The Effect of Pringle Maneuver Applied during Living Donor Hepatectomy on the Ischemia-Reperfusion Injury Observed in the Donors and Recipients.

Background and Objectives: The aim of this study is to evaluate the clinical and laboratory changes of ischemia and reperfusion injury in the remnant livers of donors with and without Pringle maneuver. Furthermore, we evaluated the recipients who have been transplanted with liver grafts from these donors. Methods and Materials: A total of 108 patients (54 living liver donors and 54 liver recipients) who underwent donor hepatectomy and recipients who living donor liver transplantation, were included in this randomized double-blind study between February 2021 and June 2021. The donors were divided into two groups: Pringle maneuver applied (n = 27) and Pringle maneuver not applied (n = 27). Similarly, recipients with implanted liver obtained from these donors were divided into two groups as the Pringle maneuver was performed (n = 27) and not performed (n = 27). Blood samples from donors and recipients were obtained on pre-operative, post-operative 0 h day (day of surgery), post-operative 1st day, post-operative 2nd day, post-operative 3rd day, post-operative 4th day, post-operative 5th day, and liver tissue was taken from the graft during the back table procedures. Liver function tests and complete blood count, coagulation tests, IL-1, IL-2, IL-6, TNF-α, and ß-galactosidase measurements, and histopathological findings were examined. Results: There was no statistically significant difference in the parameters of biochemical analyses for ischemia-reperfusion injury at all periods in the donors with and without the Pringle maneuver. Similarly, there was no statistically significant difference between in the recipients in who received liver grafts harvested with and without the Pringle maneuver. There was no statistically significant difference between the two recipient groups in terms of perioperative bleeding and early bile duct complications (p = 0.685). In the histopathological examinations, hepatocyte damage was significantly higher in the Pringle maneuver group (p = 0.001). Conclusions: Although the histological scoring of hepatocyte damage was found to be higher in the Pringle maneuver group, the Pringle maneuver did not augment ischemia-reperfusion injury in donors and recipients that was evaluated by clinical and laboratory analyses.

Ameliorative Effects of Larazotide Acetate on Intestinal Permeability and Bacterial Translocation in Acute Pancreatitis Model in Rats.

BACKGROUND: Intestinal barrier dysfunction in acute pancreatitis (AP) may progress to systemic inflammatory response syndrome (SIRS) and multi-organ failures by causing bacterial translocation. Larazotide acetate (LA) is a molecule that acts as a tight junction (TJ) regulator by blocking zonulin (Zo) receptors in the intestine. AIMS: In our study, we aimed to investigate the effects of LA on intestinal barrier dysfunction and bacterial translocation in the AP model in rats. METHODS: Thirty-two male Sprague-Dawley rats were divided into 4 groups; control, larazotide (LAR), AP, and AP + LAR. The AP model was created by administering 250 mg/100 g bm L-Arginine intraperitoneally 2 times with an hour interval. AP + LAR group received prophylactic 0.01 mg/mL LA orally for 7 days before the first dose of L-Arginine. For intestinal permeability analysis, fluorescein isothiocyanate-dextran (FITC-Dextran) was applied to rats by gavage. The positivity of any of the liver, small intestine mesentery, and spleen cultures were defined as bacterial translocation. Histopathologically damage and zonulin immunoreactivity in the intestine were investigated. RESULTS: Compared to the control group, the intestinal damage scores, anti-Zo-1 immunoreactivity H-Score, serum FITC-Dextran levels and bacterial translocation frequency (100% versus 0%) in the AP group were significantly higher (all p < 0.01). Intestinal damage scores, anti-Zo-1 immunoreactivity H-score, serum FITC-Dextran levels, and bacterial translocation frequency (50% versus 100%) were significantly lower in the AP + LAR group compared to the AP group (all p < 0.01). CONCLUSIONS: Our findings show that LA reduces the increased intestinal permeability and intestinal damage by its effect on Zo in the AP model in rats, and decreases the frequency of bacterial translocation as a result of these positive effects.

Assessment of Liver Regeneration in Patients Who Have Undergone Living Donor Hepatectomy for Living Donor Liver Transplantation.

BACKGROUND: Inflammation and the associated immune pathways are among the most important factors in liver regeneration after living donor hepatectomy. Various biomarkers, especially liver function tests, are used to show liver regeneration. The aim of this study was to evaluate the course of liver regeneration following donor hepatectomy (LDH) by routine and regeneration-related biomarkers. METHOD: Data from 63 living liver donors (LLDs) who underwent LDH in Inonu University Liver Transplant Institute were prospectively analyzed. Serum samples were obtained on the preoperative day and postoperative days (POD) 1, 3, 5, 10, and 21. Regenerative markers including alfa-fetoprotein (AFP), des carboxy prothrombin (DCP), ornithine decarboxylase (ODC), retinol-binding protein 4 (RBP4), and angiotensin-converting enzyme isotype II (ACEII) and liver function tests including alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), alkaline phosphatase (ALP) and total bilirubin levels were all analyzed. RESULTS: The median age of the LLDs was 29.7 years and 28 LLDs were female. Eight LLDs developed postoperative complications requiring relaparotomy. The routine laboratory parameters including AST (<0.001), ALT (<0.001), ALP (<0.001), and total bilirubin (<0.001) showed a significant increase over time until postoperative day (POD) 3. For the regeneration-related parameters, except for the RBP4, all parameters including ACEII (p = 0.006), AFP (p = 0.002), DCP (p = 0.007), and ODC (p = 0.002) showed a significant increase in POD3. The regeneration parameters showed a different pattern of change. In right-lobe liver grafts, ACEII (p = 0.002), AFP (p = 0.035), and ODC (p = 0.001) showed a significant increase over time. DCP (p = 0.129) and RBP4 (p = 0.335) showed no significant changes in right-lobe liver grafts. CONCLUSIONS: Regenerative markers are increased in a sustained fashion following LDH. This is more prominent following right-lobe grafts which are indicative of progenitor-associated liver regeneration.

Phenethyl isothiocyanate protects against cyclophosphamide-induced nephrotoxicity via nuclear factor E2-related factor 2 pathway in rats.

Phenethyl isothiocyanate (PEITC), a secondary metabolite in Cruciferous plants, exerts chemopreventive and antioxidant effects. However, its therapeutic potential in cyclophosphamide (CP)-induced nephrotoxicity is not clear. So, we focused to research on the effect of PEITC against renal toxicity caused by CP and its relationship to the Nrf2 signaling mechanism. Thirty female Wistar albino rats were allocated to three groups: control (n = 10), CP (n = 10), and PEITC-pretreated group (150 µmol/kg b.w. orally; n = 10). The antioxidant enzyme activities and levels of malondialdehyde (MDA), sirtuin 1 (SIRT1), glutathione-S-transferase (GST), nuclear factor E2-related factor 2 (Nrf2), nuclear factor kappa B (NF-κB), serum urea, and creatinine (Cr) were measured. In the CP group, serum urea and Cr, MDA, and NF-κB levels have risen, and the activities of antioxidant enzymes and SIRT1, Nrf2, and GST levels have reduced significantly (P < 0.05). PEITC diminished levels of Cr, urea, MDA, and NF-κB while it enhanced antioxidant enzyme activities and GST, Nrf2, and SIRT1 levels significantly (P < 0.05). Pretreatment with PEITC ameliorated kidney tissue injury. The renal protective effect of the PEITC was supported by the histological analysis of the kidney. PEITC prevented CP-induced nephrotoxicity by decreasing oxidative damage through Nrf2 and SIRT1 activation and NF-κB inhibition. Therefore, we have suggested that PEITC may be a useful agent for protection against CP-induced renal injury.

Adipose-derived stem cells in the treatment of hepatobiliary diseases and sepsis.

Determination of the mesenchymal stem cells is one of the greatest and most exciting achievements that tissue engineering and regenerative medicine have achieved. Adipose-derived mesenchymal stem cells (AD-MSC) are easily isolated and cultured for a long time before losing their stem cell characteristics, which are self-renewal and pluripotency. AD-MSC are mesenchymal stem cells that have pluripotent lineage characteristics. They are easily accessible, and the fraction of stem cells in the adipose tissue lysates is highest among all other sources of mesenchymal stem cells. It is also HLA-DR negative and can be transplanted allogenically without the need for immunosuppression. These advantages have popularized its use in many fields including plastic reconstructive surgery. However, in the field of hepatology and liver transplantation, the progress is slower. AD-MSC have the potential to modulate inflammation, ameliorate ischemia-reperfusion injury, and support liver and biliary tract regeneration. These are very important for the treatment of various hepatobiliary diseases. Furthermore, the anti-inflammatory potential of these cells has paramount importance in the treatment of sepsis. We need alternative therapeutic approaches to treat end-stage liver failure. AD-MSC can provide a means of therapy to bridge to definitive therapeutic alternatives such as liver transplantation. Here we propose to review theoretic applications of AD-MSC in the treatment of hepatobiliary diseases and sepsis.

Hepatocellular Carcinoma Tumor Microenvironment and Its Implications in Terms of Anti-tumor Immunity: Future Perspectives for New Therapeutics.

PURPOSE: Hepatocellular cancer is an insidious tumor that is often diagnosed in a later stage of life. The tumor microenvironment is the key to tumorigenesis and progression. Many cellular and non-cellular components orchestrate the intricate process of hepatocarcinogenesis. The most important feature of hepatocellular cancer is the immune evasion process. The present review aims to summarize the key components of the tumor microenvironment in the immune evasion process. METHODS: Google Scholar and PubMed databases have been searched for the mesh terms "Hepatocellular carcinoma" or "Liver Cancer" and "microenvironment." The articles were reviewed and the components of the tumor microenvironment were summarized. RESULTS: The tumor microenvironment is composed of tumor cells and non-tumoral stromal and immune cells. HCC tumor microenvironment supports aggressive tumor behavior, provides immune evasion, and is an obstacle for current immunotherapeutic strategies. The components of the tumor microenvironment are intratumoral macrophages (tumor-associated macrophages (TAM)), bone marrow-derived suppressor cells, tumor-associated neutrophils (TAN), fibroblasts in the tumor microenvironment, and the activated hepatic stellate cells. CONCLUSION: There are intricate mechanisms that drive hepatocarcinogenesis. The tumor microenvironment is at the center of all the complex and diverse mechanisms. Effective and multistep immunotherapies should be developed to target different components of the tumor microenvironment.

Neuroprotective effects of the new Na channel blocker rs100642 in global ischemic brain injury.

INTRODUCTION: RS100642, a mexiletine analogue, is a novel sodium channel blocker with neuroprotective and antioxidant activities. The protectivity of RS100642, which has been shown against focal cerebral ischemia, was investigated in global cerebral ischemia in this study. MATERIAL AND METHODS: Global cerebral ischemia was induced for five minutes in adult male Wistar Albino rats via the 4-vessel occlusion method. Intravenous administration of 1 mg/kg RS100642 following reperfusion for 30 min (RS100642 group) was compared with a sham treatment group (ischemia group) and nonischemized group (control) histologically based on morphology and caspase-3 immunohistochemistry, and biochemically based both on measurement of oxidative stress including malondialdehyde (MDA) levels, superoxide dismutase (SOD), glutathione peroxidase (GPx) and catalase (CAT) activities and on assessment of apoptosis including caspase-3 and -8 activities and tumor necrosis factor α (TNF-α) levels at the end of 6 h. RESULTS: While the RS100642 group had significantly lower MDA levels and higher SOD activities than the sham treatment group (p < 0.05), GPx and CAT activities of the RS100642 and sham treatment groups were similar (p > 0.05) and significantly lower than those of the controls (p < 0.05). Necrosis and caspase-3 activity and immunoreactivity in the RS100642 group were significantly lower than those in the sham treatment group (p < 0.05), while there was no significant difference between groups regarding caspase-8 and TNF-α (p > 0.05). CONCLUSIONS: Na+ channel blockade by RS100642 has remarkable neuroprotective effects following global brain ischemia/reperfusion damage. Further research is required to determine the optimum dose and time of administration.

Antioxidant and antimicrobial activities, and phenolic compounds of selected Inula species from Turkey.

Three Inula species, I. viscosa, I. helenium ssp. turcoracemosa and I. montbretiana, collected from different locations of Anatolia were investigated for their antioxidant and antimicrobial potential, and their total phenolic content and phenolic composition. Antioxidant activities of various extracts of the plant parts were measured using DPPH radical scavenging and ABTS assays. Antimicrobial potential of methanol extracts of the plant parts was determined by the agar dilution method against Staphylococcus aureus, Enterococcus faecalis, Escherichia coli, Pseudomonas aeruginosa, Candida albicans and Candida tropicalis. All the extracts were more active against Gram-positive bacteria and yeasts than Gram-negative bacteria. The extracts exhibited antioxidant and antimicrobial activities in different concentrations. Total phenolic concentration of the extracts was estimated with Folin-Ciocalteu reagent using gallic acid as standard. The total phenolic content varied widely in different parts of the three tested Inula species, ranging from 21.1 +/- 0.8 to 190.9 +/- 6.1 mg GAE/g extract. Phenolic components, such as chlorogenic acid, caffeic acid, rutin, myricetin, quercetin, luteolin and kaempferol were quantified by HPLC-DAD in the methanol extracts of the Inula species. It was obvious that the antioxidant and antimicrobial properties of the plants were due to the phenolics.

Evaluation of the effects of novel nafimidone derivatives on thermal hypoalgesia in mice with diabetic neuropathy.

OBJECTIVE: Diabetic neuropathy (DN) is a common complication in Diabetes Mellitus. The streptozotocin-induced diabetic rodent is the most commonly used animal model of diabetes and increased sodium channel expression and activity were revealed in this model. At this study, we evaluated the effect of three different nafimidone derivatives which have possible anticonvulsant activity on disorders of thermal pain sensation in diabetic mice. STUDY DESIGN: Randomized animal experiment. MATERIAL AND METHODS: Mice were divided randomly into five groups (5 mice per group): Control, Diabetes, Dibetes+C1, Diabetes+C2, Diabetes+C3. We used hot and cold plate, and tail-immersion tests for assessment of thermal nociceptive responses. RESULTS: Compared with the control group, the hot-plate response time and the number of paw liftings on cold plate as important indicators of loss of sensation increased, but no significant difference (p>0.05) was found in tail-immersion response time test in diabetes group. C3 compound moved it back to control group levels in the all of three tests. C1 and C2 compounds were effective only in cold-plate test. CONCLUSION: Nafimidone derivatives may be effective in the cases where epilepsy and diabetes occur together since it has shown efficacy against "loss of sensation" which evolves in diabetic neuropathy over time as well as its antiepileptic effect.

Oxidative stress in the in vivo DMBA rat model of breast cancer: suppression by a voltage-gated sodium channel inhibitor (RS100642).

Breast cancer (BCa) was induced in vivo in female rats with 7,12-dimethylbenz(a)anthracene (DMBA). Two main questions were addressed. Firstly, would the carcinogenesis be accompanied by oxidative stress as signalled by superoxide dismutase, glutathione peroxidase, malondialdehyde and total nitrate? Secondly, would treating the rats additionally with a blocker of voltage-gated sodium channel (VGSC) activity, shown previously to promote BCa progression, affect the oxidative responses? The DMBA-induced increases in the antioxidant systems were completely blocked by the VGSC inhibitor RS100642, which also significantly prolonged the lifespan. We conclude that VGSC inhibition in vivo can significantly protect against oxidative stress and improve survival from tumour burden.

Investigation of a weak magnetic field effect on the in vitro catalytic activity of adenosine deaminase and xanthine oxidase.

The effect of a weak magnetic field (MF) on adenosine deaminase (ADA) and xanthine oxidase (XOD) activities have been investigated. A 50 Hz uniform MF was generated, and the magnitude of the field was kept constant at 5.8 mT. The changes in ADA activity over time were significantly different in and out of the MF; MF caused a steeper decline in ADA activity compared to the situation when no MF is present. In addition, MF caused a significant increase in XOD activity. There were no significant time-related changes for either enzyme in the absence of the MF. We suggest that a weak MF affects enzymatic systems.