Biased G Protein-Coupled Receptor Signaling: New Player in Modulating Physiology and Pathology

G protein-coupled receptors (GPCRs) are a family of cell-surface proteins that play critical roles in regulating a variety of pathophysiological processes and thus are targeted by almost a third of currently available therapeutics. It was originally thought that GPCRs convert extracellular stimuli into intracellular signals through activating G proteins, whereas β-arrestins have important roles in internalization and desensitization of the receptor. Over the past decade, several novel functional aspects of β-arrestins in regulating GPCR signaling have been discovered. These previously unanticipated roles of β-arrestins to act as signal transducers and mediators of G protein-independent signaling have led to the concept of biased agonism. Biased GPCR ligands are able to engage with their target receptors in a manner that preferentially activates only G protein- or β-arrestin-mediated downstream signaling. This offers the potential for next generation drugs with high selectivity to therapeutically relevant GPCR signaling pathways. In this review, we provide a summary of the recent studies highlighting G protein- or β-arrestin-biased GPCR signaling and the effects of biased ligands on disease pathogenesis and regulation.

Portal hypertension treatment with candesartan plus propranolol for nine months restores normal portal circulation hemodynamic pattern

Post HCV liver cirrhosis is one of the most prominent etiologies behind the abnormal portal circulation hemodynamics. It occurs as a result of distorted balance between portal venous flow [PVF] and intrahepatic resistances [IHR]. PVF is partially controlled by using both specific and non-specific beta blockers [NSBBs] that have insignificant effects on IHR. Angiotensin receptor blockers [ARBs] inhibit the activated hepatic stellate cell [HSC] contraction and thought to reduce the dynamic portion of MR. The study aimed to slow down the venous blood flow and to reduce the IHR of portal vein vasculature to control sequelae of the enhanced post cirrhosis portal venous turbulence. We evaluated the effects of Candesartan plus propranolol compared to each of them individually in management of portal hypertension [PH]. Three groups of 25 patients each, presented with chronic HCV infection and grade II- III esophageal varices [OV], were randomly assigned to one of three treatment regimens: Propranolol or Candesartan or both. Subjects were screened every three month by Doppler Ultrasound for a total of nine months. Damping Index [DI], pulse Pulsatility index [PT], Portal Venous Flow [PVF] Volume, Portal Venous Peak Velocity [PVPV], and Portal Vein Diameter [PVD] were evaluated once every third month. Our study concluded that combined therapy [Propranolol + Candesartan] induced highly significant improvements that led to restoration of normal values of DI, PI, PVF volume and PVPV overtime compared to monotherapy regimens [P>0.001]. Data strongly recommended using Propranolol plus Candesartan in overtime management of portal hypertension

Correlation between D-dimer, N- Terminal pro atrial natriuretic peptide, and left atrial size in patients with chronic nonvalvular atrial fibrillation

In patient with chronic nonvalvular atrial fibrillation [AF], the correlation between prothrombotic marker D-dimer, N-terminal pro-atrial natriuretic peptide [NT-ANP], and left atrial [LA] size is not completely understood also, the precise effect of hypercoagulability is not well known to date. Therefore, this study was performed to determine whether prothrombotic state presented by increase level of D-dimer in patients with chronic nonvalvular AF, as well as NT-ANP were correlated with left atrial size and risk of thromboembolic events. A 43 patients with chronic nonvalvular atrial fibrillation with prior cerebrovascular cardioembolic event and 35 without cardioembolic event were studied for echocardiographic LA size, D-dimer level and NT-ANP. the LA size and D-dimer were significantly high in patients with cardioembolic stroke than patients without cardioembolic stroke [P value <0,05], no significant difference in NT-ANP in both groups [P value >0.05], a positive linear correlation was found between the increased D-dimer level and LA size [r=0.42, P<0.01]. No correlation was found between NT-ANP level and the LA size. the present study concluded that the prothrombotic marker D-dimer is elevated in patient with chronic nonvalvular AF, this marker showed positive linear correlation to the left atrial size and cardioembolic risk of stroke making it a significant marker for risk stratification for those patient whom at high risk, the result also opened a rational for use of warfarin in those patient with elevated D-dimer

Impact of percutaneous balloon mitral valvuloplasty on right and left ventricular functions assessed by tissue Doppler imaging

Pure mitral stenosis affect left ventricular performance as a result of myocardial and mechanical factors. It has been found that, with increase in pulmonary artery pressure, the right ventricle may hypertrophy and dilate, and right ventricular ejection fraction decreases. Pulsed TDI has been used for the evaluation of impaired systolic or diastolic function. Percutaneous mitral valvotomy has proven to be effective technique for the relief of obstruction in patients with mitral stenosis. However, the results of the studies about the effect of percutaneous mitral balloon valvuloplasty [PMBV] on ventricular functions are controversial. Of this study was to assess right and left ventricular functions using Doppler tissue imaging [DTI] before and after percutaneous mitral valvuloplasty two days after and at 3 months follow up. We studied 30 selected thirty patients with symptomatic mitral stenosis of rheumatic etiology, who were admitted for percutaneous mitral valvuloplasty and another twenty normal disease free subjects, as proved by electrocardiography ECG and Doppler-echocardiography, thirteen were females and seven were males. All patients were subjected to history analysis, clinical examination, ECG analysis, transthoracic echo Doppler study to asses mitral valve area and trans mitral diastolic gradient, transoesophageal echo study to exclude left atrial cavity or appendage thrombi and lastly pulsed TDI to asses right and left ventricular functions one day before and two days after percutaneous mitral valvuloplasty and then repeat at 3 months follow up. Significant increase in mitral valve area, drop of transmitral pressure gradient and increase of left and right venticular ejection fraction two days and 3 months after the procedure [p <0.05]. By TDI all the myocardial velocities significantly increased after PMV but still below the normal values of the control group [p < 0.05]. PMV results in significant improvement of systolic myocardial velocities of right and left ventricles two after and at follow up, but these velocities are still below the normal values

Waterborne viruses associated with repeated abortion

In this study we tried to find the role of some waterborne viruses in repeated abortion of women. The study includes maternal blood serum and fetal tissue. The serum of full term delivered women was taken as a control. All collected samples were inoculated on BGM and Hep2G cells to detect entero and Hepatitis E viruses. Enzyme-linked immunosorbent assay was also carried out for IgM and IgG antibodies against HEV in all serum samples. HEV-Ag was determined by dot-ELISA, which used also for enterovirus typing. Reverse transcriptase polymerase chain reaction was used for detection of entero and HE virus RNAs in the collected serum samples. To follow up the source of virus transmission, the wastewater treatment plant which serves the area of samples population was studied at the intake and the final effluent for the presence of hepatitis E virus and enteroviruses with special reference to coxsackieviruses. Wastewater samples were collected for 1 year and for enterovirus concentration the adsorption-elution on nitrocellulose membrane was used and for HEV, two methods of virus concentration were used, urea arginine phosphate buffer [U-APB] and PEG 8000.The results of HEV investigation of aborted women sera was 22% for IgG, 3% for IgM, 20% HEV-Ag, and 16% of HEV-RNA by RT-PCR. For fetal tissue, HEV-Ag was detected in 5% of the collected samples. The detected enteroviruses were coxsackieviruses types 2, 3,4and 5 in all serum samples and wastewater samples. The results showed also, that virus concentration by U-APB is much better than PEG-8000 but not highly efficient