A novel model to study mechanisms of cholestasis in human cholangiocytes reveals a role for the SIPR2 pathway.

BACKGROUND: Ductular reactivity is central to the pathophysiology of cholangiopathies. Mechanisms underlying the reactive phenotype activation by exogenous inflammatory mediators and bile acids are poorly understood. METHODS: Using human extrahepatic cholangiocyte organoids (ECOs) we developed an injury model emulating the cholestatic microenvironment with exposure to inflammatory mediators and various pathogenic bile acids. Moreover, we explored roles for the bile acid activated Sphingosine-1-phosphate receptor 2 (S1PR2) and potential beneficial effects of therapeutic bile acids UDCA and norUDCA. RESULTS: Synergistic exposure to bile acids (taurocholic acid, glycocholic acid, glycochenodeoxycholic acid) and TNF-α for 24 hours induced a reactive state as measured by ECO diameter, proliferation, lactate dehydrogenase activity and reactive phenotype markers. While NorUDCA and UDCA treatments given 8 hours after injury induction both suppressed reactive phenotype activation and most injury parameters, proliferation was improved by NorUDCA only. Extrahepatic cholangiocyte organoid stimulation with S1PR2 agonist sphingosine-1-phosphate reproduced the cholangiocyte reactive state and upregulated S1PR2 downstream mediators; these effects were suppressed by S1PR2 antagonist JET-013 (JET), downstream mediator extracellular signal-regulated kinase 1/2 inhibitor, and by norUDCA or UDCA treatments. JET also partially suppressed reactive phenotype after bile acid injury. CONCLUSIONS: We developed a novel model to study the reactive cholangiocyte state in response to pathological stimuli in cholestasis and demonstrated a contributory role of S1PR2 signaling in both injury and NorUDCA/UDCA treatments. This model is a valuable tool to further explore the pathophysiology of human cholangiopathies.

Polysaccharides (pectin, mucilage, and fructan inulin) and their fermented products: A critical analysis of their biochemical, gut interactions, and biological functions as antidiabetic agents.

Diabetes mellitus is a globally metabolic endocrine syndrome marked by a deficiency of insulin secretion (type-1 DM) or glucose intolerance arising from insulin response impairment (type-2 DM) leading to abnormal glucose metabolism. With an increasing interest in natural dietary components for diabetes management, the identification of novel agents witnessed major discoveries. Plant-derived mucilage, pectin, and inulin are important non-starch polysaccharides that exhibit effective antidiabetic properties often termed soluble dietary fiber (SDF). SDF affects sugar metabolism through multiple mechanisms affecting glucose absorption and diffusion, modulation of carbohydrate metabolizing enzymes (α-amylase and α-glucosidase), ameliorating ß-pancreatic cell dysfunction, and improving insulin release or sensitivity. Certain SDFs inhibit dipeptidyl peptidase-4 and influence the expression levels of genes related to glucose metabolism. This review is designed to discuss holistically and critically the antidiabetic effects of major SDF and their underlying mechanisms of action. This review should aid drug discovery approaches in developing novel natural antidiabetic drugs from SDF.

Ameliorating effect of erythropoietin in a severe case of COVID-19: case report.

The COVID-19 pandemic is arguably one of the greatest public health crises since the 1918 influenza pandemic. Although several vaccines have been approved and rolled out, effective antiviral treatment options are very limited. Here, we present a case of severe COVID-19 that failed to respond to the standard interventions and continued to deteriorate. On day 22 of his illness, after informed consent, the patient was administered 4000IU of erythropoietin (EPO) subcutaneously, in the hope of improving his O2 saturation. Positive response was observed in the patient within 24 hours. This prompted us to continued EPO treatment for a total of 42 days until full recovery and discharge. Our findings warrant further studies to ascertain the use of EPO in severe cases COVID-19.

Transient in-stent stenosis at mid-term angiographic follow-up in patients treated with SILK flow diverter stents: incidence, clinical significance and long-term follow-up.

BACKGROUND: Little is known about in-stent stenosis (ISS) in patients with aneurysms treated with flow diverter (FD) stents. The reported incidence in the literature varies significantly. OBJECTIVE: The aim of this study was to assess the incidence, severity, distribution, clinical significance, and possible predictors for ISS. METHODS: Between July 2012 and June 2016 we retrospectively reviewed all patients treated with SILK FDs in our center. Only cases with short-term (4±2 months) and long-term (>1 year) follow-ups with digital subtraction angiograms were included. ISS was graded as mild (<25%), moderate (25-50%) or severe (>50%). The following predictors for ISS were assessed: gender, age, the presence of subarachnoid hemorrhage, aneurysm size, location, occlusion status, and post-stenting angioplasty. RESULTS: Thirty-six patients met the inclusion criteria. At mid-term follow-up, ISS was observed in 16/36 patients (44%). Eleven patients (69%) had mild ISS, three (19%) moderate, and two (12%) severe ISS. ISS was diffuse in 11 patients (69%) and focal in five patients (31%). All patients were asymptomatic. Thirteen patients were maintained on dual antiplatelet therapy and three on aspirin alone. At long-term follow-up, complete ISS resolution was seen in 11 patients, improvement in three and worsening in two patients. No de novo ISS occurrence was observed. On univariate analysis there was no significant predictor for ISS. CONCLUSIONS: Transient ISS after FD deployment is a common asymptomatic finding on mid-term angiographic follow-up. Complete resolution or improvement at long-term follow-up is seen in most patients who are maintained on dual antiplatelet therapy.

Assessment of interleukin 28B genotype as a predictor of response to combined therapy with pegylated interferon plus ribavirin in HCV infected Egyptian patients.

BACKGROUND AND AIM: Single nucleotide polymorphisms (SNPs) of interleukin 28B (IL28B) gene is associated with spontaneous clearance and variable response to combined therapy with pegylated interferon (PEG-IFN) and ribavirin (RBV) in chronic hepatitis C virus (HCV) infected patients. This study aimed at assessing the value of IL28B rs8099917 gene polymorphism in predicting sustained virological response (SVR) among HCV infected Egyptian patients treated with PEG-IFN and RBV. METHODS: Our study was conducted on 153 chronic HCV infected patients treated with PEG-IFN and RBV. Genotyping of rs8099917 near the IL-28B gene was performed by Real Time PCR using Taq-Man probe assay. RESULTS: The overall SVR was achieved in 49.6% of patients. Patients with TT genotype showed significantly higher SVR rate than minor allele (TG/GG) carriers (74% vs. 26%, P=0.004). Logistic regression analysis revealed that TT carriers had 2.8 higher chance for SVR achievement than G allele carriers TG/GG (OR=2.8, 95% CI=1.4-5.6, P=0.004). Younger age, male sex and low activity grading were significant predictors of SVR (P=0.003, P=<0.001 and P<0.001 respectively). High pretreatment AST levels and advanced liver fibrosis were negative predictors of SVR (P=0.04 and P<0.001 respectively). CONCLUSION: IL28B genotype is a significant pre-treatment predictor of response to PEG-IFN/RBV in HCV infected Egyptian patients.

Spironolactone attenuates experimental uremic cardiomyopathy by antagonizing marinobufagenin.

Spironolactone has been noted to attenuate cardiac fibrosis. We have observed that the cardiotonic steroid marinobufagenin plays an important role in the diastolic dysfunction and cardiac fibrosis seen with experimental renal failure. We performed the following studies to determine whether and how spironolactone might ameliorate these changes. First, we studied rats subjected to partial nephrectomy or administration of exogenous marinobufagenin. We found that spironolactone (20 mg/kg per day) attenuated the diastolic dysfunction as assessed by ventricular pressure-volume loops and essentially eliminated cardiac fibrosis as assessed by trichrome staining and Western blot. Next, we examined the effects of spironolactone and its major metabolite, canrenone (both 100 nM), on marinobufagenin stimulation of rat cardiac fibroblasts. Both spironolactone and canrenone prevented the stimulation of collagen production by 1 nM marinobufagenin but not 100 nM marinobufagenin, as assessed by proline incorporation and procollagen 1 expression, as well as signaling through the sodium-potassium-ATPase, as evidenced by protein kinase C isoform delta translocation and extracellular signal regulated kinase 1/2 activation. Both spironolactone and canrenone also altered ouabain binding to cultured porcine cells in a manner consistent with competitive inhibition. Our data suggest that some of the antifibrotic effects of spironolactone may be attributed to antagonism of marinobufagenin signaling through the sodium-potassium-ATPase.

Shelf life of semifried tuna slices coated with essential oil compounds after treatment with anodic electrolyzed NaCl solution.

The main objective of this study was to evaluate the effect of two commonly used essential oils after treatment with anodic electrolyzed NaCl solution in order to extend the shelf life of coated semifried tuna slices. Samples of tuna slices were treated with 100-fold electrolyzed water and coated with an edible solution containing 1% essential oil (0.5% eugenol [E] plus 0.5% linalool [L]). The coated slices were fried at 170 degrees C for 1 min and then stored at 5 and 25 degrees C. Total volatile basic nitrogen of slices treated with electrolyzed water and 1% (E+L) decreased from 15.5 for the nontreated control slices to 9.7 immediately after treatment and remained at a low level (<30) until the end of the storage period (day 20). Treatment with 1% (E+L) significantly suppressed lipid oxidation in coated semifried tuna. Sensory evaluation and microbiological assays showed that treatment with electrolyzed water and 1% (E+L) extended the shelf life of coated semifried slices to 15 and 2 days compared with 5 and 1 days for control slices during storage at 5 and 25 degrees C, respectively.