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Annals of Biomedical Engineering Jun 2024Through their contractile and synthetic capacity, vascular smooth muscle cells (VSMCs) can regulate the stiffness and resistance of the circulation. To model the...
PURPOSE
Through their contractile and synthetic capacity, vascular smooth muscle cells (VSMCs) can regulate the stiffness and resistance of the circulation. To model the contraction of blood vessels, an active stress component can be added to the (passive) Cauchy stress tensor. Different constitutive formulations have been proposed to describe this active stress component. Notably, however, measuring biomechanical behaviour of contracted blood vessels ex vivo presents several experimental challenges, which complicate the acquisition of comprehensive datasets to inform complex active stress models. In this work, we examine formulations for use with limited experimental contraction data as well as those developed to capture more comprehensive datasets.
METHODS
First, we prove analytically that a subset of constitutive active stress formulations exhibits unstable behaviours (i.e., a non-unique diameter solution for a given pressure) in certain parameter ranges, particularly for large contractile deformations. Second, using experimental literature data, we present two case studies where these formulations are used to capture the contractile response of VSMCs in the presence of (1) limited and (2) extensive contraction data.
RESULTS
We show how limited contraction data complicates selecting an appropriate active stress model for vascular applications, potentially resulting in unrealistic modelled behaviours.
CONCLUSION
Our data provide a useful reference for selecting an active stress model which balances the trade-off between accuracy and available biomechanical information. Whilst complex physiologically motivated models' superior accuracy is recommended whenever active biomechanics can be extensively characterised experimentally, a constant 2nd Piola-Kirchhoff active stress model balances well accuracy and applicability with sparse contractile data.
PubMed: 38949730
DOI: 10.1007/s10439-024-03532-x -
The Journal of General Physiology Aug 2024
PubMed: 38949612
DOI: 10.1085/jgp.20231335506112024c -
Annals of Human Genetics Jul 2024The phenotypic consequences of the p.Arg577Ter variant in the α-actinin-3 (ACTN3) gene are suggestive of a trade-off between performance traits for speed and endurance...
INTRODUCTION
The phenotypic consequences of the p.Arg577Ter variant in the α-actinin-3 (ACTN3) gene are suggestive of a trade-off between performance traits for speed and endurance sports. Although there is a consistent association of the c.1729C allele (aka R allele) with strength/power traits, there is still a debate on whether the null allele (c.1729T allele; aka X allele) influences endurance performance. The present study aimed to test the association of the ACTN3 p.Arg577Ter variant with long-distance endurance athlete status, using previously published data with the Brazilian population.
METHODS
Genotypic data from 203 long-distance athletes and 1724 controls were analysed in a case-control approach.
RESULTS
The frequency of the X allele was significantly higher in long-distance athletes than in the control group (51.5% vs. 41.4%; p = 0.000095). The R/X and X/X genotypes were overrepresented in the athlete group. Individuals with the R/X genotype instead of the R/R genotype had a 1.6 increase in the odds of being a long-distance athlete (p = 0.012), whereas individuals with the X/X genotype instead of the R/R genotype had a 2.2 increase in the odds of being a long-distance athlete (p = 0.00017).
CONCLUSION
The X allele, mainly the X/X genotype, was associated with long-distance athlete status in Brazilians.
PubMed: 38949054
DOI: 10.1111/ahg.12571 -
The Journal of Clinical Investigation Jul 2024Mechanical stress from cardiomyocyte contraction causes misfolded sarcomeric protein replacement. Sarcomeric maintenance utilizes localized pools of mRNAs and...
Mechanical stress from cardiomyocyte contraction causes misfolded sarcomeric protein replacement. Sarcomeric maintenance utilizes localized pools of mRNAs and translation machinery, yet the importance of localized translation remains unclear. In this issue of the JCI, Haddad et al. identify the Z-line as a critical site for localized translation of sarcomeric proteins, mediated by ribosomal protein SA (RPSA). RPSA localized ribosomes at Z-lines and was trafficked via microtubules. Cardiomyocyte-specific loss of RPSA in mice resulted in mislocalized protein translation and caused structural dilation from myocyte atrophy. These findings demonstrate the necessity of RPSA-dependent spatially localized translation for sarcomere maintenance and cardiac structure and function.
Topics: Sarcomeres; Animals; Ribosomal Proteins; Mice; Protein Biosynthesis; Myocytes, Cardiac; Ribosomes; Humans; Microtubules
PubMed: 38949021
DOI: 10.1172/JCI181996 -
JPMA. the Journal of the Pakistan... Jun 2024Bladder cancer is the ninth leading cause of death worldwide and 14th leading cause of death in Pakistan. The objective of this study was to determine the frequency of...
Bladder cancer is the ninth leading cause of death worldwide and 14th leading cause of death in Pakistan. The objective of this study was to determine the frequency of urothelial carcinoma in various age groups, its gender distribution, and grades. A total of 131 cases of urothelial carcinoma, received at Department of Pathology, Peshawar Medical College, Peshawar, between January 2017 to December 2022, were included in the study; of them 107 (81.6%) were males while 24 (18.3%) were females with a mean age of 62±13 years. The most common histological subtype was papillary urothelial carcinoma in 117(89.3%) cases, followed by Squamous and Glandular in 5(3.8%) cases. Majority of the urothelial carcinoma with high grade showed a statistically significant relation with muscle invasion 38 (50.66%). Males were four times more likely to have urothelial carcinoma while older age groups were more likely to have high grade urothelial carcinoma.
Topics: Humans; Pakistan; Male; Female; Middle Aged; Aged; Tertiary Care Centers; Urinary Bladder Neoplasms; Carcinoma, Transitional Cell; Adult; Neoplasm Grading; Aged, 80 and over; Neoplasm Invasiveness; Carcinoma, Papillary; Sex Distribution; Age Distribution; Carcinoma, Squamous Cell
PubMed: 38948990
DOI: 10.47391/JPMA.9546 -
BioRxiv : the Preprint Server For... Jun 2024Pain is a prominent and debilitating symptom in myotonic disorders, yet its physiological mechanisms remain poorly understood. This study assessed preclinical pain-like...
Pain is a prominent and debilitating symptom in myotonic disorders, yet its physiological mechanisms remain poorly understood. This study assessed preclinical pain-like behavior in murine models of pharmacologically induced myotonia and myotonic dystrophy type 1 (DM1). In both myotonia congenita and DM1, impairment of the gene, which encodes skeletal muscle voltage-gated CLC-1 chloride channels, reduces chloride ion conductance in skeletal muscle cells, leading to prolonged muscle excitability and delayed relaxation after contraction. We used the CLC-1 antagonist anthracene-9- carboxylic acid (9-AC) at intraperitoneal doses of 30 or 60 mg/kg and HSA LR20b DM1 mice to model CLC-1-induced myotonia. Our experimental approach included pain behavioral testing, calcium imaging, and whole-cell current-clamp electrophysiology in mouse dorsal root ganglion (DRG) neurons. A single injection of 9-AC induced myotonia in mice, which persisted for several hours and resulted in long-lasting allodynic pain-like behavior. Similarly, HSA LR20b mice exhibited both allodynia and hyperalgesia. Despite these pain-like behaviors, DRG neurons did not show signs of hyperexcitability in either myotonic model. These findings suggest that myotonia induces nociplastic pain-like behavior in preclinical rodents, likely through central sensitization mechanisms rather than peripheral sensitization. This study provides insights into the pathophysiology of pain in myotonic disorders and highlights the potential of using myotonic mouse models to explore pain mechanisms and assess novel analgesics. Future research should focus on the central mechanisms involved in myotonia-induced pain and develop targeted therapies to alleviate this significant clinical burden.
PubMed: 38948724
DOI: 10.1101/2024.06.19.599732 -
BioRxiv : the Preprint Server For... Jun 2024Normal endothelial cell dependent vascular smooth muscle cell function is mediated by nitric oxide (NO), which stimulates soluble guanylyl cyclase (sGC) production of...
VERICIGUAT RESCUES CYCLIC GUANOSINE MONOPHOSPHATE PRODUCTION IN HUMAN AORTIC VASCULAR SMOOTH MUSCLE CELLS AND AUGMENTS VASORELAXATION IN AORTIC RINGS EXPOSED TO HIGH GLUCOSE.
BACKGROUND
Normal endothelial cell dependent vascular smooth muscle cell function is mediated by nitric oxide (NO), which stimulates soluble guanylyl cyclase (sGC) production of the second messenger, cyclic guanosine monophosphate (cGMP) leading to increased protein kinase G (PKG) activity and vascular smooth muscle relaxation. NO bioavailability is impaired in inflammatory settings, such as high glucose (HG). We examined whether the direct sGC sensitizer/stimulator vericiguat, augments cGMP production in human vascular smooth muscle cells (HVSMC) exposed to high glucose and explored its effect on vasorelaxation.
METHODS
Aortic HVSMCs were exposed to HG for 24h. In the treatment group, cells also received 1uM vericiguat for 24h. After incubation, cGMP and PKG activity were measured. Additionally, thoracic murine aortas were exposed to HG or to normal glucose (NG) control. The rings were then placed in an organ chamber bath and dose response curves to increasing doses of acetylcholine (Ach) and sodium nitroprusside were constructed for three groups: control (normal glucose), HG alone, and HG + vericiguat.
RESULTS
HVSMCs exposed to HG produced significantly less cGMP than those exposed to NG. cGMP production in the presence of HG was rescued when treated with 1uM vericiguat. Additionally, PKG activity was impaired in the presence of HG and enzyme activity was restored with vericiguat. In isolated mouse aortic rings, ACh mediated relaxation was impaired following treatment with HG, but was improved when a HG group was treated with vericiguat.
CONCLUSIONS
The sGC sensitizer/stimulator vericiguat restored cGMP production and PKG activity in the setting of HG. Vericiguat enhanced ACh-mediated vasorelaxation in the setting of HG. The findings suggest clinical studies are warranted to investigate the potential of sGC sensitization/stimulation as a therapeutic intervention to improve vascular endothelial-dependent function that is impaired in pro-inflammatory settings that are associated with the development of atherosclerotic disease.
PubMed: 38948704
DOI: 10.1101/2024.06.21.600154 -
Sichuan Da Xue Xue Bao. Yi Xue Ban =... May 2024To investigate the effect of Sanshentongmai (SSTM) mixture on the regulation of oxidative damage to rat cardiomyocytes (H9C2) through microRNA-146a and its mechanism.
OBJECTIVE
To investigate the effect of Sanshentongmai (SSTM) mixture on the regulation of oxidative damage to rat cardiomyocytes (H9C2) through microRNA-146a and its mechanism.
METHODS
H9C2 were cultured , HO was used as an oxidant to create an oxidative damage model in H9C2 cells. SSTM intervention was administered to the H9C2 cells. Then, the changes in HO-induced oxidative damage in H9C2 cells and the expression of microRNA-146a were observed to explore the protective effect of SSTM on H9C2 and its mechanism. H9C2 cells cultured were divided into 3 groups, including a control group, a model group of HO-induced oxidative damage (referred to hereafter as the model group), and a group given HO modeling plus SSTM intervention at 500 μg/L for 72 h (referred to hereafter as the treatment group). The cell viability was measured by CCK8 assay. In addition, the levels of N-terminal pro-brain natriuretic peptide (Nt-proBNP), nitric oxide (NO), high-sensitivity C-reactive protein (Hs-CRP), and angiotensin were determined by enzyme-linked immunosorbent assay (ELISA). The expression level of microRNA-146a was determined by real-time PCR (RT-PCR).
RESULT
H9C2 cells were pretreated with SSTM at mass concentrations ranging from 200 to 1500 μg/L. Then, CCK8 assay was performed to measure cell viability and the findings showed that the improvement in cell proliferation reached its peak when the mass concentration of SSTM was 500 μg/L, which was subsequently used as the intervention concentration. ELISA was performed to measure the indicators related to heart failure, including Nt-proBNP, NO, Hs-CRP, and angiotensin Ⅱ. Compared with those of the control group, the expressions of Nt-proBNP and angiotensin Ⅱ in the treatment group were up-regulated (<0.05), while the expression of NO was down-regulated (<0.05). There was no significant difference in the expression of Hs-CRP between the treatment group and the control group. These findings indicate that SSTM could effectively ameliorate oxidative damage in H9C2 rat cardiomyocytes. Finally, according to the RT-PCR findings for the expression of microRNA-146a in each group, HO treatment at 15 μmol/L could significantly reduce the expression of microRNA-146a, and the expression of microRNA-146a in the treatment group was nearly doubled compared with that in the model group. There was no significant difference between the treatment group and the control group.
CONCLUSION
SSTM can significantly resist the HO-induced oxidative damage of H9C2 cells and may play a myocardial protective role by upregulating microRNA-146a.
Topics: Myocytes, Cardiac; Animals; MicroRNAs; Rats; Oxidative Stress; Hydrogen Peroxide; Drugs, Chinese Herbal; Up-Regulation; Cell Survival; Cell Line; Drug Combinations
PubMed: 38948270
DOI: 10.12182/20240560601 -
PeerJ 2024Iron deficiency is known to impair muscle function and reduce athletic performance, while vitamin D has been reported to induce iron deficiency. However, the mechanism...
BACKGROUND
Iron deficiency is known to impair muscle function and reduce athletic performance, while vitamin D has been reported to induce iron deficiency. However, the mechanism underlying exercise-induced changes in iron metabolism and the involvement of vitamins in this mechanism are unclear. The present study examined changes in biological iron metabolism induced by continuous training and the effects of vitamin D on these changes.
METHODS
Diet, physical characteristics, and blood test data were collected from 23 female high school students in a dance club on the last day of each of a 2-month continuous training period and a 2-week complete rest periods.
RESULTS
Serum hepcidin-25 levels were significantly lower during the training period than the rest period ( = 0.013), as were the red blood cell count, hemoglobin, and hematocrit (all < 0.001). Serum erythropoietin was significantly higher ( = 0.001) during the training period. Significant positive correlations were observed between 25(OH)D levels and serum iron, serum ferritin, and transferrin saturation during the training period. Multiple regression analysis with serum 25(OH)D level as the dependent variable and serum ferritin and iron levels as independent variables during the training period revealed a significant association with serum ferritin.
CONCLUSION
Continuous training may promote hemolysis and erythropoiesis, contributing to the suppression of hepcidin expression. The relationship between serum 25(OH)D and iron may be closely related to metabolic changes induced by the exercise load.
Topics: Humans; Hepcidins; Female; Adolescent; Vitamin D; Ferritins; Athletes; Iron; Exercise
PubMed: 38948227
DOI: 10.7717/peerj.17566 -
PeerJ 2024Acute heart attack is the primary cause of cardiovascular-related death worldwide. A common treatment is reperfusion of ischemic tissue, which can cause irreversible... (Review)
Review
Acute heart attack is the primary cause of cardiovascular-related death worldwide. A common treatment is reperfusion of ischemic tissue, which can cause irreversible damage to the myocardium. The number of mitochondria in cardiomyocytes is large, which generate adenosine triphosphate (ATP) to sustain proper cardiac contractile function, and mitochondrial dysfunction plays a crucial role in cell death during myocardial ischemia-reperfusion, leading to an increasing number of studies investigating the impact of mitochondria on ischemia-reperfusion injury. The disarray of mitochondrial dynamics, excessive Ca accumulation, activation of mitochondrial permeable transition pores, swelling of mitochondria, ultimately the death of cardiomyocyte are the consequences of ischemia-reperfusion injury. -opioid receptors can alleviate mitochondrial dysfunction, regulate mitochondrial dynamics, mitigate myocardial ischemia-reperfusion injury, exert protective effects on myocardium. The mechanism of -OR activation during myocardial ischemia-reperfusion to regulate mitochondrial dynamics and reduce myocardial ischemia-reperfusion injury will be discussed, so as to provide theoretical basis for the protection of ischemic myocardium.
Topics: Myocardial Reperfusion Injury; Receptors, Opioid, kappa; Humans; Animals; Myocytes, Cardiac; Mitochondria, Heart; Mitochondrial Dynamics; Calcium
PubMed: 38948204
DOI: 10.7717/peerj.17333