|
1
|
Demirtaş H, Özer A, Yıldırım AK, Dursun AD, Sezen ŞC, Arslan M. Protective Effects of BPC 157 on Liver, Kidney, and Lung Distant Organ Damage in Rats with Experimental Lower-Extremity Ischemia-Reperfusion Injury. MEDICINA (KAUNAS, LITHUANIA) 2025; 61:291. [PMID: 40005408 PMCID: PMC11857380 DOI: 10.3390/medicina61020291] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/12/2024] [Revised: 01/16/2025] [Accepted: 02/04/2025] [Indexed: 02/27/2025]
Abstract
Background and Objectives: Ischemia-reperfusion (I/R) injury can affect multiple distant organs following I/R in the lower extremities. BPC-157's anti-inflammatory and free radical-neutralizing properties suggest its potential in mitigating ischemia-reperfusion damage. This study evaluates the protective effects of BPC-157 on remote organ damage, including the kidneys, liver, and lungs, in a rat model of skeletal muscle I/R injury. Materials and Methods: A total of 24 male Wistar albino rats were randomly divided into four groups: sham (S), BPC-157(B), lower extremity I/R(IR) and lower extremity I/R+BPC-157(I/RB). Some 45 min of ischemia of lower extremity was followed by 2 h of reperfusion of limbs. BPC-157 was applied to groups B and I/RB at the beginning of the procedure. After 2 h of reperfusion, liver, kidney and lung tissues were harvested for biochemical and histopathological analyses. Results: In the histopathological examination, vascular and glomerular vacuolization, tubular dilation, hyaline casts, and tubular cell shedding in renal tissue were significantly lower in the I/RB group compared to other groups. Lung tissue showed reduced interstitial edema, alveolar congestion, and total damage scores in the I/RB group. Similarly, in liver tissue, sinusoidal dilation, necrotic cells, and mononuclear cell infiltration were significantly lower in the I/RB group. Additionally, the evaluation of TAS, TOS, OSI, and PON-1 revealed a statistically significant increase in antioxidant activity in the liver, lung, and kidney tissues of the I/RB group. Conclusions: The findings of this study demonstrate that BPC-157 exerts a significant protective effect against distant organ damage in the liver, kidneys, and lungs following lower extremity ischemia-reperfusion injury in rats.
Collapse
Affiliation(s)
- Hüseyin Demirtaş
- Department of Cardiovascular Surgery, Faculty of Medicine, Gazi University, 06560 Ankara, Turkey; (H.D.); (A.Ö.); (A.K.Y.)
| | - Abdullah Özer
- Department of Cardiovascular Surgery, Faculty of Medicine, Gazi University, 06560 Ankara, Turkey; (H.D.); (A.Ö.); (A.K.Y.)
| | - Alperen Kutay Yıldırım
- Department of Cardiovascular Surgery, Faculty of Medicine, Gazi University, 06560 Ankara, Turkey; (H.D.); (A.Ö.); (A.K.Y.)
| | - Ali Doğan Dursun
- Department of Physiology, Faculty of Medicine, Atılım University, 06830 Ankara, Turkey;
- Vocational School of Health Services, Atılım University, 06805 Ankara, Turkey
- Home Care Services, Medicana International Ankara Hospital, 06520 Ankara, Turkey
| | - Şaban Cem Sezen
- Department of Histology and Embryology, Faculty of Medicine, Kırıkkale University, 71450 Kırıkkale, Turkey;
| | - Mustafa Arslan
- Department of Anesthesiology and Reanimation, Faculty of Medicine, Gazi University, 06560 Ankara, Turkey
- Application and Research Centre for Life Sciences, Gazi University, 06560 Ankara, Turkey
- Centre for Laboratory Animal Breeding and Experimental Research (GÜDAM), Gazi University, 06560 Ankara, Turkey
| |
Collapse
|
|
2
|
Józwiak M, Bauer M, Kamysz W, Kleczkowska P. Multifunctionality and Possible Medical Application of the BPC 157 Peptide-Literature and Patent Review. Pharmaceuticals (Basel) 2025; 18:185. [PMID: 40005999 PMCID: PMC11859134 DOI: 10.3390/ph18020185] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2025] [Revised: 01/23/2025] [Accepted: 01/28/2025] [Indexed: 02/27/2025] Open
Abstract
BPC 157, known as the "Body Protection Compound", is a pentadecapeptide isolated from human gastric juice that demonstrated its pleiotropic beneficial effects in various preclinical models mimicking medical conditions, such as tissue injury, inflammatory bowel disease, or even CNS disorders. Unlike many other drugs, BPC 157 has a desirable safety profile, since only a few side effects have been reported following its administration. Nevertheless, this compound was temporarily banned by the World Anti-Doping Agency (WADA) in 2022 (it is not currently listed as banned by the WADA). However, it has not been approved for use in standard medicine by the FDA and other global regulatory authorities due to the absence of sufficient and comprehensive clinical studies confirming its health benefits in humans. In this review, we summarize information on the biological activities of BPC 157, with particular reference to its mechanism of action and probable toxicity. This generated the attention of experts, as BPC 157 has been offered for sale on many websites. We also present recent interest in BPC 157 as reflected in a number of patent applications and granted patents.
Collapse
Affiliation(s)
- Michalina Józwiak
- Maria Sklodowska-Curie Medical Academy in Warsaw, 03-411 Warsaw, Poland;
| | - Marta Bauer
- Department of Analytical Chemistry, Faculty of Pharmacy, Medical University of Gdansk, 80-416 Gdansk, Poland
| | - Wojciech Kamysz
- Department of Inorganic Chemistry, Faculty of Pharmacy, Medical University of Gdansk, 80-416 Gdansk, Poland;
| | | |
Collapse
|
|
3
|
Sikiric P, Sever M, Krezic I, Vranes H, Kalogjera L, Smoday IM, Vukovic V, Oroz K, Coric L, Skoro M, Kavelj I, Zubcic S, Sikiric S, Beketic Oreskovic L, Oreskovic I, Blagaic V, Brcic K, Strbe S, Staresinic M, Boban Blagaic A, Skrtic A, Seiwerth S. New studies with stable gastric pentadecapeptide protecting gastrointestinal tract. significance of counteraction of vascular and multiorgan failure of occlusion/occlusion-like syndrome in cytoprotection/organoprotection. Inflammopharmacology 2024; 32:3119-3161. [PMID: 38980576 DOI: 10.1007/s10787-024-01499-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2024] [Accepted: 05/28/2024] [Indexed: 07/10/2024]
Abstract
Since the early 1990s, when Robert's and Szabo's cytoprotection concept had already been more than one decade old, but still not implemented in therapy, we suggest the stable gastric pentadecapeptide BPC 157 as the most relevant mediator of the cytoprotection concept. Consequently, it can translate stomach and gastrointestinal mucosal maintenance, epithelium, and endothelium cell protection to the therapy of other tissue healing (organoprotection), easily applicable, as native and stable in human gastric juice for more than 24 h. These overwhelm current clinical evidence (i.e., ulcerative colitis, phase II, no side effects, and no lethal dose (LD1) in toxicology studies), as BPC 157 therapy effectively combined various tissue healing and lesions counteraction. BPC 157 cytoprotection relevance and vascular recovery, activation of collateral pathways, membrane stabilizer, eye therapy, wound healing capability, brain-gut and gut-brain functioning, tumor cachexia counteraction, muscle, tendon, ligament, and bone disturbances counteraction, and the heart disturbances, myocardial infarction, heart failure, pulmonary hypertension, arrhythmias, and thrombosis counteraction appeared in the recent reviews. Here, as concept resolution, we review the counteraction of advanced Virchow triad circumstances by activation of the collateral rescuing pathways, depending on injury, activated azygos vein direct blood flow delivery, to counteract occlusion/occlusion-like syndromes starting with the context of alcohol-stomach lesions. Counteraction of major vessel failure (congested inferior caval vein and superior mesenteric vein, collapsed azygos vein, collapsed abdominal aorta) includes counteraction of the brain (intracerebral and intraventricular hemorrhage), heart (congestion, severe arrhythmias), lung (hemorrhage), and congestion and lesions in the liver, kidney, and gastrointestinal tract, intracranial (superior sagittal sinus), portal and caval hypertension, aortal hypotension, and thrombosis, peripherally and centrally.
Collapse
Affiliation(s)
- Predrag Sikiric
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia.
| | - Marko Sever
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia
- Department of Surgery, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Ivan Krezic
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Hrvoje Vranes
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Luka Kalogjera
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Ivan Maria Smoday
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Vlasta Vukovic
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Katarina Oroz
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Luka Coric
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Marija Skoro
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia
- Department of Diagnostic and Interventional Radiology, Sestre Milosrdnice University Hospital Center, Zagreb, Croatia
| | - Ivana Kavelj
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia
- Department of Diagnostic and Interventional Radiology, Sestre Milosrdnice University Hospital Center, Zagreb, Croatia
| | - Slavica Zubcic
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Suncana Sikiric
- Department of Pathology, School of Medicine, University of Zagreb, 10000, Zagreb, Croatia
| | | | - Ivana Oreskovic
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Vladimir Blagaic
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Klara Brcic
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Sanja Strbe
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Mario Staresinic
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia
- Department of Surgery, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Alenka Boban Blagaic
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Anita Skrtic
- Department of Pathology, School of Medicine, University of Zagreb, 10000, Zagreb, Croatia
| | - Sven Seiwerth
- Department of Pathology, School of Medicine, University of Zagreb, 10000, Zagreb, Croatia
| |
Collapse
|
|
4
|
Staresinic M, Japjec M, Vranes H, Prtoric A, Zizek H, Krezic I, Gojkovic S, Smoday IM, Oroz K, Staresinic E, Dretar V, Yago H, Milavic M, Sikiric S, Lovric E, Batelja Vuletic L, Simeon P, Dobric I, Strbe S, Kokot A, Vlainic J, Blagaic AB, Skrtic A, Seiwerth S, Sikiric P. Stable Gastric Pentadecapeptide BPC 157 and Striated, Smooth, and Heart Muscle. Biomedicines 2022; 10:3221. [PMID: 36551977 PMCID: PMC9775659 DOI: 10.3390/biomedicines10123221] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2022] [Revised: 11/29/2022] [Accepted: 12/01/2022] [Indexed: 12/14/2022] Open
Abstract
First, we review the definitively severed myotendinous junction and recovery by the cytoprotective stable gastric pentadecapeptide BPC 157 therapy, its healing that might combine both transected and detached tendon and transected muscle, ligament and bone injuries, applied alone, as native peptide therapy, effective in rat injury, given intraperitoneally or in drinking water or topically, at the site of injury. As a follow up, we reviewed that with the BPC 157 therapy, its cytoprotective ability to organize simultaneous healing of different tissues of and full recovery of the myotendinous junction might represent the particular muscle therapy against distinctive etiopathology muscle disabilities and weakness. In this, BPC 157 therapy might recover many of muscle disabilities (i.e., succinylcholine, vascular occlusion, spinal cord compression, stroke, traumatic brain injury, severe electrolyte disturbances, neurotoxins, neuroleptics, alcohol, serotonin syndrome and NO-system blockade and tumor-cachexia). These might provide practical realization of the multimodal muscle-axis impact able to react depending on the condition and the given agent(s) and the symptoms distinctively related to the prime injurious cause symptoms in the wide healing concept, the concept of cytoprotection, in particular. Further, the BPC 157 therapy might be the recovery for the disabled heart functioning, and disabled smooth muscle functioning (various sphincters function recovery). Finally, BPC 157, native and stable in human gastric juice, might be a prototype of anti-ulcer cytoprotective peptide for the muscle therapy with high curing potential (very safe profile (lethal dose not achieved), with suited wide effective range (µg-ng regimens) and ways of application).
Collapse
Affiliation(s)
- Mario Staresinic
- Department of Surgery, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| | - Mladen Japjec
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| | - Hrvoje Vranes
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| | - Andreja Prtoric
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| | - Helena Zizek
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| | - Ivan Krezic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| | - Slaven Gojkovic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| | - Ivan Maria Smoday
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| | - Katarina Oroz
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| | - Eva Staresinic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| | - Vilim Dretar
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| | - Haidi Yago
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| | - Marija Milavic
- Department of Pathology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| | - Suncana Sikiric
- Department of Pathology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| | - Eva Lovric
- Department of Pathology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| | | | - Paris Simeon
- Department of Endodontics and Restorative Dentistry, School of Dental Medicine, University of Zagreb, 10000 Zagreb, Croatia
| | - Ivan Dobric
- Department of Surgery, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| | - Sanja Strbe
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| | - Antonio Kokot
- Department of Anatomy and Neuroscience, School of Medicine, J.J. Strossmayer University of Osijek, 31000 Osijek, Croatia
| | - Josipa Vlainic
- Laboratory for Advanced Genomics, Division of Molecular Medicine, lnstitute Ruder Boskovic, 10000 Zagreb, Croatia
| | - Alenka Boban Blagaic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| | - Anita Skrtic
- Department of Pathology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| | - Sven Seiwerth
- Department of Pathology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| | - Predrag Sikiric
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| |
Collapse
|
|
5
|
Sikiric P, Udovicic M, Barisic I, Balenovic D, Zivanovic Posilovic G, Strinic D, Uzun S, Sikiric S, Krezic I, Zizek H, Yago H, Gojkovic S, Smoday IM, Kalogjera L, Vranes H, Sola M, Strbe S, Koprivanac A, Premuzic Mestrovic I, Mestrovic T, Pavic P, Skrtic A, Blagaic AB, Lovric Bencic M, Seiwerth S. Stable Gastric Pentadecapeptide BPC 157 as Useful Cytoprotective Peptide Therapy in the Heart Disturbances, Myocardial Infarction, Heart Failure, Pulmonary Hypertension, Arrhythmias, and Thrombosis Presentation. Biomedicines 2022; 10:2696. [PMID: 36359218 PMCID: PMC9687817 DOI: 10.3390/biomedicines10112696] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2022] [Revised: 10/08/2022] [Accepted: 10/15/2022] [Indexed: 11/30/2022] Open
Abstract
In heart disturbances, stable gastric pentadecapeptide BPC 157 especial therapy effects combine the therapy of myocardial infarction, heart failure, pulmonary hypertension arrhythmias, and thrombosis prevention and reversal. The shared therapy effect occurred as part of its even larger cytoprotection (cardioprotection) therapy effect (direct epithelial cell protection; direct endothelium cell protection) that BPC 157 exerts as a novel cytoprotection mediator, which is native and stable in human gastric juice, as well as easily applicable. Accordingly, there is interaction with many molecular pathways, combining maintained endothelium function and maintained thrombocytes function, which counteracted thrombocytopenia in rats that underwent major vessel occlusion and deep vein thrombosis and counteracted thrombosis in all vascular studies; the coagulation pathways were not affected. These appeared as having modulatory effects on NO-system (NO-release, NOS-inhibition, NO-over-stimulation all affected), controlling vasomotor tone and the activation of the Src-Caveolin-1-eNOS pathway and modulatory effects on the prostaglandins system (BPC 157 counteracted NSAIDs toxicity, counteracted bleeding, thrombocytopenia, and in particular, leaky gut syndrome). As an essential novelty noted in the vascular studies, there was the activation of the collateral pathways. This might be the upgrading of the minor vessel to take over the function of the disabled major vessel, competing with and counteracting the Virchow triad circumstances devastatingly present, making possible the recruitment of collateral blood vessels, compensating vessel occlusion and reestablishing the blood flow or bypassing the occluded or ruptured vessel. As a part of the counteraction of the severe vessel and multiorgan failure syndrome, counteracted were the brain, lung, liver, kidney, gastrointestinal lesions, and in particular, the counteraction of the heart arrhythmias and infarction.
Collapse
Affiliation(s)
- Predrag Sikiric
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| | - Mario Udovicic
- Department of Internal Medicine, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| | - Ivan Barisic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| | - Diana Balenovic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| | | | - Dean Strinic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| | - Sandra Uzun
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| | - Suncana Sikiric
- Department of Pathology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| | - Ivan Krezic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| | - Helena Zizek
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| | - Haidi Yago
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| | - Slaven Gojkovic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| | - Ivan Maria Smoday
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| | - Luka Kalogjera
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| | - Hrvoje Vranes
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| | - Marija Sola
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| | - Sanja Strbe
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| | - Antun Koprivanac
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| | | | - Tomislav Mestrovic
- Department of Surgery, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| | - Predrag Pavic
- Department of Surgery, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| | - Anita Skrtic
- Department of Pathology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| | - Alenka Boban Blagaic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| | - Martina Lovric Bencic
- Department of Internal Medicine, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| | - Sven Seiwerth
- Department of Pathology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| |
Collapse
|
|
6
|
Japjec M, Horvat Pavlov K, Petrovic A, Staresinic M, Sebecic B, Buljan M, Vranes H, Giljanovic A, Drmic D, Japjec M, Prtoric A, Lovric E, Batelja Vuletic L, Dobric I, Boban Blagaic A, Skrtic A, Seiwerth S, Predrag S. Stable Gastric Pentadecapeptide BPC 157 as a Therapy for the Disable Myotendinous Junctions in Rats. Biomedicines 2021; 9:1547. [PMID: 34829776 PMCID: PMC8615275 DOI: 10.3390/biomedicines9111547] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2021] [Revised: 10/08/2021] [Accepted: 10/23/2021] [Indexed: 12/17/2022] Open
Abstract
(1) Aim: The stable gastric pentadecapeptide BPC 157 is known to heal transected muscle, tendon, and ligament. Thereby, in this study, we investigated the effect of BPC 157 on the dissection of the quadriceps tendon from the quadriceps muscle in rats. (2) Materials and Methods: Myotendinous junction defect, which cannot heal spontaneously in rats, as evidenced with consistent macro/microscopic, biomechanical, functional assessments, eNOS, and COX-2 mRNA levels and oxidative stress and NO-levels in the myotendinous junctions. BPC 157 (10 µg/kg, 10 ng/kg) regimen was given (i) intraperitoneally, first application immediately after surgery, last 24 h before sacrifice; (ii) per-orally, in drinking water (0.16 µg/mL, 0.16 ng/mL, 12 mL/rat/day), till the sacrifice at 7, 14, 28 and 42 postoperative days. (3) Results: These BPC 157 regimens document prominent therapy effects (macro/microscopic, biomechanical, functional much like eNOS and COX-2 mRNA levels and counteracted oxidative stress and NO-levels in the myotendinous junctions), while controls have a poor presentation. Especially, in rats with the disabled myotendinous junction, along with full functional recovery, BPC 157 counteracts muscle atrophy that is regularly progressive and brings muscle presentation close to normal. Accordingly, unlike the perilous course in controls, those rats, when receiving BPC 157 therapy, exhibit a smaller defect, and finally defects completely disappear. Microscopically, there are no more inflammatory infiltrate, well-oriented recovered tissue of musculotendon junction appears in BPC 157 treated rats at the 28 days and 42 days. (4) Conclusions: BPC 157 restores myotendinous junction in accordance with the healing of the transected muscle, tendon, and ligament.
Collapse
Affiliation(s)
- Mladen Japjec
- Department of Surgery, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (M.J.); (M.S.); (B.S.); (A.P.); (I.D.)
| | - Katarina Horvat Pavlov
- Department of Pathology, School of Medicine, University of Zagreb, P.O. Box 910, Salata 10, 10000 Zagreb, Croatia; (K.H.P.); (A.P.); (E.L.); (L.B.V.); (S.S.)
| | - Andreja Petrovic
- Department of Pathology, School of Medicine, University of Zagreb, P.O. Box 910, Salata 10, 10000 Zagreb, Croatia; (K.H.P.); (A.P.); (E.L.); (L.B.V.); (S.S.)
| | - Mario Staresinic
- Department of Surgery, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (M.J.); (M.S.); (B.S.); (A.P.); (I.D.)
| | - Bozidar Sebecic
- Department of Surgery, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (M.J.); (M.S.); (B.S.); (A.P.); (I.D.)
| | - Matko Buljan
- Department of Pharmacology, School of Medicine, University of Zagreb, P.O. Box, 916, Salata 11, 10000 Zagreb, Croatia; (M.B.); (H.V.); (A.G.); (D.D.); (M.J.); (A.B.B.)
| | - Hrvoje Vranes
- Department of Pharmacology, School of Medicine, University of Zagreb, P.O. Box, 916, Salata 11, 10000 Zagreb, Croatia; (M.B.); (H.V.); (A.G.); (D.D.); (M.J.); (A.B.B.)
| | - Ana Giljanovic
- Department of Pharmacology, School of Medicine, University of Zagreb, P.O. Box, 916, Salata 11, 10000 Zagreb, Croatia; (M.B.); (H.V.); (A.G.); (D.D.); (M.J.); (A.B.B.)
| | - Domagoj Drmic
- Department of Pharmacology, School of Medicine, University of Zagreb, P.O. Box, 916, Salata 11, 10000 Zagreb, Croatia; (M.B.); (H.V.); (A.G.); (D.D.); (M.J.); (A.B.B.)
| | - Miroslav Japjec
- Department of Pharmacology, School of Medicine, University of Zagreb, P.O. Box, 916, Salata 11, 10000 Zagreb, Croatia; (M.B.); (H.V.); (A.G.); (D.D.); (M.J.); (A.B.B.)
| | - Andreja Prtoric
- Department of Surgery, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (M.J.); (M.S.); (B.S.); (A.P.); (I.D.)
| | - Eva Lovric
- Department of Pathology, School of Medicine, University of Zagreb, P.O. Box 910, Salata 10, 10000 Zagreb, Croatia; (K.H.P.); (A.P.); (E.L.); (L.B.V.); (S.S.)
| | - Lovorka Batelja Vuletic
- Department of Pathology, School of Medicine, University of Zagreb, P.O. Box 910, Salata 10, 10000 Zagreb, Croatia; (K.H.P.); (A.P.); (E.L.); (L.B.V.); (S.S.)
| | - Ivan Dobric
- Department of Surgery, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (M.J.); (M.S.); (B.S.); (A.P.); (I.D.)
| | - Alenka Boban Blagaic
- Department of Pharmacology, School of Medicine, University of Zagreb, P.O. Box, 916, Salata 11, 10000 Zagreb, Croatia; (M.B.); (H.V.); (A.G.); (D.D.); (M.J.); (A.B.B.)
| | - Anita Skrtic
- Department of Pathology, School of Medicine, University of Zagreb, P.O. Box 910, Salata 10, 10000 Zagreb, Croatia; (K.H.P.); (A.P.); (E.L.); (L.B.V.); (S.S.)
| | - Sven Seiwerth
- Department of Pathology, School of Medicine, University of Zagreb, P.O. Box 910, Salata 10, 10000 Zagreb, Croatia; (K.H.P.); (A.P.); (E.L.); (L.B.V.); (S.S.)
| | - Sikiric Predrag
- Department of Pharmacology, School of Medicine, University of Zagreb, P.O. Box, 916, Salata 11, 10000 Zagreb, Croatia; (M.B.); (H.V.); (A.G.); (D.D.); (M.J.); (A.B.B.)
| |
Collapse
|
|
7
|
Seiwerth S, Milavic M, Vukojevic J, Gojkovic S, Krezic I, Vuletic LB, Pavlov KH, Petrovic A, Sikiric S, Vranes H, Prtoric A, Zizek H, Durasin T, Dobric I, Staresinic M, Strbe S, Knezevic M, Sola M, Kokot A, Sever M, Lovric E, Skrtic A, Blagaic AB, Sikiric P. Stable Gastric Pentadecapeptide BPC 157 and Wound Healing. Front Pharmacol 2021; 12:627533. [PMID: 34267654 PMCID: PMC8275860 DOI: 10.3389/fphar.2021.627533] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Accepted: 02/03/2021] [Indexed: 12/11/2022] Open
Abstract
Significance: The antiulcer peptide, stable gastric pentadecapeptide BPC 157 (previously employed in ulcerative colitis and multiple sclerosis trials, no reported toxicity (LD1 not achieved)), is reviewed, focusing on the particular skin wound therapy, incisional/excisional wound, deep burns, diabetic ulcers, and alkali burns, which may be generalized to the other tissues healing. Recent Advances: BPC 157 has practical applicability (given alone, with the same dose range, and same equipotent routes of application, regardless the injury tested). Critical Issues: By simultaneously curing cutaneous and other tissue wounds (colocutaneous, gastrocutaneous, esophagocutaneous, duodenocutaneous, vesicovaginal, and rectovaginal) in rats, the potency of BPC 157 is evident. Healing of the wounds is accomplished by resolution of vessel constriction, the primary platelet plug, the fibrin mesh which acts to stabilize the platelet plug, and resolution of the clot. Thereby, BPC 157 is effective in wound healing much like it is effective in counteracting bleeding disorders, produced by amputation, and/or anticoagulants application. Likewise, BPC 157 may prevent and/or attenuate or eliminate, thus, counteract both arterial and venous thrombosis. Then, confronted with obstructed vessels, there is circumvention of the occlusion, which may be the particular action of BPC 157 in ischemia/reperfusion. Future Directions: BPC 157 rapidly increases various genes expression in rat excision skin wound. This would define the healing in the other tissues, that is, gastrointestinal tract, tendon, ligament, muscle, bone, nerve, spinal cord, cornea (maintained transparency), and blood vessels, seen with BPC 157 therapy.
Collapse
Affiliation(s)
- Sven Seiwerth
- Department of Pathology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Marija Milavic
- Department of Pathology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Jaksa Vukojevic
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Slaven Gojkovic
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Ivan Krezic
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | | | | | - Andrea Petrovic
- Department of Pathology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Suncana Sikiric
- Department of Pathology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Hrvoje Vranes
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Andreja Prtoric
- Department of Surgery, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Helena Zizek
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Tajana Durasin
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Ivan Dobric
- Department of Surgery, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Mario Staresinic
- Department of Surgery, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Sanja Strbe
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Mario Knezevic
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Marija Sola
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Antonio Kokot
- Department of Anatomy and Neuroscience, School of Medicine Osijek, University of Osijek, Osijek, Croatia
| | - Marko Sever
- Department of Surgery, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Eva Lovric
- Department of Pathology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Anita Skrtic
- Department of Pathology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Alenka Boban Blagaic
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Predrag Sikiric
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia
| |
Collapse
|
|
8
|
Cesar LB, Gojkovic S, Krezic I, Malekinusic D, Zizek H, Vuletic LB, Petrovic A, Pavlov KH, Drmic D, Kokot A, Vlainic J, Seiwerth S, Sikiric P. Bowel adhesion and therapy with the stable gastric pentadecapeptide BPC 157, L-NAME and L-arginine in rats. World J Gastrointest Pharmacol Ther 2020; 11:93-109. [PMID: 33251034 PMCID: PMC7667405 DOI: 10.4292/wjgpt.v11.i5.93] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2020] [Revised: 08/13/2020] [Accepted: 09/10/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND After parietal peritoneum excision with an underlying superficial layer of muscle tissue in rats, there is failed vasculature, and finally, increased adhesion formation. We hypothesized that unlike nitric oxide (NO)-agents, L-NAME and/or L-arginine, the application of the stable gastric pentadecapeptide BPC 157 with its most recent vascular effects ("vascular recruitment") means attenuated bowel adhesion formation and NO- and malondialdehyde (MDA)-tissue values. AIM To focused on the bowel adhesion and the therapy with the BPC 157, its most and application of NO-agents. METHODS Along with defect creation, medication was (1) during surgery, once, at 1 min after defect creation as an abdominal bath (1 mL/rat), BPC 157 (10 µg/kg, 10 ng/kg, 1 mL/rat), an equivolume of saline, L-NAME (5 mg/kg), L-arginine (200 mg/kg) alone and/or combined. Alternatively, medication was (2) intraperitoneally once daily, first application at 30 min after surgery, last application 24 h before assessment at d 7 or d 14. As a postponed therapy to pre-existing adhesion (3), BPC 157 (10 µg/kg, 10 ng/kg intraperitoneally, 1 mL/rat) was given once daily since d 7. RESULTS The recovery effect of the BPC 157 regimens goes with the presence of abundant vascular vessels in and near the defect, which occurs rapidly. Lastly, also applied as post-treatment, BPC 157 creates attenuated adhesions, minimal or no adhesion. Contrarily, NO-agents have diverse initial and final effects: The initial weakening of blood vessel disappearance and finally, severe worsening of adhesions (L-NAME) vs the initial weakening of blood vessel disappearance and finally, attenuation of adhesions formation (L-arginine), which counteract each other response given together. Importantly, BPC 157 maintains its beneficial effect also when given with NO-agents (L-NAME + BC 157; L-arginine + BPC 157; L-NAME + L-arginine + BPC 157). Finally, with respect to the increased NO- and MDA- values-adhesion tissue formation relation, unlike diverse effect of the NO-agents, the BPC 157 application effect regularly combines decrease on the increased NO- and MDA- values and the beneficial outcome (less adhesion formation). CONCLUSION BPC 157 therapy can be suited for the realization of the peritoneal defect healing with minimal or no adhesion formation.
Collapse
Affiliation(s)
- Lidija Berkopic Cesar
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb 10 000, Croatia
| | - Slaven Gojkovic
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb 10 000, Croatia
| | - Ivan Krezic
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb 10 000, Croatia
| | - Dominik Malekinusic
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb 10 000, Croatia
| | - Helena Zizek
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb 10 000, Croatia
| | | | - Andreja Petrovic
- Department of Pathology, School of Medicine, University of Zagreb, Zagreb 10000, Croatia
| | - Katarina Horvat Pavlov
- Department of Pathology, School of Medicine, University of Zagreb, Zagreb 10000, Croatia
| | | | - Antonio Kokot
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb 10 000, Croatia
| | | | - Sven Seiwerth
- Department of Pathology, School of Medicine, University of Zagreb, Zagreb 10000, Croatia
| | - Predrag Sikiric
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb 10 000, Croatia
| |
Collapse
|
|
9
|
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
Abstract
Recently, the pentadecapeptide BPC 157-induced counteraction of bupivacaine cardiotoxicity has been reported. Medication includes (i) lidocaine-induced local anesthesia via intraplantar application and axillary and spinal (L4-L5) intrathecal block, (ii) lidocaine-induced arrhythmias, (iii) convulsions, and (iv) lidocaine-induced HEK293 cell depolarisation. BPC 157 applications (intraplantar, intraperitoneal, and intragastric) were given (i) immediately after lidocaine, (ii) 10 min after, or (iii) 5 min before. The BPC 157/NO-system relationship was verified with NO-agents, the NOS-blocker L-NAME and the NOS-substrate L-arginine, given alone and/or together, in axillary and spinal intrathecal blocks. BPC 157 applied immediately after lidocaine or 5 min before the application of lidocaine considerably ameliorated plantar presentation. BPC 157 medication considerably counteracted lidocaine-induced limb function failure; L-NAME was counteracted; L-arginine exhibited counteraction when given immediately after lidocaine, but prolongation was seen when given later. Given together, prophylactically or therapeutically, L-NAME and L-arginine (L-NAME + L-arginine) counteracted the other's response. BPC 157 maintained its original response when given together with L-NAME or L-arginine. When BPC 157 was given together with L-NAME and L-arginine, its original response reappeared. BPC 157 antagonised the lidocaine-induced bradycardia and eliminated tonic-clonic convulsions. Also, BPC 157 counteracted the lidocaine-induced depolarisation of HEK293 cells. Thus, BPC 157 has antidote activity in its own right against lidocaine and local anesthetics.
Collapse
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
| |
Collapse
|
|
10
|
Xu C, Sun L, Ren F, Huang P, Tian Z, Cui J, Zhang W, Wang S, Zhang K, He L, Zhang W, Zhang C, Hao Q, Zhang Y, Li M, Li W. Preclinical safety evaluation of body protective compound-157, a potential drug for treating various wounds. Regul Toxicol Pharmacol 2020; 114:104665. [PMID: 32334036 DOI: 10.1016/j.yrtph.2020.104665] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2019] [Revised: 03/09/2020] [Accepted: 04/17/2020] [Indexed: 12/22/2022]
Abstract
BPC157 displays protective activity in various organs and tissues. This report presents preclinical toxicity studies with BPC157 in mice, rats, rabbits and dogs. The single-dose toxicity study did not show any test-related effects that could be attributed to the test article. In repeated-dose toxicity evaluations, BPC157 was well tolerated in dogs, with no abnormal changes between the BPC157-treated groups and the solvent control group, with the exception of a decrease in creatinine level at a dose of 2 mg/kg but not at lower doses. The animals recovered spontaneously after 2 weeks of withdrawal. This may be due to the pharmacological activity of BPC157. A local tolerance test showed that the irritation caused by BPC157 was mild. BPC157 also showed no genetic or embryo-fetal toxicity. In summary, BPC157 was well tolerated and did not cause any serious toxicity in mice, rats, rabbits and dogs. These preclinical safety data contribute to the initiation of an ongoing clinical study. Based on the stability and protective effect of BPC157, which has been widely reported, BPC157 may have a better application prospect than the widely used cytokine drugs in wound therapy.
Collapse
Affiliation(s)
- Chuanyang Xu
- State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, Fourth Military Medical University, Xi'an, 710032, China
| | - Lijuan Sun
- Department of Ophthalmology, Eye Institute of Chinese PLA, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, China
| | - FengLing Ren
- School of Public Health, Health Science Center, Xi'an Jiaotong University, Xi'an, 710061, China
| | - Ping Huang
- The Brigade of Undergraduates, The Fourth Military Medical University, Xi'an, 710032, China
| | - Zhuang Tian
- The Brigade of Undergraduates, The Fourth Military Medical University, Xi'an, 710032, China
| | - Jiazhen Cui
- The Brigade of Undergraduates, The Fourth Military Medical University, Xi'an, 710032, China
| | - Wangqian Zhang
- State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, Fourth Military Medical University, Xi'an, 710032, China
| | - Shuning Wang
- State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, Fourth Military Medical University, Xi'an, 710032, China
| | - Kuo Zhang
- State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, Fourth Military Medical University, Xi'an, 710032, China
| | - Lei He
- State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, Fourth Military Medical University, Xi'an, 710032, China
| | - Wei Zhang
- State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, Fourth Military Medical University, Xi'an, 710032, China
| | - Cun Zhang
- State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, Fourth Military Medical University, Xi'an, 710032, China
| | - Qiang Hao
- State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, Fourth Military Medical University, Xi'an, 710032, China
| | - Yingqi Zhang
- State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, Fourth Military Medical University, Xi'an, 710032, China
| | - Meng Li
- State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, Fourth Military Medical University, Xi'an, 710032, China.
| | - Weina Li
- State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, Fourth Military Medical University, Xi'an, 710032, China.
| |
Collapse
|
|
11
|
Sikiric P, Hahm KB, Blagaic AB, Tvrdeic A, Pavlov KH, Petrovic A, Kokot A, Gojkovic S, Krezic I, Drmic D, Rucman, R, Seiwerth S. Stable Gastric Pentadecapeptide BPC 157, Robert's Stomach Cytoprotection/Adaptive Cytoprotection/Organoprotection, and Selye's Stress Coping Response: Progress, Achievements, and the Future. Gut Liver 2020; 14:153-167. [PMID: 31158953 PMCID: PMC7096228 DOI: 10.5009/gnl18490] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2018] [Revised: 01/10/2019] [Accepted: 01/21/2019] [Indexed: 12/14/2022] Open
Abstract
We reviewed again the significance of the stable gastric pentadecapeptide BPC 157 as a likely mediator of Robert's stomach cytoprotection/adaptive cytoprotection and organoprotection and as novel mediator of Selye's stress coping response to reestablish homeostasis. Specific points of BPC 157 therapy and the original concept of Robert's cytoprotection/adaptive cytoprotection/organoprotection are discussed, including the beneficial effects of BPC 157. First, BPC 157 protects stomach cells and maintains gastric integrity against various noxious agents (Robert's killing cell by contact) and is continuously present in the gastric mucosa and gastric juice. Additionally, BPC 157 protects against the adverse effects of alcohol and nonsteroidal anti-inflammatory drugs on the gastric epithelium and other epithelia, that is, skin, liver, pancreas, heart (organoprotection), and brain, thereby suggesting its use in wound healing. Additionally, BPC 157 counteracts gastric endothelial injury that precedes and induces damage to the gastric epithelium and generalizes "gastric endothelial protection" to protection of the endothelium of other vessels (thrombosis, prolonged bleeding, and thrombocytopenia). BPC 157 also has an effect on blood vessels, resulting in vessel recruitment that circumvents vessel occlusion and the development of additional shunting and rapid bypass loops to rapidly reestablish the integrity of blood flow (ischemic/reperfusion colitis, duodenal lesions, cecal perforation, and inferior vena caval occlusion). Lastly, BPC 157 counteracts tumor cachexia, muscle wasting, and increases in pro-inflammatory/procachectic cytokines, such as interleukin-6 and tumor necrosis factor-α, and significantly corrects deranged muscle proliferation and myogenesis through changes in the expression of FoxO3a, p-AKT, p-mTOR, and p-GSK-3β (mitigating cancer cachexia).
Collapse
Affiliation(s)
- Predrag Sikiric
- Department of Pharmacology, Medical Faculty, University of Zagreb, Zagreb, Croatia
| | - Ki-Baik Hahm
- Digestive Disease Center, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, Korea
| | - Alenka Boban Blagaic
- Department of Pharmacology, Medical Faculty, University of Zagreb, Zagreb, Croatia
| | - Ante Tvrdeic
- Department of Pharmacology, Medical Faculty, University of Zagreb, Zagreb, Croatia
| | | | - Andrea Petrovic
- Department of Pathology, Medical Faculty, University of Zagreb, Zagreb, Croatia
| | - Antonio Kokot
- Department of Pharmacology, Medical Faculty, University of Zagreb, Zagreb, Croatia
| | - Slaven Gojkovic
- Department of Pharmacology, Medical Faculty, University of Zagreb, Zagreb, Croatia
| | - Ivan Krezic
- Department of Pharmacology, Medical Faculty, University of Zagreb, Zagreb, Croatia
| | - Domagoj Drmic
- Department of Pharmacology, Medical Faculty, University of Zagreb, Zagreb, Croatia
| | - Rudolf Rucman,
- Department of Pharmacology, Medical Faculty, University of Zagreb, Zagreb, Croatia
| | - Sven Seiwerth
- Department of Pathology, Medical Faculty, University of Zagreb, Zagreb, Croatia
| |
Collapse
|
|
12
|
Sever AZ, Sever M, Vidovic T, Lojo N, Kolenc D, Vuletic LB, Drmic D, Kokot A, Zoricic I, Coric M, Vlainic J, Poljak L, Seiwerth S, Sikiric P. Stable gastric pentadecapeptide BPC 157 in the therapy of the rats with bile duct ligation. Eur J Pharmacol 2019; 847:130-142. [PMID: 30690000 DOI: 10.1016/j.ejphar.2019.01.030] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2017] [Revised: 01/16/2019] [Accepted: 01/18/2019] [Indexed: 02/06/2023]
Abstract
Recently, stable gastric pentadecapeptide BPC 157 reversed the high MDA- and NO-tissue values to the healthy levels. Thereby, BPC 157 therapy cured rats with bile duct ligation (BDL) (sacrifice at 2, 4, 6, 8 week). BPC 157-medication (10 μg/kg, 10 ng/kg) was continuously in drinking water (0.16 μg/ml, 0.16 ng/ml, 12 ml/rat/day) since awakening from surgery, or since week 4. Intraperitoneal administration was first at 30 min post-ligation, last at 24 h before sacrifice. Local bath BPC 157 (10 µg/kg) with assessed immediate normalization of portal hypertension was given immediately after establishing portal hypertension values at 4, 6, 8 week. BPC 157 therapy markedly abated jaundice, snout, ears, paws, and yellow abdominal tegmentum in controls since 4th week, ascites, nodular, steatotic liver with large dilatation of main bile duct, increased liver and/or cyst weight, decreased body weight. BPC 157 counteracts the piecemeal necrosis, focal lytic necrosis, apoptosis and focal inflammation, disturbed cell proliferation (Ki-67-staining), cytoskeletal structure in the hepatic stellate cell (α-SMA staining), collagen presentation (Mallory staining). Likewise, counteraction includes increased AST, ALT, GGT, ALP, total bilirubin, direct and indirect and decreased albumin serum levels. As the end-result appear normalized MDA- and NO-tissue values, next to Western blot of NOS2 and NOS3 in the liver tissue, and decreased IL-6, TNF-α, IL-1β levels in liver tissue. Finally, although portal hypertension is sustained in BDL-rats, with BPC 157 therapy, portal hypertension in BDL-rats is either not even developed or rapidly abated, depending on the given BPC 157's regimen. Thus, BPC 157 may counteract liver fibrosis and portal hypertension.
Collapse
Affiliation(s)
- Anita Zenko Sever
- Department of Pathology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Marko Sever
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Tinka Vidovic
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Nermin Lojo
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Danijela Kolenc
- Department of Pathology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | | | - Domagoj Drmic
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Antonio Kokot
- Department of Anatomy and Neuroscience, J.J. Strossmayer University of Osijek, Osijek, Croatia
| | - Ivan Zoricic
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Marijana Coric
- Department of Pathology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | | | - Ljiljana Poljak
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Sven Seiwerth
- Department of Pathology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Predrag Sikiric
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia.
| |
Collapse
|
|
13
|
Nuñez D, Olavegoya P, Gonzales GF, Gonzales-Castañeda C. Red Maca (Lepidium meyenii), a Plant from the Peruvian Highlands, Promotes Skin Wound Healing at Sea Level and at High Altitude in Adult Male Mice. High Alt Med Biol 2017; 18:372-383. [PMID: 28846044 DOI: 10.1089/ham.2017.0038] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Nuñez, Denisse, Paola Olavegoya, Gustavo F. Gonzales, and Cynthia Gonzales-Castañeda. Red maca (Lepidium meyenii), a plant from the Peruvian highlands, promotes skin wound healing at sea level and at high altitude in adult male mice. High Alt Med Biol 18:373-383, 2017.-Wound healing consists of three simultaneous phases: inflammation, proliferation, and remodeling. Previous studies suggest that there is a delay in the healing process in high altitude, mainly due to alterations in the inflammatory phase. Maca (Lepidium meyenii) is a Peruvian plant with diverse biological properties, such as the ability to protect the skin from inflammatory lesions caused by ultraviolet radiation, as well as its antioxidant and immunomodulatory properties. The aim of this study was to determine the effect of high altitude on tissue repair and the effect of the topical administration of the spray-dried extract of red maca (RM) in tissue repair. Studies were conducted in male Balb/c mice at sea level and high altitude. Lesions were inflicted through a 10 mm-diameter excisional wound in the skin dorsal surface. Treatments consisted of either (1) spray-dried RM extract or (2) vehicle (VH). Animals wounded at high altitude had a delayed healing rate and an increased wound width compared with those at sea level. Moreover, wounding at high altitude was associated with an increase in inflammatory cells. Treatment with RM accelerated wound closure, decreased the level of epidermal hyperplasia, and decreased the number of inflammatory cells at the wound site. In conclusion, RM at high altitude generate a positive effect on wound healing, decreasing the number of neutrophils and increasing the number of macrophages in the wound healing at day 7 postwounding. This phenomenon is not observed at sea level.
Collapse
Affiliation(s)
- Denisse Nuñez
- 1 Department of Biological and Physiological Sciences, Faculty of Sciences and Philosophy, Universidad Peruana Cayetano Heredia , Lima, Peru .,2 Research Circle on Plants with Effects on Health , Lima, Peru
| | - Paola Olavegoya
- 1 Department of Biological and Physiological Sciences, Faculty of Sciences and Philosophy, Universidad Peruana Cayetano Heredia , Lima, Peru .,2 Research Circle on Plants with Effects on Health , Lima, Peru
| | - Gustavo F Gonzales
- 1 Department of Biological and Physiological Sciences, Faculty of Sciences and Philosophy, Universidad Peruana Cayetano Heredia , Lima, Peru .,2 Research Circle on Plants with Effects on Health , Lima, Peru .,3 Laboratory of Endocrinology and Reproduction, Instituto de Investigaciones de la Altura , Universidad Peruana Cayetano Heredia, Lima, Peru
| | - Cynthia Gonzales-Castañeda
- 1 Department of Biological and Physiological Sciences, Faculty of Sciences and Philosophy, Universidad Peruana Cayetano Heredia , Lima, Peru .,2 Research Circle on Plants with Effects on Health , Lima, Peru
| |
Collapse
|
|
14
|
Chaudhari AA, Vig K, Baganizi DR, Sahu R, Dixit S, Dennis V, Singh SR, Pillai SR. Future Prospects for Scaffolding Methods and Biomaterials in Skin Tissue Engineering: A Review. Int J Mol Sci 2016; 17:E1974. [PMID: 27898014 PMCID: PMC5187774 DOI: 10.3390/ijms17121974] [Citation(s) in RCA: 325] [Impact Index Per Article: 36.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2016] [Revised: 11/21/2016] [Accepted: 11/22/2016] [Indexed: 01/17/2023] Open
Abstract
Over centuries, the field of regenerative skin tissue engineering has had several advancements to facilitate faster wound healing and thereby restoration of skin. Skin tissue regeneration is mainly based on the use of suitable scaffold matrices. There are several scaffold types, such as porous, fibrous, microsphere, hydrogel, composite and acellular, etc., with discrete advantages and disadvantages. These scaffolds are either made up of highly biocompatible natural biomaterials, such as collagen, chitosan, etc., or synthetic materials, such as polycaprolactone (PCL), and poly-ethylene-glycol (PEG), etc. Composite scaffolds, which are a combination of natural or synthetic biomaterials, are highly biocompatible with improved tensile strength for effective skin tissue regeneration. Appropriate knowledge of the properties, advantages and disadvantages of various biomaterials and scaffolds will accelerate the production of suitable scaffolds for skin tissue regeneration applications. At the same time, emphasis on some of the leading challenges in the field of skin tissue engineering, such as cell interaction with scaffolds, faster cellular proliferation/differentiation, and vascularization of engineered tissues, is inevitable. In this review, we discuss various types of scaffolding approaches and biomaterials used in the field of skin tissue engineering and more importantly their future prospects in skin tissue regeneration efforts.
Collapse
Affiliation(s)
- Atul A Chaudhari
- Center for Nanobiotechnology Research, Alabama State University, Montgomery, AL 36104, USA.
| | - Komal Vig
- Center for Nanobiotechnology Research, Alabama State University, Montgomery, AL 36104, USA.
| | | | - Rajnish Sahu
- Center for Nanobiotechnology Research, Alabama State University, Montgomery, AL 36104, USA.
| | - Saurabh Dixit
- Center for Nanobiotechnology Research, Alabama State University, Montgomery, AL 36104, USA.
| | - Vida Dennis
- Center for Nanobiotechnology Research, Alabama State University, Montgomery, AL 36104, USA.
| | - Shree Ram Singh
- Center for Nanobiotechnology Research, Alabama State University, Montgomery, AL 36104, USA.
| | - Shreekumar R Pillai
- Center for Nanobiotechnology Research, Alabama State University, Montgomery, AL 36104, USA.
| |
Collapse
|
|
15
|
Djakovic Z, Djakovic I, Cesarec V, Madzarac G, Becejac T, Zukanovic G, Drmic D, Batelja L, Zenko Sever A, Kolenc D, Pajtak A, Knez N, Japjec M, Luetic K, Stancic-Rokotov D, Seiwerth S, Sikiric P. Esophagogastric anastomosis in rats: Improved healing by BPC 157 and L-arginine, aggravated by L-NAME. World J Gastroenterol 2016; 22:9127-9140. [PMID: 27895400 PMCID: PMC5107594 DOI: 10.3748/wjg.v22.i41.9127] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2016] [Revised: 08/28/2016] [Accepted: 09/28/2016] [Indexed: 02/06/2023] Open
Abstract
AIM To cure typically life-threatening esophagogastric anastomosis in rats, lacking anastomosis healing and sphincter function rescue, in particular. METHODS Because we assume esophagogastric fistulas represent a particular NO-system disability, we attempt to identify the benefits of anti-ulcer stable gastric pentadecapeptide BPC 157, which was in trials for ulcerative colitis and currently for multiple sclerosis, in rats with esophagocutaneous fistulas. Previously, BPC 157 therapies have promoted the healing of intestinal anastomosis and fistulas, and esophagitis and gastric lesions, along with rescued sphincter function. Additionally, BPC 157 particularly interacts with the NO-system. In the 4 d after esophagogastric anastomosis creation, rats received medication (/kg intraperitoneally once daily: BPC 157 (10 μg, 10 ng), L-NAME (5 mg), or L-arginine (100 mg) alone and/or combined or BPC 157 (10 μg, 10 ng) in drinking water). For rats underwent esophagogastric anastomosis, daily assessment included progressive stomach damage (sum of the longest diameters, mm), esophagitis (scored 0-5), weak anastomosis (mL H2O before leak), low pressure in esophagus at anastomosis and in the pyloric sphincter (cm H2O), progressive weight loss (g) and mortality. Immediate effect assessed blood vessels disappearance (scored 0-5) at the stomach surface immediately after anastomosis creation. RESULTS BPC 157 (all regimens) fully counteracted the perilous disease course from the very beginning (i.e., with the BPC 157 bath, blood vessels remained present at the gastric surface after anastomosis creation) and eliminated mortality. Additionally, BPC 157 treatment in combination with L-NAME nullified any effect of L-NAME that otherwise intensified the regular course. Consistently, with worsening (with L-NAME administration) and amelioration (with L-arginine), either L-arginine amelioration prevails (attenuated esophageal and gastric lesions) or they counteract each other (L-NAME + L-arginine); with the addition of BPC 157 (L-NAME + L-arginine + BPC 157), there was a marked beneficial effect. BPC 157 treatment for esophagogastric anastomosis, along with NOS-blocker L-NAME and/or NOS substrate L-arginine, demonstrated an innate NO-system disability (as observed with L-arginine effectiveness). BPC 157 distinctively affected corresponding events: worsening (obtained with L-NAME administration that was counteracted); or amelioration (L-arginine + BPC 157-rats correspond to BPC 157-rats). CONCLUSION Innate NO-system disability for esophagogastric anastomoses, including L-NAME-worsening, suggests that these effects could be corrected by L-arginine and almost completely eliminated by BPC 157 therapy.
Collapse
|
|
16
|
Lojo N, Rasic Z, Zenko Sever A, Kolenc D, Vukusic D, Drmic D, Zoricic I, Sever M, Seiwerth S, Sikiric P. Effects of Diclofenac, L-NAME, L-Arginine, and Pentadecapeptide BPC 157 on Gastrointestinal, Liver, and Brain Lesions, Failed Anastomosis, and Intestinal Adaptation Deterioration in 24 Hour-Short-Bowel Rats. PLoS One 2016; 11:e0162590. [PMID: 27627764 PMCID: PMC5023193 DOI: 10.1371/journal.pone.0162590] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2015] [Accepted: 08/25/2016] [Indexed: 12/11/2022] Open
Abstract
Stable gastric pentadecapeptide BPC 157 was previously used to ameliorate wound healing following major surgery and counteract diclofenac toxicity. To resolve the increasing early risks following major massive small bowel resectioning surgery, diclofenac combined with nitric oxide (NO) system blockade was used, suggesting therapy with BPC 157 and the nitric oxide synthase (NOS substrate) L-arginine, is efficacious. Immediately after anastomosis creation, short-bowel rats were untreated or administered intraperitoneal diclofenac (12 mg/kg), BPC 157 (10 μg/kg or 10 ng/kg), L-NG-nitroarginine methyl ester (L-NAME, 5 mg/kg), L-arginine (100 mg/kg) alone or combined, and assessed 24 h later. Short-bowel rats exhibited poor anastomosis healing, failed intestine adaptation, and gastrointestinal, liver, and brain lesions, which worsened with diclofenac. This was gradually ameliorated by immediate therapy with BPC 157 and L-arginine. Contrastingly, NOS-blocker L-NAME induced further aggravation and lesions gradually worsened. Specifically, rats with surgery alone exhibited mild stomach/duodenum lesions, considerable liver lesions, and severe cerebral/hippocampal lesions while those also administered diclofenac showed widespread severe lesions in the gastrointestinal tract, liver, cerebellar nuclear/Purkinje cells, and cerebrum/hippocampus. Rats subjected to surgery, diclofenac, and L-NAME exhibited the mentioned lesions, worsening anastomosis, and macro/microscopical necrosis. Thus, rats subjected to surgery alone showed evidence of deterioration. Furtheremore, rats subjected to surgery and administered diclofenac showed worse symptoms, than the rats subjected to surgery alone did. Rats subjected to surgery combined with diclofenac and L-NAME showed the worst deterioration. Rats subjected to surgery exhibited habitual adaptation of the remaining small intestine, which was markedly reversed in rats subjected to surgery and diclofenac, and those with surgery, diclofenac, and L-NAME. BPC 157 completely ameliorated symptoms in massive intestinal resection-, massive intestinal resection plus diclofenac-, and massive intestinal resection plus diclofenac plus L-NAME-treated short bowel rats that presented with cyclooxygenase (COX)-NO-system inhibition. L-arginine ameliorated only L-NAME-induced aggravation of symptoms in rats subjected to massive intestinal resection and administered diclofenac plus L-NAME.
Collapse
Affiliation(s)
- Nermin Lojo
- Department of Pharmacology, School of Medicine, University of Zagreb, POB 916, Salata 11, 10000 Zagreb, Croatia
| | - Zarko Rasic
- Department of Pharmacology, School of Medicine, University of Zagreb, POB 916, Salata 11, 10000 Zagreb, Croatia
| | - Anita Zenko Sever
- Department of Pathology, School of Medicine, University of Zagreb, Salata 9, 10000 Zagreb, Croatia
| | - Danijela Kolenc
- Department of Pathology, School of Medicine, University of Zagreb, Salata 9, 10000 Zagreb, Croatia
| | - Darko Vukusic
- Department of Pharmacology, School of Medicine, University of Zagreb, POB 916, Salata 11, 10000 Zagreb, Croatia
| | - Domagoj Drmic
- Department of Pharmacology, School of Medicine, University of Zagreb, POB 916, Salata 11, 10000 Zagreb, Croatia
| | - Ivan Zoricic
- Department of Pharmacology, School of Medicine, University of Zagreb, POB 916, Salata 11, 10000 Zagreb, Croatia
| | - Marko Sever
- Department of Pharmacology, School of Medicine, University of Zagreb, POB 916, Salata 11, 10000 Zagreb, Croatia
| | - Sven Seiwerth
- Department of Pathology, School of Medicine, University of Zagreb, Salata 9, 10000 Zagreb, Croatia
| | - Predrag Sikiric
- Department of Pharmacology, School of Medicine, University of Zagreb, POB 916, Salata 11, 10000 Zagreb, Croatia
| |
Collapse
|
|
17
|
Grgic T, Grgic D, Drmic D, Sever AZ, Petrovic I, Sucic M, Kokot A, Klicek R, Sever M, Seiwerth S, Sikiric P. Stable gastric pentadecapeptide BPC 157 heals rat colovesical fistula. Eur J Pharmacol 2016; 780:1-7. [PMID: 26875638 DOI: 10.1016/j.ejphar.2016.02.038] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2015] [Revised: 02/09/2016] [Accepted: 02/10/2016] [Indexed: 02/07/2023]
Abstract
To establish the effects of BPC 157 on the healing of rat colovesical fistulas, Wistar Albino male rats were randomly assigned to different groups. BPC 157, a stable gastric pentadecapeptide, has been used in clinical applications-specifically, in ulcerative colitis-and was successful in treating both external and internal fistulas. BPC 157 was provided daily, perorally, in drinking water (10µg/kg, 12ml/rat/day) until sacrifice or, alternatively, 10µg/kg or 10ng/kg intraperitoneally, with the first application at 30min after surgery and the last at 24h before sacrifice. Controls simultaneously received an equivolume of saline (5.0ml/kg ip) or water only (12ml/rat/day). Assessment (i.e., colon and vesical defects, fistula leaking, fecaluria and defecation through the fistula, adhesions and intestinal obstruction as healing processes) took place on days 7, 14 and 28. Control colovesical fistulas regularly exhibited poor healing, with both of the defects persisting; continuous fistula leakage; fecaluria and defecation through the fistula; advanced adhesion formation; and intestinal obstruction. By contrast, BPC 157 given perorally or intraperitoneally and in µg- and ng-regimens rapidly improved the whole presentation, with both colon and vesical defects simultaneously ameliorated and eventually healed. The maximal instilled volume was continuously raised until it reached the values of healthy rats, there were no signs of fecaluria and no defecation through the fistula, there was counteraction of advanced adhesion formation or there was an intestinal obstruction. In conclusion, BPC 157 effects appear to be suited to inducing full healing of colocutaneous fistulas in rats.
Collapse
Affiliation(s)
- Tihomir Grgic
- Department of Pharmacology, School of Medicine, University of Zagreb, POB 916, Salata 11, 10000 Zagreb, Croatia
| | - Dora Grgic
- Department of Pharmacology, School of Medicine, University of Zagreb, POB 916, Salata 11, 10000 Zagreb, Croatia
| | - Domagoj Drmic
- Department of Pharmacology, School of Medicine, University of Zagreb, POB 916, Salata 11, 10000 Zagreb, Croatia
| | - Anita Zenko Sever
- Department of Pathology, School of Medicine, University of Zagreb, Salata 9, 10000 Zagreb, Croatia
| | - Igor Petrovic
- Department of Pharmacology, School of Medicine, University of Zagreb, POB 916, Salata 11, 10000 Zagreb, Croatia
| | - Mario Sucic
- Department of Pharmacology, School of Medicine, University of Zagreb, POB 916, Salata 11, 10000 Zagreb, Croatia
| | - Antonio Kokot
- Department of Anatomy and Neuroscience, Faculty of Medicine, J.J. Strossmayer University of Osijek, J. Huttlera 4, 31000 Osijek, Croatia
| | - Robert Klicek
- Department of Pharmacology, School of Medicine, University of Zagreb, POB 916, Salata 11, 10000 Zagreb, Croatia
| | - Marko Sever
- Department of Pharmacology, School of Medicine, University of Zagreb, POB 916, Salata 11, 10000 Zagreb, Croatia
| | - Sven Seiwerth
- Department of Pathology, School of Medicine, University of Zagreb, Salata 9, 10000 Zagreb, Croatia
| | - Predrag Sikiric
- Department of Pharmacology, School of Medicine, University of Zagreb, POB 916, Salata 11, 10000 Zagreb, Croatia.
| |
Collapse
|
|
18
|
Baric M, Sever AZ, Vuletic LB, Rasic Z, Sever M, Drmic D, Pavelic-Turudic T, Sucic M, Vrcic H, Seiwerth S, Sikiric P. Stable gastric pentadecapeptide BPC 157 heals rectovaginal fistula in rats. Life Sci 2016; 148:63-70. [PMID: 26872976 DOI: 10.1016/j.lfs.2016.02.029] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2015] [Revised: 01/22/2016] [Accepted: 02/08/2016] [Indexed: 02/07/2023]
Abstract
AIM Rectovaginal fistula is a devastating condition providing more than 99% of patients for surgical treatment. We hypothesized that rectovaginal fistula may be healed by therapy with stable gastric pentadecapeptide BPC 157, in consistence with its initial clinical application and effect on external fistulas. MAIN METHODS BPC 157 (10μg/kg or 10ng/kg) was given perorally, in drinking water (0.16μg/ml or 0.16ng/ml, 12ml/rat/day) till sacrifice, or alternatively, intraperitoneally, first application at 30min after surgery, last at 24h before sacrifice. Controls simultaneously received an equivolume of saline (5.0ml/kg ip) or water only (12ml/rat/day). The assessment (i.e., rectal and vaginal defect, fistula leakage, defecation through the fistula, adhesions and intestinal obstruction as healing processes) was at day 1, 3, 5, 7, 10, 14 and 21. KEY FINDINGS Regularly, rectovaginal fistulas exhibited poor healing, with both of the defects persisting, continuous fistula leakage, defecation through the fistula, advanced adhesion formation and intestinal obstruction. By contrast, BPC 157 given perorally or intraperitoneally, in μg- and ng-regimens rapidly improved the whole presentation, with both rectal and vaginal defects simultaneously ameliorated and eventually healed. The maximal instilled volume was continuously raised till the values of healthy rats were achieved, there were no signs of defecation through the fistula. A counteraction of advanced adhesion formation and intestinal obstruction was achieved. Microscopic improvement was along with macroscopic findings. SIGNIFICANCE BPC 157 effects appear to be suited to induce a full healing of rectovaginal fistulas in rats.
Collapse
Affiliation(s)
- Marko Baric
- Department of Surgery, School of Medicine, University of Zagreb, Salata 3b, 10000 Zagreb, Croatia
| | - Anita Zenko Sever
- Department of Pathology, School of Medicine, University of Zagreb, Salata 9, 10000 Zagreb, Croatia
| | - Lovorka Batelja Vuletic
- Department of Pathology, School of Medicine, University of Zagreb, Salata 9, 10000 Zagreb, Croatia
| | - Zarko Rasic
- Department of Surgery, School of Medicine, University of Zagreb, Salata 3b, 10000 Zagreb, Croatia
| | - Marko Sever
- Department of Surgery, School of Medicine, University of Zagreb, Salata 3b, 10000 Zagreb, Croatia
| | - Domagoj Drmic
- Department of Pharmacology, School of Medicine, University of Zagreb, POB 916, Salata 11, Zagreb, Croatia
| | - Tatjana Pavelic-Turudic
- Department of Obstetrics & Gynecology, School of Medicine, University of Zagreb, Salata 3b, 10000 Zagreb, Croatia
| | - Mario Sucic
- Department of Urology, School of Medicine, University of Zagreb, Salata 3b, 10000 Zagreb, Croatia
| | - Hrvoje Vrcic
- Department of Obstetrics & Gynecology, School of Medicine, University of Zagreb, Salata 3b, 10000 Zagreb, Croatia
| | - Sven Seiwerth
- Department of Pathology, School of Medicine, University of Zagreb, Salata 9, 10000 Zagreb, Croatia
| | - Predrag Sikiric
- Department of Pharmacology, School of Medicine, University of Zagreb, POB 916, Salata 11, Zagreb, Croatia.
| |
Collapse
|
|
19
|
Mohammadi-Samani S, Kouroshfard S, Azarpira N. Effects of phosphate supplementation on Pseudomonas aeruginosa invasive behavior in burn wound infections: A simple approach to a big problem. Burns 2016; 42:428-33. [PMID: 26787129 DOI: 10.1016/j.burns.2015.09.003] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2015] [Revised: 08/30/2015] [Accepted: 09/03/2015] [Indexed: 10/22/2022]
Abstract
This study was designed to investigate the effect of inorganic phosphate supplementation on invasive behavior of Pseudomonas aeruginosa in burn wound infections. An emulsion-based lotion containing sodium dihydrogen phosphate was formulated and then 50 female Sprague-Dawley rats with burn wounds were used to assess the effect of phosphate supplementation on swarming motility of P. aeruginosa. On the second day after burn, four groups of rats were inoculated with P. aeruginosa and one group was left as negative control. The treatment was started on day 3 and the animals were followed up for 4 weeks. Significant improvement in wound healing was observed in the phosphate-receiving group after the 4-week follow-up, compared to the negative control, positive control, and silver sulfadiazine-receiving groups. Histopathological assessment of the tissue samples also indicated the healing process in phosphate-enriched lotion receiving group. The results showed that inorganic phosphate supplementation results in alteration of the virulence behavior of P. aeruginosa and improvement in the wound healing process. In conclusion, phosphate supplementation would be a rational strategy in the eradication of P. aeruginosa wound infection.
Collapse
Affiliation(s)
- Soliman Mohammadi-Samani
- Pharmaceutical Sciences Research Center, Faculty of Pharmacy, Shiraz University of Medical Science, Shiraz, Iran.
| | | | - Negar Azarpira
- Shiraz Transplant Research Center, Shiraz University of Medical Science, Shiraz, Iran
| |
Collapse
|
|
20
|
Sikiric P, Seiwerth S, Rucman R, Kolenc D, Vuletic LB, Drmic D, Grgic T, Strbe S, Zukanovic G, Crvenkovic D, Madzarac G, Rukavina I, Sucic M, Baric M, Starcevic N, Krstonijevic Z, Bencic ML, Filipcic I, Rokotov DS, Vlainic J. Brain-gut Axis and Pentadecapeptide BPC 157: Theoretical and Practical Implications. Curr Neuropharmacol 2016; 14:857-865. [PMID: 27138887 PMCID: PMC5333585 DOI: 10.2174/1570159x13666160502153022] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2016] [Revised: 03/17/2016] [Accepted: 04/21/2016] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Brain-gut interaction involves, among others, peptidergic growth factors which are native in GI tract and have strong antiulcer potency and thus could from periphery beneficially affect CNS-disorders. We focused on the stable gastric pentadecapeptide BPC 157, an antiulcer peptidergic agent, safe in inflammatory bowel disease trials and now in multiple sclerosis trial, native and stable in human gastric juice. METHODS Review of our research on BPC 157 in terms of brain-gut axis. RESULTS BPC 157 may serve as a novel mediator of Robert's cytoprotection, involved in maintaining of GI mucosa integrity, with no toxic effect. BPC 157 was successful in the therapy of GI tract, periodontitis, liver and pancreas lesions, and in the healing of various tissues and wounds. Stimulated Egr-1 gene, NAB2, FAK-paxillin and JAK-2 pathways are hitherto implicated. Initially corresponding beneficial central influence was seen when BPC 157 was given peripherally and a serotonin release in particular brain areas, mostly nigrostriatal, was changed. BPC 157 modulates serotonergic and dopaminergic systems, beneficially affects various behavioral disturbances that otherwise appeared due to specifically (over)stimulated/damaged neurotransmitters systems. Besides, BPC 157 has neuroprotective effects: protects somatosensory neurons; peripheral nerve regeneration appearent after transection; after traumatic brain injury counteracts the otherwise progressing course, in rat spinal cord compression with tail paralysis, axonal and neuronal necrosis, demyelination, cyst formation and rescues tail function in both short-terms and long-terms; after NSAIDs or insulin overdose or cuprizone encephalopathies were attenuated along with GI, liver and vascular injuries. CONCLUSION BPC 157, a gastric peptide, may serve as remedy in various CNS-disorders.
Collapse
Affiliation(s)
- Predrag Sikiric
- Department of Pharmacology and Pathology, Medical Faculty, University of Zagreb, Zagreb, Croatia
| | - Sven Seiwerth
- Department of Pharmacology and Pathology, Medical Faculty, University of Zagreb, Zagreb, Croatia
| | - Rudolf Rucman
- Department of Pharmacology and Pathology, Medical Faculty, University of Zagreb, Zagreb, Croatia
| | - Danijela Kolenc
- Department of Pharmacology and Pathology, Medical Faculty, University of Zagreb, Zagreb, Croatia
| | - Lovorka Batelja Vuletic
- Department of Pharmacology and Pathology, Medical Faculty, University of Zagreb, Zagreb, Croatia
| | - Domagoj Drmic
- Department of Pharmacology and Pathology, Medical Faculty, University of Zagreb, Zagreb, Croatia
| | - Tihomir Grgic
- Department of Pharmacology and Pathology, Medical Faculty, University of Zagreb, Zagreb, Croatia
| | - Sanja Strbe
- Department of Pharmacology and Pathology, Medical Faculty, University of Zagreb, Zagreb, Croatia
| | - Goran Zukanovic
- Department of Pharmacology and Pathology, Medical Faculty, University of Zagreb, Zagreb, Croatia
| | - Dalibor Crvenkovic
- Department of Pharmacology and Pathology, Medical Faculty, University of Zagreb, Zagreb, Croatia
| | - Goran Madzarac
- Department of Pharmacology and Pathology, Medical Faculty, University of Zagreb, Zagreb, Croatia
| | - Iva Rukavina
- Department of Pharmacology and Pathology, Medical Faculty, University of Zagreb, Zagreb, Croatia
| | - Mario Sucic
- Department of Pharmacology and Pathology, Medical Faculty, University of Zagreb, Zagreb, Croatia
| | - Marko Baric
- Department of Pharmacology and Pathology, Medical Faculty, University of Zagreb, Zagreb, Croatia
| | - Neven Starcevic
- Department of Pharmacology and Pathology, Medical Faculty, University of Zagreb, Zagreb, Croatia
| | - Zoran Krstonijevic
- Department of Pharmacology and Pathology, Medical Faculty, University of Zagreb, Zagreb, Croatia
| | - Martina Lovric Bencic
- Department of Pharmacology and Pathology, Medical Faculty, University of Zagreb, Zagreb, Croatia
| | - Igor Filipcic
- Department of Pharmacology and Pathology, Medical Faculty, University of Zagreb, Zagreb, Croatia
| | - Dinko Stancic Rokotov
- Department of Pharmacology and Pathology, Medical Faculty, University of Zagreb, Zagreb, Croatia
| | - Josipa Vlainic
- Department of Molecular Medicine, Rudjer Boskovic Institute, Zagreb, Croatia
| |
Collapse
|
|
21
|
Masnec S, Kokot A, Zlatar M, Kalauz M, Kunjko K, Radic B, Klicek R, Drmic D, Lazic R, Brcic L, Radic R, Ivekovic R, Seiwerth S, Sikiric P. Perforating corneal injury in rat and pentadecapeptide BPC 157. Exp Eye Res 2015; 136:9-15. [PMID: 25912999 DOI: 10.1016/j.exer.2015.04.016] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2014] [Revised: 04/09/2015] [Accepted: 04/22/2015] [Indexed: 12/12/2022]
Abstract
Based on its healing effects in various tissues, we hypothesized that the stable gastric pentadecapeptide BPC 157 heals corneal ulcerations in rats and effects corneal transparency. We made a penetrant linear 2-mm incision in the paralimbal region of the left cornea at the 5 o'clock position with a 20-gauge MVR incision knife at 45° under an operating microscope. Medication was BPC 157 (2 pg/mL, 2 ng/mL, and 2 μg/mL distilled water, two eye drops/left rat eye) immediately after injury induction and then every 8 h up to 120 h; controls received an equal volume of distilled water. In contrast to the poor healing response in controls, BPC 157 significantly accelerated the healing process in 2 μg and 2 ng BPC 157-treated eyes, starting 24 h after the injury, and the fluorescein and Seidel tests became negative. The epithelial defects were completely healed at 72 h (2 μg BPC 157-treated group) and at 96 h (2 ng BPC 157-treated group) after injury. Aqueous cells were absent at 96 h and 120 h after injury in the 2 μg and 2 ng BPC 157-treated groups, respectively. In conclusion, BPC 157 effects the rapid regaining of corneal transparency. Whereas controls developed new vessels that grew from the limbus to the penetrated area, BPC 157-treated rats generally had no new vessels, and those that did form in the limbus did not make contact with the penetrated area. Thus, BPC 157 eye drops successfully close perforating corneal incisions in rats.
Collapse
Affiliation(s)
- Sanja Masnec
- University Department of Ophthalmology, Zagreb University Hospital Center, Zagreb, Croatia
| | - Antonio Kokot
- Department of Anatomy and Neuroscience, School of Medicine, University of Osijek, Osijek, Croatia
| | - Mirna Zlatar
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Miro Kalauz
- University Department of Ophthalmology, Zagreb University Hospital Center, Zagreb, Croatia
| | - Kristian Kunjko
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Bozo Radic
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Robert Klicek
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Domagoj Drmic
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Ratimir Lazic
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Luka Brcic
- Department of Pathology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Radivoje Radic
- Department of Anatomy and Neuroscience, School of Medicine, University of Osijek, Osijek, Croatia
| | - Renata Ivekovic
- University Department of Ophthalmology, Sestre Milosrdnice University Hospital Center, Zagreb, Croatia
| | - Sven Seiwerth
- Department of Pathology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Predrag Sikiric
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia.
| |
Collapse
|
|
22
|
Huang T, Zhang K, Sun L, Xue X, Zhang C, Shu Z, Mu N, Gu J, Zhang W, Wang Y, Zhang Y, Zhang W. Body protective compound-157 enhances alkali-burn wound healing in vivo and promotes proliferation, migration, and angiogenesis in vitro. DRUG DESIGN DEVELOPMENT AND THERAPY 2015; 9:2485-99. [PMID: 25995620 PMCID: PMC4425239 DOI: 10.2147/dddt.s82030] [Citation(s) in RCA: 58] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Chemical burns take up a high proportion of burns admissions and can penetrate deep into tissues. Various reagents have been applied in the treatment of skin chemical burns; however, no optimal reagent for skin chemical burns currently exists. The present study investigated the effect of topical body protective compound (BPC)-157 treatment on skin wound healing, using an alkali burn rat model. Topical treatment with BPC-157 was shown to accelerate wound closure following an alkali burn. Histological examination of skin sections with hematoxylin–eosin and Masson staining showed better granulation tissue formation, reepithelialization, dermal remodeling, and a higher extent of collagen deposition when compared to the model control group on the 18th day postwounding. BPC-157 could promote vascular endothelial growth factor expression in wounded skin tissues. Furthermore, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and cell cycle analysis demonstrated that BPC-157 enhanced the proliferation of human umbilical vein endothelial cells (HUVECs). Transwell assay and wound healing assay showed that BPC-157 significantly promoted migration of HUVECs. We also observed that BPC-157 upregulated the expression of VEGF-a and accelerated vascular tube formation in vitro. Moreover, further studies suggested that BPC-157 regulated the phosphorylation level of extracellular signal-regulated kinases 1 and 2 (ERK1/2) as well as its downstream targets, including c-Fos, c-Jun, and Egr-1, which are key molecules involved in cell growth, migration, and angiogenesis. Altogether, our results indicated that BPC-157 treatment may accelerate wound healing in a model of alkali burn-induced skin injury. The therapeutic mechanism may be associated with accelerated granulation tissue formation, reepithelialization, dermal remodeling, and collagen deposition through ERK1/2 signaling pathway.
Collapse
Affiliation(s)
- Tonglie Huang
- State Key Laboratory of Cancer Biology, Department of Biopharmaceutics, School of Pharmacy, The Fourth Military Medical University, Xi'an, People's Republic of China
| | - Kuo Zhang
- National Engineering Research Center for Miniaturized Detection Systems, School of Life Sciences, Northwest University, Xi'an, People's Republic of China
| | - Lijuan Sun
- Department of Ophthalmology, Xijing Hospital, The Fourth Military Medical University, Xi'an, People's Republic of China
| | - Xiaochang Xue
- State Key Laboratory of Cancer Biology, Department of Biopharmaceutics, School of Pharmacy, The Fourth Military Medical University, Xi'an, People's Republic of China
| | - Cun Zhang
- State Key Laboratory of Cancer Biology, Department of Biopharmaceutics, School of Pharmacy, The Fourth Military Medical University, Xi'an, People's Republic of China
| | - Zhen Shu
- State Key Laboratory of Cancer Biology, Department of Biopharmaceutics, School of Pharmacy, The Fourth Military Medical University, Xi'an, People's Republic of China
| | - Nan Mu
- State Key Laboratory of Cancer Biology, Department of Biopharmaceutics, School of Pharmacy, The Fourth Military Medical University, Xi'an, People's Republic of China
| | - Jintao Gu
- State Key Laboratory of Cancer Biology, Department of Biopharmaceutics, School of Pharmacy, The Fourth Military Medical University, Xi'an, People's Republic of China
| | - Wangqian Zhang
- State Key Laboratory of Cancer Biology, Department of Biopharmaceutics, School of Pharmacy, The Fourth Military Medical University, Xi'an, People's Republic of China
| | - Yukun Wang
- State Key Laboratory of Cancer Biology, Department of Biopharmaceutics, School of Pharmacy, The Fourth Military Medical University, Xi'an, People's Republic of China
| | - Yingqi Zhang
- State Key Laboratory of Cancer Biology, Department of Biopharmaceutics, School of Pharmacy, The Fourth Military Medical University, Xi'an, People's Republic of China
| | - Wei Zhang
- State Key Laboratory of Cancer Biology, Department of Biopharmaceutics, School of Pharmacy, The Fourth Military Medical University, Xi'an, People's Republic of China
| |
Collapse
|
|
23
|
Chang CH, Tsai WC, Hsu YH, Pang JHS. Pentadecapeptide BPC 157 enhances the growth hormone receptor expression in tendon fibroblasts. Molecules 2014; 19:19066-77. [PMID: 25415472 PMCID: PMC6271067 DOI: 10.3390/molecules191119066] [Citation(s) in RCA: 69] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2014] [Revised: 11/12/2014] [Accepted: 11/13/2014] [Indexed: 12/11/2022] Open
Abstract
BPC 157, a pentadecapeptide derived from human gastric juice, has been demonstrated to promote the healing of different tissues, including skin, muscle, bone, ligament and tendon in many animal studies. However, the underlying mechanism has not been fully clarified. The present study aimed to explore the effect of BPC 157 on tendon fibroblasts isolated from Achilles tendon of male Sprague-Dawley rat. From the result of cDNA microarray analysis, growth hormone receptor was revealed as one of the most abundantly up-regulated genes in tendon fibroblasts by BPC 157. BPC 157 dose- and time-dependently increased the expression of growth hormone receptor in tendon fibroblasts at both the mRNA and protein levels as measured by RT/real-time PCR and Western blot, respectively. The addition of growth hormone to BPC 157-treated tendon fibroblasts dose- and time-dependently increased the cell proliferation as determined by MTT assay and PCNA expression by RT/real-time PCR. Janus kinase 2, the downstream signal pathway of growth hormone receptor, was activated time-dependently by stimulating the BPC 157-treated tendon fibroblasts with growth hormone. In conclusion, the BPC 157-induced increase of growth hormone receptor in tendon fibroblasts may potentiate the proliferation-promoting effect of growth hormone and contribute to the healing of tendon.
Collapse
Affiliation(s)
- Chung-Hsun Chang
- Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, 259 Wen-Hwa 1st Road, Kwei-Shan, Tao-Yuan 333, Taiwan.
| | - Wen-Chung Tsai
- Department of Physical Medicine and Rehabilitation, Chang Gung Memorial Hospital, College of Medicine, Chang Gung University, Kwei-Shan, Tao-Yuan 333, Taiwan.
| | - Ya-Hui Hsu
- Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, 259 Wen-Hwa 1st Road, Kwei-Shan, Tao-Yuan 333, Taiwan.
| | - Jong-Hwei Su Pang
- Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, 259 Wen-Hwa 1st Road, Kwei-Shan, Tao-Yuan 333, Taiwan.
| |
Collapse
|
|
24
|
Natural and synthetic polymers for wounds and burns dressing. Int J Pharm 2013; 463:127-36. [PMID: 24368109 DOI: 10.1016/j.ijpharm.2013.12.015] [Citation(s) in RCA: 630] [Impact Index Per Article: 52.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2013] [Revised: 12/10/2013] [Accepted: 12/14/2013] [Indexed: 12/15/2022]
Abstract
In the last years, health care professionals faced with an increasing number of patients suffering from wounds and burns difficult to treat and heal. During the wound healing process, the dressing protects the injury and contributes to the recovery of dermal and epidermal tissues. Because their biocompatibility, biodegradability and similarity to macromolecules recognized by the human body, some natural polymers such as polysaccharides (alginates, chitin, chitosan, heparin, chondroitin), proteoglycans and proteins (collagen, gelatin, fibrin, keratin, silk fibroin, eggshell membrane) are extensively used in wounds and burns management. Obtained by electrospinning technique, some synthetic polymers like biomimetic extracellular matrix micro/nanoscale fibers based on polyglycolic acid, polylactic acid, polyacrylic acid, poly-ɛ-caprolactone, polyvinylpyrrolidone, polyvinyl alcohol, polyethylene glycol, exhibit in vivo and in vitro wound healing properties and enhance re-epithelialization. They provide an optimal microenvironment for cell proliferation, migration and differentiation, due to their biocompatibility, biodegradability, peculiar structure and good mechanical properties. Thus, synthetic polymers are used also in regenerative medicine for cartilage, bone, vascular, nerve and ligament repair and restoration. Biocompatible with fibroblasts and keratinocytes, tissue engineered skin is indicated for regeneration and remodeling of human epidermis and wound healing improving the treatment of severe skin defects or partial-thickness burn injuries.
Collapse
|
|
25
|
Jandric I, Vrcic H, Balen MJ, Kolenc D, Brcic L, Radic B, Drmic D, Seiwerth S, Sikiric P. Salutary effect of gastric pentadecapeptide BPC 157 in two different stress urinary incontinence models in female rats. Med Sci Monit Basic Res 2013; 19:93-102. [PMID: 23478678 PMCID: PMC3940704 DOI: 10.12659/msmbr.883828] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2011] [Accepted: 07/26/2012] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND Since an originally anti-ulcer stable gastric pentadecapeptide BPC 157 (PL 14736) was shown to promote healing of injured striated muscle and smooth muscle in the gastrointestinal tract, we explored its therapeutic potentials for leak point pressure (LPP) recovery in rat stress urinary incontinence (SUI) after transabdominal urethrolysis (TU) and prolonged vaginal dilatation (VD). MATERIAL AND METHODS During a 7-day period, TU-rats and VD-rats (or healthy rats) received BPC 157, either (i) intraperitoneally, 10 µg/kg or 10 ng/kg, once daily (first administration 30 min after surgery, last 24 h before LPP-testing and sacrifice), or (ii) per-orally, 10 µg/kg in drinking water (0.16 µg/mL, 12 mL/rat/day). Vesicourethral segments were harvested for immunohistochemical evaluation. RESULTS All BPC 157 regimens counteracted decrease of LPP values in TU-rats and VD-rats. Additionally, BPC 157-TU rats (µg-intraperitoneally or per-orally) and BPC 157-VD rats (µg intraperitoneally) reached LPP values originally noted in healthy rats. Conversely, in healthy rats, BPC 157 did not alter LPP. Immunohistochemical studies revealed higher desmin (delineates striated organization of skeletal muscle), smooth muscle actin, and CD34 (angiogenic marker) positivity within the urethral wall in BPC 157-treated rats vs. controls, as well as overall preserved muscle/connective tissue ratio assessed with Mallory's trichrome staining. CONCLUSIONS Pentadecapeptide BPC 157, applied parenterally or per-orally, appears to ameliorate the SUI in rat models, improving the otherwise detrimental course of healing after VD and TU, which may be analogous to human injury. These beneficial effects may possibly be selectively used in future strategies for treatment of SUI.
Collapse
Affiliation(s)
- Ivan Jandric
- General Hospital “Dr. Josip Bencevic”, Slavonski Brod, Croatia
| | - Hrvoje Vrcic
- Department of Obstetrics and Gynecology, Medical Faculty University of Zagreb, Zagreb, Croatia
| | | | - Danijela Kolenc
- Department of Pathology, Medical Faculty University of Zagreb, Zagreb, Croatia
| | - Luka Brcic
- Department of Pathology, Medical Faculty University of Zagreb, Zagreb, Croatia
| | - Bozo Radic
- Department of Pharmacology, Medical Faculty University of Zagreb, Zagreb, Croatia
| | - Domagoj Drmic
- Department of Pharmacology, Medical Faculty University of Zagreb, Zagreb, Croatia
| | - Sven Seiwerth
- Department of Pathology, Medical Faculty University of Zagreb, Zagreb, Croatia
| | - Predrag Sikiric
- Department of Pharmacology, Medical Faculty University of Zagreb, Zagreb, Croatia
| |
Collapse
|
|
26
|
Cesarec V, Becejac T, Misic M, Djakovic Z, Olujic D, Drmic D, Brcic L, Rokotov DS, Seiwerth S, Sikiric P. Pentadecapeptide BPC 157 and the esophagocutaneous fistula healing therapy. Eur J Pharmacol 2013; 701:203-212. [PMID: 23220707 DOI: 10.1016/j.ejphar.2012.11.055] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2012] [Revised: 11/26/2012] [Accepted: 11/28/2012] [Indexed: 02/07/2023]
Abstract
Esophagocutaneous fistulas are a failure of the NO-system, due to NO-synthase blockage by the NOS-blocker L-NAME consequently counteracted by l-arginine and gastric pentadecapeptide BPC 157 (l-arginine
Collapse
Affiliation(s)
- Vedran Cesarec
- Department of Pharmacology, University of Zagreb, Zagreb, Croatia
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
27
|
Barisic I, Balenovic D, Klicek R, Radic B, Nikitovic B, Drmic D, Udovicic M, Strinic D, Bardak D, Berkopic L, Djuzel V, Sever M, Cvjetko I, Romic Z, Sindic A, Bencic ML, Seiwerth S, Sikiric P. Mortal hyperkalemia disturbances in rats are NO-system related. The life saving effect of pentadecapeptide BPC 157. REGULATORY PEPTIDES 2013; 181:50-66. [PMID: 23327997 DOI: 10.1016/j.regpep.2012.12.007] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/08/2012] [Revised: 11/23/2012] [Accepted: 12/17/2012] [Indexed: 02/07/2023]
Abstract
We demonstrate the full counteracting ability of stable gastric pentadecapeptide BPC 157 against KCl-overdose (intraperitoneal (i), intragastric (ii), in vitro (iii)), NO-system related. (i) We demonstrated potential (/kg) of: BPC 157 (10ng, 10μg ip, complete counteraction), l-arginine (100mg ip, attenuation) vs. L-NAME (5mg ip, deadly aggravation), given alone and/or combined, before or after intraperitoneal KCl-solution application (9mEq/kg). Therapy was confronted with promptly unrelenting hyperkalemia (>12mmol/L), arrhythmias (and muscular weakness, hypertension, low pressure in lower esophageal and pyloric sphincter) with an ultimate and a regularly inevitable lethal outcome within 30min. Previously, we established BPC 157-NO-system interaction; now, a huge life-saving potential. Given 30min before KCl, all BPC 157 regimens regained sinus rhythm, had less prolongation of QRS, and had no asystolic pause. BPC 157 therapy, given 10min after KCl-application, starts the rescue within 5-10min, completely restoring normal sinus rhythm at 1h. Likewise, other hyperkalemia-disturbances (muscular weakness, hypertension, low sphincteric pressure) were also counteracted. Accordingly with NO-system relation, deadly aggravation by L-NAME: l-arginine brings the values to the control levels while BPC 157 always completely nullified lesions, markedly below those of controls. Combined with l-arginine, BPC 157 exhibited no additive effect. (ii) Intragastric KCl-solution application (27mEq/kg) - (hyperkalemia 7mmol/L): severe stomach mucosal lesions, sphincter failure and peaked T waves were fully counteracted by intragastric BPC 157 (10ng, 10μg) application, given 30min before or 10min after KCl. (iii). In HEK293 cells, hyperkalemic conditions (18.6mM potassium concentrations), BPC 157 directly affects potassium conductance, counteracting the effect on membrane potential and depolarizations caused by hyperkalemic conditions.
Collapse
Affiliation(s)
- Ivan Barisic
- Department of Pharmacology, University of Zagreb, Medical School, Salata 11, 10000 Zagreb, Croatia
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
28
|
Stupnisek M, Franjic S, Drmic D, Hrelec M, Kolenc D, Radic B, Bojic D, Vcev A, Seiwerth S, Sikiric P. Pentadecapeptide BPC 157 reduces bleeding time and thrombocytopenia after amputation in rats treated with heparin, warfarin or aspirin. Thromb Res 2012; 129:652-659. [PMID: 21840572 DOI: 10.1016/j.thromres.2011.07.035] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2011] [Revised: 06/26/2011] [Accepted: 07/20/2011] [Indexed: 02/07/2023]
Abstract
Recently, in rat abdominal aorta terminoterminal-anastomosis the stable gastric pentadecapeptide BPC 157 prevents obstructive thrombus formation and rapidly destroys already formed obstructive thrombus. Also, BPC 157 wound healing may signify the clot as conductive matrix or "scaffold" to speed up wound healing process, and decrease bleeding. Here, in rats, BPC 157 (10 μg/kg, 10 ng/kg) improved always reduced bleeding time and amount of bleeding after (tail) amputation only, heparin (250 mg/kg, 25mg/kg, 10mg/kg i.v.), warfarin (1.5mg/kg i.g. once daily for 3 consecutive days), aspirin (0.1g/kg i.g. (once daily/3 consecutive days) or 1.0 g/kg i.p. once), and amputation associated with those agents application. BPC 157 counteracting regimens (i.v., i.p., i.g. (immediately after any challenge)) correspondingly follow the route of bleeding-agents application. All heparin-, warfarin-, and aspirin-rats and normal-rats that received BPC 157 exhibited lesser fall in platelets count. BPC 157 attenuated over-increased APTT-, TT-values in 10mg/kg heparin-rats, but did not influence heparin activity (anti-Xa test). Indicatively, unless counteracted in BPC 157 rats, excessive bleeding-acute thrombocytopenia (<20% of initial values in heparin-rats) approaches substantial fall in platelets count known in type II HIT. Also, BPC 157 markedly prolongs the survival time (heparin-rats, 25mg/kg, right foot amputation).
Collapse
Affiliation(s)
- Mirjana Stupnisek
- Department of Pharmacology and Pathology Medical Faculty University of Zagreb, Zagreb, Croatia
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
29
|
Chang CH, Tsai WC, Lin MS, Hsu YH, Pang JHS. The promoting effect of pentadecapeptide BPC 157 on tendon healing involves tendon outgrowth, cell survival, and cell migration. J Appl Physiol (1985) 2010; 110:774-80. [PMID: 21030672 DOI: 10.1152/japplphysiol.00945.2010] [Citation(s) in RCA: 67] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Pentadecapeptide BPC 157, composed of 15 amino acids, is a partial sequence of body protection compound (BPC) that is discovered in and isolated from human gastric juice. Experimentally it has been demonstrated to accelerate the healing of many different wounds, including transected rat Achilles tendon. This study was designed to investigate the potential mechanism of BPC 157 to enhance healing of injured tendon. The outgrowth of tendon fibroblasts from tendon explants cultured with or without BPC 157 was examined. Results showed that BPC 157 significantly accelerated the outgrowth of tendon explants. Cell proliferation of cultured tendon fibroblasts derived from rat Achilles tendon was not directly affected by BPC 157 as evaluated by MTT assay. However, the survival of BPC 157-treated cells was significantly increased under the H(2)O(2) stress. BPC 157 markedly increased the in vitro migration of tendon fibroblasts in a dose-dependent manner as revealed by transwell filter migration assay. BPC 157 also dose dependently accelerated the spreading of tendon fibroblasts on culture dishes. The F-actin formation as detected by FITC-phalloidin staining was induced in BPC 157-treated fibroblasts. The protein expression and activation of FAK and paxillin were determined by Western blot analysis, and the phosphorylation levels of both FAK and paxillin were dose dependently increased by BPC 157 while the total amounts of protein was unaltered. In conclusion, BPC 157 promotes the ex vivo outgrowth of tendon fibroblasts from tendon explants, cell survival under stress, and the in vitro migration of tendon fibroblasts, which is likely mediated by the activation of the FAK-paxillin pathway.
Collapse
Affiliation(s)
- Chung-Hsun Chang
- Graduate Institute of Clinical Medical Sciences, Chang Gung Univ., 259 Wen-Hwa 1st Rd., Kwei-Shan, Tao-Yuan 333, Taiwan, Republic of China
| | | | | | | | | |
Collapse
|
|
30
|
Jagodzinski NA, Weerasinghe C, Porter K. Crush injuries and crush syndrome - a review. Part 2: the local injury. TRAUMA-ENGLAND 2010; 12:133-148. [DOI: 10.1177/1460408610372441] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Abstract
Crush injuries can occur in considerable numbers following natural disasters or acts of war and terrorism. They can also occur sporadically after industrial accidents or following periods of unconsciousness from drug intoxication, anaesthesia, trauma or cerebral events. A common pathophysiological pathway has been elucidated over the last century describing traumatic rhabdomyolysis leading to myoglobinuric acute renal failure and a systemic ‘crush syndrome’ affecting many organ systems. If left unrecognised or untreated then mortality rates are high. If treatment is commenced early and the systemic effects are minimised then patients are often faced with significant morbidity from the crushed limbs themselves. We have performed a thorough review of the English language literature from 1940—2009 investigating crush injuries and crush syndrome and present a comprehensive, two-part summary. Part 1: The systemic injury, we concentrate on the systemic crush syndrome. We determine the pathophysiology, clinical and prognostic indicators and treatment options such as forced alkaline diuresis, mannitol therapy, dialysis and haemofiltration. We discuss more controversial treatment options such as allopurinol, potassium binders, calcium therapy and other diuretics. We also discuss the specific management issues of the secondary ‘renal disaster’ that can occur following earthquakes and other mass disasters. Part 2: The local injury, we look in more detail at the pathophysiology of skeletal muscle damage following crush injuries and discuss how to minimise morbidity by salvaging limb function. In particular we discuss the controversies surrounding fasciotomy of crushed limbs and compare surgical management with conservative techniques such as mannitol therapy, hyperbaric oxygen therapy, topical negative pressure therapy and a novel topical treatment called gastric pentadecapeptide BPC 157.
Collapse
Affiliation(s)
| | | | - Keith Porter
- Selly Oak Hospital, Raddlebarn Road, Birmingham, B29 6JD, UK
| |
Collapse
|
|
31
|
Gjurasin M, Miklic P, Zupancic B, Perovic D, Zarkovic K, Brcic L, Kolenc D, Radic B, Seiwerth S, Sikiric P. Peptide therapy with pentadecapeptide BPC 157 in traumatic nerve injury. REGULATORY PEPTIDES 2010; 160:33-41. [PMID: 19903499 DOI: 10.1016/j.regpep.2009.11.005] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/04/2009] [Revised: 09/23/2009] [Accepted: 11/01/2009] [Indexed: 12/22/2022]
Abstract
We focused on the healing of rat transected sciatic nerve and improvement made by stable gastric pentadecapeptide BPC 157 (10 microg, 10ng/kg) applied shortly after injury (i) intraperitoneally/intragastrically/locally, at the site of anastomosis, or after (ii) non-anastomozed nerve tubing (7 mm nerve segment resected) directly into the tube. Improvement was shown clinically (autotomy), microscopically/morphometrically and functionally (EMG, one or two months post-injury, walking recovery (sciatic functional index (SFI)) at weekly intervals). BPC 157-rats exhibited faster axonal regeneration: histomorphometrically (improved presentation of neural fascicles, homogeneous regeneration pattern, increased density and size of regenerative fibers, existence of epineural and perineural regeneration, uniform target orientation of regenerative fibers, and higher proportion of neural vs. connective tissue, all fascicles in each nerve showed increased diameter of myelinated fibers, thickness of myelin sheet, number of myelinated fibers per area and myelinated fibers as a percentage of the nerve transected area and the increased blood vessels presentation), electrophysiologically (increased motor action potentials), functionally (improved SFI), the autotomy absent. Thus, BPC 157 markedly improved rat sciatic nerve healing.
Collapse
Affiliation(s)
- Miroslav Gjurasin
- Department of Pharmacology, Medical Faculty, University of Zagreb Medical School, Salata 11, POB 916, 10000 Zagreb, Croatia
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
32
|
Sever M, Klicek R, Radic B, Brcic L, Zoricic I, Drmic D, Ivica M, Barisic I, Ilic S, Berkopic L, Blagaic AB, Coric M, Kolenc D, Vrcic H, Anic T, Seiwerth S, Sikiric P. Gastric pentadecapeptide BPC 157 and short bowel syndrome in rats. Dig Dis Sci 2009; 54:2070-2083. [PMID: 19093208 DOI: 10.1007/s10620-008-0598-y] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2008] [Accepted: 10/17/2008] [Indexed: 12/11/2022]
Abstract
The gastric pentadecapeptide BPC 157, which was shown to be safe as an antiulcer peptide in trials for inflammatory bowel disease (PL14736, Pliva), successfully healed intestinal anastomosis and fistula in rat. Therefore, we studied for 4 weeks rats with escalating short bowel syndrome and progressive weight loss after small bowel resection from fourth ileal artery cranially of ileocecal valve to 5 cm beneath pylorus. BPC 157 (10 microg/kg or 10 ng/kg) was given perorally, in drinking water (12 ml/rat/day) or intraperitoneally (once daily, first application 30 min following surgery, last 24 h before sacrifice). Postoperatively, features of increasingly exhausted presentation were: weight loss appearing immediately regardless of villus height, twofold increase in crypt depth and fourfold increase in muscle thickness within the first week, jejunal and ileal overdilation, and disturbed jejunum/ileum relation. In contrast, constant weight gain above preoperative values was observed immediately with BPC 157 therapy, both perorally and parenterally, and villus height, crypt depth, and muscle thickness [inner (circular) muscular layer] also increased, at 7, 14, 21, and 28 days. Moreover, rats treated with pentadecapeptide BPC 157 showed not different jejunal and ileal diameters, constant jejunum-to-ileum ratio, and increased anastomosis breaking strength. In conclusion, pentadecapeptide BPC 157 could be helpful to cure short bowel syndrome.
Collapse
Affiliation(s)
- Marko Sever
- Department of Pharmacology, Medical School, University of Zagreb, Salata 11, 10000, Zagreb, Croatia
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
33
|
Skorjanec S, Dolovski Z, Kocman I, Brcic L, Blagaic Boban A, Batelja L, Coric M, Sever M, Klicek R, Berkopic L, Radic B, Drmic D, Kolenc D, Ilic S, Cesarec V, Tonkic A, Zoricic I, Mise S, Staresinic M, Ivica M, Lovric Bencic M, Anic T, Seiwerth S, Sikiric P. Therapy for unhealed gastrocutaneous fistulas in rats as a model for analogous healing of persistent skin wounds and persistent gastric ulcers: stable gastric pentadecapeptide BPC 157, atropine, ranitidine, and omeprazole. Dig Dis Sci 2009; 54:46-56. [PMID: 18649140 DOI: 10.1007/s10620-008-0332-9] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2008] [Accepted: 05/06/2008] [Indexed: 12/18/2022]
Abstract
OBJECTIVE This study focused on unhealed gastrocutaneous fistulas to resolve whether standard drugs that promote healing of gastric ulcers may simultaneously have the same effect on cutaneous wounds, and corticosteroid aggravation, and to demonstrate why peptides such as BPC 157 exhibit a greater healing effect. Therefore, with the fistulas therapy, we challenge the wound/growth factors theory of the analogous nonhealing of wounds and persistent gastric ulcers. METHODS The healing rate of gastrocutaneous fistula in rat (2-mm-diameter stomach defect, 3-mm-diameter skin defect) validates macro/microscopically and biomechanically a direct skin wound/stomach ulcer relation, and identifies a potential therapy consisting of: (i) stable gastric pentadecapeptide BPC 157 [in drinking water (10 microg/kg) (12 ml/rat/day) or intraperitoneally (10 microg/kg, 10 ng/kg, 10 pg/kg)], (ii) atropine (10 mg/kg), ranitidine (50 mg/kg), and omeprazole (50 mg/kg), (iii) 6-alpha-methylprednisolone (1 mg/kg) [intraperitoneally, once daily, first application at 30 min following surgery; last 24 h before sacrifice (at postoperative days 1, 2, 3, 7, 14, and 21)]. RESULTS Greater anti-ulcer potential and efficiency in wound healing compared with standard agents favor BPC 157, efficient in inflammatory bowel disease (PL-14736, Pliva), given in drinking water or intraperitoneally. Even after 6-alpha-methylprednisolone aggravation, BPC 157 promptly improves both skin and stomach mucosa healing, and closure of fistulas, with no leakage after up to 20 ml water intragastrically. Standard anti-ulcer agents, after a delay, improve firstly skin healing and then stomach mucosal healing, but not fistula leaking and bursting strength (except for atropine). CONCLUSION We conclude that BPC 157 may resolve analogous nonhealing of wounds and persistent gastric ulcers better than standard agents.
Collapse
Affiliation(s)
- Sandra Skorjanec
- Department of Pharmacology, Medical School, University of Zagreb, Salata 11, 10000, Zagreb, Croatia
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
34
|
Klicek R, Sever M, Radic B, Drmic D, Kocman I, Zoricic I, Vuksic T, Ivica M, Barisic I, Ilic S, Berkopic L, Vrcic H, Brcic L, Blagaic AB, Coric M, Brcic I, Rokotov DS, Anic T, Seiwerth S, Sikiric P. Pentadecapeptide BPC 157, in clinical trials as a therapy for inflammatory bowel disease (PL14736), is effective in the healing of colocutaneous fistulas in rats: role of the nitric oxide-system. J Pharmacol Sci 2008; 108:7-17. [PMID: 18818478 DOI: 10.1254/jphs.fp0072161] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
We focused on the therapeutic effect of the stable gastric pentadecapeptide BPC 157 and how its action is related to nitric oxide (NO) in persistent colocutaneous fistula in rats (at 5 cm from anus, colon defect of 5 mm, skin defect of 5 mm); this peptide has been shown to be safe in clinical trials for inflammatory bowel disease (PL14736) and safe for intestinal anstomosis therapy. BPC 157 (10 microg/kg, 10 ng/kg) was applied i) in drinking water until the animals were sacrificed at post-operative day 1, 3, 5, 7, 14, 21, and 28; or ii) once daily intraperitoneally (first application 30 min following surgery, last 24 h before sacrifice) alone or with N(G)-nitro-L-arginine methyl ester (L-NAME) (5 mg/kg), L-arginine (200 mg/kg), and their combinations. Sulphasalazine (50 mg/kg) and 6-alpha-methylprednisolone (1 mg/kg) were given once daily intraperitoneally. BPC 157 accelerated parenterally or perorally the healing of colonic and skin defect, leading to the suitable closure of the fistula, macro/microscopically, biomechanically, and functionally (larger water volume sustained without fistula leaking). L-NAME aggravated the healing failure of colocutaneous fistulas, skin, and colon wounds (L-NAME groups). L-Arginine was effective only with blunted NO generation (L-NAME + L-arginine groups) but not without (L-arginine groups). All of the BPC 157 beneficial effects remained unchanged with blunted NO-generation (L-NAME + BPC 157 groups) and with NO substrate (L-arginine + BPC 157 groups) as well as L-NAME and L-arginine co-administration (L-NAME + L-arginine + BPC 157 groups). Sulphasalazine was only moderately effective, and corticosteroid even had an aggravating effect.
Collapse
Affiliation(s)
- Robert Klicek
- Department of Pharmacology, Medical School, University of Zagreb, Croatia
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
35
|
Novinscak T, Brcic L, Staresinic M, Jukic I, Radic B, Pevec D, Mise S, Tomasovic S, Brcic I, Banic T, Jakir A, Buljat G, Anic T, Zoricic I, Romic Z, Seiwerth S, Sikiric P. Gastric pentadecapeptide BPC 157 as an effective therapy for muscle crush injury in the rat. Surg Today 2008; 38:716-725. [PMID: 18668315 DOI: 10.1007/s00595-007-3706-2] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2007] [Accepted: 11/26/2007] [Indexed: 12/15/2022]
Abstract
PURPOSE Stable gastric pentadecapeptide BPC 157 accelerates the healing of a transected Achilles tendon and a transected quadriceps muscle. It may also be of clinical relevance as a systemic and local peptide treatment for crush injury of a major muscle, such as gastrocnemius muscle complex. BPC 157 is effective without a carrier, and it is presently undergoing trials for inflammatory bowel disease, and no toxicity has so far been reported. METHODS In crushed rats (force delivered 0.727 Ns/cm2), BPC 157 was applied either intraperitoneally or locally, as a thin cream layer, immediately after injury (sacrifice at 2 h), and once a day for 14 days. RESULTS BPC 157 improved muscle healing, macroscopically (less hematoma and edema, no post-injury leg contracture), microscopically, functionally, and also based on enzyme activity (creatine kinase, lactate dehydrogenase, aspartate aminotransferase, alanine aminotransferase). CONCLUSION BPC 157, at all investigated intervals, given locally or intraperitoneally, accelerated post-injury muscle healing and also helped to restore the full function.
Collapse
Affiliation(s)
- Tomislav Novinscak
- Department of Pharmacology, Institute of Pathology, University of Zagreb Medical School, Salata 11, 10 000, Zagreb, Croatia
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
36
|
Vuksic T, Zoricic I, Brcic L, Sever M, Klicek R, Radic B, Cesarec V, Berkopic L, Keller N, Blagaic AB, Kokic N, Jelic I, Geber J, Anic T, Seiwerth S, Sikiric P. Stable gastric pentadecapeptide BPC 157 in trials for inflammatory bowel disease (PL-10, PLD-116, PL14736, Pliva, Croatia) heals ileoileal anastomosis in the rat. Surg Today 2007; 37:768-777. [PMID: 17713731 DOI: 10.1007/s00595-006-3498-9] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2006] [Accepted: 12/04/2006] [Indexed: 02/06/2023]
Abstract
PURPOSE Gastric pentadecapeptide BPC 157 (BPC 157), which has been shown to be safe in clinical trials for inflammatory bowel disease (PL-10, PLD-116, PL14736, Pliva, Croatia), may be able to cure intestinal anastomosis dehiscence. This antiulcer peptide shows no toxicity, is limit test negative, and a lethal dose is not achieved. It is stable in human gastric juice. In comparison with other standard treatments it is more effective for ulcers and various wounds, and can be used without a carrier needed for other peptides, both locally and systemically (i.e., perorally, parenterally). We studied the effectiveness of BPC 157 for ileoileal anastomosis healing in rats. METHODS We assessed ileoileal anastomosis dehiscence macroscopically, histologically, and biomechanically (volume [ml] infused through a syringe-perfusion pump system (1 ml/10 s), and pressure [mmHg] to leak induction [catheter connected to a chamber and a monitor, at 10 cm proximal to anastomosis]), at 1, 2, 3, 4, 5, 6, 7, and 14 days. BPC 157 (10 microg, 10 ng, 10 pg/kg i.p. (or saline [5 ml/kg]) was first administered after surgery, while it was last given 24 h before either assessment or sacrifice. RESULTS Throughout the experiment, both higher doses of BPC 157 were shown to improve all parameters of anastomotic wound healing. The formation of adhesions remained slight, the blood vessels were filled with blood, and a mild intestinal passage obstruction was only temporarily observed. Anastomosis without leakage induces markedly higher volume and pressure values, with a continuous increase toward healthy values. From day 1, edema was markedly attenuated and the number of granulocytes decreased, while from days 4 or 5 necrosis decreased and granulation tissue, reticulin, and collagen formation substantially increased, thus resulting in increased epithelization. CONCLUSION This study showed BPC 157 to have a beneficial effect on ileoileal anastomosis healing in the rat.
Collapse
Affiliation(s)
- Tihomir Vuksic
- Department of Pharmacology, Medical Faculty, University of Zagreb, Salata 11, POB 916, 10000 Zagreb, Croatia
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
37
|
Dobric I, Drvis P, Petrovic I, Shejbal D, Brcic L, Blagaic AB, Batelja L, Sever M, Kokic N, Tonkic A, Zoricic I, Mise S, Staresinic M, Radic B, Jakir A, Babel J, Ilic S, Vuksic T, Jelic I, Anic T, Seiwerth S, Sikiric P. Prolonged esophagitis after primary dysfunction of the pyloric sphincter in the rat and therapeutic potential of the gastric pentadecapeptide BPC 157. J Pharmacol Sci 2007; 104:7-18. [PMID: 17452811 DOI: 10.1254/jphs.fp0061322] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Seven or fourteen days or twelve months after suturing one tube into the pyloric sphincter (removed by peristalsis by the seventh day), rats exhibit prolonged esophagitis with a constantly lowered pressure not only in the pyloric, but also in the lower esophageal sphincter and a failure of both sphincters. Throughout the esophagitis experiment, gastric pentadecapeptide BPC 157 (PL 14736) is given intraperitoneally once a day (10 microg/kg, 10 ng/kg, last application 24 h before assessment), or continuously in drinking water at 0.16 microg/ml, 0.16 ng/ml (12 ml/rat per day), or directly into the stomach 5 min before pressure assessment (a water manometer connected to the drainage port of a Foley catheter implanted into the stomach either through an esophageal or duodenal incision). This treatment alleviates i) the esophagitis (macroscopically and microscopically, at either region or interval), ii) the pressure in the pyloric sphincter, and iii) the pressure in the lower esophageal sphincter (cmH2O). In the normal rats it increases lower esophageal sphincter pressure, but decreases the pyloric sphincter pressure. Ranitidine, given using the same protocol (50 mg/kg, intraperitoneally, once daily; 0.83 mg/ml in drinking water; 50 mg/kg directly into the stomach) does not have an effect in either rats with esophagitis or in normal rats.
Collapse
Affiliation(s)
- Ivan Dobric
- Department of Pharmacology, Medical School, University of Zagreb, Croatia
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
38
|
Petrovic I, Dobric I, Drvis P, Shejbal D, Brcic L, Blagaic AB, Batelja L, Kokic N, Tonkic A, Mise S, Baotic T, Staresinic M, Radic B, Jakir A, Vuksic T, Anic T, Seiwerth S, Sikiric P. An experimental model of prolonged esophagitis with sphincter failure in the rat and the therapeutic potential of gastric pentadecapeptide BPC 157. J Pharmacol Sci 2006; 102:269-277. [PMID: 17116974 DOI: 10.1254/jphs.fp0060070] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
We report a simple novel rat model that combines prolonged esophagitis and parallel sphincters failure. The anti-ulcer gastric pentadecapeptide BPC 157, which was found to be stable in gastric juice, and is being evaluated in inflammatory bowel disease trials, is an anti-esophagitis therapy that recovers failed sphincters. Twelve or twenty months after the initial challenge (tubes sutured into sphincters for one week and then spontaneously removed by peristalsis), rats exhibit prolonged esophagitis (confluent hemorrhagic and yellowish lesions, thinner epithelium and superficial corneal layer, with stratification derangement); constantly lowered pressure of both sphincters (assessed by using a water manometer connected to the drainage port of a Foley catheter implanted into the stomach either through esophageal or duodenal incision); and both lower esophageal and pyloric sphincter failure. Throughout the esophagitis experiment, BPC 157 was given at either 10 micro g/kg, i.p., once a day (last application 24 h before assessment) or alternatively, it was given continuously in drinking water at 0.16 micro g/ml (12 ml/rat). This treatment recovers i) esophagitis (macroscopically and microscopically, at either region or investigated time period) and ii) pressure in both sphincters (cmH2O). In addition, BPC 157 (10 micro g/kg) or saline (1 ml/rat, 5 ml/kg) was specifically given directly into the stomach; pressure assessment was performed at 5 min thereafter. The effect of BPC 157 is specific because in normal rats, it increases lower esophageal sphincter-pressure, but decreases pyloric sphincter-pressure. Ranitidine, given as the standard drug using the same protocol (50 mg/kg, i.p., once daily; 0.83 mg/ml in drinking water; or 50 mg/kg directly into the stomach) had no effect.
Collapse
Affiliation(s)
- Igor Petrovic
- Department of Pharmacology, Medical Faculty, University of Zagreb, Zagreb, Croatia
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
39
|
Seveljević-Jaran D, Cuzić S, Dominis-Kramarić M, Glojnarić I, Ivetić V, Radosević S, Parnham MJ. Accelerated Healing of Excisional Skin Wounds by PL 14736 in Alloxan-Hyperglycemic Rats 1. Skin Pharmacol Physiol 2006; 19:266-74. [PMID: 16785777 DOI: 10.1159/000093982] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2005] [Accepted: 12/29/2005] [Indexed: 01/17/2023]
Abstract
PL 14736 is a synthetic peptide, originally isolated from human gastric juice, that has anti-inflammatory and tissue-protective actions in experimental models of gastrointestinal inflammation. To investigate its possible benefit in poorly healing skin wounds, the effects of the topical application of PL 14736 in a gel formulation have been studied on full-thickness excisional wounds in rats, either healthy or made hyperglycemic by alloxan (175 mg/kg s.c.) 5 days previously. The effects of becaplermin gel (platelet-derived growth factor, PDGF-BB, Regranex, a standard therapy for diabetic foot ulcers, were investigated for comparison. Healing was evaluated for up to 7 days after wounding, using digital planimetry analysis, macroscopic scoring and histology. While healing was too rapid in healthy rats to observe enhancement by either treatment, in the hyperglycemic rats which exhibited delayed healing, PL 14736 (10-1,000 microg/wound) produced a dose-dependent acceleration of wound healing (determined by macroscopic scoring) equivalent at the highest doses to that observed with becaplermin. The beneficial effect on healing was associated with increased deposition of organized granulation tissue by day 7 for both PL 14736 and becaplermin, as determined histologically. PL 14736 tended to have a greater effect than becaplermin on the formation of granulation tissue containing mature collagen. Wound contraction, as measured by planimetry, was not significantly affected. In conclusion, topical PL 14736 produces a dose-dependent acceleration of deficient skin wound healing in hyperglycemic rats by facilitating granulation tissue formation, similar to the response seen with topical becaplermin, the standard therapy for diabetic skin wounds. PL 14736 may represent an alternative therapy for delayed wound healing, such as that seen with diabetic foot ulcers, without the proliferative concerns or immunogenicity associated with growth factors.
Collapse
|
|
40
|
Staresinic M, Petrovic I, Novinscak T, Jukic I, Pevec D, Suknaic S, Kokic N, Batelja L, Brcic L, Boban-Blagaic A, Zoric Z, Ivanovic D, Ajduk M, Sebecic B, Patrlj L, Sosa T, Buljat G, Anic T, Seiwerth S, Sikiric P. Effective therapy of transected quadriceps muscle in rat: Gastric pentadecapeptide BPC 157. J Orthop Res 2006; 24:1109-1117. [PMID: 16609979 DOI: 10.1002/jor.20089] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2005] [Accepted: 09/20/2005] [Indexed: 02/04/2023]
Abstract
We report complete transection of major muscle and the systemic peptide treatment that induces healing of quadriceps muscle promptly and then maintains the healing with functional restoration. Initially, stable gastric pentadecapeptide BPC 157 (GEPPPGKPADDAGLV, M.W. 1419, PL-10, PLD-116, PL 14736 Pliva, Croatia; in trials for inflammatory bowel disease; wound treatment; no toxicity reported; effective alone without carrier) also superiorly accelerates the healing of transected Achilles tendon. Regularly, quadriceps muscle completely transected transversely 1.0 cm proximal to patella presents a definitive defect that cannot be compensated in rat. BPC 157 (10 microg, 10 ng, 10 pg/kg) is given intraperitoneally, once daily; the first application 30 min posttransection, the final 24 h before sacrifice. It consistently improves muscle healing throughout the whole 72-day period. Improved are: (i) biomechanic (load of failure increased); (ii) function (walking recovery and extensor postural thrust/motor function index returned toward normal healthy values); (iii) microscopy/immunochemistry [i.e., mostly muscle fibers connect muscle segments; absent gap; significant desmin positivity for ongoing regeneration of muscle; larger myofibril diameters on both sides, distal and proximal (normal healthy rat-values reached)]; (iv) macroscopic presentation (stumps connected; subsequently, atrophy markedly attenuated; finally, presentation close to normal noninjured muscle, no postsurgery leg contracture). Thus, posttransection healing-consistently improved-may suggest this peptide therapeutic application in muscle disorders.
Collapse
Affiliation(s)
- Mario Staresinic
- Department of Pharmacology, School of Medicine, University of Zagreb, Salata 11, P.O.B. 916, 10000 Zagreb, Croatia
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
41
|
Becić F, Mulabegović N, Mornjaković Z, Kapić E, Prasović S, Becić E, Kusturica J. Topical treatment of standardised burns with herbal remedies in model rats. Bosn J Basic Med Sci 2005; 5:50-7. [PMID: 16351599 PMCID: PMC7202178 DOI: 10.17305/bjbms.2005.3233] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Experimental studies of burns require the use of different animal models. The aim of this work was to establish experimental model of thermal injuries and to evaluate the effects of topical agents on healing of the burn wounds. Forty female Wistar rats were randomly classified in 4 groups and isolated for 2 weeks before the onset of experiment. Animals were primarily anaesthetized with pentobarbital-sodium and then shaved (skin area of their back with diameters 5 cm x 5 cm). A round metal stamp with contact area of 5 cm2 and total weight of 100 g was heated up to 80 degrees C and then applied without additional pressure on the depilated skin of the back for 14 seconds. This procedure produced a standardized burn wound. Induced burn wounds were immediately drowned in the 4 degrees C- water for 3 s in order to maintain microcirculation. After the inducement of thermal injures, all rats were treated with 1% silver sulfadiazine cream, herbal topical preparations or were not treated at all. Burn wounds were treated twice a day until the healing completion. The result of treatment application was a significant reduction of burn wound diameters. Herbal topical preparations expressed positive therapeutic effects on the parameters of burn wounds. The efficiency of silver sulfadiazine cream in burn wound healing was significantly more expressed in comparison to healing process in control group of animals (p < or = 0,001). We conclude that herbal topical preparations efficiently caused the completion of burn wound healing process without scar formation.
Collapse
Affiliation(s)
- Fahir Becić
- Institute of Pharmacology, clinical pharmacology and toxicology, Faculty of Medicine, Sarajevo, Bosnia and Herzegovina
| | | | | | | | | | | | | |
Collapse
|
|
42
|
Bilic M, Bumber Z, Blagaic AB, Batelja L, Seiwerth S, Sikiric P. The stable gastric pentadecapeptide BPC 157, given locally, improves CO2 laser healing in mice. Burns 2005; 31:310-315. [PMID: 15774286 DOI: 10.1016/j.burns.2004.10.013] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2004] [Accepted: 10/05/2004] [Indexed: 02/06/2023]
Abstract
The stable gastric pentadecapeptide BPC 157 (GEPPPGKPADDAGLV; mol. wt. 1419), which is at present in phase II clinical trials for the treatment of inflammatory bowel disease, has been shown to counteract healing impairment by systemic corticosteroids in burned mice, both in vivo and in vitro, in the absence of carrier or protease inhibitor. Because of the particular healing problems associated with laser use, we have now studied the effect of pentadecapeptide BPC 157 on CO(2) laser injuries (Sharplan 1075 laser: 20 W, distance 12.5 cm, spot size 0.8 mm and exposure time 1s) created on the dorsal skin of anaesthetised male NMRI-Hannover mice. The injury was either not treated or treated by topical application of a thin layer of neutral cream containing pentadecapeptide BPC 157 (1 microg, 1 ng or 1 pg (dissolved in saline)/g) or vehicle only, once daily, with the first application 60 min after injury and the last 24 h before killing (1, 7 and 21 days after the laser application). BPC 157 consistently improved healing after the CO(2) laser injury, both macroscopically and microscopically. The effect was produced with a simple method of application and favourable peptide stability (no carrier), and confirms the effectiveness of an ointment containing 1 microg BPC 157 (dissolved in saline)/g neutral cream.
Collapse
Affiliation(s)
- M Bilic
- Department of Pharmacology, Medical Faculty, University of Zagreb, Salata 11, P.O. Box 916, 10000 Zagreb, Croatia
| | | | | | | | | | | |
Collapse
|
|
43
|
Wood JD. The First Nobel Prize for Integrated Systems Physiology: Ivan Petrovich Pavlov, 1904. Physiology (Bethesda) 2004; 19:326-30. [PMID: 15546849 DOI: 10.1152/physiol.00034.2004] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023] Open
Affiliation(s)
- Jackie D Wood
- College of Medicine and Public Health, The Ohio State University, Columbus, Ohio 43210, USA.
| |
Collapse
|
|
44
|
Xue XC, Wu YJ, Gao MT, Li WG, Zhao N, Wang ZL, Bao CJ, Yan Z, Zhang YQ. Protective effects of pentadecapeptide BPC 157 on gastric ulcer in rats. World J Gastroenterol 2004; 10:1032-6. [PMID: 15052688 PMCID: PMC4717094 DOI: 10.3748/wjg.v10.i7.1032] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
AIM: To investigate the protective effects of gastric pentadecapeptide BPC 157 on acute and chronic gastric ulcers in rats and to compare the results in therapy of human gastric ulcers by different administration methods.
METHODS: Gastric pentadecapeptide BPC 157 was administered (initial single or continuous administration) into rats either intragastrically or intramuscularly before (induced acute gastric ulcer) or after (induced chronic gastric ulcer) the applications of inducing agents, and each animal was sacrificed to observe the protective effects of BPC 157 on gastric ulcers.
RESULTS: Both intramuscular (im) and intragastric (ig) administration of BPC 157 could apparently reduce the ulcer area and accelerate the healing of induced ulcer in different models and the effect of im administered BPC 157 was better than that of ig. The rats treated with higher dosages (400 ng/kg, 800 ng/kg) of BPC 157 (im and ig) showed significantly less lesion (P < 0.01 vs excipient or saline control), the inhibition ratio of ulcer formation varied between 45.7% and 65.6%, from all measurements except 400 ng/kg BPC 157 in pylorus ligation induced model (P < 0.05), in which the inhibition rate was 54.2%. When im administered (800 ng/kg BPC 157) in three models, the inhibition ratio of ulcer formation was 65.5%, 65.6% and 59.9%, respectively, which was better than that of famotidine (its inhibition rate was 60.8%, 57.2% and 34.3%, respectively). Continuous application of BPC 157 (in chronic acetate induced gastric ulcer) could accelerate rebuilding of glandular epithelium and formation of granulation tissue (P < 0.05 at 200 ng/kg and P < 0.01 at 400 ng/kg and 800 ng/kg vs excipient or saline control).
CONCLUSION: Both im and ig administered gastric pentadecapeptide BPC 157 can apparently ameliorate acute gastric ulcer in rats and antagonize the protracted effect of acetate challenge on chronic ulcer. The effect of im administration of BPC 157 is better than that of ig, and the effective dosage of the former is lower than that of the latter.
Collapse
Affiliation(s)
- Xiao-Chang Xue
- Biotechnology Centre, Fourth Military Medical University, 169 West Changle Road, Xi'an 710032, Shaanxi Province, China.
| | | | | | | | | | | | | | | | | |
Collapse
|
|
45
|
Staresinic M, Sebecic B, Patrlj L, Jadrijevic S, Suknaic S, Perovic D, Aralica G, Zarkovic N, Borovic S, Srdjak M, Hajdarevic K, Kopljar M, Batelja L, Boban-Blagaic A, Turcic I, Anic T, Seiwerth S, Sikiric P. Gastric pentadecapeptide BPC 157 accelerates healing of transected rat Achilles tendon and in vitro stimulates tendocytes growth. J Orthop Res 2003; 21:976-983. [PMID: 14554208 DOI: 10.1016/s0736-0266(03)00110-4] [Citation(s) in RCA: 39] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
In studies intended to improve healing of transected Achilles tendon, effective was a stable gastric pentadecapeptide BPC 157 (GEPPPGKPADDAGLV, M.W. 1419). Currently in clinical trials for inflammatory bowel disease (PLD-116, PL 14736, Pliva), it ameliorates internal and external wound healing. In rats, the right Achilles tendon transected (5 mm proximal to its calcaneal insertion) presents with a large tendon defect between cut ends. Agents (/kg b.w., i.p., once time daily) (BPC 157 (dissolved in saline, with no carrier addition) (10 microg, 10 ng or 10 pg) or saline (5.0 ml)), were firstly applied at 30 min after surgery, the last application at 24 h before autopsy. Achilles functional index (AFI) was assessed once time daily. Biomechanical, microscopical and macroscopical assessment was on day 1, 4, 7, 10 and 14. Controls generally have severely compromised healing. In comparison, pentadecapeptide BPC 157 fully improves recovery: (i) biomechanically, increased load of failure, load of failure per area and Young's modulus of elasticity; (ii) functionally, significantly higher AFI-values; (iii) microscopically, more mononuclears and less granulocytes, superior formation of fibroblasts, reticulin and collagen; (iv) macroscopically, smaller size and depth of tendon defect, and subsequently the reestablishment of full tendon integrity. Likewise, unlike TGF-beta, pentadecapeptide BPC 157, presenting with no effect on the growth of cultured cell of its own, consistently opposed 4-hydroxynonenal (HNE), a negative modulator of the growth. HNE-effect is opposed in both combinations: BPC 157+HNE (HNE growth inhibiting effect reversed into growth stimulation of cultured tendocytes) and HNE+BPC 157(abolished inhibiting activity of the aldehyde), both in the presence of serum and serum deprived conditions. In conclusion, these findings, particularly, Achilles tendon transection fully recovered in rats, peptide stability suitable delivery, usefully favor gastric pentadecapeptide BPC 157 in future Achilles tendon therapy.
Collapse
Affiliation(s)
- M Staresinic
- Department of Pharmacology, Medical Faculty, University of Zagreb, Salata 11, Post Box 916, 10000 Zagreb, Croatia
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
46
|
Bedekovic V, Mise S, Anic T, Staresinic M, Gjurasin M, Kopljar M, Kalogjera L, Drvis P, Boban Blagaic A, Batelja L, Seiwerth S, Sikiric P. Different effect of antiulcer agents on rat cysteamine-induced duodenal ulcer after sialoadenectomy, but not gastrectomy. Eur J Pharmacol 2003; 477:73-80. [PMID: 14512101 DOI: 10.1016/j.ejphar.2003.08.013] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The focus was on salivary glands in cysteamine-induced duodenal ulcer and the different effects of antiulcer agents on cysteamine-induced duodenal ulcer in sialoadenectomized but not gastrectomized rats. We tested antiulcer agents on cysteamine-induced duodenal ulcer in rats (agents/kg i.p.) simultaneously with cysteamine 400 mg/kg s.c., rat killed 24 h thereafter subjected to no surgery (normal), to gastrectomy (24 h before) or sialoadenectomy, acute (24 h before) or chronic (21 days before). (i) Ulcerogenesis: cysteamine-induced duodenal ulcer had the same severity and incidence in normal, gastrectomized or acutely or chronically sialoadenectomized rats. (ii) Antiulcer effect under normal conditions or following gastrectomy: in normal or gastrectomized rats all agents tested, gastric pentadecapeptide BPC 157 [currently in clinical trials for inflammatory bowel disease (PL-10, PLD-116, PL-14736, Pliva) (10.0 microg or 10.0 ng), ranitidine (10 mg), atropine (10 mg), omeprazole (10 mg)] inhibited cysteamine-induced duodenal ulcers, acting through gastric acid-independent mechanisms. Following sialoadenectomy, acute or chronic: ranitidine, omeprazole and atropine were completely ineffective, while pentadecapeptide BPC 157 could protect. Thus, we found that contrary to stomach, salivary glands are implicated in cytoprotective agent activity (standard agents were ineffective after sialoadenectomy). Also, gastric pentadecapeptide BPC 157 was consistently associated with a cytoprotective effect, suggesting a beneficial activity distinctive from that of H2-receptor blockers, proton-pump inhibitors and anticholinergics; but probably replacing missing salivary glands factors.
Collapse
Affiliation(s)
- Vlado Bedekovic
- Department of Pharmacology, Medical Faculty University of Zagreb, Salata 11, POB916, 10000 Zagreb, Croatia
| | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
47
|
|
|
48
|
Sikiric P, Seiwerth S, Mise S, Staresinic M, Bedekovic V, Zarkovic N, Borovic S, Gjurasin M, Boban-Blagaic A, Batelja L, Rucman R, Anic T. Corticosteroid-impairment of healing and gastric pentadecapeptide BPC-157 creams in burned mice. Burns 2003; 29:323-334. [PMID: 12781609 DOI: 10.1016/s0305-4179(03)00004-4] [Citation(s) in RCA: 37] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The amelioration of corticosteroid-impairment of healing by a stable gastric pentadecapeptide BPC-157 (GEPPPGKPADDAGLV, M(w) 1419, currently in early clinical trials for inflammatory bowel disease) was studied in thermally injured mice. Its effects on corticosteroid impaired healing of deep partial skin thickness burns, and burn-gastric lesions were investigated. Male NMRI-Hannover mice (sacrificed at 1-3,7,14 and 21 days following burning 20% of total burn area at the back (open flame for 7s) received intraperitoneally (per kg bw) 6alpha-methylprednisolone (Depo-medrol, 1.0 or 10.0mg), or an equal volume of saline (5.0 ml), once daily, first application 30 min after injury, last 24h before sacrifice. The injury was subsequently treated by topical application of a thin layer of pentadecapeptide BPC-157 cream at three different levels a neutral cream of no treatment. Pentadecapeptide BPC-157 consistently improved given burn healing (both microscopical and tensionmetry assessment), and counteracted corticosteroid-impairment of burn healing. In burn-gastric lesions investigation of the effects of BPC showed an anti-ulcer effect of its own in burned non-corticosteroid-treated mice and potentiated the anti-ulcer effect observed in 6alpha-methylprednisolone-treated mice. Pentadecapeptide BPC-157 inhibited corticosteroid immunosuppression. In vitro, in spleenic cells assessment, animals (sacrificed at day 21) treated with 6alpha-methylprednisolone 1mg showed decreased reactivity to nitrogen in comparison with control, healthy animals, while the addition of BPC-157 (1 microg/g cream) returned cell reactivity to values noted in control healthy animals.
Collapse
Affiliation(s)
- P Sikiric
- Department of Pharmacology Medical Faculty, University of Zagreb, Salta 11, PO Box 916, Zagreb 10000, Croatia.
| | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
49
|
Stancic-Rokotov D, Sikiric P, Seiwerth S, Slobodnjak Z, Aralica J, Aralica G, Perovic D, Anic T, Zoricic I, Buljat G, Prkacin I, Gjurasin M, Rucman R, Petek M, Turkovic B, Ivasovic Z, Jagic V, Staresinic M, Boban-Blagaic A. Ethanol gastric lesion aggravated by lung injury in rat. Therapy effect of antiulcer agents. JOURNAL OF PHYSIOLOGY, PARIS 2001; 95:289-293. [PMID: 11595452 DOI: 10.1016/s0928-4257(01)00040-7] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Hemorrhagic mucosal lesions in the stomach in the rat induced by an intragastrical application of 1 ml of 50 or 75% ethanol were aggravated by preceding lung damage provoked by an intratracheal instillation of pyrogen-free saline or HCl (pH 1.75) or 50-h exposure to 100% oxygen. Due to the particular preceding aggravating circumstances, these lesions were taken to be of a special kind, rather than ordinary. So far, it is not known whether and how antiulcer agents may influence these lesions. Rats received an intratracheal (i.t.) HCl instillation [1.5 ml/kg HCl (pH 1.75)] (lung-lesion), and an intragastric instillation of 96% ethanol (gastric lesion; 1 ml/rat, 24 h after i.t. HCl instillation), and were sacrificed 1 h after ethanol. Basically, in lung injured rats, the subsequent ethanol-gastric lesion was markedly aggravated. This aggravation, however, in turn, did not affect the severity of the lung lesions in the further period, at least for a 1-h observation. Taking intratracheal HCl-instillation as time 0, a gastric pentadecapeptide, GEPPPGKPADDAGLV, M.W.1419, coded BPC 157 (PL-10, PLD-116; 10 microg, 10 ng, 10 pg), ranitidine (10 mg), atropine (10 mg), omeprazole (10 mg), were given [/kg, intraperitoneally (i.p.)] (1) once, only prophylactically [as a pre-treatment (at -1 h), or as a co-treatment (at 0)], or only therapeutically (at +18 h or +24 h); (2) repeatedly, combining prophylactic/therapeutic regimens [(-1 h)+(+24 h) or (0)+(+24 h)], or therapeutic/therapeutic regimens [(+18 h)+(+24 h)]. In general, the antiulcer agents did protect against ethanol gastric lesions regardless of the presence of the severe lung injury, in all of the used regimens. Of note, combining their prophylactic and salutary regimens (at -1 h/+24 h, or at 0/+24 h) may increase the antiulcer potential, and the effect that had been not seen already with single application, became prominent after repeated treatment.
Collapse
Affiliation(s)
- D Stancic-Rokotov
- Clinic for Thoracic Surgery Jordanovac, Medical Faculty University of Zagreb, Zagreb, Croatia
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
50
|
Prkacin I, Aralica G, Perovic D, Separovic J, Gjurasin M, Lovric-Bencic M, Stancic-Rokotov D, Ziger T, Anic T, Sikiric P, Seiwerth S, Staresinic M, Mise S, Rotkvic I, Jagic V, Rucman R, Petek M, Turkovic B, Marovic A, Sjekavica I, Sebecic B, Boban-Blagaic A, Ivasovic Z. Chronic cytoprotection: pentadecapeptide BPC 157, ranitidine and propranolol prevent, attenuate and reverse the gastric lesions appearance in chronic alcohol drinking rats. JOURNAL OF PHYSIOLOGY, PARIS 2001; 95:295-301. [PMID: 11595453 DOI: 10.1016/s0928-4257(01)00041-9] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Unlike severe gastric damage acutely induced by ethanol administration in rat, the ulcerogenic effect of chronic alcohol administration (3.03 g/kg b.w. or 7.28 g/kg b.w.) given in drinking water, producing liver lesions and portal hypertension, is far less investigated. Therefore, focus was on the antiulcer effect of the gastric pentadecapeptide BPC 157, GEPPPGKPADDAGLV, M.W. 1419, known to have a beneficial effect in variety of gastrointestinal lesions models (10 microg or 10 ng/kg b.w. i.p. or i.g.), ranitidine (10 mg/kg b.w. i.g.) and propranol (10 mg/kg b.w. i.g.) or saline (5 ml/kg b.w. i.p./i.g.; control). They were given once daily (1) throughout 10 days preceding alcohol consumption, (2) since beginning of alcohol drinking till the end of the study, (3) throughout the last month of alcohol consumption, 2 months after alcohol drinking had been initiated. Gastric lesions were assessed, at the end of 3 months drinking [(1), (2)] or with respect to therapeutic effect of medication before medication or at the end of therapy. Pentadecapeptide BPC 157, ranitidine and propranolol may prevent gastric lesion development if given prophylactically, before alcohol drinking. Likewise, they attenuate the lesion appearance given once daily throughout the drinking period. Importantly, when given therapeutically, they may antagonize otherwise pertinent lesion presence in stomach mucosa of the drinking rats. Thus, these results demonstrate that pentadecapeptide BPC 157, ranitidine and propranol may prevent, attenuate or reverse the gastric lesions appearance in chronically alcohol drinking rats, and may be used for further therapy, while the other studies showed that their effect (except to ranitidine) is parallel with their beneficial effect on liver lesion and portal hypertension.
Collapse
Affiliation(s)
- I Prkacin
- Department of Pharmacology, Medical Faculty University of Zagreb, Salata 11, PO Box 916, Zagreb, Croatia
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|