bluuebunny/crossref_metadata_2025_split huggingface dataset:
Brain dysmorphologies associated with Alzheimer disease in Down syndrome
Authors: Martínez Abadías Neus , Pardina Helena , Echeverry Luis M. , Carmona‐Iragui María , Sevillano Xavier , Heuzé Yann , Fortea Juan 
Published: May 2022

Down syndrome (DS) is a genetic disorder occurring in 1 out of every 700 to 1,000 live births caused by trisomy of chromosome 21. The overexpression of the Amyloid Precursor Protein (APP) gene located on this chromosome leads to an early onset and rapid accumulation of ß‐amyloid (Aß) in the brain that invariably results in Alzheimer Disease (AD) in people with DS. Therefore, AD, the most common form of dementia, is currently one of the most relevant medical issues in people with DS. In this study, we assessed brain morphological patterns to quantify dysmorphologies associated with AD in Down syndrome.Brain shape and size analyses were performed using Geometric Morphometrics in a sample of 243 adults, including 153 euploid healthy controls (EU) and 90 individuals with DS at different stages of dementia: asymptomatic DS with no signs of AD‐related cognitive impairment (N=58), individuals with DS and prodromal AD (N=21) and individuals diagnosed with AD dementia (N=11). A set of 38 3D brain landmarks representing the overall shape of the brain and internal brain structures (ventricles, corpus callosum, cerebellum and pons) were located on magnetic resonance images of the head.Results showed a significant separation between EU and DS populations based on both global and local brain shape and size analyses. Individuals with DS displayed a smaller cerebellum, a protruding posterior midbody in the corpus callosum, a frontally projected brain and expanded ventricles. Significant brain shape differences were detected in individuals diagnosed with AD, which mainly affected the shape of enlarged brain ventricles. Remarkably, individuals at advanced stages of the disease displayed more severe dysmorphologies as compared to those individuals at prodromal stages and individuals with no signs of dementia, confirming a phenotypic continuum associated with the severity of dementia that highlights the impact of this neurodegenerative disorder in brain morphology.
Effect of Mediators in the Plasma of E‐Cigarette Users on Endothelial and Epithelial Cell Metabolism
Authors: Chitteti Ramamurthy , Hertz Juan P. Z. , Masso‐Silva Jorge A. , Shin John , Alexander Laura E. C. , Patel Hemal H. , Roth David M. 
Published: May 2022

BackgroundTobacco smoking is a major risk factor for cardiovascular and lung disease. Inhalation of aerosols formed by electronic nicotine delivery systems (ENDS) such as E‐cigarettes (E‐cigs) may expose the user to harms beyond those of nicotine alone. Data on the cardiovascular risks of E‐cigs and vaping devices remain inconclusive. However, exposure to E‐cigs induces the release of multiple substances, including exosomes and metabolites, into the bloodstream. There is limited information on the role of these exosomes and metabolites on cellular homeostasis. Mitochondria are highly sensitive to cigarette smoke, however E‐cig aerosol induced changes in mitochondrial function are not well studied. We investigated the effects of E‐cig plasma mediators on metabolism and function in human vascular endothelial (EA.hy 926) and lung epithelial cells (A549).HypothesisPlasma from E‐cig users will induce alterations in the metabolism and mitochondrial function of endothelial and lung epithelial cells.MethodsA longitudinal cohort study was conducted on subjects who exclusively used E‐cigarettes (n=21) and 10 non‐smoking, non‐vaping subjects. We included active E‐cig use without known lung disease and with normal lung function, between the ages of 18‐30 years. E‐cig use was confirmed with in‐person interviews and plasma cotinine levels. Active E‐cig use was defined as use of >0.5‐1 mL e‐liquid/day or 3.5‐7 mL/week for >6 months. Plasma was isolated and stored at ‐70°C until exosomes were profiled. The effects of E‐cig plasma (1%, 1h conditioning) mediators were assessed in vitro on endothelial cells (8x104/well) and epithelial cells (5x104/well) using the Seahorse XF Cell Mito Stress Test.ResultsResults were standardized for cell number and FCCP concentrations for both EA.hy 926 and A549 cells. Maximal mitochondrial respiration and spare capacity were decreased in human vascular endothelial cells and epithelial cells treated with E‐cig plasma relative to plasma from non‐smoker/non‐vapers. Basal respiration and ATP‐linked respiration was not different after treatment with plasma from E‐cig users versus non‐smoker/non‐vapers in either cell type.ConclusionsTo our knowledge, our results are the first to suggest that factors in the plasma of E‐cig users lead to reduction in maximal metabolic rates of human endothelial and lung cells in vitro. These results have important implications regarding the effects of E‐cig use on cellular metabolism and mitochondrial function and eventual public health recommendations. We are currently investigating the underlying mechanisms of action of E‐cig plasma components on mitochondrial biology.
Cardiopulmonary protection against nicotine‐induced pulmonary hypertension and right ventricular remodeling in mice is not mediated by ovarian hormones
Authors: Fried Nicholas D. , Whitehead Anna K. , Garcia‐Sanchez Idanis Z. , Lazartigues Eric , Yue Xinping , Gardner Jason D. 
Published: May 2022

IntroductionElectronic cigarette use has increased globally prompting a joint committee of international cardiovascular research organizations to call for improved understanding of the health effects of nicotine. Our group has previously demonstrated that chronic, inhaled nicotine induces pulmonary hypertension (PH) and right ventricular (RV) remodeling in male but not female mice, suggesting sex differences in nicotine‐related pathology. Clinically, biological females develop PH more often, but have less severe disease than biological males, likely due to the cardiopulmonary protective effects of estrogen. Nicotine is also metabolized more rapidly in biological females due to sex hormone‐mediated differences in cytochrome P450 activity. These findings led us to hypothesize that female mice are protected against nicotine‐induced PH by a sex hormone‐dependent mechanism. Here, we assessed the role of ovarian hormones in a murine model of nicotine‐induced PH.MethodsFemale C57BL/6J mice were ovariectomized (OVX) one week prior to nicotine exposure. Intact and OVX mice were exposed to nicotine vapor or room air for 12 hours per day for 8 weeks. Nicotine exposure was measured using serum cotinine, which was comparable to human electronic cigarette users, and was not significantly different between intact (421 ± 101 ng/mL) and OVX (314 ± 61 ng/mL) mice. Cardiac structure and function were assessed using echocardiography and RV catheterization.ResultsIn contrast to previous findings in male mice, inhaled nicotine does not cause PH (measured by RV systolic pressure, RVSP) in intact female mice (24.0 ± 0.5 mmHg, n=7 in air vs. 22.7 ± 0.4 mmHg, n=9 in nicotine). RVSP was also unaffected by OVX (24.4 ± 0.9 mmHg, n=9 in air vs. 23.6 ± 0.6 mmHg, n=10 in nicotine). RV free wall thickness during diastole (RV FWT;d) was not significantly different between air‐exposed intact mice (0.328 ± 0.023 mm, n=8), nicotine‐exposed intact mice (0.292 ± 0.015 mm, n=10), air‐exposed OVX mice (0.315 ± 0.021 mm, n=8), and nicotine‐exposed OVX mice (0.293 ± 0.013 mm, n=10). RV internal diameter during diastole (RVID;d) was, likewise, not significantly different between air‐exposed intact mice (1.30 ± 0.03 mm, n=8), nicotine‐exposed intact mice (1.34 ± 0.04 mm, n=10), air‐exposed OVX mice (1.23 ± 0.05 mm, n=8), and nicotine‐exposed OVX mice (1.24 ± 0.05 mm, n=10).ConclusionIn this study, we found no differences in serum cotinine, RVSP, RV FWT;d, or RVID;d between intact and OVX females, leading us to conclude that ovarian hormones do not mediate cardiopulmonary protection against nicotine‐induced PH. Due to profound sex differences in clinical PH pathogenesis and nicotine metabolism, further studies (including exploration of androgen‐driven RV remodeling) are necessary to illuminate mechanisms underlying protection from nicotine‐induced pathology in female mice.
NOR‐1 Knockdown Reduces Mitochondrial Function in C2C12 Myotubes
Authors: Paez Hector G. , Pitzer Christopher R. , Ferrandi Peter J. , Mohamed Junaith S. , Alway Stephen E. 
Published: May 2022

IntroductionSkeletal muscle is critical for whole‐body metabolic health and a prime determinant of quality of life. Mitochondrial health is compromised by several pathological states that alter muscle metabolism. Exercise is among the most effective means of preserving muscle mitochondrial health, yet rigorous exercise is often impossible in patients suffering from muscle‐related pathologies. Thus, the investigation of exercise responsive molecular targets is a requisite to identify therapeutics that improve muscle metabolic health. Neuron‐derived orphan receptor‐1 (NOR‐1) is highly responsive to exercise and is reduced in preclinical models of obesity and diabetes. The objective of the current study was to investigate the impact of NOR‐1 loss on C2C12 metabolic signaling. We hypothesized that knockdown (KD) of NOR‐1 in myotubes would perturb mitochondrial‐associated gene expression.MethodsC2C12 myotubes were transfected with control or NOR‐1 targeting siRNA to knock down NOR‐1. Protein and RNA were isolated from cells for immunoblotting and qPCR analysis, respectively. Cells were also stained with JC‐1 to evaluate alterations in mitochondrial membrane potential (MMP). NAD+ and NADH+ content was also measured in myotubes. Gene expression was normalized to ß‐actin mRNA whereas protein levels were normalized to total protein. Data were analyzed by an unpaired T‐Test with significance set at p < 0.05 and presented as means ± SEM.ResultsNOR‐1 KD cells had lower gene expression of PGC‐1α, TFAM, and MFN2 and several proteins involved in energy production were altered (ND2, CYCS, CPT‐1ß, FABP4). Myosin protein content and gene expression of MYHI, MYHIIA, and MYHIIX were also reduced. Protein abundance of mitochondrial electron transport system complexes were reduced and both BAX and DRP1 abundance were enhanced after NOR‐1 KD, which was coincident with a diminished NADH content, and a shift towards the green monomeric spectra after JC‐1 staining, indicating a reduced mitochondrial membrane potential. Surprisingly, NOR‐1 KD also reduced mTORC1 signaling, evidenced by reduced P70S6K and S6K phosphorylation.ConclusionsThese data suggest loss of NOR‐1 reduces oxidative gene expression, induces mitochondrial depolarization, and reduces NADH content, implicating NOR‐1 as an important regulator of energy homeostasis and muscle metabolic signaling. Investigations into the molecular hierarchy between NOR‐1 and PGC‐1α will delineate between primary and secondary effects of NOR‐1 deficiency.
Transferrin receptor‐mediated iron uptake is essential for colon tissue homeostasis
Authors: Kim Hyeoncheol , Xue Xiang 
Published: May 2022

Background and aimsTransferrin receptor (TFRC) is the major mediator for iron entry into a cell. Under excessive iron conditions, TFRC is expected to be downregulated via the iron regulatory protein and the iron‐responsive element machinery to reduce iron uptake and toxicity. However, the mechanism by which the expression of TFRC is maintained high in iron‐enriched cancer cells and its contribution to cancer development are enigmatic.MethodsThe regulation and function of TFRC‐mediated iron uptake in colon were tested in mouse models with colon‐specific TFRC disruption and colon‐derived cell lines. Transcriptome analysis of patient‐derived tumor colonoids was performed to identify molecular targets of iron.ResultsOur work shows TFRC is induced by adenomatous polyposis coli gene loss‐driven β‐catenin activation in colorectal cancer, whereas TFRC‐mediated intratumoral iron accumulation potentiates β‐catenin signaling via directly enhancing the activity of tankyrase. TFRC‐mediated iron import is at the center of this novel feed‐forward loop to facilitate colonic epithelial cell survival. Mechanistically, disruption of TFRC led to a reduction of colonic iron levels and iron‐dependent tankyrase activity, which caused stabilization of Axin2 and subsequent repression of the b‐catenin/c‐Myc/E2F1/DNA polymerase delta1 (POLD1) axis. POLD1 knockdown, iron chelation and TFRC disruption increased DNA replication stress, DNA damage response, apoptosis and reduced colon tumor growth. Strikingly, a combination of iron chelators and DNA damaging agents caused a synergistic effect in inducing DNA damage response and reducing colon tumor cell growth.ConclusionTogether, the TFRC/iron/tankyrase/Axin2/b‐catenin/c‐Myc/E2F1/POLD1 axis is essential for colon homeostasis and may provide potential novel strategies for colorectal cancer therapy.
New Insights into the Structure‐Function Relationships of G Proteins Containing Disease‐Associated Mutations
Authors: Anazia Kara , Petrraco Enzo , Ferré Guillaume , Eddy Matthew T. 
Published: May 2022

G proteins regulate intracellular signaling processes through their interactions with guanine nucleotides, GDP and GTP, and initiate numerous physiological responses. In normal conditions, G protein functions are regulated in a tightly controlled signaling network through complex formation with partner proteins, especially G protein‐coupled receptors (GPCRs). However, loss‐of‐function or gain‐of‐function mutations in the Gα subunit of G proteins disrupt this process, circumventing the usual control mechanisms and causing changes in G protein activity that result in serious illnesses. Our studies focused on the stimulatory class of trimeric G proteins, Gs, and mutations in Gαs associated with multiple cancers1. While the structure of one Gαs variant has been determined and additional Gαs variants have been characterized biochemically, there remains a need for an overall mechanistic framework for relating mutations in Gαs to changes in G protein signaling.To fill in this gap in knowledge, we investigated the interactions of Gαs variants with nucleotides using saturation transfer difference nuclear magnetic resonance (STD‐NMR) spectroscopy in aqueous solutions. In STD‐NMR experiments, we observed interactions between nucleotides and the Gαs variant proteins at atomic resolution, which provided information on nucleotide binding modes. STD‐NMR data of one Gαs variant closely correlated with literature data of the structure and activity of the same variant protein2, establishing a foundation for extending the analysis of NMR data to seven additional disease‐associated Gαs variant proteins for which no structures are available. These NMR data were combined with correlative biophysical data that measured the overall fold of the Gαs‐nucleotide complexes and with functional data reporting on the relative affinities of the Gαs variants for GDP and GTP. Integrating these data together provided a conceptual framework for categorizing variations in Gαs amino acid sequences with changes in signaling activity. Surprisingly, differences in the binding modes of the Gαs variants did not always directly correlate with their different functions, suggesting that mutations in Gαs that impact nucleotide exchange are nuanced and complex. These results imply that strategies for the development of small molecule drugs may need to be specifically tailored for each disease associated Gαs variant.References

O’Hayre, M. et. al. The emerging mutational landscape of G proteins and G protein‐coupled receptors in cancer. Nat. Rev. Cancer. 13, 412‐424 (2013).
Hu, Q. & Shokat, K. M. Disease‐Causing Mutations in the G Protein Gαs Subvert the Roles of GDP and GTP. Cell. 173, 1254–1264 (2018).
Sensitivity to Iron‐Mediated Pro‐Inflammatory Signaling in NZBWF1 Mice, a Model of Systemic Lupus Erythematosus
Authors: Dsouza Del L. , Boesen Erika I. 
Published: May 2022

IntroductionThe autoimmune disease systemic lupus erythematosus predominantly affects women and can lead to lupus nephritis (LN) as a common and severe complication in approximately 50% of patients. The F1 hybrid of New Zealand Black (NZB) X New Zealand White (NZW) mice (NZBWF1) is a well‐established mouse model to study LN. Our previous data indicated that the onset of albuminuria in female 34‐week NZBWF1 mice was associated with renal iron accumulation, and iron may contribute to renal injury. This study tests the hypothesis that 34‐week NZBWF1 lupus mice are sensitized to iron's injurious and pro‐inflammatory effects compared to 8‐week normal NZBWF1 mice. As a means to differentiate effects of age as opposed to development of lupus, parallel experiments were performed in 8 and 34‐week‐old NZW mice as healthy controls.Methods and ResultsFemale 8‐week (pre‐autoimmune) and 34‐week NZBWF1 (autoimmune, pre‐albuminuric) mice together with age‐matched healthy control NZW mice underwent 24 h urine collection to confirm non‐albuminuric status. Mice were then were injected i.v. with a single dose of iron‐sucrose (2 mg elemental iron) or vehicle (saline) and sacrificed 24 h later. Plasma blood urea nitrogen (BUN) was measured to determine renal health, SRY‐Box Transcription Factor 9 (SOX‐9)‐ positive cells were quantified in kidney sections as an early tubular injury marker, and plasma monocyte chemoattractant protein‐1 (MCP‐1) was measured by ELISA as an inflammatory marker. Lupus (NZBWF1) and control mice (NZW) were compared within strains by age (8‐week vs. 34‐week) and treatment (Vehicle vs. Treatment). All statistical analyses were done by 2‐way ANOVA (n=7‐12/group), and post‐hoc testing was done using Bonferroni. Iron‐sucrose treatment significantly increased plasma MCP‐1 concentrations in the NZBWF1 and the control NZW mice (PTreatment < 0.01). There was no significant effect of age on this effect for NZW mice (PTreatment*Age = 0.2); however, in NZBWF1 mice, the iron‐sucrose induced increase in MCP‐1 was significantly greater in 34‐week compared to 8‐week mice (PTreatment*Age < 0.05; P<0.05 by posthoc test). BUN was significantly increased with age in both strains (PAge<0.05), but there was no significant effect of iron‐sucrose (PTreatment>0.05). The numbers of SOX‐9+ tubular cells increased in the 34‐week NZBWF1 mice compared to 8‐week mice (Page<0.05), consistent with early stages of renal injury, but iron sucrose treatment did not show any significant effect (PTreatment= 0.9).ConclusionOur data suggest that at the autoimmune but pre‐albuminuric stage, 34‐week NZBWF1 mice show increased pro‐inflammatory responsiveness to iron‐mediated stress. Further studies to determine whether the enhanced pro‐inflammatory effects of iron contribute to pathology in lupus nephritis are ongoing.
Cardioprotective effects of redox regulator MnTnBuOE‐2‐PyP 5+ in myocardial ischemia/reperfusion injury
Authors: Sharma Sudha , Patel Foram , Bhattarai Susmita , Ara Hosne , Subedi Utsab , Bhuiyan Md. Shenuarin , Batinic‐Haberle Ines , Panchatcharam Manikandan , Miriyala Sumitra 
Published: May 2022

BackgroundMyocardial infarction is a leading cause of death worldwide and occurs due to decrease or complete blockage of coronary blood flow. Re‐establishment of blood flow after a brief period of ischemia is accompanied by exacerbation of the cardiomyocytes and its death, a phenomenon known as myocardial ischemia‐reperfusion (I/R) injury. Much evidence suggests that oxidative stress is involved in the pathogenesis of myocardial ischemia‐reperfusion injury and is potential target for therapeutic interventions. The aim of this study is to evaluate cardioprotective role of redox active Mn(III) N‐n‐butoxyethylpyridinium‐2‐yl)porphyrin, MnTnBuOE‐2‐PyP5+ (BMX‐001) in myocardial I/R injury. This drug is now in 4 Phase II clinical trials where the radioprotection of normal issue and anticancer efficacy have been evaluated.MethodsMyocardial I/R injury in mice C57BL/6 was induced by ligating left anterior descending artery for 1 hour followed by 24 hours of reperfusion. At the end of reperfusion, hearts were sectioned (1mm) and stained with 1% 2, 3, 5‐Triphenyltetrazolium chloride (TTC) to determine infarct size. Cardiac function was evaluated by M‐mode echocardiography at the end of the reperfusion. For in vitro model, H9c2 cells were subjected to hypoxia for 3 hours followed by 24 hours of reperfusion. Cell apoptosis was measured by TUNEL assay. Mitochondrial superoxide and Cardiolipin peroxidation were measured by using MitoSOX and 10‐N‐nonyl‐Acridin Orange, respectively.ResultsIn the current study, we demonstrated that treatment with MnTnBuOE‐2‐PyP5+ (2mg/kg) 4 hours before I/R injury in mice ameliorate cardiac injury as evident by limited infarct size and improved cardiac function (P<0.05). Consistently, MnTnBuOE‐2‐PyP5+ improved mitochondrial SOD2 expression (P<0.05) and reduced cardiomyocytes apoptosis in mice heart (P<0.05). In our in vitro model of hypoxia/reoxygenation injury in H9c2 cells, treatment with MnTnBuOE‐2‐PyP5+ (10µM) 24 hours before hypoxia/ reoxygenation injury decreased cardiolipin peroxidation, mitochondrial superoxide level and 4‐HNE adducted proteins (P<0.01). Additionally we explored role of MnTnBuOE‐2‐PyP5+ on cell apoptosis following ischemia/reperfusion injury in H9c2 cells. Redox regulator significantly reduced TUNEL positive cells following I/R injury indicating reduced cardiomyocytes apoptosis (p<0.05). In‐vitro, redox‐active Mn porphyrin improved cell viability and lactate dehydrogenase release following hypoxia/reoxygenation in H9c2 cells (p<0.05).ConclusionThis result provided evidence that MnTnBuOE‐2‐PyP5+ elicited cytoprotective effects through reduction of mitochondrial oxidative stress and cardiomyocyte apoptosis suggesting prospective therapeutics in myocardial I/R Injury.