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Biochemical and Biophysical Research... Jun 2024Versican is a large chondroitin sulfate proteoglycan in the extracellular matrix. It plays a pivotal role in the formation of the provisional matrix. S100a4, previously...
Versican is a large chondroitin sulfate proteoglycan in the extracellular matrix. It plays a pivotal role in the formation of the provisional matrix. S100a4, previously known as fibroblast-specific protein, functions as a calcium channel-binding protein. To investigate the role of versican expressed in fibroblasts, we generated conditional knockout mice in which versican expression is deleted in cells expressing S100a4. We found that S100a4 is expressed in adipose tissues, and these mice exhibit obesity under a normal diet, which becomes apparent as early as five months. The white adipose tissues of these mice exhibited decreased expression levels of S100a4 and versican and hypertrophy of adipocytes. qRT-PCR showed a reduced level of UCP1 in their white adipose tissues, indicating that the basic energy metabolism is diminished. These results suggest that versican in adipose tissues maintains the homeostasis of adipose tissues and regulates energy metabolism.
PubMed: 38936224
DOI: 10.1016/j.bbrc.2024.150309 -
Archives of Dermatological Research Jun 2024Current strategies for hypertrophic scar prevention and treatment are limited.
BACKGROUND
Current strategies for hypertrophic scar prevention and treatment are limited.
OBJECTIVE
To facilitate these efforts, a minimally invasive hypertrophic scar model was created in a rabbit ear for the first time based on previous methods used to induce ischemia.
METHODS
Six New Zealand white rabbits (12 ears total) were studied. First, ischemia was achieved by ligating the cranial artery, cranial vein and central artery, while preserving the caudal artery, caudal vein and central vein, respectively. The relative level of ischemia induced at time of surgery, both baseline and maximum perfusion, was assessed with a fluorescent light-assisted angiography and demonstrated lower rates of perfusion in the ischemic ears. Following vascular injury, a 2-cm full thickness linear wound was created on the ventral ear and closed with 4 - 0 Nylon sutures under high tension. For each rabbit, one ear received a combination of ischemia and wounding with suture tension (n = 6), while the other ear was non-ischemic with wounding and suture tension alone (n = 6).
RESULTS
Four weeks post-operatively, ischemic ears developed scar hypertrophy (histological scar thickness: 1.1 ± 0.2 mm versus 0.5 ± 0.1 mm, p < 0.05).
CONCLUSION
Herein, we describe a novel, prototypical minimally invasive rabbit ear model of hypertrophic scar formation that can allow investigation of new drugs for scar prevention.
Topics: Animals; Rabbits; Cicatrix, Hypertrophic; Disease Models, Animal; Minimally Invasive Surgical Procedures; Ear; Ischemia; Humans; Wound Healing; Suture Techniques
PubMed: 38935157
DOI: 10.1007/s00403-024-03185-9 -
Medicine and Science in Sports and... Jun 2024Androgen receptor (AR) expression and signaling has been regarded as a mechanism for regulating muscle hypertrophy. However, little is known about the associations...
PURPOSE
Androgen receptor (AR) expression and signaling has been regarded as a mechanism for regulating muscle hypertrophy. However, little is known about the associations between acute and chronic changes in skeletal muscle total AR, cytoplasmic AR (cAR), nuclear AR (nAR) and AR DNA-binding (AR-DNA) induced by resistance training (RT) and hypertrophy outcomes in women and men. This study aimed to investigate the acute and chronic effects of RT on skeletal muscle total AR, cAR, nAR contents and AR-DNA in women and men. Additionally, we investigated whether these acute and chronic changes in these markers were associated with muscle hypertrophy in both sexes.
METHODS
Nineteen women and 19 men underwent 10 weeks of RT. Muscle biopsies were performed at baseline, 24 h after the first RT session and 96-120 h after the last session. AR, cAR and nAR were analyzed using Western blotting, and AR-DNA using an ELISA-oligonucleotide assay. Fiber cross-sectional area (fCSA) was analyzed through immunohistochemistry and muscle cross-sectional area (mCSA) by ultrasound.
RESULTS
At baseline, men demonstrated greater nAR than women. Baseline cAR was significantly associated with type II fCSA hypertrophy in men. Acutely, both sexes decreased AR and cAR, whereas men demonstrated greater decreases in nAR. After 10 weeks of RT, AR and nAR remained unchanged, men demonstrated greater cAR compared to women, and both sexes decreased AR-DNA activity. Acute and chronic changes in AR markers did not correlate with muscle hypertrophy (type I/II fCSA and mCSA) in women or men.
CONCLUSIONS
Baseline cAR content may influence hypertrophy in men, while neither RT-induced acute nor chronic changes in AR, cAR, nAR, and AR-DNA are associated with muscle hypertrophy in women or men.
PubMed: 38934511
DOI: 10.1249/MSS.0000000000003509 -
Current Pharmaceutical Design Jun 2024Growth Differentiation Factor 15 (GDF15) has emerged as a pivotal signaling molecule implicated in diverse physiological processes, spanning metabolic regulation,...
Growth Differentiation Factor 15 (GDF15) has emerged as a pivotal signaling molecule implicated in diverse physiological processes, spanning metabolic regulation, inflammation, and cardiovascular health. This studyprovides a comprehensive exploration of GDF15's multifaceted role, primarily focusing on its association with obesity-related complications and therapeutic potential. GDF15's involvement in energy homeostasis, specifically its regulation of body weight and appetite through hindbrain neuron activation and the GFRAL-RET signaling pathway, underscores its significance as an appetite-regulating hormone. GDF15's intricate modulation within adipose tissue dynamics in response to dietary changes and obesity, coupled with its influence on insulin sensitivity, highlights its critical role in metabolic health. The manuscript delves into the intricate crosstalk between GDF15 and pathways related to insulin sensitivity, macrophage polarization, and adipose tissue function, elucidating its potential as a therapeutic target for metabolic disorders associated with obesity. GDF15's association with chronic low-grade inflammation and its impact on cardiovascular health, particularly during hyperlipidemia and ischemic events, are explored. The intricate relationship between GDF15 and cardiovascular diseases, including its effects on endothelial function, cardiac hypertrophy, and heart failure, emphasizes its multifaceted nature in maintaining overall cardiovascular well-being. Challenges regarding the therapeutic application of GDF15, such as long-term safety concerns and ongoing clinical investigations, are discussed. Lastly, future research directions exploring GDF15's potential in addressing obesity-related complications and cardiovascular risks are proposed, highlighting its promising role as a therapeutic target in reshaping treatment strategies for obesity and associated health conditions.
PubMed: 38934286
DOI: 10.2174/0113816128318741240611114448 -
Histology and Histopathology Jun 2024Five cases of patients with systemic connective tissue diseases (CTD) who developed connective tissue disease-associated interstitial lung disease (CTD-ILD) with...
Five cases of patients with systemic connective tissue diseases (CTD) who developed connective tissue disease-associated interstitial lung disease (CTD-ILD) with progressive pulmonary fibrosis (PPF) are reported here. Unspecified ILD was diagnosed using high-resolution computed tomography (HRCT). Histologically, all cases were usual interstitial pneumonia (UIP) with findings of advanced (3/5) to diffuse (2/5) fibrosis, with a partially (4/5) to completely (1/5) formed image of a honeycomb lung. The fibrosis itself spread subpleurally and periseptally to more central parts (2/5) of the lung, around the alveolar ducts (2/5), or even without predisposition (1/5). Simultaneously, there was architectural reconstruction based on the mutual fusion of fibrosis without compression of the surrounding lung parenchyma (1/5), or with its compression (4/5). The whole process was accompanied by multifocal (1/5), dispersed (2/5), or organized inflammation in aggregates and lymphoid follicles (2/5). As a result of continuous fibroproduction and maturation of the connective tissue, the alveolar septa thickened, delimiting groups of alveoli that merged into air bullae. Few indistinctly visible (2/5), few clearly visible (1/5), multiple indistinctly visible (1/5), and multiple clearly visible (1/5) fibroblastic foci were present. Among the concomitant changes, areas of emphysema, bronchioloectasia, and bronchiectasis, as well as bronchial and vessel wall hypertrophy, and mucostasis in the alveoli and edema were observed. The differences in the histological appearance of usual interstitial pneumonia associated with systemic connective tissue diseases (CTD-UIP) versus the pattern associated with idiopathic pulmonary fibrosis (IPF-UIP) are discussed here. The main differences lie in spreading lung fibrosis, architectural lung remodeling, fibroblastic foci, and inflammatory infiltrates.
PubMed: 38934227
DOI: 10.14670/HH-18-777 -
Journal of Neurochemistry Jun 2024Gut dysbiosis is linked to metabolic and neurodegenerative diseases and comprises a plausible link between high-fat diet (HFD) and brain dysfunction. Here we show that...
Gut dysbiosis is linked to metabolic and neurodegenerative diseases and comprises a plausible link between high-fat diet (HFD) and brain dysfunction. Here we show that gut microbiota modulation by either antibiotic treatment for 5 weeks or a brief 3-day fecal microbiota transplantation (FMT) regimen from low-fat (control) diet-fed mice decreased weight gain, adipose tissue hypertrophy, and glucose intolerance induced by HFD in C57BL/6 male mice. Notably, gut microbiota modulation by FMT completely reversed impaired recognition memory induced by HFD, whereas modulation by antibiotics had less pronounced effect. Improvement in recognition memory by FMT was accompanied by decreased HFD-induced astrogliosis in the hippocampal cornu ammonis region. Gut microbiome composition analysis indicated that HFD diminished microbiota diversity compared to control diet, whereas FMT partially restored the phyla diversity. Our findings reinforce the role of the gut microbiota on HFD-induced cognitive impairment and suggest that modulating the gut microbiota may be an effective strategy to prevent metabolic and cognitive dysfunction associated with unfavorable dietary patterns.
PubMed: 38934224
DOI: 10.1111/jnc.16156 -
Journal of Molecular and Cellular... Jun 2024Heart failure remains one of the largest clinical burdens globally, with little to no improvement in the development of disease-eradicating therapeutics. Integrin...
Heart failure remains one of the largest clinical burdens globally, with little to no improvement in the development of disease-eradicating therapeutics. Integrin targeting has been used in the treatment of ocular disease and cancer, but little is known about its utility in the treatment of heart failure. Here we sought to determine whether the second generation orally available, αvβ3-specific RGD-mimetic, , was cardioprotective. Male mice were subjected to transverse aortic constriction (TAC) and treated with 50 μg/kg or volume-matched saline as Vehicle control. At 3 weeks post-TAC, echocardiography showed that treatment significantly restored cardiac function and structure indicating the protective effect of treatment in this model of heart failure. Importantly, treatment improved cardiac function giving improved fractional shortening, ejection fraction, heart weight and lung weight to tibia length fractions, together with partial restoration of Ace and Mme levels, as markers of the TAC insult. At a tissue level, reduced cardiomyocyte hypertrophy and interstitial fibrosis, both of which are major clinical features of heart failure. RNA sequencing identified that, mechanistically, this occurred with concomitant alterations to genes involved molecular pathways associated with these processes such as metabolism, hypertrophy and basement membrane formation. Overall, targeting αvβ3 with provides a novel strategy to attenuate pressure-overload induced cardiac hypertrophy and fibrosis, providing a possible new approach to heart failure treatment.
PubMed: 38933087
DOI: 10.1016/j.jmccpl.2024.100069 -
Journal of Diabetes and Metabolic... Jun 2024Non-dipping status is associated with increased total and cardiovascular mortality in many disease conditions including diabetes mellitus. The pattern and its...
Abnormal blood pressure dipping pattern: frequency, determinants, and correlates in Diabetes Mellitus patients in the Cardiovascular Health Risk Assessment in Diabetes Mellitus (CHiD) study.
PURPOSE
Non-dipping status is associated with increased total and cardiovascular mortality in many disease conditions including diabetes mellitus. The pattern and its implications are not well described among Africans. This study was done to describe the frequency of abnormal blood pressure (BP) dipping among T2DM subjects, its determinants and correlates in Ogbomoso, Nigeria.
METHODS
This was a cross-sectional study done at the LAUTECH Teaching Hospital, Ogbomoso. One hundred individuals diagnosed with T2DM were recruited and they had 24-hour ambulatory BP monitoring, echocardiography, ECG, and carotid Doppler among other evaluations. Statistical analysis was done using SPSS 27.0 (Chicago Ill, USA).
RESULTS
The mean age of the participants was 59.3 ± 10.8 years, mean body mass index 27.7 ± 5.9 kg/m with a mean duration of diabetes of 7.52 ± 5.54 years. Abnormal BP dipping was present in 89% (consisting of 41% or reverse dippers and 48% non-dippers). T2DM subjects with abnormal dipping pattern were more likely to be females, had higher glycated haemoglobin, lower fractional shortening, higher left atrial volume and left ventricular mass index, and a higher DM duration than those with normal BP dipping status. The major determinants of abnormal dipping pattern were the duration of diabetes and low HDL-C concentration.
CONCLUSION
Abnormal BP dipping pattern is highly prevalent in T2DM subjects, especially among females. Abnormal BP dipping was also associated with markers of increased cardiovascular risk such as impaired kidney function, left ventricular hypertrophy, postural hypotension, history of intermittent claudication, and presence of plaques on carotid Doppler studies.
SUPPLEMENTARY INFORMATION
The online version contains supplementary material available at 10.1007/s40200-023-01337-8.
PubMed: 38932843
DOI: 10.1007/s40200-023-01337-8 -
Journal of Applied Physiology... Jun 2024Resistance training (RT) remains the most effective treatment for age-related declines in muscle mass. However, many older adults experience attenuated muscle...
Resistance training (RT) remains the most effective treatment for age-related declines in muscle mass. However, many older adults experience attenuated muscle hypertrophy in response to RT when compared to younger adults. This may be attributed to underlying molecular processes that are dysregulated by aging and exacerbated by improperly prescribed RT weekly volume, intensity, and/or frequency doses. MicroRNA (miRNA) are key epigenetic regulators that impact signaling pathways and protein expression within cells, are dynamic and responsive to exercise stimuli, and are often dysregulated in diseases. In this study, we used untargeted miRNA-seq to examine miRNA in skeletal muscle and serum-derived exosomes of older adults (n = 18, 11M/7F, 66±1y) who underwent 3x/wk RT for 30 weeks [e.g., high intensity 3x/wk (HHH, n = 9) or alternating high-low-high intensity (HLH, n = 9)], after a standardized four-week wash-in. Within each tissue, miRNAs were clustered into modules based on pairwise correlation using Weighted Gene Correlation Network Analysis (WGCNA). Modules were tested for association with the magnitude of RT-induced thigh lean mass (TLM) change (as measured by DXA). While no modules were unique to training dose, we identified miRNA modules in skeletal muscle associated with TLM gains irrespective of exercise dose. Using miRNA-target interactions, we analyzed key miRNAs in significant modules for their potential regulatory involvement in biological pathways. Findings point toward potential miRNAs that may be informative biomarkers and could also be evaluated as potential therapeutic targets as an adjuvant to RT in order to maximize skeletal muscle mass accrual in older adults.
PubMed: 38932684
DOI: 10.1152/japplphysiol.00680.2023 -
Viruses May 2024HIV-associated neurocognitive disorders (HAND) are highly prevalent in those ageing with HIV. High-income country data suggest that vascular risk factors (VRFs) may be...
HIV-associated neurocognitive disorders (HAND) are highly prevalent in those ageing with HIV. High-income country data suggest that vascular risk factors (VRFs) may be stronger predictors of HAND than HIV-disease severity, but data from sub-Saharan Africa are lacking. We evaluated relationships of VRFs, vascular end-organ damage and HAND in individuals aged ≥ 50 in Tanzania. c-ART-treated individuals were assessed for HAND using consensus criteria. The prevalence of VRFs and end organ damage markers were measured. The independent associations of VRFs, end organ damage and HAND were examined using multivariable logistic regression. Data were available for 153 individuals (median age 56, 67.3% female). HAND was highly prevalent (66.7%, 25.5% symptomatic) despite well-managed HIV (70.5% virally suppressed). Vascular risk factors included hypertension (34%), obesity (10.5%), hypercholesterolemia (33.3%), diabetes (5.3%) and current smoking (4.6%). End organ damage prevalence ranged from 1.3% (prior myocardial infarction) to 12.5% (left ventricular hypertrophy). Measured VRFs and end organ damage were not independently associated with HAND. The only significant association was lower diastolic BP ( 0.030, OR 0.969 (0.943-0.997). Our results suggest that vascular risk factors are not major drivers of HAND in this setting. Further studies should explore alternative aetiologies such as chronic inflammation.
Topics: Humans; Female; Male; Tanzania; Middle Aged; Risk Factors; HIV Infections; Aged; Prevalence; AIDS Dementia Complex; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Neurocognitive Disorders
PubMed: 38932112
DOI: 10.3390/v16060819