bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Role of Hepatic MDM2 in the Regulation of Energy and Lipid Metabolism in Obesity
Authors: Wang L. , Liu Z. , Hui X. , Xu A. , Cheng K.K.Y. 
Published: June 2021

IntroductionVery‐low‐density‐lipoprotein (VLDL) is a major vehicle for transporting lipids from liver to peripherals in plasma. VLDL‐triglyceride secretion is an important pathway for disposition of hepatic fat, and its inhibition results in hepatic steatosis. VLDL assembly and secretion are controlled by lipid availability and insulin resistance. MDM2, an E3 ligase mediating the final step of ubiquitination. We previously found that MDM2 regulates glucosestimulated insulin secretion via regulation of pyruvate carboxylase (PC) in the pancreatic islet. As PC is a key metabolic enzyme that mediates gluconeogenesis in the liver and MDM2 has been shown to control hepatic fatty acid oxidation. Therefore, we here investigated the role of MDM2 in hepatic energy and lipid metabolism using a hepatocyte‐specific MDM2 knockout mouse model.MethodsMDM2floxed/floxed mice were crossed with transgenic mice with Cre expression under the control of albumin promoter to generate hepatocyte‐specific MDM2 knockout (HMDM2‐ KO) mice. Mice were fed with a high‐fat‐high‐cholesterol (HFHC) diet for 16 weeks to induce obesity, insulin resistance and hepatic steatosis. Basic metabolic parameters and VLDL secretion rate were monitored.ResultsHepatocyte‐specific deletion of MDM2 has no obvious effect on body weight, insulin sensitivity, glucose tolerance and energy expenditure under HFHC diet feeding. HMDM2‐KO mice are characterized by postprandial hypertriglyceridemia, which results from increased hepatic VLDL secretion. Moreover, HMDM2‐KO mice displayed attenuated hepatic steatosis and downregulated mRNA and protein level of inflammatory markers in the liver when compared to their wild‐type littermates.ConclusionOur study proposes a novel role of hepatic MDM2 in regulation VLDL‐triglyceride secretion independent of insulin resistance.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Effects of Transcutaneous Application of Carbon Dioxide on diabetic muscle atrophy
Authors: Kondo Hiroyo , Tani Tomomi , Naito Kana , Niimi Yurina , Nakane Moemi , Sugiyama Yui , Okayasu Kanako , Takemoto Hatsumi , Matsumoto Tomohiro , Takuwa Miho , Hirabayashi Takumi , Ikeji Takuya , Ono Kohei , Fujino Hidemi 
Published: June 2021

IntroductionDiabetes results in muscle atrophy, also called diabetic myopathy. Both the increase in muscle proteolysis and the decrease in muscle protein synthesis contribute to diabetic muscle atrophy. Transcutaneous application of carbon dioxide (CO2) has been used for cardiac disease and skin problems for a long time. In addition, it has been reported the CO2 treatment leads to an increase of muscle mass in normal rats. Therefore, the transcutaneous application of CO2 would have a therapeutic potential for diabetic muscle atrophy. The aim of the present study was to investigate the effects of transcutaneous application of CO2 on diabetic muscle atrophy.MethodsMale Goto‐kakizaki rats were divided into control and CO2 treatment groups. The hair on the lower limbs was shaved and the hydrogel was applied. The CO2 adaptor was attached to the limbs and sealed, and CO2 was administered into the adaptor for 30 min. This treatment was performed everyday for 8 weeks.ResultsThe body weight, epididymal and retroperitoneal fat were lower in the CO2 treatment group than in the control. In addition, the level of fasting blood glucose in the CO2 treatment group was significantly decreased compared with the control. Furthermore, the muscle masses of lower limbs in the CO2 treatment group were higher than those in the control.ConclutionThese results indicate that the transcutaneous CO2 treatment may have a therapeutic potential for diabetic muscle atrophy.Support or Funding InformationSupported by Grants‐in‐Aid for Science Research from the Japanese MEXT.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Appendicular Muscle Mass is Lower in Late‐ Compared to Early‐perimenopausal Women
Authors: Park Young‐Min , Jankowski Catherine M , Ozemek Cemal , Hildreth Kerry L , Kohrt Wendy M , Moreau Kerrie L 
Published: June 2021

OBJECTIVEThe age‐related decline in skeletal muscle mass (i.e. sarcopenia) and bone mineral density (BMD; i.e. low bone mass, osteoporosis) contribute to physical disability in older women. Although menopause‐related loss of BMD is well documented, whether menopause influences muscle mass and sarcopenia is unclear. We determined the extent to which appendicular lean mass (ALM) and BMD differ across the stages of menopause in healthy women.METHODS145 women (aged 30–70 years) classified as premenopausal (Pre; regular menstrual cycles; n=30, 38±6yrs; mean ± SD), early perimenopausal (Eperi; > 2 cycles with cycle length changes of ≥7 days; n=31, 50±3yrs), late perimenopausal (Lperi; ≥2 but <12 months of amenorrhea; n=30, 50±4yrs), early postmenopausal (Epost; ≤5 yrs since menopause; n=26, 55±3yrs), or late postmenopausal (Lpost; >5 yrs since menopause; n=28, 62±4yrs) were enrolled. Dual‐energy x‐ray absorptiometry (DEXA) was used to assess ALM (kg/m2), BMD, total body lean mass, and fat mass.RESULTSALM was lower (p<0.05) in Lperi and Lpost compared to Eperi with no significant differences between other groups (Pre, 6.6±0.6; Eperi, 6.8±0.8; Lperi, 6.1±0.8; Epost, 6.5±1.1; and Lpost, 6.2±0.9 kg/m2). The prevalence of sarcopenia (ALM ≤5.67 kg/m2) was 7, 3, 30, 27, and 32% in Pre, Eperi, Lperi, Epost, and Lpost, respectively. BMD tends to be lower (p=0.05, both) in Lperi and Epost compared to Eperi, and was lower (p<0.05) in Lpost compared to Eperi (Pre, 1.108±0.100; Eperi, 1.164±0.104; Lperi, 1.092±0.100; Epost, 1.088±0.107; and Lpost, 1.045±0.113 gm/cm2). There was a consistent increase in total fat mass and decrease in total lean mass from Pre to each subsequent stage (both, p<0.05 for Pre vs. Lpost).CONCLUSIONIn addition to the menopause‐related decline in bone mass, the menopause transition appears to be a vulnerable period for the loss of skeletal muscle mass that may begin during the late perimenopausal transition. Potential mechanisms underlying menopause‐related loss of muscle mass such as estrogen receptor signaling and protein metabolism should be explored in future studies.Support or Funding InformationNIH R01AG049762, R01AG027678, R56HL114073, P30DK048520, P50HD073063, NCATS Colorado CTSA UL1TR001082, and Eastern Colorado VA GRECCThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
FTY720P Increases, at 2 hrs, the Activity of the Na+/K+ ATPase in Caco‐2 cells via PKC and PI3K
Authors: Noureddine Maysoon , Kreydiyyeh Sawsan 
Published: June 2021

Fingolimod phosphate (FTY720P), an analogue of sphingosine‐1‐phosphate (S1P), was shown previously to modulate, in a time‐dependent manner, the activity of hepatic Na+/K+ ATPase with an inhibitory effect appearing at 15 min and a stimulatory one at 2hrs. Because in the colon, the ATPase plays a pivotal role in the absorption of sodium and water, a time response study was conducted in human epithelial colorectal adenocarcinoma (Caco‐2) cells to examine if FTY720P regulates the activity of the ATPase in a similar fashion. An inhibitory effect was already demonstrated at 15 min. This work investigates the effect of FTY720P at 2 hrs and attempts to determine the major signaling molecules involved. The activity of the Na+/K+ ATPase was assayed by measuring the amount of inorganic phosphate released in presence and absence of ouabain, a specific inhibitor of the enzyme. FTY720P exerted a significant and prominent stimulatory effect on the ATPase at 2 hours. This effect disappeared completely in presence of JTE‐013, a blocker of S1P receptor 2 (S1PR2), as well as in presence of each of calphostin and wortmannin, respective inhibitors of protein kinase C (PKC) and phosphoinositide 3‐kinase (PI3K). Moreover, Phorbol‐12‐Myristate‐13‐Acetate (PMA), an activator of PKC, simulated the stimulatory effect of FTY720P on Na+/K+ ATPase further confirming the involvement of PKC. BAPT/AM, a chelator of calcium ions, cancelled the effect of FTY720P on the ATPase, indicating thus an involvement of calcium ions in the signaling pathway. Since only conventional PKC isomers require the presence of calcium ions for their activation, FTY720P probably acts via a conventional PKC isomer. The stimulatory effect of PMA disappeared in presence of wortmannin, suggesting that PKC is upstream of PI3K. It was concluded that at 2 hours, FTY720‐P binds to S1PR2 leading to the activation of conventional PKC which, in turn, activates directly or indirectly PI3K, resulting in Na+/K+ ATPase stimulation.Support or Funding InformationUniversity Research BoardThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
PGE2 and NO Mediate the Inhibitory Effect Exerted by FTY720P at 15 Minutes on Colonic Na+/K+ ATPase
Authors: Rida Reem , Kreydiyyeh Sawsan 
Published: June 2021

Inflammatory Bowel Disease was shown to be accompaniedwith higher levels of sphingosine‐1‐ phosphate (S1P) and lower Na+/K+ ATPase activity. This work was undertaken to see if a cause‐effect relationship exists between S1P and the ATPase, and in case it does to determine the main mediators involved, using Caco‐2 cells as a model and fingolimod phosphate (FTY720P), a S1P analogue. The activity of the Na+/K+ ATPase was assayed by measuring the amount of inorganic phosphate liberated in presence and absence of ouabain, a specific inhibitor of the Na+/K+ATPase. Western blot analysis showed that sphingosine‐1‐phosphate receptor 2 (S1PR2) is the mostly expressed receptor in Caco‐2 cells. FTY720P, applied for 15 min, reduced significantly the activity of the Na+/K+ ATPase, with a maximal inhibition observed at a concentration of 7.5nM. The effect of FTY720P disappeared completely in presence of JTE‐013 (a specific blocker of S1PR2) and indomethacin (an inhibitor of cyclooxygenase enzymes), and was mimicked by CYM5520 (a S1PR2 agonist), prostaglandin E2 (PGE2), and sulprostone (an agonist of E prostanoid receptor 3 (EP3)). Carboxy‐PTIO a nitric oxide scavenger, abrogated the effect of FTY720P as well as that of PGE2. Treating the cells with Glyco‐SNAP (nitric oxide donor) reduced significantly the ATPase activity. It was concluded that FTY720‐P inhibits the ATPase by binding to S1PR2 leading to PGE2 production. PGE2 binds to EP3 receptors and increases nitric oxide levels resulting in an inhibitory effect on the Na+/K+ ATPase.Support or Funding InformationUniversity Research BoardThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Thyroid Transcription Factor‐1 modulation of secretome alters sensitivity to cisplatin in lung cancer
Authors: Phelps Cody Alan , Mu David 
Published: June 2021

Thyroid Transcription Factor‐1 (TTF‐1, alternatively known as NKX2‐1) is essential for lung development. Mice homozygous null for TTF‐1 fail to develop lungs and will die in utero. Like many developmental genes, TTF‐1 has also been shown to play a role in cancer development. Its role was originally elucidated when our lab and others showed that TTF‐1 resides in the 14q13.3 region that undergoes focal amplification in roughly 15% of lung adenocarcinomas, and knockdown of TTF‐1 retarded cell growth, suggesting a role as an oncogene. Since this finding, many tumor suppressive roles have been discovered, and TTF‐1 positivity in lung cancer is correlated with a better patient outcome. Our lab is interested in how TTF‐1 can alter lung cancer sensitivity to cisplatin, a common chemotherapy drug used in lung cancer. Our findings reveal that TTF‐1 can sensitize A549 cells to cisplatin. Furthermore, this sensitivity can be found in the secretome of TTF‐1 expressing cells, as conditioned media collected from TTF‐1 transfected cells can sensitize recipient cells to cisplatin relative to controls. We dissected the secretome between vesicle and soluble fractions. Exosomes failed to alter sensitivity to cisplatin. By probing the soluble secreted factors altered by TTF‐1 we found that GM‐CSF was the most differentially regulated. By adding a GM‐CSF neutralizing antibody to A549 cells expressing TTF‐1, we found a conferral of resistance to cisplatin. Conversely, by adding a recombinant GM‐CSF to A549 control cells not expressing TTF‐1, we found that it had the ability to confer sensitivity to cisplatin. Patient data from The Cancer Genome Atlas and the Director's Challenge Lung Study have found a strong positive correlation with TTF‐1 and GM‐CSF in patients. Intriguingly other chemotherapy drugs including carboplatin and gemcitabine did not show a differential effect with TTF‐1, suggesting that TTF‐1 may confer a special sensitivity to cisplatin and could serve as a guide for deciding patient treatment strategies.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
The oculocerebrorenal syndrome of Lowe protein (OCRL) inhibits the Na/bicarbonate cotransporter NBCe1 expressed in Xenopus laevis oocytes.
Authors: Michenkova Marie , Thornell Ian M. , Peng Ji‐Ben , Bevensee Mark O. 
Published: June 2021

The electrogenic Na/HCO3 cotransporter NBCe1 regulates intracellular pH in many tissues and contributes to solute reabsorption/secretion in epithelia. NBCe1 is modulated by hormones, classic second messengers, and other signaling molecules/ions. We previously reported that both the phospholipid PIP2 itself and its hydrolysis to IP3 (Ca2+) stimulates the activity of NBCe1 expressed in oocytes. In this preparation, activating a co‐expressed voltage‐sensitive phosphatase (VSP) that dephosphorylates PIP2 to PIP without stimulating IP3/Ca2+ signaling decreases NBCe1 activity. In the current study, we examined the effect of the PIP2‐lowering phosphatase, inositol polyphosphate 5‐phosphatase encoded by the oculocerebrorenal syndrome of Lowe gene (OCRL) on the activity of NBCe1 variants expressed in oocytes. Mutations and variants of OCRL lead to Dent disease type 2, as well as Lowe Syndrome, which is characterized by cataracts, intellectual disability, basal ganglia calcification, and proximal renal tubular acidosis (pRTA). Using the 2‐electrode voltage‐clamp technique, we found that oocytes co‐expressing human OCRL with NBCe1‐A (both HA tagged) displayed a characteristic NBC‐mediated, HCO3–‐induced outward current (INBC) that was 59% smaller than oocytes expressing NBCe1‐A. We also observed OCRL inhibition of HA‐tagged NBCe1‐B and ‐C. We obtained similar results after replacing the HA tag on NBCe1‐A with a FLAG tag. The OCRL‐induced decrease in INBC could be explained by a decrease in NBCe1 expression at the plasma membrane. Co‐expressing OCRL caused a 44% decrease in INBC and a parallel 33% decrease in FLAG‐tagged NBCe1‐A oocyte surface expression as determined by single‐oocyte chemiluminescence. Thus, a physiological phosphatase that lowers PIP2 can regulate the activity and/or expression of NBCe1. Altered activity/expression of NBCe1 caused by mutant OCRL variants seen in Dent disease and Lowe Syndrome may contribute to observed patient symptoms, especially pRTA.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
CHRONIC NEURO ‐ SPINAL DEGENERATIVE DISEASE AND EFFECTIVE INTEGRATIVE DYNAMIC SIGMA QUANTUM REGENERATION NEURAL CELLS SIGNALING STIMULATION THERAPIES ‐ Case Study
Authors: TULP ORIEN LEE , Einstein George P , Konyk Carla M 
Published: June 2021

BackgroundComplex spinal conditions may be the result of multiple disorders and pathologies, that interact together to generate back pain, discomfort and depression. At Einstein Medical Institute USA, ‐ University of Science Art and Technology developing research in Integrative therapies by applications Mathematical Functions of Sigma Quanta Coherence E.M. Energy and Einstein Matrix Dose Protocol in diverse case study treatments.Materials and MethodsProgressive degenerative diseases affect nerve cells in the brain and the spinal cord. Motor neurons reach from the brain to the spinal cord and from the spinal cord to the muscles throughout the body. Patient had failed back syndrome of 16 years duration with chronic pain, eight spine surgeries, 100 spinal injections, nerve blocks, an implanting pump, a spinal simulator and countless prescribed medications. The multiple diagnostic matrix approach was performed. For major analysis of the electrical signals generated by the brain represent not only the brain function but also the status of the whole body was applied. The treatment protocol included detox, acupuncture, different frequency low laser therapies ‐ LLT, Sigma Quanta Coherence E.M.E and G.P. Einstein Matrix Dose Protocol for stimulation neural signaling in Brain and Spinal cord.ResultEEG has been found to be a very powerful tool in the field of neurology and clinical neurophysiology. The electrical signals generated by the brain represent not only the brain function but also the status of the whole body. The patient after several diagnostic EEG with Integrative therapies by applications Mathematical Functions of Sigma Quanta Coherence E.M. Energy and Einstein Matrix Doses Protocol in neuro therapeutic sessions was able to walk again with low pain. The general equation for stimulation neural signaling is Sigma Quantum E= h · ∑ fN. where h represents the Planck's constant, and ∑fN is sum all frequencies in stimulation the cell signaling in brain and in neural system of total body.ConclusionThe G.P. Einstein Mathematical Functions of Sigma Quanta Coherence E.M. Energy with Einstein Matrix Doses is safe, can be applied and designed for personal therapies by MD with extensive training in Quantum Physics, Electromagnetics Energy Systems and electro‐electronic bio‐currents in human neuro‐physiological system.Support or Funding InformationSupport from Institutional Resources of USAT Montserrat and the Einstein Medical Institute.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Plasticity of sympathetic post‐ganglionic neuron after spinal cord injury
Authors: Li Yaqing , McKinnon Michael L. , Hochman Shawn 
Published: June 2021

Autonomic dysreflexia (AD) is a hypertensive crisis seen in high‐thoracic spinal cord injured (ht‐SCI) patients normally triggered by noxious stimuli below the injury level. Previous animal research on mechanisms underlying AD have mostly focused on neural plasticity within the injured spinal cord. No studies have assessed whether there is also plasticity in the sympathetic post‐ganglionic neurons (SPNs) ‐ the final neural element responsible for vasoconstriction.Thoracic sympathetic post‐ganglionic neurons (tSPNs) are located in paravertebral ganglia and provide the dominant sympathetic control of blood pressure. Their cellular properties are understudied. The few previous ex vivo studies used sharp electrodes that likely leads to significant impalement injury‐induced changes [1, 2]. We undertook whole‐cell patch clamp recordings in an adult mouse tSPN ex vivo preparation. Compared to earlier reports using sharp electrodes, we observed an order of magnitude greater passive membrane properties (cell resistance and membrane time constant) and repetitive rather than phasic firing properties. Together these observations support much greater excitability and integrative actions of tSPNs than previously assumed.Using the same methodology we then studied whether these neurons undergo plastic changes after high‐thoracic (T2) spinal cord transection (ht‐SCI), an animal model of AD. Recordings were obtained from T3‐T9 tSPNs at 3 weeks and 6 weeks post injury. Preliminary data suggest that early after injury (3 weeks), tSPNs are hypo‐active compared to normal animal, including more hyperpolarized resting membrane potential and higher rheobase and threshold voltage. At 6 weeks post‐SCI, tSPN passive membrane properties are similar to control mice. However, several neurons show spontaneously unstable membrane potential (55% of recorded neurons), which is rarely seen in control. Evidences that tSPNs may become more excitable include lower rheobase and threshold voltage values on average and an increased incidence of nifedipine sensitive persistent inward currents (PIC; 69% of recorded neurons after SCI has PIC comparing to 22% in control). Also, tSPNs appear to receive more frequent spontaneous cholinergic synaptic input after SCI.Support or Funding InformationThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
The Development and Progression of Mechanical Allodynia in UC, Davis Type 2 Diabetic Rats
Authors: Crawford Charles Kikutaro , Ybarbo Kai , Grotle Ann‐Katrin , Huo Yu , Graham James , Stanhope Kimber , Havel Peter J , Stone Audrey J 
Published: June 2021

Type 2 diabetes (T2DM) is a metabolic disorder that can lead to many neuropathic complications such as mechanical allodynia, which is perceived pain caused by a normally non‐painful stimulus. T2DM is also associated with exaggerated pressor and cardioaccelerator responses to skeletal muscle contraction, namely the exercise pressor reflex. The mechanisms by which diabetes elicits these effects are not fully understood; however, both mechanical allodynia and the exercise pressor reflex are evoked by thin‐fiber afferent activity. The purpose of this study was to utilize noninvasive techniques to monitor the development and progression of diabetes‐induced neuropathy in thin‐fiber afferents. We used male UC Davis T2DM (n=9) rats from the age of 4 to 7 months to model the progression of T2DM. We took monthly measurements of blood glucose, HbA1c, and body weight. We also measured changes in mechanical sensitivity using von Frey filaments. Filaments were applied to the L5 dermatome on the plantar side of the left and right hind paws, between the footpads; the lowest force eliciting an abrupt paw withdrawal was measured and averaged between paws. We found that blood glucose (4mo: 255±28 mg/dl, 5mo: 366±50 mg/dl, 6mo: 417±58 mg/dl, 7mo: 453±49 mg/dl) and HbA1c (4mo: 5.7±0.2%, 5mo: 6.6±0.4%, 6mo: 9.3±1.2%, 7mo: 10.3±1.2%) were above the diabetic threshold (300 mg/dl, 6.5%) at 5, 6, and 7 months of age; they were significantly higher at 6 and 7 months, compared to 4 months, p<0.05. Body weight was significantly higher at 5, 6, and 7 months compared to 4 months (4mo: 525±4g, 5mo: 609±3g, 6mo: 620±21g, 7mo: 610±31g; p<0.05). Sensitivity to von Frey filaments was significantly greater, indicating mechanical allodynia, at 6 and 7 months compared to 4 months (4mo: 29±3.2 g, 5mo: 26.3±4.5 g, 6mo: 14.1±3.3 g, 7mo: 9.7±1.7 g; p<0.05). We conclude that mechanical allodynia progresses in severity as the rats develop and progress with T2DM. Moreover, these observations may provide insight to diabetes‐induced changes in thin‐fiber dependent reflexes, such as the exercise pressor reflex.Support or Funding InformationN/AThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.