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Ozan Yetis ◽  
Ozge Guner ◽  
Ibrahim Akkaya ◽  
M. Ensari Guneli ◽  
H. Alper Bagriyanik ◽  

2021 ◽  
Maria Francesca Evaristi ◽  
Bruno Poirier ◽  
Xavier Chénedé ◽  
Anne-Marie Lefebvre ◽  
Alain Roccon ◽  

Aim: Heart failure with preserved ejection fraction (HFpEF) is a major cause of death worldwide with no approved treatment. Left ventricular hypertrophy (LVH) and diastolic dysfunction represent the structural and functional components of HFpEF, respectively . Endothelial dysfunction is prevalent in HFpEF and predicts cardiovascular events. We investigated if SAR247799, a G-protein-biased sphingosine-1-phosphate receptor 1 (S1P 1 ) agonist with endothelial-protective properties, could improve cardiac and renal functions in a rat model of metabolic syndrome LVH and diastolic function. Methods: 31- and 65-week-old obese ZSF1 (Ob-ZSF1) rats, representing young and old animals with LVH and diastolic dysfunction, were randomized to a chow diet containing 0.025% (w/w) of SAR247799, or control (CTRL) chow for 4 weeks. Age-matched lean ZSF1 (Le-ZSF1) rats were fed control chow. Echocardiography, telemetry, biochemical and histological analysis were performed to evaluate the effect of SAR247799. Results: Echocardiography revealed that Ob-ZSF1 rats, in contrast to Le-ZSF1 rats, developed progressive diastolic dysfunction and cardiac hypertrophy with age. SAR247799 blunted the progression of diastolic dysfunction in young and old animals: in young animals E/e’ was evaluated at 21.8 ± 1.4 for Ob-ZSF1-CTRL, 19.5 ± 1.2 for Ob-ZSF1-SAR247799 p<0.01, and 19.5 ± 2.3 for Le-ZSF1-CTRL (median ± IQR). In old animals E/e’ was evaluated at 23.15 ± 4.45 for Ob-ZSF1-CTRL, 19.5 ± 5 for Ob-ZSF1-SAR247799 p<0.01, and 16.69 ± 1.7 for Le-ZSF1-CTRL, p<0.01 (median ± IQR). In old animals, SAR247799 reduced cardiac hypertrophy (mean ± SEM of heart weight/tibia length 0.053 ± 0.001 for Ob-ZSF1-CTRL vs 0.046 ± 0.002 for Ob-ZSF1-SAR247799 p<0.01, Le-ZSF1-CTRL 0.035 ± 0.001) and myocardial perivascular collagen content (p<0.001), independently of any changes in microvascular density. In young animals, SAR247799 improved endothelial function as assessed by the very low frequency bands of systolic blood pressure variability (mean ± SEM 67.8 ± 3.41 for Ob-ZSF1-CTRL  55.8 ± 4.27 or Ob-ZSF1-SAR247799, p<0.05  and 57.3 ± 1.82 Le-ZSF1-CTRL), independently of any modification of arterial blood pressure. In old animals, SAR247799 reduced urinary protein/creatinine ratio, an index of glomerular injury, (10.3 ± 0.621 vs 8.17 ± 0.231 for Ob-ZSF1-CTRL vs Ob-ZSF1-SAR247799, respectively, p<0.05 and 0.294 ± 0.029 for Le-ZSF1-CTRL, mean ± SEM) and the fractional excretion of electrolytes. Circulating lymphocytes were not decreased by SAR247799, confirming lack of S1P 1 desensitization.   Conclusions: These experimental findings suggest that S1P 1 activation with SAR247799 could improve LVH, cardiac diastolic and renal function in HFpEF patients .

2021 ◽  
Yang Ruan ◽  
Shuai Meng ◽  
Ruofei Jia ◽  
Xiaojing Cao ◽  
zening Jin

Abstract Objective: A large cohort of studies have addressed the therapeutic importance of microRNA (miR) in the treatment of myocardial infarction (MI). The current paper gives prominence to the role of miR-322-5p in MI by regulating B-cell translocation gene 2 (BTG2).Methods: In a rat model of MI miR-322-5p and BTG2 expression was estimated. Adenovirus that altered miR-322-5p or BTG2 expression was injected into MI rats. After that, cardiac function, inflammation, myocardial injury, pathological condition, apoptosis, and the NF-κB pathway-related genes in the myocardial tissue of MI rats after targeted treatment were evaluated. The targeting relationship between miR-322-5p and BTG2 was assessed.Results: miR-322-5p was lowly expressed and BTG2 was highly expressed in the myocardial tissue of MI rats. Restored miR-322-5p improved cardiac function, relived inflammation and myocardial injury, suppressed pathological condition and apoptosis and inactivated NF-κB pathway in MI rats. BTG2 expression was negatively mediated by miR-322-5p. Overexpressed BTG2 rescued miR-322-5p-induced cardioprotection on MI rats.Conclusion: It is evident that miR-322-5p protects against MI through suppressing BTG2 expression.

2021 ◽  
Vol 16 (1) ◽  
Rong-Bin Chen ◽  
Ying-Dong Yang ◽  
Kai Sun ◽  
Shan Liu ◽  
Wei Guo ◽  

Abstract Background Amending from ancient classic, Ziyin Tongluo Formula (ZYTLF) has been prescribed to treat postmenopausal osteoporosis (PMOP) for decades with good curative effect. However, the possible mechanisms of it are still unknown. Methods Ovariectomized rat model was established to validate the therapeutic effect of ZYTLF on PMOP by Micro-CT bone analysis and pathological observation. Subsequently, active ingredients of ZYTLF and corresponding putative targets were identified by online databases. Overlapping genes were first obtained from mining genes associated with PMOP and then overlapped them with the putative targets. Key genes were selected from the multiple constructed and analyzed networks. GO and KEGG pathway enrichment analysis were performed by importing the key genes to the DAVID database. Moreover, validation of the binding association between key targets and their corresponding active compounds were accomplished by AutoDock Tools and other software. Lastly, Enzyme linked immunosorbent assay (Elisa) detection and Western blot analysis were utilized to further explore the possible mechanism of ZYTLF on PMOP. Results With 129 target genes interacting with PMOP, 92 active compounds of ZYTLF corresponded to 243 targets, and 50 key genes were chosen. Network analysis revealed the top 10 active ingredients, such as quercetin and kaempferol and the top 50 key genes, such as ERα, p38 MAPK, p-AKT and TGF-β1. Enrichment analysis uncovered multiple signaling pathways, including estrogen signaling pathway, TNF signaling pathway, PI3K-Akt signaling pathway and MAPK signaling pathway. Furthermore, our finding of the foremost active compounds was tightly bound to the core proteins, which were verified by molecular docking analysis. Through experimental studies, we confirmed that the prescription of ZYTLF could ameliorate the OVX-induced bone loss, suppress the osteoclast activity and boost osteoblast ability through experimental studies. Conclusion The potential mechanisms and therapeutic effects of ZYTLF against PMOP may be ascribed to inhibition of osteoclast activity, boost of osteoblast activity and enhancement of the expression of ERα.

2021 ◽  
somayeh Ebrahimi-barough ◽  
Md Shahidul Islam ◽  
Mamun Al Mahtab ◽  
Sadegh Shirian ◽  
Hamid Reza Aghayan ◽  

Abstract Osteoarthritis (OA) is the most common form of degenerative joint disease, affecting more than 25% of the adult though prevalent in the elderly population. Most of the current therapeutic modalities aim at symptomatic treatment and lingering the disease progression. In recent years, regenerative medicine such as stem cell transplantation and tissue engineering has been suggested as a potential curative intervention for OA. The objective of current study was to assess the safety and efficacy of an injectable tissue-engineered construct composed of BMMSCs, PRP, and Collagen type I in rat model of OA.To produce collagen type I, PRP and BMMSCs, male Wistar rats were ethically euthanized. After expansion and characterization of rat BMMSCs (rBMMSCs), tissue-engineered construct was formed by combination of appropriate amount of collagen type I, PRP and rBMMSCs. In vitro studies were conducted to evaluate the effect of PRP on chondrogenic differentiation capacity of encapsulated cells. Then tissue-engineered construct was injected in knee joint of rat model of OA (24 rat in 4 groups:OA, OA+MSC, ‎OA+Collagen+MSC+PRP, OA+MSC+Collagen).After 6 weeks, the animals were euthanized and knee joint histopathology examinations were performed to evaluate the effect of each treatment on OA.Tissue-engineered construct was successfully manufactured and in vitro assays demonstrated that relevant chondrogenic genes and proteins expression were higher in PRP group than the others. Histopathological findings of the knee joint samples showed favorable regenerative effect of rBMMSCs+PRP+Collagengroup comparing to others.In this study, we introduced an injectable tissue-engineered product composed of rBMMSCs+PRP+Collagenwith potential regenerative effect on cartilage damage caused by OA.

2021 ◽  
Vol 21 (1) ◽  
Jianjie Wang ◽  
Jingru Li ◽  
Bihua Chen ◽  
Yiming Shen ◽  
Juan Wang ◽  

Abstract Purpose Previous clinical studies have suggested an effect of gender on outcome after out-of-hospital cardiac arrest, but the results are conflicting and there is no uniform agreement regarding gender differences in survival and prognosis. The present study was aimed to investigate the interaction between gender and post resuscitation interventions on neurological outcome in an asphyxial rat model of cardiac arrest. Methods Asphyxia was induced by blocking the endotracheal tube in 120 adult Sprague–Dawley rats (60 males and 60 females) at the same age. Cardiopulmonary resuscitation (CPR) was started after 5 min of untreated cardiac arrest. Animals were randomized into one of the three post resuscitation care intervention groups (n = 40, 20 males) immediately after resuscitation: (1) normothermic control (NC): ventilated with 2% N2/98% O2 for 1 h under normothermia; (2) targeted temperature management (TTM): ventilated with 2% N2/98% O2 for 1 h under hypothermia; (3) hydrogen inhalation (HI): ventilated with 2% H2/98% O2 for 1 h under normothermia. Physiological variables were recorded during the 5 h post resuscitation monitoring period. Neurological deficit score (NDS) and accumulative survival were used to assess 96 h outcomes. Mutual independence analysis and Mantel–Haenszel stratified analysis were used to explore the associations among gender, intervention and survival. Results The body weights of female rats were significantly lighter than males, but CPR characteristics did not differ between genders. Compared with male rats, females had significantly lower mean arterial pressure, longer onset time of the electroencephalogram (EEG) burst and time to normal EEG trace (TTNT) in the NC group; relatively longer TTNT in the TTM group; and substantially longer TTNT, lower NDSs, and higher survival in the HI group. Mutual independence analysis revealed that both gender and intervention were associated with neurological outcome. Mantel–Haenszel stratified analysis demonstrated that female rats had significantly higher survival rate than males when adjusted for the confounder intervention. Conclusion In this rat model cardiac arrest and CPR, gender did not affect resuscitation but associated with neurological outcome. The superiority of female rats in neurological recovery was affected by post resuscitation interventions and female rats were more likely to benefit from hydrogen therapy.

Carlos Menendez-Castro ◽  
Nada Cordasic ◽  
Fabian B. Fahlbusch ◽  
Arif B. Ekici ◽  
Philipp Kirchner ◽  

Abstract In malignant hypertension, far more severe kidney injury occurs than in the “benign” form of the disease. The role of high blood pressure and the renin–angiotensin–aldosterone system is well recognized, but the pathogenesis of the renal injury of malignant hypertension (MH) remains incompletely understood. Using the rat model of two-kidney, one-clip renovascular hypertension in which some but not all animals develop MH, we performed a transcriptomic analysis of gene expression by RNA sequencing to identify transcriptional changes in the kidney cortex specific for MH. Differential gene expression was assessed in three groups: MH, non-malignant hypertension (NMH), and normotensive, sham-operated controls. To distinguish MH from NMH, we considered two factors: weight loss and typical renovascular lesions. Mean blood pressure measured intraarterially was elevated in MH (220 ± 6.5 mmHg) as well as in NMH (192 ± 6.4 mmHg), compared to controls (119 ± 1.7 mmHg, p < 0.05). Eight hundred eighty-six genes were exclusively regulated in MH only. Principal component analysis revealed a separated clustering of the three groups. The data pointed to an upregulation of many inflammatory mechanisms in MH including pathways which previously attracted relatively little attention in the setting of hypertensive kidney injury: Transcripts from all three complement activation pathways were upregulated in MH compared to NMH but not in NMH compared with controls; immunohistochemistry confirmed complement deposition in MH exclusively. The expression of chemokines attracting neutrophil granulocytes (CXCL6) and infiltration of myeloperoxidase-positive cells were increased only in MH rats. The data suggest that these pathways, especially complement deposition, may contribute to kidney injury under MH. Key messages The most severe hypertension-induced kidney injury occurs in malignant hypertension. In a rat model of malignant hypertension, we assessed transcriptional responses in the kidney exposed to high blood pressure. A broad stimulation of inflammatory mechanisms was observed, but a few specific pathways were activated only in the malignant form of the disease, notably activation of the complement cascades. Complement inhibitors may alleviate the thrombotic microangiopathy of malignant hypertension even in the absence of primary complement abnormalities.

2021 ◽  
Jin Shang ◽  
Yiding Zhang ◽  
Ruixue Guo ◽  
Wenli Liu ◽  
Jun Zhang ◽  

Abstract OBJECTIVE: Membranous nephropathy (MN) is one of the most common causes of nephrotic syndrome in adults. Here we aim to establish a non-invasive diagnostic model using differential gut microbiome and to explore the relationship between gut microbiome and the pathogenesis of MN in animal experiment.DESIGN: A total of 825 fecal samples including MN patients and healthy controls (HC) were collected from Central, East and South China. We obtained crucial operational taxonomic units (OTUs) by 16S rRNA sequencing and then established a diagnostic model using five-fold cross-validation on random forest model. We subsequently validated its efficiency in cross regional cohort. MN rat model was induced by Sheep Anti-Rat Fx1A Serum and was used to explore the relationship between gut microbiome and the pathogenesis of MN.RESULTS: The diversity and richness of gut microbiome was significantly decreased in MN patients. The diagnostic model based on 7 operational OTUs achieved excellent efficiency with an area under curve (AUC) of 98.36% in training group. The different disease states and cross regional cohort validated high diagnostic efficiency. In rat model, urinary protein was significantly relieved by intestine cleaning, while increased again by fecal microbiome transplant (FMT). Interestingly, fecal microbiome from MN patients seems to play a protective role when compared with that from healthy people.CONCLUSION: Gut microbiome can be used as a non-invasive tool for MN diagnosis. The onset of MN depends partially on the existence of naturally colonized microbiome. Adaptive changes of gut microbiome during MN may help relieve urinary protein.

2021 ◽  
Vol 2021 ◽  
pp. 1-8
Saba Shaygan ◽  
Sajad Fakhri ◽  
Gholamreza Bahrami ◽  
Khodabakhsh Rashidi ◽  
Mohammad Hosein Farzaei

Background and Aim. Pumpkin (Cucurbita moschata Duchesne) is a medicinal plant with different pharmacological effects such as antioxidant, antidiabetic, hepatoprotective, and anticancer effects. In the present study, we aimed to investigate wound-healing activity of pumpkin fruit peel in a rat model of excision wound repair. Materials and Methods. Hydroalcoholic extractions of pumpkin fruit peel were obtained and used to prepare two different cold cream-based formulations, namely, 10% and 20% pumpkin peel extracts (PPEs). These formulations, phenytoin cream, and cold cream were topically used once daily for 14 days to compare their wound-healing effects in a rat model of excision wound repair. Wound sizes were monitored at different intervals. Skin tissue samples were subject to H&E staining for histopathological analysis. Blood samples were also taken on day 14 to measure serum levels of nitrite. Results. Both 10% and 20% PPE formulations resulted in a significant reduction of wound sizes compared to positive and negative controls. Wound closure rate was estimated to be higher in 20% PPE-treated rats. According to histopathological analysis, treatment with 20% PPE improved parameters associated with efficient wound repair, including better regeneration of epidemic layer, higher density of dermis collagen fibers, and lower presence of inflammatory cells. Also, both formulations lowered serum concentrations of nitrite. Conclusion. Given the obtained data from our study, the hydroalcoholic extract of Cucurbita moschata Duchesne fruit peel is proposed to be effective in accelerating the process of excision wound repair partly due to its antioxidant effect in terms of decreasing nitrite concentration.

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