scholarly journals Neuroinflammation in Cerebral Ischemia and Ischemia/Reperfusion Injuries: From Pathophysiology to Therapeutic Strategies

2021 ◽  
Vol 23 (1) ◽  
pp. 14
Author(s):  
Anamaria Jurcau ◽  
Aurel Simion
Keyword(s):  
Clinical Trials ◽  
Tissue Repair ◽  
Ischemia Reperfusion ◽  
Animal Experiments ◽  
Cell Types ◽  
Hemorrhagic Transformation ◽  
Therapeutic Strategies ◽  
Parenchymal Injury ◽  
Made In

Its increasing incidence has led stroke to be the second leading cause of death worldwide. Despite significant advances in recanalization strategies, patients are still at risk for ischemia/reperfusion injuries in this pathophysiology, in which neuroinflammation is significantly involved. Research has shown that in the acute phase, neuroinflammatory cascades lead to apoptosis, disruption of the blood–brain barrier, cerebral edema, and hemorrhagic transformation, while in later stages, these pathways support tissue repair and functional recovery. The present review discusses the various cell types and the mechanisms through which neuroinflammation contributes to parenchymal injury and tissue repair, as well as therapeutic attempts made in vitro, in animal experiments, and in clinical trials which target neuroinflammation, highlighting future therapeutic perspectives.

scholarly journals Molecular Aspects of Volatile Anesthetic-Induced Organ Protection and Its Potential in Kidney Transplantation

2021 ◽  
Vol 22 (5) ◽  
pp. 2727
Author(s):  
Gertrude J. Nieuwenhuijs-Moeke ◽  
Dirk J. Bosch ◽  
Henri G.D. Leuvenink
Keyword(s):  
Kidney Transplantation ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Animal Experiments ◽  
Volatile Anesthetic ◽  
Organ Protection ◽  
Graft Outcome ◽  
Molecular Aspects

Ischemia reperfusion injury (IRI) is inevitable in kidney transplantation and negatively impacts graft and patient outcome. Reperfusion takes place in the recipient and most of the injury following ischemia and reperfusion occurs during this reperfusion phase; therefore, the intra-operative period seems an attractive window of opportunity to modulate IRI and improve short- and potentially long-term graft outcome. Commonly used volatile anesthetics such as sevoflurane and isoflurane have been shown to interfere with many of the pathophysiological processes involved in the injurious cascade of IRI. Therefore, volatile anesthetic (VA) agents might be the preferred anesthetics used during the transplantation procedure. This review highlights the molecular and cellular protective points of engagement of VA shown in in vitro studies and in vivo animal experiments, and the potential translation of these results to the clinical setting of kidney transplantation.

scholarly journals Peptide hormone relaxin: from bench to bedside

2018 ◽  
Vol 314 (6) ◽  
pp. R753-R760 ◽  
Author(s):  
Maria Jelinic ◽  
Sarah A. Marshall ◽  
Dennis Stewart ◽  
Elaine Unemori ◽  
Laura J. Parry ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Animal Models ◽  
Animal Studies ◽  
Ischemia Reperfusion ◽  
Peptide Hormone ◽  
The Body ◽  
Cervical Ripening ◽  
Matrix Remodeling ◽  
Vitro Fertilization

The peptide hormone relaxin has numerous roles both within and independent of pregnancy and is often thought of as a “pleiotropic hormone.” Relaxin targets several tissues throughout the body, and has many functions associated with extracellular matrix remodeling and the vasculature. This review considers the potential therapeutic applications of relaxin in cervical ripening, in vitro fertilization, preeclampsia, acute heart failure, ischemia-reperfusion, and cirrhosis. We first outline the animal models used in preclinical studies to progress relaxin into clinical trials and then discuss the findings from these studies. In many cases, the positive outcomes from preclinical animal studies were not replicated in human clinical trials. Therefore, the focus of this review is to evaluate the various animal models used to develop relaxin as a potential therapeutic and consider the limitations that must be addressed in future studies. These include the use of human relaxin in animals, duration of relaxin treatment, and the appropriateness of the clinical conditions being considered for relaxin therapy.

Abstract 11710: Poloxamer 188 Protects Coronary Artery Endothelial Cells After Extended Hypoxia and Reoxygenation in an in vitro Model of Simulated Ischemia/Reperfusion Injury

Circulation ◽  
2021 ◽  
Vol 144 (Suppl_2) ◽  
Author(s):  
zhu li ◽  
Matthew J Hampton ◽  
Matthew B Barajas ◽  
Matthias L Riess
Keyword(s):  
Endothelial Cells ◽  
Coronary Artery ◽  
Myocardial Ischemia ◽  
Ischemia Reperfusion Injury ◽  
Calcium Influx ◽  
Ischemia Reperfusion ◽  
Cell Types ◽  
Membrane Function ◽  
Ldh Release

Reperfusion restores blood flow after myocardial ischemia but can cause additional cellular injury by the sudden reintroduction of oxygen and nutrients. There is still no effective remedy for myocardial ischemia/reperfusion (IR) injury. Our previous study using cardiomyocytes (CMs) found that, after 3 hrs hypoxia followed by 2 hrs reoxygenation, viability decreased, and release of lactate dehydrogenase (LDH), calcium influx, membrane leakage (insertion of fluorescent probe FM1-43) significantly increased, indicating that cell membrane function was negatively affected. This was attenuated by the triblock copolymer Poloxamer (P)188. Here, we first hypothesized that endothelial cells are also susceptible to simulated IR injury, albeit requiring longer hypoxia times. We further hypothesized that P188 can also attenuate simulated IR injury in endothelial cells when given upon reoxygenation. Mouse coronary artery endothelial cells (MCAECs) were exposed to different durations of hypoxia (2, 3, 12 and 24 hrs) in serum- and glucose-free media +/- reoxygenation for 2 hrs in regular media. P188 was administered upon reoxygenation at 0, 100, 300 or 1,000 μM in experiments of 24 hrs hypoxia / 2 hrs reoxygenation. LDH release was measured and compared to appropriately timed normoxic control experiments. Reoxygenation and hypoxia times significantly longer than 3 hrs were required to elicit sufficient injury (panel A). When P188 was given upon reoxygenation after 24 hrs hypoxia, it dose-dependently attenuated LDH release (panel B). These findings contrast to the higher susceptibility of CMs to IR injury that only allowed shorter hypoxia durations. They also confirm a protective effect of P188 on the endothelium, not just on CMs. These findings have important implications for co-culture models with MCAECs and CMs to elucidate the interplay of both cell types on each other when studying mechanisms of cardioprotective strategies and compounds like P188.

scholarly journals Effects of the Delta Opioid Receptor Agonist DADLE in a Novel Hypoxia-Reoxygenation Model on Human and Rat-Engineered Heart Tissue: A Pilot Study

Biomolecules ◽  
2020 ◽  
Vol 10 (9) ◽  
pp. 1309
Author(s):  
Sandra Funcke ◽  
Tessa R. Werner ◽  
Marc Hein ◽  
Bärbel M. Ulmer ◽  
Arne Hansen ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Ischemia Reperfusion ◽  
Heart Tissue ◽  
Contractile Force ◽  
Neonatal Rat ◽  
Rat Cardiomyocytes ◽  
Engineered Heart Tissue ◽  
Hypoxia Reoxygenation

Intermittent hypoxia and various pharmacological compounds protect the heart from ischemia reperfusion injury in experimental approaches, but the translation into clinical trials has largely failed. One reason may lie in species differences and the lack of suitable human in vitro models to test for ischemia/reperfusion. We aimed to develop a novel hypoxia-reoxygenation model based on three-dimensional, spontaneously beating and work performing engineered heart tissue (EHT) from rat and human cardiomyocytes. Contractile force, the most important cardiac performance parameter, served as an integrated outcome measure. EHTs from neonatal rat cardiomyocytes were subjected to 90 min of hypoxia which led to cardiomyocyte apoptosis as revealed by caspase 3-staining, increased troponin I release (time control vs. 24 h after hypoxia: cTnI 2.7 vs. 6.3 ng/mL, ** p = 0.002) and decreased contractile force (64 ± 6% of baseline) in the long-term follow-up. The detrimental effects were attenuated by preceding the long-term hypoxia with three cycles of 10 min hypoxia (i.e., hypoxic preconditioning). Similarly, [d-Ala2, d-Leu5]-enkephalin (DADLE) reduced the effect of hypoxia on force (recovery to 78 ± 5% of baseline with DADLE preconditioning vs. 57 ± 5% without, p = 0.012), apoptosis and cardiomyocyte stress. Human EHTs presented a comparable hypoxia-induced reduction in force (55 ± 5% of baseline), but DADLE failed to precondition them, likely due to the absence of δ-opioid receptors. In summary, this hypoxia-reoxygenation in vitro model displays cellular damage and the decline of contractile function after hypoxia allows the investigation of preconditioning strategies and will therefore help us to understand the discrepancy between successful conditioning in vitro experiments and its failure in clinical trials.

scholarly journals Epoxide metabolites of arachidonate and docosahexaenoate function conversely in acute kidney injury involved in GSK3β signaling

2017 ◽  
Vol 114 (47) ◽  
pp. 12608-12613 ◽  
Author(s):  
Bing-Qing Deng ◽  
Ying Luo ◽  
Xin Kang ◽  
Chang-Bin Li ◽  
Christophe Morisseau ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Molecular Mechanisms ◽  
Glycogen Synthase ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Therapeutic Strategies ◽  
Epoxyeicosatrienoic Acid ◽  
Renal Tubular

Acute kidney injury (AKI) causes severe morbidity and mortality for which new therapeutic strategies are needed. Docosahexaenoic acid (DHA), arachidonic acid (ARA), and their metabolites have various effects in kidney injury, but their molecular mechanisms are largely unknown. Here, we report that 14 (15)-epoxyeicosatrienoic acid [14 (15)-EET] and 19 (20)-epoxydocosapentaenoic acid [19 (20)-EDP], the major epoxide metabolites of ARA and DHA, respectively, have contradictory effects on kidney injury in a murine model of ischemia/reperfusion (I/R)-caused AKI. Specifically, 14 (15)-EET mitigated while 19 (20)-EDP exacerbated I/R kidney injury. Manipulation of the endogenous 19 (20)-EDP or 14 (15)-EET by alteration of their degradation or biosynthesis with selective inhibitors resulted in anticipated effects. These observations are supported by renal histological analysis, plasma levels of creatinine and urea nitrogen, and renal NGAL. The 14 (15)-EET significantly reversed the I/R-caused reduction in glycogen synthase kinase 3β (GSK3β) phosphorylation in murine kidney, dose-dependently inhibited the hypoxia/reoxygenation (H/R)-caused apoptosis of murine renal tubular epithelial cells (mRTECs), and reversed the H/R-caused reduction in GSK3β phosphorylation in mRTECs. In contrast, 19 (20)-EDP dose-dependently promoted H/R-caused apoptosis and worsened the reduction in GSK3β phosphorylation in mRTECs. In addition, 19 (20)-EDP was more metabolically stable than 14 (15)-EET in vivo and in vitro. Overall, these epoxide metabolites of ARA and DHA function conversely in I/R-AKI, possibly through their largely different metabolic stability and their opposite effects in modulation of H/R-caused RTEC apoptosis and GSK3β phosphorylation. This study provides AKI patients with promising therapeutic strategies and clinical cautions.

scholarly journals Anthocyanins as Antidiabetic Agents—In Vitro and In Silico Approaches of Preventive and Therapeutic Effects

Molecules ◽  
2020 ◽  
Vol 25 (17) ◽  
pp. 3813 ◽  
Author(s):  
Hélder Oliveira ◽  
Ana Fernandes ◽  
Natércia F. Brás ◽  
Nuno Mateus ◽  
Victor de Freitas ◽  
...  
Keyword(s):  
In Silico ◽  
Functional Foods ◽  
Therapeutic Strategies ◽  
Therapeutic Effects ◽  
Metabolizing Enzymes ◽  
The Past ◽  
The Matrix ◽  
Made In

Many efforts have been made in the past two decades into the search for novel natural and less-toxic anti-diabetic agents. Some clinical trials have assigned this ability to anthocyanins, although different factors like the food source, the amount ingested, the matrix effect and the time of consumption (before or after a meal) seem to result in contradictory conclusions. The possible mechanisms involved in these preventive or therapeutic effects will be discussed—giving emphasis to the latest in vitro and in silico approaches. Therapeutic strategies to counteract metabolic alterations related to hyperglycemia and Type 2 Diabetes Mellitus (T2DM) may include: (a) Inhibition of carbohydrate-metabolizing enzymes; (b) reduction of glucose transporters expression or activity; (c) inhibition of glycogenolysis and (d) modulation of gut microbiota by anthocyanin breakdown products. These strategies may be achieved through administration of individual anthocyanins or by functional foods containing complexes of anthocyanin:carbohydrate:protein.

scholarly journals The Necessity of a Systematic Approach for the Use of MSCs in the Clinical Setting

2013 ◽  
Vol 2013 ◽  
pp. 1-10 ◽  
Author(s):  
Christophe Michel Raynaud ◽  
Arash Rafii
Keyword(s):  
Clinical Trials ◽  
Stromal Cells ◽  
Therapeutic Strategy ◽  
Systematic Approach ◽  
Cell Types ◽  
Clinical Applications ◽  
Physiological Properties ◽  
Different Cell Types

Cell therapy has emerged as a potential therapeutic strategy in regenerative disease. Among different cell types, mesenchymal stem/stromal cells have been wildly studiedin vitro,in vivoin animal models and even used in clinical trials. However, while clinical applications continue to increase markedly, the understanding of their physiological properties and interactions raises many questions and drives the necessity of more caution and supervised strategy in their use.

scholarly journals Study of the Effects of Total Flavonoids of Astragalus on Atherosclerosis Formation and Potential Mechanisms

2012 ◽  
Vol 2012 ◽  
pp. 1-10 ◽  
Author(s):  
Deqing Wang ◽  
Yuan Zhuang ◽  
Yaping Tian ◽  
Graham Neil Thomas ◽  
Mingzhong Ying ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Ischemia Reperfusion ◽  
Animal Experiments ◽  
Hdl Cholesterol ◽  
Total Flavonoids ◽  
Protective Effects ◽  
In Vivo Experiments ◽  
Cholesterol Levels

Astragalus mongholicusBunge has long been used to treat cardiovascular disease in Chinese traditional medicine. However, its mechanisms are not fully understood. In this study, we explored potential mechanisms and protective effects of total flavonoids of Astragalus (TFA) on cardiovascular disease using in vitro experiments and diet-induced atherosclerotic rabbits. We identified six components and their proportion in TFA. The animal experiments showed that TFA significantly reduced plasma levels of total cholesterol and LDL cholesterol (P<0.05to 0.01), increased HDL cholesterol levels (P<0.01), and reduced the aortic fatty streak area by 43.6 to 63.6% (P<0.01). We also found that TFA scavenged superoxide and hydroxyl radicals and this effect increased with higher TFA concentration. In in vivo experiments, TFA effectively inhibited the free radical spectrum in the ischemia-reperfusion module. In conclusion, TFA was the active component ofAstragalus mongholicusBunge, which benefits cardiovascular disease attributing to the potent antioxidant activity to improve the atherosclerosis profile.

scholarly journals An immunocytochemical study of a rat pituitary multipotential clone.

1978 ◽  
Vol 26 (2) ◽  
pp. 94-97 ◽  
Author(s):  
E P Bowie ◽  
H Ishikawa ◽  
M Shiino ◽  
E G Rennels
Keyword(s):  
Growth Hormone ◽  
General Circulation ◽  
Cell Types ◽  
Hypothalamic Region ◽  
In Vitro System ◽  
Culture Cells ◽  
Rat Pituitary ◽  
Made In

The 2A8 clone, a normal diploid rat anterior pituitary cell strain, was investigated by immunocytochemistry to determine the cell types into which the clonal cells differentiated in vivo and in vitro. The in vivo study was carried out by injecting the 2A8 clone preparation either into the hypothalamic region or under the kidney capsule. After thirty days the implants were removed and studied by immunocytochemistry. In vitro, many prolactin cells and a few growth hormone cells were found. In vivo, however, prolactin, growth hormone, ACTH and TSH cells and gonadotrophs were identified. We concluded that the 2A8 clone was multipotential. Since the gonadotrophs of the implants made in the hypothalamic region were larger and more plentiful than those in the kidney implants, and since gonadotrophs were lacking in the in vitro system, it appeared that the hypophysiotrophic environment was the most conducive to gonadotrophic differentiation and maintenance, and that the factor or factors necessary for cyto-differentiation were apparently present in the general circulation of the rat but absent in the growth medium of our culture cells.

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