bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Effect of BPC 157 on Tracheocutaneous Fistula Healing in Rat
Authors: Madzarac Goran , Cesarec Vedran , Djakovic Zeljko , Becejac Tomislav , Hirsl Dorian , Drmic Domagoj , Seiwerth Sven , Stancic‐Rokotov Dinko , Sikiric Predrag 
Published: June 2021

IntroductionOne of the common late complications of a tracheotomy is tracheocutaneous fistula. The surgical procedure is needed to close such fistulas. BPC 157, anti‐ulcer peptide (GEPPPGKPADDAGLV, M.W. 1419) successful in trials for inflammatory bowel disease, wound treatment, effective alone without a carrier. BPC 157 interferes with NO‐system in vitro/in vivo on different models and different animal species. The impact of BPC 157 and NO‐system on gastrocutaneous, colocutaneous and oesophagocutaneous fistulas healing process indicates potential effect of BPC 157 in tracheocutaneous fistula healing process, which has not yet been investigated.MethodsAlbino Wistar male rats were used in this experiment, 220–280 g. Tracheocutaneous fistula, 4 mm trachea and skin defect, was surgically made under anaesthesia. Animals were treated according to the experiment protocol: a) drinking water p.o., b) BPC 157 (10 μg/kg, 12 ml/rat/day) p.o., c) BPC 157 (10 ng/kg, 12 ml/rat/day) p.o., d) saline 5ml/kg/day i.p., e) BPC 157 (10μg/kg, 5ml/kg/day) i.p., f) BPC 157 (10 ng/kg, 5 ml/kg/day) i.p., g) L‐NAME (5 mg/kg/day) i.p., h) L‐arginine (100 mg/kg/day) i.p., i) L‐NAME L‐arginine i.p., j) L‐NAME BPC 157 (μg) i.p., k) L‐arginine BPC 157 (μg) i.p., l) L‐NAME L‐arginine BPC 157 (μg) i.p., m) L‐NAME BPC 157 (ng) i.p., n) L‐arginine BPC 157 (ng) i.p., o) L‐NAME L‐arginine BPC 157 (ng) i.p.. Third, fifth and seventh postoperative day animals were euthanized. Fistula specimens were harvested and macroscopic and histological analysis was made.ResultsA consistent counteracting beneficial effect was shown in all animals treated with BPC 157, alone and with (L‐NAME) and/or L‐arginine in a 7‐day interval. BPC 157 accelerated healing of tracheocutaneous fistulas and showed macroscopic and histological healing improvements. Tracheocutaneous fistulas healing was improved speedily (BPC 157 completely counteracted L‐NAME effects (L‐NAME+BPC 157 and L‐NAME+L‐arginine+BPC 157 groups), or with delay and to less extent (L‐arginine) or aggravated, rapidly and prominently (L‐NAME). L‐arginine reduces aggravation by NOS‐blockade (L‐NAME) to the control levels. Also, BPC 157 more than nullifies the effect of L‐NAME.ConclusionBPC 157 improved healing of both tracheal and skin defects and mediated fistula closing. This effect was shared by L‐arginine, with an opposite effect seen by L‐NAME, thereby portraying NO‐system involvement in the healing of tracheocutaneous fistula.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Influence of liver‐specific ablation of gp78 E3‐ligase on hepatic cytochrome P450‐ dependent drug metabolism: Clinical implications
Authors: Kwon Doyoung , Kim Sung‐Mi , Correia Maria Almira 
Published: June 2021

The autocrine motility factor receptor (AMFR)/gp78 is a membrane‐anchored E3 ligase involved in ubiquitin (Ub)‐dependent proteasomal degradation (UPD). We have previously documented that gp78 is involved in the UPD of two clinically relevant hepatic cytochromes P450 Cyp2E1 and Cyp3A4 engaged in therapeutic drug and/or xenobiotic metabolism. To determine the role of gp78 in the UPD of other hepatic P450s, we generated a liver specific gp78 knockout (KO) mouse model. Cultured primary hepatocytes from KO and wild type (WT) mice were untreated or treated with P450 inducer β‐naphthoflavone (Cyp1a2), phenobarbital (Cyps2a, 2b and 2c), isoniazid (Cyp2e1) or dexamethasone (Cyp3a). Immunoblotting and selective functional marker analyses revealed that the functional content of Cyps1a2, 2a, 2c, 2e1 and 3a was increased, but that of Cyp2b or Cyp2d was decreased/unchanged in KO relative to WT. To determine the potential clinical relevance of these findings, the in culture metabolism of tamoxifen, a breast cancer chemotherapeutic prodrug, to its active metabolite endoxifen was monitored by LC/MS. Upon 8 h of tamoxifen incubation, the levels of Cyp3a‐generated metabolites N‐desmethyltamoxifen and endoxifen were significantly increased in KO over WT hepatocytes, but the Cyp2d‐generated metabolite 4‐hydroxytamoxifen was unchanged, consistent with the corresponding functional levels of hepatic Cyps3a and 2d. Collectively, our findings reveal that hepatic gp78 deficiency significantly increased the functional levels of several drug‐metabolizing P450s most likely by impairing their UPD. These increases in turn enhanced the hepatic metabolic activation of a clinically relevant anti‐cancer drug. Because gp78 genetic polymorphisms exist, and gp78 is overexpressed in certain malignant tumors and human cancers (i.e. breast and colon) that correlates well with their progression and poor prognosis, our findings suggest that gp78 be considered a significant modulator of P450‐mediated metabolism of clinically relevant/chemotherapeutic drugs and associated drug‐drug interactions.Support or Funding InformationSupported by NIH grants GM44037, DK26506 and DK26743.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Evaluation of Pharmacokinetic Compatibility of XueBiJing Injection with Antibiotics Co‐administered in Management of Sepsis
Authors: Li Chuan 
Published: June 2021

Sepsis is life‐threatening organ dysfunction caused by a dysregulated host response to infection. XueBiJing, an intravenous injection approved by the China FDA in 2004, has been incorporated into conventional sepsis management, which relies on timely and appropriate antibiotics and resuscitation therapies. In China, about 800,000 patients use XueBiJing injection each year and 80% of them are patients with sepsis or septic shock. The injection is prepared from a combination of Carthamus tinctorius flowers (Honghua in Chinese), Paeonia lactiflora roots (Chishao), Ligusticum chuanxiong rhizomes (Chuanxiong), Angelica sinensis roots (Danggui), and Salvia miltiorrhiza roots (Danshen). Many clinical studies in China suggested that adding XueBiJing injection to conventional management of sepsis reduces patients' 28‐day mortality and incidence of complications, improves their Acute Physiology and Chronic Health Evaluation II scores and prognosis, and shortens their stay in intensive care units, with low incidence of side effects. Despite the promising results of clinical studies, success of such combination drug therapies containing XueBiJing injection also relies on PK compatibility, i.e., exhibiting limited pharmacokinetic interaction problems that can counteract the drugs' synergistic or additive pharmacodynamic effects, as well as their safety. In this presentation, the speaker will report evaluation, by his lab, of pharmacokinetic compatibility of XueBiJing injection with antibiotics co‐administered in management of sepsis.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Synergistic Effect of Combined Inhibition of the Checkpoint kinase 1 and G9a Methyltransferase Pathways in Pancreatic Cancer
Authors: Urrutia Guillermo , Salmonson Ann , Lomberk Gwen 
Published: June 2021

Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer‐related deaths in the United States with a devastating overall five‐year survival rate of less than five percent. Consequently, there is an urgent need to further improve our understanding of molecular mechanisms underlying PDAC development to identify innovative therapeutic targets. Our laboratory is focused on utilizing epigenetic inhibitors in novel therapeutic approaches. Our experimental design involves harnessing the capacity of cell cycle inhibitors to arrest cells in G2/M while combining them with epigenetic inhibitors, which by altering chromatin structure can give rise to an aberrant mitotic checkpoint response leading to rapid death (Mol Cancer Res; 15(8): 984–97). In the present study, we have optimized and tested an experimental combinatorial therapy for pancreatic cancer using the CHK1 inhibitor LY2606368 and the G9a (Eukaryotic Histone Methyltransferase 2) inhibitor BRD4770. Using MTS assay, we show that the growth of pancreatic cancer cells grown in monolayer is reduced by both LY2606368 and BRD4770 individually, while their combination achieves a synergistic effect, as calculated using the Chou and Talalay method. In addition, this synergistic effect is also observed using pancreatic cancer cells grown as 3D spheroids. Moreover, the combination of LY2606368 with either of two additional G9a inhibitors, BIX01294 or UNC0631, reveals similar synergy, further supporting the specificity of this effect. FACS analysis of cells treated with the LY2606368 and BRD4770 combination shows an increased population in G2/M at 24 hours and an apoptotic pre‐G1 signal. The apoptotic response coincides with the activation of caspases 3 and 7. In vivo studies demonstrate that targeting these pathways reduces pancreatic tumor growth in a subcutaneous pancreatic cancer xenograft model. In summary, these data establish that targeting the epigenetic regulator G9a in the context of cell cycle inhibition holds promise as a novel combinatorial therapy for pancreatic cancer.Support or Funding InformationNIH R01CA178627; Advancing a Healthier Wisconsin EndowmentThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Searching for a new cancer drug: Kentucky Hemp‐induced modulation of ovarian cancer cell proliferation and total cell death
Authors: Duff Adam , Wang Annie , Biela Sara , Sumanasekera Wasana 
Published: June 2021

Marijuana (cannabis sativa), a schedule 1 drug has been recently approved by some of states in the US for its therapeutic benefit. Although few reports discuss about its anti‐cancer potential, currently it has been used mainly for epilepsy and to alleviate pain associated with many diseases. However, due to marijuana's addictive potential there are restrictions for its use. Hemp, which belongs to the same genus and species as marijuana shows similar therapeutic benefits with much less addictive potential due to the low level of the addictive component, tetrahydrocannabinol (THC). Both marijuana and hemp are rich in therapeutically valuable cannabidiol (CBD) and cannabidiolic acid (CBD‐A). The major objective of the current study is to investigate KY hemp's therapeutic potential against ovarian cancer. Our laboratory is interested in searching for alternative therapies for ovarian cancer. As a candidate drug we have investigated the anti‐cancer potential of KY grown hemp using two different epithelial ovarian cancer cell (OCC) lines, which are A2780 and MES‐OV. KY Hemp extracts were made using supercritical CO2 extraction method by KY Commonwealth Extracts Company. Following High Performance Liquid Chromatography (HPLC) analysis by MRX laboratories we have obtained this extract to study its anti‐cancer potential. There are no reports on anti‐cancer activity of KY hemp against ovarian cancer or any type of cancer yet. Therefore, this study provides novelty.MethodsFollowing serum starvation, OCCs were treated with vehicle (negative control), 80 μM doxorubicin and cisplatin, and different concentrations of hemp extracts that contain 8.5–335 μM CBD. Hemp‐induced modulation of ovarian cancer cell viability was assessed spectrophotometrically by MTT cell proliferation assay and Calcein AM assay. The MTT assay detects formazan product formed due to mitochondrial reductase enzyme present in viable cells. The Calcein assay detects the esterase enzyme activity present in viable cells. Ethidium homodimer dye (ETHD‐1) was used to detect total cell death. ETHD‐1 penetrates only damaged cell membranes and binds different molecules such as cell debris, single stranded DNA, double stranded DNA, and peptides. Calcein AM and ETHD‐1 fluorescence was also detected microscopically. KY Hemp extract has significantly decreased OCC proliferation and caused total cell death. KY Hemp extract has shown anti‐cancer properties comparable to doxorubicin and cisplatin. Based on the data here we conclude that KY Hemp has significant anti‐cancer potential against ovarian cancerSupport or Funding InformationFunding is provided by the Sullivan University System via a faculty development grant awarded to Dr. Sumanasekera. Grant number: RG‐1‐PS‐2017‐04
Structure‐Activity Analysis of Bisphenol‐Z Derivatives for Anticancer Activity
Authors: Stang Christopher R.T. , Inbody Laura R. , Stitzlein Lea M. , Dick Matt J. , Eichel Amanda M. , Orahood Cassandra B. , Mohamed Ahmed H. , Dudley Richard W. , Schneider Ryan A. 
Published: June 2021

Much of the research surrounding bisphenol derivatives focuses on their use as polymers and plasticizers for industry. Research has demonstrated that bisphenol‐A (BPA) adversely affects humans via endocrine disruption through hormonal modulation. Despite the recent explosion in BPA research, little effort has been devoted to researching the biological activities of other bisphenol derivatives, including bisphenol‐Z (BPZ). Initial screening of BPZ revealed moderate in vitro anticancer activity against four diverse human cancer cell lines (A375 malignant melanoma, A‐172 glioblastoma, HT‐29 colorectal adenocarcinoma, and MCF7 breast adenocarcinoma) with IC50 values of approximately 65 μM following 24 hour treatments. In an attempt to enhance the activity of BPZ, seven analogs with varying degrees of polarity, lipophilicity, and sterics on the cyclohexane ring were synthesized. Screening of these analogs revealed that polar substitutions resulted in a loss of activity, while a simple methyl substitution had similar activity to BPZ. Anticancer activity was enhanced relative to BPZ following substitution with an ethyl, isopropyl, or N‐palmitoyl group at the 4‐ position. The most active compounds from this structure‐activity study were the N‐palmitoyl (LS4) and isopropyl (LS6) derivatives with 24 hour IC50 values ranging from 25 to 53 μM and 33 to 42 μM respectively.Given the increased activity of LS4 and LS6, additional studies were performed including a trypan blue exclusion assay and a Caspase‐Glo® 3/7 assay. The results of these studies revealed exclusion of trypan blue at supra‐IC50 concentrations six hours after treatments, suggestive of a non‐necrotic mechanism of death. To determine if caspase‐dependent apoptosis was involved, we performed a Caspase‐Glo® 3/7 assay. Functional screening of executioner caspase‐3 and ‐7 revealed significant increases in activity following a 12 hour treatment with LS4 in all cells lines. This effect was least evident in the MCF7 cells, potentially due to a mutation wherein these cells lack expression of caspase‐3. In contrast, LS6 failed to activate executioner caspases‐3 and ‐7 in these same cell lines.In conclusion, this structure‐activity study revealed that nonpolar substitution at the 4‐ position of BPZ enhanced anticancer activity. Additionally, membrane integrity remained intact following exposure to LS4 and LS6. While LS4 activated executioner caspases‐3/7, LS6 failed to activate this hallmark pathway of apoptotic death. Further investigations are ongoing to elucidate the mechanisms of cell death, identify putative cellular targets, and determine potential selectivity against normal human cell lines.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Evaluation of the anticancer activity of a newly synthetic combretastatine analogue against hepatocellular carcinoma.
Authors: El‐Moselhy Mohamed A. , Aboubakr Esam Mohamed , Aly Omar Mohamed , Taye Ashraf 
Published: June 2021

Combretastatin A‐4 has been emerged as a promising vascular disrupting agent, which displayed potent cytotoxic activities against a wide range of human cancer cell lines. Therefore, the present study was conducted to evaluate the anticancer activity of a newly synthesized combretastatin A‐4 analogue (1‐(3,4‐Dimethoxyphenyl)‐N‐(2‐methoxyphenyl)‐5‐(3,4,5‐trimethoxyphenyl)‐1H‐1,2,4‐triazole‐3‐carboxamide) against hepatocellular carcinoma (HCC) both in vitro and in vivo. In vitro study used HepG2 cell lines to evaluate the cytotoxic (antitumour) activity, tubulin protein inhibition and cell cycle analysis. While, in vivo study used DENA + CCl4 as a well‐established model for HCC induction in rats. Animal groups were divided as following: Normal non‐treated group, DENA + CCl4 group, CA4‐P treated group and CA4‐P analogue treated group. The following parameters were determined: hepatic relative weight, number of hepatic nodules, relative volume of hepatic nodules, hepatic tissue content of tubulin, histopathological examination of the hepatic tissue, hepatic tissue lipid peroxidation, hepatic tissue carbonyl content, serum ALT, serum AST, hepatic tissue TNF‐α and hepatic AFP concentrations. CA4‐P analogue significantly decreased liver relative weight, number of hepatic nodules and there relative volumes, tubulin content of the hepatic tissue, GSH and AFP which were more pronounced than CA4‐P group. Whereas a marked increase in MDA, carbonyl content and TNF‐a inside hepatic tissue were observed in the CA4‐P analogue treated group, which were higher than CA4‐P group. In conclusion CA4‐P analogue has a potential anti‐cancer activity against hepatocellular carcinoma and this effect was more noticeable than its parent drug (CA4‐P).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
SHetA2 and its Analogs Induce Growth Inhibition in Human Glioblastoma Cells
Authors: Chan Allen , Liu Shengquan , Rajagopalan Vanishree 
Published: June 2021

SHetA2, a flexible heteroarotinoid and new cancer‐preventative drug candidate, has exhibited growth inhibition in many human cancer cell lines such as lung, kidney, ovarian, and colon and in animal models of cancer. Because SHetA2 has high lipophilicity (Log P of 7.09), indicating low bioavailability, this suggests that SHetA2 is not an ideal drug candidate (Ideal Log P between 0 and 5). In order to address this issue, modifications were done to the thiochroman ring, resulting in SL‐analogs with lower Log P values. In this study, we examined the growth inhibitory effects of SHetA2 and three thiochroman analogs, SL‐01‐39, SL‐01‐30, and SL‐01‐18 on T98‐G cells, a human glioblastoma cell line.After T98‐G cells were treated for 48 hours with SHetA2 and its analogs at 0.5, 1, 5, 10, and 20 μM, MTS assays were performed to measure cell proliferation and calculate their GI50 values (drug concentration which causes 50% inhibition of cell growth). In addition, trypan blue exclusion assays were performed, using a Vi‐Cell XR cell counter, to determine percent cell viability and relative cell counts of T98‐G cells after treatment with SHetA2 or its analogs. GraphPad Prism statistical software was used to generate a non‐linear regression model from the MTS assay readings to calculate the GI50 values. Results from trypan blue exclusion were analyzed, using Microsoft Excel, to determine the trend in cell viability and viable cell counts with respect to drug concentrations.GI50 values of SHetA2, SL‐01‐39, SL‐01‐30, and SL‐01‐18 were calculated to be 5.57 μM, 5.38 μM, 6.41 μM, and 5.31 μM, respectively, using a one‐phase decay model. With trypan blue exclusion assay, percent cell viability remained relatively unaffected in T98‐G cells treated with SHetA2 and its analogs, despite increasing concentrations. On the contrary, trypan blue exclusion assay results showed a significant decrease in relative cell counts in cells treated with SHetA2 or its analogs when compared to the untreated cells.This is the first report showing the growth inhibitory effects of SHetA2 in T98‐G human glioblastoma cells. The GI50 value of SHetA2 in T98‐G cells is in low micromolar range (~5 μM), comparable to its GI50 values in other cell lines published in literature. In addition, the GI50 values of the three analogs, SL‐01‐39, SL‐01‐30, and SL‐01‐18, were comparable to that of SHetA2. SHetA2 and its analogs decreased the relative cell number of T98‐G cells without significantly affecting cell viability, suggesting that these agents primarily inhibit cell growth of T98‐G cells without inducing cytotoxic effects. Further investigation on the mechanism of growth inhibition is ongoing.Support or Funding InformationTouro CA COP‐MS Program for funding this research.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Endothelial TRPV4 Channel Function is Impaired in Pulmonary Arterial Hypertension
Authors: Marziano Corina , Hong Kwangseok , Cope Eric Lee , Sonkusare Swapnil K. 
Published: June 2021

Endothelial dysfunction contributes to the pathogenesis of pulmonary arterial hypertension (PAH) by reducing arterial vasodilation. Endothelium‐dependent vasodilation is an important regulator of pulmonary vascular resistance (PVR) and overall pulmonary arterial pressure (PAP). We recently identified endothelial TRPV4 (transient receptor potential vanilloid 4) channels as important regulators of vasodilation in pulmonary arteries (PAs), and showed that unitary Ca2+ influx events through TRPV4 channels, termed TRPV4 sparklets, activate endothelial nitric oxide synthase (eNOS) to cause vasodilation. Reduced NO bioavailability is a hallmark of endothelial dysfunction in PAH. However, the mechanisms underlying reduced NO bioavailability in PAH are not well understood. We hypothesized that impairment of TRPV4 channel function attenuates NO release in PAH. PAH was induced in mice using three‐week chronic hypoxia (CH) and Sugen 5416 + CH models. Mouse right ventricular pressures (RVP) were measured as an indicator of PAP. RVP was significantly higher in TRPV4−/− mice when compared to the control mice after three weeks of CH. High‐speed Ca2+ imaging was used to analyze TRPV4 sparklets in the native endothelium from resistance‐sized, fourth‐order PAs. Vascular diameter studies were performed on isolated, pressurized (15 mmHg), small PAs. Ca2+ imaging studies were also performed in PAs obtained from control and PAH patients. In CH and Sugen 5416 + CH models, TRPV4 sparklet activity and TRPV4 channel‐dependent vasodilation were significantly lower compared to normoxic control mice. However, TRPV4 mRNA expression and immunofluorescence were not altered in both mouse models of PAH, suggesting an impairment in the regulation of channel function rather than channel expression. TRPV4 sparklet activity was also consistently lower in PAs from PAH patients, when compared to control patients. Elevated levels of superoxide radicals have been shown to contribute to the development of PAH. Superoxides can react with NO to form peroxynitrite (PN). A PN scavenger, uric acid, restored TRPV4 channel activity in CH mice. We, therefore, hypothesized that PN‐induced impairment of TRPV4‐dependent Ca2+ signaling inhibits endothelial function in PAH. Indeed, PN attenuated TRPV4 sparklet activity in a reversible manner. Our results support the concept that PN‐induced regulation of TRPV4‐dependent Ca2+ signaling may contribute to the development of PAH. Moreover, altered TRPV4 channel activity may contribute to the reduced NO bioavailability in PAH.Support or Funding Information1R56HL138496, 5R00HL121484, 17PRE33660762This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.