Therapeutic potential of probiotics - Lactobacillus plantarum UBLP40 and Bacillus clausii UBBC07 on thioacetamide-induced acute hepatic encephalopathy in rats.

PURPOSE: Hepatic encephalopathy (HE) or hepatic coma is a demanding, not utterly understood complication of acute and chronic liver dysfunction and portosystemic shunting. In HE, hyperammonemia and inflammatory responses are believed to act in synergism. Probiotics, Lactobacillus plantarum UBLP40 and Bacillus clausii UBBC07 reduce small intestinal bacterial overgrowth and hyperammonemia, thereby preventing HE development. METHODS: The effect of probiotics-Lactobacillus plantarum UBLP40 (107 CFU/day, 14 days) and Bacillus clausii UBBC07 (107 CFU/day, 14 days) combination and standard drug-lactulose (2.5 ml/kg in 3 divided doses, 14 days) was studied in thioacetamide (250 mg/kg for three days) induced acute HE in rats by measuring behavioural parameters, biochemical parameters (serum AST, ALT, ALP and ammonia level), neurochemical parameters and histopathology study in brain and liver. RESULTS: In contrast to only thioacetamide treated rats, probiotics treatment substantially (p < 0.001) reduced liver function parameters, i.e. serum AST, ALT, ALP, and ammonia, improved behaviour parameters, i.e. decreased motor disruption, improved memory impairment. Probiotics treated rats have also shown a substantial improvement in oxidative stress parameters i.e. reduced lipid peroxidation and increased glutathione level in brain tissue and ameliorated the histopathological changes induced by thioacetamide in the brain and liver. CONCLUSIONS: It can be concluded based on the findings that the combination therapy of Lactobacillus plantarum UBLP40 and Bacillus clausiiUBBC07 proves to be effective in acute hepatic encephalopathy in the preclinical stage, and further studies are required to assess this therapy potential in the clinical setting.

Enhanced oral bioavailability of nintedanib esylate with nanostructured lipid carriers by lymphatic targeting: In vitro, cell line and in vivo evaluation.

The present research work was aimed to explore the ability of nanostructured lipid carriers (NLCs) to improve oral bioavailability of Nintedanib esylate (NE) via lymphatic uptake. The NE loaded NLCs (NE-NLCs) were fabricated using high speed homogenization followed by probe sonication method and physiochemically characterized. The NE-NLCs had particle size of 125.7 ± 5.5 nm, entrapment efficiency of 88.5 ± 2.5% and zeta potential of -17.3 ± 3.5 mV. DSC and XRD studies indicated that NE was converted to amorphous form. TEM images showed uniformly distributed spherical shaped particles. In vitro release study of NE-NLCs showed drug release of 6.87 ± 2.72% in pH 1.2 and 92.72 ± 3.40% in phosphate buffer pH 6.8 and obeyed higuchi model. Lipolysis study showed higher amount of drug in aqueous layer in NE-NLCs compared to NE-suspension. Tissue distribution study showed deeper penetration of FITC loaded NLCs compared to FITC solution. The cellular uptake across Caco-2 cells exhibited more uptake of FITC loaded NLCs. Cytotoxicity study using A549 cell line revealed higher potential of NE-NLCs in inhibiting tumor cell growth in comparison to that of suspension. The oral bioavailability of NE was ameliorated over 26.31 folds after inclusion into NLCs in contrast to NE-suspension. Intestinal lymphatic uptake of NE-NLCs in cycloheximide treated mice was lower as compared to control without cycloheximide treatment. Thus, the developed NE-NLCs can be an encouraging delivery strategy for increasing oral bioavailability of NE via lymphatic uptake.

Nanostructured Lipid Carriers- A Versatile Carrier for Oral Delivery of Lipophilic Drugs.

BACKGROUND: Around 40% of newly discovered chemical entities in pharmaceutical industries have poor water solubility and hence they suffer from low oral bioavailability owing to undesirable physicochemical and pharmacokinetic properties. So, it is the challenge for the formulation scientists to develop the oral formulation that can mitigate the pitfalls associated with such lipophilic drugs. METHODS: Lipid nanoparticles hold a promising tool to decrease the pitfalls of lipophilic drugs as lipid components can effectively increase the absorption of drugs, which leads to improvement in oral bioavailability. They are also considered as safe because they are made up of physiological lipids, which are biocompatible and biodegradable in nature. Amongst the lipid nanoparticles, Nanostructured Lipid Carriers (NLCs) are the second-generation lipid nanoparticles and were developed to conquer the limitations of solid lipid nanoparticles. They increase the solubility, permeability, reduce metabolism, P-glycoprotein efflux, and thereby increase the bioavailability of poorly soluble drugs. CONCLUSION: This review highlights the various aspects of NLCs, such as structural components, types, in vivo fate, pharmacokinetic, toxicity, recent applications, and patent reviews of NLCs in drug delivery.

Therapeutic Prospective of a Spore-Forming Probiotic-Bacillus clausii UBBC07 Against Acetaminophen-Induced Uremia in Rats.

To screen Bacillus clausii UBBC07 as a putative probiotic strain and to examine the protective effect of probiotic-B. clausii UBBC07 spore on uremia on rats induced by acetaminophen. In vitro tests performed to screen potential probiotic strains were gastric and bile acid resistance and ability to reduce pathogen adhesion to surfaces. An in vivo study was performed on rats (n = 18) which were randomly divided into three groups: group I, control-receives normal food and water, groups II and III receive acetaminophen i.p. at the dose of 550 mg/kg/day for 10 days, groups III was treated with B. clausii UBBC07 at a dose of 1 × 109 CFU/day for 15 days. Urea, creatinine, malondialdehyde (MDA), and GSH levels and antioxidant enzymes like super oxide dismutase (SOD) and catalase activity were considered to analyze renal failure. Plasma urea and creatinine levels (p < 0.05) significantly increase and SOD, catalase, and GSH activity level significantly decrease in group II as compared with the control group. After treatment with probiotic, there was a significant increase in SOD and catalase (p < 0.05) and a significant decrease in serum urea, creatinine, and MDA (p < 0.05) in group III in response to group II. The results also revealed that probiotic was able to tolerate pH 3.0-9.0 and 0.3% bile salt. The present study suggests that B. clausii UBBC07 could be used as a novel alternative natural therapy for uremia, a major syndrome of CKD.

Oxidative stress induces club cell proliferation and pulmonary fibrosis in Atp8b1 mutant mice.

Atp8b1 (ATPase, aminophospholipid transporter, class I, type 8B, member 1) is a cardiolipin transporter in the apical membrane of lung epithelial cells. While the role of Atp8b1 in pneumonia-induced acute lung injury (ALI) has been well studied, its potential role in oxidative stress-induced ALI is poorly understood. We herein show that Atp8b1G308V/G308V mice under hyperoxic conditions display exacerbated cell apoptosis at alveolar epithelium and aberrant proliferation of club cells at bronchiolar epithelium. This hyperoxia-induced ambivalent response in Atp8b1G308V/G308V lungs was followed by patchy distribution of non-uniform interstitial fibrosis at late recovery phase under normoxia. Since this club cell abnormality is commonly observed between Atp8b1G308V/G308V lungs under hyperoxic conditions and IPF lungs, we characterized this mouse fibrosis model focusing on club cells. Intriguingly, subcellular morphological analysis of IPF lungs, using transmission electron microscopy (TEM), revealed that metaplastic bronchiolar epithelial cells in fibrotic lesions and deformed type II alveolar epithelial cells (AECs) in alveoli with mild fibrosis, have common morphological features including cytoplasmic vacuolation and dysmorphic lamellar bodies. In conclusion, the combination of Atp8b1 mutation and hyperoxic insult serves as a novel platform to study unfocused role of club cells in IPF.

The Prevalence and Effect of Comorbid Cystic Fibrosis and Attention Deficit Hyperactivity Disorders on Hospitalizations: A Retrospective Analysis.

INTRODUCTION: The prevalence of attention-deficit/hyperactivity disorder (ADHD) in pediatric cystic fibrosis (CF) patients is comparable to the general population, but the effects of ADHD on CF treatment and the outcomes have been minimally investigated. METHODS: Two cohorts were retrospectively reviewed, pediatric patients with comorbid CF/ADHD and patients with CF only. Each patient with CF/ADHD was age and sex-matched to a CF-only patient based on their most recent pulmonary office visit. Each patient was reviewed for forced expiratory volume in one-second percent predicted (FEV1%pred), body mass index (BMI) percentile, and hospitalizations for one year prior to the last pulmonary visit. RESULTS: A total of 624 patients with CF were identified, with 52 having co-morbid CF/ADHD (8.3%). Of those identified, 46 met inclusion criteria and were analyzed in the CF/ADHD cohort. The mean total hospital admissions between the CF/ADHD cohort and the CF-only cohort were not statistically significant (2.22 vs 1.834, p=.467). The difference between the BMI percentiles was not statistically significant (48.634 vs 38.634, p=.135). The difference between FEV1%pred was statistically significant at 84% for the CF/ADHD group and 74% for the CF-only group (p=.042). CONCLUSION: The difference in total hospital admissions between the CF/ADHD cohort and the CF-only cohort did not reach statistical significance, but the study was underpowered. There was a significant difference between FEV1%pred between the two groups, in favor of the comorbid CF/ADHD population. More research is needed to further evaluate the effects of a comorbid ADHD diagnosis on outcomes in the CF pediatric population.

The role of club cell phenoconversion and migration in idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is an age-related multifactorial disease featuring non-uniform lung fibrosis. The decisive cellular events at early stages of IPF are poorly understood. While the involvement of club cells in IPF pathogenesis is unclear, their migration has been associated with lung fibrosis. In this study, we labeled club cells immunohistochemically in IPF lungs using a club cell marker Claudin-10 (Cldn10), a unique protein based on the recent report which demonstrated that the appearance of Cldn10 in developing and repairing lungs precedes other club cell markers including club cell secretory protein (CCSP). Cldn10-positive cells in IPF lungs displayed marked pleomorphism and were found in varied arrangements, suggesting their phenoconversion. These results were corroborated by immunogold labeling for Cldn10. Further, immunohistochemical double-labeling for Cldn10 and α-smooth muscle actin (α-SMA) demonstrated that aberrant α-SMA signals are frequently encountered near disorganized Cldn10-positive cells in hyperplastic bronchiolar epithelium and thickened interstitium of IPF lungs. Collectively, these data indicate that club cells actively participate in the initiation and progression of IPF through phenoconversion involving the acquisition of proliferative and migratory abilities. Thus, our new findings open the possibility for club cell-targeted therapy to become a strategic option for the treatment of IPF.

Association between maternal symptoms of sleep disordered breathing and fetal telomere length.

STUDY OBJECTIVES: Our investigation aims to assess the impact of symptoms of maternal sleep-disordered breathing, specifically sleep apnea risk and daytime sleepiness, on fetal leukocyte telomere length. PARTICIPANTS AND SETTING: Pregnant women were recruited upon hospital delivery admission. INTERVENTIONS: Sleep exposure outcomes were measured using the Berlin Questionnaire to quantify sleep apnea and the Epworth Sleepiness Scale to measure daytime sleepiness. Participants were classified as "High Risk" or "Low Risk" for sleep apnea based on responses to the Berlin, while "Normal" or "Abnormal" daytime sleepiness was determined based on responses to the Epworth. DESIGN: Neonatal umbilical cord blood samples (N = 67) were collected and genomic DNA was isolated from cord blood leukocytes using Quantitative PCR. A ratio of relative telomere length was derived by telomere repeat copy number and single copy gene copy number (T/S ratio) and used to compare telomere lengths. Bootstrap and ANOVA statistical procedures were employed. MEASUREMENTS AND RESULTS: On the Berlin, 68.7% of participants were classified as Low Risk while 31.3% were classified as High Risk for sleep apnea. According to the Epworth scale, 80.6% were determined to have Normal daytime sleepiness, and 19.4% were found to have Abnormal daytime sleepiness. The T/S ratio among pregnant women at High Risk for sleep apnea was significantly shorter than for those at Low Risk (P value < 0.05), and the T/S ratio among habitual snorers was significantly shorter than among non-habitual snorers (P value < 0.05). Although those with Normal Sleepiness had a longer T/S ratio than those with Abnormal Sleepiness, the difference was not statistically significant. CONCLUSION: Our results provide the first evidence demonstrating shortened telomere length among fetuses exposed to maternal symptoms of sleep disordered breathing during pregnancy, and suggest sleep disordered breathing as a possible mechanism of accelerated chromosomal aging.