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2.
Int J Mol Sci ; 24(9)2023 Apr 25.
Article in English | MEDLINE | ID: mdl-37175557

ABSTRACT

The mechanistic target of rapamycin (mTOR) kinase is one of the top drug targets for promoting health and lifespan extension. Besides rapamycin, only a few other mTOR inhibitors have been developed and shown to be capable of slowing aging. We used machine learning to predict novel small molecules targeting mTOR. We selected one small molecule, TKA001, based on in silico predictions of a high on-target probability, low toxicity, favorable physicochemical properties, and preferable ADMET profile. We modeled TKA001 binding in silico by molecular docking and molecular dynamics. TKA001 potently inhibits both TOR complex 1 and 2 signaling in vitro. Furthermore, TKA001 inhibits human cancer cell proliferation in vitro and extends the lifespan of Caenorhabditis elegans, suggesting that TKA001 is able to slow aging in vivo.


Subject(s)
Caenorhabditis elegans Proteins , Neoplasms , Animals , Humans , Caenorhabditis elegans/metabolism , Longevity , MTOR Inhibitors , Molecular Docking Simulation , TOR Serine-Threonine Kinases/metabolism , Caenorhabditis elegans Proteins/metabolism , Sirolimus/pharmacology , Cell Proliferation , Artificial Intelligence , Neoplasms/drug therapy
3.
Front Aging ; 3: 935220, 2022.
Article in English | MEDLINE | ID: mdl-35874275

ABSTRACT

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.

4.
Pharmaceuticals (Basel) ; 14(2)2021 Jan 25.
Article in English | MEDLINE | ID: mdl-33504008

ABSTRACT

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.

5.
Eur J Pharmacol ; 847: 130-142, 2019 Mar 15.
Article in English | MEDLINE | ID: mdl-30690000

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-1ß 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.


Subject(s)
Bile Ducts/drug effects , Gastric Mucosa/metabolism , Peptide Fragments/pharmacology , Peptides/pharmacology , Proteins/pharmacology , Animals , Apoptosis/drug effects , Cell Proliferation/drug effects , Hepatic Stellate Cells , Hypertension, Portal/drug therapy , Inflammation/drug therapy , Ligation/methods , Liver/drug effects , Liver Cirrhosis/drug therapy , Male , Rats , Rats, Wistar
6.
Vascul Pharmacol ; 106: 54-66, 2018 07.
Article in English | MEDLINE | ID: mdl-29510201

ABSTRACT

Rat inferior caval vein (ICV) ligation (up to the right ovarian vein (ROV)) commonly represents a recapitulation of Virchow: with ligation leading to vessel injury, stasis, thrombosis and hemodynamic changes. We revealed that BPC 157's therapy collectively attenuated or counteracted all these events and the full syndrome. METHODS: We applied BPC 157 (10 µg, 10 ng/kg) as an early regimen or as a delayed therapy. Assessment includes gross assessment by microcamera; microscopy, venography, bleeding, blood pressure, ECG, thermography, MDA and NO-level in plasma and ICV, and gene expression. RESULTS: Direct vein injury, thrombosis, thrombocytopenia, prolonged bleeding were all counteracted. Also, rapid presentation of collaterals and redistribution of otherwise trapped blood volume (bypassing through the left ovarian vein (LOV) and other veins), with venous hypertension, arterial hypotension and tachycardia counteraction were shown. BPC 157-rats presented raised plasma NO-values, but normal MDA-values; in ICV tissue reverted low NO-values and counteracted increased MDA-levels. Altered expression of EGR, NOS, SRF, VEGFR and KRAS in ICV, ROV and LOV revealed increased or decreased levels, while some genes continuously remained unchanged. CONCLUSION: As a new insight, BPC 157 application largely attenuated or even completely eliminated all consequences of ICV ligation in rats.


Subject(s)
Fibrinolytic Agents/pharmacology , Peptide Fragments/pharmacology , Proteins/pharmacology , Vena Cava, Inferior/surgery , Venous Thrombosis/prevention & control , Animals , Biomarkers/blood , Collateral Circulation/drug effects , Disease Models, Animal , Electrocardiography , Female , Gene Expression Regulation , Hemodynamics/drug effects , Hemorrhage/prevention & control , Ligation , Male , Malondialdehyde/blood , Nitric Oxide/blood , Phlebography , Rats, Wistar , Real-Time Polymerase Chain Reaction , Reverse Transcriptase Polymerase Chain Reaction , Thermography , Thrombocytopenia/blood , Thrombocytopenia/prevention & control , Time Factors , Vena Cava, Inferior/metabolism , Vena Cava, Inferior/pathology , Vena Cava, Inferior/physiopathology , Venous Thrombosis/blood , Venous Thrombosis/genetics , Venous Thrombosis/physiopathology
7.
World J Gastroenterol ; 24(48): 5462-5476, 2018 Dec 28.
Article in English | MEDLINE | ID: mdl-30622376

ABSTRACT

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.


Subject(s)
Anti-Ulcer Agents/therapeutic use , Cecum/injuries , Intestinal Perforation/drug therapy , Wound Healing/drug effects , Animals , Anti-Ulcer Agents/pharmacology , Arginine/pharmacology , Arginine/therapeutic use , Cecum/blood supply , Cecum/drug effects , Disease Models, Animal , Drug Therapy, Combination/methods , Humans , 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
8.
World J Gastroenterol ; 24(47): 5366-5378, 2018 Dec 21.
Article in English | MEDLINE | ID: mdl-30598581

ABSTRACT

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.


Subject(s)
Colitis, Ischemic/drug therapy , Collateral Circulation/drug effects , Duodenum/pathology , Protective Agents/pharmacology , Venous Thrombosis/complications , Animals , Arginine/pharmacology , Arginine/therapeutic use , Colitis, Ischemic/etiology , Disease Models, Animal , Duodenum/blood supply , Duodenum/drug effects , Humans , Male , NG-Nitroarginine Methyl Ester/pharmacology , NG-Nitroarginine Methyl Ester/therapeutic use , Nitric Oxide/metabolism , Oxidative Stress/drug effects , Peptide Fragments/pharmacology , Peptide Fragments/therapeutic use , Protective Agents/therapeutic use , Proteins/pharmacology , Proteins/therapeutic use , Random Allocation , Rats , Rats, Wistar , Treatment Outcome , Veins/drug effects
9.
Inflammopharmacology ; 25(2): 255-264, 2017 Apr.
Article in English | MEDLINE | ID: mdl-28255738

ABSTRACT

We revealed a new point with cyclophosphamide (150 mg/kg/day intraperitoneally for 7 days): we counteracted both rat stomach and duodenal ulcers and increased NO- and MDA-levels in these tissues. As a NO-system effect, BPC 157 therapy (10 µg/kg, 10 ng/kg, intraperitoneally once a day or in drinking water, till the sacrifice) attenuated the increased NO- and MDA-levels and nullified, in rats, severe cyclophosphamide-ulcers and even stronger stomach and duodenal lesions after cyclophosphamide + L-NAME (5 mg/kg intraperitoneally once a day). L-arginine (100 mg/kg intraperitoneally once a day not effective alone) led L-NAME-values only to the control values (cyclophosphamide + L-NAME + L-arginine-rats). Briefly, rats were sacrificed at 24 h after last administration on days 1, 2, 3, or 7, and assessment included sum of longest lesions diameters (mm) in the stomach and duodenum, oxidative stress by quantifying thiobarbituric acid reactivity as malondialdehyde equivalents (MDA), NO in stomach and duodenal tissue samples using the Griess reaction. All these parameters were highly exaggerated in rats who underwent cyclophosphamide treatment. We identified high MDA-tissue values, high NO-tissue values, ulcerogenic and beneficial potential in cyclophosphamide-L-NAME-L-arginine-BPC 157 relationships. This suggests that in cyclophosphamide damaged rats, NO excessive release generated by the inducible isozyme, damages the vascular wall and other tissue cells, especially in combination with reactive oxygen intermediates, while failing endothelial production and resulting in further aggravation by L-NAME which was inhibited by L-arginine. Finally, BPC 157, due to its special relations with NO-system, may both lessen increased MDA- and NO-tissues values and counteract effects of both cyclophosphamide and L-NAME on stomach and duodenal lesions.


Subject(s)
Arginine/administration & dosage , Cyclophosphamide/toxicity , NG-Nitroarginine Methyl Ester/administration & dosage , Nitric Oxide/metabolism , Peptic Ulcer/metabolism , Peptide Fragments/administration & dosage , Proteins/administration & dosage , Amino Acid Sequence , Animals , Anti-Ulcer Agents/administration & dosage , Drug Therapy, Combination , Female , Nitric Oxide/antagonists & inhibitors , Peptic Ulcer/chemically induced , Peptic Ulcer/drug therapy , Random Allocation , Rats , Rats, Wistar
10.
World J Gastroenterol ; 23(48): 8465-8488, 2017 Dec 28.
Article in English | MEDLINE | ID: mdl-29358856

ABSTRACT

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.


Subject(s)
Anti-Ulcer Agents/therapeutic use , Colitis/drug therapy , Peptide Fragments/therapeutic use , Proteins/therapeutic use , Reperfusion Injury/drug therapy , Animals , Anti-Ulcer Agents/pharmacology , Arginine/therapeutic use , Colitis/blood , 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 , Proteins/pharmacology , Rats , Rats, Wistar , Reperfusion Injury/blood , Reperfusion Injury/etiology , Reperfusion Injury/pathology
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