Pentadecapeptide BPC 157 and Rac 1 inhibitors

UVOD: Rac1 je mali signalizirajući G-protein koji može aktivirati NF-kappaB. Pentadekapeptid BPC 157 smanjuje transkripciju Vcam-1 u NF-kappaB signalnom putu kao i neki NF-kappaB inhibitori te suprimira da ERK inducira Vcam-1 preko NF-kappaB aktivacije. Pentadekapeptid BPC 157 može biti Rac1 aktivator ili inhibitor, te bi to moglo ovisiti o mjestu fosforilacije FAK/paksilin signalnog puta. METODE: Pregled učinaka pentadekapeptida BPC 157 i Rac1 inhibitora na tumorski rast, ishemijsko-reperfuzijske ozljede, ulcerozni kolitis, virusne infekcije, multiplu sklerozu, depresiju i cijeljenje te usporedba sa učincima NF-kappaB inhibitora. REZULTATI: Pentadekapeptid BPC 157 bi mogao biti novi NF-kappaB inhibitor. Dok je većina istraživanja o Rac1 inhibitorima napravljena na modelima inhibicije tumorskog rasta gdje je pronađena prekomjerna ekspresija Rac1, BPC 157 je najviše istraživan u modelima upalnih bolesti i cijeljenja. Transkripcijski faktor NF-kappaB povezuje upalne bolesti i tumore, te je moguće da je NF-kappaB signalni put poveznica između pentadekapeptida BPC 157 i Rac1 inhibitora. Pentadekapeptid BPC 157 i NF-kappaB inhibitori pozitivno utječu na sve navedene modele, dok Rac1 inhibitori nisu učinkoviti u modelima cijeljenja i depresije. ZAKLJUČAK: Postoji mogućnost da je transkripcijski faktor NF-kappaB uzrok sličnosti između pentadekapeptida BPC 157 i Rac1 inhibitora u nekim modelima. Treba uzeti u obzir i druge signalne puteve kao što su CREB i ERK te da je moguće da je učinak BPC 157, kao i Rac1 inhibitora na te puteve stanično-specifičan.BACKGROUND: Rac 1 is a small G-protein which can activate NF-kappaB. Pentadecapeptide BPC 157 decreases transcription of Vcam1 in NF-kappaB signalling pathway like some NF-kappaB inhibitors and supresses ERK induction of Vcam1 through NF-kappaB activation. Pentadecapeptide BPC 157 can be Rac1 activator or inhibitor, and that could depend on phosphorylation site of FAK/Paxillin pathway. METHODS: Review of pentadecapeptide BPC 157 and Rac1 inhibitor effects on tumour growth, ischemia-reperfusion injuries, ulcerative colitis, viral infections, multiple sclerosis, depression and healing, as well as comparison with the effects of NF-kappaB inhibitors. RESULTS: Pentadecapeptide BPC 157 could be a novel NF-kappaB inhibitor. While most of the research on Rac1 inhibitors is done in models of tumour growth inhibition where Rac1 overexpression is found, the research on BPC 157 is focused on inflammation diseases and healing. The NF-kappaB transcription factor is a link between inflammation and cancer, so it is possible that NF-kappaB pathway is a connection between pentadecapeptide BPC 157 and Rac1 inhibitors. Pentadecapeptide BPC 157 and NF-kappaB inhibitors have positive result in all of the models reviewed, while Rac1 inhibition is not affective in models of healing and depression. CONCLUSION: It is possible that the NF-kappaB transcription factor is a cause of the similirality between BPC 157 and Rac1 inhibitors in some of the models. Other signalling pathways , like ERK and CREB must be considered, as well as the fact the effect of BPC 157 and Rac1 inhibitors on NF-kappaB could be cell specific

Pentadecapeptide BPC 157 and Rac 1 inhibitors

UVOD: Rac1 je mali signalizirajući G-protein koji može aktivirati NF-kappaB. Pentadekapeptid BPC 157 smanjuje transkripciju Vcam-1 u NF-kappaB signalnom putu kao i neki NF-kappaB inhibitori te suprimira da ERK inducira Vcam-1 preko NF-kappaB aktivacije. Pentadekapeptid BPC 157 može biti Rac1 aktivator ili inhibitor, te bi to moglo ovisiti o mjestu fosforilacije FAK/paksilin signalnog puta. METODE: Pregled učinaka pentadekapeptida BPC 157 i Rac1 inhibitora na tumorski rast, ishemijsko-reperfuzijske ozljede, ulcerozni kolitis, virusne infekcije, multiplu sklerozu, depresiju i cijeljenje te usporedba sa učincima NF-kappaB inhibitora. REZULTATI: Pentadekapeptid BPC 157 bi mogao biti novi NF-kappaB inhibitor. Dok je većina istraživanja o Rac1 inhibitorima napravljena na modelima inhibicije tumorskog rasta gdje je pronađena prekomjerna ekspresija Rac1, BPC 157 je najviše istraživan u modelima upalnih bolesti i cijeljenja. Transkripcijski faktor NF-kappaB povezuje upalne bolesti i tumore, te je moguće da je NF-kappaB signalni put poveznica između pentadekapeptida BPC 157 i Rac1 inhibitora. Pentadekapeptid BPC 157 i NF-kappaB inhibitori pozitivno utječu na sve navedene modele, dok Rac1 inhibitori nisu učinkoviti u modelima cijeljenja i depresije. ZAKLJUČAK: Postoji mogućnost da je transkripcijski faktor NF-kappaB uzrok sličnosti između pentadekapeptida BPC 157 i Rac1 inhibitora u nekim modelima. Treba uzeti u obzir i druge signalne puteve kao što su CREB i ERK te da je moguće da je učinak BPC 157, kao i Rac1 inhibitora na te puteve stanično-specifičan.BACKGROUND: Rac 1 is a small G-protein which can activate NF-kappaB. Pentadecapeptide BPC 157 decreases transcription of Vcam1 in NF-kappaB signalling pathway like some NF-kappaB inhibitors and supresses ERK induction of Vcam1 through NF-kappaB activation. Pentadecapeptide BPC 157 can be Rac1 activator or inhibitor, and that could depend on phosphorylation site of FAK/Paxillin pathway. METHODS: Review of pentadecapeptide BPC 157 and Rac1 inhibitor effects on tumour growth, ischemia-reperfusion injuries, ulcerative colitis, viral infections, multiple sclerosis, depression and healing, as well as comparison with the effects of NF-kappaB inhibitors. RESULTS: Pentadecapeptide BPC 157 could be a novel NF-kappaB inhibitor. While most of the research on Rac1 inhibitors is done in models of tumour growth inhibition where Rac1 overexpression is found, the research on BPC 157 is focused on inflammation diseases and healing. The NF-kappaB transcription factor is a link between inflammation and cancer, so it is possible that NF-kappaB pathway is a connection between pentadecapeptide BPC 157 and Rac1 inhibitors. Pentadecapeptide BPC 157 and NF-kappaB inhibitors have positive result in all of the models reviewed, while Rac1 inhibition is not affective in models of healing and depression. CONCLUSION: It is possible that the NF-kappaB transcription factor is a cause of the similirality between BPC 157 and Rac1 inhibitors in some of the models. Other signalling pathways , like ERK and CREB must be considered, as well as the fact the effect of BPC 157 and Rac1 inhibitors on NF-kappaB could be cell specific

Identification of 37 Heterogeneous Drug Candidates for Treatment of COVID-19 via a Rational Transcriptomics-Based Drug Repurposing Approach

A year after the initial outbreak, the COVID-19 pandemic caused by SARS-CoV-2 virus remains a serious threat to global health, while current treatment options are insufficient to bring major improvements. The aim of this study is to identify repurposable drug candidates with a potential to reverse transcriptomic alterations in the host cells infected by SARS-CoV-2. We have developed a rational computational pipeline to filter publicly available transcriptomic datasets of SARS-CoV-2-infected biosamples based on their responsiveness to the virus, to generate a list of relevant differentially expressed genes, and to identify drug candidates for repurposing using LINCS connectivity map. Pathway enrichment analysis was performed to place the results into biological context. We identified 37 structurally heterogeneous drug candidates and revealed several biological processes as druggable pathways. These pathways include metabolic and biosynthetic processes, cellular developmental processes, immune response and signaling pathways, with steroid metabolic process being targeted by half of the drug candidates. The pipeline developed in this study integrates biological knowledge with rational study design and can be adapted for future more comprehensive studies. Our findings support further investigations of some drugs currently in clinical trials, such as itraconazole and imatinib, and suggest 31 previously unexplored drugs as treatment options for COVID- 19

Counteraction of perforated cecum lesions in rats: effects of pentadecapeptide BPC 157, L-NAME and L-arginine

AIM: To study the counteraction of perforated cecum lesion using BPC 157 and nitric oxide (NO) system agents. ----- METHODS: 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. ----- RESULTS: 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). ----- CONCLUSION: 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

Bypassing major venous occlusion and duodenal lesions in rats, and therapy with the stable gastric pentadecapeptide BPC 157, L-NAME and L-arginine

AIM: To investigate whether duodenal lesions induced by major venous occlusions can be attenuated by BPC 157 regardless nitric oxide (NO) system involvement. ----- METHODS: Male Wistar rats underwent superior anterior pancreaticoduodenal vein (SAPDV)-ligation and were treated with a bath at the ligated SAPDV site (BPC 157 10 μg, 10 ng/kg per 1 mL bath/rat; L-NAME 5 mg/kg per 1 mL bath/rat; L-arginine 100 mg/kg per 1 mL bath/rat, alone and/or together; or BPC 157 10 μg/kg instilled into the rat stomach, at 1 min ligation-time). We recorded the vessel presentation (filled/appearance or emptied/disappearance) between the 5 arcade vessels arising from the SAPDV on the ventral duodenum side, the inferior anterior pancreaticoduodenal vein (IAPDV) and superior mesenteric vein (SMV) as bypassing vascular pathway to document the duodenal lesions presentation; increased NO- and oxidative stress [malondialdehyde (MDA)]-levels in duodenum. ----- RESULTS: Unlike the severe course in the SAPDV-ligated controls, after BPC 157 application, the rats exhibited strong attenuation of the mucosal lesions and serosal congestion, improved vessel presentation, increased interconnections, increased branching by more than 60% from the initial value, the IAPDV and SMV were not congested. Interestingly, after 5 min and 30 min of L-NAME and L-arginine treatment alone, decreased mucosal and serosal duodenal lesions were observed; their effect was worsened at 24 h, and no effect on the collateral vessels and branching was seen. Together, L-NAME+L-arginine antagonized each other's response, and thus, there was an NO-related effect. With BPC 157, all SAPDV-ligated rats receiving L-NAME and/or L-arginine appeared similar to the rats treated with BPC 157 alone. Also, BPC 157 in SAPDV-ligated rats normalized levels of NO and MDA, two oxidative stress markers, in duodenal tissues. ----- CONCLUSION: BPC 157, rapidly bypassing occlusion, rescued the original duodenal flow through IAPDV to SMV flow, an effect related to the NO system and reduction of free radical formation

Stable gastric pentadecapeptide BPC 157 in the treatment of colitis and ischemia and reperfusion in rats: new insights

AIM: To provide new insights in treatment of colitis and ischemia and reperfusion in rats using stable gastric pentadecapeptide BPC 157. ----- METHODS: 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. ----- RESULTS: 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. ----- CONCLUSION: 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

Pentadecapeptide BPC 157 and Rac 1 inhibitors

UVOD: Rac1 je mali signalizirajući G-protein koji može aktivirati NF-kappaB. Pentadekapeptid BPC 157 smanjuje transkripciju Vcam-1 u NF-kappaB signalnom putu kao i neki NF-kappaB inhibitori te suprimira da ERK inducira Vcam-1 preko NF-kappaB aktivacije. Pentadekapeptid BPC 157 može biti Rac1 aktivator ili inhibitor, te bi to moglo ovisiti o mjestu fosforilacije FAK/paksilin signalnog puta. METODE: Pregled učinaka pentadekapeptida BPC 157 i Rac1 inhibitora na tumorski rast, ishemijsko-reperfuzijske ozljede, ulcerozni kolitis, virusne infekcije, multiplu sklerozu, depresiju i cijeljenje te usporedba sa učincima NF-kappaB inhibitora. REZULTATI: Pentadekapeptid BPC 157 bi mogao biti novi NF-kappaB inhibitor. Dok je većina istraživanja o Rac1 inhibitorima napravljena na modelima inhibicije tumorskog rasta gdje je pronađena prekomjerna ekspresija Rac1, BPC 157 je najviše istraživan u modelima upalnih bolesti i cijeljenja. Transkripcijski faktor NF-kappaB povezuje upalne bolesti i tumore, te je moguće da je NF-kappaB signalni put poveznica između pentadekapeptida BPC 157 i Rac1 inhibitora. Pentadekapeptid BPC 157 i NF-kappaB inhibitori pozitivno utječu na sve navedene modele, dok Rac1 inhibitori nisu učinkoviti u modelima cijeljenja i depresije. ZAKLJUČAK: Postoji mogućnost da je transkripcijski faktor NF-kappaB uzrok sličnosti između pentadekapeptida BPC 157 i Rac1 inhibitora u nekim modelima. Treba uzeti u obzir i druge signalne puteve kao što su CREB i ERK te da je moguće da je učinak BPC 157, kao i Rac1 inhibitora na te puteve stanično-specifičan.BACKGROUND: Rac 1 is a small G-protein which can activate NF-kappaB. Pentadecapeptide BPC 157 decreases transcription of Vcam1 in NF-kappaB signalling pathway like some NF-kappaB inhibitors and supresses ERK induction of Vcam1 through NF-kappaB activation. Pentadecapeptide BPC 157 can be Rac1 activator or inhibitor, and that could depend on phosphorylation site of FAK/Paxillin pathway. METHODS: Review of pentadecapeptide BPC 157 and Rac1 inhibitor effects on tumour growth, ischemia-reperfusion injuries, ulcerative colitis, viral infections, multiple sclerosis, depression and healing, as well as comparison with the effects of NF-kappaB inhibitors. RESULTS: Pentadecapeptide BPC 157 could be a novel NF-kappaB inhibitor. While most of the research on Rac1 inhibitors is done in models of tumour growth inhibition where Rac1 overexpression is found, the research on BPC 157 is focused on inflammation diseases and healing. The NF-kappaB transcription factor is a link between inflammation and cancer, so it is possible that NF-kappaB pathway is a connection between pentadecapeptide BPC 157 and Rac1 inhibitors. Pentadecapeptide BPC 157 and NF-kappaB inhibitors have positive result in all of the models reviewed, while Rac1 inhibition is not affective in models of healing and depression. CONCLUSION: It is possible that the NF-kappaB transcription factor is a cause of the similirality between BPC 157 and Rac1 inhibitors in some of the models. Other signalling pathways , like ERK and CREB must be considered, as well as the fact the effect of BPC 157 and Rac1 inhibitors on NF-kappaB could be cell specific

Longevity-Promoting Pathways and Transcription Factors Respond to and Control Extracellular Matrix Dynamics During Aging and Disease

Aging is one of the largest risk factors for cancer, type 2 diabetes, osteoarthritis, cardiovascular diseases, and other age-related pathologies. Here, we give a detailed description of the interplay of chronic age-related pathologies with the remodeling of the extracellular matrix during disease development and progression. Longevity-promoting signaling pathways slow or prevent age-related diseases. In particular, we focus on the mTOR signaling pathway, sirtuins, and canonical longevity-promoting transcription factors, such as FOXO, NF-κB, and Nrf2. We extend our analysis using chromatin immunoprecipitation (ChIP) sequencing and transcriptomic data and report that many established and emerging longevity-promoting transcription factors, such as CREB1, FOXO1,3, GATA1,2,3,4, HIF1A, JUN, KLF4, MYC, NFE2L2/Nrf2, RELA/NF-κB, REST, STAT3,5A, and TP53/p53, directly regulate many extracellular matrix genes and remodelers. We propose that modulation of these pathways increases lifespan and protects from age-related diseases in part due to their effects on extracellular matrix remodeling. Therefore, to successfully treat age-related diseases, it is necessary to better understand the connection between extracellular matrix components and longevity pathways.ISSN:2673-621