bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effects of Resveratrol in CXCR4 Expression and Apoptotic Markers in Normal Cell Lines Derived from a Breast Cancer Patient
Authors: Arroyo Gerardo Antonio , Figueroa Maria , Muñoz‐Forti Kevin , Maldonado Alexandra , Torres Bryan , Bernard Faviola , Almodovar Sharilyn , Suarez Edu , Ruiz Abigail 
Published: November 2023

The cellular and molecular environment of normal cells from breast cancer patients are particulary understood. Chemokines and their receptors have roles in cellular proliferation, metastasis, and angiogenesis. Specifically, CXCR4, a G‐protein coupled receptor is expressed in high levels in breast neoplastic tissues and in low levels in normal breast tissue. CXCR4 expression may induce proliferation, migration, invasion and angiogenesis. Recent studies have identify resveratrol (a natural polyphenol) to play a role on inflammation, apoptosis, and neovascularization. Due to limited scientific literature on the effects of resveratrol on CXCR4, the biological process in which both coincide, (inflammation, apoptosis, and neovascularization), and the potential use of resveratrol, as a therapeutic agent in cancer, we studied the effect of this polyphenol on CXCR4. In addition, we explored the effects on the apoptosis mediator Bax. We hypothesized that resveratrol increases the expression of CXCR4 in normal cells from a breast cancer patient. We determined the effects of resveratrol at concentrations of 25, 50, 100, 200 μM after 24 hours of treatment in the protein levels of CXCR4 and Bax‐2 by western blot using CCD1097 a fibroblastic cell line, derived from normal skin from the breast of a patient undergoing biopsy of a grade III infiltrating ductal carcinoma. Our preliminary results indicate that higher doses increased expression of CXCR4 in a dose‐dependent compared to control vehicle treated cells. Similarly, Bax expression increased in all treated cells but in a non‐dependent dose manner. These results may suggest that resveratrol have an effect on CXCR4 protein levels, leading to an increase in proliferation in normal cells from cancer patients. As reported, at lower doses resveratrol may have antiapoptotic effects and at higher doses may induce apoptosis. Resveratrol may prompt for clearance of cancer cells using different pathways but additional experiments will be necessary to identify the exact mechanism of action. Additional experiments are underway to identify the proliferative effects of resveratrol including apoptosis (caspases) and inflammation (TNF‐α and SOD‐2).Support or Funding InformationThis work was supported by UPR PRISE Program NIH Grant #R25GM096955.
Discovery of Potent GOAT inhibitors to Elucidate the In Vivo and In Vitro Mechanism Of Action of GOAT
Authors: Yang HsiuChiung , Chen Yanyun , Reynolds Nichole A , Mosior Marian K , Brier Richard A , Hembre Erik J 
Published: November 2023

Ghrelin (AG) is the only known orexigenic peptide in human and rodents. It is converted from its precursor, unacylated ghrelin (UAG), to the biologically active peptide, acylghrelin. Two independent groups (Yang et al., 2008; Gutierrez et al 2009) using different approaches identified the same protein, Ghrelin O‐Acyl Transferase (GOAT), as the long sought enzyme which is responsible for the bioactivation of ghrelin peptide. Results from GOAT gene knockout mice confirmed that GOAT is the principal enzyme responsible for the acylation of ghrelin. ( Zhao et al 2010)To enable the discovery of GOAT inhibitors, we have developed GOAT enzymatic and cellular assays. Using these assays, we have discovered potent GOAT inhibitors. In rodent models, these inhibitors exhibited similar effects on the acylated ghrelin and unacylated ghrelin to that observed in the GOAT gene knockout mice. In addition, we utilized GOAT inhibitors to elucidate the detailed molecular mechanism of the GOAT enzymatic reaction, which involves two substrates, c‐CoA. These pharmacological agents also allowed us to build an in vivo ghrelin processing model. The ghrelin processing model provided us with important insights to answer key questions regarding ghrelin metabolism and regulation in vivo.
Combretastatin augments the anticancer effect of vincristine either in vivo or in vitro
Authors: El‐Moselhy Mohamed Ahmed , Aboubakr Esam Mohamed , Ali Omar Mohamed , Taye Ashraf 
Published: November 2023

Hepatocellular carcinoma (HCC) is a serious healthcare problem worldwide especially in the Middle East because of its increasing morbidity and mortality.AimThe present study was conducted both in vivo and in vitro to investigate the anti‐cancer effect of combretastatin either alone or in combination with vincristine and the mechanisms underlying this effect.MethodsIn vivo study: a total 50 Wister albino rats were divided into five groups 10 rats for each, first group was i.p injected with normal saline and used as a normal groups. The other four group were injected i.p with 200mg/kg DENA. Two weeks later animals were orally administered 3ml/kg CCl4 once a week for 8 successive weeks. At the end of 8th week animals were divided into the following groups: Normal group, control group (hepatocellular carcinoma induced), combretastatin (200mg/kg) i.p treated group, combretastatin (100 mg/kg) i.p + vincristine (25 mg/kg) i.p treated group and vincristine (50 mg/kg) i.p treated group. The following parameters were assessed GSH, MDA, AFP, ALT, AST, tissue carbonyl content, number of hepatic nodules, histopathological examination of the hepatic tissue, tubulin inhibition in the hepatic tissue and the relative hepatic weight. In vitro study human hepatocarcinoma cell line (HepG2) were used to evaluate the cytotoxic and tubulin protein inhibitory effects of the tested drugs.ResultsThe results of the in vivo study revealed that combretastatin, combretastatin + vincristine and vincristine groups showed a significant decrease in GSH, AFP, number of hepatic nodules, ALT, AST and tubulin concentration in the hepatic tissue compare to the control group.Moreover the co‐administration of combretastatin with vincristine showed a significant increment in these parameters compared to single administration of combretastatin or vincristine, also MDA concentration and tissue carbonyl content concentrations were significantly increased compared to control group. On the other hand tubulin concentration and the relative hepatic weight were significantly less than control group. Also the results of the in vitro study revealed that both combretastatin and vincristine showed significant cytotoxic and tubulin inhibitory effects, while these effects were significantly enhanced by simultaneous administration of both drugs.Conclusioncombretastatin showed a promising anticancer activity against hepatocellular carcinoma by three mechanisms; tubulin inhibition leading to hepatic tumor blood supply shutdown, decrease reduced glutathione concentrations and oxidative stress generation. Furthermore these effects were greatly enhanced by co‐administration with vincristine.Moreover the present study suggests that we can greatly enhance the anti‐cancer activity of narrow therapeutic windows drugs such as vincristine by co‐administration with combretatstatin leading to fewer side effects.
Investigation of the regulatory effects of saccharin on cytochrome P450s in male ICR mice
Authors: Jo Jun Hyeon , Kim Sun Joo , Lee Sangkyu 
Published: November 2023

Saccharin, the first artificial sweetener, was discovered in 1879. Saccharin does not have any calories and is approximately 200–700 times sweeter than sugar. Saccharin was the most common domestically produced sweetener in Korea in 2010, and it has been used as an alternative to sugar in many products. The interaction between artificial sweeteners and drugs may affect the drug metabolism in patients with diabetes, cancer, and liver damage, this interaction has not been clarified thus far. Here, we examined the effects of the potential saccharin‐drug interaction on the activities of 5 cytochrome P450 (CYPs) in male ICR mice; further, we examined the effects of saccharin (4,000 mg/kg) on the pharmacokinetics of bupropion after pretreatment of mice with saccharin for 7 days and after concomitant administration of bupropion and saccharin. Our results showed that compared to control, saccharin did not have a significant effect on the 5 CYPs in the S9 fractions obtained from the liver of male ICR mice. In addition, we observed no differences in the pharmacokinetic parameters of bupropion between the control group and the groups pretreated with saccharin and that receiving concomitant administration of saccharin. Thus, our results showed that saccharin is safe and the risk of saccharin‐drug interaction is very low.Support or Funding InformationThe National Research Foundation of Korea (NRF) grant funded by the Korea government (Ministry of Science, ICT and Future Planning) (No. NRF‐2014M3A9D9069714).
Lactucopicrin suppresses oxidative stress initiated by scopolamine‐induced neurotoxicity through activation of NRF2 pathway
Authors: Subedi Lalita , Venkatesan Ramu , Park Yong Un , Kim Sun Yeou 
Published: November 2023

The cholinergic antagonist scopolamine induced dementia with impairment of memory and cognitive functions, as seen in Alzheimer's disease (AD). This scopolamine‐induced AD model has been used worldwide to understand, identify, and characterize beneficial therapeutic targets. The present study initiate to investigate the molecular mechanisms underlying scopolamine‐induced cholinergic neuronal dysfunction and the neuroprotective effect of lactucopicrin, an inhibitor of acetylcholine esterase. We focused on apoptotic cell death, caspase activation, reactive oxygen species (ROS) generation, mitochondrial dysfunction, and the expressions of anti‐ and pro‐apoptotic proteins in C6 cells. We also analyzed the expression of antioxidant enzymes and their transcription factor nuclear factor (erythroid‐derived 2)‐like 2 (NRF2) in C6 cells, along with neurite outgrowth in N2a neuroblastoma cells. Our results revealed that scopolamine pre‐treated for 1 h induce cytotoxicity by increasing apoptotic cell death via oxidative stress‐mediated caspase 3 activation and mitochondrial dysfunction. Scopolamine also downregulated the expression of antioxidant enzymes, such as superoxide dismutase, glutathione peroxidase, and catalase, and NRF2 expression. Lactucopicrin treatment protected C6 cells from the scopolamine‐induced toxicity by reversing the effects on these toxicity markers. In addition, scopolamine attenuated the secretion of neurotrophic nerve growth factor (NGF) in C6 cells and neurite outgrowth in N2a cells. As expected, lactucopicrin enhanced NGF secretion and neurite outgrowth in these neuronal cells. Our study suggests that first report about lactucopicrin, a potential neuroprotective candidate, ameliorating scopolamine‐induced cholinergic dysfunction via NRF2 activation and subsequent expression of antioxidant enzymesSupport or Funding InformationThis research was supported by the Bio & Medical Technology Development Program of the NRF funded by the Korean government, MSIP (NRF‐2014M3A9B6069338)
Stapled B chain analogues of relaxin‐3 retain biological activity
Authors: Dawe Gavin Stewart , Jayakody Tharindunee , Mawari Subhi 
Published: November 2023

Relaxin‐3, the most recently discovered member of the relaxin/insulin‐like family of peptides, is involved in regulating stress and anxiety, feeding, metabolism and cognition. Mature relaxin‐3 consists of two peptide chains (A and B) held together by disulphide bonds. Structure activity relationship studies have revealed that the relaxin‐3 B chain is more important in binding and activating the cognate receptor of relaxin‐3, relaxin/insulin‐like family peptide receptor 3 (RXFP3), than the A chain. Stapling renders peptide drugs less prone to proteolysis and can increase activity by locking the peptide conformation. We synthesized stapled B chains of relaxin‐3, hypothesizing that stapling mimics the function of the A chain in stabilizing the B chain and does not compromise activation of RXFP3. Relaxin‐3 B chain was stapled at the 14th and 18th positions or the 18th and 22nd positions by i and i+4 ring‐closing metathesis hydrocarbon stapling. In order to determine RXFP3 activation, we tested the peptides for cAMP inhibition and ERK1/2 activation. Both peptides significantly activated RXFP3 as observed in the inhibition of forskolin induced cAMP assay and ERK1/2 activation assay. We conclude that stapling of the relaxin‐3 B chain does not prevent its ability to activate RXFP3. Stapling of the relaxin‐3 B chain holds promise for development of stable peptide agonists and antagonists of RXFP3 to aid relaxin‐3/RXFP3 research.Support or Funding InformationThis work was supported by the Biomedical Research Council of Singapore (BMRC 10/1/21/19/645), the National Medical Research Council of Singapore (NMRC/1287/2011) and the Ministry of Education, Singapore, Academic Research Fund Tier 1 Seed Fund for Basic Science Research (T1‐BSRG 2014‐03).
G protein‐coupled Receptor 30 (GPR30) PDZ‐dependently and Constitutively Increases ERK1/2 Signaling Through Calcineurin and Kinase Suppressor of Ras 2 (KSR2)
Authors: Olde Bjorn , de Valdivia Ernesto Gonzalez , Broselid Stefan , Kahn Robin , Leeb‐Lundberg Lars M. F. 
Published: November 2023

The objective of the present study was to map the mechanism whereby G protein‐coupled receptor 30 (GPR30), also called G protein‐coupled estrogen receptor (GPER), stimulates extracellular signal‐regulated kinase (ERK)1/2 signaling. GPR30 plays important roles in cancer and cardiometabolic regulation. We showed recently that GPR30 forms a plasma membrane complex through its C‐terminal type I PSD‐95/Discs‐large/ZO‐1 homology (PDZ) motif with a membrane‐associated guanylate kinase (MAGUK) and protein kinase A (PKA)‐anchoring protein 5 (AKAP5), and AKAP5‐anchored PKA regulatory subunit RII suppresses receptor endocytosis and enables the receptor to constitutively inhibit cAMP production. Here, we investigated if this PDZ‐dependent GPR30 complex also regulates ERK1/2 signaling. To do so, human and mouse GPR30 were ectopically expressed in HEK293 cells and MDCK cells, and receptors and effectors were monitored by immunoblotting, immunoprecipitation, confocal immunofluorescence microscopy, split luciferase reporter techniques, and reporter gene assays. We found that GPR30 constitutively increased extracellular signal‐regulated kinase (ERK) 1/2 activity in several cell systems. The response was dependent on an intact receptor PDZ motif. Furthermore, knocking down AKAP5 or inhibiting calcineurin with FK506 inhibited the receptor response. GPR30 PDZ‐dependently inhibited basal NFAT signaling, consistent with the receptor favoring AKAP5‐anchoring of calcineurin. The calcineurin substrate kinase suppressor of Ras 2 (KSR2), a mitogen‐activated protein kinase (MAPK) scaffold, enhanced the GPR30‐promoted response, also dependently on the receptor PDZ motif. GPR30 also PDZ‐dependently favored a membrane KSR2 complex at the expense of the monomeric form. On the other hand, disrupting AKAP5‐PKA RII interaction with St‐Ht31, or inhibiting protein kinase C (PKC) with GF109203X or epidermal growth factor receptor (EGFR) tyrosine kinase with AG1478 had no effect on the GPR30‐stimulated response. FK506 also increased the amount of GPR30 in the plasma membrane, thus acting opposite to St‐Ht31, which increased receptor endocytosis. We conclude that the PDZ‐dependent GPR30 complex with AKAP5 includes calcineurin, which favors GPR30 endocytosis and enables the receptor to constitutively increase ERK1/2 signaling through KSR2.Support or Funding InformationSwedish Cancer Foundation
Osteomeles schwerinae extracts inhibits the binding to receptors of advanced glycation end products and TGF‐β1 expression in mesangial cells under diabetic conditions
Authors: Kim Young Sook , Jung Dong Ho , Lee Ik‐Soo , Pyun Bo‐Jeong , Kim Jin Sook 
Published: November 2023

BackgroundOsteomeles schwerinae C. K. Schneid. (Rosaceae, OSSC) is a medicinal plant traditionally used to treat various diseases in Asia. The chemical constituents of OSSC have an inhibitory effect on aldose reductase activity, which has been implicated in the pathogenesis of diabetic complications. However, the protective effects of the pharmacological activity and potential mechanisms in diabetic nephropathy are still not known.ObjectiveIn the present study we investigated that OSSC extracts and major compounds were examined for their effects on binding to the receptors of advanced glycation end products (RAGE) and on transforming growth factor‐beta1 (TGF‐β1) expression‐related signal mechanisms in mouse glomerular mesangial cells (GMCs).Materials and methodsA simple, rapid and efficient method was developed for the simultaneous determination of the marker compounds in the ethanol extract of the leaves and twigs of OSSC using HPLC‐diode array detector (DAD). In this study, we determined the effects of OSSC extract and hyperoside on AGE and RAGE binding, and studied the mechanism of OSSC extract effects on AGE‐bovine serum albumin (BSA)‐treated GMCs. GMCs overexpressing human RAGE were cultured in AGE‐BSA labelled with Alexa 488, and OSSC extract. AGE/RAGE binding were measured using fluorescence (excitation 485 nm/emission 528 nm). TGF‐β1 protein expression levels were determined by western blot analyses.ResultsOSSC extracts of leaves and twigs (1 mg/ml) inhibited on AGE/RAGE binding and TGF‐β1 protein expression in a dose‐dependent manner in GMCs. Furthermore, OSSC extracts reduced the effects on AGE‐BSA‐induced reactive oxidative species (ROS) formation and nuclear translocalization of transcription factor NF‐κB. OSSC extracts inhibited phosphorylation of extracellular signal‐regulated protein kinases1/2 (ERK1/2), p38 mitogen‐activated protein kinases (p38MAPK), and IκB. Hyperoside also inhibited AGE/RAGE binding and ROS formation, and reduced TGF‐β1 expression and IkB phosphorylation.ConclusionsOSSC extracts and hyperoside may attenuate AGE/RAGE binding and expression of TGF‐β1 by downregulating of pERK1/2, p38MAPK and IκB phosphorylations in GMCs under diabetic condition and retard the development of diabetic complications such as diabetic nephropathy.Support or Funding InformationThis research was supported by Grants (K14040 and K15270) from the Korea Institute of Oriental Medicine (KIOM).
Development and progression of overactive bladder urinary in heart failure rat
Authors: Claudino Mário Angelo , Furquim Silas Ramos , Tartarotti Sabrina , Mora Aline Gonçalves , Priviero Fernanda , Antunes Edson 
Published: November 2023

Heart failure (HF) and urinary symptoms (US) is highly prevalence and affects approximately 37% of man and 67% of woman have a significant impact on quality of life. There is evidence that HF and US share risk factors that are associated with autonomic nervous system dysfunction, which has also been implicated in overactive bladder (OAB). Thus, the aim of study was evaluated the possible relationship in the progression OAB associate to HF in rats submitted to arteriovenous fistula (HF model). After 4 or 12 weeks, cystometric parameters (ex vivo) were assessed: Threshold pressure (the intravesical pressure immediately before micturition); Post‐void pressure (the intravesical pressure immediately after micturition); Contraction micturition (the peak pressure reached during micturition); Capacity (the volume of saline needed to induce the first micturition); Frequency of non‐voiding contractions. The histomorphometry (in vitro), also were performed. After 4 weeks, HF animals have an increase of micturition contraction and threshold pressure associated with a decrease of capacity (P<0.05) when compared to group sham. Moreover, after 12 weeks, HF animals increase of micturition contraction, threshold pressure and frequency of non‐voiding contractions and keep the decreased of bladder capacity (P<0.05) when compared to Sham group. In addition, HF group (12 weeks) increase the frequency of non‐voiding contractions (P<0.05) when compare to HF group (4 weeks). Histomorphometry showed that HF group (4 weeks) present an increase of urothelium thickness (P<0.05) compared to sham group, whereas, HF group (12 weeks) present an increase in the detrusor muscle (P<0.05) when compared to sham group. Thus, HF rats, using the arteriovenous fistula, promote structural changes in the detrusor muscle contributing to the development of OAB and impaired of urinary function. Furthermore, our data suggest that OAB is progressive and is associated with the HF time course.Support or Funding InformationFinancial support: FAPESP
Betaine Supplementation Accelerates Elimination of Acetaldehyde from Blood in Rats Challenged with Ethanol Acutely
Authors: Jun Doo S , Ahn Chul W , Kim Jung I , Kim Young C 
Published: November 2023

Earlier studies in our laboratory showed that betaine administration may modify the metabolic reactions for sulfur‐containing amino substances in the liver. In this study we determined the changes in elimination of ethanol from blood induced by betaine supplementation. Male adult rats were provided with betaine (1 %) in drinking water for 2 weeks prior to a challenge with an acute dose of ethanol (3 g/kg, ip). Blood ethanol and acetaldehyde levels were monitored for 330 min after ethanol treatment. Ethanol concentrations in blood reached a peak in 30 min and declined rapidly thereafter in both groups. Ethanol concentrations and its elimination rate in blood were unaffected by betaine intake. Blood concentrations of acetaldehyde, a toxic metabolite of ethanol, were elevated gradually, reaching a plateau in around 150 min. However, blood acetaldehyde concentrations appeared to be significantly lower in the rats supplemented with betaine. The area under the curve (AUC) calculated for acetaldehyde was markedly lower in the rats supplemented with betaine (1.25 ± 0.08 mg·min/ml) than in the control rats (2.07 ± 0.18 mg min/ml). Methionine, glutathione, and S‐adenosylmethionine contents in the liver were significantly decreased by ethanol treatment, which were all prevented in the rats supplemented with betaine. Lipid peroxidation in liver tissue was also inhibited by betaine intake. It is suggested that the reduction of acetaldehyde concentrations in blood by betaine intake may be associated with the enhanced production of sulfur‐containing substances in the liver.Support or Funding InformationSupported by National Research Foundation (NRF) grants (No. 2014‐R1A2A1A11052967 and No. 2009‐0083533) funded by the Ministry of Education, Science and Technology (MEST), Korea.