Dendritic cells (DCs) are unique immune cells that can link innate and adaptive immune responses and Immunometabolism greatly impacts their phenotype. Rapamycin is a macrolide compound that has immunosuppressant functions and is used to prevent graft loss in kidney transplantation. The current study evaluated the therapeutic potential of ex-vivo Rapamycin treated DCs to protect kidneys in a mouse model of acute kidney injury (AKI). For the Rapamycin single (S) treatment (Rapa-S-DC), Veh-DCs were treated with Rapamycin (10 ng/ml) for 1 hour before LPS. In contrast, Rapamycin multiple (M) treatment (Rapa-M-DC) were exposed to 3 treatments over 7 days. Only multiple ex-vivo Rapamycin treatments of DCs induced a persistent reprogramming of mitochondrial metabolism. These DCs had 18-fold more mitochondria, had almost 4-fold higher oxygen consumption rates, and produced more ATP compared to Veh-DCs (Veh treated control DCs). Pathway analysis showed IL10 signaling as a major contributing pathway to the altered immunophenotype after Rapamycin treatment compared to vehicle with significantly lower cytokines Tnfa, Il1b, and Il6, while regulators of mitochondrial content Pgc1a, Tfam, and Ho1 remained elevated. Critically, adoptive transfer of Rapamycin treated DCs to WT recipients 24 hrs before bilateral kidney ischemia significantly protected the kidneys from injury with a significant 3-fold improvement in kidney function. Last, the infusion of DCs containing higher mitochondria numbers (treated ex-vivo with healthy isolated mitochondria (10 µg/ml) one day before) also partially protected the kidneys from IRI. These studies demonstrate that pre-emptive infusion of ex-vivo reprogrammed DCs that have higher mitochondria content has therapeutic capacity to induce an anti-inflammatory regulatory phenotype to protect kidneys from injury.

Achieving neuroprotection in ischemic stroke patients has been a multi-decade medical challenge. Numerous clinical trials were discontinued in futility and many were terminated in response to deleterious treatment effects. Recently however, several positive reports have generated the much-needed excitement surrounding stroke therapy. In this review, we describe the clinical studies that significantly expanded the time window of eligibility for patients to receive mechanical endovascular thrombectomy. We summarize the results available thus far for nerinetide, which can be considered the most promising neuroprotective agent yet for stroke treatment. Lastly, we reflect upon aspects of these successful trials in our own studies targeting the Kv2.1-mediated cell death pathway in neurons for neuroprotection. We propose that recent changes in the clinical landscape must be adapted by preclinical research in order to continue progressing toward the development of efficacious neuroprotective therapies for ischemic stroke.

The shortage of donor organs is a major global concern. Organ failure requires the transplantation of functional organs. Organ donors are preserved in warm or cold ischemia. Ischemia and reperfusion damage the organs, due to the lack of oxygen during the ischemia step and the oxidative stress during the reperfusion step. Different methodologies were developed to prevent or diminish the level of injuries. Preservation solutions were first developed, followed by the addition of chemical compounds. In addition of inhibitors of mitogen activated protein kinase, inhibitors of the proteasome, mesenchymal stem cells started to be used 13 years ago to prevent or diminish the organ’s injuries. Mesenchymal stem cells (e.g bone marrow stem cells, adipose derived stem cells) have proven to be powerful tools in repairing damaged organs. This review will focus on the use of some bone marrow stem cells, adipose derived stem cells and umbilical cord stem cells on preventing or decreasing the injuries due to ischemia-reperfusion.

Metformin（Met） is a commonly used drug in the treatment of type 2 diabetes. Currently, it has been found that Met can effectively reduce the incidence of stroke and exert anti-inflammatory effects. However, its role in ischemia-reperfusion (I/R) induced nerve injury remains unclear. This study aims to investigate the neuroprotective effects of Met in I/R-induced neuron injury as well as the underlying mechanism.A middle cerebral artery occlusion (MCAO) model was established in SD rats, which were then treated with different doses of Met.Neurological deficits of rats were measured at different times post-surgery. TTC staining to observe the volume of cerebral infarction.HE staining was performed to observe pathological changes of brain tissues .Immunohistochemistry was performed to observe the expression of inflammatory factors in the cerebral tissues .qRT-PCR method was used to detect the relative expression of PI3K、Akt mRNA in cells after 24 h of drug action.Western blot method was used to detect the expression of PI3K、p-PI3K、Akt and p-Akt in hippocampus.What’s more, in vitro experiments were performed on BV2 microglia to verify the role of Met against oxygen-glucose deprivation (OGD). As a result, Met dose-dependently attenuated neurological deficits and neuronal apoptosis. Besides, Met administration also significantly reduced BV2 cells apoptosis and inflammatory response. Mechanistically, Met inactivated PI3K/Akt pathway induced by I/R and OGD, while upregulated PI3K. In conclusion, Met protected rats from cerebral I/R injury via reducing neuronal apoptosis and microglial inflammation through PI3K/Akt pathway.

Despite existing strong evidence on oxidative markers overproduction following ischemia/reperfusion (I/R), the mechanism by which oxidative enzyme Cytochrome P450-2E1 (CYP2E1) contributes to I/R outcomes is not clear. In this study, we sought to evaluate the functional significance of CYP2E1 in I/R. CYP2E1 KO mice and controls were subjected to middle cerebral artery occlusion (MCAo-90min) followed by 24hr of reperfusion to induce focal I/R injury models. Then, histological and chemical analyses were conducted to investigate the role of CYP2E1 in lesion volume, oxidative stress, and inflammation exacerbation. Also, the role of CYP2E1 on the BBB integrity was investigated by measuring 20-Hydroxyecosatetraenoic acid (20-HETE) activity, as well as, in vivo BBB transfer rate. Following I/R, the CYP2E1 KO mice exhibited a significantly lower lesion volume, and neurological deficits compared to controls (p<0.005). Also, ROS production, apoptosis, and the neurodegeneration were significantly lower in the CYP2E1(-/-) I/R group (p<0.001). The BBB damage was significantly lower in CYP2E1(-/-) mice compared to WT (p<0.001), while 20-HETE production was increased by 41%. Besides, inflammatory cytokines expression and the number of activated microglia were significantly lower in CYP2E1(-/-) mice following I/R. CYP2E1 suppression ameliorates I/R injury and protects BBB integrity by reducing both oxidative stress and inflammation.

Inflammatory reaction after ischemia-reperfusion contributes significantly to prognosis, and microglia activation is the main resource of inflammation in nervous system. STAT5 is proving to be a highly effective anti-inflammatory therapy with great potential, and inhibition of STAT5 has demonstrated significant anti-inflammation and therapeutic effects, but rarely focus on mechanism of neuroinflammation and brain injury from ischemia-reperfusion. It is the first time to found that the anti-inflammation of dauricine is mainly through STAT5-NF-κB pathway, might act as a STAT5 inhibitor. Dauricine suppressed the inflammation cytokines Eotaxin, KC, TNF-α, IL-1α, IL-1β, IL-6, IL-12β, IL-17α, and also inhibited the microglia activation. STAT5b mutant at Tyr-699 reversed the protective effect of dauricine on oxygen-glucose deprivation-reperfusion injury of neurons, and reactivated the suppression of dauricine on P-NF-κB of microglia. These results suggest that dauricine might suppress the neuroinflammation and protect the neuron from the injury of post-ischemia-reperfusion via mediating the microglia activation through STAT5-NF-κB pathway, and ss a potential therapeutic target for neuroinflammation, STAT5 needs to be raised concern in ischemic stroke.

Regulated autophagy is involved in the repair of renal ischemia-reperfusion injury (IRI). ω3-Polyunsaturated fatty acids (ω3-PUFAs) show protective effects against various renal injuries. It was recently reported that ω3-PUFAs regulate autophagy. We assessed whether ω3-PUFAs attenuated IR-induced acute kidney injury (AKI) and evaluated associated mechanisms. C57Bl/6 background fat-1 mice and wild-type mice (wt) were divided into four groups: wt sham (n = 10), fat-1 sham (n = 10), wt IRI (reperfusion 35 min after clamping both the renal artery and vein; n = 15), and fat-1 IRI (n = 15). Kidneys and blood were harvested 24 h after IRI. Renal histological and molecular data were collected. The kidneys of fat-1 mice showed better renal cell survival, renal function, and pathological damage than those of wt mice after IRI. In addition, fat-1 mice showed less oxidative stress and autophagy impairment; greater amounts of LC3, Beclin-1, and Atg7; lower amounts of p62; and higher levels of renal cathepsin D and ATP6E than wt kidneys. They also showed more AMPK activation, which resulted in the inhibition of phosphorylation of the mammalian target of rapamycin (mTOR). Collectively, ω3-PUFAs in fat-1 mice contributed to AMPK mediated autophagy activation, leading to a renoprotective response.

Objective: The purpose of this study was to investigate the effect of aerobic exercise on myocardial injury induced by I/ R in rats by regulating SIRT3/SOD2/NF-κB signaling pathway, and to provide theoretical guidance for clinical treatment of myocardial I/R injury.Methods:SPF Male Sprague-Dawley(SD) rats were randomly assigned to 4 groups: Sham operation group(n=10), I/R group(n=10), Aerobic exercise group(n=10)and Aerobic exercise+κ-receptor antagonist group(Pro DTC group，n=10). The left anterior descending coronary artery(LAD) of rats was ligated and re-canalized to establish I/R rat model. Hematoxylin-eosin(HE) staining was performed to examine histological morphology in myocardial tissues of each group. The biological analysis was performed to measure cTnI、CK-MB、BNP levels in blood samples of each group. The expression levels of SOD2, TLR4, and p65 in myocardial tissues were measured by immunohistochemical assay. The influence of aerobic exercise on Beclin-1 、LC3II/I、SIRT3, TLR4, and phosphorylated p65 was measured by Western blotting.Results: The result of histological morphology examination revealed that Aerobic exercise group exhibited integrated cardiac myofilament, less inflammatory cell infiltration, as much as significantly decreased cellular edema. Measurement of cTnI、CK-MB、BNP revealed that oxycodone post-treatment reduces the injury of myocardial tissues(P<0.05). Immunohistochemical staining results revealed that aerobic exercise clearly decreased the expression of TLR4 and p65, and increased the expression of SOD2(P<0.05). Besides, Western blotting revealed that aerobic exercise down-regulated the expression of Beclin-1 、LC3II/I、TLR4 and phosphorylated p65, up-regulated the expression of SIRT3(P<0.05).Conclusions: Aerobic exercise significantly improved myocardial I/R injury. The mechanisms may be associated with activating κ-receptor to regulate SIRT3/SOD2/NF-κB pathway.

Acute kidney injury (AKI) is a frequent and critical complication in the clinical setting. In rodents AKI can be prevented effectively through caloric restriction (CR), which has also been shown to increase lifespan in many species. In Caenorhabditis elegans (C. elegans) longevity studies revealed that a marked CR-induced reduction of endocannabinoids may be a key mechanism. Thus, we hypothesized that regulation of endocannabinoids, in particular arachidonoyl ethanolamide (AEA), might also play a role in CR-mediated protection from renal ischemia-reperfusion injury (IRI) in mammals including humans. In male C57Bl6J mice, CR significantly reduced renal IRI and led to a significant decrease of AEA. Supplementation of AEA to near-normal serum concentrations by repetitive intraperitoneal administration in CR mice, however, did not abrogate the protective effect of CR. We also analyzed serum samples taken before and after CR from patients of three different pilot trials of dietary interventions. In contrast to mice and C. elegans, we detected an increase of AEA. We conclude that endocannabinoid levels in mice are modulated by CR, but CR-mediated renal protection does not depend on this effect. Moreover, our results indicate that modulation of endocannabinoids by CR in humans may differ fundamentally from the effects in animal models.

Preeclampsia is a multifactorial cardiovascular disorder diagnosed after 20 weeks of gestation that is the leading cause of death for both mothers and babies in pregnancy. The pathophysiology remains poorly understood due to variability and unpredictability of disease manifestation when studied in animal models. After preeclampsia, both mothers and offspring have a higher risk of cardiovascular disease (CVD) including myocardial infarction or heart attack and heart failure (HF). Myocardial infarction is an acute myocardial damage that can be treated through reperfusion, however, that therapeutic approach leads to ischemic/reperfusion injury (IRI) often leading to HF. In this review, we compared the current in vivo, in vitro and ex vivo model systems used to study preeclampsia, IRI and HF. Future studies aiming at evaluating CVD in preeclampsia patients could benefit from novel models that better mimic the complex scenario described in this article.

Ischemia stroke is one of a clinically common cerebrovascular disease. And Inhibition of brain tissue ischemia and reperfusion-induced damage, especially apoptosis, has an irreplaceable protective effect on ischemic nerves, and has special significance for the treatment of patients after treatment. However, the development of neuroprotective drugs still has certain challenges. Radix scrophulariae as a valuable medicine, has been discovered to has neuroprotective effects. Our researches initially proved that Radix scrophulariae aqueous extract (RSAE) exerting a neuroprotective effects on cerebral ischemia and reperfusion (I/R) injury in oxygen glucose deprivation and reperfusion (OGD/R)-induced PC12 cells and middle cerebral artery occlusion/reperfusion (MCAO/R) model mice, were associated with attenuation of infarct volume, brain water content, nitric oxide (NO) and malondialdehyde (MDA), inhibiting I/R-induced damage by reducing the levels of LDH release, improving anti-oxidant capacity by upregulating the SOD, GSH-Px and CAT activity, stabilizing mitochondrial membrane potential, reducing neuronal apoptosis, necrosis and neuronal loss by regulating the expression of anti-apoptotic BCL-2and pro-apoptotic protein Bax, and elucidating downregulate the phosphorylation levels of MAPK pathways. Our findings may elaborate the neuroprotective effects and potential mechanisms of RSAE on focal cerebral I/R injury in mice. Since, Radix scrophulariae, as a potential neuroprotective natural plant, has originally been identified to, our results may offer directions and clues for discovering new active compounds or drugs for treatment of ischemic stroke, which allows us to discover many new natural active chemicals by chemical separation and identification, and provide new insights into therapeutic targets in stroke patients.

The transient vanilloid receptor potential type 1 (TRPV1) regulates neuronal and vascular functions mediated by nitric oxide (NO) and by the calcitonin gene-related peptide (CGRP). Here we study the participation of TRPV1 in the regulation of myocardial injury caused by ischemia-reperfusion and in the regulation of NO, tetrahydrobiopterin (BH4), the cGMP pathway, CGRP, total antioxidant capacity (TAC), malondialdehyde (MDA) and phosphodiesterase-3 (PDE-3). Isolated hearts of Wistar rats were used (according to Langendorff) to study the effects of capsaicin (CS), capsazepine (CZ) and CZ+CS treatments. The hearts were divided into three subgroups; 1) perfusion, 2) ischemia and 3) ischemia-reperfusion. In all groups we studied cardiac work and levels of NO, cGMP, BH4, CGRP, TAC, MDA and PDE-3 in ventricular tissue. Western blots were used to determine the expressions of eNOS, iNOS and phosphorylated NOS (pNOS). Structural changes were determined by histological evaluation. CS prevented damage caused by ischemia-reperfusion by improving cardiac work and the levels of NO, cGMP, BH4, TAC and CGRP. TRPV1 and iNOS expression were increased under ischemic conditions, while eNOS and pNOS were not modified. We conclude that the activation of TRPV1 constitutes a therapeutic possibility to counteract the damage caused by ischemia and reperfusion by regulating the NO pathway through CGRP.

We performed a systematic search and meta-analysis of available literature to determine the safety profile of Cerebrolysin in acute ischemic stroke, filling existing safety information gaps and inconsistent results. We searched EMBASE, PubMed and Cochrane Databases of Systematic Reviews and Clinical Trials up to the end of February 2021. Data collection and analysis was conducted using methods described in the Cochrane Handbook for Systematic Reviews of Interventions. All safety outcomes were analyzed based on risk ratios (RR) and their 95% confidence intervals. The meta-analysis pooled 2202 patients from twelve randomized clinical trials, registering non-statistically significant (p>0.05) differences between Cerebrolysin and placebo throughout main and subgroup analyses. The lowest rate of Serious Adverse Events (SAE), as compared to placebo, was observed for the highest dose of Cerebrolysin (50 mL), highlighting a moderate reduction (RR = 0.6). We observed a tendency of superiority of Cerebrolysin regarding SAE in high dose treatment courses for moderate-severe ischemic stroke, suggesting some effect of the agent against adverse events. This comprehensive safety meta-analysis confirms the safety profile for patients treated with Cerebrolysin after acute ischemic stroke, as compared to placebo.

Background and objectives: The correlation of cardiac troponin I with early in-hospital outcomes in acute myocardial infarction is not well established. This study aims to assess the role of troponin I in predicting in-hospital outcomes and early left ventricular systolic dysfunction in patients with ST-segment elevation myocardial infarction (STEMI). Patients and methods: In a prospective study, 116 patients (74males and 42 females), with STEMI who had been admitted to the Coronary CareUnit from March 2015 to September 2015 were enrolled. Patients were divided according to the level of troponin I on admission into 3 groups (low, medium and high elevation). Results: The mean age (+ SD) of the patients was 60+11.4 years. The troponin level of 66.2% of males was high compared with 52.4% of females (p=0.002). The incidence of acute pulmonary edema (21.1%), cardiogenic shock (7%) and early left ventricular systolic dysfunction (49.3%) was significantly higher among patients with high troponin level compared with (0%, 0% and 16%, respectively) among patients with low troponin level. All deaths and cardiac arrest were of high troponin level. Conclusions: High admission troponin I in STEMI permits early identification of patients at increased risk of major cardiac complications and death.

Metabolic and ionic changes during ischaemia predispose the heart to the damaging effects of reperfusion. Such changes and the resulting injury differ between immature and adult heart. Therefore, cardioprotective strategies for adults need to be tested in immature heart. We have recently shown that simultaneous activation of PKA and EPAC confers marked cardioprotection in adult hearts. The aim of this study is to investigate the efficacy of this intervention in immature hearts and determine whether the mitochondrial permeability transition pore (MPTP) is involved. Isolated perfused Langendorff hearts from both adult and immature rats were exposed to global ischaemia and reperfusion injury (I/R) following control perfusion or perfusion after an equilibra-tion period with activators of PKA and/or EPAC. Functional outcome and reperfusion injury were measured and in parallel, mitochondria were isolated following 5 min reperfusion to determine whether cardioprotective interventions involved changes in MPTP opening behaviour. Perfusion for 5 minutes preceding ischaemia of injury- matched adult and immature hearts with 5 µM 8-Br (8-Br-cAMP-AM), an activator of both PKA and EPAC, led to significant reduction in post-reperfusion CK release and infarct size. Perfusion with this agent also led to a reduction in MPTP opening propensity in both adult and immature hearts. These data show that immature hearts are innately more resistant to I/R injury than adults, and that this is due to a reduced ten-dency to MPTP opening following reperfusion. Further, simultaneous stimulation of PKA & EPAC causes cardioprotection which is additive to the innate resistance.

(1) Background: In patients suffering from heart failure, the main causes of death are either he-modynamic failure, or ventricular arrhythmias. The only tool to significantly reduce arrhythmic sudden death is the implantable cardioverter defibrillator (ICD), but not all patients benefit to the same extend of these devices. (2) Methods: The primary outcome of this single center study was defined as cardiovascular death in patients with ischemic and non-ischemic heart failure who have benefited from ICD therapy. The secondary outcomes were death from any cause, sudden cardiac death, ICD-related therapies (appropriate antitachycardia pacing or shock therapy for ventricular tachycardia or fi-brillation) and recurrences of ventricular tachyarrhythmias. (3) Results: A total of 403 consecutive ICD recipients – symptomatic heart failure patients with ICD for the primary prevention of sudden cardiac death – were included retrospectively: 59% is-chemic cardiomyopathy (ICMP) and 41% non-ischemic cardiomyopathy (NICMP). Within a median follow-up period of 36 months, the incidence of cardiovascular mortality was not signif-icantly different in patients with NICMP and ICMP: the primary outcome had occurred in 9 pa-tients (5.4%) in the NICMP group and in 14 patients (5.9%) in the ICMP group (hazard ratio 1; 95%confidence interval [CI] 0.45 to 2.28; p =0.97). All-cause mortality occurred in 14 of 166 pa-tients (8.4%) in NICMP group and 18 of 237 patients (7.6%) in ICMP group. Sudden cardiac death occurred in 2 patients (1.2%) in the NICMP group and in 4 patients (1.7%) in the ICMP group (hazard ratio 0.71; 95% CI, 0.13 to 3.88; P=0.69). The rate of appropriate device therapies was comparable in both groups. (4) Conclusion: In this study, ICD implantation for primary prevention of sudden cardiac death in patients with symptomatic systolic heart failure was associated with similar rates of cardiovas-cular and all-cause mortality in patients with ischemic heart disease, and in patients with heart failure from other causes. NICMP and ICMP showed comparable rates of recurrent ventricular tachyarrhythmias and appropriate ICD therapies.

Objectives To delineate the features of ischemic stroke patients and their caregivers that may predict distress, depression, and anxiety symptoms in the caregivers. Methods The Hospital Anxiety and Depression Score (HADS), Zarit Burden Interview (22 item-ZBI), and Perceived Stress Scale (PSS-10) were used to assess caregivers' burden, stress, depressive, and anxiety symptoms. We performed partial least square-structural equation modeling (PLS-SEM) in order to delineate a multi-step mediation model.Results In this study, 97 stroke patients and their caregivers were included. Multiple regression analysis revealed that ZBI-personal strain and stroke of other determined etiology explained 15.0 percent of the variance in the HADS depression score (p=0.001). We discovered that the caregiver's underlying disease and the National Institute Stroke Score (NIHSS) of the patients explained 13.6 percent of the variance in the total ZBI score of the caregivers (p=0.001). The total ZBI score, the presence of lacunar circulation infarction in the patients, and the caregiver's underlying disease explained 40.9 percent of the variance in the total PSS score of the caregivers (p <0.001). Moreover, PLS analysis showed that the NIHSS and the caregiver's underlying disease had significant indirect effects on the HADS score which were mediated by the ZBI score. Conclusions A large part of the variance in stress and depressive scores in caregivers of ischemic stroke patients is determined by the patient's disability, dependency, cognition, and stroke phenotypes, as well as the caregiver's health status and burden. Screening for the aforementioned factors in ischemic stroke caregivers is critical.

Background: Acute ischemic stroke is among the main causes of mortality worldwide; a rapid and opportune diagnosis is crucial to improve a patient's outcome. MicroRNAs are quite useful for a rapid and accurate diagnosis.Methods: We perform both structural networks approach and a meta-analysis (using a random-effect model to evaluate the heterogeneity and risk bias, according to the PRISMA statement) to analyze the feasibility to develop a microRNA-based biomarker panel for an opportune AIS diagnosis. Results: Structural networks identify a set of eight miRNAs (miR-16, miR-124-3p, miR-484, miR-15a, miR-4454, miR-107, miR-125b-5p and miR-320b) as preliminary microRNA-based biomarker panel, from these only three microRNAs are significantly associated with the main risk factors of AIS, (miR-107: hypertension, 95% CI 9.74-53.24 p<0.0001, type 2 Diabetes mellitus, 95% CI 2.18-19.26); p=0.0008; miR-16 hypertension, 95% CI 1.26-3.56 p=0.0046, smoking, 95% CI 1.07-3.54 p=0.0277; and miR-15a hypertension, 95% CI 1.26-3.56 p=0.0046; smoking, 95% CI 1.07-3.54 p=0.0277). However, the meta-analysis reveals that data is highly heterogeneous and biased; and only microRNAs isolated from plasma samples and further processed in microarrays are the most reliable to distinguish AIS patients.Conclusions: Together our results show that although there are some miRNAs that seem to be associated with AIS, we are still far to develop a miRNA-based biomarker for AIS diagnosis and it is necessary to harmonize the protocols, results and include more populations for further studies otherwise we will remain throwing punches in the dark.

Objective: It was aimed to investigate the cerebral vascular territories in stroke patients with NVAF as an etiologic factor. Material and Methods: A total of 104 patients who were referred to our hospital between January 2015 and September 2016, who were over 55 years of age, identified or documented as having a standard ECG or Holter ECG record on their medical history, and diagnosed with stroke were included. Our study was designed as a retrospective analysis of prospective data. Detailed history, physical examination and electrocardiography (ECG) evaluations of the patients were performed. Descriptive statistics were used in the detection of findings, and t-test, Pearson-square test and Fisher's exact test were used for differences analysis. Results: 53.8% (N = 56) of the patients were male and 46.2% (N = 48) were female. The mean age was 73.5. MCA was the most common site of vascular involvement in NVAF-dependent strokes. In MCA vascular territory, ischemic infarcts were detected most frequently in the upper and lower divisions. SCA and PCA followed MCA. Approximately 64% of the NVAF-related strokes were anterior circulation infarction (ASE) and 22% were posterior circulation infarct (PSE). There was a significant difference in age and past stroke history factors in favor of ASE (p<0.05). There was no significant difference between ASE and PSE in HT, cardiac history and DM factors (p>0.05). Conclusion: It was emphasized that the area of the vessel that underwent ischemia in the acutely displayed infarcts and the etiological factor for this vessel area could be predicted

Acute and chronic transplant rejections due to alloreactivity are essential contributors to graft loss. However, the strength of alloreactivity is biased by non-immunological factors such as ischemia reperfusion injury (IRI). Accordingly, protection from IRI could be favorable in terms of limiting graft rejection. Caveolin-1 (Cav-1) is part of the cell membrane and an important regulator of intracellular signaling. Cav-1 has been demonstrated to limit IRI and to promote survival of a variety of cell types including renal cells under stress conditions. Accordingly, Cav-1 could also play a role in limiting anti-graft immune responses. Here, we evaluated a possible association between pretransplant serum concentrations of Cav-1 and the occurrence of rejection during follow up in a pilot study. Therefore, Cav-1-serum concentrations were analyzed in 91 patients at the time of kidney transplantation and compared to the incidence of acute and chronic rejection. Higher Cav-1 levels were associated with lower occurrence of acute rejection episodes. Moreover, Cav-1 could be therapeutically useful for attenuating graft rejection.

We aimed to reveal the disease burden of aphasia after acute ischemic stroke (AIS) at the national level and investigate the impact of aphasia on tertiary care resources and patient outcomes. The local database from the Cluj-Napoca Emergency County Hospital (CNECH), the second largest stroke center in Romania was used to export demographics, baseline clinical and laboratory data, inpatient length of stay (LOS), NIH Stroke Scale (NIHSS), and discharge modified Rankin Scale (mRS) score data for all AIS patients admitted during March 2019. Of 92 patients included in the study, 30 (32.6 %) had aphasia on admission. In a marginally significant unadjusted hierarchical multiple regression model, individuals with aphasia had a LOS of 1.86 days longer than stroke survivors without aphasia. In an adjusted version of the model, the NIHSS score at baseline was a significant predictor for LOS. In addition, the presence of aphasia was associated with a 1.49 increase in the mean mRS score. Aphasia was a marginally significant predictor for increased LOS. Presence of aphasia was more likely to produce a poor functional outcome. Considering an estimated impact of approximately EUR 3 million on direct medical expenditure annually, future policymaking efforts should improve prevention of stroke and improved access to post-stroke aphasia care in Romania.

It has been demonstrated that brief cycles of ischemia followed by reperfusion (IR) applied before exercise can improve performance and, IR intervention, applied immediately after exercise (post-exercise ischemic conditioning – PEIC) exerts a potential ergogenic effect to accelerate recovery. Thus, the purpose of this systematic review with meta-analysis was to identify the effects of PEIC on exercise performance, recovery and the responses of associated physiological parameters, such as creatine kinase, perceived recovery and muscle soreness, over 24 h after its application. From 3281 studies, six involving 106 subjects fulfilled the inclusion criteria. Compared to sham (cuff administration with low pressure) and control interventions (no cuff administration), PEIC led to faster performance recovery (p=0.004; ES=-0.49) and lower increase in creatine kinase (p&lt;0.001; ES=-0.71) and muscle soreness (p&lt;0.001; ES=-0.89) over 24 h. The effectiveness of this intervention is more pronounced in subjects with low/moderate fitness level and at least a total time of 10 min of ischemia (e.g. 2 cycles of 5 min) is necessary to promote positive effects.

Metabolic syndrome, diabetes and ischemic heart disease are among the leading causes of death and disability in Western countries. Diabetic cardiomyopathy is responsible for the most severe signs and symptoms. An important strategy for reducing the incidence of cardiovascular disease is regular exercise. Remote ischemic conditioning has some similarity with exercise, and can be induced by short periods of ischemia and reperfusion of a limb, and it can be performed in people who cannot exercise. There is abundant evidence that exercise is beneficial in diabetes and ischemic heart disease, but there is a need to elucidate the specific cardiovascular effects of emerging and unconventional forms of exercise in people with diabetes. Also, remote ischemic conditioning may be considered among the options to induce beneficial effects in these patients. The characteristics and interactions of diabetes and ischemic heart disease, and the known effects of exercise and remote ischemic conditioning in the presence of metabolic syndrome and diabetes, are analyzed in this brief review.

Rapid diagnosis of acute myocardial infarction is critical for intervention and treatment to decrease morbidity and mortality. For this reasons, this study aimed to design a sensitive biosensor for cardiac troponin I (cTnI) for early prediction and intervention. The sensor was designed from golden plate immobilized with anti- cTnI antibody conjugated with horseradish peroxidase (HRP) enzyme. The rate of degradation of H2O2 is directly related to serum cTnI level. Serum cTnI level was quantified from 3 studied groups including; healthy subjects and patients with ischemic heart (IHD) diseases and myocardial infarction (MI) by ELISA and biosensor techniques to achieve the improved sensitivity of the biosensor. It was found that cTnI levels in healthy subjects ranged from 8-13 ng/dl and in patients with IHD ranged from 20 - 41 ng/dl and MI range from 57- 180 ng/dl. The sensitivity of biosensor was ranged from 85-95% compared with ELISA technique. The developed biosensor is promising in ICU hospitals for early diagnosis and prevent complications of the stroke. It is recommended to apply this biosensor in the large scale of patients with different stages of the cardiac disease.

Background: To evaluate the effect of systemic erythropoietin, as well as oral steroids, in the management of recent onset non-arteritic anterior ischemic optic neuropathy (NAION). Method: Ninety-nine eyes of 99 patients diagnosed with NAION within 5 days of onset were included in this single masked randomized clinical trial. Thirty-four patients were randomized into group 1 (systemic erythropoietin), group 2 (oral steroids), and group 3 (control). Group A received 10,000 units of erythropoietin twice a day for three days. Group B received oral prednisone 75 mg daily for two weeks followed by a tapering dose (70 mg for 5 days, 60 mg for 5 days, and 5 mg reductions thereafter every 5 days). Functional and structural outcomes were analyzed at 3 and 6 months following treatment. Best corrected visual acuity (BCVA) was the main outcome measure, and mean deviation (MD) of visual field (VF) test and peripapillary retinal nerve fiber layer thickness (PRNFLT) were secondary outcome measures. Results:The mean BCVA (±SD) at the time of presentation was 1 ± 0.56, 1.01 ± 0.6, and 0.94 ± 0.47 logMAR in groups A, B, and C, respectively (P = 0.140); corresponding values were 0.72 ± 0.45, 0.83 ± 0.46, and 0.78 ± 0.4 logMAR (P = 0.417), and at 6-month follow-up, they were 0.70 ± 0.44, 0.73 ± 0.35, and 0.75 ± 0.39 logMAR, respectively (P = 0.597). Fifty-five percent of patients in group A vesus 34.3% in group B, and 31.2% in group C had an improvement of at least 3 lines in the BCVA values at the 6th-month follow-up visit. (P= 0.04) The mean deviation (MD) at the time of presentation was 19.67 ± 6.2, 20.83 ± 4.83, and 18.94 ± 6.92 decibels (db), respectively (P= 0.483).The corresponding values at month 3 were 18.22 ± 7.5, 19.82 ± 7.15, and 17.65 ± 7.22 db, (P = 0.848); and at month 6 they were 16.56 ± 7.08, 18.15 ± 6.57, and 15.9 ± 5.97 db, respectively. (P = 0.699) PRNFLT at presentation was 189 ± 58, 193 ± 64, and 199 ± 62 micrometers, respectively (P = 0.779), which decreased to 110 ± 45, 127 ± 37, and 119 ± 37 at month 3 (P = 0.423). The corresponding values for month 6 were 88 ± 12, 74 ± 25, and 71 ± 18, respectively (P = 0.041). Conclusion: The findings of our study indicate the beneficial effects of systemic erythropoietin in preserving the function and structure of the optic nerve in recent onset NAION.

Background. Specific clinical risk factors that may be associated with ambulatory outcome following thrombolysis therapy in ischemic stroke patients with pre-stroke depression is not fully understood. This was investigated. Methods. Multivariate analyses were performed to identify predictors of functional ambulatory outcomes. Patient demographics and clinical risk factors served as predictive variables, while improvement or no improvement in ambulatory outcome was considered as the primary outcome. Results. A total of 595 of these patients received rtPA of which 310 patients presented with pre-stroke depression, 217 had no improvement in functional outcome, while 93 patients presented with an improvement in functional outcome. Carotid artery stenosis (OR= 11.577, 95% CI, 1.281 – 104.636, P=0.029) and peripheral vascular disease (OR= 18.040, 95% CI, 2.956-110.086, P=0.002) were more likely to be associated with an improvement in ambulation. Antihypertensive medications (OR= 7.810, 95% CI, 1.401 –43.529, P=0.019),previous TIA (OR= 0.444, 95% CI, 0.517 –0.971, P=0.012), and congestive heart failure (OR= 0.217, 95% CI, 0.318 –0.402, P=0.030) were associated with a no improvement in ambulation. Conclusion. After adjustment for covariates, more clinical risk factors were associated with no improvement when compared with improvement in functional outcome following thrombolysis therapy in an acute ischemic stroke population with pre-stroke depression.

Ischemia/reperfusion (I/R) injury results in cell death by inducing apoptosis. During I/R, early generation of mitochondrial reactive oxygen species (mtROS) can induce neighboring mitochondria to release additional ROS, a toxic cycle resulting in significant mitochondrial and cellular injury. Oxidative damage in the mitochondria contributes to various pathologies, including I/R injury. Accordingly, preventing mitochondrial oxidative damage should be therapeutically relevant for many disorders, including cardiovascular diseases. We recently discovered an Indole-Peptide-Tempo Conjugate (IPTC) that served as a novel bifunctional agent with both antioxidant and autophagy-modulating capacity. Here, we demonstrate that IPTC can protect H9C2 cardiomyocytes from hypoxia/reoxygenation (H/R) injury that results from mtROS overproduction due to impaired mitophagy and resultant mitochondrial dysfunction. We hypothesize that the mechanism of action of IPTC involves the capacity to decrease mtROS combined with induction of mitophagy.

Citrus flavonoids are well-known for beneficial effects at the cardiovascular and cardio-metabolic level, but often the encouraging in vitro results are not confirmed by in vivo approaches; also clinical trials are inconsistent. The limited bioavailability of them can be, at least in part, the reason of these discrepancies. Therefore many efforts were performed towards the improvement of their bioavailability. Hydrodynamic cavitation methods were successfully applied to the extraction of byproducts of the Citrus fruits industry, showing high process yields and affording stable phytocomplexes, known as IntegroPectin, endowed with great amounts of bioactive compounds and high water solubility. Cardioprotective effects of grapefruit IntegroPectin were evaluated by an ex vivo ischemia/reperfusion protocol. A further pharmacological characterization was carried out to assess the involvement of mitochondrial potassium channels. Grapefruit IntegroPectin, where naringin represented 98% of flavonoids, showed anti-ischemic cardioprotective activity, better than pure naringenin (the bioactive aglycone of naringin). On cardiac isolated mitochondria, this extract confirmed that naringenin/naringin were involved in the activation of mitochondrial potassium channels. The hydrodynamic cavitation-based extraction confirmed a valuable opportunity for the exploitation of Citrus fruits waste, with the end product presenting high levels of Citrus flavonoids and an improved bioaccessibility that enhances its nutraceutical and economic value.

Beyond their significant contribution to the dietary and industrial supplies, marine algae are considered to be a potential source of some unique metabolites with diverse health benefits. The pharmacological properties, such as antioxidant, anti-inflammatory, cholesterol homeostasis, protein clearance and anti-amyloidogenic potentials of algal metabolites endorse their protective efficacy against oxidative stress, neuroinflammation, mitochondrial dysfunction, and impaired proteostasis which are known to be implicated in the pathophysiology of neurodegenerative disorders and the associated complications after cerebral ischemia and brain injuries. As was evident in various preclinical studies, algal compounds conferred neuroprotection against a wide range of neurotoxic stressors, such as oxygen/glucose deprivation, hydrogen peroxide, glutamate, amyloid β, or 1-methyl-4-phenylpyridinium (MPP+) and, therefore, hold therapeutic promise for brain disorders. While a significant number of algal compounds with promising neuroprotective capacity have been identified over the last decades, a few of them have had access to clinical trials. However, the recent approval of an algal oligosaccharide, sodium oligomannate, for the treatment of Alzheimer's disease enlightened the future of marine algae-based drug discovery. In this review, we briefly outline the pathophysiology of neurodegenerative diseases and brain injuries for identifying the targets of pharmacological intervention, and then review the literature on the neuroprotective potentials of algal compounds along with the underlying pharmacological mechanism, and present an appraisal on the recent therapeutic advances. We also propose a rational strategy to facilitate algal metabolites-based drug development.

Acute kidney injury (AKI) caused by ischemia followed by reperfusion (I/R) is characterized by intense anion superoxide (O2•-) production and oxidative damage. We investigated whether extracellular vesicles secreted by adipose tissue mesenchymal cells (EVs) administrated during reperfusion can suppress the exacerbated mitochondrial O2•- formation after I/R. We used Wistar rats submitted to bilateral renal arterial clamping (30 min) followed by 24 h of reperfusion. The animals received EVs (I/R+EVs group) or saline, I/R group) in the kidney subcapsular space. The 3rd group was of the false-operated rats (SHAM). Mitochondria were isolated from proximal tubule cells and immediately used. Amplex Red™ was used to measure mitochondrial O2•- formation and MitoTracker® Orange to evaluate Δψ. In vitro studies were carried out by using human renal proximal tubular cells (HK-2) co-cultured or not with EVs under hypoxia conditions. Administration of EVs restored O2•- formation to SHAM levels in all mitochondrial functional conditions. The expression of catalase and superoxide dismutase remained unmodified; transcription of heme oxygenase-1 (HO-1) was upregulated. The co-cultures of HK-2 cells with EVs revealed an intense decrease in apoptosis. We conclude that the mechanisms by which EVs recover the renal structure and function after I/R are related to the normalization of the mitochondrial redox environment. The intravesicular catalase is central in the preservation mechanisms that, with the aid of the upregulated antioxidant HO-1/Nuclear factor erythroid 2-related factor 2 system, depress early processes of cell death after I/R and open new vistas for the treatment of AKI.

Cardiovascular disease (CVD) comprises a group of heart and circulatory disorders, which are regarded as a global medical issue with high prevalence and mortality rates. Currently, vascular regenerative surgery represents the most employed therapeutic option to treat ischemic disorders, even though not all the patients are amenable to surgical revascularization. Therefore, more efficient therapeutic approaches are urgently required to promote neovascularization. Therapeutic angiogenesis represents an emerging strategy that aims at reconstructing the damaged vascular network by stimulating local angiogenesis and/or promoting de novo blood vessel formation according to a process known as vasculogenesis. Circulating endothelial colony forming cells (ECFCs), in turn, represent truly endothelial precursors able to aggregate into bidimensional tube networks and to originate patent vessels. Accordingly, ECFCs provide the most rationale and promising cellular candidate for therapeutic purposes. The current review provides a brief outline on the origin and characterization of ECFCs and a summary of the progress in preclinical studies aiming at assessing their efficacy in a variety of ischemic disorders, including AMI, PAD, ischemic brain disease and retinopathy. We also describe how to enhance the vasoreparative potential of ECFCs by boosting specific pro-angiogenic signalling pathways either pharmacologically or through gene manipulation. Taken together, these observations suggest that ECFCs represent a useful strategy to treat ischemic diseases.

Ischemic stroke is one of the most disabling diseases and a leading cause of death globally. Despite advances in medical care, the global burden of stroke continues to grow, as no effective treatments to limit or reverse ischemic injury to the brain are available. However, recent preclinical findings have revealed the potential role of transient receptor potential cation 6 (TRPC6) channels as endogenous protectors of neuronal tissue. Activating TRPC6 in various cerebral ischemia models has been found to prevent neuronal death, whereas blocking TRPC6 enhances sensitivity to ischemia. Evidence has shown that Ca2+ influx through TRPC6 activates cAMP response element-binding protein (CREB), an important transcription factor linked to neuronal survival. Additionally, TRPC6 activation may counter excitotoxic damage resulting from glutamate release by attenuating the activity of NMDA receptors of neurons by posttranslational means. Unresolved though, are the roles of TRPC6 channels in non-neuronal cells such as astrocytes and endothelial cells. Moreover, TRPC6 channels may have detrimental effects on the blood-brain barrier, although their exact role in neurovascular coupling requires further investigation. This review discusses evidence-based cell-specific aspects of TRPC6 in the brain to assess the potential targets for ischemic stroke management.

Background: Substance use continues to be on the rise in the United States and has been linked to new onset cardiovascular (CVDs) and cerebrovascular disorders (CeVDs) leading to hospitalizations. We aimed to study the association of different subtypes of substance use disorders (SUDs) among hospitalized patients, with the different subtypes of CVDs and CeVDs, using the National Inpatient Sample (NIS) Database. Additionally, we aimed to assess the odds of hospitalizations with new onset CVDs and CeVDs among patients with different types of SUDs. Methods: A retrospective study of the NIS database (2016-2017) using the ICD-10-CM codes was performed. The hospitalizations with a secondary diagnosis of SUDs were identified. Weighted univariate analysis using the chi-square test and multivariate survey logistic regression analysis was performed to evaluate for the incidence, prevalence, and odds of association between vascular events and SUDs. Results: There were a total of 58,259,589 hospitalizations, out of which 21.42% had SUDs. Out of all the hospitalized patients between the age 18-50, more patients had SUDs than not (31.83%, p< 0.0001). This difference existed for all the different subtypes of SUDs including alcohol related disorder (42.61%), amphetamine dependence (76.17% vs 31.83%), cannabis related disorder (75.17%), cocaine related disorders (57.87%), hallucinogen related disorder (82.91%), inhalant related disorders (67.25%), opioid related disorders (52.86%), and nicotine dependence (35.72%). We found a significant association of acute ischemic stroke with amphetamine dependence (OR 1.23, 95%CI 1.14-1.33), cocaine related disorders (1.17, 1.12-1.23) and nicotine dependence (1.42, 1.40-1.43). Similarly, the association of intracerebral hemorrhage was higher with amphetamine dependence (2.58, 2.26-2.93), and cocaine related disorders (1.62, 1.46-1.79). The association of subarachnoid hemorrhage was noted to be higher with amphetamine dependence (1.82, 1.48-2.24) and nicotine dependence (1.47, 1.39-1.55). In terms of association of cardiovascular disorders with SUDs,the patients with myocardial infarction had higher odds of nicotine dependence (1.85, 1.83-1.87) than not, Similarly, the patients with angina pectoris were noted to have a higher association with cocaine related disorders (2.21, 1.86-2.62), and those with atrial fibrillation had a higher association alcohol related disorders (1.14, 1.11-1.17). Conclusion: Our study demonstrates the variability of CVD and CeVD in patients hospitalized for SUD. Findings from our study may help promote increased awareness and early management of these events. Further studies are needed to evaluate specific effects of frequency and dose on the incidence and prevalence of CVD and CeVD in patients with SUD.

Background: Risk tratification based on pre-test probability may improve the diagnostic accuracy of temporal artery high-resolution compression sonography (hrTCS) in the diagnostic workup of cranial giant cell arteriitis (cGCA). Methods: A logistic regression model with candidate items was derived from a cohort of patients with suspected cGCA (n = 87). The diagnostic accuracy of the model was tested in the derivation cohort and in an independent validation cohort (n = 114) by receiver operator characteristics (ROC)-analysis. The clinical items were composed to a clinical prediction rule, integrated into a stepwise diagnostic algorithm together with CRP-values and hrTCS-values. Results: The model consisted of 4 clinical variables (age &gt; 70, headache, jaw claudication, anterior ischemic optic neuropathy). The diagnostic accuracy of the model for discrimination of patients with and without a final clinical diagnosis of cGCA was excellent in both cohorts (AUC 0.96 and AUC 0.92, respectively). The diagnostic algorithm improved the positive predictive value of hrCTS substantially. Within the algorithm, 32.8% of patients (derivation cohort) and 49.1% (validation cohort) would not have been tested by hrtCS. None of these patients had a final diagnosis of cGCA. Conclusion: A diagnostic algorithm based on a clinical prediction rule improves the diagnostic accuracy of hrTCS.

Medical brain image analysis is a necessary step in the Computers Assisted /Aided Diagnosis (CAD) systems. Advancements in both hardware and software in the past few years have led to improved segmentation and classification of various diseases. In the present work, we review the published literature on systems and algorithms that allow for classification, identification, and detection of White Matter Hyperintensities (WMHs) of brain MRI images specifically in cases of ischemic stroke and demyelinating diseases. For the selection criteria, we used the bibliometric networks. Out of a total of 140 documents we selected 38 articles that deal with the main objectives of this study. Based on the analysis and discussion of the revised documents, there is constant growth in the research and proposal of new models of deep learning to achieve the highest accuracy and reliability of the segmentation of ischemic and demyelinating lesions. Models with indicators (Dice Score, DSC: 0.99) were found, however with little practical application due to the uses of small datasets and lack of reproducibility. Therefore, the main conclusion is to establish multidisciplinary research groups to overcome the gap between CAD developments and their complete utilization in the clinical environment.

Background: Antiplatelet medications such as aspirin and clopidogrel are used following thrombotic stroke or transient ischemic attack (TIA) to prevent a recurrent stroke. However, the antiplatelet treatments fail frequently, and patients experience recurrent stroke. One approach to lower the rates of recurrence, may be the individualized antiplatelet therapies (antiplatelet therapy modification (ATM)) based on the results of platelet function analysis (PFA). This review was undertaken to gather and analyse the evidence about the effectiveness of such approaches. Methods: We searched Medline, CINAHL, Embase, Web of Science and Cochrane databases to 7 January 2020. Results: Two observational studies involving 1136 patients were included. The overall effects of PFA-based ATM on recurrent strokes (OR 1.05; 95% CI 0.69 to 1.58), any bleeding risk (OR 1.39; 95% CI 0.92 to 2.10) or death hazard from any cause (OR 1.19; 95% CI 0.62 to 2.29) were not significantly different from the standard antiplatelet therapy without ATM. Conclusions: The two studies showed opposite effects of PFA-guided ATM on the recurrent strokes in aspirin non-responders, leading to an insignificant difference in the subgroup meta-analysis (OR 1.59; 95% CI 0.07 to 33.77), while the rates of any bleeding events (OR 1.04; 95% CI 0.49 to 2.17) or death from any cause (OR 1.17; 95% CI 0.41 to 3.35) were not significantly different between aspirin non-responders with ATM and those without ATM. There is a need for large randomized controlled trials which account for potential confounders such as ischemic stroke subtypes, technical variations in the testing protocols, patient adherence to therapy, and pharmacogenetic differences.