bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identifying Molecular Mechanisms and Biomarkers for Arterial Stiffness in Vitamin D Deficiency, Obese, and Diabetic Patients
Authors: Elmoselhi Adel , Seif Allah Mohamed , Bouzid Amal , Ibrahim Zeinab , Bajbouj khuloud , Abou Assaleh Rebal , Venkatachalam Thenmozhi , Siddiqui Ruqaiyyah , Khan Naveed , Hamoudi Rifat 
Published: May 2023

Background and Aims: Patients who suffer from vitamin D3 deficiency, obesity, and diabetes mellitus (DM) are at higher risk of cardiovascular diseases (CVDs). Arterial stiffness is also shown to be increased and linked with those patients. In this study, we intended to identify circulating MicroRNAs (miRNAs) biomarkers and explore molecular mechanisms of arterial stiffness in those patients as early predictors of CVDs. Methods and Results: Twenty-three adult Emiratis patients were recruited and divided in the following groups: A control healthy group with vitamin D ≥ 20ng, and BMI ≤ 30 (C1 group =11 individuals); a second group with vitamin D deficiency (Vit D level ≤ 20 ng) and obesity (BMI ≥ 30) (A1 group = 9 patients); and a third group with vitamin D deficiency, obesity, plus Diabetes Mellitus (DM) (A2 group = 3 patients). Pulse wave velocity (PWV) was measured and the whole transcriptome analysis with qPCR validation for miRNA in plasma samples were tested. PWV relative to age was significantly higher in A1 and A2 groups 19.4 ± 4.7 m/s and 18.3 ± 1.3 m/s respectively, compared to the control group 14.7 ± 2.1 m/s (p < 0.05). Whole RNA-Sequencing revealed miR-182-5p; miR-199a-5p; miR-193a-5p; and miR-155-5p were differentially over-expressed (logFC > 1.5) in A1 and A2 groups. Additionally, the expression of the following oxidative stress and inflammatory biomarkers were significantly (p <0.05) higher in the A1 group vs C1 group: HIF-1alpha, NOX-I, NOX-II, cytokine IL-1b, IL-6, IL-8, IL-10, and VEGF. Conclusion: We identify 4 miRNAs for arterial stiffness in patients with vitamin D deficiency, obesity and DM. Furthermore, several oxidative stress and inflammatory genes and biomarkers seem to underlie the culprits of arterial stiffness in vitamin D deficiency and obese patients. Those biomarkers could serve as diagnostic and therapeutic targets for the early prevention of CVDs. Sheikh Hamdan Bin Rashid Al Maktoum Award for Medical Sciences, Ref: MRG/38, and Targeted Research Grant from University of Sharjah, Office of Research and Graduate Studies. 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.
Effect of doxycycline in autonomic modulation of the heart, assessed by heart rate variability, in rats with myocardial infarction
Authors: Durand Marina , Sanches Elen , Costa Lucas , Silva Carlos , Buzinari Tereza , Salgado Helio , Fazan Jr Rubens 
Published: May 2023

Treatment with doxycycline (DOXI) reduces ventricular remodeling and decreases the susceptibility of arrhythmias after myocardial infarction (MI), probably due to its inhibitory effect on metalloproteinases, inflammatory mediators, and oxidative stress. We evaluated the effect of DOXI on heart rate variability (HRV) in rats with MI. Infarcted rats (coronary ligation) or control animals (sham-operated), were treated with DOXI (30 mg/kg/day) or vehicle for 4 weeks (N=7-10/group). Rats were implanted with subcutaneous electrodes and, on the following day, had ECG recorded for 30 min. Series of RR intervals were generated to calculate HRV indices. DOXI-treated control rats had lower heart rate (HR) than vehicle-treated counterparts (327±7 vs. 352±7 bpm). Infarcted rats, treated or not, had similar heart rate (344±7 and 350±6 bpm). The standard deviation of RR intervals was similar among groups, but the differences between successive RR (RMSSD) were smaller in DOXI-treated sham-operated rats (4.0±0.5 vs. 6.3±0.9 ms). No differences were observed in RMSSD in rats with MI. Spectral analysis showed that the LF/HF ratio was lower in DOXI-treated control rats (0.32±0.05 vs. 0.62 ± 0.07). There was no difference in the LF/HF ratio in infarcted rats treated with DOXI or vehicle. The symbolic analysis, as described by Porta et al., showed a lower occurrence of 0V patterns (19±4 vs. 33±3%) and a higher 2UV (38±5 vs. 22±2%) in sham-operated rats that received DOXI. In rats with MI, DOXI symbolic indices were found to be similar. Our findings strongly suggest that 4-weeks of treatment with DOXI lead to a change in sympathovagal balance to the parasympathetic side. Curiously this effect was seen only in sham-operated but not in infarcted rats. Funding Sources: Fundação de Amparo à Pesquisa do Estados de São Paulo - FAPESP, 2020/06043-7. Conselho Nacional de Desenvolvimento Científico e Tecnológico - CNPq, Process 306994/2021-6. 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.
Efferent network of Neuromedin B neurons in the retrotrapezoid nucleus in mice
Authors: Abbott Stephen , Berry Faye , Stornetta Daniel , Bayliss Douglas , Souza George 
Published: May 2023

In the parafacial region of the medulla, the peptide Neuromedin B (NMB) is expressed in retrotrapezoid nucleus (RTN) neurons that are proposed to be central respiratory chemoreceptors. The efferent network of RTN Nmb neurons has been established in rats, but has not been examined in mice in detail. To map the downstream connections of RTN Nmb neurons we performed genetically-targeted tracing using novel Nmb-Cre knock-in mice. Adult Nmb-Cre mice were injected in the RTN unilaterally with a Cre-dependent AAV producing expression of red fluorescent protein (AAV-CreON-mScarlet). Expression of Nmb was identified by fluorescent in situ hybridization (FISH). Injections of AAV-CreON-mScarlet in the RTN (N=3) transduced 58 ± 11 % of Nmb-expressing neurons with a selectivity for Nmb neurons of 98 ± 1 %. Intensely labelled axons and terminals were observed in regions overlapping with the medullary and pontine respiratory network. We observe an intra-RTN network of fibers with close appositions between RTN Nmb neurons, as well as moderate projections to areas dorso-medial to the facial nucleus and medially adjacent to the locus coeruleus. There was a modest contralateral projection to the medullary respiratory network, but none to the pontine respiratory network. No labelled fibers were found rostral of the parabrachial nucleus. Anterograde tracing of RTN Nmb neurons was complemented using retrograde transport of Cre-recombinase (AAVrg-Cre) in R26-loxSTOPlox-L10-GFP mice (eGFP-reporter) mice combined with labelling of transcript for Nmb by FISH. Small volumes (3-6 nL) of AAVrg-Cre were unilaterally injected in the Pre-Bötzinger complex (PreBöt), lateral parabrachial nucleus (LPB), caudal ventral respiratory group (cVRG), and the nucleus of the solitary tract (NTS). We determined the proportion of total RTN Nmb neurons that were retro-labelled from each target (PreBöt- 75 ± 3%, n=3; LPB- 65 ± 3%, n=4; cVRG- 54 ± 6%, n=3; NTS- 38 ± 3%, n=3). This result suggests that RTN neurons have a high degree of collateralization within the medullary and pontine respiratory network. Injections of AAVrg-Cre in the PreBöt labelled 16 ± 11% of RTN Nmb neurons contralateral to the injection site. Collectively, these neuroanatomical observations show that the efferent network of RTN Nmb neurons broadly innervate and selectively the central respiratory network in alignment with prior descriptions in rat. Furthermore, we provide evidence for novel connectivity between RTN Nmb neurons. This anatomy supports the idea that RTN neurons generate a coordinated widespread excitation of the respiratory rhythm and pattern generating network in order to promote alveolar ventilation. Funding from NIH-HLBI #HL148004 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 effect of chronic unpredictable stress on renal mitochondrial function in female mice
Authors: Frambes Noelle , Crockett Alexia , Stegmann Kyle , Churillo Amelia , Hollis Fiona , Spinale Francis , Wood Susan , Webb R , Ryan Michael 
Published: May 2023

Background: Chronic stress can induce high blood pressure and lead to decreased renal function by mechanisms that remain unclear. The exposure of rodents to chronic unpredictable stress (CUS) is a translational model used for investigating the physiological impact of stress. The CUS protocol consists of unpredictable and random stressors that mimic real life exposure to stress. While stress is known to impact mitochondrial function, little is understood about the direct impact of chronic stress on renal mitochondrial respiration. Moreover, while studies have shown a link between estrogen and mitochondria through estrogen receptors, the relation between stress induced renal mitochondrial dysfunction and estrous cycle is unknown. Hypothesis: Exposing female mice to CUS will increase blood pressure and cause decreased renal mitochondrial respiration. Methods: We exposed adult female C57BL/6 mice to CUS for 28 days. Before and after stress, all control (CON, n=8) and CUS (n=10) mice were placed in metabolic cages for overnight urine collection. Urine albumin was measured by dipstick assay. On day 28, mice were assessed for blood pressure measurement via tail cuff. 24 hours later, mice were euthanized, and vaginal lavage was performed. The left kidney was removed, transected into thirds, and the poles were placed in relaxing buffer. Kidney mitochondrial oxygen consumption was assessed using high-resolution respirometry. Results: Data were stratified by phases of the estrus cycle. Neither blood pressure nor urinary albumin was significantly altered by CUS in stressed females. Females in estrus and proestrus exposed to CUS (n=5) exhibited a decrease of 20.8% ± 5.1 (n=5, p=0.03) in renal mitochondrial maximal uncoupled respiration compared to non-stressed CON. Renal mitochondrial respiration in diestrus was similar between CUS and CON. Conclusion: Results from this study reveal a link between the female estrus cycle, stress, and mitochondrial function. This work was supported by NIH grants P20GM109091 (F.H.), R01HL130972-01A1 (F.G.S.), R01HL5949 (F.G.S.), RO1DK132948 (C.W. & F.P.) and R01 MH129798 (SKW); VA grants: VISN7 RDA (F.H.), Merit awards: BX000168-10A1 (F.G.S.), BX005320 (F.G.S.), and BX002604 (M.J.R.). 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.
ETA receptor activation on vascular smooth muscle cells mediates inflammation via IL-6
Authors: Newberry Madison , Wilson Natalie , Moore Daniel , Speed Joshua 
Published: May 2023

In obesity, there is a shift to a pro-inflammatory immune cell profile in adipose tissue, producing adipocyte dysfunction that leads to dyslipidemia and insulin resistance. Endothelin-1 (ET-1) is a proinflammatory peptide produced by endothelial cells that is increased in obesity. Our lab recently demonstrated that blockade of ET-1 type A receptors (ET A) attenuates the pro-inflammatory immune cell profile in adipose tissue of obese mice. This is not due to activation of ET A receptors on adipocytes because adipocyte-specific ET A knockout did not attenuate adipose tissue inflammation in obese mice. Given the abundance of ET A on vascular smooth muscle cells (VSMC), we hypothesize that ET-1 binds ET A on vascular smooth muscle cells leading to release of proinflammatory cytokines. To test this hypothesis, human vascular smooth muscle cells were treated with ET-1 and co-treated with either vehicle, BQ-123 (ET A antagonist), or BQ-788 (ET B antagonist) and mRNA and protein release of several cytokines were measured. Treatment with ET-1 led to a significant increase in interleukin-6 (IL-6) mRNA expression (77993 ± 9716 vs. 142133 ± 19181 copy count/50ng RNA) and protein release into the media (315±27 vs. 569±17 pg/mL). The increase in IL-6 production was attenuated by treatment with BQ-123 (331±7 pg/mL), but not BQ-788 (583±4 pg/mL). There was no difference in tumor necrosis factor alpha, transforming growth factor beta, or interferon gamma in cells treated with ET-1 compared to vehicle. These data suggest that elevated ET-1 may promote inflammation in obesity by increasing IL-6 production by vascular smooth muscle cells. 5R01DK124327-02 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.
Impaired mitochondrial quality control in skeletal muscles from C57 and D2 mdx model of Duchenne Muscular Dystrophy
Authors: Rosen Grace , Whitley Kennedy , ReyesNegron Alexander , Berger Nicolas , Lourie Jared , Cleverdon Riley , Fajardo Val , Zou Kai 
Published: May 2023

Mitochondrial dysfunction is an early pathological feature of Duchenne muscular dystrophy (DMD) and precedes myopathy. Balanced mitochondrial quality control (e.g., fission, fusion, biogenesis, autophagy, and mitophagy) is essential to maintain the overall mitochondrial health and skeletal muscle function. DBA/2J mdx (D2- mdx) has emerged as a more relevant mouse model of DMD as it more closely mirrors early stage of DMD pathology in humans than the C57BL/10 mdx (C57 -mdx) model. The purpose of this study was to determine whether the expression of proteins responsible for mitochondrial quality control were dysregulated in skeletal muscles from these two mouse models of DMD. We hypothesized that the expression of protein markers of mitochondrial fission and mitophagy would be higher, while markers of mitochondrial fusion would be lower in both models of DMD with greater alterations in D2- mdx mice. 8-10-week-old male C57 -mdx and D2- mdx mice, and their respective wildtype (WT) mice were used in this study. Muscle strength was measured using hang wire test. Gastrocnemius muscles were collected for immunoblot analysis to assess mitochondrial quality control proteins. Hang wire impulse, an indicator of muscle strength, was significantly lower in both models of DMD in comparison to their WT controls (main effect of mdx, P = 0.01). Regarding mitochondrial fission, while there was no difference in protein expression and phosphorylation (Ser 616) of Dynamin-Related Protein 1 (Drp1) between any groups, mitochondrial fission 1 protein (Fis1) was markedly higher in skeletal muscles from both models of DMD when compared to WT controls (main effect of mdx, P=0.0001). Greater expression of Fis1 was observed in D2- mdx than C57- mdx when compared to their respective WT controls (~5.7-fold vs. 3.8-fold). Furthermore, mitochondrial fusion marker Mitofusion 1 (Mfn1) was significantly lower in both models of DMD (main effect of mdx, P=0.029), however, it appears to be mainly driven by the reduction in D2-mdx (mdx x strain interaction, P=0.019). No difference of Mfn1 expression was found in C57-mdx mice. Finally, expression of protein markers of mitochondrial biogenesis (PGC1 a) and autophagy (LC3B) were higher in both models of DMD when compared to their respective WT controls (main effect of mdx, P=0.0001 and P=0.001, respectively). In conclusion, these data suggest that there is dysregulated mitochondrial dynamics towards pro-fission state in skeletal muscle from mdx mice with an exacerbated effect in D2- mdx model, which may contribute to the muscle weakness phenotype associated with DMD 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.
Effect of 20-hydroxyecdysone on the immune response following eccentric muscle injury in C57BL/6 mice
Authors: Zwetsloot Kevin , van Onselen Lisha , Moorefield Erin , Rao Anika , Hill Levi 
Published: May 2023

Previously, we demonstrated that the phytoecdysteroid, 20-hydroxyecdysone (20E), accelerates the recovery of skeletal muscle function 7 days following eccentric contraction-induced injury. We hypothesized that 20E may influence the inflammatory response during recovery from eccentric muscle injury; therefore, male mice (3-6 mo) were subjected to eccentric damage of the anterior crural muscles via 150 eccentric contractions, then treated with either 20E (50mg/kg body mass) or vehicle daily until sacrifice (12 hours, 2 days or 4 days post-injury). Using immunohistochemical techniques, infiltration of neutrophils, M1-like, and M2-like macrophages were examined in sectioned tibialis anterior muscle. Our findings revealed that pro-inflammatory responses (infiltration of neutrophils and M1-like macrophages) appear to be attenuated in 20E-treated mice at 12 hours and 2 days post-injury, respectively; whereas anti-inflammatory responses (infiltration of M2-like macrophages) appeared to increase with 20E treatment at 4 days after eccentric muscle injury. Taken together, it is possible that 20E may attenuate the overall early pro-inflammatory response, while bolstering the later anti-inflammatory response to eccentric muscle injury, leading to accelerated muscle repair/regeneration. This research was partly funded by the Appalachian State University Office of Student Research. 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.
Nonmuscle myosin II proteins, Myh9 and Myh10, interacts with unconventional myosin Myo18A in immortalized mouse thick ascending limb epithelial cells
Authors: Zimmerman Jenna , Busselman Brook , Otterpohl Karla , Chandrasekar Indra 
Published: May 2023

Conventional nonmuscle myosin II (NM2) and unconventional myosin 18A (Myo18A) belong to an evolutionarily conserved family of molecular motor proteins that slide or walk on the actin cytoskeleton to facilitate a myriad of cellular functions including cargo transport pathways. NM2 and Myo18A are known to copolymerize into filaments in vitro in cell-free systems and in cells. Our previous work demonstrated the crucial role for Myh9&10 proteins in regulating transport of uromodulin (UMOD) and the sodium, potassium, chloride cotransporter (NKCC2) in the thick ascending limb (TAL) of mouse kidney using a Myh9&10 conditional knockout mouse model (Otterpohl, et al; 2020). Myo18A is expressed in the proximal tubule and TAL cells in the murine kidney and localizes to the apical membrane. Our results show reduced expression of Myo18A in the TAL cells of the Myh9&10 cKO mouse kidney sections. Furthermore, we identified Myo18A as a major interaction partner to the Myh10 heavy chain in a BioID screen performed in renal epithelial cells. Given that Myo18A alpha is the only myosin with a PDZ domain, we hypothesize that Myo18A coordinates with Myh9&10 in the TAL cells to regulate membrane remodeling during vesicular transport, including the targeting and stabilization of TAL proteins like UMOD and NKCC2. To test this hypothesis, we stably expressed GFP-tagged Myo18A alpha construct in immortalized, mouse thick ascending limb (imTAL) cells generated in the lab. We performed coimmunoprecipitation (Co-IP) experiments that showed interaction between Myo18A alpha, Myh9 and Myh10 proteins. Immunostaining experiments show colocalization of GFP-Myo18A alpha with Myh9 and Myh10 in imTAL cells. These results strongly support the coordinated functions of Myo18A and Myh9&10 proteins in TAL epithelia and warrants further experiments to determine their role in regulating UMOD and NKCC2 transport in the TAL cells. 1R01DK131020-01A1 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.
Viral vector-mediated overexpression of mitochondrial ATP-binding cassette subfamily B member7 does not protect against doxorubicin-induced cardiotoxicity
Authors: Dowllah Imtiaz Masfique , Nguyen Branden , Doerr Vivian , Jacintho Moritz Cesar , Smuder Ashley 
Published: May 2023

Doxorubicin (DOX)-induced cardiotoxicity results in an increased risk of mortality among chemotherapy recipients. Cardiomyocyte dysfunction is caused by the off-target accumulation of DOX in cardiac mitochondria, stimulating oxidative damage and impaired oxidative phosphorylation. Prior research showed that exercise preconditioning may prevent DOX-induced cardiotoxicity by enhancing the abundance of mitochondrial ATP-binding cassette (ABC) transporters, potentially accelerating the rate of DOX clearance from cardiomyocytes. Mitochondrial ABC subfamily B member7 (ABCB7) has been implicated in drug export and multidrug resistance. Therefore, to further understand whether, independent of exercise, overexpression of a mitochondria-localized ABC transporter can prevent acute cardiotoxic effects of DOX, we examined the effects of adeno-associated virus (AAV)-mediated overexpression of ABCB7 on cardiac function, exercise tolerance, and mitochondrial accumulation of DOX and its metabolites (doxorubicinol) in animals treated acutely with DOX (20 mg/kg IP). Female Sprague-Dawley rats were randomized into four experimental groups (n=10/ group): 1) Saline-treatment (CON), 2) DOX-treatment (DOX), 3) ABCB7 overexpression, saline-treatment (ABCB7), and 4) ABCB7 overexpression, DOX-treatment (ABCB7+DOX). Our findings show that DOX treatment results in detriments to left ventricular fractional shortening percentage 48 hours following administration, and overexpression of ABCB7 could partially protect from such DOX-induced dysfunction. However, the effect of ABCB7 overexpression on cardiac function was not related to a reduction in mitochondrial DOX and doxorubicinol concentration, nor does it improve exercise tolerance in acute DOX-treated animals. Further work is needed to elucidate the effects of ABCB7 on mitochondrial and cardiac function. Funding Source: R01 HL144858 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.