bluuebunny/crossref_metadata_2025_split huggingface dataset:
Correlating the Reversal of Multidrug Resistance in Cancers by Novel P‐glycoprotein Inhibitors to the Expression of ABC Transporters
Authors: Sunshine Alexis L. , Follit Courtney A. , Marchesseault Collette , Wise John G. , Vogel Pia D. 
Published: November 2023

P‐glycoprotein (P‐gp) is a transmembrane protein that has evolved to eliminate toxic compounds from cells. It functions by using the hydrolysis of ATP to generate a conformational change that physically pushes xenobiotics that are bound in the drug‐binding domain of P‐gp from the cytosolic side of the membrane into the extracellular space. This broad functionality of the pump relies on the inherently non‐discriminating character of multiple binding sites within the drug binding domains and allows P‐gp to transport a variety of substances including most currently approved chemotherapeutics. Overexpression of P‐gp in a cell, therefore, results in a remarkable resistance to the presence of toxic chemicals, even enabling cancerous cells to survive chemotherapy treatments, which ultimately renders such therapy ineffective. It is possible, however, for an inhibitory agent to bind to P‐gp and to inactivate its function. In recent computational ultra‐high throughput searches followed by biochemical, biophysical and cell culture evaluations, we have identified several compounds that reverse multidrug resistance in cancer cells in culture (Brewer, F. K., Follit, C. A., Vogel, P. D., & Wise, J. G. (2014) Molecular pharmacology, 86(6), 716–726; Follit, C. A., Brewer, F. K., Wise, J. G., & Vogel, P. D. (2015) Pharmacology Research & Perspectives, 3(5) doi:10.1002/prp2.170). In the present study, we aim to extend these findings by quantifying the expression levels of P‐gp and other multidrug resistance proteins in various multi‐drug resistant cancer cell lines. Correlating the level of reversal of multidrug resistances with the level of expression of the various ABC transporter proteins that have been associated with the multidrug resistance phenotype, will allow us to determine the ABC transporter specificity of the discovered compounds. Such an approach may in the future be used to develop personalized medical treatment for patients with multi‐drug resistant cancers conferred by specific ABC transporters.Support or Funding InformationThis work is supported by NIH NIGMS [Grants R15‐GM094771‐01A1 and R15‐GM094771‐02] to PDV and JGW, SMU University Research Council, SMU Engaged Learning program, the SMU Center for Drug Discovery, Design and Delivery, the Communities Foundation of Texas, New England Biolabs / Lynn McBee, the Hamilton Undergraduate Research Scholarship Program, and a private gift from Ms. Suzann Ruff of Dallas, Texas.
Inhibition of ABC‐Transporters by in silico Identified Small Molecules
Authors: Follit Courtney A , Nanayakkara Amila K , Wise John G , Vogel Pia D 
Published: November 2023

Multidrug resistance (MDR) is a complex phenotype characterized by simultaneous resistance to structurally and functionally dissimilar drugs. MDR is frequently associated with overexpression of transmembrane efflux proteins belonging to the ATP‐binding cassette (ABC) transporter superfamily including P‐glycoprotein (P‐gp), multidrug resistance associated protein (MRP1), and breast cancer resistance protein (BCRP). Normally expressed at tissue barriers, these proteins protect vulnerable cells from xenobiotic attack by pumping a wide range of toxins out of the cell. Unfortunately, this broad substrate range, characteristic of these transporters, poses a major obstacle to the successful chemotherapeutic treatment of cancers since the majority of clinically relevant chemotherapeutic drugs can be effluxed by P‐gp, MRP1, and BCRP. Treatment and prevention of MDR have been studied extensively for decades, and yet, there are still no effective FDA‐approved therapies available.Using targeted molecular dynamics and massively parallel drug docking studies, we have screened millions of drug‐like molecules and identified hundreds of compounds that are predicted to inhibit P‐gp by specifically interacting with its ATP binding domain. We have previously shown that of four of these in silico identified compounds inhibited P‐gp catalyzed ATP hydrolysis (Brewer, F. K., Follit, C. A., Vogel, P. D., & Wise, J. G. (2014) Molecular Pharmacology, 86(6), 716–726). When tested in cell culture, three of these compounds restored chemotherapeutic sensitivity in a multidrug resistant human cancer cell line which overexpresses P‐gp (Follit CA, Brewer FK, Wise JG, Vogel PV (2015) Pharmacology Research & Perspectives 3(5): e00170). In this study, we expand our cell culture screening to evaluate 46 potential inhibitors identified by our in silico screening methods and report that over 30% of these compounds restored chemosensitivity to MDR human cancer cell lines. The best of these compounds will be further investigated to determine toxicity and specificity. With future chemical optimization, we are working towards developing powerful co‐therapeutics to treat and prevent MDR in human cancers.Support or Funding InformationThis work is supported by NIH NIGMS [Grants R15‐GM094771‐01A1 and R15‐GM094771‐02] to PDV and JGW, SMU University Research Council, SMU Engaged Learning program, the SMU Center for Drug Discovery, Design and Delivery, the Communities Foundation of Texas, and a private gift from Ms. Suzann Ruff of Dallas, Texas.
Plasma Concentrations Of FAM3D Protein Is Higher In Individuals With Type 2 Diabetes Mellitus Treated With Sulfonylureas
Authors: NEVES JOSE ANTONIO JANUARIO , FELICIANO REGIANE , GIANNELLA‐NETO DANIEL 
Published: November 2023

BackgroundAmong the new cytokine Family with Sequence Similarity 3 (FAM3), a subfamily of proteins similar to cytokines known as FAM3D was identified. FAM3D is predominantly expressed in the gastrointestinal tract of normal individuals. Plasma concentrations of FAM3D range according to the nutritional status presenting a postprandial increase and a reduction in the later post‐absorptive period. It might be speculated that FAM3D is an inhibitor of insulin secretion, as it has been observed a significant increase in patients with pancreatic adenocarcinoma associated with T2D.AimsQuantitatively determine the plasma concentration of FAM3D, in a group of patients with T2D and comparing with patients with pre‐Type 2 Diabetes Mellitus (pT2D) and Control (CTRL) individuals paired according to gender, age and body mass index in order to better elucidate the physiology of FAM3D as well as its pathophysiological role in T2D.MethodsWe selected 90 patients comprising 15 male and 14 females diagnosed with T2D; 12 male and 15 female diagnosed pT2D; and 7 male and 9 female CTRL. Seventeen patients were excluded according to the inclusion and exclusion criteria. In total, 73 patients were included.All were submitted to measurement of anthropometric and biochemical tests, including HOMA‐IR calculation and the determination of plasma concentrations of FAM3D by ELISA. The Kruskal‐Wallis tests were used in the comparison of study groups, and the regression coefficient r of Spearman was calculated on correlation between plasma concentrations of FAM3D and other anthropometric and biochemical variables. The level of statistical significance was set at p <0.05.ResultsAmong the groups there were no significant difference in the concentration of FAM3D, and the median±Q for the CTRL group (24.92ng/mL ±9.11); pT2D (14.65ng/mL ±6.02) and T2D (19.87ng/mL ±5.39).The group of DM2 patients on sulfonylurea (23.42ng/mL ±6.1) had higher values compared to the group treated with other oral antidiabetic drugs (14.9 ng/mL ± 7.30), p <0.05.ConclusionsThere was no correlation of FAM3D between groups. Patients with T2D on sulfonylurea presented a higher concentration of FAM3D when compared with T2D patients treated with other oral antidiabetic drugs. Although further studies are necessary, the increased concentrations of FMA3D in patients with T2D on sulfonylurea could be due to the inhibitory effect of the secretagogue on FAM3D.Support or Funding InformationUniversidade Nove de Julho
Liraglutide Induces Brown Adipocyte Specific Genes in Mice Skeletal Muscle Tissue
Authors: Li Lixin , Zhou Joseph Yi , Bahaee Jamsheed 
Published: November 2023

Obesity is a risk factor for type 2 diabetes, coronary artery disease, and stroke. Glucagon like peptide ‐1 (GLP‐1) is synthesized by the L cells of ileal mucosa and is released after nutrients ingestion to potentiate glucose stimulated insulin secretion. Liraglutide, a full agonist of the GLP‐1 receptor (GLP‐R), has long‐lasting effects due to its increased resistance to enzymatic degradation. Clinical data has demonstrated the protective effect of liraglutide on weight gain in type 2 diabetes subjects. However, the underlying mechanisms of this protective effect have not been identified. Brown adipose tissue plays a major role in control of energy balance in rodents, whether GLP‐1 activate brown fat differentiation has not been studied. C2C12 myoblasts are known to be able to differentiate into adipocytes after stimulation. By treating the undifferentiated C2C12 myoblast with 5nM liraglutide, we observed a significant induction of GLP‐1 receptor after 24 h. C2C12 cells were cultured to confluence, and then exposed to brown adipocyte differentiation medium in the presence or absence of 5nM liraglutide, the mRNA level of brown fat enriched genes including peroxisome proliferator‐activated receptor α (PPAR‐α) and cell death activator‐A (Cidea) were upregulated after 6 days of induction of differentiation compare to control cells. Induction of peroxisome proliferator‐activated receptor‐γ coactivator (PGC)‐1α mRNA was observed as early as 3 d post‐induction. In vivo study was performed by injecting C57 black/6 mice with liragludie daily for 5 weeks. Both mRNA and protein levels of uncoupling protein‐1(UCP‐1), a brown fat specific gene, are significantly induced in skeletal muscle tissue after liraglutide treatment. Lirglutide also upregulated other brown fat enriched gene including PGC‐1α, Cidea, and PPAR‐α. Our study indicates that liraglutide induces brown adipogenesis. GLP‐1 and its analogues are potential therapies for obesity and obesity related metabolic disorders.Support or Funding InformationCentral Michigan University Faculty Startup Fund.
Effects of Paternal High Fat Diet on Plasma Leptin, Adiponectin, and Insulin in Offspring of C57BL/6 Mice
Authors: Zontini Alexis , Slyvka Yuriy , Zhang Yizhu , Nowak Felicia V 
Published: November 2023

Parental obesity is a predictor of childhood excess weight. Having a father, mother or sibling with a BMI of 40 increases the risk of adult obesity 5 fold compared to individuals who have normal weight first degree relatives. The rise in obesity in the U.S. has played a major role in the increasing number of instances of cardiovascular disease, diabetes, and even some types of cancer. This study aims to determine phenotypic effects on leptin, adiponectin, glucose tolerance (GTT), and HOMA in offspring of non‐obese (Group 1) and high‐fat diet‐induced obese (Group 2) fathers in C57BL/6 mice. Male mice were fed a low fat diet (LFD, 10% fat) or a high fat diet (HFD, 45% fat) for 12 weeks then mated to females fed LFD. Pups were fed regular chow and tested at 6 weeks, and 6 and 12 months of age. Glucose was measured using One Touch glucometer. Circulating levels of insulin, leptin and adiponectin were quantified by immunoassay. The results showed that leptin is higher at 6 months of age in Group 2, and is significant in females. It tends to be lower in Group 2 at 12 months, but not significant. Adiponectin on the other hand is higher at 6 weeks and 12 months in Group 2 of either sex but lower at 6 months, and concentrations at 12 months show parallel sex and group differences with the high molecular weight (HMW) form. Leptin is higher overall in males than females while adiponectin is higher in females. Results from HOMA and GTT insulin show a significant increase in both parameters at 6 weeks in males from Group 2 with a similar trend in both sexes at 6 and 12 months. We can conclude that there is an overall increase in insulin resistance in Group 2 and the group differences of leptin and adiponectin are overall inversely related, as would be expected. As part of a larger study looking at paternal transmission of epigenetic modifications to offspring, the ultimate goal is to find candidate genes for targeted intervention aimed at preventing obesity and diabetes in high‐risk offspring.Support or Funding InformationHeritage College Research Award and an Ohio University Research Council Award
Determining the Role of Skeletal Muscle microRNA‐133a in Early‐Onset Insulin Resistance
Authors: da Silva Rosa Simone , Mughal Wajihah , Nguyen Lucas , Chapman Donald , Aliani Michel , Pereira Troy , Rampitsch Christof , Dolinsky Vernon , Gordon Joseph 
Published: November 2023

Fetal exposure to diabetes during pregnancy increases the risk for early‐onset insulin resistance in the offspring; however, the key molecular regulators responsible for fetal metabolic programming have not been characterized in muscle tissue. We demonstrate that prenatal exposure to gestational diabetes decreased the soleus muscle expression of microRNA‐133a in offspring. Using tandem mass spectrometry techniques we identify a conserved phosphorylation motif within the MEF2 and SRF transcription factors that is targeted by PKCδ and regulates microRNA‐133a expression and mitochondrial function in response to a lipotoxic signal. Reconstitution of MEF2 function in cultured myotubes by expression of a neutralizing mutation in this identified phosphorylation motif restores microRNA‐133a expression and mitochondrial membrane potential during lipotoxicity. Furthermore, overnight exposure to palmitate reduced mitochondrial oxygen consumption and insulin‐stimulated glucose uptake, which were reversed when cells were transfected with microRNA‐133a mimicking oligonucleotides. Mechanistically, we demonstrate that microRNA‐133a regulates mitochondrial function through translational inhibition of a mitophagy and cell death modulating protein, called Nix. In addition, Nix‐and palmitate‐induced mitochondrial depolarization were attenuated by the beta2‐adrenergic agonist clenbuterol. Finally, we show that rodents exposed to gestational diabetes during fetal development display muscle diacylglycerol accumulation, concurrent with insulin‐resistance, PKCδ activation, and elevated Nix expression as young adult rats. Our data identifies a novel pathway whereby fetal exposure to diabetes reduces microRNA‐133a, alters skeletal muscle metabolism, and may predispose the offspring to early‐onset insulin resistance.Support or Funding InformationSupported by Children's Hospital Foundation of Manitoba, and NSERC Canada to Joseph Gordon and CIHR to Vernon Dolinsky.
Genesis of Antibiotic Resistance (AR) XVII Population Dynamics That contravenes Hardy‐Weinberg‐Castle Principle (HWCP) augment AR Pandemic
Authors: Moody Nadine , Carrizales Diana , Carrizales Tania , Kannan Subburaj 
Published: November 2023

The impending onset of an AR pandemic is a plausible scenario. Based on the elements of HWCP, we have identified the potential contributors for this debacle. Here, we present the potential contributors of a fiasco that has a multi factorial disposition. Foremost of all factors, the medical professionals are constantly exposed a variety of infectious disease with diverse in patient and also outpatient population on a daily basis. These members often do not take time off the job to go to a doctor because they work with many doctors who can prescribe antibiotics at the workplace. The healthcare workers may expose other workers, patients, or their own family to the illness while waiting for the antibiotic to work. In the event that the antibiotic prescribed does not work or the illness is of a viral nature, a week later, many people may have been exposed. Based on a large sample of U.S. acute care hospitals, the survey found that on any given day, about 1 in 25 hospital patients has at least one healthcare‐associated infections (HAI). There were an estimated 722,000 HAIs in U.S acute care hospitals in 2011. About 75,000 hospital patients with HAIs died during their hospitalizations. More than half of all HAI occurred outside of the intensive care unit (N Engl J Med 2014; 370:1198–208). http://www.cdc.gov/HAI/surveillance/(Verbatim). Another key factor in the impending AR pandemic is that the under utilization of diagnostic assays is to be ascertain of microbe sensitivity to antibiotics. Incessantly, contrived and brooked deplorable economic disparity in general population like that of third world countries such as India, appropriate use of antibiotics is impractical. Taken together, both medical professionals, along with socioeconomically deprived section of the global population, pose an imminent risk factor for an impending AR pandemic.Support or Funding InformationSupported by professional development funds by SWTJC, to S.Kannan for 2014–205
Spatial distribution of the abundance and antibiotic sensitivity of Staphlyococcus aureus in the Hillsborough River
Authors: Seferian Rhianna , Williams Ann , Froeschke Bridgette 
Published: November 2023

The Hillsborough River is Tampa's primary potable water supply and used frequently for recreational activities including boating, kayaking, fishing, and swimming. However, the Florida Department of Environmental Protection (FDEP) has identified regions of the poor water quality. The overall purpose of our study was to quantify the abundance and determine antibiotic susceptibility of Staphylococcus aureus from seven discharge locations in a one‐mile section of Hillsborough River (from The University of Tampa (UT) to Tampa General Hospital). The concentration of S. aureus, at each site, was quantified using water filtration methods following EPA standards. Overall, there was a significant higher abundance (cfu/mL) of S. aureus at UT than any other site. Antibiotic susceptibility was tested using the Kirby‐Bauer method on 10 random isolates from each site for each event. Out of the 470 isolates, 166 were classified as Methicillin Resistant S. aureus (MRSA). The MRSA isolates were further tested with tetracycline and vancomycin. Out of the 166 MRSA isolates, 88 were also resistant to vancomycin (VRSA) and one MRSA isolate was resistant to both vancomycin and tetracycline. DNA extraction and Next Generation sequencing was conducted on 10 random isolates of collected MRSA, 9 random isolated of VRSA and 1 isolate resistant to vancomycin and tetracycline to examine the MecA gene, a candidate known to have multiple variants that allows for resistance in S. aureus. This can help aid in the correct administration of antibiotics for those infected with S. aureus from the river.Support or Funding InformationUniversity of Tampa: BIology Department Undergraduate Summer Research FellowshipUniversity of Tampa: Honors College Research Fellowship
Genesis of Antibiotic Resistance XX: CDC (Frieden's) report on AR and executive strategy to mitigate AR pandemic fail to account human migration (immigrants) and Hardy‐Weinberg ‐ Castle Principle§
Authors: Kannan Subburaj , Alvarez Angelica , Carrizales Diana , Carrizales Tania , Jouregui Suzzette , Moody Nadine 
Published: November 2023

Human mobility is causing an increase spread of antimicrobial drug–resistant organisms and drug‐resistant infectious diseases. International population movement is an integral component of the globalization process. Current population movement dynamics rapidly and effectively link regions of marked health disparity, and these linkages can be associated with risk for introduction / importation of drug‐resistant infectious diseases to population that are susceptible for diseases such as Tuberculosis and leprosy. The International Labor Organization (ILO) stated that in 2004, an estimated 175 million persons lived permanently outside their country (regions) of birth and that there were 81 million migrant workers excluding refugees globally. They are, however, one of the more likely populations to evolve (in comparison to medical community, underprivileged) because they meet multiple criteria of the HWCP principle (but not all of the conditions). Immigrants meet the condition of small populations. Even though many immigrant populations are large (2015 ‐Syrian ‐ Iraqi refugees in Europe; Approximately 11 million immigrants in United States, originating many Latin American countries including Mexico), they are not as large compared to the native population of the country which they are immigrating to. Systematic analysis of 2014 National Population Projections, as per HWCP, https://www.census.gov/population/projections/data/national/2014 shows that there is a gene flow due to intermixing of ethnic groups (for example a Cuban immigrating to the U.S. has children with a native U.S. citizen). Due to enhanced immunocompetency and innate immunity to diverse pathogens, immigrants tend to have the highest possibility of evolving. We have identified that immigrants fit three of the five categories defining HWCP: Natural selection, small population size, and gene flow. And lastly, immigrants (especially 2nd and 3rd generation) tend to mate with the people of their new home, and therefore, there is a sustained gene flow as defined by HWCP.Support or Funding InformationSupported by professional development funds by SWTJC to S.Kannan for 2014–2015