bluuebunny/crossref_metadata_2025_split huggingface dataset:
Stable Pentadecapeptide BPC 157 and Vesicovaginal Fistulas in Rats
Authors: Rasic Domagoj , Sever Marko , Sever Anita Zenko , Pavlov Katarina Horvat , Baric Marko , Drmic Domagoj , Blagaic Alenka Boban , Seiwerth Sven , Sikiric Predrag 
Published: June 2021

AimFrequently, large vesicovaginal fistulas need operation treatment. Stable gastric pentadecapeptide BPC 157, tested in clinical trials for ulcerative colitis therapy and now multiple sclerosis (Curr Pharm Des. 2017;23(27):4012–4028; Curr Pharm Des. 2014;20(7):1126–35; Curr Pharm Des. 2010;16(10):1224–34), already resolved the healing of various fistulas (Eur J Pharmacol. 2016 Jun 5;780:1–7; Life Sci. 2016 Mar 1;148:63–70; J Physiol Pharmacol. 2015 Aug;66(4):581–90; Eur J Pharmacol. 2013 Feb 15;701(1–3):203–12; J Pharmacol Sci. 2008 Sep;108(1):7–17; Dig Dis Sci. 2009 Jan;54(1):46–56). Thus, BPC 157 may be a successful therapy of vesicovaginal fistulas in rats.MethodsVesicovaginal fistulas were created in Wistar rats. The vesicovaginal fistula was surgically created (4mm length between posterior wall of the urinary bladder and anterior vaginal wall ). Medication. Pentadecapaptide BPC 157 (10 μg/kg/day, 10ng/kg/day) was given intraperitoneally (5 ml/kg) or in drinking water (0.16 μg/ml, 0.16 ng/ml, 12 ml/rat/day) while controls received equivolume of saline or drinking water only. Assessment (the pressure required for leakage of fluid through fistula (mLH2O), diameter of the fistula defects (mm) (bladder, vaginal side), macro/microscopical evaluation, urinary stone presentation) was 1, 2, 3, 4, and 6 weeks. Prophylactic regimen. Medication was started immediately after fistulas creation. Therapy regimen. Medication was initiated with already advanced fistula formation, after 2 weeks.ResultsUnlike poor healing in controls, BPC 157 reduced fistulas diameters (7th day) leading to the complete closure at 46th day and considerable volume needed to leakage of fluid through fistula (V: 5.3+/−0.3 mL). Finally, the fistula was successfully healed and microscopically confirmed in BPC 157 rats (day 46, 0+/−0 mm (diameter, bladder/vagina), unlike open defects in controls: 3.1+/−0.6 (mm, bladder), 3.3+/−0.8 (mm, vagina)) diameter and small volume sustained before leakage (V: 1.2+/−0.4 mL, day 14). In posttreatment BPC 157 group we noticed reducing of fistula diameter since a first posttreatment week ( con 3.8 +/−0.2 mm, BPC 157 3.1 +/−0.1 mm) leading to fistula closing during the 4th posttreatment week. In all control animals, we noticed urinary bladder stone creation which was absent in BPC 157 animals. In posttreatment animals, BPC 157 (therapy regimen) stopped further urinary stone creation.ConclusionPentadecapeptide BPC 157 improved vesicovaginal fistula healing, and it could be the pharmacological solution for the complex clinical problem of vesicovaginal fistulas healing. Vesicovaginal fistula could be used as a urinary stone animal model. BPC157 reduces urinary stone creation.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Effects of FXR Deficiency in Acute Phase Response After Bacterial Infection
Authors: Chung Sammi , Armstrong Laura , Kong Bo , Guo Grace L. 
Published: June 2021

Farnesoid X receptor (FXR) is a ligand‐activated nuclear receptor and a transcription factor, regulating bile acid synthesis and transport. FXR is highly expressed in the liver, and more recently FXR has been shown to play a key role in modulating inflammation. Studies have shown that FXR, when activated, acts as a protective agent against liver inflammation and potentially liver diseases such as nonalcoholic steatohepatitis, a part of fatty liver disease. Furthermore, FXR may regulate acute phase proteins, which are secreted as a result of acute phase response (APR)—a systemic reaction that is important for innate immunity and is caused by infection, trauma, or tissue injury. However, the exact mechanism is not well‐established. Thus, the purpose of this study was to investigate the role of FXR in the regulation of the hepatic APR using a bacterial infection model. To understand the mechanism and the effects, hepatocyte‐specific FXR knockout mice (FXRhep −/−) and wild‐type control mice (WT) were injected with Escherichia coli (E. coli) intraperitoneally. Serum, liver, and spleen were isolated 24 hrs following bacterial exposure, and in vivo bacterial counts were determined in whole blood, liver, and spleen. Gene expression of inflammatory cytokines (Tnfα, Il‐1β, Il‐6,) and acute phase proteins (LCN2, Mcp‐1, and Saa3) were measured using quantitative PCR (qPCR) in both liver and spleen. Compared to WT mice, FXRhep −/− mice had significantly increased bacterial load in the liver and spleen following the E.coli treatment, suggesting that they were more susceptible to bacterial infection; however, there was no significant increase in bacterial load in the blood. Serum activities of ALT and AST in FXRhep −/− mice were also elevated, indicating increased liver damage after E.coli treatment. In addition, following the E.coli treatment, gene expression showed a diminished induction of acute phase proteins, Mcp‐1 and Saa3, along with cytokines IL‐1β, IL‐6, and Tnfα in FXRhep −/− mice compared to WT mice. Furthermore, this infection resulted in high levels of LCN2 induction for both the WT and FXRhep −/− mice. In conclusion, the study demonstrates that FXR might be a putative regulator of hepatic acute phase proteins.Support or Funding InformationR25ES020721, R01GM104037 and ASPET SURF Intern ProgramThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Characterization and Evaluation of Sunitinib and Janus Kinase Inhibitors in a Renal Cell Carcinoma Cell Line, Caki‐2
Authors: Budd Kaitlin Mary , Hege Katie , LePage Bernie , Walker Zachary , Wilson George , Hafron Jason , Banes‐Berceli Amy 
Published: June 2021

Kidney cancer is one of the leading cancers detected in middle‐aged men and women. The clear‐cell form of renal cell carcinoma (RCC) is the deadliest form of urogenital cancer; 5‐year prognosis once metastasis has occurred is only 5%. The main challenge of RCC diagnosis is that most symptoms of kidney cancer only appear after it has advanced to metastasis, the most common subtype being clear cell renal carcinoma (ccRCC). At this point, the cancer may have already gained resistance to current treatments. One intracellular signaling pathway, the Janus kinase 2 and signal transducers and activator of transcription 1 and 3 (JAK2/STAT1&3) pathway, has already been implicated in multiple other cancers and is involved in perpetuating many hallmarks of cancer including evasion of apoptosis, angiogenesis, tissue invasion, and metastasis. Microtubule associated protein 7 (MAP7) is a protein involved in tubulin and microtubule stability. High MAP7 expression has been correlated with poor prognosis in colon cancer. Additionally, MAP7 has been shown to be involved in chemo resistance via a STAT1 mechanism. Therefore, we hypothesized that increased MAP7 expression via increased JAK/STAT signaling is a cause of increased chemo resistance and cell proliferation in RCC. Therefore, inhibition of this pathway should increase efficacy of current chemotherapies. Available drugs demonstrate different molecular and physical reactions in RCC cells such as those that effect the cancer promoting unregulated JAK/STAT pathway. MTT analysis of the commercial ccRCC cell line, Caki‐2, with a current chemotherapy drug, sunitinib, shows increased cell viability prior to reaching its EC50 value at 24, 48, and 72 hours of 30 uM, 16.5 uM, and 12 uM, respectively, suggesting therapy resistant mechanisms are taking place. When the known JAK inhibitor Zerumbone was evaluated in Caki‐2 via MTT analysis, EC50 values were 175 uM, 32 uM, and 15 uM at 24, 48, and 72 hours, respectively, with increased cell viability observed only in the 24 hour assay. When these two drugs are used in combination with Caki‐2, MTT data suggests resistance to sunitinib and zerumbone exists in Caki‐2 and co‐treatment aided the ability to decrease cell viability by sunitinib, but not Zerumbone. Based on these results, more studies must be completed to determine whether the inhibition of JAK would be a viable and effective option in treatment of RCC. However, preliminary evaluation of Zerumbone in combination with sunitinib has not proven to be effective.Support or Funding InformationOakland University Center For Biomedical Research, Zafarna Grant, Oakland University Honors CollegeThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
K145, a sphingosine kinase 2 inhibitor, inhibits solitary plasmacytoma cell growth
Authors: Li Jessica , Li Xiao Jiaoyang , Zhao Derrick , Wang Xuan , Liu Runping 
Published: June 2021

Solitary plasmacytoma (SP) is a rare disease. It is characterized by a localized proliferation of neoplastic monoclonal plasma cells either in the bone (solitary bone plasmacytoma, SBP) or in soft tissue (solitary extramedullary plasmacytoma, SEP). The prognosis of SBP is poorer than SEP due to its higher rate of progression to multiple myeloma (MM). There is no uniform consensus regarding the disease prognosis and treatment due to a very limited understanding of the disease pathophysiology. Sphingosine 1‐phosphate (S1P) has been identified as an important signaling molecule promoting various cancer cell growth. S1P is synthesized by two protein kinases, sphingosine kinase 1 and 2 (SphK1 and SphK2, in cytosol and nuclear respectively). Extensive studies have been done with SphK1 in various cancer cells. However, the contribution of SphK2‐mediated signaling in cancer cell growth remains largely unknown, especially in SP. The current study is aimed to examine the expression of SphK2 in SP cells and further define the role of SphK2 in cell growth.MethodsStudies were conducted in the human SP cell lines, AMO‐1, NCI‐H929 and RPMI8226. The expression of SphK1 and Sphk2 was determined by real‐time RT‐PCR and Western blot analysis and confirmed by DNA sequencing. The SphK2 inhibitor, K145, and gene‐specific shRNA were used to inhibit SphK2 activation and expression. Cell proliferation was determined using a CCK‐8 kit. Cell apoptosis was analyzed by Annexin V‐FITC/PI staining followed by flow cytometry.ResultsThe expression level of SphK2 in all tested SP cell lines was significantly higher than SphK1. S1P significantly induced cell proliferation, migration and invasion of SP cells, which was inhibited by K145 as well as gene specific shRNA targeting SphK2. AMO‐1 has the highest SphK2 expression level among all three tested cell lines both at the mRNA and protein levels. The SphK2 expression level is correlated to invasiveness of SP cell growth and inversely related to the sensitivity to K145‐induced apoptosis.Discussion/ConclusionSphK1 and SphK2 are all expressed in human SP cancer cells. However, SphK2 expression level is much higher than SphK1. In this study, by using a chemical inhibitor and gene‐specific shRNA, we were able to show that SphK2 plays a critical role in SP cell growth. Due to the limited efficacy of conventional chemotherapy, there is an urgent need to develop new therapeutics. The results in this study suggest that targeting SphK2 may represent a novel therapy for SP.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
A potent and selective allosteric PTP4A3 phosphatase inhibitor enhances microvascular barrier function and inhibits human tumor cell growth.
Authors: Lazo John Stephen , McQueeney Kelley E. , Salamoun Joseph M. , Barabutis Nektarios , Catravas John D. , Wipf Peter 
Published: June 2021

The metastasis‐associated protein tyrosine phosphatase PTP4A3 is highly expressed in both tumor and endothelial cells. Deletion of the Ptp4a3 gene results in tumors with a decreased vascularity. PTP4A phosphatases appear to regulate several key malignant processes, such as invasion, migration, and angiogenesis, suggesting a pivotal regulatory role in cancer and endothelial signaling pathways. We have identified a potent, selective, reversible, and noncompetitive PTP4A3 inhibitor, 7‐imino‐2‐phenylthieno[3,2‐c]pyridine‐4,6(5H,7H)‐dione or JMS‐053, which markedly enhanced microvascular barrier function after exposure of endothelial cells to vascular endothelial growth factor or lipopolysaccharide. JMS‐053 also blocked the concomitant increase in RhoA activation and loss of Rac1. In human cancer cells, JMS‐053 impeded migration, disrupted spheroid growth, and decreased RhoA activity. These data demonstrate that PTP4A3 phosphatase can be targeted in both endothelial and ovarian cancer cells, and further confirm that RhoA signaling cascades are regulated by the PTP4A3.Support or Funding InformationThe work was supported by grants from the National Institutes of Health (R21 CA191944, R01 CA207288, S10 OD021723, and F31 CA196062), the Fiske Drug Discovery Fund, the Owens Foundation, 4‐VA Collaborative Research Grant, the Cure Alzheimer's Fund, and the Ivy Foundation.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Development of inhibitors for activated Cdc42‐associated kinase (ACK) to reverse v‐Ras‐induced cancerous phenotype of mammalian cells
Authors: Shepherd Jaleel , Nur‐E‐Kamal Alam , Ahmed Ijaz 
Published: June 2021

The superfamily of Ras GTPase has been reported to control different aspects of mammalian cell growth. Our lab demonstrated a possible role of Ras‐Cdc42‐ACK signaling in the survival of v‐Ras‐transformed cells. We also found that ACK‐deficient v‐Ras transformed NIH 3T3 cells undergo apoptosis while the parental NIH 3T3 cells grow normally. We proposed a hypothesis that “ACK‐induced phosphorylation plays a critical role in the survival of Ras‐induced transformed cells”. Based on three‐dimensional structure of ACK, our lab in collaboration with other group screens chemicals to identify potential specific inhibitors for ACK. In this report, I will present computer aided screening protocol and the effect of these inhibitors on growth of v‐Ras‐induced transformed and parental NIH 3T3 cells. I have used software to screen and identify potential inhibitors for ACK. These inhibitors were then used to treat v‐Ras transformed and parental NIH 3T3 cells. The cell growth was monitored by MTT assay. I have further studied the effect of these inhibitors on gene expression using immunostaining, immunoblotting, and polymerase chain reaction. I have identified some compounds that have strong affinity for ACK and inhibit growth of v‐Ras transformed cells. Treatment of v‐Ras cells with these inhibitors was found to activate apoptosis. I have used several markers of apoptosis. These results will be described in this report. We are designing novel compounds with more specific binding to ACK. Development of specific ACK inhibitors will be useful in better understanding the role of ACK in the growth of normal and cancer cells.Support or Funding InformationNIH‐RISEThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Endothelial Dysfunction as a result of Hypercaloric Intake: Underlying Mechanism in Absence of Hyperglycemia
Authors: Alaaeddine Rana , El‐khateeb Mohamed , Saad Evan I. , Fouad Hosny H. , El‐Sabban Marwan , Plane Frances , El‐Yazbi Ahmed F. 
Published: June 2021

Endothelial dysfunction is a common occurrence in diabetes, secondary to hyperglycemia. However, little is known about the mechanism underlying the early endothelial damage occurring in the course of diabetes development prior to impaired glycemic control. We used a high‐calorie (HC) diet rat model with delayed development of hyperglycemia to address this question. Aortic rings from HC rats exhibited impaired endothelium‐dependent relaxation of phenylephrine (PE)‐induced tone to acetylcholine (ACh), where higher concentrations of ACh caused an increase in contractile tone. On the other hand, similar relaxation patterns to the exogenous nitric oxide (NO) donor, sodium nitroprusside, were observed indicating that the defect is endothelial in origin. Hence, the possible role of an endothelium‐derived contractile agent, such as endothelin‐1 and 20‐HETE, or an increased production of reactive oxygen species due to uncoupling of endothelial NO synthase, as the basis of increased tone caused by higher ACh concentrations was ruled out. In aortic rings from control rats, endothelium‐dependent relaxation to ACh was comprised of a major NO component with a lesser contribution from inward rectifier potassium channel (Kir)‐dependent mechanisms, particularly at higher ACh concentrations. While both components of the response were affected, HC‐feeding appears to abolish the Kir‐dependent pathway completely. Protein levels of Kir 2.1 subunit were down‐regulated in aortic tissues from HC‐fed rats. Using U‐46619, a thromboxane analogue, to evoke contraction involving calcium sensitization, rather than depolarization, aortic rings from control rats demonstrated a NO‐dependent, hyperpolarization‐independent pattern of relaxation in response to ACh. Despite a slightly more blunted response to ACh, HC rings pre‐contracted with U‐46619 did not show the terminal contraction observed in tissues contracted with PE. These results potentially implicate impaired myoendothelial coupling as the underlying mechanism for endothelial dysfunction in diabetes. Further examination of the role and expression of gap junctions in these tissues in under way.Support or Funding InformationSupported by AUB MPP fund #320148This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Effects of Resveratrol on Contractions of the Rat Tail Artery: Role of the Endothelium
Authors: Peuler Jacob D. , VanAntwerp Ian R. , Phelps Laura E. 
Published: June 2021

Our aims were to determine 1) if chemical removal of the endothelium from rat tail arterial tissue was less likely than mechanical removal to compromise long‐term stability of phenylephrine (PE)‐induced contractions of the smooth muscle, and 2) if resveratrol's previously reported abilities to initially transiently enhance and then produce sustained relaxation of such PE‐induced contractions were dependent on the presence of intact endothelium. We found no indication that chemical removal with saponin was more likely than mechanical removal to compromise PE stability, and saponin perfusion was significantly better in regards to the degree of endothelium removal. We also found that after removal of the endothelium using saponin, resveratrol transiently enhanced PE‐induced contractions (average peak time of 8–9 minutes) and then produced sustained relaxations (at the end of 2 hours) in all tissues and to the same degree as observed for all endothelium‐intact tissues. This suggests that endothelium‐independent mechanisms are responsible for resveratrol's initial contraction‐enhancing and sustained relaxing actions. We also discovered a significant correlation between both actions for both endothelium‐intact and endothelium‐removed rings alike such that with greater initial contraction‐enhancing action there is less of the sustained relaxing action. This suggests that the mechanism responsible for resveratrol's contraction‐enhancing action may not be transient at all (even though the action itself is), but rather present over the full duration in which sustained relaxation occurs. Thus, this enhancing mechanism could potentially limit the long‐term ability of resveratrol to lower arterial pressures by way of its relaxing mechanism.Support or Funding InformationBiomedical Sciences Program of Midwestern UniversityThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
New Fossil Discoveries from the Miocene Santa Cruz Formation of Argentina
Authors: Perry Jonathan Marcus Glen , Toledo Néstor 
Published: June 2021

The Miocene Santa Cruz Formation of Patagonian Argentina yields well preserved skeletons of many groups of mammals, notably platyrrhine primates and sloths – groups known today from only tropical/subtropical environments and occupying purely arboreal niches. The classic high latitude (51 degrees South) Patagonian localities of this formation have been worked by many paleontologists for more than a century. Our project shifts the emphasis from the classical localities of the Lower Member (ELCm) to the comparatively less studied Upper Member (ELAm) farther south. The ELAm was originally reconstructed as a cooler, drier, and more open‐woodland environment. This paleoecological reconstruction is at odds with recent radiometric dates placing the Mid Miocene Climatic Optimum within the ELAm; the new dates imply that the ELAm was generally warmer and wetter than the ELCm. Our recent field expedition focused on three known localities of the ELAm. One of these (Monte Tigre) yielded abundant mammalian remains, including a diverse assemblage of sloths some of which appear to have been semi‐arboreal. There we also collected the first plant macrofossils known from the ELAm (mostly Nothofagus leaf impressions). Another locality (Cañadon Palos) yielded abundant small mammal remains, including the rare marsupial Abderites. The third locality (Cabo Buen Tiempo) yielded sporadic small mammal fossils (mainly rodents and small armadillos) from a tuffaceous sediment. Future work at these localities will include 1. stratigraphic correlation across 25 kilometers of beach cliffs and shelf, 2. continued fossil collecting at the known ELAm localities, 3. prospecting for new ELAm localities, and 4. paleobiological comparisons between ELAm and ELCm mammals focusing on primates and sloths. New fossils from other vertebrate groups and plant remains will permit a richer paleoecological reconstruction of the ELAm than was previously possible.Support or Funding InformationGenerous support for this study was provided by an American Association of Anatomists Fellows Grant to J. Perry.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.