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For: Chen Y, Wang W, Wang H, Li Y, Shi M, Li H, Yan J. Rapamycin Attenuates Splenomegaly in both Intrahepatic and Prehepatic Portal Hypertensive Rats by Blocking mTOR Signaling Pathway. PLoS One 2016;11:e0141159. [PMID: 26734934 PMCID: PMC4703391 DOI: 10.1371/journal.pone.0141159] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [What about the content of this article? (0)] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2015] [Accepted: 10/03/2015] [Indexed: 02/07/2023] Open

For:	Chen Y, Wang W, Wang H, Li Y, Shi M, Li H, Yan J. Rapamycin Attenuates Splenomegaly in both Intrahepatic and Prehepatic Portal Hypertensive Rats by Blocking mTOR Signaling Pathway. PLoS One 2016;11:e0141159. [PMID: 26734934 PMCID: PMC4703391 DOI: 10.1371/journal.pone.0141159] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [What about the content of this article? (0)] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2015] [Accepted: 10/03/2015] [Indexed: 02/07/2023] Open

Number

Cited by Other Article(s)

Ye Y, Tang S, Tai Y, Zhao C, Tang C, Huang Z, Gao J. The transcriptomic profile shows the protective effects of celecoxib on cirrhotic splenomegaly. Immunopharmacol Immunotoxicol 2024;46:117-127. [PMID: 38047472 DOI: 10.1080/08923973.2023.2281282] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2023] [Accepted: 11/04/2023] [Indexed: 12/05/2023]

Abstract

BACKGROUND

Splenomegaly can exacerbate liver cirrhosis and portal hypertension. We have previously demonstrated that cyclooxygenase-2 (COX-2) inhibitor can attenuate cirrhotic splenomegaly. However, the mechanism of cirrhotic splenomegaly remains unclear, thus becoming the focus of the present study.

MATERIALS AND METHODS

Thioacetamide (TAA) intraperitoneal injection was used to induce cirrhotic splenomegaly. Rats were randomized into the control, TAA and TAA + celecoxib groups. Histological analysis and high-throughput RNA sequencing of the spleen were conducted. Splenic collagen III, α-SMA, Ki-67, and VEGF were quantified.

RESULTS

A total of 1461 differentially expressed genes (DEGs) were identified in the spleens of the TAA group compared to the control group. The immune response and immune cell activation might be the major signaling pathways involved in the pathogenesis of cirrhotic splenomegaly. With its immunoregulatory effect, celecoxib presents to ameliorate cirrhotic splenomegaly and liver cirrhosis. Furthermore, 304 coexisting DEGs were obtained between TAA vs. control and TAA + celecoxib vs. TAA. Gene ontology (GO) and KEGG analyses collectively indicated that celecoxib may attenuate cirrhotic splenomegaly through the suppression of splenic immune cell proliferation, inflammation, immune regulation, and fibrogenesis. The impacts on these factors were subsequently validated by the decreased splenic Ki-67-positive cells, macrophages, fibrotic areas, and mRNA levels of collagen III and α-SMA.

CONCLUSIONS

Celecoxib attenuates cirrhotic splenomegaly by inhibiting splenic immune cell proliferation, inflammation, and fibrogenesis. The current study sheds light on the therapeutic strategy of liver cirrhosis by targeting splenic abnormalities and provides COX-2 inhibitors as a novel medical treatment for cirrhotic splenomegaly.

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Tan BG, Tang Z, Ou J, Zhou HY, Li R, Chen TW, Zhang XM, Li HJ. An improved model based on quantitative features of right liver lobe, maximum varices, and portal vein system measured on magnetic resonance imaging to predict oesophagogastric variceal haemorrhage secondary to hepatitis B-related cirrhosis. Quant Imaging Med Surg 2023;13:7741-7752. [PMID: 38106265 PMCID: PMC10722043 DOI: 10.21037/qims-23-353] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2023] [Accepted: 09/12/2023] [Indexed: 12/19/2023]

Abstract

BACKGROUND

In patients with hepatitis B-related cirrhosis, it is important to predict those at high-risk of oesophagogastric variceal haemorrhage (OVH) to decide upon prophylactic treatment. Our published model developed with right liver lobe volume and diameters of portal vein system did not incorporate maximum variceal size as a factor. This study thus aimed to develop an improved model based on right liver lobe volume, diameters of maximum oesophagogastric varices (OV) and portal vein system obtained at magnetic resonance imaging (MRI) to predict OVH.

METHODS

Two hundred and thirty consecutive individuals with hepatitis B-related cirrhosis undergoing abdominal enhanced MRI were randomly grouped into training (n=160) and validation sets (n=70). OVH was confirmed in 51 and 23 participants in the training and validation sets during 2-year follow-up period, respectively. Spleen, total liver, right lobe, caudate lobe, left lateral lobe, and left medial lobe volumes, together with diameters of maximum OV and portal venous system were measured on MRI. In the training set, univariate analyses and binary logistic regression analyses were conducted to determine independent predictors. The performance of the model for predicting OVH constructed based on independent predictors from the training set was evaluated with receiver operating characteristic (ROC) analysis and validated in the validation set.

RESULTS

The model for predicting OVH was established based on right liver lobe volume and diameters of the maximum OV, left gastric vein, and portal vein [odds ratio (OR) =0.991, 2.462, 1.434, and 1.582, respectively; all P values <0.05]. The logistic regression model equation [-0.009 × right liver lobe volume + 0.901 × maximum OV diameter (MOVD) + 0.361 × left gastric vein diameter (LGVD) + 0.459 × portal vein diameter (PVD) - 7.842] with a cutoff value of -0.656 for predicting OVH obtained excellent performance with an area under ROC curve (AUC) of 0.924 [95% confidence interval (CI): 0.878-0.971]. The Delong test showed negative statistical difference in the model performance between the training and validation sets, with a P value >0.99.

CONCLUSIONS

The model could help well screen those patients at high risk of OVH for timely intervention and avoiding the fatal complications.

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Tan BG, Tang Z, Ou J, Zhou HY, Li R, Chen TW, Zhang XM, Li HJ, Hu J. A novel model based on liver/spleen volumes and portal vein diameter on MRI to predict variceal bleeding in HBV cirrhosis. Eur Radiol 2023;33:1378-1387. [PMID: 36048206 DOI: 10.1007/s00330-022-09107-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Revised: 07/14/2022] [Accepted: 08/11/2022] [Indexed: 02/03/2023]

Abstract

OBJECTIVE

To develop a novel logistic regression model based on liver/spleen volumes and portal vein diameter measured on magnetic resonance imaging (MRI) for predicting oesophagogastric variceal bleeding (OVB) secondary to HBV cirrhosis.

METHODS

One hundred eighty-five consecutive cirrhotic patients with hepatitis B undergoing abdominal contrast-enhanced MRI were randomly divided into training cohort (n = 130) and validation cohort (n = 55). Spleen volume, total liver volume, four liver lobe volumes, and diameters of portal venous system were measured on MRI. Ratios of spleen volume to total liver and to individual liver lobe volumes were calculated. In training cohort, univariate analyses and binary logistic regression analyses were to determine independent predictors. Performance of the model for predicting OVB constructed based on independent predictors from training cohort was evaluated by receiver operating characteristic (ROC) analysis, and was validated by Kappa test in validation cohort.

RESULTS

OVB occurred in 42 and 18 individuals in training and validation cohorts during the 2 years' follow-up, respectively. An OVB prediction model was constructed based on the independent predictors including right liver lobe volume (RV), left gastric vein diameter (LGVD) and portal vein diameter (PVD) (odds ratio = 0.993, 2.202 and 1.613, respectively; p-values < 0.001 for all). The logistic regression model equation (-0.007 × RV + 0.79 × LGVD + 0.478 × PVD-6.73) for predicting OVB obtained excellent performance with an area under ROC curve of 0.907. The excellent performance was confirmed by Kappa test with K-value of 0.802 in validation cohort.

CONCLUSION

The novel logistic regression model can be reliable for predicting OVB.

KEY POINTS

• Patients with oesophagogastric variceal bleeding are mainly characterized by decreased right lobe volume, and increased spleen volume and diameters of portal vein system. • The right liver lobe volume, left gastric vein diameter and portal vein diameter are the independent predictors of oesophagogastric variceal bleeding. • The novel model developed based on the independent predictors performed well in predicting oesophagogastric variceal bleeding with an area under the receiver operating characteristic curve of 0.907.

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Abdelrahman SA, Abdelfatah MM, Keshta AT. Rapamycin-filgrastim combination therapy ameliorates portal hypertension-induced splenomegaly: Role of β actin and S100A9 proteins modulation. IRANIAN JOURNAL OF BASIC MEDICAL SCIENCES 2022;25:732-744. [PMID: 35949314 PMCID: PMC9320204 DOI: 10.22038/ijbms.2022.64034.14101] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/25/2022] [Accepted: 06/07/2022] [Indexed: 11/06/2022]

Abstract

Objectives

Thioacetamide (TAA) was administered to induce an animal model of liver disease with secondary splenomegaly to assess the mechanisms underlying the effects of rapamycin and filgrastim when taken separately or in combination on the biochemical and histopathological aspects of the liver and spleen.

Materials and Methods

Thirty adult male albino rats were divided into five groups (control, TAA-treated group, TAA+rapamycin, TAA+filgrastim, and TAA+rapamycin+filgrastim group). We measured relative liver and spleen weights, serum levels of alanine transaminase (ALT), aspartate transaminase (AST), and albumin. Molecular docking modeling and histopathological examination of liver and spleen sections with hematoxylin and eosin and Masson trichrome staining with immunohistochemical detection of splenic CD3 and CD20 lymphocytes, S100A9 and β actin antibodies were detected. Morphometric and statistical analyses of the results were performed.

Results

TAA administration altered the histological structure of the liver and spleen and impaired liver function. It increased the expression of splenic CD3, CD20 lymphocytes, and S100A9 while diminishing the expression of β actin. Each of rapamycin and filgrastim, when administered separately, improved liver and spleen indices and liver function, but rapamycin did not affect the albumin level. They lowered splenic B and T lymphocyte levels. Expression levels of S100A9 showed down-regulation while β actin levels were up-regulated when compared with TAA. Combination therapy improved liver and spleen tissue pathology and significantly ameliorated the expression of splenic lymphocytes through regulation of S100A9 and β actin expression.

Conclusion

The synergistic effect of combination therapy was dependent on the regulation of splenic S100A9 and β actin levels.

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Huang WQ, Zou Y, Tian Y, Ma XF, Zhou QY, Li ZY, Gong SX, Wang AP. Mammalian Target of Rapamycin as the Therapeutic Target of Vascular Proliferative Diseases: Past, Present, and Future. J Cardiovasc Pharmacol 2022;79:444-455. [PMID: 34983907 DOI: 10.1097/fjc.0000000000001208] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2021] [Accepted: 12/16/2021] [Indexed: 11/26/2022]

Affiliation(s)

Wen-Qian Huang Institute of Clinical Research, Affiliated Nanhua Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, PR China Department of Physiology, Institute of Neuroscience Research, Hengyang Key Laboratory of Neurodegeneration and Cognitive Impairment, Hengyang Medical School, University of South China, Hengyang, Hunan, PR China
Yan Zou Department of Hand and Foot Surgery, Affiliated Nanhua Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, PR China ; and
Ying Tian Institute of Clinical Research, Affiliated Nanhua Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, PR China
Xiao-Feng Ma Institute of Clinical Research, Affiliated Nanhua Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, PR China
Qin-Yi Zhou Institute of Clinical Research, Affiliated Nanhua Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, PR China Department of Physiology, Institute of Neuroscience Research, Hengyang Key Laboratory of Neurodegeneration and Cognitive Impairment, Hengyang Medical School, University of South China, Hengyang, Hunan, PR China
Zhen-Yu Li Institute of Clinical Research, Affiliated Nanhua Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, PR China Department of Physiology, Institute of Neuroscience Research, Hengyang Key Laboratory of Neurodegeneration and Cognitive Impairment, Hengyang Medical School, University of South China, Hengyang, Hunan, PR China
Shao-Xin Gong Department of Pathology, First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, PR China
Ai-Ping Wang Institute of Clinical Research, Affiliated Nanhua Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, PR China Department of Physiology, Institute of Neuroscience Research, Hengyang Key Laboratory of Neurodegeneration and Cognitive Impairment, Hengyang Medical School, University of South China, Hengyang, Hunan, PR China

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Gojkovic S, Krezic I, Vranes H, Zizek H, Drmic D, Horvat Pavlov K, Petrovic A, Batelja Vuletic L, Milavic M, Sikiric S, Stilinovic I, Samara M, Knezevic M, Barisic I, Sjekavica I, Lovric E, Skrtic A, Seiwerth S, Sikiric P. BPC 157 Therapy and the Permanent Occlusion of the Superior Sagittal Sinus in Rat: Vascular Recruitment. Biomedicines 2021;9:744. [PMID: 34203464 PMCID: PMC8301421 DOI: 10.3390/biomedicines9070744] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Revised: 05/28/2021] [Accepted: 06/04/2021] [Indexed: 12/13/2022] Open

Abstract

We show the complex syndrome of the occluded superior sagittal sinus, brain swelling and lesions and multiple peripheral organs lesions in rat. Recovery goes centrally and peripherally, with the stable gastric pentadecapeptide BPC 157, which alleviated peripheral vascular occlusion disturbances, rapidly activating alternative bypassing pathways. Assessments were gross recording, venography, ECG, pressure, microscopy, biochemistry. The increased pressure in the superior sagittal sinus, portal and caval hypertension, aortal hypotension, arterial and venous thrombosis, severe brain swelling and lesions (cortex (cerebral, cerebellar), hypothalamus/thalamus, hippocampus), particular veins (azygos, superior mesenteric, inferior caval) dysfunction, heart dysfunction, lung congestion as acute respiratory distress syndrome, kidney disturbances, liver failure, and hemorrhagic lesions in gastrointestinal tract were all assessed. Rats received BPC 157 medication (10 µg/kg, 10 ng/kg) intraperitoneally, intragastrically, or topically to the swollen brain at 1 min ligation-time, or at 15 min, 24 h and 48 h ligation-time. BPC 157 therapy rapidly attenuates the brain swelling, rapidly eliminates the increased pressure in the ligated superior sagittal sinus and the severe portal and caval hypertension and aortal hypotension, and rapidly recruits collateral vessels, centrally ((para)sagittal venous collateral circulation) and peripherally (left superior caval vein azygos vein-inferior caval vein). In conclusion, as shown by all assessments, BPC 157 acts against the permanent occlusion of the superior sagittal sinus and syndrome (i.e., brain, heart, lung, liver, kidney, gastrointestinal lesions, thrombosis), given at 1 min, 15 min, 24 h or 48 h ligation-time. BPC 157 therapy rapidly overwhelms the permanent occlusion of the superior sagittal sinus in rat.

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Affiliation(s)

Slaven Gojkovic Departments of Pharmacology, School of Medicine, University of Zagreb, 10 000 Zagreb, Croatia; (S.G.); (I.K.); (H.V.); (H.Z.); (D.D.); (I.S.); (M.S.); (M.K.); (I.B.)
Ivan Krezic Departments of Pharmacology, School of Medicine, University of Zagreb, 10 000 Zagreb, Croatia; (S.G.); (I.K.); (H.V.); (H.Z.); (D.D.); (I.S.); (M.S.); (M.K.); (I.B.)
Hrvoje Vranes Departments of Pharmacology, School of Medicine, University of Zagreb, 10 000 Zagreb, Croatia; (S.G.); (I.K.); (H.V.); (H.Z.); (D.D.); (I.S.); (M.S.); (M.K.); (I.B.)
Helena Zizek Departments of Pharmacology, School of Medicine, University of Zagreb, 10 000 Zagreb, Croatia; (S.G.); (I.K.); (H.V.); (H.Z.); (D.D.); (I.S.); (M.S.); (M.K.); (I.B.)
Domagoj Drmic Departments of Pharmacology, School of Medicine, University of Zagreb, 10 000 Zagreb, Croatia; (S.G.); (I.K.); (H.V.); (H.Z.); (D.D.); (I.S.); (M.S.); (M.K.); (I.B.)
Katarina Horvat Pavlov Departments of Pathology, School of Medicine, University of Zagreb, 10 000 Zagreb, Croatia; (K.H.P.); (A.P.); (L.B.V.); (M.M.); (S.S.); (E.L.); (S.S.)
Andrea Petrovic Departments of Pathology, School of Medicine, University of Zagreb, 10 000 Zagreb, Croatia; (K.H.P.); (A.P.); (L.B.V.); (M.M.); (S.S.); (E.L.); (S.S.)
Lovorka Batelja Vuletic Departments of Pathology, School of Medicine, University of Zagreb, 10 000 Zagreb, Croatia; (K.H.P.); (A.P.); (L.B.V.); (M.M.); (S.S.); (E.L.); (S.S.)
Marija Milavic Departments of Pathology, School of Medicine, University of Zagreb, 10 000 Zagreb, Croatia; (K.H.P.); (A.P.); (L.B.V.); (M.M.); (S.S.); (E.L.); (S.S.)
Suncana Sikiric Departments of Pathology, School of Medicine, University of Zagreb, 10 000 Zagreb, Croatia; (K.H.P.); (A.P.); (L.B.V.); (M.M.); (S.S.); (E.L.); (S.S.)
Irma Stilinovic Departments of Pharmacology, School of Medicine, University of Zagreb, 10 000 Zagreb, Croatia; (S.G.); (I.K.); (H.V.); (H.Z.); (D.D.); (I.S.); (M.S.); (M.K.); (I.B.)
Mariam Samara Departments of Pharmacology, School of Medicine, University of Zagreb, 10 000 Zagreb, Croatia; (S.G.); (I.K.); (H.V.); (H.Z.); (D.D.); (I.S.); (M.S.); (M.K.); (I.B.)
Mario Knezevic Departments of Pharmacology, School of Medicine, University of Zagreb, 10 000 Zagreb, Croatia; (S.G.); (I.K.); (H.V.); (H.Z.); (D.D.); (I.S.); (M.S.); (M.K.); (I.B.)
Ivan Barisic Departments of Pharmacology, School of Medicine, University of Zagreb, 10 000 Zagreb, Croatia; (S.G.); (I.K.); (H.V.); (H.Z.); (D.D.); (I.S.); (M.S.); (M.K.); (I.B.)
Ivica Sjekavica Department of Diagnostic and Interventional Radiology, University Hospital Centre, 10 000 Zagreb, Croatia;
Eva Lovric Departments of Pathology, School of Medicine, University of Zagreb, 10 000 Zagreb, Croatia; (K.H.P.); (A.P.); (L.B.V.); (M.M.); (S.S.); (E.L.); (S.S.)
Anita Skrtic Departments of Pathology, School of Medicine, University of Zagreb, 10 000 Zagreb, Croatia; (K.H.P.); (A.P.); (L.B.V.); (M.M.); (S.S.); (E.L.); (S.S.)
Sven Seiwerth Departments of Pathology, School of Medicine, University of Zagreb, 10 000 Zagreb, Croatia; (K.H.P.); (A.P.); (L.B.V.); (M.M.); (S.S.); (E.L.); (S.S.)
Predrag Sikiric Departments of Pharmacology, School of Medicine, University of Zagreb, 10 000 Zagreb, Croatia; (S.G.); (I.K.); (H.V.); (H.Z.); (D.D.); (I.S.); (M.S.); (M.K.); (I.B.)

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Non-invasive laboratory, imaging and elastography markers in predicting varices with high risk of bleeding in cirrhotic patients. ROMANIAN JOURNAL OF INTERNAL MEDICINE = REVUE ROUMAINE DE MÉDECINE INTERNE 2021;59:194-200. [PMID: 33544557 DOI: 10.2478/rjim-2021-0001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/29/2020] [Indexed: 11/21/2022]

Duffy P, Castro-Aragon I, Tivnan P, Volberg FM, Kipervasser E, Harkanyi Z, Paltiel HJ. Spleen and Peritoneal Cavity. PEDIATRIC ULTRASOUND 2021:481-561. [DOI: 10.1007/978-3-030-56802-3_13] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]

Mirković I, Kralj T, Lozić M, Stambolija V, Kovačević J, Vrdoljak L, Zlatar M, Milanović K, Drmić D, Predović J, Masnec S, Jurjević M, Bušić M, Seiwerth S, Kokot A, Sikirić P. Pentadecapeptide BPC 157 shortens duration of tetracaine- and oxybuprocaine-induced corneal anesthesia in rats. Acta Clin Croat 2020;59:394-406. [PMID: 34177048 PMCID: PMC8212645 DOI: 10.20471/acc.2020.59.03.02] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2019] [Accepted: 01/31/2020] [Indexed: 12/30/2022] Open

Chen Y, Cai N, Lai Y, Xu W, Li J, Huang L, Huang Y, Hu M, Yang H, Chen J. Thalidomide for the Treatment of Thrombocytopenia and Hypersplenism in Patients With Cirrhosis or Thalassemia. Front Pharmacol 2020;11:1137. [PMID: 32792958 PMCID: PMC7394185 DOI: 10.3389/fphar.2020.01137] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2019] [Accepted: 07/13/2020] [Indexed: 12/16/2022] Open

Kolovrat M, Gojkovic S, Krezic I, Malekinusic D, Vrdoljak B, Kasnik Kovac K, Kralj T, Drmic D, Barisic I, Horvat Pavlov K, Petrovic A, Duzel A, Knezevic M, Mirkovic I, Kokot A, Boban Blagaic A, Seiwerth S, Sikiric P. Pentadecapeptide BPC 157 resolves Pringle maneuver in rats, both ischemia and reperfusion. World J Hepatol 2020;12:184-206. [PMID: 32547687 PMCID: PMC7280862 DOI: 10.4254/wjh.v12.i5.184] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2019] [Revised: 03/25/2020] [Accepted: 03/30/2020] [Indexed: 02/06/2023] Open

Abstract

BACKGROUND

The Pringle maneuver [portal triad obstruction(PTO)] provides huge disturbances during ischemia and even more thereafter in reperfusion. Contrarily, a possible solution may be stable gastric pentadecapeptide BPC 157, with already documented beneficial effects in ischemia/reperfusion conditions. Recently, BPC 157, as a cytoprotective agent, successfully resolved vessel occlusions in rats (ischemic colitis; deep vein thrombosis, superior anterior pancreaticoduodenal vein; bile duct cirrhosis) through rapid collateral vessel recruitment to circumvent vessel occlusion. Thereby, medication BPC 157 regimens were administered as a single challenge before and during ischemia or, alternatively, at various time points during reperfusion.

AIM

To introduce BPC 157 therapy against pringle maneuver-damage.

METHODS

In deeply anesthetised rats, the portal triad was clamped up for 30 min. Rats then underwent reperfusion for either 15 min or 24 h. Medication [(10 µg, 10 ng/kg) regimens, administered as a single challenge] picked (a) ischemia, PTO period [at 5 min before (ip) or at 5 or 30 min of ligation time (as a bath to PTO)] or (b) reperfusion, post-PTO period [at 1 or 15 min (bath during surgery) or 24 h (ip) reperfusion-time]. We provided gross, microscopy, malondialdehyde, serum enzymes, electrocardiogram, portal, caval, and aortal pressure, thrombosis and venography assessments.

RESULTS

BPC 157 counteracts electrocardiogram disturbances (increased P wave amplitude, S1Q3T3 QRS pattern and tachycardia). Rapidly presented vascular pathway (portal vein-superior mesenteric vein-inferior mesenteric vein-rectal veins-left ileal vein-inferior caval vein) as the adequate shunting immediately affected disturbed haemodynamics. Portal hypertension and severe aortal hypotension during PTO, as well as portal and caval hypertension and mild aortal hypotension in reperfusion and refractory ascites formation were markedly attenuated (during PTO) or completely abrogated (reperfusion); thrombosis in portal vein tributaries and inferior caval vein or hepatic artery was counteracted during portal triad obstruction PTO. Also, counteraction included the whole vicious injurious circle [i.e., lung pathology (severe capillary congestion), liver (dilated central veins and terminal portal venules), intestine (substantial capillary congestion, submucosal oedema, loss of villous architecture), splenomegaly, right heart (picked P wave values)] regularly perpetuated in ischemia and progressed by reperfusion in Pringle rats.

CONCLUSION

BPC 157 resolves pringle maneuver-damage in rats, both for ischemia and reperfusion.

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Affiliation(s)

Marijan Kolovrat Departments of Pharmacology and Pathology, School of Medicine, University of Zagreb, Zagreb 10000, Croatia
Slaven Gojkovic Departments of Pharmacology and Pathology, School of Medicine, University of Zagreb, Zagreb 10000, Croatia
Ivan Krezic Departments of Pharmacology and Pathology, School of Medicine, University of Zagreb, Zagreb 10000, Croatia
Dominik Malekinusic Departments of Pharmacology and Pathology, School of Medicine, University of Zagreb, Zagreb 10000, Croatia
Borna Vrdoljak Departments of Pharmacology and Pathology, School of Medicine, University of Zagreb, Zagreb 10000, Croatia
Katarina Kasnik Kovac Departments of Pharmacology and Pathology, School of Medicine, University of Zagreb, Zagreb 10000, Croatia
Tamara Kralj Departments of Pharmacology and Pathology, School of Medicine, University of Zagreb, Zagreb 10000, Croatia
Domagoj Drmic Departments of Pharmacology and Pathology, School of Medicine, University of Zagreb, Zagreb 10000, Croatia
Ivan Barisic Departments of Pharmacology and Pathology, School of Medicine, University of Zagreb, Zagreb 10000, Croatia
Katarina Horvat Pavlov Departments of Pharmacology and Pathology, School of Medicine, University of Zagreb, Zagreb 10000, Croatia
Andreja Petrovic Departments of Pharmacology and Pathology, School of Medicine, University of Zagreb, Zagreb 10000, Croatia
Antonija Duzel Departments of Pharmacology and Pathology, School of Medicine, University of Zagreb, Zagreb 10000, Croatia
Mario Knezevic Departments of Pharmacology and Pathology, School of Medicine, University of Zagreb, Zagreb 10000, Croatia
Ivan Mirkovic Departments of Pharmacology and Pathology, School of Medicine, University of Zagreb, Zagreb 10000, Croatia
Antonio Kokot Departments of Pharmacology and Pathology, School of Medicine, University of Zagreb, Zagreb 10000, Croatia
Alenka Boban Blagaic Departments of Pharmacology and Pathology, School of Medicine, University of Zagreb, Zagreb 10000, Croatia
Sven Seiwerth Departments of Pharmacology and Pathology, School of Medicine, University of Zagreb, Zagreb 10000, Croatia
Predrag Sikiric Departments of Pharmacology and Pathology, School of Medicine, University of Zagreb, Zagreb 10000, Croatia.

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Lozic M, Stambolija V, Krezic I, Dugandzic A, Zivanovic-Posilovic G, Gojkovic S, Kovacevic J, Vrdoljak L, Mirkovic I, Kokot A, Petrovic A, Pavlov KH, Drmic D, Suran J, Blagaic AB, Seiwerth S, Sikiric P. In relation to NO-System, Stable Pentadecapeptide BPC 157 Counteracts Lidocaine-Induced Adverse Effects in Rats and Depolarisation In Vitro. Emerg Med Int 2020;2020:6805354. [PMID: 32566305 PMCID: PMC7273470 DOI: 10.1155/2020/6805354] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2020] [Revised: 04/28/2020] [Accepted: 04/30/2020] [Indexed: 02/07/2023] Open

Affiliation(s)

Marin Lozic Department of Pharmacology, School of Medicine, Medical Faculty, University of Zagreb, Salata 11, P.O. Box 916, 10000 Zagreb, Croatia
Vasilije Stambolija Department of Pharmacology, School of Medicine, Medical Faculty, University of Zagreb, Salata 11, P.O. Box 916, 10000 Zagreb, Croatia
Ivan Krezic Department of Pharmacology, School of Medicine, Medical Faculty, University of Zagreb, Salata 11, P.O. Box 916, 10000 Zagreb, Croatia
Aleksandra Dugandzic Department of Pharmacology, School of Medicine, Medical Faculty, University of Zagreb, Salata 11, P.O. Box 916, 10000 Zagreb, Croatia
Gordana Zivanovic-Posilovic Department of Pharmacology, School of Medicine, Medical Faculty, University of Zagreb, Salata 11, P.O. Box 916, 10000 Zagreb, Croatia
Slaven Gojkovic Department of Pharmacology, School of Medicine, Medical Faculty, University of Zagreb, Salata 11, P.O. Box 916, 10000 Zagreb, Croatia
Josip Kovacevic Department of Pharmacology, School of Medicine, Medical Faculty, University of Zagreb, Salata 11, P.O. Box 916, 10000 Zagreb, Croatia
Luka Vrdoljak Department of Pharmacology, School of Medicine, Medical Faculty, University of Zagreb, Salata 11, P.O. Box 916, 10000 Zagreb, Croatia
Ivan Mirkovic Department of Pharmacology, School of Medicine, Medical Faculty, University of Zagreb, Salata 11, P.O. Box 916, 10000 Zagreb, Croatia
Antonio Kokot Department of Pharmacology, School of Medicine, Medical Faculty, University of Zagreb, Salata 11, P.O. Box 916, 10000 Zagreb, Croatia
Andreja Petrovic Department of Pharmacology, School of Medicine, Medical Faculty, University of Zagreb, Salata 11, P.O. Box 916, 10000 Zagreb, Croatia
Katarina Horvat Pavlov Department of Pharmacology, School of Medicine, Medical Faculty, University of Zagreb, Salata 11, P.O. Box 916, 10000 Zagreb, Croatia
Domagoj Drmic Department of Pharmacology, School of Medicine, Medical Faculty, University of Zagreb, Salata 11, P.O. Box 916, 10000 Zagreb, Croatia
Jelena Suran Department of Pharmacology, School of Medicine, Medical Faculty, University of Zagreb, Salata 11, P.O. Box 916, 10000 Zagreb, Croatia
Alenka Boban Blagaic Department of Pharmacology, School of Medicine, Medical Faculty, University of Zagreb, Salata 11, P.O. Box 916, 10000 Zagreb, Croatia
Sven Seiwerth Department of Pharmacology, School of Medicine, Medical Faculty, University of Zagreb, Salata 11, P.O. Box 916, 10000 Zagreb, Croatia
Predrag Sikiric Department of Pharmacology, School of Medicine, Medical Faculty, University of Zagreb, Salata 11, P.O. Box 916, 10000 Zagreb, Croatia

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The role of spleen stiffness using ARFI in predicting esophageal varices in patients with Hepatitis B and C virus-related cirrhosis. ACTA ACUST UNITED AC 2020;57:334-340. [PMID: 31301679 DOI: 10.2478/rjim-2019-0017] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2019] [Indexed: 02/07/2023]

Gojkovic S, Krezic I, Vrdoljak B, Malekinusic D, Barisic I, Petrovic A, Horvat Pavlov K, Kolovrat M, Duzel A, Knezevic M, Kasnik Kovac K, Drmic D, Batelja Vuletic L, Kokot A, Boban Blagaic A, Seiwerth S, Sikiric P. Pentadecapeptide BPC 157 resolves suprahepatic occlusion of the inferior caval vein, Budd-Chiari syndrome model in rats. World J Gastrointest Pathophysiol 2020;11:1-19. [PMID: 32226643 PMCID: PMC7093306 DOI: 10.4291/wjgp.v11.i1.1] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2019] [Revised: 12/20/2019] [Accepted: 01/19/2020] [Indexed: 02/06/2023] Open

Abstract

BACKGROUND

Recently, as a possible therapy resolving solution, pentadecapeptide BPC 157 therapy, has been used in alleviating various vascular occlusion disturbances. BPC 157 was previously reviewed as novel mediator of Robert cytoprotection and endothelium protection in the stomach, and gut-brain axis, beneficial therapy in gastrointestinal tract, with particular reference to vascular recruitment, ulcerative colitis and tumor cachexia, and other tissues healing. Here we raised new hypothesis about BPC 157 therapy in the Budd-Chiari syndrome in rats, rapid bypassing of the suprahepatic inferior caval vein occlusion, and rats recovery with the active and effective pharmacotherapy treatment.

AIM

To investigate Budd-Chiari syndrome model (inferior caval vein suprahepatic occlusion) resolution, since BPC 157 resolves various rat vascular occlusion.

METHODS

We assessed the activated bypassing pathways between the inferior and superior caval veins and portocaval shunt, counteracted caval/portal hypertension, aortal hypotension, venous/arterial thrombosis, electrocardiogram disturbances, liver and gastrointestinal lesions (i.e., stomach and duodenum hemorrhages, in particular, congestion). Rats with suprahepatic occlusion of the inferior vena cava by ligation were medicated at 1 min, 15 min, 24 h, or 48 h post-ligation. Medication consisted of 10 µg/kg BPC 157, 10 ng BPC 157 or 5 mL/kg saline, administered once as an abdominal bath or intragastric application. Gross and microscopic observations were made, in addition to assessments of electrical activity of the heart (electrocardiogram), portal and caval hypertension, aortal hypotension, thrombosis, hepatomegaly, splenomegaly and venography. Furthermore, levels of nitric oxide, malondialdehyde in the liver and serum enzymes were determined.

RESULTS

BPC 157 counteracted increased P wave amplitude, tachycardia and ST-elevation, i.e., right heart failure from acute thrombotic coronary occlusion. The bypassing pathway of the inferior vena cava-azygos (hemiazygos) vein-superior vena cava and portocaval shunt occurred rapidly. Even with severe caval ˃ portal hypertension, BPC 157 antagonized portal and caval hypertension and aortal hypotension, and also reduced refractory ascites. Thrombosis of portal vein tributaries, inferior vena cava, and hepatic and coronary arteries was attenuated. In addition, there was reduced pathology of the lungs (severe capillary congestion) and liver (dilated central veins and terminal portal venules), decreased intestine hemorrhagic lesions (substantial capillary congestion, submucosal edema and architecture loss), and increased liver and spleen weight. During the period of ligation, nitric oxide- and malondialdehyde-levels in the liver remained within normal healthy values, and increases in serum enzymes were markedly reduced.

CONCLUSION

BPC 157 counteracts Budd Chiari syndrome in rats.

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Affiliation(s)

Slaven Gojkovic Departments of Pharmacology and Pathology, Medical Faculty University of Zagreb, Zagreb 10000, Croatia
Ivan Krezic Departments of Pharmacology and Pathology, Medical Faculty University of Zagreb, Zagreb 10000, Croatia
Borna Vrdoljak Departments of Pharmacology and Pathology, Medical Faculty University of Zagreb, Zagreb 10000, Croatia
Dominik Malekinusic Departments of Pharmacology and Pathology, Medical Faculty University of Zagreb, Zagreb 10000, Croatia
Ivan Barisic Departments of Pharmacology and Pathology, Medical Faculty University of Zagreb, Zagreb 10000, Croatia
Andreja Petrovic Departments of Pharmacology and Pathology, Medical Faculty University of Zagreb, Zagreb 10000, Croatia
Katarina Horvat Pavlov Departments of Pharmacology and Pathology, Medical Faculty University of Zagreb, Zagreb 10000, Croatia
Marijan Kolovrat Departments of Pharmacology and Pathology, Medical Faculty University of Zagreb, Zagreb 10000, Croatia
Antonija Duzel Departments of Pharmacology and Pathology, Medical Faculty University of Zagreb, Zagreb 10000, Croatia
Mario Knezevic Departments of Pharmacology and Pathology, Medical Faculty University of Zagreb, Zagreb 10000, Croatia
Katarina Kasnik Kovac Departments of Pharmacology and Pathology, Medical Faculty University of Zagreb, Zagreb 10000, Croatia
Domagoj Drmic Departments of Pharmacology and Pathology, Medical Faculty University of Zagreb, Zagreb 10000, Croatia
Lovorka Batelja Vuletic Departments of Pharmacology and Pathology, Medical Faculty University of Zagreb, Zagreb 10000, Croatia
Antonio Kokot Departments of Pharmacology and Pathology, Medical Faculty University of Zagreb, Zagreb 10000, Croatia
Alenka Boban Blagaic Departments of Pharmacology and Pathology, Medical Faculty University of Zagreb, Zagreb 10000, Croatia
Sven Seiwerth Departments of Pharmacology and Pathology, Medical Faculty University of Zagreb, Zagreb 10000, Croatia
Predrag Sikiric Departments of Pharmacology and Pathology, Medical Faculty University of Zagreb, Zagreb 10000, Croatia

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Kumar V, Dong Y, Kumar V, Almawash S, Mahato RI. The use of micelles to deliver potential hedgehog pathway inhibitor for the treatment of liver fibrosis. Am J Cancer Res 2019;9:7537-7555. [PMID: 31695785 PMCID: PMC6831471 DOI: 10.7150/thno.38913] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2019] [Accepted: 08/28/2019] [Indexed: 12/11/2022] Open

Abstract

Rationale: Hedgehog (Hh) pathway plays an essential role in liver fibrosis by promoting the proliferation of hepatic stellate cells (HSCs) by enhancing their metabolism via yes-associated protein 1 (YAP1). Despite the presence of several inhibitors, Hh signaling cannot be controlled exclusively due to their poor efficacy and the lack of a suitable delivery system to the injury site. Therefore, it is rationale to develop new potent Hh inhibitors and suitable delivery carriers.

Methods: Based on the structure and activity of Hh inhibitor GDC-0449, we replaced its sulfonamide group with two methylpyridine-2yl at amide nitrogen to synthesize MDB5. We compared the Hh pathway inhibition and anti-fibrotic effect of MDB5 with GDC-0449 in vitro. Next, we developed MDB5 loaded micelles using our methoxy poly(ethylene glycol)-blockpoly(2-methyl-2-carboxyl-propylene carbonate-graft-dodecanol (PEG-PCC-g-DC) copolymer and characterized for physicochemical properties. We evaluated the therapeutic efficacy of MDB5 loaded micelles in common bile duct ligation (CBDL) induced liver fibrosis, mouse model. We also determined the intrahepatic distribution of fluorescently labeled micelles after MDB5 treatment.

Results: Our results show that MDB5 was more potent in inhibiting Hh pathway components and HSC proliferation in vitro. We successfully developed MDB5 loaded micelles with particle size of 40 ± 10 nm and drug loading up to 10% w/w. MDB5 loaded micelles at the dose of 10 mg/kg were well tolerated by mice, without visible sign of toxicity. The serum enzyme activities elevated by CBDL was significantly decreased by MDB5 loaded micelles compared to GDC-0449 loaded micelles. MDB5 loaded micelles further decreased collagen deposition, HSC activation, and Hh activity and its target genes in the liver. MDB5 loaded micelles also prevented liver sinusoidal endothelial capillarization (LSEC) and therefore restored perfusion between blood and liver cells.

Conclusions: Our study provides evidence that MDB5 was more potent in inhibiting Hh pathway in HSC-T6 cells and showed better hepatoprotection in CBDL mice compared to GDC-0449.

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Saruwatari J, Dong C, Utsumi T, Tanaka M, McConnell M, Iwakiri Y. Integrated analysis of microRNA and mRNA expression profiles in splenomegaly induced by non-cirrhotic portal hypertension in rats. Sci Rep 2018;8:17983. [PMID: 30573742 PMCID: PMC6301948 DOI: 10.1038/s41598-018-36297-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2018] [Accepted: 11/08/2018] [Indexed: 02/07/2023] Open

Ling L, Li G, Meng D, Wang S, Zhang C. Carvedilol Ameliorates Intrahepatic Angiogenesis, Sinusoidal Remodeling and Portal Pressure in Cirrhotic Rats. Med Sci Monit 2018;24:8290-8297. [PMID: 30448852 PMCID: PMC6253986 DOI: 10.12659/msm.913118] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2018] [Accepted: 11/01/2018] [Indexed: 12/13/2022] Open

Li L, Duan M, Chen W, Jiang A, Li X, Yang J, Li Z. The spleen in liver cirrhosis: revisiting an old enemy with novel targets. J Transl Med 2017;15:111. [PMID: 28535799 PMCID: PMC5442653 DOI: 10.1186/s12967-017-1214-8] [Citation(s) in RCA: 100] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2017] [Accepted: 05/16/2017] [Indexed: 12/15/2022] Open

Affiliation(s)

Liang Li National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, The Second Affiliated Hospital, Xi'an Jiaotong University, No.157, Xiwu Road, Xi'an, 710004, Shaanxi, China.,Liver and Spleen Diseases Research Center, Shaanxi Province, No.157, Xiwu Road, Xi'an, 710004, Shaanxi, China
Mubing Duan Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science (LIMS), La Trobe University, Bundoora, VIC, Australia
Weisan Chen National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, The Second Affiliated Hospital, Xi'an Jiaotong University, No.157, Xiwu Road, Xi'an, 710004, Shaanxi, China.,Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science (LIMS), La Trobe University, Bundoora, VIC, Australia
An Jiang National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, The Second Affiliated Hospital, Xi'an Jiaotong University, No.157, Xiwu Road, Xi'an, 710004, Shaanxi, China.,Liver and Spleen Diseases Research Center, Shaanxi Province, No.157, Xiwu Road, Xi'an, 710004, Shaanxi, China.,Department of General Surgery, The Second Affiliated Hospital, Xi'an Jiaotong University, No.157, Xiwu Road, Xi'an, 710004, Shaanxi, China
Xiaoming Li National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, The Second Affiliated Hospital, Xi'an Jiaotong University, No.157, Xiwu Road, Xi'an, 710004, Shaanxi, China
Jun Yang National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, The Second Affiliated Hospital, Xi'an Jiaotong University, No.157, Xiwu Road, Xi'an, 710004, Shaanxi, China. .,Liver and Spleen Diseases Research Center, Shaanxi Province, No.157, Xiwu Road, Xi'an, 710004, Shaanxi, China. .,Department of Pathology, The Second Affiliated Hospital, Xi'an Jiaotong University, No.157, Xiwu Road, Xi'an, 710004, Shaanxi, China.
Zongfang Li National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, The Second Affiliated Hospital, Xi'an Jiaotong University, No.157, Xiwu Road, Xi'an, 710004, Shaanxi, China. .,Liver and Spleen Diseases Research Center, Shaanxi Province, No.157, Xiwu Road, Xi'an, 710004, Shaanxi, China.

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Liverani E. Lung injury during LPS-induced inflammation occurs independently of the receptor P2Y₁. Purinergic Signal 2016;13:119-125. [PMID: 27815804 DOI: 10.1007/s11302-016-9543-2] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2016] [Accepted: 10/20/2016] [Indexed: 11/30/2022] Open