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Human amniotic membrane mesenchymal stem cells-derived conditioned medium (hAM-MSCs-CM) has positive effects against myocardial ischemia/reperfusion (MI/R) injury. However, it needs further investigations how hAM-MSCs-CM leads to the cell survival under MI/R via modulation of autophagy. The purpose of this study is investigating the effects of hAM-MSCs-CM in a rat model of MI/R injury by focusing on the role of autophagy as one of its possible mechanisms. Male Wistar rats (44 rats, 175–200 g) were randomly divided into four groups: Sham, MI/R, culture media-receiving and conditioned medium-receiving. MI/R was induced by 30 min of left anterior descending coronary artery ligation. After 15 min reperfusion, culture media or hAM-MSCs-CM (150 μl) were injected intramyocardially. At the end of the experiment, CK-MB, autophagy markers, phosphorylated and total forms of mTOR and ULK1, cardiac function and fibrosis were measured. hAM-MSCs-CM significantly decreased CK-MB levels (P < 0.0001), and also the mRNA levels of Beclin1 (P < 0.0001), LC3 (P = 0.012) and p62 (P = 0.003). In addition, hAM-MSCs-CM significantly reduced Beclin1, LC3II/LC3I and p62 protein levels (P < 0.0001), and increased p-mTOR/mTOR (P = 0.022) and p-ULK1/ULK1 (P < 0.0001) expressions. Moreover, hAM-MSCs-CM improved cardiac function and decreased fibrosis (P < 0.0001). This study showed cardioprotective effects of hAM-MSCs-CM against MI/R injury through modulation of autophagy via mTOR/ULK1 pathway. Based on these findings, it can be concluded that hAM-MSCs-CM can be offered as an attractive candidate for attenuation of MI/R injury in future, but needs further investigations.

A common cause of mortality around the world is ischemic myocardial injury. The study was conducted to examine the ability of amniotic membrane mesenchymal stem cells (AMSCs) for protection against isoproterenol (ISO)-induced myocardial injury and attempted to show the possible mechanisms by which AMSCs that can be linked to inhibition of inflammation by targeting inflammatory MAPK/NF-κB pathway. Model was established by subcutaneous injection of 170 mg/kg/day of ISO for four consecutive days. Flow cytometry and echocardiography were carried out to evaluate characterization of hAMSCs and cardiac function, respectively. The expression of inflammatory cytokines was determined using ELISA assay. The activities of NF-κB and phosphorylated p38 MAPK were measured using immunohistochemical assessments. The results showed that ISO administration was resulted in cardiac dysfunction, increased levels of inflammatory cytokines that reversed by intramyocardially administration of AMSCs (P < 0. 05). Cardioprotective effects of AMSCs were associated with a significant decreased expression of NF-κB and reduced levels of phosphorylated p38 MAPK (P < 0. 05). In conclusion, our finding showed that intramyocardially administration of AMSCs could contribute to improvement of heart function and inhibition of inflammation in the site of injury by targeting inflammatory MAPK/NF-κB pathway.

It has been reported that the therapeutic potential of stem cells is mainly mediated by their paracrine factors. In order to identify the effects of conditioned medium of mesenchymal stem cells (MSC-CM) against stroke, a systematic review was conducted. We searched PubMed, Scopus, and ISI Web of Science databases for all available articles relevant to the effects of MSC-CM against the middle cerebral artery occlusion (MCAO) model of ischemic stroke until August 2022. The quality of the included studies was evaluated using The STAIR scale. During the systematic search, a total of 356 published articles were found. A total of 15 datasets were included following screening for eligibility. The type of cerebral ischemia was the MCAO model and CM was obtained from MSCs. The results showed that the therapeutic time window can be considered a crucial factor when researchers use MSC-CM for stroke therapy. In addition, MSC-CM therapy contributes to functional recovery and reduces infarct volume after stroke by targeting different cellular signaling pathways. Our findings showed that MSC-CM therapy has the ability to improve functional recovery and attenuate brain infarct volume after ischemic stroke in preclinical studies. We hope our study accelerates needed progress towards clinical trials.

Nesfatin-1 as a new energy-regulating peptide has been known to display a pivotal role in modulation of cardiovascular functions and protection against ischemia/reperfusion injury. However, the detailed knowledge about molecular mechanisms underlying this protection has not been completely investigated yet. This study was designed to clarify the molecular mechanisms by which nesfatin-1 exert cardioprotection effects against myocardial ischemia–reperfusion (MI/R). Left anterior descending coronary artery (LAD) was ligated for 30 min to create a MI/R model in rats. MI/R rats were treated with three concentrations of nesfatin-1 (10, 15 and 20 µg/kg) then expression of necroptosis and necrosis mediators were measured by western blotting assay. Fibrosis, morphological damages, cardiac function, myocardial injury indictors and oxidative stress factors were evaluated as well. Induction of MI/R model resulted in cardiac dysfunction, oxidative stress, increased activity of RIPK1-RIPK3-MLKL axis and RhoA/ROCK pathway, extension of fibrosis and heart tissue damage. Highest tested concentration of nesfatin-1 markedly improved cardiac function. Moreover, it reduced oxidative stress, collagen deposition, and morphological damages, through inhibiting the expression of necroptosis mediators and also, necrosis including RIPK1, RIPK3, MLKL, ROCK1, and ROCK2 proteins. The lowest and middle tested concentrations of nesfatin-1 failed to exert protective effects against MI/R. These findings have shown that nesfatin-1 can exert cardioprotection against MI/R in a dose dependent manner by suppressing necroptosis via modulation of RIPK1-RIPK3-MLKL axis and RhoA/ROCK/RIP3 signaling pathway.

Hydrogen sulfide (H 2 S), a well-known toxic gas, is regarded as endogenous neuromodulator and plays multiple roles in the central nervous system under physiological and pathological states, especially in secondary neuronal injury. Recent studies have shown relatively high concentrations of hydrogen sulfide (H 2 S) in the brain and also cytoprotective effects of endogenous and exogenous H 2 S in models of in vitro and in vivo ischemic injury. H 2 S protects neurons by functioning as an anti-oxidant, anti-inflammatory, and anti-apoptotic mediator and by improving neurological function. Moreover, it protects neurons from glutamate toxicity. Therefore, the present study aimed to determine whether H 2 S provides protection in transient focal cerebral ischemia. Focal ischemia was induced by 60-min middle cerebral artery occlusion (MCAO), followed by 23-h reperfusion. Saline as a vehicle and NaHS (H 2 S donor; 1 and 5 mg) were intraperitoneally injected (IP) at the beginning of ischemia. Infarct volume, brain edema, and apoptosis were assessed 24 h after MCAO. Treatment with NaHS at doses of 1 and 5 mg markedly reduced total infarct volumes by 29 and 51 %, respectively ( P  < 0.001). In addition, NaHS at doses of 1 and 5 mg reduced brain edema ( P  < 0.05) and inhibited apoptosis by decreasing positive TUNEL cells ( P  < 0.001). The present study shows that treatment with H 2 S reduces brain injuries and postischemic cerebral edema in a dose-dependent manner likely through the blocking programmed cell death. We propose that H 2 S might be a promising therapeutic target for stroke, although more researches are necessary to take into account the potential therapeutic effects of H 2 S in stroke patients.

The adipocytokine apelin is a peptide that was isolated from a bovine stomach for the first time. This peptide and its receptor are abundantly expressed in the nervous and cardiovascular systems. According to previous studies, apelin-13 protects cardiomyocytes from ischemic injury as well as apoptosis. In addition, this peptide has a neuroprotective effect on hippocampal and cultured mouse cortical neurons against NMDA receptor-mediated excitotoxicity. The present study was conducted to determine whether apelin-13 provides protection in transient focal cerebral ischemia. Focal ischemia was induced by 60-min middle cerebral artery occlusion (MCAO), followed by 23-h reperfusion. Saline as a vehicle and apelin-13 at doses of 25, 50, and 100 μg were injected intracerebroventriculary (ICV) at the beginning of ischemia. Infarct volume ,brain edema, motor dysfunction, and apoptosis were assessed 24 h after MCAO. Treatment with apelin-13 at doses of 50 and 100 μg ICV markedly reduced total infarct volumes by 45 and 55 %, respectively ( P  < 0.001), but injection of apelin at lower dose (25 μg) did not change infarct volume significantly ( P  > 0.05). In addition, apelin-13 at doses of 50 and 100 μg reduced brain edema ( P  < 0.001) and inhibited apoptosis by decreasing caspase-3 activation ( P  < 0.001). Apelin-13 did not significantly change neurological dysfunction ( P  > 0.05).

Background This study is designed to compare the menstrual blood stem cells (MenSCs) and bone marrow stem cells (BMSCs)-secreted factors with or without pre-treatment regimen using basic fibroblast growth factor (bFGF) and 5-aza-2ʹ-deoxycytidine (5-aza) and also regenerative capacity of pre-treated MenSCs and/or BMSCs in a rat model of myocardial infarction (MI). Methods BMSCs and MenSCs were pre-treated with bFGF and 5-aza for 48 h and we compared the paracrine activity by western blotting. Furthermore, MI model was created and the animals were divided into sham, MI, pre-treated BMSCs, and pre-treated MenSCs groups. The stem cells were administrated via tail vain. 35 days post-MI, serum and tissue were harvested for further investigations. Results Following pre-treatment, vascular endothelium growth factor, hypoxia-inducible factor-1, stromal cell-derived factor-1, and hepatocyte growth factor were significantly increased in secretome of MenSCs in compared to BMSCs. Moreover, systemic administration of pre-treated MenSCs, leaded to improvement of cardiac function, preservation of myocardium from further subsequent injuries, promotion the angiogenesis, and reduction the level of NF-κB expression in compared to the pre-treated BMSCs. Also, pre-treated MenSCs administration significantly decreased the serum level of Interleukin 1 beta (IL-1β) in compared to the pre-treated BMSCs and MI groups. Conclusions bFGF and 5-aza pre-treated MenSCs offer superior cardioprotection compare to bFGF and 5-aza pre-treated BMSCs following MI.

Stroke is the sixth leading cause of death and lifelong disability for millions of people in the United States. Cerebral ischemia leads to oxidative stress, excitotoxicity, inflammation, and apoptosis; additionally, impairment in memory and learning occurs in the majority of subjects with ischemic stroke. The lack of definitive treatment has sparked extensive research into novel therapeutic strategies, including the use of 4-methylumbelliferone (4-MU), a coumarin derivative with potential neuroprotective properties. The present study examines the impact of 4-MU on reducing cerebral ischemia-reperfusion (I/R) injury and learning and memory impairments in male Wistar rats. Animals were exposed to middle cerebral artery occlusion (MCAO) and treated with a single dose of 4-MU (25 mg/kg) dissolved in 0.9% DMSO. An automated shuttle box and Morris water maze (MWM) tests were employed to evaluate learning and memory impairments. Western blot assay, TTC staining, and Nissl staining were used to measure protein expression, infarct volume, and cell death, respectively. Treatment with 4-MU reduced infarct volume and improved learning and memory impairments by downregulating HAS1 and HAS2. 4-MU modulated the release of proinflammatory cytokines including TNF- and IL-1 , as well as anti-inflammatory markers like IL-10, and reduced oxidative stress markers in the brain. The neuroprotective effects of 4-MU against cerebral I/R injury can be attributed to the downregulation of HAS1 and HAS2.

The current study was designed with the aim of conducting a systematic review and meta-analysis to determine the circulating levels of visfatin in patients with chronic obstructive pulmonary disease (COPD) compared to healthy individuals. Until March 2024, we searched the Web of Science, PubMed/Medline, and Scopus databases. The analysis included case-control studies assessing the association between circulating visfatin and COPD. The random effects model was utilized to analyse the results with the help of Standard Mean of Differences (SMD) and 95% confidence interval (CI). The heterogeneity of the data was assessed using Cochrane Q and I values. Seven studies were eligible to be included in the meta-analysis, with the COPD and healthy (control) groups having 265 and 244 subjects, respectively. The pooled results showed that although the circulating concentration of visfatin was lower in patients with COPD, no significant difference was observed (SMD: -0.48 mg/L; 95% CI: -1.67 to 0.70;  = 0.43). Subgroup analysis revealed that visfatin levels were significantly reduced in FEV1 less than 50% (  < 0.001) and in GOLD grade I-II (  < 0.05). Visfatin was shown to be significantly associated with IL-6 (  < 0.001) and TNF-α (  < 0.01) in the correlation meta-analysis. Meta-regression analysis revealed a significant correlation between the pooled SMD visfatin and pooled SMD age (  < 0.01), BMI (  < 0.001), FEV1 (  < 0.001), and IL-6 (  < 0.001). The findings showed an insignificant decline in visfatin level among COPD patients, but additional research is necessary due to the heterogeneity in study results. PROSPERO (CRD42023450851), https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42023450851.

Emerging evidence has shown that ELA peptide plays a pivotal role in cardiac development and modulation of vascular and cardiac function. In the current work, we sought to examine the possible therapeutic potential of ELA peptide to reduce I/R injury following MI and elucidate the possible mechanisms by which ELA peptide may ameliorate injury and improve heart function after MI. 5 µg/kg of ELA peptide was administrated intraperitoneally in rats once per day for 4 days after ischemia of heart for 30 min. Male Wistar rats were sacrificed at 24 h and 2 weeks after reperfusion. The infarct size was determined by TTC staining 2 weeks after reperfusion. ELISA was employed to measure serum level of myocardial injury markers such as LDH, CK-MB and Troponin I and oxidative stress markers such as membrane lipid peroxidation (MDA), GSH and SOD activities in the first 24 h. Cardiac function was evaluated using echocardiography prior to MI and 2 weeks after reperfusion. After administration of ELA peptide in MI rats, infarct size, serum levels of LDH, CK-MB, Troponin I and tissue levels of MDA were significantly reduced; GSH and SOD activities were markedly increased (p < 0.05). Likewise, ELA peptide improved cardiac function 2 weeks after MI (p < 0.05). ELA peptide administration for 4 days after MI could reduce injury by targeting oxidative stress and improvement of cardiac function. These findings establish a fundamental foundation for future peptide research and therapy.