bluuebunny/crossref_metadata_2025 huggingface dataset:
Prolonged therapeutic effects of exosomes from light treated-adipose-derived stem cells on obesity-associated insulin resistance
Authors: Wu Jianbo , Wu Jiaqi
Published: May 2023

Background: Obesity induces adipose tissue chronic inflammation resulting in insulin resistance and metabolic disorders. With light activation, we recently showed that in situ transplantation of photoactivated adipose-derived stem cells (ASCs) improves glucose metabolism by suppressing adipose tissue macrophages in obese mice. Still, the mechanisms have not been thoroughly investigated. Methods: Cultured ASCs were subjected to light treatment, and exosomes (Exos) were subsequently harvested and injected intraperitoneally into HFD mice. High-throughput miRNA sequencing was performed to detect the miRNA profiles of light-activated ASCs-Exos. The roles of miRNA and target gene were predicted and analyzed in vitro or in vivo by dual-luciferase reporter gene assay, specific miRNA mimic, miRNA inhibitor, and siRNA. Results: We showed that light-activated ASCs produce miRNA-containing exosomes (Exos), which significantly prolonged therapeutic effects on the improvement of obesity-associated insulin tolerance when injected intraperitoneally into obese mice. Mechanistically, light-activated ASCs-Exos shift M1 macrophages toward the M2 via miR-3572-5p–mediated targeting of ELVAL1 in vitro and in vivo. Moreover, miR-3572-5p inhibitor delivery significantly modulated insulin sensitivity and macrophage phenotype. Conclusions: These data suggest that light activation is a simple and effective method for generating the functionality of ASCs-Exos, and miR-3572-5p could be a new therapeutic target of adipose tissue inflammation for insulin resistance.

This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Inhibition of EB3 promotes acute lung injury resolution by promoting the regenerative FOXM1 pathway in endothelial cells
Authors: Chan Wan Ching , Kwok Man Long , Qu Xinyan , Zhao Shuangping , Le Jonathan , Komarova Yulia
Published: May 2023

Acute respiratory distress syndrome (ARDS) is the acute onset of non-cardiogenic pulmonary edema, hypoxemia, and respiratory failure. ARDS is frequently caused by bacterial and viral lung infections including the recent SARS-CoV-2. Development of therapeutic approaches to combat ARDS have become an urgent unmet medical need. We address this medical problem by developing a pharmacological treatment for pulmonary vascular leakage, a culprit of alveolar damage and lung inflammation. Our novel therapeutic target is the microtubule accessory factor End Binding protein 3 (EB3), which contributes to pulmonary vascular leakage by amplifying pathological calcium signaling in endothelial cells. Using a structure-activity-relationship approach by Nuclear Magnetic Resonance, we have identified a drug candidate Vascular Therapeutics (VT)-109, an allosteric EB3 inhibitor with optimized physicochemical and biochemical properties. The VT-109 shows marked therapeutic benefits in treating lung injury and inflammation in various models of ARDS including high-volume mechanical ventilation, polymicrobial and SARS-CoV-2 infections. Transcriptome analysis of lung endothelial cells in mice challenged with endotoxin shows that VT-109 upregulates FOXM1 target genes suggesting that the treatment not only mitigates vascular injury but also promotes endothelial cell regeneration by activating the FOXM1 pathway. Our work demonstrates that VT-109 is a promising drug candidate for future clinical studies.

Funding for this work is provided by the Congressionally Directed Medical Research Programs through the Peer Reviewed Medical Research Program (PRMRP) under award No. W81XWH-21-1-0639. Opinions, interpretations, conclusions, and recommendations are those of the author and are not necessarily endorsed by the Department of Defense.

This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
GCPII Inhibition Delays Age-related Loss of Muscle Mass and Function in Mice
Authors: Su Yu
Published: May 2023

Sarcopenia, the age-related loss of skeletal muscle mass and function, is a significant problem that reduces the quality of life in the elderly. Despite the growing prevalence of sarcopenia, there is still a lack of effective therapies for this disease. Recent research has focused on the role of the enzyme glutamate carboxypeptidase II (GCPII) in regulating muscle function and neuromuscular junction (NMJ) integrity. We have previously shown that inhibition of GCPII with the potent inhibitor 2-(Phosphonomethyl)-pentanedioic acid (2-PMPA) can significantly delay muscle function loss and NMJ denervation in an animal model of ALS. Given that sarcopenia shares similarities with ALS in terms of NMJ deterioration, we aimed to investigate whether 2-PMPA treatment could also preserve muscle function during aging. We measured the activity of GCPII in the gastrocnemius muscles of 4-month-old and 20-month-old mice, and found that GCPII activity was significantly increased in the 20-month-old mice (3188±182 fmol/mg/h) compared to 4-month-old mice (2009±317 fmol/mg/h). Then we treated 15-month-old C57BL6/J mice with 100mg/kg of 2-PMPA IP daily for 5 months and monitored muscle function. After 5 months of 2-PMPA treatment, we observed preservation of gastrocnemius muscle mass (164.8±5.6 vs. 143.6±6.4 mg, 2-PMPA vs. vehicle treated group) and a significant delay in age-related loss in grip strength (-4.75±3.22% vs. -20.98±3.73%, 2-PMPA vs. vehicle). We also found that 2-PMPA treatment increased the mean single-fiber cross-sectional area (759.4±5.2 vs. 722.4±5.1 μm2, 2-PMPA vs. vehicle), delayed the decline of nerve signals to the muscles as observed by compound muscle action potential (CMAP) amplitude decline (-7.37±6.16% vs. -26.05±3.71%, 2-PMPA vs. vehicle), and improved ambulation in old mice (3941±153 vs. 3216±188 beam brakes, 2-PMPA vs. vehicle) as observed by open-field test. Immunofluorescent staining showed that GCPII expression in aged muscle is associated with infiltrating macrophages, indicating inflammation as one potential target for the role of 2-PMPA in preserving muscle function during aging. Overall, our current results support that excessive GCPII activity is associated with muscle aging and GCPII inhibition is a potential therapeutic strategy for sarcopenia. This study highlights the potential of GCPII inhibition as a new therapeutic approach to preserving muscle function in the elderly.

This work was supported by NIH R01 AG078181-01 (to BSS), R01 AG068130 (to BSS), R01NS093416 (to BSS), and R25GM109441 (Hopkins PREP support for TRJ).

This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Co-exposure to cannabis and nicotine during pregnancy alters fetal lung development
Authors: El Alam Imad , Belgacemi Randa , Rehan Virender , Glass Ian , Danopoulos Soula , Alalam Denise
Published: May 2023

Rationale: The co-use of cigarettes and cannabis is increasing especially in regions where recreational marijuana use has become legal. However, the use of these dependent substances during pregnancy poses a serious risk on fetal development and health (low birth weight, preterm birth, and perinatal death). Nevertheless, the impact of co-exposure to the most prominent cannabinoids found in Cannabis sativa (Trans-Δ-9-tetrahydrocannabinol (THC) and cannabidiol (CBD)) with nicotine on fetal lung development is not well understood. This study aims to determine the effect of nicotine, CBD, and THC, alone or combined, on human lung development through investigating cellular senescence. Methods: In vitro human fetal lung explants from 10–20 weeks gestation were cultured on air-liquid interface and treated with physiological concentrations of CBD, THC, and nicotine, alone or combined, for 72h. Similarly, lung mesenchymal cells (LMCs) were isolated from the same samples and treated for 48h. Both culture types were either fixed for immunofluorescent staining or used for RNA extraction and qRT-PCR. Results: Our results showed that nicotine and CBD induce thickening of the mesenchymal compartment of lung explants. Furthermore, treatment with either CBD or THC, or the two combined, induced an increase in epithelial cysting. Ki-67 staining demonstrated increased proliferation following treatment with nicotine, THC and CBD+THC+nicotine. ACTA2 staining, a marker for smooth muscle cells, decreased following treatment with THC, CBD, and nicotine as well as all 3 combined, while the senescence marker p21 increased following exposure to nicotine, CBD+THC, as well as CBD+THC+nicotine. qRT-PCR data showed decreased expression of ACTA2 in the presence of CBD, THC, CBD+THC, and CBD+THC+nicotine, and increased expression of CDKN1A (encoding p21) and CDKN2A (encoding p16) in response to CBD+THC+nicotine. LMCs treated with nicotine, CBD, and THC demonstrated an increase in cell proliferation and senescence as shown by Ki-67 and p21 staining respectively, and a decrease in ACTA2. These data were confirmed by qRT-PCR that showed a decrease in ACTA2 for the LMCs treated with either nicotine or CBD+THC+nicotine and an increase in senescence genes CDKN1A and CDKN2A. Moreover, the expression of these genes was higher in the LMCs derived from second trimester samples in comparison to those of the first trimester. Conclusion: Our results showed that the co-exposure to nicotine and cannabis induces senescence and alters lung fetal cellular proliferation, especially when used in conjunction. Furthermore, this effect appears to be age dependent.

This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Lactic acid bacteria and their lysate ameliorate skin inflammation in a UVB irradiation-induced skin photoaging mouse model
Authors: Cheon Se Jin , Kim Jae Young , Kim Gyu Wan , Lee Jung Yun , Kim Sae Hun
Published: May 2023

Skin photoaging is premature skin aging caused by over exposure to ultraviolet (UV) radiation. Photoaged skin is characterized by epidermal thickening, dryness, deep wrinkles, loss of elasticity, delayed wound healing and susceptibility to cancer and closely related to skin inflammation. Meanwhile, it had been reported that lactic acid bacteria (LAB) lysate has lots of beneficial components such as fatty acid, vitamin B, and amino acids, and LAB has the anti-inflammatory effects and the potentials as therapeutics for many chronic inflammatory diseases. Because skin photoaging is recovered by reducing inflammation, co-treatment of LAB and their lysate may alleviate the skin conditions caused by UV-induced skin photoaging via the anti-inflammatory effects. Therefore, the aim of this study is to find out whether co-treatment of LAB and their lysate has beneficial effects on skin conditions and ameliorates skin photoaging. LAB and their lysate were treated in vitro and in vivo. LAB lysate decreased the expression levels of pro-inflammatory cytokines including TNF-α and other inflammation-related biomarkers such as cyclooxygenase 2 (COX-2) and toll-like receptor 4 (TLR4) significantly in HaCaT, the human keratinocyte cell line. LAB and their lysate was evaluated in UVB-induced skin photoaged HR-1 mice model, and it decreased the pro-inflammatory cytokines including TNF-α in serum. LAB and their lysate also decreased pro-inflammatory cytokines in skin, colon, and spleen. Moreover, LAB and their lysate changed the composition of fecal microbiome and short chain fatty acids in mice. In conclusion, the topical treatment of lactic acid bacteria and their lysate may have a potential to ameliorate skin photoaging by reducing inflammation.

This work was supported by Korea Testing Laboratory

This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Probiotics supplementation attenuates high cholesterol diet-induced hypercholesterolemia in rat model
Authors: Seo Eun Jin , Kim Jae Young , Kim Sae Hun
Published: May 2023

Hypercholesterolemia is characterized by elevated total serum cholesterol levels, reflecting a high LDL (low-density lipoprotein cholesterol) level, a high TG (triglyceride) level and a low HDL (high-density lipoprotein cholesterol) level. Hypercholesterolemia may cause cardiovascular diseases such as heart attack, stroke and coronary artery diseases. Nowadays, several drugs like statins that lower serum cholesterol are used to treat hypercholesterolemia. However, the cholesterol-lowering drugs have side effects including liver damage and kidney failure. For these reasons, alternatives like probiotics are expected to attenuate hypercholesterolemia instead. Recent studies have shown that probiotics protect against hypercholesterolemia and liver dysfunction via gut-liver axis. Probiotics such as lactic acid bacteria (LAB) may modulate gut microbiota, regulate lipid metabolism and lead to alleviate liver disease. This study aims to determine whether LABs have a protective effect on hypercholesterolemia. LAB strains were selected by acid tolerance, bile tolerance, and antibiotic activity through in vitro screening. 6-week SD rats were fed normal diet or high cholesterol diet (HCD) for 7 weeks. Treatment groups were fed HCD with statin and LABs respectively. LAB supplements effectively improved serum lipid profiles. LABs prevented HCD-induced intestinal and liver damage by enhancing tight junction, reducing inflammation. LABs suppressed lipid accumulation in the liver and enhanced the inhibition of the liver toxicity. Also, LAB supplements changed HCD-induced gut microbiota composition and influenced diversity of gut microbiome. The concentration of bile acid and short chain fatty acids in feces were increased by LAB supplements. Thus, results suggest that LABs are potential therapeutic agents for HCD-induced intestine and liver dysfunction.

This work is supported by Cellbiotech Co., Ltd.

This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Liver Androgen Receptor Knockout Delayed the Onset of High Fructose Diet-Induced Dysglycemia in Female Mice
Authors: Andrisse Stanley
Published: May 2023

Introduction: Previous research has indicated that a lipid-independent pathogenic mechanism plays a role in androgen-induced hepatic insulin resistance where liver androgen receptors may play a role in modulating disease. Consequently, this study aims to investigate the pathophysiology of high fructose diet (HFrD) induced dysglycemia in male and female liver androgen receptor knockout (LivARKO) mice. Andrisse et al 2021 showed that deleting the liver androgen receptor prevented female mice from developing hyperandrogenemia (HA)-induced insulin resistance. From this, we asked the question, does LivARKO prevent HFrD induced dysglycemia? Hypothesis: It was hypothesized that HFrD LivARKO female mice would display impaired whole body glucose metabolism in comparison to the Control diet fed LivARKO female mice, suggesting that AR does not play a significant role in regulating HFrD-induced dysglycemia.Methods: We performed insulin tolerance tests (ITT), glucose tolerance tests (GTT), pyruvate tolerance tests (PTT), and glucose stimulated insulin secretion (GSIS) tests on LivARKO female mice fed a high fat diet (HFD) or a control diet (CD) (from Research Diets Inc) during months 1 or 2 after starting the diet. Results: After 1-month, LivARKO female mice fed a Control diet had impaired glucose tolerance compared to LivARKO-HFrD female mice; however, after 2-months, the LivARKO-HFrD female mice displayed impaired glucose tolerance above that of the Control diet LivARKO female mice. LivARKO female mice fed a high fructose diet (HFrD) did not display increased fasting insulin levels compared to LivARKO female mice on a control diet. HFrD LivARKO mice did not display any increase in GSIS at 15-min or 30-min. Conclusion: These findings suggest that LivARKO delayed the onset of HFrD-Induced dysglycemia in female mice. Further research may consist of molecular data to elucidate the mechanistic pathways involved in these whole body phenotypes observed.

The cellular molecular regulation of differing mechanisms of insulin resistance. 1R01DK126892-01A1

This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Blocking purinergic signaling alters platelet and macrophage crosstalk and phagocytic ability in the peritoneal cavity during intra-abdominal sepsis
Authors: Entsie Philomena , Amoafo Emmanuel , Kang Ying , Dorsam Glenn , Liverani Elisabetta
Published: May 2023

Intra-abdominal sepsis is a life-threatening complex syndrome caused by dysregulation of the host response to infection and is one of the major complications of intra-abdominal surgery. To date, only supportive therapies such as ventilation support, antibiotics and organ replacement are available. However, an increase in antibiotic resistance and the invasiveness of organ transplant has necessitated therapies targeting pathophysiological mechanisms. Platelets, which express the purinergic receptors P2Y1 and P2Y12, mediate macrophage polarization and secretion of pro-inflammatory markers contributing to tissue injury during sepsis. Previously, our group has shown that blocking purinergic signaling through P2Y1 and P2Y12 antagonism significantly lowered inflammatory cytokine levels and improved survival in a murine model of sepsis in a sex specific manner. We hypothesize that the inhibition of P2Y1 and P2Y12 signaling pathways improves the sex-specific outcomes of intra-abdominal sepsis by modulating the crosstalk between platelets and macrophages. Male and female mice underwent sham surgery or cecal ligation and puncture (CLP) to induce sepsis followed by intraperitoneal administration of ticagrelor (P2Y12 antagonist) or MRS2279 (P2Y1 antagonist). The peritoneal cavity fluid (PCF) was collected 4 and 24 hours post-surgery and analyzed. At 4 hours post-surgery, PCF macrophages exhibited increased bacterial phagocytosis from ticagrelor and MRS2279 treated groups in female mice only compared to CLP group. At 24 hours post-CLP surgery, platelet counts did not change but soluble p-selectin and TBX-2 levels were significantly decreased in male groups treated with either ticagrelor or MRS2279, compared to controls. In contrast, soluble p-selectin and TBX-2 levels did not change in female samples.Thus, we conclude that pharmacologically blocking P2Y1 and P2Y12 receptors can enhance the ex-vivo phagocytic activity of macrophages in a sex-related manner, and overall modulate platelet secretion and influence macrophages’ recruitment and activation in the PC during sepsis.

National Institute of Health AI156627-01 to EL

This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Sex differences in arterial stiffness and sympathetic activity in older CKD patients
Authors: Zanuzzi Matias , Jeong Jinhee , DaCosta Dana , Park Jeanie
Published: May 2023

Chronic kidney disease (CKD) is characterized by sympathetic nervous system overactivity that contributes to increased arterial stiffness and cardiovascular risk. While premenopausal females are relatively protected from cardiovascular disease in healthy individuals, older postmenopausal females without kidney disease have similar degrees of sympathetic overactivity, vascular stiffness and cardiovascular risk compared to older age-matched males in the general population. However, in the CKD population, cardiovascular mortality risk remains higher in older males compared to age-matched females and whether sex differences in neural and vascular function exist in older CKD patients is unknown. Therefore, we tested the hypothesis that compared to older females, older males with CKD have higher baseline sympathetic activity that is related to increased arterial stiffness. In 207 CKD patients (N=90 females, 62 ± 9 years; and N=117 males, 60 ± 9 years), we measured resting sympathetic nerve activity directed to muscle (MSNA) by microneurography at the peroneal nerve. At a separate visit, arterial stiffness was determined by carotid-to-femoral pulse wave velocity (PWV) using transcutaneous Doppler flow velocity (SphygmoCor®). Office blood pressure (BP) and 24-hour ambulatory BP monitoring (ABPM; Spacelabs) were performed using standard techniques. Resting MSNA was higher in males versus females with CKD (43 ± 10 vs 31 ± 14 bursts/min; p= 0.039). Both office and 24-hour ambulatory diastolic BP (79 ± 11 vs 67 ± 14 mmHg, p<0.001) and mean arterial pressure (96 ± 10 vs 88 ± 13 mmHg, p<0.001) were also higher in males versus females. PWV was not different between male and female groups (p= 0.157). There was no association between PWV and resting MSNA in males, while in females, there was an inverse relationship between PWV and MSNA burst frequency (r2=0.271; p=0.039) and burst incidence (r2=0.310; p=0.025). Older male CKD patients have higher resting MSNA, office and ambulatory BP compared to older females with CKD. In contrast, there were no differences in arterial stiffness measured as PWV between sexes. In males, increased MSNA was not associated with increased arterial stiffness, while MSNA was negatively correlated with PWV in females. Sex differences in neural and vascular function may impact cardiovascular outcomes in older patients with CKD.

Supported by NIH grants R01HL135183, R33AT010457.

This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Resveratrol supplementation improves endothelial function in chronic kidney disease
Authors: Gimblet Colin , Kruse Nicholas , Geasland Katharine , Mickelson Jeni , Sun Mingyao , Rehman Safur , Wendt Linder , Ten-Eyck Patrick , Ernst Jackson , Pierce Gary , Jalal Diana
Published: May 2023

Introduction: Chronic kidney disease (CKD) associates with increased risk of cardiovascular disease (CVD), in part, due to lower endothelial function. Thus, interventions that increase endothelial function could mitigate CVD in CKD. Resveratrol is a polyphenol that improves endothelial function in obese and aging adults. Whether resveratrol supplementation increases endothelial function in patients with CKD is unknown. Our objective was to test the effects of resveratrol supplementation on endothelial function in CKD. We hypothesized that resveratrol supplementation would increase endothelial function in patients with CKD. Methods: 25 adults with stage 3 CKD and type 2 diabetes were enrolled in a randomized, double-blind, placebo-controlled, crossover study to investigate the effects of 6-week resveratrol supplementation (400 mg/day) on endothelial function. Endothelial function was assessed via brachial artery flow-mediated dilation (BA-FMD). Vascular smooth muscle reactivity was determined from nitroglycerin-mediated dilation. Estimated glomerular filtration rate (eGFR) was calculated from serum cystatin C using the CKD-EPI formula. A mixed effects generalized linear model was used to evaluate differences in treatment arms over time. Results: The median age of the subjects was 70 (67, 74) years and 86% of the patients were male. The mean (SD) GFR and hemoglobin A1c were 42(9) ml/min/1.73m2 and 7.36(0.77)%, respectively. Within-group comparisons revealed BA-FMD increased by 0.91% after resveratrol supplementation (p=0.002), but not placebo (p=0.44), and between-group comparisons indicate resveratrol increased BA-FMD greater than placebo (p=0.001). Nitroglycerin mediated dilation was unchanged after both resveratrol supplementation and placebo (p>0.05). GFR, hemoglobin A1c and blood pressure were unchanged following resveratrol supplementation suggesting that other mechanisms may underlie resveratrol-mediated benefits on endothelial function in this study. Conclusion: Resveratrol supplementation increases endothelial function in patients with CKD. Larger clinical trials for longer duration are needed to confirm our findings and to evaluate the mechanisms by which resveratrol improves endothelial function in CKD.

Funding: This study was supported by the Renal Hypertension Training Grant (NIH NRSA T32 award) and Dr. Jalal's grant R01HL134738-01A1. Colin Gimblet is supported by the American Heart Association predoctoral fellowship grant (23PRE1012593).

This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Maternal obesity suppresses embryonic myogenesis via enhancing H19 lncRNA expression
Authors: Gao Yao , Zhao Liang , Liu Xiangdong , Hossain Md Nazmul , de Avila Jeanene M. , Du Min
Published: May 2023

Background: Maternal obesity (MO) impairs fetal skeletal muscle development, which programs long-term metabolic dysfunction of offspring muscle, but the underlying mechanisms remain poorly defined. Gene imprinting is an allelic epigenetic modification derived from gametes, resulting in gene expression only from one parental allele. H19, the first discovered imprinting gene, is a paternally imprinted and maternally expressed long non-coding long RNA (lncRNA). H19 is highly expressed in placental and fetal tissues but rapidly downregulated after birth except skeletal muscle, underscoring its roles in regulating muscle development. Up to now, the regulatory roles of H19 in prenatal myogenesis and muscle development affected by MO remain to be examined. We hypothesized that MO suppresses embryonic myogenesis by altering H19 expression. Method: High-fat diet (45% calories from the fat) was used to induce MO in mice. Briefly, total 32 of C57BL/6 mice (8-week-old) were randomly chosen and divided into control (CT, chow diet, n=16) and MO (n=16) groups. After 2-month feeding, female mice were mated with age-matched males. Successful mating was confirmed by the presence of vaginal plug. Embryos were collected at E11.5. To analyze allelic expression, CAST/EiJ mice were crossed with C57BL/6, which resulted in 8 single nucleotide polymorphisms (SNPs) between two alleles at the H19 gene. Single cell-RNA sequencing (scRNA-seq) was conducted using E11.5 embryos. To analyze its mediatory role, H19 was overexpressed in P19 cells and the resulting myogenesis was analyzed. Results: MO mice were 23% heavier than the CT group. MO embryos displayed suppressed muscle development, shown by reduced myogenic genes expression. Both scRNA-seq and RT-qPCR showed that H19 expression was increased in MO embryos. The imprinting pattern of H19 was disrupted, showing a bi-allelic expression of H19. To establish causality, we overexpressed H19 in cells which strongly inhibited myogenesis, indicated by lower myogenic genes expression and less myotube formation. Conclusion: MO impedes embryonic myogenesis by elevating H19 expression. The imprinting of H19 in the paternal allele was disrupted by MO, resulted in H19 expression from both maternal and paternal alleles.

R01HD067449

This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
The impact of aortic valve regurgitation on the combination therapy of VA-ECMO and Imeplla support in severe cardiogenic shock: a simulation study
Authors: Matsushita Hiroki , Nishikawa Takuya , Yokota Shohei , Kakuuchi Midori , Yokoi Aimi , Nishiura Akitsugu , Unoki Takashi , Meihua Li , Uemura Kazunori , Kawada Toru , Saku Keita
Published: May 2023

Background: The utilization of a combination of veno-arterial extracorporeal membrane oxygenation (VA-ECMO) and Impella, ECPELLA, has become widespread among patients with cardiogenic shock. The utilization of VA-ECMO in the presence of aortic regurgitation (AR) can result in significant left ventricular (LV) distention. Additionally, the implantation of Impella via the aortic valve frequently induces AR clinically. We established a simulation model and evaluated the impact of AR on hemodynamics under ECPELLA. Furthermore, assuming that the reverse flow of AR is strongly determined by aortic pressure (AP) level, we simulated a scenario where AP was further decreased. Methods: We employed Simulink® (Mathworks, Inc.). The systemic and pulmonary circulations were modeled using a 5-element resistance-capacitance network. Four cardiac chambers were represented by time-varying elastance. We compared the aortic regurgitant flow (Far), total systemic flow (Ftotal), and LV pressure-volume relationship under various severities of AR and varying Impella (0-3.7 L/min) and VA-ECMO (0-5 L/min) flows. AR grades were adjusted by the regurgitant resistance and classified as mild, moderate, and severe, mimicking a clinical scenario. Results: Without AR, ECMO significantly increased Ftotal and raised LV end-diastolic pressure (LVEDP). Impella increased Ftotal and decreased LVEDP. The concomitant presence of AR exacerbated the increase of LVEDP by ECMO and the reduction of LVEDP by Impella. Under ECPELLA support (VA-ECMO: 3 L/min) with mild AR, the increase of Impella support (1 to 3.5 L) increased Ftotal and Far, while decreasing LVEDP, indicating the prevention of AR-induced LV distention. Additionally, the presence of mild AR prevented the Impella-induced left ventricular suction that is commonly observed under ECPELLA support with high-flow VA-ECMO. In the case of moderate AR, while the hemodynamic trends were similar to those observed under mild AR, Impella was unable to prevent the increment of LVEDP to a critical level (< 20 mmHg). However, by decreasing AP through reducing resistance (e.g. vasodilators), both Far and LVEDP were dramatically reduced and Ftotal was increased under ECPELLA support. Conclusion: The concomitant presence of AR in ECPELLA condition increased LV load, while prevented LV suction. The use of vasodilator in ECPELLA with AR could attenuate AR, increase systemic perfusion, and reduce LV load. The optimal control of Impella and VA-ECMO flows and AP can maximize the hemodynamic and LV unloading impacts of ECPELLA.

no funding

This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Endothelial Specific Deletion of Autotaxin Improves Stroke Outcomes
Authors: Panchatcharam Manikandan , Bhattarai Susmita , Subedi Utsab , Manikandan Shrivats , Sharma Sudha , Sharma Papori , Miller Chole , Bhuiyan Md Shenuarin , Kidambi Srivatsan , Aidinis Vassilis , Sun Hong , Miriyala Sumitra
Published: May 2023

Autotaxin (ATX) is an extracellular secretory enzyme (lysophospholipase D) that catalyzes the hydrolysis of lysophosphatidyl choline to lysophosphatidic acid (LPA). The ATX-LPA axis is a well-known pathological mediator of liver fibrosis, metastasis in cancer, pulmonary fibrosis, atherosclerosis, and neurodegenerative diseases. Also, it is believed that LPA may cause vascular permeability. In ischemic stroke, vascular permeability leading to hemorrhagic transformation is a major limitation for therapies and an obstacle to stroke management. So, in this study, we generated an endothelial-specific ATX deletion in mice (ERT2 ATX-/-) to observe stroke outcomes in a mouse stroke model to analyze the role of endothelial ATX. The AR2 probe and Evans Blue staining were used to perform the ATX activity and vascular permeability assays, respectively. Laser speckle imaging was used to observe the cerebral blood flow following stroke. In this study, we observed that stroke outcomes were alleviated with endothelial deletion of ATX. Permeability and infarct volume was reduced in ERT2 ATX-/- mice compared to ischemia-reperfusion (I/R) only mice. In addition, cerebral blood flow was retained in ERT2 ATX-/- compared to I/R mice. The outcomes in the stroke model are alleviated due to limited LPA concentration, reduced ATX concentration, and ATX activity in ERT2 ATX-/- mice. In this study, we observed that ATX produced by the endothelium could be a major factor responsible for increases in permeability and infarcts, and adverse effects on the cerebral blood flow during cerebral ischemic reperfusion. LPA produced specifically by endothelial cells in the vasculature can disrupt the BBB leading ultimately to neuronal loss and glial activation. With the deletion of ATX from the endothelium, the microvasculature might be more resilient due to reduced LPA. We found evidence that the functional outcomes of ischemic stroke were alleviated with ATX deletion. Therefore, endothelial ATX can be targeted to make better and more effective therapies for stroke management.

his research was supported by Louisiana State University Health Sciences-Shreveport Intramural Grant 110101074A to SM; National Institutes of Health grants HL141998 and HL141998-01S1 to SM; grants AA025744, AA026708, and AA025744-02S1 to MP; grants HL122354 and HL145753 to MSB; P20GM12130 to Dr. Christopher Kevil.

This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Characterization of Ghrelin O-acyltransferase mRNA in channel catfish
Authors: Johnson Emily , Miller Sarah , Kobayashi Yass
Published: May 2023

Food intake is regulated by the reaction between hypothalamic neurotransmitters and peripheral signals. Ghrelin, known as a hunger hormone, stimulates food intake. Ghrelin O-acyltransferase (GOAT) catalyzes the acylation of medium-chain fatty acids to ghrelin to modify ghrelin activity. GOAT is found in all vertebrates, including fish, and is critical for modifying the activity of ghrelin. We hypothesized that GOAT is critical for regulating food intake because it modifies the activity of ghrelin in channel catfish. However, very little is known about GOAT in channel catfish, including the tissue distribution of its mRNA. We identified the nucleotide sequence that corresponds to the GOAT mRNA in GenBank. The sequencing alignment analysis showed that the sequence similarity between channel catfish GOAT mRNA and those of other fish species was high (>65%) in the region that corresponded to the open reading frame of the channel catfish GOAT mRNA. Examination of the tissue distribution of GOAT mRNA, including the brain, liver, muscle, kidneys, spleen, heart, and small and large intestines, revealed that GOAT mRNA expression was detectable in the brain, small intestine, and muscles. We are currently verifying the results of tissue distribution analysis using quantitative real-time PCR. We are also examining the relationship between changes in food intake and the expression of GOAT mRNA in the brain and muscle using real-time PCR.

This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Dapagliflozin Attenuates Sodium Chloride Cotransporter (NCC) Protein Expression while Improving Urine Osmolality and Decreasing Blood Pressure in Hypertensive Diabetic db/db Mice
Authors: Gholam Mohammed , Alli Abdel
Published: May 2023

The prevalence of hypertension in diabetic patients varies depending on age, gender, ethnicity, body mass index (BMI), glycemic management history, and the presence of kidney disease. In addition, hypertension is a major contributor to the development of atherosclerotic cardiovascular disease (ASCV), heart failure, and microvascular consequences. In the kidney, NCC is expressed in cells of the distal convoluted tubules. About 10% of the filtered load of sodium is reabsorbed by renal NCC. Recently, dapagliflozin, a sodium-glucose co-transporter 2 (SGLT2) inhibitor, was introduced as an effective class of glucose-lowering agents for the treatment of type 2 diabetes. We hypothesize that dapagliflozin mitigates blood pressure by restoring normal renal functions. Twelve week-old male db/db mice with a blood glucose of more than 300 mg/dl were salt-loaded (4% NaCl) for 10 days to induce hypertension. The mice were subjected to metabolic cage studies for 24-hour urine collections to measure urinary electrolytes. Blood pressure was measured by the tail-cuff method to evaluate the effect of dapagliflozin (n=8), or vehicle (n=8) given by oral gavage (1 mg/kg of body weight per day for 2 weeks). Total NCC protein expression was reduced in kidney cortex membrane fractions, while there was increased urinary sodium levels, from dapagliflozin treated mice compared to vehicle treated mice. Urine osmolality was improved in the dapagliflozin treated group compared to the vehicle treated. Additionally, blood glucose, systolic blood pressure, and urinary potassium levels were reduced in the dapagliflozin treated group. Taken together, these results suggest blood pressure is normalized after dapagliflozin treatment in a mechanism involving reduced renal NCC and increased excretion of sodium.

This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Dietary cannabidiol activates PKA/ERK/AMPK signaling and attenuates chronic inflammation and leaky gut in DSS-induced colitis mice
Authors: Sun Qi , Iniguez Alejandro , Tian Qiyu , Du Min , Zhu Meijun
Published: May 2023

Study objectives: This study is aimed to examine the impact of dietary cannabidiol (CBD), a phytocannabinoid isolated from cannabis plants, on dextran sulfate sodium (DSS)-induced experimental colitis in mice. Hypothesis: Dietary CBD exerts beneficial effects against DSS-induced experimental colitis in mice colon through protecting barrier function and suppressing inflammatory response. Methodology: Eight-week-old C57BL/6J female mice were fed a standard rodent diet supplemented with or without CBD (200 milligrams per kilogram) for 5 weeks. In the 4th week of dietary treatments, mice were subjected to 2.5% DSS induction for 7 days followed by 7 days of recovery to induce colitis. The disease activity index was monitored daily during the induction and recovery periods. After recovery, mice were euthanized, and colon tissues were collected for analysis. Data CBD supplementation reduced body weight loss, gross bleeding, fecal consistency score, and disease activity index. In addition, CBD supplementation protected the colonic structure and ameliorated mucosal damage and macrophage infiltration in the colonic tissue, which is associated with activated cAMP-protein kinase A (PKA), extracellular signal-regulated kinase (ERK) 1/2 and AMP-activated protein kinase (AMPK) signaling pathways. CBD supplementation also suppressed NLRP3 inflammasome activation and pro-inflammatory cytokine secretion. Consistently, CBD feeding decreased the contents of pore-forming tight junction protein claudin-2 and myosin light chain kinase in DSS-treated mice. Summary of results Dietary CBD improves DSS-induced colitis and activates PKA and AMPK signaling pathways to suppress inflammation and enhance gut barrier function. Conclusions: Dietary CBD protects against inflammation and colitis symptoms induced by DSS, providing an alternative approach to IBD management.

Funding Sources: Washington State University Dedicated Marijuana Account (DMAc) grant and Agricultural Research Center Emerging Research Issues Competitive Grant.

This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Dietary purple potato mediates intestinal oxidative phosphorylation and mitochondrial unfolded protein response in DSS-induced colitis mice
Authors: Sun Qi , Bibi Shima , Xue Yansong , Du Min , Zhu Meijun
Published: May 2023

Study objectives: This study is to evaluate the beneficial role of purple potato (PP) supplementation against colitis symptom on dextran sulfate sodium (DSS)-induced murine colon colitis and further explore the underlying mechanisms. Hypothesis: Dietary PP enhances intestinal mitochondrial biogenesis and protect against DSS-induced colitis. Methodology: Six-week-old C57BL/6J male mice were randomized into 4 groups feeding a standard rodent diet supplemented with or without 10% PP powder for 7 weeks. At the 5th week of dietary treatments, mice in each group were further divided into two groups and received with or without 2.5% DSS induction for 7 days followed by 7 days of recovery, when mice were euthanized for tissue collection. Data PP supplementation ameliorated the disease activity index in DSS-treated mice and reversed the colonic structure loss, mucosal damage, macrophage infiltration, and proinflammatory cytokine secretion induced by DSS in the colonic tissue. Dietary PP restored the protein contents of tight junction proteins and caudal-type homeobox 2 (CDX2) in DSS-treated mice. Furthermore, dietary PP activated AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor-γ coactivator (PGC)-1α signaling pathways as well as enhanced mitochondrial oxidative phosphorylation and mitochondrial proteostasis. Summary of results: Dietary PP ameliorated DSS-induced colitis and enhanced gut structures and barrier function which were associated with improved mitochondrial function. Conclusions: Data collectively showed PP supplementation had protective effects against colitis and is a promising dietary strategy for colitis management.

Funding Sources: United States Department of Agriculture-National Institute of Food and Agriculture (USDA-NIFA) (2018-67017-27517) and Washington State University Agricultural Research Center Emerging Research Issues Competitive Grant.

This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Contributions of ATP12A, a non-gastric proton pump alpha subunit, to the pathogenesis of idiopathic pulmonary fibrosis
Authors: Li Xiaopeng , Abdelgied Mohamed , Uhl Katie , Chen Oliver , Schultz Chad , Tripp Kaylie , Peraino Angela , Paithankar Shreya , Chen Bin , Tamae Kakazu Maximiliano , Castillo Bahena Alicia , Jager Tara , Lawson Cameron , Chesla Dave , Pestov Nikolay , Modyanov Nikolai , Prokop Jeremy , Neubig Richard , Uhal Bruce , Girgis Reda
Published: May 2023

Background: Idiopathic Pulmonary Fibrosis (IPF) is a pathological condition of unknown etiology which results from injury to the lung and an ensuing fibrotic response that leads to the thickening of the alveolar walls and obliteration of the alveolar space. The pathogenesis is not clear and there are currently no effective therapies for IPF. Small airway disease and mucus accumulation are prominent features in IPF lungs, similar to Cystic Fibrosis (CF) lung disease. The ATP12A gene encodes the alpha-subunit of the non-gastric H+, K+-ATPase, which functions to acidify the airway surface liquid (ASL) and impairs mucociliary transport function in cystic fibrosis patients. Hypothesis: We hypothesize that the ATP12A protein may play a role in the pathogenesis of IPF. Methods: ATP12A expression level was evaluated by immunohistochemical staining and RNAscope in situ hybridization in normal and IPF human distal lungs. Primary human small airway culture model was used to elucidate the potential roles of ATP12A in the activation of latent TGF-beta activation. Viral vector mediated ATP12A overexpression was used in the bleomycin-induced lung fibrosis mouse model. A potassium-competitive proton pump blocker, vonoprazan was used to block ATP12A functions both in vitro and in vivo. Results: Our studies demonstrate that ATP12A protein is overexpressed in distal small airways from IPF patient lungs compared to normal human lungs. Potassium competitive proton pump blocker vonoprazan decreased airway surface liquid (ASL) pH and TGF-β1 activation in IPF small airway epithelial cells. In addition, overexpression of the ATP12A protein in mouse lungs worsened the Bleomycin (BLEO)-induced experimental pulmonary fibrosis. This was prevented by a potassium-competitive proton pump blocker, vonoprazan. Conclusion: Those data support that the ATP12A protein plays an important role in the pathogenesis of lung fibrosis. Inhibition of the ATP12A protein has the potential as a novel therapeutic strategy in IPF.

This work was funded by the National Institutes of Health (HL153165-01A1 to X.L.), the Cystic Fibrosis Foundation (LI19XX0), Cystic Fibrosis Research Institute, and Spectrum Health-MSU Alliance Corporation funds.

This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.