bluuebunny/crossref_metadata_2025_split huggingface dataset:
Naringenin, a citrus flavanone, enhances isoproterenol‐stimulated thermogenic activation of 3T3‐L1 adipocytes
Authors: Zhao Ling , Bae Jiyoung , Chen Jiangang 
Published: November 2023

Promoting thermogenesis through increasing the activities of functional brown adipocytes has promised new hope for obesity treatment and prevention. Recent evidence has suggested that naringenin, a citrus flavanone, is beneficial for preventing obesity and obesity associated chronic diseases and naringenin is capable of activating nuclear receptors, including PPARγ; however, it has not been reported whether naringenin promotes activities of functional brown adipocytes, similar to what has been reported for rosiglitazone, a synthetic ligand for PPARγ. Here, we investigated the effects of naringenin on browning and isoproterenol (ISO)‐stimulated thermogenic activation of 3T3‐L1 adipocytes. 3T3‐L1 cells were induced to differentiate in the presence or absence of naringenin, followed by stimulation with ISO. We report that naringenin did not increase UCP‐1 expression at basal state; however, it significantly increased the ISO‐stimulated upregulation of UCP‐1 and PGC‐1α and enhanced ISO‐stimulated thermogenesis. Moreover, naringenin enhanced PKA activation and phosphorylation of p38 MAPK downstream of ISO stimulation; and inhibition of either PKA or p38 by their respective pharmacological inhibitors blocked naringenin‐induced upregulation of UCP‐1 mRNA. Our results demonstrate that naringenin enhances ISO‐induced thermogenic activation of 3T3‐L1 adipocytes via PKA/p38 pathways.Support or Funding InformationThe work was supported in part by UT professional development award to LZ.
Diosmetin: An Anti‐Leukemic Flavonoid Targeting the Estrogen Receptor β
Authors: Rota Sarah G. , Roma Alessia , Spagnuolo Paul A. 
Published: November 2023

Acute myeloid leukemia (AML) is an aggressive hematological malignancy resulting from the accumulation of immature myeloid cells in the peripheral blood and bone marrow. It is associated with poor prognosis, especially in older patients where the 2‐year survival rate is approximately 10%. Leukemia stem cells (LSCs) are the cells responsible for AML development. To prevent relapse and improve patient prognosis, new therapies targeting LSCs are needed. Thus, to identify novel anti‐AML agents, we created a unique library consisting of food‐derived bioactive compounds (i.e., nutraceuticals). We screened this library (n= 288) using the MTS assay against TEX cells, a surrogate LSC line. Among the 288 compounds, diosmetin, a flavonoid derived from various citrus fruits, was found to be the most potent (EC50: 6.1 ± 0.5 μM, p<0.001). Most importantly, diosmetin did not affect the non‐LSC K562 cells, suggesting that diosmetin may selectively target leukemia stem cells. This was further demonstrated by clonogenic growth assays which showed that diosmetin (10 μM) reduced clonogenic growth in primary AML patient samples (n=6) but not in CD34+ normal hematopoietic cells (n=3). Finally, AML mouse xenografts showed that, compared to vehicle control, diosmetin treated mice had slower tumor growth and reduced tumor weights up on sacrifice (p<0.01). Collectively, this highlights diosmetin as a novel and selective anti‐AML agent.Diosmetin induced caspase 3 mediated apoptosis, as determined by caspase activation, Annexin V/Propidium iodide and DNA fragmentation assays. To identify diosmetin's molecular target we utilized online bioinformatics tools (e.g., protein data base, PoSSuM and DAVID tool), which identified the estrogen receptor (ER) as diosmetin's potential molecular target. To assess the cell and molecular role of ERs, we measured ERα and ERβ levels in diosmetin sensitive and insensitive cell lines. Interestingly, diosmetin sensitive cell lines (TEX, LP1) display significantly elevated ERβ protein and mRNA levels (4 fold, as determined by Western blotting and qtPCR, respectively) compared to diosmetin insensitive cell lines (K562, DU145). This pattern was not observed for ERα. Furthermore, this ER expression pattern was also observed in patient‐derived AML cells, as cells sensitive to diosmetin displayed elevated ERβ, but not ERα, mRNA. Genetic knockdown using shRNA confirmed that ERβ is diosmetin's target, as cells lacking ERβ were resistant to diosmetin. Finally, ER reporter assays demonstrated that diosmetin binds and acts as an agonist in ERβ but not ERα reporter cells. Together, these results show that diosmetin binds to ERβ and that ERβ is functionally important to diosmetin's activity.In summary, these studies highlight diosmetin binding to ERβ as a potential novel strategy for the treatment of AML.Support or Funding InformationStem Cell Network, University of Waterloo
TURMERIC POWDER GAVAGE IMPROVES LIPID PROFILE OF NORMAL ALBINO RATS
Authors: Iwueke Adaku Vivien , Iheanacho Kizito , Nwodu Judith 
Published: November 2023

Dyslipidemia is one of the key risk factors for Cardiovascular disease, which is a leading cause of global morbidity and mortality. This study was designed to investigate the effect of powdered Curcuma longa (turmeric) tubers on lipid profile of normolipidemic albino rats. Twenty four male albino rats were randomly divided into four groups (A–D), receiving once daily administration of distilled water, 50, 100 and 200 mg/kg of the powder respectively. The body weights of the animals were measured weekly, while lipid profile was determined after three weeks. The result showed that daily oral administration of graded doses of the C. longa powder for three weeks resulted in a non‐significant increase in the body weights of the animals. Daily oral turmeric powder (200 mg/kg) treatment significantly (p ≤ 0.05) lowered the serum total cholesterol and triglyceride concentrations, while those that received 100 mg/kg significantly increased HDL and reduced LDL‐Cholesterol.Turmeric powder has positive effect on lipid profile by lowering total cholesterol, triglyceride and LDL cholesterol and increasing HDL cholesterol in albino rats at the indicated doses.Support or Funding InformationNIL
Xylobiose ameliorates hyperglycemia and dyslipidemia via regulating hepatic lipogenic genes in db/db mice
Authors: Kim Eunju , Lim Eunjin , Jung Sangwon , Yoo Sang‐Ho , Kim Yuri 
Published: November 2023

Diabetes mellitus (DM) is a metabolic disorder in glucose and fat metabolism and has become a major public concern in worldwide. Xylobiose consists of two molecules of xylose and is a major disaccharide in a well‐known sweetener, xylo‐oligosaccharide. Although it has been reported the hypoglycemic effect of xylo‐oligosaccharide, the physiological effect of xylobiose on blood glucose and lipogenesis has not been evaluated. The objective of study was to evaluate the hypoglycemic and hypolipogenic effect of xylobiose in db/db mice. Five‐ week old male C57BL/KsJ‐db/db mice were randomized into 3 groups as follows: (1) a control group of C57BL/6 mice that received AIN93G (Ctrl), (2) a diabetic control group of C57BL/KsJ‐db/db mice that received AIN93G (DB), and (3) a group that supplemented with 5% xylobiose as part of the total sucrose content of the diet (XB5). Mice were fed the experimental diets for 6 weeks. Supplementation of xylobiose reduced food and water intake and improved glucose tolerance by reducing the levels of oral glucose tolerance test area under the curve, fasting blood glucose, HbA1c, insulin, and HOMA‐IR. These results indicate xylobiose attenuates hyperglycemia by regulating insulin and blood glucose metabolism. In addition, xylobiose supplementation significantly decreased the levels of TG, total cholesterol, and LDL‐C. Histopathologically, fat accumulation in liver tissues was reduced in XB 5 group. Expressions of lipogenic genes, including, FAS, PPARγ, SREBP‐1C, SREBP‐2, ACC, and HMG‐CoA reductase in liver tissues were significantly down‐regulated by xylobiose supplementation. Furthermore, xylobiose supplementation suppressed the mRNA expressions of pro‐inflammatory cytokines, TNF‐α, IL‐1β, IL‐6, and MCP‐1 and phosphorylation of three MAPK, such as JNK/SAPK, p38, and ERK (1/2). Taken together, xylobiose exhibits considerable anti‐diabetic, hypolipogenic, and anti‐inflammatory alternation in db/db mice.Support or Funding InformationThis research was supported by High Value‐added Food Technology Development Program (Project number: 313024‐03‐2‐HD040), Ministry for Food, Agriculture, Forestry and Fisheries, Republic of Korea, and Brain Korea 21 Plus (Project No. 22A20130012143)
Novel Nutritional Formula Protects Against Cellular Damage
Authors: Wood Steve M , Gray Russell , Hester Shelly N , Mastaloudis Angela F , Kern Dale , Namkoong Jin , Draelos Zoe D 
Published: November 2023

Human cells possess protection and repair mechanisms that may be described as “aging defense mechanisms—ADMs.” Nutrients are important cofactors for cellular function and protection; similarly, natural ingredients, including phytonutrients, have been shown to support key ADMs. The purpose of this study was to determine the effects of a novel nutritional supplement—NNS (containing fish oil, vitamins K2 and D, alpha‐lipoic acid, co‐enzyme Q10, quercetin, citrus bioflavonoids—naringin and hesperidin, d‐limonene, resveratrol, carotenoids—lycopene, lutein, and astaxanthin, purple corn and rosemary extracts) on ADMs (i.e. cellular protection). Forty healthy, nonsmoking men and women between the ages of 40 and 75 years of age with Fitzpatrick skin types I and II were recruited to participate. Cellular injury was induced by 1 minimal erythema dose (MED), 2MED, and 3 MED solar simulated ultraviolet (UV) radiation exposure to non‐sun exposed skin. Assessments at baseline and 8 weeks post supplementation included: skin erythema at all three MED doses and biopsy of the 3MED site to determine # of apoptotic cells. In addition, total skin carotenoid levels were assessed non‐invasively using the BioPhotonic Scanner (Nu Skin Enterprises, Provo, Utah). There was a dramatic effect of the NNS on ADMs following 8 weeks supplementation. Decreases in skin erythema at all three MED doses: 1MED (p=0.019), 2MED (p<0.001), and 3MED (p=0.001) were observed. Supplementation with the NNS led to a significant reduction in the mean number of apoptotic cells, 11.6 at baseline vs. 5.7 cells/mm2 at the 3MED dose at week 8, suggesting that the NNDS protected against both uv‐induced DNA damage and apoptosis. Finally, skin carotenoid levels increased from 28,600 Raman Intensity Units (RIUs) to 38,775 RIUs (p<0.001) indicative of an increase in antioxidant protection in the skin tissue post‐supplementation. In conclusion, 8 weeks supplementation with the NNS supported key ADMs related to cellular health and function including protection against UV induced cellular damage, apopotosis, inflammation and erythema.Support or Funding InformationThe study was funded by Nu Skin Enterprises and registered on ClinicalTrials.gov (#NCT02525224)
Cyanidin, a Natural Anti‐Glycation Agent, Inhibits Methylglyoxal‐ and Glucose‐Mediated Protein Glycation in vitro
Authors: Suantawee Tanyawan , Cheng Henrique , Adisakwattana Sirichai 
Published: November 2023

IntroductionProtein glycation and advanced glycation end products (AGEs) formation are associated with developing macrovascular and microvascular complications of diabetes mellitus. Cyanidin, a natural anthocyanidin abundant in various fruits and vegetables, has been reported a number of beneficial health effects attributed to its antioxidant properties. However, there are no studies related to the antiglycation activity of cyanidin.ObjectiveThe aim of the study was to investigate the inhibitory activity of cyanidin on in vitro protein glycation in bovine serum albumin (BSA) models; BSA/methylglyoxal (MG) and BSA/glucose systems.MethodsThe various concentrations of cyanidin were incubated with BSA and 1 mM methylglyoxal or 0.50 M glucose for 14 days at 37°C, pH 7.4. The fluorescent AGEs and non‐fluorescent Nɛ‐(carboxymethyl) lysine (CML) was assessed using a spectrofluorometer and an enzyme‐linked immunosorbent assay (ELISA). The protein oxidation was measured using the level of protein carbonyl content and protein thiol groups. The MG‐trapping capacity was performed by using high‐performance liquid chromatography (HPLC).ResultsThe results demonstrated that cyanidin (0.125–1 mM) significantly inhibited the formation of fluorescent AGEs in BSA/MG (9.10–43.48%) and BSA/glucose (8.95–32.93%) systems in a concentration‐dependent manner. Correspondingly, cyanidin (1 mM) significantly decreased the level of CML in BSA/MG (55.77%) and BSA/glucose (49.42%) systems. Cyanidin prevented oxidative protein damage by protecting the depletion of protein thiol groups. Interestingly, cyanidin directly trapped MG and then significantly inhibited the formation of AGEs (5.92–36.95%).DiscussionThese results demonstrated that cyanidin was capable to inhibit MG‐and glucose‐mediated protein glycation and oxidative‐induced protein damage in BSA model. It suggested that cyanidin inhibited MG‐induced formation of AGEs related to its trapping ability to MG.ConclusionCyanidin might be a new promising antiglycation agent for preventing or ameliorating AGEs‐mediated diabetic complications.
INDOLEAMINE2,3‐DIOXYGENASE INHIBITION DECREASES VEGF‐A EXPRESSION IN HUMAN BLADDER CANCER CELLS AND DIMINISHES ANGIOGENESIS IN COCULTURE WITH HUMAN UMBILICAL VEIN ENDOTHELIAL CELLS (HUVEC)
Authors: Malta Camila Soares , de Oliveira Brito Rodrigo Barbosa , Matos Yves Teles , de Souza Diego Mota , Matheus Luiz Henrique Gomes , Dellê Humberto 
Published: November 2023

Indoleamine 2,3‐dioxygenase (IDO) is an enzyme with immunomodulatory properties and it is expressed in the placental tissue, therefore, it has a role in protecting the embryo against the maternal immune system. The expression of IDO has been found in several types of cancer, including bladder cancer, being related to tumor development. In addition, IDO is expressed in tumor vessels, hypothesizing that IDO could be involved in the tumoral angiogenesis process.The aim was to verify if IDO has an influence on the angiogenesis process induced by bladder cancer cells underwent to hypoxia, analyzing the effect of IDO inhibition on VEGF expression and in vitro angiogenesis.In the first step, human bladder cancer cells (T24, ATCC) were cultured under normoxia or hypoxia for 1h, 8h, 24h or 48h, in order to identify the better period to induce high VEGF‐A expression (qPCR). The hypoxia was induced by AnaeroGen System (O2<1%, Oxoid). Then, the T24 cells were treated with the IDO inhibitor (MT, 1‐methyl‐D‐tryptophan) to analyzed the effect of MT on VEGF‐A expression in hypoxia condition. HIF‐1alpha was also analyzed by qPCR and Western Blot (WB).In the second step, T24 cells were cocultured with matrigel‐coated HUVEC cells (ATCC) under hypoxia for 48h, with or without MT, and the vascular tubes were counted. MTT method was used to evaluate the viability of the MT‐treated HUVEC cells.VEGF‐A expression increased in a time‐depending fashion under hypoxia, reaching the higher value at 48h (relative expression of 13.16±0.83 vs. 1.00±0.51 in normoxia; p<0.05). The transcriptional expression (mRNA) of HIF‐1alpha was not altered by hypoxia, however, an expressive increase was observed by WB (qualitative analysis). Treatment with MT significantly reduced the VEGF‐A expression on T24 cells and decreased HIF‐1alpha by WB. When T24 cells were cocultured with HUVEC, a significant reduction of vascular tube formation was observed under hypoxia (31.57±3.02 tubes/field in non‐treated cells vs. 18.08±2.06 tubes/field in MT‐treated cells; p<0.05). The MTT analysis revealed that MT treatment significantly reduced the HUVEC viability (reduction of 30%; p<0.05).These preliminary results demonstrated that IDO modulates angiogenesis in bladder cancer, being a possible target to alternative therapeutic strategies.
Renal subcapsular space of Balb/c nude mice as a route to evaluate differentiation of human bladder carcinoma T24 cells subpopulations
Authors: Souza Diego Mota , Matheus Luiz Henrique Gomes , de Oliveira Brito Rodrigo Barbosa , Matos Yves Silva Teles , Malta Camila Soares , Ferreira Janaina Mendes , Silva Chrisna Souza , Dellê Humberto 
Published: November 2023

Recurrence of bladder cancer after resections with progression to more aggressive forms are critical to promote cancer‐specific death and metastasis. Subpopulations of cancer cells, including cancer stem‐like cells, have been found inside the bladder tumors, having different abilities for malignancy and chemotherapy resistance. Subpopulations have been described and isolated from a culture of T24 cells, which represent major human epithelial bladder cancer cell with clinical relevance. However, in situ influences can not be assessed by another way except by animal model. Since T24 cells are not tumorigenic in nude mice when inoculated subcutaneously and technical limits exist in orthotopic procedures, we evaluated the renal subcapsular space as an alternative route to analyze these cells in vivo.Balb/c nude mice underwent renal subcapsular inoculation of 1×106 T24 cells, suspended in two different volumes of PBS (50 μl and 10 μl). Four weeks post‐inoculation, grafted kidneys were harvested and fixed for histology and immunohistochemistry analysis. Other tissues were investigated for metastasis.Inoculation of the cells in a volume of 50 μl was unsuccessful. However, a very high success rate was reached when 10μl volume was used (87.5%). It was possible to identify the formation of a pseudo‐bladder structure on renal subcapsular space, as well as a clear cellular differentiation, which was immunohistochemically characterized for epithelial to mesenchymal transition (cytokeratin for epithelial cells and vimentin for mesenchymal cells). Subpopulations of T24 cells were found infiltrating the renal parenchyma toward the medulla, besides surrounding renal vessels.Renal subcapsular inoculation is an effective route to analyze subpopulations and differentiation of T24 cells in vivo.Support or Funding InformationFAPESP (2012/04423‐0)
Lactate Dehydrogenase A (LDH‐A) May Not Be Primarily Responsible for Maintaining High Tumor Lactic Acid Levels in Aggressive Breast Cancer
Authors: Mack Nzinga , Mazzio Elizabeth , Soliman Karam 
Published: November 2023

A well‐known characteristic of tumor cells is the propensity to produce excessive amounts of lactic acid when deprived of normal levels of oxygen, and also when exposed to normal oxygen levels, also referred to as the Warburg effect. High levels of lactate are believed to be associated with elevated expression of lactate dehydrogenase A (LDHA), a protein up‐regulated in diverse aggressive malignancies. In this study, shRNAs were used to permanently knock down the expression of LDHA in human MDA‐MB 231 and MDA‐MB 468 cells. LDHA knockdown was confirmed by both Western Blot and qPCR. Furthermore, metabolic analysis included assessment of changes in cell viability, glucose utilization, lactate levels and cellular energy production by quantification of ATP. Silencing of the LDHA gene and protein had no effect on lactate production, glucose utilization, cellular metabolic activity and ATP in MDA‐MB 231 and MDA‐MB 468 tumor cells. These findings show no relationship between LDH‐A expression in both cells lines examined and production of lactate, nor is there any correlation to changes in the way glucose is utilized to produce ATP. The results obtained with the MDA‐MB 468 cell line confirm data previously obtained with the MDA‐MB 231 cell line. The data also suggest that cells readily adapt to knockdown conditions to continue their normal metabolic activities. Further analysis will require genomic profiling to discover shifts in gene expression that are responsible for this sustained production of lactate.Support or Funding InformationSupported by grants from the National Institute on Minority Health and Health Disparities, NIMHD G12 MD007582 and P20 MD006738.
PEDF Reduction Induced by Cigarette Smoke: A Potential Role for Breast Tumor Development
Authors: Kispert Shannon E , McHowat Jane 
Published: November 2023

There are many risk factors for cancer development and subsequent metastasis which include lifestyle choices such as diet, alcohol, and cigarette smoking. Smoking has been linked to several cancers including breast cancer. Many cohort studies have described the link between patients with breast cancer and those with long term smoking history. Despite the claim of correlation, the mechanism by which cigarette smoke alters breast epithelial cells and contributes to tumor cell growth and metastasis remains undefined. Pigment epithelium‐derived factor (PEDF) is a potent anti‐angiogenic factor and is shown to have inhibitory effects in numerous cancers. PEDF is often decreased or absent in tumor tissue when compared to surrounding stroma and its absence has resulted in cellular atypia. Female PEDF knockout mice show histologic changes in the breast at six months of age consistent with atypical ductal hyperplasia. We have shown that cigarette smoke exposure of breast tumor cells resulted in decreased PEDF expression. In order to assess the effects of cigarette smoke on the breast in‐vivo, we exposed six month old female mice to cigarette smoke using the SCIREQ inExpose system for up to six months and harvested mammary tissue for histological and biochemical analysis. Histological analysis revealed changes that include atypical epithelial growth in mammary tissue from mice exposed to six months of cigarette smoke when compared to those exposed to room air only. Immunohistochemistry showed increases in expression of proteins commonly upregulated in breast cancer including Ki‐67, VEGF, and COX‐2 in mammary tissue exposed to six months of smoking when compared to room air controls. Smoke exposure also caused a decrease in PEDF expression when compared to room air tissue. We have shown here for the first time that cigarette smoke alters the histology of the mammary tissue in mice and alters expression of important markers involved in human breast tumor development and progression.Support or Funding InformationPresidents Research Fund Saint Louis University School of Medicine