Effect of silibinin on the expression of MMP2, MMP3, MMP9 and TIMP2 in kidney and lung after hepatic ischemia/reperfusion injury in an experimental rat model.

PURPOSE: The protective effect of silibinin on kidney and lung parenchyma during hepatic ischemia/reperfusion injury (IRI) is explored. METHODS: Sixty-three Wistar rats were separated into three groups: sham; control (45 min IRI); and silibinin (200 µL silibinin administration after 45 min of ischemia and before reperfusion). Immunohistochemistry and real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) were used to evaluate the expression levels of MMP2, MMP3, MMP9, and TIMP2 on kidney and lung. RESULTS: Comparing sham vs. control groups, confirmed that hepatic IRI increased both renal and lung MMP2, MMP3, MMP9 and TIMP2 expressions starting at 180 min (p<0.001). Comparison of the control vs. silibinin groups showed a statistically significant decrease in the expression levels of MMP2, MMP3, and MMP9 and increase of TIMP2 in kidney and lung parenchyma. The starting point of this decrease was at 120 min after reperfusion, both for kidney and lung parameters, and it was statistically significant at 240 min (p<0.001) for kidney, while silibinin showed a peak of lung protection at 180 min after hepatic reperfusion (p<0.001). CONCLUSIONS: Hepatic IRI causes distant kidney and lung damage, while a statistically significant protective action, both on kidney and lung parenchyma, is conveyed by the intravenous administration of silibinin.

Differential effects of cisplatin combined with the flavonoid apigenin on HepG2, Hep3B, and Huh7 liver cancer cell lines.

The potential of apigenin (APG) to enhance cisplatin's (CDDP) chemotherapeutic efficacy was investigated in HepG2, Hep3B, and Huh7 liver cancer cell lines. The presence of 20 µM APG sensitized all cell lines to CDDP treatment (degree of sensitization based on the MTT assay: HepG2>Huh7>Hep3B). As reflected by sister chromatid exchange levels, the degree of genetic instability as well as DNA repair by homologous recombination differed among cell lines. CDDP and 20 µM APG cotreatment exhibited a synergistic genotoxic effect on Hep3B cells and a less than additive effect on HepG2 and Huh7 cells. Cell cycle delays were noticed during the first mitotic division in Hep3B and Huh7 cells and the second mitotic division in HepG2 cells. CDDP and CDDP + APG treatments reduced the clonogenic capacity of all cell lines; however, there was a discordance in drug sensitivity compared with the MMT assay. Furthermore, a senescence-like phenotype was induced, especially in Hep3B and Huh7 cells. Unlike CDDP monotherapy, the combined treatment exhibited a significant anti-invasive and anti-migratory action in all cancer cell lines. The fact that the three liver cancer cell lines responded differently, yet positively, to CDDP + APG cotreatment could be attributed to variations they present in gene expression. Complex mechanisms seem to influence cellular responses and cell fate.

The hepatoprotective effect of silibinin after hepatic ischemia/reperfusion in a rat model is confirmed by immunohistochemistry and qRT-PCR.

OBJECTIVES: We investigated the positive effect of silibinin after IV administration as silibinin-hydroxypropyl-ß-cyclodextrin lyophilized product, by measuring gene expression and liver tissue protein levels of tumor necrosis factor-α, interleukin-6, monocyte chemoattractant protein-1, matrix metalloproteinases matrix metalloproteinases and tissue inhibitor of matrix metalloproteinases-2. METHODS: 63 Wistar rats of age 13.24±4.40 weeks underwent ischemia/reperfusion (I/R) injury of the liver. The animals were randomized into three groups: Sham (S; n = 7); Control (C; n-28); silibinin (Si; n-28). The C and Si groups underwent 45 min ischemia. Si received silibinin-hydroxypropyl-ß-cyclodextrin intravenously immediately before reperfusion at a dose of 5 mg/kg. Both groups were further divided into 4 subgroups, based on euthanasia time (i.e., 60, 120, 180 and 240 min). KEY FINDINGS: qRT-PCR results confirmed the statistically significant reduction of the expression of the pro-inflammatory factors at 240 min after I/R injury (tumor necrosis factor-α: P < 0.05; MCR1: P < 0.05) and matrix metalloproteinases (matrix metalloproteinases 2: P < 0.05; matrix metalloproteinases 3: P < 0.05) and the increase of tissue inhibitor of matrix metalloproteinases-2 in liver tissue in the Si group. Moreover, results of immunohistochemistry levels confirmed that at 240 min pro-inflammatory factors (tumor necrosis factor-α: P < 0.05; MCR1: P < 0.05) and matrix metalloproteinases ( matrix metalloproteinases 2: P < 0.05; matrix metalloproteinases 3: P < 0.05) had a statistically significantly lower expression in the Si group while tissue inhibitor of matrix metalloproteinases-2 had a higher expression. CONCLUSIONS: Silibinin may have a beneficial effect on the protection of the liver.

The positive effect of eugenol on acute pancreatic tissue injury: a rat experimental model.

INTRODUCTION: we present a rat experimental model used to evaluate the possible reduction in the extent of pancreatic tissue injury in acute pancreatitis cases, after administration of eugenol. METHODS: one hundred and twenty Wistar rats were used, which were randomly assigned in 3 groups: sham (n=20), control (n=50) and eugenol (n=50). Acute pancreatitis was induced by biliopancreatic ligation in the control and eugenol groups, but not in the Sham group. In the eugenol group, eugenol was administered per-os. Five histopathological parameters, such as edema, inflammatory infiltration, duct dilatation, hemorrhage and acinar necrosis were evaluated. RESULTS: at 72 h from acute pancreatitis induction, the total histological score was diminished in the eugenol group (p<0.0005) and duct dilatation and inflammatory infiltration were reduced compared to the control group (p<0.05). In addition, at 72 h, eugenol reduced pancreatic myeloperoxidase activity (p<0.0005). CONCLUSION: eugenol, a highly free radical scavenger agent, may have a preventive role in acute pancreatic injury, as it was evident in our rat experimental model.

Artificial Intelligence in Colorectal Cancer Screening, Diagnosis and Treatment. A New Era.

The development of artificial intelligence (AI) algorithms has permeated the medical field with great success. The widespread use of AI technology in diagnosing and treating several types of cancer, especially colorectal cancer (CRC), is now attracting substantial attention. CRC, which represents the third most commonly diagnosed malignancy in both men and women, is considered a leading cause of cancer-related deaths globally. Our review herein aims to provide in-depth knowledge and analysis of the AI applications in CRC screening, diagnosis, and treatment based on current literature. We also explore the role of recent advances in AI systems regarding medical diagnosis and therapy, with several promising results. CRC is a highly preventable disease, and AI-assisted techniques in routine screening represent a pivotal step in declining incidence rates of this malignancy. So far, computer-aided detection and characterization systems have been developed to increase the detection rate of adenomas. Furthermore, CRC treatment enters a new era with robotic surgery and novel computer-assisted drug delivery techniques. At the same time, healthcare is rapidly moving toward precision or personalized medicine. Machine learning models have the potential to contribute to individual-based cancer care and transform the future of medicine.

Effect of silibinin on the expression of MMP2, MMP3, MMP9 and TIMP2 in kidney and lung after hepatic ischemia/reperfusion injury in an experimental rat model

ABSTRACT Purpose: The protective effect of silibinin on kidney and lung parenchyma during hepatic ischemia/reperfusion injury (IRI) is explored. Methods: Sixty-three Wistar rats were separated into three groups: sham; control (45 min IRI); and silibinin (200 μL silibinin administration after 45 min of ischemia and before reperfusion). Immunohistochemistry and real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) were used to evaluate the expression levels of MMP2, MMP3, MMP9, and TIMP2 on kidney and lung. Results: Comparing sham vs. control groups, confirmed that hepatic IRI increased both renal and lung MMP2, MMP3, MMP9 and TIMP2 expressions starting at 180 min (p<0.001). Comparison of the control vs. silibinin groups showed a statistically significant decrease in the expression levels of MMP2, MMP3, and MMP9 and increase of TIMP2 in kidney and lung parenchyma. The starting point of this decrease was at 120 min after reperfusion, both for kidney and lung parameters, and it was statistically significant at 240 min (p<0.001) for kidney, while silibinin showed a peak of lung protection at 180 min after hepatic reperfusion (p<0.001). Conclusions: Hepatic IRI causes distant kidney and lung damage, while a statistically significant protective action, both on kidney and lung parenchyma, is conveyed by the intravenous administration of silibinin.

Silibinin-hydroxypropyl-ß-cyclodextrin (SLB-HP-ß-CD) complex prevents apoptosis in liver and kidney after hepatic ischemia-reperfusion injury.

BACKGROUND: We investigated the protective effect of silibinin on rat liver and kidney after hepatic inschemia/reperfusion (I/R) injury. METHODS AND MATERIALS: Sixty three male Wistar-type rats (median age 13 weeks; average weight 314 g) were subjected to I/R injury of the liver. They were randomly divided into three groups: Sham (n = 7), Control (C, n = 28) and Silibinin (Si, n = 28). The last group received intravenously silibinin. The C and Si groups were each subdivided in four subgroups according to euthanasia times (i.e., 60, 120, 180, 240 min). We assessed expression of caspase-3 and TUNEL assay, and biochemical and histological parameters. RESULTS: At 240 min, expression of caspase-3 and TUNEL assay were statistically significantly lower in the Si compared to the C group for both liver and kidney. SGOT and SGPT were also statistically significantly lower in the Si than in the C group at all time points. Histological parameters of the liver were also improved in the Si group. CONCLUSION: Silibinin was found to exhibit a protective effect on liver and kidney after hepatic I/R injury. The present results are encouraging for further studies and future clinical application.

Glycoprotein non-metastatic melanoma B expression after hepatic ischemia reperfusion and the effect of silibinin.

BACKGROUND: Glycoprotein non-metastatic melanoma B (GPNMB) is a transmembrane glycoprotein with various roles in inflammation regulation, tissue remodeling and oncogenesis. Clinical situations implicating alterations in its expression include ischemic injury, cirrhosis and fatty liver disease amongst other. We examine its expression in hepatic and renal tissue following hepatic ischemia-reperfusion (I/R) in a rat model, with and without intravenous silibinin administration, as a silibinin-hydroxypropyl-ß-cyclodextrin lyophilized complex (SLB-HP-ß-CD). METHODS: Sixty-three Wistar rats were divided into 3 groups: sham group (virtual intervention; 7 animals), control (C) group (45 min of ischemia, followed by reperfusion and euthanasia at 60, 120, 180 and 240 min; 28 animals equally divided), and silibinin (Si) group (45 min of ischemia, intravenous administration of SLB-HP-ß-CD, reperfusion and euthanasia at the same time points; 28 animals equally divided). GPNMB expression was examined in liver and kidney tissue. RESULTS: GPNMB expression was significantly increased following hepatic I/R in the control group, in kidney tissue, in a time dependent manner. In the silibinin group, GPNMB expression significantly decreased with time compared to the control group in both liver and kidney tissue (P<0.05). CONCLUSIONS: Hepatic I/R causes increase of GPNMB levels both in liver and kidney tissues, which may reflect tissue injury. Silibinin seems to act protectively on both liver and kidney, and can be potentially used as a therapeutic approach against hepatic I/R injury.

Effect of laparoscopic liver resection versus the open technique on hepatocyte regenerating activity in the rat.

BACKGROUND: Laparoscopic liver resection offers a safe and feasible option primarily for the excision of hepatic neoplasms. Timely recovery of liver volume is a key factor for improving prognosis and post-operative mortality of patients undergone liver resection. The aim of the present study was to compare liver regeneration after laparoscopic over open partial hepatectomy. METHODS: Wistar rats were subjected to laparoscopic 70% hepatectomy (group LAP-HEP), open 70% hepatectomy (group HEP), sham operation (group Sham) or no intervention (group Control). At various timepoints following operation (1 h-2 weeks), the liver was excised to assess relative liver weight, thiobarbituric acid reactive substances (TBARS) levels, mitotic activity, tissue expression of Nuclear Factor-κB (NFκB), Intercellular Adhesion Molecule-1 (ICAM-1) and Vascular Cell Adhesion Molecule-1 (VCAM-1) and the histopathologic profile. RESULTS: No differences were seen in relative liver weight between hepatectomy groups. Mitotic index was increased in all operative study groups, being higher in group LAP-HEP than in group HEP. TBARS levels were higher in group LAP-HEP compared to group HEP. NFκB and VCAM-1 tissue expression scores were increased in all operative study groups with VCAM-1 being higher in group HEP, while ICAM-1 was overexpressed only in hepatectomy groups. Mild histopathologic lesions were noted in hepatectomy groups with the histopathologic score being higher in group HEP (24 h). CONCLUSIONS: Laparoscopic liver resection enhanced hepatocyte mitotic activity which was accompanied by mild oxidative stress and a less pronounced local inflammatory response and tissue injury to that of the open technique.

Spontaneous pancreatic undifferentiated pleomorphic sarcoma in a laboratory rat: A case report.

We present a case of spontaneous undifferentiated/unclassified sarcoma, of a pleomorphic subtype formerly known as malignant fibrous histiocytoma (UPS/MFH), arising from the pancreas of a laboratory rat. The mass was excised after laparotomy from a 6-month-old female laboratory Wistar rat. It presented a giant multilobulated mass of irregular shape, which had arisen from the pancreas and occupied almost the entire peritoneal cavity. Histologically the tumor was characterized by a highly variable morphological pattern, with frequent transitions from storiform to pleomorphic areas. An extensive immunohistochemical examination revealed no specific lines of differentiation. Immunohistochemical positivity was observed only to MIB-1 (high Ki-67 proliferation index), vimentin and CD68 antibodies. The diagnosis was compatible with UPS/MFH. To the best of our knowledge, the present case is the first report of a spontaneous primary UPS/MFH arising from the pancreas of a laboratory rat.

Simultaneous, Delayed and Liver-First Hepatic Resections for Synchronous Colorectal Liver Metastases: A Systematic Review and Network Meta-Analysis.

BACKGROUND: Systematic reviews and meta-analyses that compare simultaneous, delayed and liver-first approach for synchronous colorectal liver metastases have found no significant differences. The aim of this study was to determine the best treatment strategy on the basis of effect sizes and the probabilities of treatment ranking by using a network meta-analysis. Moreover, first-time pairwise and network meta-analyses were used to estimate the existing evidence, and their results were compared to detect any discrepancies between them. METHODS: Systematic review, pairwise meta-analysis and network meta-analysis were performed. The primary and secondary outcomes were 5-year overall survival and postoperative major morbidity, respectively. RESULTS: No significant differences in long-term survival and major morbidity were found amongst the three approaches. The hazard ratios (95% confidence interval) for 5-year overall survival for the simultaneous, delayed and liver-first approaches were 0.93 (0.69 - 1.24, P = 0.613), 0.97 (0.87 - 1.07, P = 0.596) and 0.90 (0.67 - 1.22, P = 0.499), respectively. Moreover, the liver-first approach with a surface under the cumulative ranking area score of 89% was ranked as the potentially best treatment option based on probabilities of treatment ranking. CONCLUSIONS: On the basis of the relative ranking of treatments, the liver-first approach ranked first, followed by the delayed and simultaneous approaches. Therefore, a three-arm randomized controlled trial that compares the liver-first, simultaneous and delayed approaches needs to shed further light as to which is the best treatment option.

Apigenin Exerts Anti-inflammatory Effects in an Experimental Model of Acute Pancreatitis by Down-regulating TNF-α.

BACKGROUND/AIM: This study investigated the anti-inflammatory effect of apigenin in an experimental model of acute pancreatitis. Inflammatory response was reflected by tissue expression of the cytokine TNF-α coupled with histological examination. MATERIALS AND METHODS: Wistar rats were divided into three groups: Sham-group animals underwent laparotomy only, without any other interventions. Control-group animals underwent laparotomy and bilio-pancreatic duct ligation to induce pancreatitis without apigenin administration. Apigenin group animals were further treated with apigenin. Euthanasia was performed at 6, 12, 24, 48 and 72 h post-operatively. RESULTS: Over-expression of TNF-α in relation to postoperative time was observed in the control group (p<0.001). In the apigenin group, under-expression of TNF-α in relation to postoperative time was observed (p<0.013). At 72 h, apigenin reduced pancreatic TNF-α expression and prevented pancreatic necrosis. CONCLUSION: Apigenin slows progression and reduces severity of acute pancreatitis. Apigenin may serve as an adjunct to a more successful therapeutic strategy in acute pancreatitis.

Hyperthermia Suppresses Post - In Vitro Proliferation and Tumor Growth in Murine Malignant Melanoma and Colon Carcinoma.

BACKGROUND: Several studies have highlighted hyperthermia's ability to enhance the effectiveness of radiation and chemotherapy in various in vitro and in vivo cancer models. MATERIALS AND METHODS: In vivo murine models of malignant melanoma and colon carcinoma were utilized for demonstrating hyperthermia's therapeutic effectiveness by examining levels of caspase 3, COX-2 and phospho-H2A.X (Ser139) as endpoints of apoptosis, proliferation and DNA damage respectively. RESULTS: Hyperthermia induced in vitro cytotoxicity in malignant melanoma (B16-F10) and colon carcinoma (CT26) cell lines. In addition, it reduced post-in vitro proliferation and suppression of tumor growth by inducing the expression of caspase-3 and phospho-H2A.X (Ser139) while reducing the expression of COX-2 in both murine cancer models. CONCLUSION: Hyperthermia can exert therapeutic effectiveness against melanoma and colon carcinoma by inhibiting a number of critical cellular cascades including apoptosis, proliferation and DNA damage.

PAK1 Expression in Pancreatic Cancer: Clinicopathological Characteristics and Prognostic Significance.

BACKGROUND: Improvement of the management of pancreatic cancer requires a better understanding of the genetic and molecular changes responsible for the development of the disease. The family of p21-activated kinases (PAKs) and especially PAK1 appears to mediate many cellular processes that contribute to the development and progression of pancreatic cancer, but the clinical relevance of PAK1 expression with the disease still remains unclear. Aim of the study was to assess the clinical value and the potential prognostic significance of PAK1 in pancreatic adenocarcinoma. METHODS: We investigated the relationship between the PAK1 expression and the clinical and histopathologic characteristics of pancreatic cancer patients and the potential significance of PAK1 on survival. We examined tissue samples from 51 patients operated for pancreatic cancer. PAK1 expression was investigated with immunohistochemistry and correlated to clinicopathological parameters. RESULTS: PAK1 was detected in all tumor samples and high expression was found in most patients. High PAK1 expression was also associated with younger age and well-differentiated tumors, but no association was found between PAK1 expression and Tumor-Node-Metastasis stage as well as deceased or alive status on follow-up. Moderate to high PAK1 expression favored higher 6-month and 1-year survival and low PAK1 expression 2-year survival but without statistical significance. CONCLUSIONS: Our results indicate that PAK1 could potentially be used as a prognostic marker in pancreatic cancer. Further studies could clarify whether utilization of PAK1 in therapeutic protocols for the treatment of pancreatic cancer will render them more effective.

Spatial distribution of the full-length members of the Grg family during embryonic neurogenesis reveals a "Grg-mediated repression map" in the mouse telencephalon.

The full-length members of the Groucho/Transducin-like Enhancer of split gene family, namely Grg1-4, encode nuclear corepressors that act either directly, via interaction with transcription factors, or indirectly by modifying histone acetylation or chromatin structure. In this work we describe a detailed expression analysis of Grg1-4 family members during embryonic neurogenesis in the developing murine telencephalon. Grg1-4 presented a unique, complex yet overlapping expression pattern; Grg1 and Grg3 were mainly detected in the proliferative zones of the telencephalon, Grg2 mainly in the subpallium and finally, Grg4 mainly in the subpallial post mitotic neurons. In addition, comparative analysis of the expression of Grg1-4 revealed that, at these stages, distinct telencephalic progenitor domains or structures are characterized by the presence of different combinations of Grg repressors, thus forming a "Grg-mediated repression map".

Incidence and predictors of synchronous liver metastases in patients with gastrointestinal stromal tumors (GISTs).

BACKGROUND: The liver is the most common metastatic site in patients with gastrointestinal stromal tumors (GISTs). The purpose of this study is to identify the incidence and predictive factors associated with synchronous liver metastases among patients with GISTs. METHODS: A retrospective review of the Surveillance Epidemiology and End Results (SEER) database was performed. RESULTS: Overall, 2757 patients were identified, of which 276 (10%) had synchronous liver metastases. The two-year survival of patients with synchronous liver metastases was 31.9% overall and 37.1% after undergoing surgery with curative intent. Primary tumor size >5 cm (5-10 cm: OR 2.97, 95% CI: 1.03-8.55, p = 0.044, >10 cm: OR 5.59, 95% CI: 1.95-16.07, p = 0.001), presence of nodal metastases (OR 4.09, 95% CI: 2.01-8.33, p < 0.001) and mitotic count >5/50 HPF (OR 1.58, 95% CI: 1.01-2.47, p = 0.044) were associated with the presence of liver metastases. CONCLUSIONS: One out of ten patients with GISTs presents with hepatic metastases. Primary tumor size >5 cm, presence of nodal metastases and mitotic count >5/50 HPF are associated with a higher risk of synchronous hepatic metastases.

E and P Selectins as Potential Markers in the Assessment of the Severity of Acute Pancreatitis.

OBJECTIVES: Acute pancreatitis (AP) is commonly associated with the release of adhesion molecules such as E and P selectins. We designed the present study to evaluate the role of selectins as potential markers that could reflect the severity of the disease. METHODS: One hundred fifty patients with AP constituted the patient group, whereas 70 healthy volunteers established the control group. In both groups, blood samples were taken for measurements of E selectin, P selectin, caspase-cleaved cytokeratin 18, and total soluble cytokeratin 18 levels on admission and days 1, 2, 4, and 6. RESULTS: Values of E and P selectins on admission were both elevated compared with control subjects (P < 0.01). The nonsurvivors had higher values of E selectin (P < 0.04) and P selectin (P < 0.03) on admission. Levels of E and P selectin showed positive correlation with the length of stay (P < 0.05). E selectin on admission yielded a sensitivity of 75% and 78% specificity, whereas P selectin had a sensitivity of 67% and 91% specificity. CONCLUSIONS: Selectin values in the early course of AP may play a role as indicators of overall prognosis, which may help physicians in better understanding the pathophysiology of a benign disease that may have serious and detrimental complications.

Conditional survival analysis for patients with intraductal papillary mucinous neoplasms (IPMNs) undergoing curative resection.

BACKGROUND: Conditional survival (CS) analysis represents a novel method that may provide more clinically relevant perspectives to cancer management compared to conventional survival analysis. The purpose of this study was to evaluate conditional survival for patients with intraductal papillary mucinous neoplasms (IPMNs) undergoing curative resection. METHODS: A retrospective search of the Surveillance Epidemiology and End Results (SEER) database was performed. Three-year conditional survival (i.e. probability that a patient will survive an additional 3 years if they have already survived x years) was calculated using the formula 3-CS(x)=OS(x+3)/OS(x), where OS represents overall survival. RESULTS: Overall, 1303 patients were identified, with mean age of 65.2 ± 12.2 years. 3-CS at 1, 3 and 5 years after diagnosis was 35.8%, 47.5% and 44.7%. Patients with stage III/IV disease demonstrated small differences in 3-CS at 1-3 years after diagnosis compared to patients with stage I/II disease (I/II: 35.1%-46.9%, III/IV: 22.1%-42.3%, d range 0.09-0.28), while their 3-CS was superior at 4-5 years after diagnosis (I/II: 41.5%-45.7%, III/IV: 57.9%-64.7%, d range 0.24-0.47). Differences in 3-CS based on tumor grade displayed a different pattern, with small differences at 1-3 years after diagnosis (well-differentiated (WD)/moderately-differentiated (MD): 34.6%-50%, poorly-differentiated (PD)/undifferentiated (UD): 23.2%-40%, d range 0.18-0.24), before becoming prominent at 4-5 years after diagnosis (WD/MD: 50%-51.7%, PD/UD: 24.1%-30%, d range 0.4-0.55). CONCLUSIONS: Conditional survival for patients with IPMNs undergoing resection improves over time, especially for patients with high-risk features. This information may be used to provide individualized approaches to surveillance and treatment.

Silibinin Improves TNF-α and M30 Expression and Histological Parameters in Rat Kidneys After Hepatic Ischemia/Reperfusion.

BACKGROUND: Remote kidney damage is a sequel of hepatic ischemia-reperfusion (I/R) injury. Silibinin is the main ingredient of the milk thistle plant seed extract with known antioxidant and hepatoprotective activity. Our study investigates the nephroprotective potential of intravenously administered silibinin, as a lyophilized SLB-hydoxypropyl-beta-cyclodextrin product, in hepatic I/R injury. MATERIAL AND METHODS: 63 Wistar rats were divided into three groups: Sham (virtual intervention); Control (45 min ischemia and reperfusion); and Silibinin (200 µL intravenous silibinin administration after 45 min of ischemia). Kidney tissues were collected to determine TNF-α, M30 and histopathological changes at predetermined time intervals. RESULTS: Comparing Sham vs. Control groups, proved that hepatic I/R injury increased renal TNF-α and M30 expression. Deterioration was observed in hyperemia/filtration of renal parenchyma and tubules, cortical filtration, tubular necrosis and edema (tissue swelling index). Intravenous silibinin administration and comparison of the Control vs. Silibinin groups showed a statistically significant decrease in TNF-α levels at 240 min following I/R (p < 0.0001), and in M30 at 180 min (p = 0.03) and 240 min (p < 0.0001). Renal parameters have significantly decreased in: hyperemia/filtration of renal parenchyma at 120 min (p = 0.003), 180 min (p = 0.0001) and 240 min (p = 0.0002); hyperemia/filtration of renal tubules at 120 min (p = 0.02), 180 min (p = 0.0001) and 240 min (p = 0.0005); cortical filtration (240 min - p = 0.005); tubular necrosis (240 min - p = 0.021); and edema (240 min - p = 0.001). CONCLUSION: Our study confirms that hepatic I/R injury causes remote renal damage while the intravenous administration of silibinin leads to statistically significant nephroprotective action.

Silibinin Effect on Fas/FasL, HMGB1, and CD45 Expressions in a Rat Model Subjected to Liver Ischemia-Reperfusion Injury.

PURPOSE: We investigated the hepatoprotective effect of Silibinin (SLB) to ischemia-reperfusion (I/R) rat model, by evaluating the histological expression of the tissue markers Fas/FasL, HMGB-1 and CD45, and SLB pharmacokinetics. METHODS: Seventy-three Wistar-type male rats were randomized in 11 groups: Sham control group (open-close laparotomy); four I/R control groups (laparotomy, 45 min vascular occlusion, reperfusion, euthanasia after 60, 120, 180, and 240 min); four SLB (Si) groups (laparotomy, 45 min vascular occlusion, IV administration of SLB, reperfusion, euthanasia after 60, 120, 180, and 240 min); two SLB pharmacokinetics (PK) groups (IV administration of SLB, euthanasia after 45 and 240 min). RESULTS: Fas/FasL increased with reperfusion time in I/R control groups and decreased in the Si groups, reaching, respectively, the highest and lowest values at 240 min of reperfusion (p <.0001). HMGB1 and CD45 increased with time in the I/R control groups up to 240 min and decreased in the Si groups, approaching zero expression after 180 and 60 min, respectively. Pharmacokinetic data showed higher liver accumulation and slower plasma elimination of SLB in ischemic animals. CONCLUSIONS: The hepatoprotective effect of SLB was demonstrated through the reduction of the expression of Fas/FasL, HMGB-1 and CD45 in liver tissue under I/R conditions, and in the pharmacokinetic study. The results document the efficacy of silibinin in the protection of the liver, and are particularly encouraging for its use in hepatic surgery.