• Cytoprotection
• Occlusion/occlusion-like syndromes
• Organoprotection
• Selye’s stress response
• Stable gastric pentadecapeptide BPC 157
• Therapy
• Vascular recovery

• Multiple Organ Failure/etiology
• Multiple Organ Failure/physiopathology
• Multiple Organ Failure/prevention & control
• Cytoprotection/drug effects
• Gastrointestinal Tract/blood supply
• Gastrointestinal Tract/cytology
• Gastrointestinal Tract/drug effects
• Gastrointestinal Tract/physiopathology
• Peptide Fragments/pharmacology
• Peptide Fragments/therapeutic use
• Brain-Gut Axis/drug effects
• Brain-Gut Axis/physiology
• Arterial Occlusive Diseases/complications
• Arterial Occlusive Diseases/drug therapy
• Arterial Occlusive Diseases/physiopathology
• Venous Thrombosis/complications
• Venous Thrombosis/drug therapy
• Venous Thrombosis/physiopathology
• Humans
• Animals
• Disease Models, Animal
• Protective Agents/pharmacology
• Protective Agents/therapeutic use

• 10106-22-3071 Sveučilište u Zagrebu

Using rat stomach perforation as a prototypic direct lesion applied in cytoprotection research, we focused on the first demonstration of the severe occlusion/ occlusion-like syndrome induced by stomach perforation. The revealed stomach-induced occlusion/occlusion-like syndrome corresponds to the previously described occlusion/occlusion-like syndromes in rats suffering multicausal pathology and shared severe vascular and multiorgan failure. This general point was particularly reviewed. As in all the described occlusion/occlusion-like syndromes with permanent occlusion of major vessels, peripheral and central, and other similar noxious procedures that severely affect endothelium function, the stable gastric pentadecapeptide BPC 157 was resolving therapy.

To reveal the stomach perforation-induced general occlusion/occlusion-like syndrome and BPC 157 therapy effect.

The procedure included deeply anesthetized rats, complete calvariectomy, laparotomy at 15 min thereafter, and stomach perforation to rapidly induce vascular and multiorgan failure occlusion/occlusion-like syndrome. At 5 min post-perforation time, rats received therapy [BPC 157 (10 µg or 10 ng/kg) or saline (5 mL/kg, 1 mL/rat) (controls)] into the perforated defect in the stomach). Sacrifice was at 15 min or 60 min post-perforation time. Assessment (gross and microscopy; volume) included: Brain swelling, peripheral vessels (azygos vein, superior mesenteric vein, portal vein, inferior caval vein) and heart, other organs lesions (i.e., stomach, defect closing or widening); superior sagittal sinus, and peripherally the portal vein, inferior caval vein, and abdominal aorta blood pressures and clots; electrocardiograms; and bleeding time from the perforation(s).

BPC 157 beneficial effects accord with those noted before in the healing of the perforated defect (raised vessel presentation; less bleeding, defect contraction) and occlusion/occlusion-like syndromes counteraction. BPC 157 therapy (into the perforated defect), induced immediate shrinking and contraction of the whole stomach (unlike considerable enlargement by saline application). Accordingly, BPC 157 therapy induced direct blood delivery via the azygos vein, and attenuated/eliminated the intracranial (superior sagittal sinus), portal and caval hypertension, and aortal hypotension. Thrombosis, peripherally (inferior caval vein, portal vein, abdominal aorta) and centrally (superior sagittal sinus) BPC 157 therapy markedly reduced/annihilated. Severe lesions in the brain (swelling, hemorrhage), heart (congestion and arrhythmias), lung (hemorrhage and congestion), and marked congestion in the liver, kidney, and gastrointestinal tract were markedly reduced.

We revealed stomach perforation as a severe occlusion/occlusion-like syndrome, peripherally and centrally, and rapid counteraction by BPC 157 therapy. Thereby, further BPC 157 therapy may be warranted.

• Stomach perforation
• General occlusion/occlusion-like syndrome
• Stable gastric pentadecapeptide BPC 157
• Cytoprotection
• Therapy
• Rats

• Rats
• Animals
• Rats, Wistar
• Syndrome
• Stomach Diseases/drug therapy
• Stomach Diseases/etiology
• Peptide Fragments/pharmacology
• Peptide Fragments/therapeutic use
• Hemorrhage
• Anti-Ulcer Agents/therapeutic use

With the stable gastric pentadecapeptide BPC 157 therapy known to heal various both external and internal rat fistulas, we attempt to approach vesicovaginal fistula, continuous urine leaking through vagina, bladder stones, and a possible therapy solution among rats with well-formed 2 week-fistulas (vaginal/vesical 4 mm large defects) started with delayed therapy. Subsequent control fistula course (the subsequent 1, 2, 4, and 6 weeks) since beginning revealed the failed healing, fistula leaking, adhesions, urinary leaking through vagina, failed epithelization, collagenization, granulation tissue and neovascularization, increased inflammation, and necrosis. Thereby, the later intervals revealed the persistent inability to sustain even minimal volume, vesical, and vaginal defects and stone formation at the end of the experiment (fistula-time day 56). BPC 157 therapy (10 µg/kg, 10 ng/kg, intraperitoneally once time daily or perorally in drinking water until sacrifice) was initiated with a considerable delay (at 2 weeks after fistula formation). Already within 1 week therapy, all BPC 157 regimens stopped urinary leaking through vagina, reversed the otherwise resistant poor healing course to the increased epithelization, collagenization, granulation tissue and neovascularization, decreased inflammation, and decreased necrosis. Thereby, at later intervals, all BPC 157 rats exhibited a five times larger volume that can be sustained before leaking as in healthy, vesical, and vaginal defects completely closed and no stone formation. Thus, macro/microscopic and functional recovery, and counteracted stone formation. Concluding, BPC 157 therapy’s beneficial effects resulted in healing and no stone formation, with µg- and ng-regimens, either given daily perorally in drinking water or intraperitoneally.

• rats
• stable gastric pentadecapeptide BPC 157
• stone formation
• vesicovaginal fistula

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.

• bleeding disorder
• concept practical applicability
• fistula
• stable gastric pentadecapeptide BPC 157
• wound healing

• Stable gastric pentadecapeptide BPC 157
• colovesical
• esophagoduodenal
• fistulas healing
• rectovaginal
• therapy

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.

To focused on the bowel adhesion and the therapy with the BPC 157, its most and application of NO-agents.

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.

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).

BPC 157 therapy can be suited for the realization of the peritoneal defect healing with minimal or no adhesion formation.

• Abdominal wall defect
• Adhesions
• BPC 157
• Vascular recruitment
• Nitric oxide-agents
• Rats

• Adaptive cytoprotection
• Mediator
• Organoprotection concept
• Robert's cytoprotection
• Stsblr gsstric petnadecapeptide BPC 157 therapy

• Adaptation, Physiological/drug effects
• Cytoprotection/drug effects
• Gastric Mucosa/drug effects
• Gastrointestinal Tract/drug effects
• Humans
• Peptide Fragments/pharmacology
• Protective Agents/pharmacology
• Proteins/pharmacology

• BPC 157
• Cyclophosphamide
• Hemorrhagic cystitis
• NO-System
• Rats

To study the counteraction of perforated cecum lesion using BPC 157 and nitric oxide (NO) system agents.

Alongside with the agents’ application (after 1 min, medication (/kg, 10 mL/2 min bath/rat) includes: BPC 157 (10 μg), L-NAME (5 mg), L-arginine (100mg) alone or combined, and saline baths (controls)) on the rat perforate cecum injury, we continuously assessed the gross reappearance of the vessels (USB microcamera) quickly propagating toward the defect at the cecum surface, defect contraction, bleeding attenuation, MDA- and NO-levels in cecum tissue at 15 min, and severity of cecum lesions and adhesions at 1 and 7 d.

Post-injury, during/after a saline bath, the number of vessels was significantly reduced, the defect was slightly narrowed, bleeding was significant and MDA-levels increased and NO-levels decreased. BPC 157 bath: the vessel presentation was markedly increased, the defect was noticeably narrowed, the bleeding time was shortened and MDA- and NO-levels remained normal. L-NAME: reduced vessel presentation but not more than the control, did not change defect and shortened bleeding. L-arginine: exhibited less vessel reduction, did not change the defect and prolonged bleeding. In combination, mutual counteraction occurred (L-NAME + L-arginine) or the presentation was similar to that of BPC 157 rats (BPC 157 + L-NAME; BPC 157 + L-arginine; BPC 157 + L-NAME + L-arginine), except the defect did not change. Thereby at day 1 and 7, saline, L-NAME, L-arginine and L-NAME + L-arginine failed (defect was still open and large adhesions present).

The therapeutic effect was achieved with BPC 157 alone or in combination with L-NAME and L-arginine as it was able to consolidate the stimulating and inhibiting effects of the NO-system towards more effective healing recruiting vessels.

• BPC 157
• Perforated cecum
• L-arginine
• L-NAME
• Vessels
• Rats

• Animals
• Anti-Ulcer Agents/pharmacology
• Anti-Ulcer Agents/therapeutic use
• Arginine/pharmacology
• Arginine/therapeutic use
• Cecum/blood supply
• Cecum/drug effects
• Cecum/injuries
• Disease Models, Animal
• Drug Therapy, Combination/methods
• Humans
• Intestinal Perforation/drug therapy
• Male
• NG-Nitroarginine Methyl Ester/pharmacology
• NG-Nitroarginine Methyl Ester/therapeutic use
• Nitric Oxide/metabolism
• Peptide Fragments/pharmacology
• Peptide Fragments/therapeutic use
• Proteins/pharmacology
• Proteins/therapeutic use
• Rats
• Rats, Wistar
• Treatment Outcome
• Wound Healing/drug effects

• Nosema ceranae
• honeybee colonies
• stable gastric pentadecapeptide BPC 157

To provide new insights in treatment of colitis and ischemia and reperfusion in rats using stable gastric pentadecapeptide BPC 157.

Medication [BPC 157, L-NAME, L-arginine (alone/combined), saline] was bath at the blood deprived colon segment. During reperfusion, medication was BPC 157 or saline. We recorded (USB microscope camera) vessel presentation through next 15 min of ischemic colitis (IC-rats) or reperfusion (removed ligations) (IC + RL-rats); oxidative stress as MDA (increased (IC- and IC + RL-rats)) and NO levels (decreased (IC-rats); increased (IC + RL-rats)) in colon tissue. IC + OB-rats [IC-rats had additional colon obstruction (OB)] for 3 d (IC + OB-rats), then received BPC 157 bath.

Commonly, in colon segment (25 mm, 2 ligations on left colic artery and vein, 3 arcade vessels within ligated segment), in IC-, IC + RL-, IC + OB-rats, BPC 157 (10 μg/kg) bath (1 mL/rat) increased vessel presentation, inside/outside arcade interconnections quickly reappeared, mucosal folds were preserved and the pale areas were small and markedly reduced. BPC 157 counteracted worsening effects induced by L-NAME (5 mg) and L-arginine (100 mg). MDA- and NO-levels were normal in BPC 157 treated IC-rats and IC + RL-rats. In addition, on day 10, BPC 157-treated IC + OB-rats presented almost completely spared mucosa with very small pale areas and no gross mucosal defects; the treated colon segment was of normal diameter, and only small adhesions were present.

BPC 157 is a fundamental treatment that quickly restores blood supply to the ischemically injured area and rapidly activates collaterals. This effect involves the NO system.

• Ischemic colitis
• Blood flow rescue
• Collaterals
• BPC 157
• L-NAME
• L-arginine
• Oxidative stress
• NO
• Rats

• Animals
• Anti-Ulcer Agents/pharmacology
• Anti-Ulcer Agents/therapeutic use
• Arginine/therapeutic use
• Colitis/blood
• Colitis/drug therapy
• Colitis/etiology
• Colitis/pathology
• Collateral Circulation/drug effects
• Colon/blood supply
• Colon/drug effects
• Colon/metabolism
• Disease Models, Animal
• Humans
• Male
• Malondialdehyde/blood
• NG-Nitroarginine Methyl Ester/therapeutic use
• Nitric Oxide/analysis
• Oxidative Stress/drug effects
• Peptide Fragments/pharmacology
• Peptide Fragments/therapeutic use
• Proteins/pharmacology
• Proteins/therapeutic use
• Rats
• Rats, Wistar
• Reperfusion Injury/blood
• Reperfusion Injury/drug therapy
• Reperfusion Injury/etiology
• Reperfusion Injury/pathology

To cure typically life-threatening esophagogastric anastomosis in rats, lacking anastomosis healing and sphincter function rescue, in particular.

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.

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).

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.

• Esophagogastric anastomosis
• L-NAME
• Aggravation
• BPC 157
• L-arginine
• Curative treatment
• Rats

• Anastomosis, Surgical/adverse effects
• Anastomotic Leak/etiology
• Anastomotic Leak/prevention & control
• Animals
• Arginine/pharmacology
• Esophageal Sphincter, Lower/drug effects
• Esophageal Sphincter, Lower/pathology
• Esophageal Sphincter, Lower/physiopathology
• Esophagitis/etiology
• Esophagitis/prevention & control
• Esophagus/drug effects
• Esophagus/metabolism
• Esophagus/pathology
• Esophagus/surgery
• Gastric Mucosa/metabolism
• Male
• NG-Nitroarginine Methyl Ester/toxicity
• Nitric Oxide/metabolism
• Nitric Oxide Synthase/antagonists & inhibitors
• Nitric Oxide Synthase/metabolism
• Peptide Fragments/pharmacology
• Pressure
• Proteins/pharmacology
• Rats, Wistar
• Stomach/drug effects
• Stomach/pathology
• Stomach/surgery
• Time Factors
• Wound Healing/drug effects

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.

• Anastomosis, Surgical/adverse effects
• Animals
• Anti-Inflammatory Agents, Non-Steroidal/adverse effects
• Anti-Inflammatory Agents, Non-Steroidal/pharmacology
• Arginine/pharmacology
• Brain/drug effects
• Diclofenac/adverse effects
• Diclofenac/pharmacology
• Gastrointestinal Tract/drug effects
• Intestine, Small/drug effects
• Intestine, Small/surgery
• Liver/drug effects
• Male
• NG-Nitroarginine Methyl Ester/pharmacology
• Peptide Fragments/pharmacology
• Proteins/pharmacology
• Rats
• Rats, Wistar
• Wound Healing/drug effects

• Ministarstvo Obrazovanja, Znanosti i Sporta