Chemopreventive and Therapeutic Efficacy of Enhalus Acoroides Against Diethylnitrosamine Induced Hepatocellular Carcinoma in Wistar Albino Rats

Background: Hepatocellular carcinoma plays an inadequate mention in the second cause of death because of cancer worldwide. An alternative therapy with high rate of prognosis and also without side effects. Several data indicated the therapeutic efficacy of Enhalus acoroides. There were no scientific studies on chemopreventive and antioxidant potential of Enhalus acoroides against hepatocellular carcinoma.Purpose: To investigate the hepatoprotective efficacy of ethanolic extract of Enhalus acoroides (EEEA) against DEN induced hepatocellular carcinoma using wistar albino rats.Study design: Animals were divided into five groups each comprising six rats. Normal saline given to Group I- Control rats. By using DEN, liver cancer was induced to Group II, III, IV and V rats as single intraperitoneally injection (100 mg/kg body weight). At the beginning of 6th week, Groups III rats received EEEA (200mg/kg body weight/day) upto 16 weeks. Group IV rats received EEEA for one week before the administration of DEN and continued till the 16th week. After the administration of DEN, Group V positive control rats received Silymarin (100 mg/kg body weight) at the beginning of 6th week and continued upto 16 weeks. The efficacy of Enhalus acoroides for its Hepatoprotective and antioxidant properties during its simultaneous treatment against DEN induced liver damage was evaluated in rats. Methods: The hepatoprotective efficacy of EEEA (200 mg/kg) was investigated against DEN (100 mg/kg/b.w) induced hepatotoxicity, was measured by evaluating serum liver markers levels (ALT, AST, GGT and ALP), Kidney markers (Urea and Creatinine), Lipid profile (TG, HDL, LDL & Total cholesterol) and Serum tumor markers (DNA, RNA, AFP and CEA). EEEA-aided antioxidant defence against hepatotoxic insult of DEN was measured by evaluating various Antioxidant biomarkers (GSH, SOD, CAT, GPx, Vit C and Vit E) Morphometric gross analysis and Histopathological studies were done to support the outcomes of the present study.Results: A significant increased antioxidant defence and reduced MDA levels in the serum of EEEA treated animals compared to the DEN induced animals. The resulting data showed that the administration of EEEA decreased the serum liver markers levels, kidney markers, Lipid profile and serum tumor markers when compared to the untreated rats. The histopathological anomalies were altered on administration of EEEA indicating its protective effects on hepatocytes when compared with untreated rats.Conclusions: Our consequences established that crude ethanolic extract of Enhalus acoroides shown an effective impact against DEN-induced hepatocellular carcinoma, and serves as a better option for chemopreventive treatments.

Proinflammatory and Hepatic Features Related to Morbidity and Fatal Outcomes in COVID-19 Patients

Objective: to screen putative associations between liver markers and proinflammatory-related features concerning infectious morbidity and fatal outcomes in COVID-19 patients. Methods: a total of 2094 COVID-19 positive patients from the COVID-DATA-SAFE-LIFES cohort (HM hospitals consortium) were classified according to median values of hepatic, inflammatory, and clinical indicators. Logistic regression models were fitted and ROC cures were generated to explain disease severity and mortality. Results: intensive care unit (ICU) assistance plus death outcomes were associated with liver dysfunction, hyperinflammation, respiratory insufficiency, and higher associated comorbidities. Four models including age, sex, neutrophils, D-dimer, oxygen saturation lower than 92%, C-reactive protein (CRP), Charlson Comorbidity Index (CCI), FIB-4 and interactions with CRP, neutrophils, and CCI explained ICU plus death variance in more than 28%. The predictive values of ROC curves were: FIB-4 (0.7339), AST/ALT ratio (0.7107), CRP (0.7003), CCI index (0.6778), neutrophils (0.6772), and platelets (0.5618) concerning ICU plus death outcomes. Conclusions: the results of this research revealed that liver and proinflammatory features are important determinants of COVID-19 morbidity and fatal outcomes, which could improve the current understanding of the COVID-19 physiopathology as well as to facilitate the clinical management and therapy decision-making of this disease under a personalized medicine scope.

Effects of silybin supplementation on nutrient digestibility, hematological parameters, liver function indices, and liver-specific mi-RNA concentration in dogs

Background Hepatopathies are an important group of disorders in dogs where proper nutritional care is crucial. Supplementation with a hepatoprotectant like silybin can improve liver function and should not interfere with nutrient digestibility. The purpose of this study was to investigate the effect of both pure silybin and commercial hepatoprotectant on nutrients digestibility, liver function indices and health status in healthy dogs (EXP1). Moreover, the second experiment (EXP2) investigated the effect of commercial hepatoprotectant on liver function tests and liver-associated miRNAs concentration in dogs with idiopathic liver disorder. Results Nutrient digestibility was not affected by treatment in EXP1. Supplementation did alter the serum fatty acid profile, with no clinical relevance. The levels of liver markers such as ALT, AST and GGT significantly decreased. In EXP2, supplementation with commercial hepatoprotectant containing silybin improved liver function tests. A decrease was observed in liver serum markers such as ALT, AST and miR122 concentration. Conclusions EXP1 confirmed that silybin (whether pure or as a commercial hepatoprotectant) does not interfere with digestion which subsequently exerts no detrimental effect on dogs’ health and metabolism. In EXP2, dietary supplementation with commercial hepatoprotectant containing silybin resulted in a decreased activity of serum liver markers, accompanied by a decrease in the concentration of liver-specific miRNA molecules. Liver function indices were consequently improved. Silybin supplementation can thus serve as an effective therapeutical tool in dogs with hepatopathies.

Hepatoprotective Effects of Chitosan on Thioacetamide-Induced Liver Toxicity in Male Albino Rats

Chitosan, a natural product derived from chitin, has attracted much attention as a promising polysaccharide compound, owing to its unique biological activities. This study was designed to explore the possible improving potential of chitosan, as a natural marine product, on liver regeneration in hepatotoxicity induced by thioacetamide in male albino rats. Fifty animals were divided into 5 groups, including the control group; a group which was injected intraperitoneally with a single dose of thioacetamide(300 mg/kg b. wt) for induction of liver toxicity; a group received a diet containing 5% chitosan for 14 days; a group received a diet containing 5% chitosan for 14 days then they were injected with thioacetamide(300 mg/kg b. wt) once, and the last group which was injected with thioacetamide(300 mg/kg b. wt) once then received a diet containing 5% chitosan for 14 days. The biochemical results revealed that the intake of chitosan before or after thioacetamide intoxication improved liver markers (ALAT, ASAT, GGT, ALP, albumin) and kidney functions and also plasma TNF-α. QRT- PCR analysis revealed that chitosan downregulated hepatic TNF-α, survivin, and c-Myc quantitative gene expression. Moreover, chitosan improved the histological picture of the liver. This study indicated the promising action of chitosan in liver regeneration.

Edoxaban, a direct oral factor Xa inhibitor, ameliorates coagulation, microvascular thrombus formation, and acute liver injury in a lipopolysaccharide-induced coagulopathy model in rats

Infection increases the risk of thrombosis through the activation of inflammation and coagulation. Edoxaban, a direct oral factor Xa inhibitor, is used for the prevention and treatment of thrombotic diseases. The aim of this study was to determine the effects of edoxaban on microvascular thrombus formation in a rat model of lipopolysaccharide (LPS)-induced coagulopathy. Rats were intravenously injected with 7.5 mg/kg of LPS (Escherichia coli 055:B5). Immediately after LPS injection, the rats were treated with subcutaneous injection of edoxaban. At 2 and 6 h after the injection of LPS, biomarkers of coagulation and organ damages and inflammatory cytokines were measured. Microvascular thrombus formation in organs was evaluated using 125I-fibrinogen (human) or by the pathological analysis. Mortality was examined 24 h after LPS injection. After the injection of LPS, D-dimer and thrombin-antithrombin complex increased and platelet numbers decreased, indicating the activation of coagulation. Microvascular thrombi were found in the liver. Markers of liver injury (aspartate aminotransferase and alanine aminotransferase) also increased. Treatment with edoxaban attenuated the changes in the coagulation markers and microvascular thrombus formation in the liver. Edoxaban suppressed the increase in the liver injury markers and reduced the mortality. Edoxaban did not affect the levels of inflammatory cytokines. In conclusions, edoxaban significantly inhibited the activation of coagulation, the formation of microvascular thrombus in the liver and the liver damage, and reduced mortality in rats injected with LPS. These results suggest that the FXa inhibition by edoxaban might be a beneficial therapy for the management of infection-associated thrombosis.

Effects of Silybin Supplementation on Nutrient Digestibility, Hematological Parameters, Liver Performance, and Liver-specific mi-RNA Concentration in Dogs

BackgroundHepatopathies are an important group of disorders in dogs, where proper nutritional care is crucial. Supplementation with a hepatoprotectant like silybin can improve liver performance, subsequently it should not interfere with nutrient digestibility. The purpose of the study was to investigate the effect of either pure silybin or commercial hepatoprotectant on nutrients digestibility, liver performance and health status in healthy dogs (EXP1). Moreover, the second experiment (EXP2) investigated the effect of commercial hepatoprotectant on liver laboratory test and liver-associated miRNA concentrations in dogs with idiopathic liver disorder. ResultsNutrient digestibility was not affected by treatment in EXP1. Supplementation did not affect serum fatty acid profile, with the exception of C20:5 n3. The levels of liver markers such as ALT, AST and GGT significantly decreased. In EXP2, supplementation with commercial hepatoprotectant containing silybin improved liver laboratory test. A decrease was observed in liver serum markers and miR122 concentration.ConclusionsEXP1 confirmed that silybin (whether pure or as a commercial hepatoprotectant) does not interfere with digestion and subsequently exerts no detrimental effect on dogs’ health and metabolism. In EXP2, dietary supplementation with commercial hepatoprotectant containing silybin resulted in decreased activity of serum liver markers, accompanied by a decrease in the concentration of liver-specific miRNA molecules. Liver performance was consequently improved. Silybin supplementation can thus serve as an effective therapeutical tool in dogs with hepatopathies.

Placenta Morphological and Amniotic Fluid Biochemical Changes Associated with Mid-Gestation Single and Twin Pregnancies in Red Sokoto Goats

Fetal fluids and placentas, which are important in feto-maternal homeostasis, could be affected by the number of developing fetuses. Therefore, placenta morphological and amniotic fluid biochemical changes associated with single and twin pregnancies in Red Sokoto goats were studied. Using Richardson’s formula, 2.1 × [CRL (cm) + 17], 12 intact gravid uteri (7 single-pregnant and 5 twin-pregnant) from mid-gestation [≈70-100 days gestational age (dGA)] pregnant goats were purposively selected. Feto-maternal biometrics [gravid uterine weight (GUW), total placental fluid volume (TPFV), average placentome diameter (APD), mean crown-rump length (MCRL), mean gestational age (MGA), mean fetal weight (MFW), total placentome number (TPN), and average interplacentomal distance (AID)]; amniotic fluid electrolytes [sodium (Na), potassium (K), chloride (Cl), calcium (Ca) and phosphorus (P)]; total protein; glucose; liver markers (AST and ALT); kidney markers (urea and creatinine), and cortisol concentrations were measured. The histology of the placentomes and the interplacentomal areas was also studied. The twin-pregnant (TP) goats had significantly higher (P<0.05) GUW, TPFV, APD, amniotic fluid glucose and cortisol; and lower (P<0.05) Ca levels. The rest of the parameters assessed did not differ between the TP and single-pregnant (SP) groups. Placentomes and the interplacentomal areas from the TP group had more diffuse villous inter-digitations and thicker luminal endothelium, respectively. It was concluded that TP Red Sokoto goats regulated placentome morphology, calcium, glucose and cortisol levels in order to achieve optimal conditions for the dams and the fetuses.

Abstract 15924: Identification of Gender- and Age-specific Top Predictors of Hospitalization Due to Heart Failure Using Machine Learning in TOPCAT

Background: NHLBI supported Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist trial (TOPCAT) (NCT00094302) investigated whether treatment with spironolactone reduces hospitalization due to heart failure (hHF) in 3,445 adults with prior heart failure and a left ventricular ejection fraction over 45%. We reused publicly available individual patient-level data from NHLBI Data Repository (BioLINCC) to perform hypothesis-generating secondary analyses by machine learning (ML) on the American TOPCAT cohort (n=1767) to identify gender and age groups specific baseline (bl) predictors of hHF. Methods: The subjects were stratified into subgroups based on gender (male and female) and age (50-59, 60-69, 70-79, 80-90). Random Survival Forest (RSF), a non-parametric ML approach, evaluated 172 bl variables as predictors of hHF. Top 10 predictors were subsequently included in a multivariate Cox proportional hazards model. Results: The top 10 predictors of hHF are shown in Figure 1. Overall, renal and hematological biomarkers appeared prominently in the top 10 predictors for these patients. While liver markers were among top predictors for hHF in males, diabetes treatment and diabetic complications were top predictors for females. Also, diabetic treatment was a top predictor among age group 50-59, diabetic complications were top predictors among age groups 50-59 and 70-79, liver markers were top predictors among age groups 70-79, and race and years of smoking were top predictors among age group 60-69. Importantly, the use of potassium sparing diuretic at bl was the top predictor among age group 80-90. Conclusion: Using ML, we uncovered in an unbiased fashion, otherwise overlooked bl predictors of hHF in a large, international, multi-center trial like TOPCAT. Thus, ML can help to identify similarities and differences of disease and treatment outcomes among gender, race, ethnicity, and age specific subgroups and advance precision medicine.

Impact of A Cargo-Less Liposomal Formulation on Dietary Obesity-Related Metabolic Disorders in Mice

Current therapeutic options for obesity often require pharmacological intervention with dietary restrictions. Obesity is associated with underlying inflammation due to increased tissue macrophage infiltration, and recent evidence shows that inflammation can drive obesity, creating a feed forward mechanism. Therefore, targeting obesity-induced macrophage infiltration may be an effective way of treating obesity. Here, we developed cargo-less liposomes (UTS-001) using 1,2-dioleoyl-sn-glycero-3-phosphocholine, DOPC (synthetic phosphatidylcholine) as a single-agent to manage weight gain and related glucose disorders due to high fat diet (HFD) consumption in mice. UTS-001 displayed potent immunomodulatory properties, including reducing resident macrophage number in both fat and liver, downregulating liver markers involved in gluconeogenesis, and increasing marker involved in thermogenesis. As a result, UTS-001 significantly enhanced systemic glucose tolerance in vivo and insulin-stimulated cellular glucose uptake in vitro, as well as reducing fat accumulation upon ad libitum HFD consumption in mice. UTS-001 targets tissue residence macrophages to suppress tissue inflammation during HFD-induced obesity, resulting in improved weight control and glucose metabolism. Thus, UTS-001 represents a promising therapeutic strategy for body weight management and glycaemic control.