To evaluate the level of oxidative stress and antioxidative response in the transplanted liver and its role in acute cellular rejection (ACR). Particular attention was paid to ACR diagnosis in ...patients with hepatitis C (HCV), as histopathological features of ACR and viral disease recurrence overlap.
This retrospective study included 40 liver transplant patients who underwent liver transplantation with two consecutive liver biopsies performed during one hospitalization period: 1.) initial biopsy of the donor liver (before implantation) and 2.) indication biopsy (after suspected ACR). Based on the etiology, patients were divided into two groups: 22 patients with alcoholic liver cirrhosis (EtOH group) and 18 patients with hepatitis C cirrhosis (HCV group). We analyzed the presence of acrolein, HNE (4-hydroxynonenal), and the major antioxidant transcription factor NRF2 (nuclear factor erythroid 2-related factor 2) in both biopsies.
The presence of acrolein and HNE in both biopsies indicates increased oxidative stress, while the decrease in these aldehydes in the indication biopsies indicates a decrease in oxidative stress over time, reflecting liver graft recovery. The absence of NRF2 in both biopsies reflects significantly reduced antioxidant protection in patients undergoing liver transplantation.
The results support the role of oxidative stress in the pathogenesis of ACR. The presence of acrolein and the absence of HNE in the indication biopsy in patients with ACR could contribute to the diagnosis of ACR in clinical practice when functional antibodies are tested in the clinical setting.
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This review is focused on the healing of fistulas and stable gastric pentadecapeptide BPC 157. Assuming that the healing of the various wounds is essential also for the gastrointestinal fistulas ...healing, the healing effect on fistulas in rats, consistently noted with the stable gastric pentadecapeptide BPC 157, may raise several interesting possibilities. BPC 157 is originally an anti-ulcer agent, native to and stable in human gastric juice (for more than 24 h). Likely, it is a novel mediator of Robert's cytoprotection maintaining gastrointestinal mucosal integrity. Namely, it is effective in the whole gastrointestinal tract, and heals various wounds (i.e., skin, muscle, tendon, ligament, bone; ulcers in the entire gastrointestinal tract; corneal ulcer); LD1 is not achieved. It is used in ulcerative colitis clinical trials, and now in multiple sclerosis, and addressed in several reviews. Therefore, it is not surprising that BPC 157 has documented consistent healing of the various gastrointestinal fistulas, external (esophagocutaneous, gastrocutaneous, duodenocutaneous, colocutaneous) and internal (colovesical, rectovaginal). Taking fistulas as a pathological connection, this rescue is verified with the beneficial effects in rats with the various gastrointestinal anastomoses, esophagogastric, jejunoileal, colo-colonic, ileoileal, esophagojejunal, esophagoduodenal, and gastrojejunal. This beneficial effect occurs equally when the gastrointestinal anastomoses are impaired with the application of NSAIDs, cysteamine, large bowel resection, as well as concomitant esophageal, gastric, and duodenal lesions and/or ulcerative colitis presentation, short bowel syndrome progression, liver and brain disturbances presentation. Particular aspects of the BPC 157 healing of the fistulas are especially emphasized.
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.
Components of carotid atherosclerotic plaque can be analysed preoperatively by non-invasive advanced imaging modalities such as magnetic resonance imaging (MRI). The expression of matrix ...metalloproteinase-9 protein (MMP-9), which has a potential role in remodelling of atherosclerotic plaques, can be analysed immunohistochemically. The aim of the present prospective pilot study is to analyse histological characteristics and expression of MMP-9 in carotid plaques of patients undergoing carotid endarterectomy (CEA) and to investigate the correlation with preoperative clinical symptoms and MRI features. Preoperative clinical assessment, MRI imaging, postoperative histological and immunohistochemical analyses were performed. Fifteen patients with symptomatic (7/15; 47%) and asymptomatic carotid artery stenosis undergoing CEA were included. Among symptomatic patients, 5 (71%) had recent stroke and 2 (29%) had recent transient ischaemic attack with a median timing of 6 weeks (IQR: 1, 18) before the surgery. Both groups did not significantly differ in respect to preoperative characteristics. Prevalence of unstable plaque was higher in symptomatic than asymptomatic patients, although it was not significant (63% vs. 37%,
= 0.077). The expression of MMP-9 in CD68 cells within the plaque by semiquantitative analysis was found to be significantly higher in symptomatic as compared to asymptomatic patients (86% vs. 25% with the highest expression,
= 0.014). The average microvascular density was found to be higher and lipid core area larger among both symptomatic patients and unstable carotid plaque specimens, although this did not reach statistical significance (
= 0.064 and
= 0.132,
= 0.360 and
= 0.569, respectively). Our results demonstrate that MRI is reliable in classifying carotid lesions and differentiating unstable from stable plaques. We have also shown that the expression of MMP-9 is significantly higher among symptomatic patients undergoing CEA.
Recently, the stable gastric pentadecapeptide BPC 157 was shown to counteract major vessel occlusion syndromes, i.e., peripheral and/or central occlusion, while activating particular collateral ...pathways. We induced abdominal compartment syndrome (intra-abdominal pressure in thiopental-anesthetized rats at 25 mmHg (60 min), 30 mmHg (30 min), 40 mmHg (30 min), and 50 mmHg (15 min) and in esketamine-anesthetized rats (25 mmHg for 120 min)) as a model of multiple occlusion syndrome. By improving the function of the venous system with BPC 157, we reversed the chain of harmful events. Rats with intra-abdominal hypertension (grade III, grade IV) received BPC 157 (10 µg or 10 ng/kg sc) or saline (5 ml) after 10 min. BPC 157 administration recovered the azygos vein via the inferior-superior caval vein rescue pathway. Additionally, intracranial (superior sagittal sinus), portal, and caval hypertension and aortal hypotension were reduced, as were the grossly congested stomach and major hemorrhagic lesions, brain swelling, venous and arterial thrombosis, congested inferior caval and superior mesenteric veins, and collapsed azygos vein; thus, the failed collateral pathway was fully recovered. Severe ECG disturbances (i.e., severe bradycardia and ST-elevation until asystole) were also reversed. Microscopically, transmural hyperemia of the gastrointestinal tract, intestinal mucosa villi reduction, crypt reduction with focal denudation of superficial epithelia, and large bowel dilatation were all inhibited. In the liver, BPC 157 reduced congestion and severe sinusoid enlargement. In the lung, a normal presentation was observed, with no alveolar membrane focal thickening and no lung congestion or edema, and severe intra-alveolar hemorrhage was absent. Moreover, severe heart congestion, subendocardial infarction, renal hemorrhage, brain edema, hemorrhage, and neural damage were prevented. In conclusion, BPC 157 cured primary abdominal compartment syndrome.
Conceptually, a wide beneficial effect, both peripherally and centrally, might have been essential for the harmony of brain-gut and gut-brain axes' function. Seen from the original viewpoint of the ...gut peptides' significance and brain relation, the favorable stable gastric pentadecapeptide BPC 157 evidence in the brain-gut and gut-brain axes' function might have been presented as a particular interconnected network. These were the behavioral findings (interaction with main systems, anxiolytic, anticonvulsive, antidepressant effect, counteracted catalepsy, and positive and negative schizophrenia symptoms models). Muscle healing and function recovery appeared as the therapeutic effects of BPC 157 on the various muscle disabilities of a multitude of causes, both peripheral and central. Heart failure was counteracted (including arrhythmias and thrombosis), and smooth muscle function recovered. These existed as a multimodal muscle axis impact on muscle function and healing as a function of the brain-gut axis and gut-brain axis as whole. Finally, encephalopathies, acting simultaneously in both the periphery and central nervous system, BPC 157 counteracted stomach and liver lesions and various encephalopathies in NSAIDs and insulin rats. BPC 157 therapy by rapidly activated collateral pathways counteracted the vascular and multiorgan failure concomitant to major vessel occlusion and, similar to noxious procedures, reversed initiated multicausal noxious circuit of the occlusion/occlusion-like syndrome. Severe intracranial (superior sagittal sinus) hypertension, portal and caval hypertensions, and aortal hypotension were attenuated/eliminated. Counteracted were the severe lesions in the brain, lungs, liver, kidney, and gastrointestinal tract. In particular, progressing thrombosis, both peripherally and centrally, and heart arrhythmias and infarction that would consistently occur were fully counteracted and/or almost annihilated. To conclude, we suggest further BPC 157 therapy applications.
Even before behavioral disturbances, neuroleptics, amphetamine, and domperidone application rapidly emerged severe occlusion/occlusion-like syndrome, shared innate vascular and multiorgan failure in ...rats, comparable to occlusion/occlusion-like syndrome described with vessel(s) occlusion or similar noxious procedures application. As therapy, i.e., activation of the collateral pathways, "bypassing key" (activated azygos vein pathway, direct blood flow delivery), the stable gastric pentadecapeptide BPC 157 is a novel solution. Recently, BPC 157 therapy particularly counteracted neuroleptic- or L-NAME-induced catalepsy, lithium intoxication, and schizophrenia positive and negative symptoms (amphetamine/methamphetamine/apomorphine/ketamine). In rats with complete calvariectomy, medication (BPC 157 10 µg/kg, 10 ng/kg ip or ig) was given 5 min after distinctive dopamine agents (mg/kg ip) (haloperidol (5), fluphenazine (5), clozapine (10), risperidone (5), olanzapine (10), quetiapine (10), or aripiprazole (10), domperidone (25), amphetamine (10), and combined amphetamine and haloperidol) and assessed at 15 min thereafter. All neuroleptic-, domperidone-, and amphetamine-induced comparable vascular and multiorgan failure severe syndrome was alleviated with BPC 157 therapy as before major vessel(s) occlusion or other similar noxious procedures. Specifically, all severe lesions in the brain (i.e., immediate swelling, hemorrhage), heart (i.e., congestion, arrhythmias), and lung (i.e., congestion, hemorrhage), as well as congestion in the liver, kidney, and gastrointestinal (stomach) tract, were resolved. Intracranial (superior sagittal sinus), portal, and caval hypertension and aortal hypotension were attenuated or eliminated. BPC 157 therapy almost annihilated arterial and venous thrombosis, peripherally and centrally. Thus, rapidly acting Virchow triad circumstances that occur as dopamine central/peripheral antagonists and agonist essential class-points, fully reversed by BPC 157 therapy, might be overwhelming for both neuroleptics and amphetamine.
The aim of this study was to identify the reliability of carotid artery stump pressure (SP) in predicting the neurologic changes and correlation with contralateral internal carotid artery (ICA) ...occlusion in patients undergoing eversion carotid endarterectomy (CEA). The optimal method for monitoring cerebral perfusion during CEA, performed under either local or general anesthesia, is still controversial.
We prospectively analyzed 118 consecutive patients undergoing eversion CEA under local anesthesia. We had 78 symptomatic (66%) and 40 asymptomatic patients (33.9%). Selective shunting was performed in patients who developed neurologic changes after carotid clamping regardless of SP. Correlation of preoperative symptom status, a degree of stenosis, status of contralateral ICA, arterial blood pressure, SP value, and the intraoperative need for shunting due to neurologic changes was evaluated for both groups: shunted and nonshunted.
Selective shunting was performed in 12 patients (10%). There was no significant difference among the groups regarding the demographic characteristics. Mean carotid clamping time was 14.57 minutes. We had no perioperative mortality, stroke, or myocardial infarction. None of the patients required conversion to general anesthesia. We found a mean SP of 31 mm Hg as a reliable threshold for shunting (P < .001; sensitivity 92.3%; specificity 91.3%). Contralateral carotid occlusion was correlated with the significantly lower SP (27 ± 13 mm Hg; P = .001) and the higher need for shunt (50%).
SP measurement is a reliable and simple method for monitoring the collateral cerebral perfusion and can predict the need for shunting during CEA. Patients with the contralateral ICA occlusion showed significantly lower SP, although it did not have impact on the outcome.
We highlight the particular aspects of the stable gastric pentadecapeptide BPC 157 pleiotropic beneficial activity (not destroyed in human gastric juice, native and stable in human gastric juice, as ...a cytoprotection mediator holds a response specifically related to preventing or recovering damage as such) and its possible relations with neurotransmitter activity. We attempt to resolve the shortage of the pleiotropic beneficial effects of BPC 157, given the general standard neurotransmitter criteria, in classic terms. We substitute the lack of direct conclusive evidence (i.e., production within the neuron or present in it as a precursor molecule, released eliciting a response on the receptor on the target cells on neurons and being removed from the site of action once its signaling role is complete). This can be a network of interconnected evidence, previously envisaged in the implementation of the cytoprotection effects, consistent beneficial particular evidence that BPC 157 therapy counteracts dopamine, serotonin, glutamate, GABA, adrenalin/noradrenalin, acetylcholine, and NO-system disturbances. This specifically includes counteraction of those disturbances related to their receptors, both blockade and over-activity, destruction, depletion, tolerance, sensitization, and channel disturbances counteraction. Likewise, BPC 157 activates particular receptors (i.e., VGEF and growth hormone). Furthermore, close BPC 157/NO-system relations with the gasotransmitters crossing the cell membrane and acting directly on molecules inside the cell may envisage particular interactions with receptors on the plasma membrane of their target cells. Finally, there is nerve-muscle relation in various muscle disturbance counteractions, and nerve-nerve relation in various encephalopathies counteraction, which is also exemplified specifically by the BPC 157 therapy application.
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