Neuroprotective Effects of Conditioned Medium of Mesenchymal Stem Cells (MSC-CM) as a Therapy for Ischemic Stroke Recovery: A Systematic Review.

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.

Simvastatin-loaded nano-niosomes efficiently downregulates the MAPK-NF-κB pathway during the acute phase of myocardial ischemia-reperfusion injury.

BACKGROUND: Simvastatin can potentially mitigate acute inflammatory phase of myocardial ischemia-reperfusion injury. However, these effects negatively influenced by its poor bioavailability, low water solubility and high metabolism. Here, we investigated the effects of SIM-loaded nano-niosomes on a rat model of MI/R injury to find a drug delivery method to tackle the barriers. METHODS: Nano-niosomes' characteristics were identified using dynamic light scattering and transmission electron microscopy. Fifty male Wistar rats were divided into five groups: Sham; MI/R; MI/R + nano-niosome; MI/R + SIM; MI/R + SIM-loaded nano-niosomes. Left anterior descending artery was ligated for 45 min, and 3 mg/kg SIM, nano-niosomes, or SIM-loaded nano-niosomes was intramyocardially injected ten min before the onset of reperfusion. ELISA assay was used to assess cardiac injury markers (cTnI, CK-MB) and inflammatory cytokines (TNF-α, IL-6, TGF-ß, MPC-1). Expression level of MAPK-NF-κB and histopathological changes were evaluated by western blot and hematoxylin & eosin staining, respectively. RESULTS: the size of nano-niosome was 137 nm, reached to 163 nm when simvastatin was loaded. To achieve optimized niosomes span 80, a drug/cholesterol ratio of 0.4 and seven min of sonication time was applied. Optimized entrapment efficiency of SIM-loaded nano-niosomes was 98.21%. Inflammatory cytokines and the expression level of MAPK and NF-κB were reduced in rats receiving SIM-loaded nano-niosomes compared to MI/R + SIM and MI/R + SIM-loaded nano-niosomes. CONCLUSION: Our results showed that SIM-loaded nano-niosomes could act more efficiently than SIM in alleviating the acute inflammatory response of reperfusion injury via downregulating the activation of MAPK-NF-κB.

ERK/HIF-1α/VEGF pathway: a molecular target of ELABELA (ELA) peptide for attenuating cardiac ischemia-reperfusion injury in rats by promoting angiogenesis.

BACKGROUND: Myocardial ischemia-reperfusion (I/R) injury is caused by a chain of events such as endothelial dysfunction. This study was conducted to investigate protective effects of ELABELA against myocardial I/R in Wistar rats and clarify its possible mechanisms. METHODS AND RESULTS: MI model was established based on the left anterior descending coronary artery ligation for 30 min. Then, 5 µg/kg of ELA peptide was intraperitoneally infused in rats once per day for 4 days. Western blot assay was used to assay the expression of t-ERK1/2, and p-ERK1/2 in different groups. The amount of myocardial capillary density, the expression levels of VEGF and HIF-1α were evaluated using immunohistochemistry assay. Masson's trichrome staining was utilized to assay cardiac interstitial fibrosis. The results showed that establishment of MI significantly enhanced cardiac interstitial fibrosis and changed p-ERK1/2/ t-ERK1/2 ratio. Likewise, ELA post-treatment markedly increased myocardial capillary density, the expression of several angiogenic factors (VEGF-A, HIF-1α), and reduced cardiac interstitial fibrosis by activation of ERK1/2 signaling pathways. CONCLUSION: Collectively, ELA peptide has ability to reduce myocardial I/R injury by promoting angiogenesis and reducing cardiac interstitial fibrosis through activating ERK/HIF-1α/VEGF pathway.

Greater angiogenic and immunoregulatory potency of bFGF and 5-aza-2'-deoxycytidine pre-treated menstrual blood stem cells in compare to bone marrow stem cells in rat model of myocardial infarction.

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-2'-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-1ß) 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.

Human amniotic membrane mesenchymal stem cells exert cardioprotective effects against isoproterenol (ISO)-induced myocardial injury through suppression of inflammation and modulation of inflammatory MAPK/NF-κB pathway.

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.

Association of D299G Polymorphism of TLR4 Gene and CagA Virulence Factor of H. pylori among the Iranian Patients with Colorectal Cancer.

Background: Colorectal cancer (CRC) represents 9% of all malignancies globally. TLR4 gene defenses against Helicobacter pylori infection (HPI), so its mutations are a risk factor for CRC. As there is a correlation between (HPI) and gastric cancer, we investigated whether there is an association between CagA virulence factor in HPI and D299G polymorphism of TLR4 gene with developing CRC among Iranians. Methods: This retrospective study included 85 biopsies of confirmed colorectal lesions out of 230 subjects, which were divided into two age groups. Single nucleotide polymorphism (SNP) D299G in the TLR4 gene was assessed using Tetra-primer ARMS-PCR. The expression of TLR4 and the CagA virulence factor in H.pylori was assessed using real-time PCR (RT-PCR). Results: Chi-squared test showed genotype frequencies of GG were 79% and 62%in patients 51> and 51

Human amniotic membrane mesenchymal stem cell-conditioned medium reduces inflammatory factors and fibrosis in ovalbumin-induced asthma in mice.

NEW FINDINGS: What is the central question of this study? Is mesenchymal stem cell-conditioned medium capable of improving the pathological alterations of ovalbumin-induced asthma in mice? What is the main finding and its importance? Our study indicated that human amniotic membrane mesenchymal stem cell-conditioned medium is capable of modulating inflammation, fibrosis, oxidative stress and the pathological consequences of ovalbumin-induced allergic asthma in mice. ABSTRACT: Paracrine factors secreted by mesenchymal stem cells (MSCs) have immunomodulatory, anti-inflammatory and antifibrotic properties, and the conditioned medium (CM) of these cells might have functional capabilities. We examined the effects of human amniotic membrane MSC-CM (hAM-MSC-CM) on ovalbumin (OVA)-induced asthma. Forty male Balb/c mice were randomly divided into the following four groups: control; OVA (sensitized and challenged with OVA); OVA+CM (sensitized and challenged with OVA and treated with hAM-MSC-CM); and OVA+Placebo (sensitized and challenged with OVA and treated with placebo). Forty-eight hours after the last challenge, serum and bronchoalveolar lavage fluid samples were collected and used for evaluation of inflammatory factors and cells, respectively. Lung tissue sections were stained with Haematoxylin and Eosin or Masson's Trichrome to evaluate pathological changes, and oxidative stress was assessed in fresh lung tissues. Treatment with hAM-MSC-CM significantly hindered histopathological changes and fibrosis and reduced the total cell count and the percentage of eosinophils and neutrophils in bronchoalveolar lavage fluid. Furthermore, it reduced serum levels of immunoglobulin E, interleukin-4, transforming growth factor-ß and lung malondialdehyde. It also increased serum levels of interferon-γ and interleukin-10, in addition to the enzymatic activity of glutathione peroxidase, catalase and superoxide dismutase in lung tissue in comparison to the OVA and OVA+Placebo groups. This study showed that administration of hAM-MSC-CM can improve pathological conditions, such as inflammation, fibrosis and oxidative stress, in OVA-induced allergic asthma.

Modulation of autophagy as the target of mesenchymal stem cells-derived conditioned medium in rat model of myocardial ischemia/reperfusion injury.

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.

Necroptosis and RhoA/ROCK pathways: molecular targets of Nesfatin-1 in cardioprotection against myocardial ischemia/reperfusion injury in a rat model.

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.

Donepezil attenuates injury following ischaemic stroke by stimulation of neurogenesis, angiogenesis, and inhibition of inflammation and apoptosis.

Donepezil has proven to be an effective drug to reduce neuronal death and subsequently injury in neurodegenerative diseases. The current study evaluated the neuroprotective effects of donepezil in a rat model of ischaemic stroke and explored possible mechanisms which by this drug may reduce cell death. Temporary middle cerebral artery occlusion (tMCAO) was exerted for 45 min to induce ischaemic stroke. The animals were assigned into five groups: sham, control, and three groups treated with different doses of donepezil. Donepezil was intraperitoneally (IP) injected 4 h after reperfusion for 10 consecutive days. Infarct size was determined using TTC staining. The expression of proteins was evaluated using immunohistochemistry assays. Compared with the control group, infarct size was significantly reduced in tMCAO rats treated with different doses of donepezil. Moreover, our results showed significant decreased expression levels of apoptotic markers and pro-inflammatory mediators after treatment with different doses of donepezil for 10 days (P < 0.05). Likewise, significant increase of brain-derived neurotrophic factor (BDNF) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) proteins were found in tMCAO rats treated with donepezil compared with the control group (P < 0.05). Collectively, our findings show the validity of donepezil as a new therapeutic agent for attenuation of injury following ischaemic stroke through attenuation of inflammation and improvement of mitochondrial function, neurogenesis, and angiogenesis.

Human mesenchymal stem cells derived from amniotic membrane attenuate isoproterenol (ISO)-induced myocardial injury by targeting apoptosis.

Background: Currently, stem cell therapy has been proposed as an efficient strategy to prevent or treat myocardial injuries. The current study was conducted to examine cardioprotective effects of human mesenchymal stem cells derived from amniotic membrane (hAMSCs) against isoproterenol (ISO)-induced myocardial injury and explore its potential mechanisms. Methods: The hAMSCs were injected intramyocardially in male Wistar rats 28 days after last injection of ISO (170 mg/kg body weight for 4 consecutive days). The echocardiography was performed to confirm induction of myocardial damage and cardiac function 28 days after last injection of ISO and 4 weeks hAMSCs transplantation after HF induction. The expression of apoptotic markers such as Bcl-2, Bax and P53 was evaluated using Western blotting assay. Masson's trichrome staining was used to determine fibrosis. The cytoarchitecture of myocardial wall and morphology of cells were investigated using hematoxylin and eosin (H&E) staining. Results: As compared to ISO group, hAMSCs transplantation after heart failure (HF) induction significantly blunted the increasing of cardiac dimensions and restored ejection fraction (EF) and fractional shortening (FS) parameters (p<0.05). Moreover, hAMSCs transplantation after HF induction increased the expression of antiapoptotic markers such as Bcl-2 and decreased the expression of pro-apoptotic markers such as P53 and Bax (p<0.05). As compared to ISO group, hAMSCs transplantation after HF induction markedly reduced interstitial myocardial fibrosis and contributed to maintain of normal cytoarchitecture of myocardial wall and morphology of cells. Conclusion: Collectively, the results of current study suggest that transplantation of hAMSCs confers cardioprotection by targeting ISO-induced mitochondria-dependent (intrinsic) pathway of apoptosis.

Protective effects of Nesfatin-1 peptide on cerebral ischemia reperfusion injury via inhibition of neuronal cell death and enhancement of antioxidant defenses.

Nesfatin-1 is a novel peptide with anorexigenic and anti-hyperglycemic properties. According to previous studies, this multi-functional peptide protects dopaminergic cells against neurotoxicity via anti-apoptotic effects. In addition, Nesfatin-1 protects myocardial tissue after myocardial infarction via anti-inflammatory and anti-apoptotic mechanisms. In this study, we investigated the neuroprotective effects of nesfatin-1 against cerebral ischemia reperfusion injury in the CA1 area of hippocampus in rats. 56 male Wistar rats (240-270 g) were randomly selected and allocated into four groups: (1) sham, (2) nesfatin-1, (3) ischemia/reperfusion, (4) ischemia/reperfusion+nesfatin-1. Cerebral ischemia induced by the occlusion of the common carotid arteries for 20 min was followed by reperfusion. Saline as a vehicle and nesfatin-1 (20 µg/kg) were injected intraperitoneally (IP) at the start of cerebral reperfusion. Apoptotic and necrotic cell death was detected by TUNEL and Nissl staining. Malondialdehyde (MDA) and antioxidant enzymes (GSH and SOD) levels were measured by the ELISA method. The results showed that cerebral ischemia increased the apoptotic and necrotic cell death in the CA1 area of hippocampus, while, treatment with nesfatin-1significantly reduced apoptotic and necrotic cell death. Moreover, the MDA levels of the hippocampus in ischemic rats were higher, whereas in nesfatin-1-treated rats the MDA levels were decreased. Furthermore, the SOD and GSH levels in the ischemic rats were decreased, whilst in ischemic rats treated with nesfatin-1, the SOD and GSH levels were increased. This study for the first time found that nesfatin-1 treatment improves CA1 hippocampus injuries after cerebral ischemia through preventing neuronal cell death and enhancement of antioxidant defenses.

Natural lavender oil (Lavandula angustifolia) exerts cardioprotective effects against myocardial infarction by targeting inflammation and oxidative stress.

BACKGROUND: The study was conducted to examine therapeutic effects of lavender oil (LO) against myocardial infarction (MI) and its potential mechanisms. METHODS: A rat model of MI was established and LO (100, 200 and 300 mg/kg) was intraperitoneally administrated immediately after ischemia. Anti-inflammatory and antioxidant activity of LO were evaluated by immunohistochemical assay and measurement of SOD, GSH, and MDA. The myocardial injury markers, apoptotic activity and infarct volume were examined by ELISA, TUNEL and TTC staining, respectively. RESULTS: Compared with the control I/R-Vehicle, the expression of tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß) significantly reduced 8 h after reperfusion and expression of interleukin-10 (IL-10) elevated 48 h after reperfusion in LO-treated rats (P < 0.05). Likewise, significant decreases in apoptotic activity, infarct volume and significant restoration of antioxidant endogenous defenses were observed in LO-treated rats (P < 0.05). CONCLUSION: Collectively, these findings confirm that LO can be a good candidate to reduce injury after MI.

The association of obesity and serum leptin levels with complete blood count and some serum biochemical parameters in Iranian overweight and obese individuals.

Background: Obesity has been suggested to be well correlated with altered levels of complete blood count (CBC) parameters. In this study, the relationship of body mass index (BMI) and circulating leptin levels with CBC among obese and overweight adults was examined. Methods: CBC and biochemical parameters, WBC and hematological profiles, leptin levels, related factors to liver, and kidney and lipid profiles were measured among 184 obese and overweight people aged 18-60 years. Statistical analysis was performed using SPSS software. To assess the normality of data, the Kolmogorov-Smirnov test was used. Logarithmic transformation was performed for some variables with non-normal distribution. The association between 2 quantitative variables was measured using bivariate correlation (Pearson or Spearman). Pearson correlations and multiple regression analysis were performed to assess the correlation between variables. Simple and multiple regression analyses were performed to predict some variables. P- value <0.05 was considered significant. Results: Hematocrit, insulin, fasting blood sugar, uric acid, TG, LDL-C, VLDL-C, and ALT were positively correlated with BMI (p=0.041, r=0.149 for hematocrit; p≤0.001, r=0.520 for insulin; p≤0.001, r=0.363 for FBS; p≤0.001, r=0.309 for uric acid; p=0.015, r=0.189 for TG; p=0.030, r=161 for LDL-C; p=0.019, r=0.181 for VLDL-C; p≤0.001, r=0.299 for ALT), whereas urea and HDL-C were negatively correlated with BMI (p≤0.001, r=-0.368 for urea; p≤0.001, r=-0.297 for HDL-C). Moreover, LDL-C and insulin were positively correlated with leptin (P = 0.011, r = 0.194 for LDL-C, P = 0.013, r = 0.114 for insulin) and hematocrit, urea, creatinine, TG and VLDL-C were negatively correlated with leptin (p=0.040, r=-0.162 for hematocrit; p≤0.001, r=-0.305 for urea; p=0.007, r=-0.219 for creatinine; p=0.025, r=0.188 for TG; p=0.007, r=-0.218 for VLDL-C). Our analysis showed that white blood cell was positively correlated with leptin (ß=17.36, p=0.048). Also, other CBC parameters had no significant correlations with BMI and leptin. Conclusion: According to the findings of this study, BMI had a negative association with urea and HDL-C, while BMI had a positive association with insulin, hematocrit, FBS, uric acid, TG, VLDL-C, LDL-C, and ALT. Furthermore, leptin had a negative association with hematocrit, creatinine, and urea, TG, VLDL-C and a positive association with LDL-C and insulin among the participants of this study.

Preconditioning with morphine protects hippocampal CA1 neurons from ischemia-reperfusion injury via activation of the mTOR pathway.

The signaling pathway of chronic morphine treatment to prevent neuronal damage following transient cerebral ischemia is not clear. In this study, we examined the role of mammalian target of rapamycin (mTOR) to identify the neuroprotective effects of chronic morphine preconditioning on the hippocampus following ischemia-reperfusion (I/R) injury. Morphine was administered for 5 days, twice a day, before inducing I/R injury. The possible role of mTOR was evaluated by the injection of rapamycin (5 mg/kg body weight, by intraperitoneal injection) before I/R was induced. The passive avoidance test was used to evaluate memory performance. Neuronal density and apoptosis were measured in the CA1 region, 72 h after I/R injury. The expressions of mTOR and phosphorylated mTOR (p-mTOR), as well as superoxide dismutase (SOD) activity were determined 24 h after I/R injury. Chronic morphine treatment attenuated apoptosis and neuronal loss in the hippocampus after I/R injury, which led to improvement in memory (P < 0.05 vs. untreated I/R) and increase in the expression of p-mTOR (P < 0.05 vs. untreated I/R) and SOD activity (P < 0.05 vs. untreated I/R) in the hippocampus. Pretreatment with rapamycin abolished all the above-mentioned protective effects. These results describe novel findings whereby chronic morphine preconditioning in hippocampal CA1 neurons is mediated by the mTOR pathway, and through increased phosphorylation of mTOR can alleviate oxidative stress and apoptosis, and eventually protect the hippocampus from I/R injury.

Association between the circulating leptin levels and the biomarkers of oxidative stress and inflammation among Iranian overweight and obese adults.

Background: Oxidative stress in obese people is an important pathogenic mechanism of an obesity-associated metabolic syndrome. We evaluated the association between circulating leptin levels with biomarkers of oxidative stress in overweight and obese participants. Methods: This study was performed on 189 overweight and obese people aged 18-60 years old. Serum leptin, superoxide dismutase (SOD), high-sensitivity C-reactive protein (hs-CRP), homocysteine (Hcy), thiobarbituric acid reactive substances (TBARS) and amyloid A (SAA) concentrations were measured. Pearson correlation and multiple linear regressions were used to assess the relationships. Results: We found that among the biomarkers of oxidative stress and inflammation in participants, serum hs-CRP and SAA were positively correlated with BMI (ß=0.003, P<0.001 and ß=7.83, P<0.001, respectively). This relationship remained significant even after controlling other oxidative stress and inflammatory indicators (ß=0.003, p<0.001 for hs-CRP), but this association disappeared for SAA. In addition, serum hs-CRP was positively correlated with leptin (ß=0.001, p=0.003). Regression analysis showed that there was no association between serum Hcy, SAA, TBARS and SOD with serum leptin concentrations Conclusion: Overall, the current study demonstrated that serum hs-CRP and SAA levels were independently correlated with BMI. Furthermore, serum hs-CRP was positively correlated with leptin. Focusing on such strategies may lead to promises for alleviating obesity and its co-morbidities.

Protective effects of 4-methylumbelliferone on myocardial ischemia/reperfusion injury in rats through inhibition of oxidative stress and downregulation of TLR4/NF-κB/NLRP3 signaling pathway.

Myocardial ischemia-reperfusion injury (MI/R) has been found to be one of the important risk factors for global cardiac mortality and morbidity. The study was conducted to inquire into the protective effect of 4-methylumbilliferon (4-MU) against MI/R in rats and clarify its potential underlying mechanism. Animals were divided into four groups (n = 15) including sham, MI/R, MI/R + vehicle, and MI/R + 4-MU. MI/R was established in Wistar rats by occluding the left anterior descending (LAD) coronary artery for 30 min. 4-MU (25 mg/kg) was injected intraperitoneally before the induction of reperfusion. Cardiac function, fibrosis, oxidant/antioxidant markers, and inflammatory cytokines were evaluated using echocardiography, ELISA, and Western blot assay. As a result of MI/R induction, a decrease in left ventricular contractile function occurred along with increased cardiac fibrosis and tissue damage. The serum levels of TNF-α, IL-1ß, and IL-18 increased, while IL-10 decreased. Oxidant/antioxidant changes were evident with increased MDA levels and decreased GSH, SOD, and CAT in the MI/R group. Furthermore, the protein levels of TLR4, NF-κB, and NLRP3 were significantly increased in the heart tissue of MI/R group. Treatment with 4-MU significantly prevented the reduction of cardiac contractile function and its pathological changes as a result of MI/R by inhibiting the increase of serum inflammatory factors and improving the oxidant/antioxidant balance probably through the TLR4/NF-κB/NLRP3 axis. The results of a current study showed that 4-MU had a potential ability to attenuate the cardiac injury by reducing oxidative stress and inflammation in a TLR4/NF-κB/NLRP3-dependent mechanism.

Gallic acid ameliorates behavioral dysfunction, oxidative damage, and neuronal loss in the prefrontal cortex and hippocampus in stressed rats.

Gallic acid (GA) is known to be a natural phenolic compound with antioxidant and neuroprotective effects. This study aims to investigate the impact of GA against restraint stress-induced oxidative damage, anxiety-like behavior, neuronal loss, and spatial learning and memory impairment in male Wistar rats. The animals were divided into four groups (n = 8) and subjected to restraint stress for 4 h per day for 14 consecutive days or left undisturbed (control without inducing stress). In the treatment group, the animals were treated with 2 mL normal saline plus 100 mg/kg GA per day for 14 consecutive days (STR + GA group). The animals received the drug or normal saline by gavage 2 h before inducing restraint stress. ELISA assay measured oxidative stress factors. Elevated-plus maze and Morris water maze tests assessed anxiety-like behavior and spatial learning and memory, respectively. Also, neuronal density was determined using Nissl staining. Restraint stress significantly increased MDA and reduced the activities of GPX and SOD in the stressed rats, which were reserved by treatment with 100 mg/kg GA. Restraint stress markedly enhanced the anxiety-like behavior and spatial learning and memory impairment that were reserved by GA. In addition, treatment with GA reduced the neuronal loss in the stressed rats in the hippocampus and prefrontal cortex (PFC) regions. Taken together, our findings suggest that GA has the potential to be used as a good candidate to attenuate neurobehavioral disorders as well as neuronal loss in the hippocampus and PFC induced by restraint stress via reducing oxidative damage.