The Role of the JAK-STAT Signaling Pathway in the Protective Effects of Hepatic Ischemia Post-conditioning Against the Injury Induced by Ischemia/Reperfusion in the Rat Liver.

Purpose: Hepatic ischemic post-conditioning (IPOC) is shown to protect the liver from injury induced by ischemia/reperfusion (IR). However, the mechanism underlying this protection has remained elusive. The present study aimed to investigate the role of the interleukin 6-Janus kinase-signal transducers and activators of transcription (IL-6-JAK-STAT) pathway in the protective effect of hepatic IPOC against the IR-induced injury in the liver. Methods: Twenty-five rats were randomly divided into 5 groups of (1) sham-operated, (2) IR, (3) IR+hepatic IPOC, (4) IR+tofacitinib (TOFA), and (5) IR+TOFA+hepatic IPOC. The changes induced by IR and the effects of different treatments were assessed by enzyme release, histopathological observations, the serum level of IL-6, and the occurrence of apoptosis detected via the expression of the Bax/Bcl-2 ratio. Results: The hepatic IPOC improved the liver injury induced by IR as shown by histological changes, reduction of IL-6 level, aspartate aminotransferase (AST), and alanine aminotransferase (ALT) compared to the IR group (P<0.001, P<0.05, P<0.05, respectively). There was also downregulation of the Bax/Bcl2 ratio in the rats exposed to IR+hepatic IPOC compared with those in the IR group (P<0.05). However, TOFA, an inhibitor of JAK-STAT activity, inhibited the protective effect of hepatic IPOC. Conclusion: It suggests that the protective effect of hepatic IPOC against IR-induced injury may be mediated by activating the IL-6-JAK-STAT pathway.

Efficacy of probiotics for managing infantile colic due to their anti-inflammatory properties: a meta-analysis and systematic review.

BACKGROUND: Infantile colic (IC) is excessive crying in otherwise healthy children. Despite vast research efforts, its etiology remains unknown. PURPOSE: Most treatments for IC carry various side effects. The collection of evidence may inform researchers of new strategies for the management and treatment of IC as well as new clues for understanding its pathogenesis. This review and meta-analysis aimed to evaluate the efficacy and possible mechanisms of probiotics for mananaging IC. METHODS: Ten papers met the study inclusion and exclusion criteria, and the meta-analysis was conducted using Review Manager (RevMan) software and a random-effects model. RESULTS: This meta-analysis revealed that probiotics are effective for treating infantile colic, while the review showed that this efficacy may be due to their anti-inflammatory effects. CONCLUSION: Probiotics may be an important treatment option for managing infantile colic due to their anti-inflammatory properties.

Comparative effects of probiotic and paraprobiotic addition on microbiological, biochemical and physical properties of yogurt.

Paraprobiotics are inactivated probiotics that exert various health and technological benefits making them suitable for production of functional yogurt. In the present study, probiotic yogurt containing Lactobacillus acidophilus ATCC SD 5221 and Bifidobacterium lactis BB-12 and paraprobiotic yogurt containing inactivated form of the mentioned bacteria were produced and were compared regarding microbiological, biochemical, and physical properties during 28 days of storage at refrigerated temperature. Results revealed that the greatest mean pH drop rate, mean acidity increase rate, mean redox potential increase rate, final acidity and final redox potential were observed in yogurt containing inactivated L. acidophilus added before fermentation. The highest lactic acid after 28 days of storage was obtained in samples prepared by addition of paraprobiotic form of L. acidophilus after fermentation. Yogurt samples with B. lactis and L. acidophilus added after fermentation showed the highest and lowest acetic acid level, respectively after 28 days of storage. The samples containing L. acidophilus and B. lactis had the highest acetaldehyde on day 0 while on day 28, L. acidophilus had more impact on acetaldehyde generation in yogurts. Addition of paraprobiotics increased viability of starter cultures. In addition, incorporation of inactivated probiotic cells into yogurt resulted in lower syneresis and the higher WHC compared to probiotic yogurt samples. Regarding color parameters, it was observed that color parameters (a*, b* and L*) were not influenced by paraprobiotic in probiotic and paraprobiotic yogurts. Overall, it can be concluded that incorporation of paraprobiotics into yogurt involves less technological challenges and can be considered as a suitable appropriate alternative for probiotics in development of functional yogurt.

Protective Effect of Opuntia dillenii Haw Fruit against Lead Acetate-Induced Hepatotoxicity: In Vitro and In Vivo Studies.

Lead is one of the most common environmental contaminants in the Earth's crust, which induces a wide range of humans biochemical changes. Previous studies showed that Opuntia dillenii (OD) fruit possesses several antioxidant and anti-inflammatory properties. The present study evaluates OD fruit hydroalcoholic extract (OHAE) hepatoprotective effects against lead acetate- (Pb-) induced toxicity in both animal and cellular models. Male rats were grouped as follows: control, Pb (25 mg/kg/d i.p.), and groups 3 and 4 received OHAE at 100 and 200 mg/kg/d + Pb (25 mg/kg/d i.p.), for ten days of the experiment. Thereafter, we evaluated the levels of alkaline phosphatase (ALP), alanine aminotransferase (ALT), and aspartate aminotransferase (AST), catalase (CAT) activity and malondialdehyde (MDA) in serum, and liver histopathology. Additionally, the cell study was also done using the HepG2 cell line for measuring the direct effects of the extract on cell viability, oxidative stress MDA, and glutathione (GSH) and inflammation tumor necrosis factor-α (TNF-α) following the Pb-induced cytotoxicity. Pb significantly increased the serum levels of ALT, AST, ALP, and MDA and liver histopathological scores but notably decreased CAT activity compared to the control group (p < 0.001 for all cases). OHAE (100 and 200 mg/kg) significantly reduced the levels of serum liver enzyme activities and MDA as well as histopathological scores while it significantly increased CAT activity compared to the Pb group (p < 0.001-0.05 for all cases). OHAE (20, 40, and 80 µg/ml) concentration dependently and significantly reduced the levels of MDA and TNF-α, while it increased the levels of GSH and cell viability in comparison to the Pb group (p < 0.001-0.05 for all cases). These data suggest that OHAE may have hepatoprotective effects against Pb-induced liver toxicity both in vitro and in vivo by its antioxidant and anti-inflammatory activities.

Scale up and pharmacokinetic study of a novel mutated chimeric tissue plasminogen activator (mt-PA) in rats.

Because of high mortality caused by cardiovascular diseases, various fibrinolytic agents with diverse pharmacokinetic and pharmacodynamic properties have been developed. A novel mutated chimeric tissue plasminogen activator (mt-PA) was developed by the removal of first three domains of t-PA, insertion of GHRP sequence and mutation towards resistance to plasminogen activator inhibitor-1 (PAI-1). Mt-PA protein was expressed in Expi293F cells. The expression level of mt-PA was found to be 5000 IU/mL. Following purification, the pharmacokinetic properties of mt-PA were evaluated in three doses in rats. Data related to mt-PA were best fitted to two compartment model. With the increase in dose, the Area Under the plasma concentration-time Curve (AUC0→∞) increased. The elimination half-life (t1/2) of mt-PA was in the range of 19.1-26.1 min in three doses while that of Alteplase was 8.3 min. The plasma clearance (CLp) of mt-PA ranged from 3.8 to 5.9 mL/min in three doses, which was several times lower than that of Alteplase (142.6 mL/min). The mean residence time (MRT) of mt-PA ranged from 23.3-31.8 min in three doses, which was 4-5 times greater than that of Alteplase (6 min). Mt-PA showed extended half-life and mean residence time and is a good candidate for further clinical studies.

Population Pharmacokinetic Analysis of the Oral Absorption Process and Explaining Intra-Subject Variability in Plasma Exposures of Imatinib in Healthy Volunteers.

BACKGROUND AND OBJECTIVE: Imatinib mesylate is presently the first-line treatment for chronic myeloid leukemia (CML). The aim of this study was to investigate the absorption and distribution kinetics of imatinib in healthy Iranian volunteers using nonlinear mixed effects modeling (NLMEM) to assess the overall, intra- and inter-subject variabilities in pharmacokinetic parameters after oral administration. METHODS: This analysis was based on data from 24 healthy subjects who participated in a bioequivalence study after administering a single dose of 200 mg of each formulation. Imatinib concentrations were quantified using a validated liquid chromatography method. To simultaneously describe the imatinib pharmacokinetic profiles obtained with both formulations, a population pharmacokinetic model was applied to data using SAEM algorithm implemented in MONOLIX, whilst simulations were used by numerical solving of ordinary differential equations to calculate secondary parameters in individuals for bioequivalence studies. RESULTS: According to goodness-of-fit criteria, a two-compartment open model with sequential zero- then first-order absorption and first-order elimination was used as the structural pharmacokinetic model. Inter-individual variability (IIV) was considered for all parameters. Typical population estimates (% IIV) were fraction of the drug absorbed with a zero-order kinetic (Fr) of 0.153 (47.9 %) in period (Tk0) of 0.714 h (47.4 %), first-order absorption rate constant (k a) of 0.94 h(-1)(31.2 %), oral clearance of 19 L/h (27.9 %), central volume of distribution (V c/F) of 139 L (21.5 %), apparent peripheral volume of distribution (V p/F) of 130 L (29.7 %) and the apparent inter-compartment clearance (Q/F) of 29.6 L/h (41.8 %). Body mass index (BMI) was the only covariate found to significantly affect V p /F. The coefficient of variation for intra-individual plasma exposure (AUC0-∞) was 27.8 %. CONCLUSIONS: Analyses using NLMEM for imatinib exhibited absorption complexities such as two input rates and medium to high intra-individual variability in drug exposure.

Doxorubicin loaded folate-targeted carbon nanotubes: preparation, cellular internalization, in vitro cytotoxicity and disposition kinetic study in the isolated perfused rat liver.

The objective of this study was to use the functionalized multi-wall carbon nanotubes (CNTs) for the delivery of doxorubicin (DOX). Polyethylene glycol (PEG) chains are attached to CNTs then folate-conjugation of PEGylated CNTs was prepared. The amount of drug loading was calculated by the Multivariate Calibration Method for simultaneous quantification of DOX and CNTs. Cytotoxicity was evaluated using the folate receptor-positive HeLa cell line. To assess distribution and elimination of free DOX and drug-loaded CNTs, a recirculating rat liver perfusion system was used and pharmacokinetic parameters were calculated using non-compartmental analysis. Loading efficiency of 84.3±3.1% and 49.3±5.4% was calculated for low-PEGylated and high-PEGylated CNTs respectively. A higher release rate of DOX was achieved at a higher amount of PEGylation. Folate-targeted CNTs expressed a 3.2-fold decrease in IC50 value compared with non-targeted CNTs. The result from liver perfusion experiments revealed that DOX accumulation in the liver was higher when PEGylation was lower. There was a 2.4-fold decrease in the elimination rate constant compared to free DOX, which was attributed to the redistribution of DOX from hepatocytes in a sustained release pattern that is consistent with an increase in the mean residence time and prolonged circulation. In conclusion, folate-targeted CNTs show great potential as a targeted anticancer delivery system.

Population pharmacokinetics of imatinib in Iranian patients with chronic-phase chronic myeloid leukemia.

PURPOSE: We evaluated the population pharmacokinetics (PPK) and exposure-response relationship of imatinib mesylate in Iranian patients with chronic myeloid leukemia (CML).This study was designed to assess steady state (SS) imatinib trough concentrations (Cmin) and pharmacokinetics parameters of imatinib in patients with CML in chronic phase after at least 12-month treatment. METHODS: Plasma concentrations from a randomized controlled trial consist of 61 patients who received oral imatinib at doses ranged between 300 and 800 mg in various dosing interval, which were quantified using a validated reversed-phase high-performance liquid chromatographic method with UV detection method on different occasions at SS and evaluated using PPK model. RESULTS: A one-compartment model with zero-order absorption and a lag time was sufficient in describing the concentration-time profile. Inter-individual variability (IIV) was modeled for all parameters. Oral clearance (CL/F) and the volume of distribution (V/F) were estimated to 10.8 L/h with 30 % IIV and 265 L with 53 % IIV, respectively. Inter-occasion variability (IOV) was included in CL/F (17 %) and V/F (22 %).The proportional residual error of the model was 8 %. CONCLUSIONS: Simulation analysis from individual parameters shows exposure to imatinib is highly variable among patients. Imatinib trough plasma levels <1,257 ng/mL were associated with lower rates of major molecular response. Because of the wide IIV compared with IOV with imatinib in our study, trough levels may play a role in investigating instances of suboptimal response.

Optimization of the simultaneous determination of imatinib and its major metabolite, CGP74588, in human plasma by a rapid HPLC method using D-optimal experimental design.

A simple, rapid and specific HPLC method has been developed and validated for the simultaneous determination of imatinib, a tyrosine kinase inhibitor, and its major metabolite, CGP74588, in human plasma. The optimization of the HPLC procedure involved several variables, of which the influences of each was studied. After a series of preliminary-screening experiments, the composition of the mobile phase and the pH of the added buffer solution were set as the investigated variables, while the resolution between imatinib and CGP74588 peaks, the retention time and the imatinib peak width were chosen as the dependent variables. Applying D-optimal design, the optimal chromatographic conditions for the separation were defined. The method proved to show good agreement between the experimental data and predictive values throughout the studied parameter range. The optimum assay conditions were achieved with a Chromolith™ Performance RP-8e 100 mm × 4.6 mm column and a mixture of methanol/acetonitrile/triethylamine/diammonium hydrogen phosphate (pH 6.25, 0.048 mol L(-1)) (20:20:0.1:59.9, v/v/v/v) as the mobile phase at a flow rate of 2 mL min(-1) and detection wavelength of 261 nm. The run time was less than 5 min, which is much shorter than the previously optimized methods. The optimized method was validated according to FDA guidelines to confirm specificity, linearity, accuracy and precision.