bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tackling liver cancer by a novel combination between OSU‐2S and sorafenib
Authors: Omar Hany A. , Tolba Mai F. , Hung Jui‐Hsiang , Al‐Tel Taleb H. 
Published: November 2023

BackgroundSorafenib is an FDA‐approved systemic therapy for advanced hepatocellular carcinoma (HCC). However, the low efficacy and adverse effects at high doses limit the clinical application of sorafenib and strongly recommend its combination with other agents aiming at ameliorating its drawbacks. OSU‐2S, a PKCδ activator, was selected as a potential candidate anticancer agent to be combined with sorafenib to promote the anti‐cancer activity through synergistic interaction.MethodsThe antitumor effects of sorafenib, OSU‐2S and their combination were assessed by MTT assay, caspase activation, Western blotting, migration/invasion assays in four different HCC cell lines. The synergistic interactions were determined by Calcusyn analysis. PKCδ knockdown was used to elucidate the role of PKCδ activation as a mechanism for the synergy. The knockdown/over‐expression of p53 was used to explain the differential sensitivity of HCC cell lines to sorafenib and/or OSU‐2S.ResultsOSU‐2S synergistically enhanced the anti‐proliferative effects of sorafenib in the four used HCC cell lines with combination indices < 1. This effect was accompanied by parallel increases in caspase 3/7 activity, PARP cleavage, PKCδ activation and HCC cell migration/invasion. In addition, PKCδ knockdown abolished the synergy between sorafenib and OSU‐2S. Furthermore, p53 restoration in Hep3B cells through the over‐expression rendered them more sensitive to both agents while p53 knockdown from HepG2 cells increased their resistance to both agents.ConclusionsOSU‐2S augments the anti‐proliferative effect of sorafenib in HCC cell lines, in part, through the activation of PKCδ. The p53 status in HCC cells predicts their sensitivity towards both sorafenib and OSU‐2S. The proposed combination represents a therapeutically relevant approach that can lead to a new HCC therapeutic protocol.Support or Funding InformationThis study was funded by grant number AJF201424 from Al Jalila Foundation, United Arab Emirates.
Etrasimod, a Novel Sphingosine‐1‐Phosphate Receptor (S1PR1) Modulator, Lacks Functional Activity at S1P2 Receptors
Authors: Adams John W , Unett David J. , Chen Xiaohua , Gaidarov Ibragim 
Published: November 2023

The S1P1 receptor modulator FTY720 (Fingolimod), a prodrug that is phosphorylated in vivo, possesses potent immunomodulatory activities and has been approved for the treatment of multiple sclerosis. FTY720 phosphate also possesses functional activity at S1P3, 4, and 5 receptor subtypes but, until recently, was thought to lack activity at the S1P2 subtype. We sought to develop methods to reliably detect functional activity at S1PR2 and to investigate whether structurally diverse S1PR1 modulators, including Etrasimod (APD334) a novel S1P receptor modulator, possess activity at this receptor.FTY720 phosphate and a panel of S1P receptor modulators were evaluated for their abilities to interact with S1PR2 using a broad panel of functional assays. Treatment of an S1PR2 expressing cell line with FTY720 phosphate produced rapid and robust receptor internalization. As observed with the S1P1 receptor, internalization was sustained following compound wash‐out. A number of additional S1PR modulators were found to induce the same internalization, while Etrasimod was inactive. Unlike the natural ligand S1P, these modulators failed to recruit b‐arrestin to S1PR2. However, label free Dynamic Mass Redistribution assays (Corning®, Epic®) readily detected S1PR2 mediated agonist like functional responses. Pretreatment of S1PR2 expressing cells with these modulators significantly blunted subsequent responses of S1PR2 toward its natural ligand S1P and reversed S1P‐mediated inhibition of fibronectin‐induced migration in S1P2 receptor expressing HEK293 cells.These data demonstrate that, in addition to FTY720, a wide range of S1PR modulators can also modulate S1PR2 while Etrasimod lacked such activity. Dynamic Mass Redistribution and receptor internalization assays appear suitable for quickly assessing S1PR2 activity. While S1PR1 is a chemotactic receptor, our data support the prevailing view that S1PR2 is a chemorepellant receptor, through which S1P negatively regulates cell migration. S1PR2 also mediates the antiproliferative activity of S1P in normal and cancer cell lines. S1PR2 ablation has been shown to result in stimulation of tumor development and metastasis in various animal models of cancer. Our data suggest that some S1PR1 modulators may have a negative effect on signaling pathways involved in regulation of cancer cell growth and metastasis.Support or Funding InformationFunding: Arena Pharmaceuticals, Inc.
Peptide Ligand of the Epidermal Growth Factor Receptor for Sensitizing Lung Cancer Cells to Gefitinib
Authors: ALHamar Zahrah Ali , Andey Terrick 
Published: November 2023

BackgroundBy the end of 2016, 13.3% and 26.5% of new lung cancer diagnoses and deaths respectively is anticipated in the United States. Effective treatment of lung cancer is, however, hampered by adverse effects and the rapid acquisition of resistance to therapies. The epidermal growth factor receptor (EGFR) is an important lung cancer target. However, resistance to EGFR‐targeted therapies such as the receptor tyrosine kinase inhibitors, RTKIs (e.g. gefitinib) limits favorable long‐term therapeutic outcomes. The current study investigates the sensitization of EGFR‐expressing, gefitinib‐resistant lung cancer cells by the lung surfactant protein D (SPD).MethodsResazurin reduction‐based cell viability assay was performed to validate resistance to gefitinib in a panel of seven non‐small cell lung cancer (NSCLC) cells. Sensitization studies with single and combination treatments of SPD and geftinib were carried out in H1573 cells. The effect of SPD‐mediated H1573 sensitization to gefitinib on EGFR signaling examined by western blot.ResultsGefitinib inhibited lung cancer cell viability in HCC827, H661, A549, H460, H1299, H1975, and H1573 [IC50 = 0.06±0.01 μM, 4.82±0.77 μM, 5.44±0.16 μM, 5.88±1.02 μM, 7.38±0.75 μM, 7.65±0.58 μM, 23.61±2.21 μM respectively]. SPD (0.5 μg/mL) inhibited H1573 cell viability (43.78±1.72 %), and significantly sensitized the cells to 5.0 μM gefitinib (13.16±0.82 % cell viability). SPD and gefitinib mediated EGFR degradation (phospho‐EGFR Tyr 1045) and inhibited Ras signaling (phospho‐EGFR Tyr 1086) in H1573 cells.ConclusionThe lung surfactant protein D (SPD) was effective in sensitizing highly resistant H1573 cells to gefitinib treatment by inhibiting EGFR activating signaling. SPD may represent a viable candidate for adjunctive therapy in chemo‐refractory lung cancer overexpressing EGFR.
The role of p90 ribosomal S6 kinase in lung adenocarcinoma and as a mediator of the cytotoxic effects induced by cisplatin
Authors: Mraiche Fatima , Abdulrahman Nabeel 
Published: November 2023

p90 ribosomal S6 kinase (p90RSK) constitutes a family of serine/threonine kinases that have been shown to be involved in cell proliferation of various malignancies via direct or indirect effects on the cell‐cycle machinery. We investigated the role of p90RSK in lung adenocarcinomas and whether the inhibition of p90RSK diminishes cancer progression. Anti‐apoptotic and pro‐apoptotic markers including Bcl2 and Bax were measured by reverse transcription polymerase chain reaction. In addition, the A549 lung adenocarcinoma cell line was characterized for cell proliferation using the MTT assay and cell migration using the scratch migration assay. Our study revealed that total RSK1 protein expression is over expressed in the A549 human lung adenocarcinoma cell line, an effect which is significantly reduced upon pretreatment with BID (69.32 ± 12.41 % of control; P < 0.05). The inhibition of p90RSK also showed a significant suppression of cell proliferation (54.3 ± 6.73 % of control; P < 0.01) and cell migration (187.90 ± 16.10 % of control; P < 0.01). Treatment of the A549 cells with BID regressed the expression of Bcl2 mRNA (56.92 ± 6.07 % of control; P < 0.01). Clearly, p90RSK has an essential role in promoting tumor growth and proliferation in non‐small cell lung cancer (NSCLC). Cisplatin, one of the most widely used drug for NSCLC adjuvant chemotherapy, has been demonstrated to improve survival among patients with NSCLC. Unfortunately, the outcome of cisplatin therapy on NSCLC seems to have reached a plateau. To overcome the treatment plateau on NSCLC, the biological mechanisms of cisplatin action need to be understood. Interestingly, cisplatin decreased RSK1 expression in A549 cells. In addition, BID gave rise to enhanced cisplatin sensitivity as indicated by the decrease in gap closure. Our findings demonstrate that BID may serve as an alternative cancer treatment in NSCLC. In addition, RSK inhibition may increase the response of lung adenocarcinomas that have become resistant to platinum based chemotherapy.Support or Funding InformationThis work was supported by a Qatar University Internal Grant.
COMPARISON STUDY OF THE EFFECTS OF ZERUMBONE AND AG490 IN HUMAN RENAL CELL CARCINOMA ON THE ACTIVATION OF THE JANUS KINASE PATHWAY AND CELL SURVIVAL
Authors: Walker Zachary , Duncan Anthony , Bellomo Tiffany , Budd Kaitlin , Polina Aws , Hafron Jason , Banes‐Berceli Amy 
Published: November 2023

In the United States, Renal Cell Carcinoma (RCC) accounts for 9 out of 10 cases of kidney cancer. Approximately 33% of the patients present with metastatic disease and of those initially treated by surgical resection 40–50% will develop recurrent metastatic disease.13,860 people are estimated to die from RCC in 2016 due to poor responsiveness to the current chemotherapy medications. Development of new therapies is limited because the molecular mechanisms of RCC and the chemoresistance are poorly understood. However, we and others have shown that alterations in the levels of the Janus Kinase (JAK2) and Signal transducers of activators of transcription (STAT) pathway may be involved as it has been implicated in invasiveness and cell survival in RCC cell lines.We hypothesize that altered activation of the JAK/STAT/SHP‐1 pathway contributes to the development of RCC and the chemoresistance observed. To test this hypothesis we used the RCC cell line (ATCC) and we treated the cells for 24 hours with the JAK2 inhibitor AG490 and sunitinib (standard chemotherapy agent) alone and in combination. After 24 hrs we found a 20% decrease in cell viability in the AG490 treated cells but not in the sunitinib treated cells. Combination of AG490 and sunitinib for 24 hrs resulted in a 40% decrease in cell viability. We also treated cells for 24, and 48 hrs with AG490 to directly inhibit JAK2 and with zerumbone, an inducer of SHP‐1 activity, which will indirectly decrease JAK2 phosphorylation and activation. At 24 hrs we found significant decreases in JAK2 phosphorylation levels with both and almost undetectable levels by 48 hrs. The STAT1 and STAT3 levels were only decreased significantly after 48 hrs of treatment with both zerumbone and AG490. We also treated cells with these inhibitors and measured cell viability for 24, 48, 72 and 96 hrs. We found an 80% reduction in cell viability at 96 hrs of treatment with both the zerumbone and AG490. There data suggest that inhibition of JAK2 is a viable clinical target for future therapy as it enhanced the response to sunitinib as well as decreased cell viability on its own.Support or Funding InformationOakland University Center for Biomedical Research
Aryl Hydrocarbon Receptor/Cytochrome P4501 Pathway Mediates Breast Cancer Stem Cells Expansion through β‐Catenin/Akt Activation and Pten Inhibition
Authors: Al‐Dhfyan Abdullah O , Alhoshani Ali R. , Korashy Hesham M. 
Published: November 2023

Breast cancer stem cells (CSCs) are small sub‐type of the whole cancer cells that drive tumor initiation, progression and metastasis. Recent studies have demonstrated a role for the aryl hydrocarbon receptor (AhR)/cytochrome P4501 pathway in CSCs expansion. However, the exact molecular mechanisms remain unclear. Thus the current study was designed to determine the effect of AhR activation and inhibition on breast CSCs development, maintenance, self‐renewal, and chemoresistance and to explore the role of β‐catenin, PI3K/Akt, and Pten signaling pathways. To test this hypothesis, CSCc characteristics in three human breast cancer cells SKBR‐3, MCF‐7, and MDA‐MB‐231, treated with AhR activators or inhibitors were determined using Aldefluor assay, side population, and mammosphere formation. The mRNA and protein expression of the target genes were determined by RT‐PCR and Western blot analysis respectively. Our results showed that the constitutive mRNA expression and cellular content of CYP1A1 and CYP1B1 were markedly higher in CSCs more than differentiating non‐CSCs of the three different human breast cancer cells. Activation of AhR/CYP1 in MCF‐7 cells by TCDD and DMBA, strong AhR activators, significantly increased CSC‐specific markers, mammosphere formation, aldehyde dehydrogenase (ALDH) activity, and percentage of Side Population (SP) cells, whereas inactivation of AhR/CYP1A1 using chemical inhibitor, α‐naphthoflavone (α‐NF), or by genetic shRNA knockdown, significantly inhibited the upregulation of ALDH activity and SP cells. Importantly, inactivation of the AhR/CYP1 significantly increased sensitization of CSCs to the chemotherapeutic agent doxorubicin. Mechanistically, Induction of AhR/CYP1A1 by TCDD and DMBA was associated with significant increase in β‐catenin mRNA and protein expression, nuclear translocation and its downstream target Cyclin D1, whereas AhR or CYP1A1 knockdown using shRNA dramatically inhibited β‐catenin cellular content and nuclear translocation. This was associated with significant inhibition of PTEN, and induction of total and phosphorylated Akt protein expressions. Importantly, inhibition of PI3K/Akt pathway by LY294002 completely blocked the TCDD‐induced SP cells expansion. In conclusions, the present study provides the first evidence that AhR/CYP1A1 signaling pathway is controlling breast CSCs proliferation, development, self‐renewal and chemoresistance through activation of β‐catenin and Akt and inhibition of the Pten pathways.Support or Funding InformationNational Plan for Science, Technology and Innovation (MAARIFAH), King Abdulaziz City for Science and Technology, Kingdom of Saudi Arabia, Award Number (12‐MED3131‐02).
Functional Upregulation of STIM‐1/Orai‐1‐Mediated Store‐Operated Ca2+ Entry Contributing to the Aortic Remodeling and Hypertension Development by Chronic EtOH Consumption
Authors: Bomfim Guilherme Henrique Souza , Méndez‐López Iago , Arranz‐Tagarro Juan Alberto , Musial Diego Castro , Carbonel Adriana Aparecida Ferraz , Padín Juan Fernando , García Antonio García , Jurkiewicz Aron Aparecida Ferraz , Jurkiewicz Neide Hyppolito 
Published: November 2023

Chronic ethanol (EtOH) consumption has been associated with deleterious effects on the cardiovascular system by abnormal calcium (Ca2+) handling. Store‐operated Ca2+ entry (SOCE) is related to cardiovascular remodeling which leads to the hypertension development, and the coupling between STIM‐1 (Ca2+ sensor) and Orai‐1 (channel pore) is a key mechanism to control SOCE through of store‐operated Ca2+ channels (SOCCs). However, the role of STIM‐1/Orai‐1‐mediated SOCE and its cross‐talk with EtOH‐triggered vascular remodeling and hypertension remain poorly understood. We address this subject in the present study by evaluating how chronic EtOH consumption induces alterations in Ca2+ handling via SOCE. Male Wistar Kyoto (WKY) and Spontaneously Hypertensive (SHR) rats were subjected to the intake of increasing EtOH concentrations (5–20%, for 30 days). Systolic blood pressure (SBP) and EtOH concentration were measured; cardiovascular remodeling was assessed by histomorphometry; and function/expression of STIM‐1/Orai‐1‐mediated Ca2+ influx were evaluated by isometric contraction and western blot experiments. Compared to the WKY‐Control, our results show that: (1) chronic EtOH consumption caused a significant elevation of SBP in both strains; (2) cardiac hypertrophy and hypertrophic aortic wall remodeling much more pronounced in WKY‐EtOH; (3) decreased capacity of reticulum to store and release Ca2+; (4) increased STIM‐1/Orai‐1‐mediated SOCCs activation, which was selectively inhibited by YM‐58483; and (5) increased expression of STIM‐1 in WKY‐EtOH and SHR‐Control rats. These findings suggest that hypertension developed by EtOH consumption has as one of its origins the hypertrophic aortic remodeling and abnormal contraction triggered mainly by Ca2+ overload via STIM‐1/Orai‐1‐mediated SOCE through SOCCs.Support or Funding InformationThis work was supported by the Fundação Coordenação de Aperfeiçoamento de Pessoal de Nível Superior‐CAPES (BEX 8477/13‐2); the Fundação de Amparo a Pesquisa do Estado de São Paulo‐FAPESP (2014/01569‐0); the Ministerio de Economía y Competitividad, España (SAF: 2013‐44108‐P and FPI BES‐2014‐069005).
Dantrolene and Nimodipine Reduce Arterial Tone Synergistically in Aortic Rings from Type‐1 Diabetic Rats
Authors: Roman Marie , Alemar Stephanie , Matias Jonathan , Torres‐Grajales Manuel , Zack Richard , Morales Myrna , Torres Hector , Crespo Maria J. 
Published: November 2023

Diabetic patients have a high risk of developing cerebral vasospasms (CVSP). The current treatment of this condition is similar for diabetics and non‐diabetics, and includes the use of nimodipine and other calcium channel antagonists to reduce vasoconstriction. Concomitant administration of the ryanodine receptor (RyR) blocker dantrolene with these antagonists may be beneficial to diabetic patients, knowing that this combination reduces vasoconstriction in non‐diabetic patients. In this study, we evaluated the effects of dantrolene (50 μM), nimodipine (50 nM), and both drugs in combination, on the phenylephrine (PHE)‐induced contraction of aortic rings from streptozotocin (STZ)‐induced Type‐1 diabetic rats. Age‐matched non‐diabetic rats were used as controls (CT). PHE‐induced concentration response curves from 0.1 nM to 10 μM were performed on aortic rings in the presence and absence of dantrolene, nimodipine, or their combination. After a 30‐minute incubation period, the PHE‐induced contraction was reduced to the same percentages in diabetic and non‐diabetic rats by dantrolene (37 %; N=5, P<0.05) and nimodipine (about 50%; N=5, P<0.050). In contrast, the combination of these drugs reduced the PHE‐induced contraction by 81% in CT, but only by 69% in diabetic rats. In addition, endothelium‐independent relaxation with 10 μM sodium nitroprusside (SNP) was not affected by dantrolene or nimodipine in either diabetic or CT rats. Our results suggest that the combination of dantrolene and nimodipine may have beneficial effects in both diabetics and non‐diabetics with CVSP by decreasing arterial tone more than either drug alone. Supported by RCMI Grant G12‐RR03051.Support or Funding InformationSupported by RCMI Grant G12‐RR03051.
Novel RAGE Antagonist, FPS‐ZM1, Reverses Mesenteric Arteriolar Remodeling in Type 2 Diabetic db/db Mice.
Authors: Labazi Hicham , McCallinhart Patricia , Sunyecz Ian , Trask Aaron 
Published: November 2023

Type II diabetes (T2D) is a major risk factor for cardiovascular diseases. Recently, our laboratory established a differential effect of T2D on vascular remodeling that was dependent upon vessel size and location. In addition, our preliminary data showed an increase in circulating levels of advanced glycation end products (AGE) in T2D mice. Activation of AGE receptors (RAGE) was shown to be associated with vascular dysfunction and vascular smooth muscle proliferation, which may result in vascular remodeling. In the present study, we hypothesized that pharmacological RAGE blockade using a novel antagonist would reverse microvascular remodeling observed in T2D. Using a pressure myograph system, passive vascular mechanics were assessed in aortae and mesenteric arterioles (MA) isolated from 16 week‐old lean control mice (Db/db), obese T2D mice (db/db) and T2D mice (db/db+FPS) treated with RAGE antagonist (FPS‐ZM1, 1mg/Kg/day ip, 28 days). Body weight (BW) and fasting blood glucose (BG) were significantly increased in diabetic db/db compared to control Db/db mice (BW: 29.8±0.5 in Db/db vs. 47.3± 1.5 g db/db, p<0.05 and BG: 185 Db/db ± 13 vs 687 ± 20 mg/dL in db/db, p<0.05). FPS‐ZM‐1 treatment did not affect BW (46.3±1.5g) nor BG (679±17 mg/dL) in T2D mice. In aorta, neither diabetes nor RAGE antagonism in diabetic mice affected the macrovascular mechanical properties. In contrast, MAs isolated from T2D mice exhibited a significant increase in internal diameter (158±2 in Db/db vs. 208±13 μm in db/db at 100mmHg, p<0.05), external diameter (180±3 in Db/db vs. 233±14 μm in db/db at 100mmHg, p<0.05) and cross‐sectional area (CSA) (6066±597 in Db/db vs. 8753±881 μm2 in db/db at 100mmHg, p<0.05). RAGE antagonism in T2D significantly reduced MAs internal diameter (178±5 in db/db+FPS vs. 208±13 μm in db/db at 100mmHg, p<0.05), external diameter (200±5 in db/db+FPS vs. 233±14 μm in db/db at 100mmHg, p<0.05) and CSA (6453±400 in db/db+FPS vs. 8753±881 μm2 in db/db at 100mmHg, p<0.05). Together, our data showed a variation in macrovascular vs. microvascular remodeling in T2D as we have previously shown. Furthermore, our data suggest that AGE/RAGE signaling contributes to the microvascular remodeling observed in T2D and that RAGE blockade using a novel antagonist may present a potential therapeutic target to reduce or reverse diabetes‐mediated vascular complications.Support or Funding InformationR00 HL116769 and Nationwide Children's Hospital
Chronic Deep Vein Thrombosis: Pentadecapeptide BPC 157 Effect on Vein Thrombi
Authors: Siroglavic Marko , Vukojevic Jaksa , Drmic Domagoj , Tvrdeic Ante , Seiwerth Sven , Sikiric Predrag 
Published: November 2023

AimTo determine the effect of stable gastric pentadecapeptide BPC 157 on vein thrombi in deep vein thrombosis in rats.Materials and methodsFemale Wistar Albino rats (200g b.w.) underwent an inferior vena cava ligation according to deep vein thrombosis model in rodents. Control groups received 1ml of saline intraperitoneally immediately after surgery. Treated groups received either 1ml of 10μg/kg or 10ng/kg BPC 157 immediately after surgery, respectively. Both control and treated groups were sacrificed either on 4th or 7th day after surgery. Blood samples for platelet count were taken and phlebography was performed prior to sacrifice. After sacrifice vein thrombi were extracted, evaluated macroscopically for length assessment and weighed on a microgram weighing scale.ResultsControl groups on 4th and 7th day had larger thrombi (weight on 4th day 0.096±0.005g and on 7th day 0.064±0.002g, length on 4th day 1.93±0.43cm and on 7th day 1.74±0.35cm) than either BPC 157 10μg/kg groups (weight on 4th day 0.043±0.004g and on 7th day 0.032±0.003g, length on 4th day 1.05±0.14cm and on 7th day 0.87±0.07cm) or BPC 157 10ng/kg groups (weight on 4th day 0.063±0.009g and on 7th day 0.049±0.005g, length on 4th day 1.35±0.16cm and on 7th day 1.17±0.08cm) respectively (Figure 1, Figure 2). Platelet count in control groups on 4th (427±53×109/L) and 7th day (774±63×109/L) was lower than either BPC 157 10μg/kg groups (on 4th day 711±83×109/L and on 7th day 1153±103×109/L) or BPC 157 10ng/kg groups (on 4th day 595±75×109/L and on 7th day 1045±89×109/L). All shown differences were statistically significant (P<0.05).ConclusionsThis study has shown a significant beneficial effect of pentadecapeptide BPC 157 in both decrease of thrombi length and mass as well as reduction of thrombocytopenia after a thrombotic incident.Support or Funding InformationMinistry of Science, Education and Sports, Republic of Croatia (grant number 108‐1083570‐3635) University of Zagreb, Croatia (grant number BM099)