVID-19: Can it provide rescue therapy in those who are critically ill?

Arising from the city of Wuhan, Hubei province in China, a novel coronavirus named severe acute respiratory syndrome coronavirus 2 has been rapidly spreading since its first presentation in late 2019. The World Health Organization declared a pandemic on the 11th March 2020, and as of 29th of April 2020 more than 3 million cases have been reported worldwide with over 225 000 confirmed deaths. Where mechanical ventilation may not be enough, extracorporeal membrane oxygenation (ECMO) could play a role as a form of rescue therapy and may provide beneficial results in the hands of skilled clinicians in centers with experience of using ECMO appropriately in selected patients. Our understanding of COVID-19 is ever-changing and the need for intensive care beds is rising, which means that ECMO will surely play a key role in the near future.     

Protective effects of Ficus carica leaves on glucose and lipids levels,carbohydrate metabolism enzymes and β-cells in type 2 diabetic rats

Context: The decoctions of Ficus carica Linn. (Moraceae) leaves are used in the folklore treatment of diabetes.

Objective: To evaluate the effect of F. carica on glucose and lipids levels, carbohydrate metabolism enzymes and β-cells protective effects in type 2 diabetes.

Material and methods: Diabetes was induced in 15 days high-fat diet (HFD)-fed Wistar rats by intraperitoneal injection of streptozotocin (STZ) (40?mg/kg). The ethyl acetate extract (250 and 500?mg/kg) of F. carica leaves was administered for 28 days. Oral glucose tolerance (OGTT) and intraperitoneal insulin tolerance tests (ITT) were evaluated on 15th and 25th days, respectively.

Results: The ethyl acetate extract (250 and 500?mg/kg) of n F. carica leaves showed significant effect (p?F. carica (250 and 500?mg/kg) significantly (p?F. carica enhanced the glucose utilization significantly (p?<?0.005) over 30 and 60?min compared to diabetic control. Further, the altered activities of key carbohydrate metabolizing enzymes such as glucose-6-phosphatase, fructose-1,6-bisphosphatase and hexokinase in the liver tissue of diabetic rats were significantly (p?F. carica. Immumohistochemical studies of islets substantiated the cytoprotective effect on pancreatic β-cells.

Discussion and conclusions: F. carica leaves exerted significant effect on carbohydrate metabolism enzymes with promising hypoglycemic and hypolipidemic activities in type 2 diabetic rats.