bluuebunny/crossref_metadata_2025_split huggingface dataset:
Anti‐tumor activity of the ethanolic extract of Micromeria fruticosa on human breast and colon cancer cells
Authors: Abu-Gharbieh Eman , El-Huneidi Waseem , Shehab Naglaa G. , Bajbouj Khuloud , Vinod Arya , El-Serafi Ahmed , Malhab Lara Bou , Abdel-Rahman Wael M. 
Published: April 2020

Micromeria fruticosa (L.) Druce subsp. Serpyllifolia (Lamiaceae) is a perennial, aromatic shrub that usually distributed in the Mediterranean regions. The aerial parts of the plant are widely used to treat many diseases, including abdominal pains, diarrhea, colds, eye infections, heart disorders and wounds. A few reports have confirmed various therapeutic potentialities of its extract, such as anti‐inflammatory, gastroprotective, analgesic activities, antiobesity, and antidiabetic activities.AimTo investigate the mechanistic pathway for the antitumor activity of the ethanolic extract of M. fruticosa on two different cancer cell lines, namely human breast adenocarcinoma (MCF‐7), human colorectal cancer (HCT‐116) cell lines.MethodsCell viability assay, DNA profile with PI staining, Annexin‐V/PI apoptosis assay, microarray analysis, qRT‐PCR were used to assess the effect of M. fruticosa on cytotoxicity, cell cycle proliferation, apoptosis, and genes expression profile in treated cell lines.ResultsM. fruticosa is found to exhibit potential and effective cytotoxic activity against MCF‐7 and HCT‐116 cancer cell lines by attenuating cell proliferation and inducing cell cycle arrest. Microarray analysis revealed a significant reduction in cdk1, cyclin B1 and survivin levels upon M. fruticosa treatment. The qRT‐PCR confirmed the downregulation of cdk1, cyclin B1 that correlates with the observed G2 arrest in both cell lines. Moreover, results showed that the decreased levels of the cell death inhibitor, survivin is correlated to the promoted cell death in the treated cell lines.ConclusionThe findings suggest promising antiproliferative potential Micromeria fruticosa in breast and colon cancers. Further studies are needed to characterize the potential active constituent.Support or Funding InformationThis research was funded by University of Sharjah Seed Grant no.1701090113‐P and UOS‐Boehringer Ingelheim award.
Nicotine exposure during pregnancy alters the maternal gut microbiome and both cecal and plasma short chain fatty acids in Sprague Dawley rats.
Authors: Hayward Linda , Watkins Jacqueline , Bautista Byrell , Lin Cindy , Malphurs Wendi , Zubcevic Jasenka 
Published: April 2020

Children of mothers that smoke during pregnancy are more likely to be obese and develop high blood pressure, suggesting a developmental origin of these diseases. Evidence now suggests that an imbalance of the bacterial microbes in the gastrointestinal tract may also play an important role these diseases. Thus, the present study was undertaken to test the hypothesis that nicotine‐exposure during pregnancy alters the maternal gut‐microbiome, inducing gut dysbiosis that may be passed on to the child during birth and/or shifts in bacterial metabolites, such as short chain fatty acids (SCFAs), that the fetus is exposed to in utero. To test our hypothesis, age‐matched virgin and pregnant female rats were exposed to nicotine (6 mg/kg/day) or vehicle (saline) via osmotic mini pump, including days 6–18 of pregnancy. Cecal contents, tissue from the proximal colon, and plasma were collected on day 14 of treatment. A two‐way ANOVA (pregnant state x treatment) identified that pregnancy decreased the abundance of bacteria in the phyla Firmicutes, while increasing the abundance of Actinobacteria and Verrucomicrobia compared to virgin rats (P<0.02). Nicotine exposure, independent of pregnancy, further increased the abundance of Actinobacteria (P<0.03) and tended to increase the proportion of Firmicutes and decrease the abundance of Verrucomicrobia. Evaluation of cecal SCFAs identified that pregnancy upregulated the abundance of acetate and propionic acid (P<0.02) and tended to upregulate butyric and hexanoic acid. Conversely, nicotine exposure, independent of pregnancy, decreased cecal acetate (P<0.02), propionic acid (P<0.007), and hexanoic acid (P<0.009) concentrations. Similarly, plasma levels of acetate, propionic, butyric, and valeric acid were upregulated by pregnancy, and nicotine exposure, independent of pregnant state, reversed this trend (P<0.05). Finally, gene expression in the proximal colon identified that pregnancy triggered an upregulation of multiple genes, including the protective enzyme 11‐beta HSD2, the sodium channel ENAC, Ffar2, the SCFA acetate and propionate transporter, the solute carrier SMCT1, and Tph2, the rate limiting enzyme for serotonin production (P<0.05). Independent of pregnancy status, nicotine downregulated the expression of all five genes. These results confirm our hypothesis that nicotine exposure during pregnancy can significantly alter the maternal gut microbiome and affect fetal exposure to specific circulating factors linked to gut microbial metabolism. These findings provide a new link between changes in the maternal gut microbiome and the fetal origins of adult diseases.Support or Funding InformationFL DOH James and Esther King Biomedical Research Program 8JK06
Neuroinflammation and Microglial Activation in The Central Amygdala in Rats with Heart Failure
Authors: Althammer Ferdinand , Neto Hildebrando Candido Ferreira , Stern Javier Eduardo 
Published: April 2020

Cardiovascular diseases (CVDs), such as heart failure (HF) are the most common cause of death globally. Moreover, clinical studies support a high degree of comorbidity between CVDs cognitive impairment, and emotional distress, with 20–40% of all HF patients displaying depression and anxiety levels significantly higher than the healthy population. Still, the precise underlying mechanisms causing those cognitive and emotional impairments remain elusive. The paraventricular nucleus of the hypothalamus (PVN) is a key brain structure involved in emotional control and directly communicates with the central lateral part of the amygdala (CeA), which actively participates in the regulation of emotion and fear memories. While markers of neuroinflammation (NI) have been previously described in the PVN of HF rats, it is at present unknown whether the CeA is also affected. To address this question, we used an ischemic HF rat model (ejection fraction <35%). We developed a comprehensive quantitative microglial profiler using the IMARIS software along with immunohistochemical staining with the microglial marker IBA‐1 to assess changes in various microglial parameters indicative of different microglia activity stages. At early stages of the established HF (8wks post‐surgery), we found elevated indexes of microglial activation in the PVN compared to sham controls (15.4% decrease in surface area, 29.9% decrease in cell volume, 15.5% decrease in filament length and 35.1% increase in IBA‐1 immunoreactivity intensity, p<0.001 in all cases). These changes became more pronounced at later (14wks) stages of the disease. While no changes were observed in the CeA at the early stage, significant changes were observed at 14wks after HF compared to sham controls (21.2% increase in cell volume, 9.7% decrease in filament length and 12.3% increase in IBA‐1 immunoreactivity intensity, p<0.05 in all cases). These morphometric changes are indicative of de‐ramification and somatic swelling of microglial cells. These findings were corroborated by elevated mRNA levels of IBA‐1, TNF‐a, IL‐1β and IL‐6 measured via qPCR in PVN and CeA punches from HF rats. Importantly, no microglial changes were observed in cortical areas suggesting that HF‐induced NI was not a diffuse phenomenon affecting the entire brain. To the best of our knowledge, our results highlight for the first time that in addition to the PVN, HF also results in a robust microglial cell activation in the CeA, a critical forebrain region involved in emotion and cognition. NI‐related changes in the CeA occurred at a later stage of the disease, and could potentially contribute to cognitive impairment and mood disorders in HF patients.Support or Funding InformationNational Institutes of Health grants R01NS094640 and R01HL090948 to JES
Quantifying Cardiac Injury with Donation after Circulatory Death Process: Impact of Donor Age and Obesity
Authors: Akande Oluwatoyin Elizabeth , Chen Qun , Toldo Stefano , Lesnefsky Edward , Quader Mohammed 
Published: April 2020

IntroductionHeart transplantation, the gold standard treatment for patients with advanced heart failure, is limited due to shortage of suitable donor hearts, which at the present are procured from Brain Death Donors (DBD) only. Recent advancement in organ procurement and retrieval techniques have shown that Donation after Circulatory Death (DCD) promises to expand the heart donor pool. While ischemic insult is inherent in the DCD process, subsequent reperfusion injury is inevitable in these hearts. Donor age and obesity may adversely affect the function of a DCD heart. We herein hypothesize that age and obesity may influence the outcome of cardiac injury in DCD hearts.MethodsSD rats ages between 13 and 17 weeks, weighing between 340 and 430 grams were subjected to 25min of warm ischemia following the DCD protocol. Hearts from these DCD rat models were reanimated on Langendorff system primed with KH buffer at 37°C, and perfused at steady 73mmHg for 60 minutes, to obtain cardiac function (left ventricle developed pressure‐LVDP, positive and negative dP/dt) data.ResultsFollowing 25 min of warm ischemia in vivo, we observed lower LVDP (43±10 mmHg) in DCD hearts from rats older than16 weeks or weighing more than 370 grams when compared with LVDP ( 64±12 mmHg ) in hearts from rats younger than 16 weeks of age or weighing less than 370 grams. Similar trend was noted in positive and negative dP/dt values. The decrease in DCD heart function was near linear with both increasing age and weight (Figure 1).ConclusionsBased on our findings, age and obesity of DCD donor influences susceptibility to warm ischemia. These donor factors need to be taken into consideration when designing studies involving DCD rat hearts.
The equal pressure point is greater in men than women near total lung capacity
Authors: Gideon Elizabeth A. , Coriell Catherine L. , Betts Aaron W. , Cross Troy J. , Duke Joseph W. 
Published: April 2020

The equal pressure point (EPP) states that expiratory flow limitation occurs at the precise location along the tracheobronchial tree where intraluminal and peribronchial pressures are equal (i.e., where the local transmural pressure is 0 cmH2O). The EPP may be determined numerically via the expiratory isovolume pressure flow (IVPF) curve. For instance, using data from a given isovolume curve, the EPP is determined as the point along the x‐axis at which pressure‐flow data fails to conform to Rohrer’s equation: driving pressure = k1(flow) + k2(flow2). The probability of incurring expiratory flow‐limitation can be greatly determined by the EPP such that a lower EPP at a given lung volume requires only minimal pressure development to create a flow‐limiting segment during expiration. The EPP is affected by two principal factors: lung elastic recoil (PLUNG) & airway geometry. Given recent evidence suggesting that airway geometry is different between men & women, we sought to determine whether the EPP is likewise affected by sex in healthy adults.PurposeDetermine whether or not there is an effect of sex on the magnitude of the EPP.MethodsTo address this question, 11 men (23.1 ± 4.8 years) and 12 women (21.2 ± 1.0 years) completed a study requiring two visits to the laboratory. On the initial visit, we obtained written informed consent and conducted spirometry to ensure subjects met the inclusion criteria of normal (>85% of predicted) lung function. During the second visit, a balloon catheter was passed intranasally to the lower one‐third of the esophagus and remained there for the duration of the visit to measure esophageal pressure (PES). Subjects then performed a minimum of 10–15 graded vital capacity maneuvers from 100‐5% of maximal effort. Data were imported into Matlab and, using custom‐written code, multiple calculations were performed. First, the lowest effort vital capacity efforts were taken as quasi‐static expiratory deflations of the lung and the negative sign of PES was taken to equal PLUNG. Second, alveolar pressure (PALV) was taken to equal PES + PLUNG. Finally, the EPP was determined by iteratively fitting Rohrer’s equation to pressure‐flow data at a given iso‐volume. The pressure at which Rohrer’s equation no longer adequately fit the data (>5% error) was termed the EPP. To test for an effect of sex and lung volume, a two‐way ANOVA was computed. Pairwise comparisons were adjusted for multiple comparisons using the Tukey‐Sidak post hoc test.ResultsThere was no effect of sex on PLUNG, but PALV was greater in men than women throughout the entire VC range. EPP was significantly greater in men than women during the initial half of VC (95‐55% of VC) (p < 0.05), but not the remaining half (p > 0.05).ConclusionBecause PLUNG did not differ between men and women, the differing location of EPP was the result of a greater PES in men. This suggests that the larger airways present in men are more resistant to compression than those of women.
Lack of Uncoupling Protein 3 Protects from High‐Fat Diet‐Induced Obesity, Systemic Inflammation and Insulin Resistance in Rats
Authors: Lomax Tyler , Ashraf Sadia , Yilmaz Gizem , Harmancey Romain 
Published: April 2020

Introduction. Uncoupling protein 3 (UCP3), a mitochondrial anion carrier with antioxidant properties, is downregulated in animal models with obesity, insulin resistance and type 2 diabetes. Although mutations in UCP3 have been linked to obesity in humans, their contribution to increased adiposity and insulin resistance is still unclear. The goal of this study was to investigate the impact of UCP3 loss on the development of high‐fat diet‐induced obesity in rats.Methods. Male UCP3 knockout (KO) rats and their wild type (WT) littermates were maintained on a high‐fat diet (45% kcal from fat) for up to 21 weeks starting at 8 weeks of age. Body composition was analyzed by EchoMRI. Whole‐body insulin sensitivity and tissue‐specific glucose uptake were determined during hyperinsulinemic‐euglycemic clamps studies. White and brown adipose tissue morphologies were assessed by histology and electron microscopy. Potential molecular alterations in brown adipose tissue (BAT) physiology were further investigated by RNA sequencing, quantification of total protein S‐sulfenylation, and determination of tissue glutathione levels.Results. Loss of UCP3 unexpectedly decreased body weight gain on a high‐fat diet in spite of increased food intake. The decrease in body weight gain was driven by a decrease in body fat mass leading to smaller white adipocytes and a decrease in circulating tumor necrosis factor alpha levels. Consequently, the KO rats exhibited preserved insulin sensitivity and glucose tolerance which correlated with increased glucose uptake in BAT. While high‐fat feeding induced lipid accumulation and whitening of BAT in WT rats, this phenomenon was markedly reduced in KO rats. Surprisingly, protein S‐sulfenylation was decreased in BAT from KO rats, suggesting decreased mitochondrial reactive oxygen species generation in spite of UCP3 loss. The RNA sequencing analysis of BAT transcriptome revealed increased expression of multiple enzymes linked to glutathione synthesis. Direct quantification of glutathione confirmed a 44% increase of the antioxidant molecule levels in BAT of KO rats when compared to high‐fat fed WT rats.Conclusions. Lack of UCP3 protects from high‐fat diet‐induced obesity and insulin resistance in rats. We propose that this protective effect is driven by a compensatory increase in synthesis of the antioxidant glutathione in BAT, thereby protecting mitochondrial function and substrate utilization in this tissue. The findings suggest that loss of UCP3 function in humans may unexpectedly decrease whole‐body fat accumulation, inflammation and the development of insulin resistance.Support or Funding InformationThis work was supported by grants R01HL136438, P20GM104357 and P01HL051971 from the National Institutes of Health.
Effective Reinnervation of Skeletal Muscle is Impaired by Disrupting Microvascular Regeneration Following Acute Injury
Authors: Morton Aaron B , Cornelison DDW , Segal Steven S 
Published: April 2020

Acute injury of skeletal muscle damages myofibers, microvessels and neuromuscular junctions (NMJs). Although myofiber regeneration is well‐characterized, little is known of concurrent events in microvessels and motor nerves during skeletal muscle regeneration. Because growth and patterning are coordinated between nerves and microvessels during development, we tested the hypothesis that effective microvascular regeneration is required for restoring neuromuscular structure and function post injury in the adult. To impair angiogenesis, mice were bred for endothelial cell (EC)‐specific deletion of ephrin‐B2. Male mice (3–6 months old; n=2–3/group) were injected with tamoxifen to delete ephrin‐B2 in ECs (EfnB2CKO; confirmed with PCR); uninjected mice of the same genotype were used as controls. The gluteus maximus (GM) or tibialis anterior (TA) muscle was injured by local injection of 1.2% BaCl2 and muscles were evaluated at 10 days post injury, by which time morphological and functional myofiber regeneration will have occurred. Intravascular injection of fluorescent wheat germ agglutinin (WGA; stains only perfused vessels) or immunolabeling for CD31 (stains all ECs) revealed microvessels of the GM in EfnB2CKO to be vacuolated with disorganized ECs vs. intact microvascular networks with aligned ECs in control mice. Using indirect stimulation via the sciatic nerve, isometric force production in the TA was 19±6 N/cm2 in EfnB2CKO vs. 33±3 N/cm2 in control mice; force produced with direct electrical field stimulation was similar between groups. Immunostaining for neurofilament‐heavy revealed reduced presynaptic coverage of NMJs in EfnB2CKO vs. control [60±9% vs. 74±10% of acetylcholine receptors (AChRs) per 200 μm2 NMJ area]; postsynaptic staining with α‐bungarotoxin revealed dispersed AChRs [200±118 vs. 92±43 fragments/200 μm2, respectively]. These preliminary findings indicate that the loss of ephrin‐B2 in ECs results in functional deficits for neuromuscular transmission and NMJ morphology in association with impaired microvascular regeneration following acute injury. We conclude that regeneration of intact NMJs with functional reinnervation of myofibers requires effective revascularization and recovery of the microcirculation following skeletal muscle injury.Support or Funding InformationSupport: APS Postdoctoral Fellowship (ABM), R01AR067450 (DDWC), R37HL041026 (SSS)
Metabolic Effects of Whey Protein Isolate Supplementation on Cholesterol and Triglycerides in Women with Polycystic Ovary Syndrome
Authors: Balcom-Luker Shenavia , Kaiser Kayleigh , Zumbro Emily L. , Rao Manisha , Low Irene , Broughton K. Shane , LeMieux Monique J. 
Published: April 2020

The current study examined the acute‐ and chronic effects of whey protein isolate ingestion on plasma cholesterol and triglyceride concentrations in women with polycystic ovary syndrome (PCOS). PCOS, an endocrine abnormality in women of reproductive age, is characterized by menstrual cycle disturbance, hyperandrogenism and obesity. Women with PCOS have altered metabolic profiles and are more likely to develop type 2 diabetes and/or liver disorders such as non‐alcoholic fatty liver disease (NAFLD). Nutritional management options are severely limited. Whey protein isolate (WPI) improves metabolic parameters in patients with and without type 2 diabetes, but its therapeutic potential in polycystic women has yet to be realized. Given the association between PCOS and NAFLD, we hypothesized that supplementation with WPI may attenuate circulating cholesterol and triglycerides in a polycystic population. Fifteen premenopausal women with PCOS and eleven healthy, regularly menstruating women underwent three 150‐min oral glucose tolerance tests (OGTT): (i) OGTT without protein preload, (ii) OGTT on 1st, and (iii) 40th day of protein preload. Participants consumed 35g protein daily with protein intake 30 min before carbohydrate load on test days. Plasma levels of cholesterol and triglycerides were assessed at baseline, day 1 and day 40 to determine acute and chronic effects on cholesterol and triglycerides using a Biolis 24i chemistry analyzer. (Participant recruitment, data collection and analyses in progress.) Protocols used in this study were approved by the TWU Institutional Review Board. Mixed Model Repeated Measure ANOVA indicates that time and condition (PCOS vs control) did not have a significant effect on cholesterol or triglyceride levels within and between groups (p > .05). However, preliminary data indicate that disease condition had a significant impact on cholesterol (p< .001) and triglyceride (p = .001) concentrations at baseline. Changes in cholesterol and triglyceride levels after 40 days of protein preload are currently being analyzed. Women with PCOS have higher levels of cholesterol and triglycreides than those without this condition. While acute effects of 35g WPI ingestion do not seem to alter these levels, a longer duration of supplementation may induce more beneficial effects (currently being conducted). Findings from this study will provide foundational support for WPI as a nutritional treatment for PCOS and reveal insights into cholesterol metabolism mechanisms that are affected by PCOS and NAFLD.Support or Funding InformationGlanbia Nutritionals, INC; Human Nutrition Research Funds, Texas Woman’s University; Research Enhancement Program, Texas Woman’s University
Skeletal Muscle Reflex‐Induced Dysregulation of Sympathetic Nerve Activity in Type 1 Diabetic Rats
Authors: Kim Han-Kyul , Ishizawa Rie , Hotta Norio , Iwamoto Gary , Vongpatanasin Wanpen , Mitchell Jere , Smith Scott , Mizuno Masaki 
Published: April 2020

The pressor response to physical exercise is exaggerated in the early stages of type 1 diabetes mellitus (T1DM). This augmented blood pressure (BP) response has been further shown to be mediated by an overactive skeletal muscle exercise pressor reflex (EPR). However, whether alterations in sympathetic responsiveness contribute to this EPR overactivity is unknown. The purpose of this study was to test the hypothesis that the potentiated BP response to exercise in T1DM is mediated by EPR‐induced sympathetic overactivity. Sprague‐Dawley rats were intraperitoneally given either 50 mg/kg streptozotocin (T1DM) or saline (control). We measured renal sympathetic nerve activity (RSNA) and mean arterial pressure (MAP) responses to activation of the EPR, as well as its functional components, the mechanoreflex and metaboreflex, in decerebrate animals at 1–3 weeks after administration. Compared to control rats, selective activation of the EPR evoked significantly greater increases in RSNA (Δ = 58±7 vs. 96±15 %, P<0.05) and MAP (Δ = 11±2 vs. 33±5 mmHg, P<0.05) in T1DM rats. The sympathetic and pressor responses to the individual stimulation of the mechanoreflex and metaboreflex were also significantly larger in T1DM animals than in control animals (P<0.05). These findings suggest that in untreated T1DM, abnormally large muscle reflex‐evoked sympathetic overactivity contributes significantly to exaggerations in BP during exercise. Importantly, the results implicate sympathetic overactivity as a potential therapeutic target for improving/preventing the abnormally high BP response to exercise in T1DM.Support or Funding InformationThe Southwestern School of Health Professions Interdisciplinary Research Grant Program, the Lawson & Rogers Lacy Research Fund in Cardiovascular Disease and the JSPS KAKENHI JP17K01769