bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sex Differences in Obesity‐Associated Vascular/Perivascular Remodeling and Adipokine Production in Obese Patients Undergoing Roux‐en‐Y Bariatric Surgery
Authors: Mui Ryan K , Fernandes Roxanne N , Galligan James J , Fink Gregory D , Pereira‐Hicks Cristiane N , Watson Ralph E , Lane Mindy K , Xu Hui 
Published: November 2023

IntroductionIn obese humans, inflammation and adipokine production affect mortality and cardiovascular tissue remodeling independent of BMI. Studies of plasma adipokine levels suggest that anti‐inflammatory adipokines including omentin‐1, secreted frizzled‐related protein 5 (SFRP5), and adiponectin improve cardiovascular function while pro‐inflammatory adipokines, like resistin, impair cardiovascular function. Furthermore, adipokine production and function differ in males and females. Therefore, we tested the hypothesis that in human obesity, the degree of vascular/perivascular pathology is sex‐dependent and associated with a distinct adipokine profile.MethodsMesenteric vessels and perivascular adipose tissue were obtained from 26 obese patients (4 males, 22 females) undergoing Roux‐en‐Y bariatric surgery. A blinded semi‐quantitative approach was used to assess 4 criteria: Fibrosis, adventitial wall thickening, angiogenesis, and immune cell infiltration. Samples with 2+ criteria were considered abnormal (pathology). Expression levels of adiponectin, omentin‐1, resistin, and SFRP5 in perivascular fat (PVAT) were evaluated by qRT‐PCR. All collected data were analyzed by histopathology and sex.Results60% of female tissue samples displayed significant pathology, which consistently involved fibrosis and adventitial wall thickening. Significant pathology was not observed in male tissues. When categorized by histopathology alone, females with pathology had 3‐fold lower omentin‐1 mRNA and 2‐fold higher resistin mRNA vs. females and males without pathology. When compared to males, females without pathology had 10‐fold higher omentin‐1 mRNA whereas obese females with pathology had only 1.6‐fold higher omentin‐1 mRNA and 1.6‐fold higher resistin mRNA. In females only, females with pathology had 5‐fold lower omentin‐1 mRNA, 2‐fold higher resistin mRNA and 2‐fold higher SFRP5 mRNA vs. females without pathology. None of these findings were associated with age, BMI, type II diabetes, dyslipidemia, or hypertension.ConclusionsIn the mesentery, females are more susceptible to obesity‐associated vascular/perivascular tissue remodeling than males. When compared to obese females without pathology, obese females with pathology have lower omentin‐1 mRNA and higher mRNA levels of resistin and SFRP5. Therefore, omentin‐1, resistin and SFRP5 may be useful adipokines in identifying obese females at risk of worsening cardiovascular tissue quality.Support or Funding InformationSupported by NIH 2P01HL070687
Reduced Uterine Perfusion Pressure‐Induced Preeclampsia Acquires Salt‐Sensitivity Characteristics in Postpartum
Authors: Matsuura Taku , Shinohara Keisuke , Kishi Takuya , Tsutsui Hiroyuki , Hirooka Yoshitaka 
Published: November 2023

BackgroundPreeclampsia, a hypertensive disorder during pregnancy, occurs in 3% to 8% of pregnancies, and the risk of future cardiovascular diseases is 2 to 4 times higher in women with preeclampsia than in women without. Women with a history of severe preeclampsia also have a tendency toward salt‐sensitive hypertension. However, it is not yet clear whether preeclampsia leads to salt‐sensitive hypertension later in life as an acquired characteristic or as a manifestation of the original predisposition. We hypothesized that preeclampsia results in postpartum salt‐sensitive hypertension as an acquired characteristic.Methods and resultsWe established a rat with reduced uterine perfusion pressure model (RUPP) as a model of acquired preeclampsia, by placing a silver clip (0.203‐mm ID) around the aorta above the iliac bifurcation and branches of bilateral ovarian arteries (0.100‐mm ID). Pregnant Sprague‐Dawley rats were divided into two groups that underwent the RUPP operation or sham operation (SHAM) at day 14 after gestation. Mean arterial pressure (MAP) at day 19 after gestation was significantly higher in RUPP than in SHAM rats (116 ± 4 mmHg vs. 100 ± 5 mmHg, n's=7 and 3, respectively; p<0.05). At 2 weeks postpartum, MAP similarly returned to normal levels between RUPP and SHAM rats (92.9±3.0 mmHg vs. 87.4±5.4 mmHg, n=6 and 4). At 3 weeks postpartum, a high‐salt (8% NaCl) diet for 1 week was initiated. Surprisingly, the high‐salt diet further increased MAP in RUPP (110.8±3.2 mmHg, n=6), compared to SHAM (99.8±5.0 mmHg, n=4).ConclusionPreeclampsia results in postpartum salt‐sensitive hypertension as an acquired characteristic.
Reciprocal control of apoptotic cell death and synaptic plasticity by DAPK1 depletion in focal cerebral ischemic brain
Authors: Won Jinyoung , Park Sookyoung , Hong Yonggeun 
Published: November 2023

Death‐associated protein kinase 1 (DAPK1) has been identified as a key player in different types of cell death that includes apoptosis, autophagy and necrosis. Recent studies indicated a close relationship between DAPK1 and ischemic brain injury. The present study investigated the effect of DAPK1 deficiency on the synaptic plasticity of cortical pyramidal neurons in DAPK1 knockout mice after focal cerebral ischemia. The subjected C57BL/6 mice exhibited neurological deficits and altered behavioral outcomes after ischemic brain injury. Progressive dendritic change and synaptic degeneration were observed in cortical pyramidal neuron. Apoptosis signaling pathway activated by increase of dephosphorylated DAPK1, which is active form under pathological condition including ischemic stroke. However, DAPK1 knockout mice exhibit significantly reduced infarct volumes and enhanced functional recovery. In addition, abnormal dendrite and dendritic spine morphology were decreased in DAPK1 knockout mice. The expression of BAX and caspase‐3 as pro‐apoptotic marker was significantly decreased and BCL‐2 as anti‐apoptotic marker was significantly increased in DAPK1 knockout mice. These results indicate that activation of DAPK1 during ischemic insult was exclusively associated with dendritic pathology and neurodegeneration via DAPK1 dependent apoptotic cell death. Thus, regulation of the expression and activity of DAPK1 could be a novel interventional strategy for ischemic brain injury.Support or Funding InformationNRF 2013R1A2A2A01067169 to Y.H., NRF‐2014R1A1A3051724 to S.P., KRIBB Research Initiative Program (KGM4611613), Republic of Korea
Behavioral and Inflammatory Response in Animals Exposed to a Low‐Pressure Blast Wave and Supplemented with β‐Alanine
Authors: Hoffman Jay R , Zuckerman Amitai , Ram Omri , Sadot Oren , Stout Jeffrey R , Ostfeld Ishay , Cohen Hagit 
Published: November 2023

This study investigated the benefit of β‐alanine (BA) supplementation on reducing behavioral and cognitive responses relating to mild traumatic brain injury (mTBI) and post‐traumatic stress disorder (PTSD) in rats exposed to a low‐pressure blast‐wave. In addition, inflammatory, neurotrophin and tau protein expression in the hippocampus was also examined. Animals were fed a normal diet with or without (PL) BA supplementation (100mg·kg−1) for 30‐days, prior to being exposed to a low‐pressure blast‐wave. Diets were maintained until the end of the study. A third group of animals served as a control (CTL). These animals were fed a normal diet, but were not exposed to the blast. Validated cognitive‐behavioral paradigms were used to assess both mTBI and PTSD‐like behavior on days 7–14 following the blast. Brain‐derived neurotrophic factor (BDNF), neuropeptide Y, glial fibrillary acidic protein (GFAP), and tau protein expressions were analyzed a day later. In addition, brain carnosine and histidine content was assessed as well. The prevalence of animals exhibiting mTBI‐like behavior was significantly lower (p=0.044) in BA than PL (26.5% and 46%, respectively), but no difference (p=0.930) was noted in PTSD‐like behavior between the groups (10.2% and 12.0%, respectively). Carnosine content in the cerebral cortex was higher (p=0.048) for BA compared to PL, while a trend towards a difference was seen in the hippocampus (p=0.058) and amygdala (p=0.061). BDNF expression in the CA1 subregion of PL was lower than BA (p = 0.009) and CTL (p<0.001), while GFAP expression in CA1 (p=0.003) and CA3 (p=0.040) subregions were higher in PL than other groups. Results indicated that BA supplementation for 30‐days increased resiliency to mTBI in animals exposed to a low‐pressure blast‐wave.Support or Funding InformationNatural Alternatives International (Carlsbad, CA, USA)
The Glycolysis Regulatory Enzyme PFK‐FB3 Enhances Endothelial Barrier Restoration in Acute Lung Injury
Authors: Wang Li , Chaturvedi Pallavi , Krantz Sarah , Klomp Jennifer , Pohl‐Avila Nicole M , Ray Anne‐Marie , Toth Peter T , Carmeliet Peter , Karginov Andrei , Malik Asrar B , Rehman Jalees 
Published: November 2023

Acute lung injury (ALI) is a devastating inflammatory complication of infectious lung disease, characterized by a breakdown of the pulmonary vascular barrier and the subsequent formation of protein‐rich alveolar edema. In recent years, considerable advances have been made in the understanding of how intracellular signaling regulates the disruption and re‐assembly of adherens junctions (AJs) which are mediators of the endothelial barrier function. Little is known about the role of endothelial metabolism as a modulator of endothelial barrier function and its restoration in the setting of lung vascular injury. We hypothesized that the glycolysis regulatory enzyme PFK‐FB3 would support re‐annealing of the endothelial barrier because glycolysis allows for the local generation of ATP at the AJs. We observed a 2–3‐fold upregulation of PFK‐FB3, an enzyme which is a critical regulator of glycolytic activity, in response to inflammatory injury in human lung endothelial cells (p<0.05). ATP levels also increased at the AJs during recovery after LPS‐induced injury. Depletion of the hypoxia‐regulator transcription factor Hif1α attenuated the upregulation of PFK‐FB3, suggesting that hypoxic signaling activates PFK‐FB3 mediated upregulation of glycolysis. Suppression of PFK‐FB3 activity by either pharmacologic inhibition or genetic depletion delayed restoration of the endothelial barrier. In vivo delivery of liposomal PFK‐FB3, on the other hand, enhanced restoration of lung vascular barrier function in a model of experimental acute lung injury by 24 h (p<0.05). These findings suggest that upregulation of glycolysis via enhanced PFK‐FB3 activity serves as an endogenous metabolic adaptation to inflammatory vascular injury and facilitates endothelial barrier restoration.Support or Funding Informationsupported by NIH grant P01 HL60678‐16A1.
Divergent effects of DHA treatment and AMPK activation on protein synthesis rate and signaling in palmitate‐treated skeletal muscle
Authors: Perry Ben Douglas , Rahnert Jill A , Xie Yang , Zhang Peng , Espinosa Daniel , Price S. Russ 
Published: November 2023

Circulating levels of saturated fatty acids, such as palmitate (PA), are elevated in type II diabetes mellitus. In skeletal muscle, PA impairs insulin sensitivity, induces ER stress and impairs protein synthesis. Both insulin resistance and ER stress are reversed with treatment of n‐3 polyunsaturated fatty acids like docosahexaenoic acid (DHA). However, it remains unclear whether DHA reverses the PA‐induced impairment in protein synthesis. This study investigated the effects of PA and DHA on protein synthesis and related signaling proteins, including eukaryotic initiation factor 2α (eIF2α) and p70S6K in skeletal muscle cells. Due to its potential role in reducing ER stress and altering protein synthesis through mTOR signaling, we also investigated the effects of 5′ AMP‐activated protein kinase (AMPK) on these processes. C2C12 myotubes were treated with vehicle (2% BSA), DHA (100 μM), PA (500 μM) or co‐treated with PA+DHA. Protein synthesis was inhibited after 6h (−34.7%) and 24h (−40.8%) of treatment with PA and co‐treatment with DHA restored protein synthesis to the control level; DHA alone increased protein synthesis. PA treatment for 6–24 h also increased eIF2α phosphorylation, a response that reduces protein translation; co‐treatment with DHA prevented the responses. Surprisingly, the phosphorylation of p70S6K was increased after 6 h of PA treatment but restored to normal levels after 24 h. Moreover, AMPK phosphorylation was also increased after treatment with PA for 6 h but reduced after 24 h; in both cases, DHA co‐treatment normalized AMPK phosphorylation. Co‐treating myotubes with PA plus metformin, an activator of AMPK, caused a drastic decrease in protein synthesis and p70S6K phosphorylation after 24 h. In summary, PA induced a global reduction in protein synthesis rate that was prevented by co‐treatment with DHA. Changes in the phosphorylation of eIF2α, but not p‐p70S6K coincided with those in protein synthesis after both 6 and 24 h. Despite the widely reported beneficial effects of AMPK activation in PA‐treated cells, impaired protein synthesis and increased p‐eIF2α preceded the PA‐induced reduction in AMPK.Support or Funding InformationSupported by NIH RO1 DK95610, NIH T32 DK007656 and VA Merit I01BX001456
Contribution of Membrane Repair Defects to Skeletal Muscle Inflammation
Authors: McElhanon Kevin E. , Young Nicholas , Hampton Jeffrey , Beck Eric X , Sahenk Zarife , Aggarewal Rohit , Oddis Chester V. , Jarjour Wael N. , Weisleder Noah E. 
Published: November 2023

Inflammation is a significant contributor to multiple skeletal muscle diseases, however the mechanisms that facilitate these inflammatory responses have not been fully characterized. Idiopathic immune myopathies are a group of disorders involving chronic damage to skeletal muscle due to extensive inflammation triggered by autoimmune responses and provides a model to further understand general mechanisms of inflammation. Chronic inflammation leads to degeneration of muscle structure and function resulting in severe proximal muscle weakness. T‐cell‐ and antibody‐mediated processes are involved in the progression of disease, however the mechanism leading to pathogenesis remains unknown. Two animal models have recently provided insight into the pathogenic mechanisms of myositis. Synaptotagmin VII null (SytVII−/−) mice display impaired sarcolemmal repair capacity and develop mild myositis, suggesting that antigen presentation of internal skeletal muscle proteins may play a role in initiating an autoimmune response. A more robust model of myositis combines the Syt VII−/− model with a FoxP3 mutation (FoxP3−/Y/Syt VII−/−). This mouse strain combines impaired membrane repair with regulatory T‐cell deficiency. Adoptive transfer of lymph node cells from FoxP3−/Y/Syt VII−/− mice to RAG‐1 mice lacking T‐ or B‐cells results in significant muscle inflammation. The current project examined the contribution of defective sarcolemmal repair to the pathogenesis of myositis. Sarcolemmal membrane repair is a conserved process where disruptions in the lipid bilayer are actively resealed to maintain cellular integrity. Previous studies established the cellular framework of the membrane repair process utilizes exocytotic and endocytotic vesicle trafficking to restore membrane integrity. Previous work by our lab and others identified TRIM72, a member of the Tripartite Motif family of E3 ubiquitin ligases, as a critical component of the membrane repair process. Our studies here identified novel autoantibodies against TRIM proteins in patient sera. Using an adoptive transfer model to induce myositis in mice, we show that membrane repair is compromised in skeletal muscle distal to the initial site of inflammation. We also demonstrate that exogenous delivery of antibodies against TRIM proteins can compromise membrane repair in healthy skeletal muscle. Our data indicate that defects in membrane repair associated with the progression of myositis lead to TRIM protein exposure to the extracellular space and that the autoantibodies produced against TRIM proteins further compromise membrane repair and exacerbate inflammation.Support or Funding InformationNational Institute of Arthritis and Musculoskeletal and Skin Diseases, MDA, The Ohio State University Center for Clinical and Translational Science
Muscle gp130 Receptor Regulation of Oxidative Metabolism During Cancer Cachexia
Authors: Fix Dennis , Hardee Justin , Gao Song , VanderVeen Brandon , Carson James A. 
Published: November 2023

IntroductionMuscle oxidative metabolism is disrupted by the cachectic environment brought on by cancer. Processes related to mitochondrial biogenesis, dynamics, and mitophagy are all altered. The IL‐6 family of cytokines have an established regulatory role in cachectic signaling in several preclinical mouse models through the activation of intracellular signaling pathways initiated by receptor complexes involving glycoprotein 130 (gp130). Therefore, we examined muscle gp130 role in the disruption of muscle oxidative metabolism induced by a cachectic environment.MethodsMale, C57BL/6 (B6, N=5), ApcMin/+ (MIN; N=5), skeletal muscle specific gp130 knockout (KO; N=5), ApcMin/+ KO (MIN KO; N=5) mice were sacrificed at 20 weeks of age. Additionally, Lewis Lung Carcinoma (LLC) injected B6 (N=5) and KO (N=5) mice were examined 30 days after injection. C2C12 myotubes were treated with a small molecule STAT3 inhibitor (C188‐9) and incubated in LLC conditioned media (24 hours). Oxidative metabolism, mitochondrial content, and dynamics were examined.ResultsLLC and MIN increased muscle gp130 protein expression and STAT3, which was suppressed by gp130 KO. COX activity was decreased in LLC and MIN, and not rescued by the KO. MIN and LLC increased FIS‐1 protein expression, and this induction was ablated by KO in both mice. MIN decreased MFN‐1 protein expression which was not altered by KO. Beclin‐1 and 4HNE protein expression increased in MIN and LLC, and the KO blocked this induction. LLC media activation of myotube STAT3 was blocked using the C188‐9 inhibitor. Inhibiting the LLC induction of STAT3 in cultured myotubes did not affect the induction if FIS‐1, Beclin‐1 and 4HNE protein expression.ConclusionsThese results implicate direct signaling through the muscle gp130 receptor for the cachexia regulation of muscle mitochondrial dynamics and autophagy, and this regulation may be independent of STAT3.Support or Funding InformationThis work was supported by National Institutes of Health grant # NCI‐R01CA121249 (JAC)
Hydrogen Sulfide Attenuates Homocysteine‐Induced Mitochondrial Toxicity in MC3T3‐E1 Pre‐osteoblastic Cells
Authors: Zhai Yuankun , Behera Jyotirmaya , Tyagi Suresh , Tyagi Neetu 
Published: November 2023

INTRODUCTIONOsteoporosis is a bone disorder which leads to an increased risk of fracture, and the main treatments always aimed at increasing bone formation but inhibiting bone resorption. Homocysteine (Hcy) have been reported to induce bone loss, but the detailed mechanism still not very clear. In this study, we want to clarify the negative effects of Hcy on bone formation and the rescue effects of hydrogen sulfide (H2S).METHODSMC3T3‐E1 cells were cultured in vitro, and were divided into 5 groups, contained control, 300μM homocysteine, 30μM H2S, 300μM Hcy plus 30μM H2S, 100μM H2O2, and then cell viability were measured by MTT method and Hoechst 33342 staining, while ALP activity and positive colony formation were detected after osteogenic induced for 9 days, and calcified nodules were stained by alizarin red S after osteogenic induced 21 days. Total mRNA and protein were isolated, some related factors were measured by western‐blot and RT‐PCR, including OPG, RANKL, HO‐1, Nrf‐2, COX‐2, NOX‐2 and NOX‐4 etc. ROS production were detected by flow cytometry and confocal, the mitochondria function were present by several assays, such as JC‐1 intake, expression of Mfn2 and Drp1, ATP production and also oxygen consumption. Meanwhile, MMPs (MMP3, MMP9, and MMP13) expression also were measured by RT‐PCR, western‐blot and zymography.RESULTSWe found Hcy could decrease the MC3T3‐E1 osteoblastic cells viability, ALP activity, and calcified nodules, decrease OPG but increase RANKL expression, both increase expression of antioxidant and oxidant factors, including HO‐1, Nrf2, COX‐2, NOX‐2 and NOX‐4 respectively. Moreover, we also found Hcy promote the intracellular ROS production, decreased in mitochondria membrane potential, mitochondria copy number, ATP production, oxygen consumption, also less Mfn2 and more Drp1 expression which represents mitochondria fusion and fission, therefore induced dysfunction of mitochondria. NaHS, an H2S donor, increased cell viability, reduced ROS production and mitochondria dysfunction, reverse the factor changes induced by Hcy, and then protect MC3T3‐E1 cell from apoptosis. Meantime, we also found NaHS inhibit the enhancing of MMP3 and MMP13 which induced by Hcy, and MMPs were known as degradation factors for extracellular bone matrix.CONCLUSIONIn summary, Hcy stimulate intracellular ROS production and mitochondria dysfunction, then decrease the cell viability and bone formation activity, the mechanism may depend on increasing MMPs, ROS production, and also dysfunction of mitochondria, but all these effects could be inhibited by the H2S supplement. So our findings suggested that H2S may have a potentially therapeutic value for osteoporosis patients which also with hyperhomocysteine levels.Support or Funding InformationAcknowledgement: Financial support from National Institute of health grant AR‐067667 and HL‐107640 are greatly acknowledged.