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Cellular and Molecular Mechanisms of Ischemic Acute Renal Failure and Repair
Published in Robin S. Goldstein, Mechanisms of Injury in Renal Disease and Toxicity, 2020
Joseph V. Bonventre, Ralph Witzgall
With the goal of specifically blocking calcium uptake without reducing extracellular [Ca2+], Ca2+ channel blockers have been used to explore the role of Ca2+ in ischemic cell injury. There are studies in vivo which demonstrate efficacy of these agents to protect against ischemic injury (Burke, et al., 1984; Goldfarb, et al., 1983). Protection is associated with less calcium loading of mitochondria and preservation of mitochondrial function (Widener and Mela-Riker, 1984). There has been some controversy over the interpretation of these results. Some have concluded that the effects are due to direct action of the pharmacologic agents to prevent calcium from entering the epithelial cell (Burke, et al., 1984). In a model of fixed ischemia in vivo and in the isolated rat kidney, under conditions where verapamil did not alter renal blood flow, we found no protection with this agent (Malis, et al., 1983). Verapamil did protect against ischemic injury in a norepinephrine model of acute renal failure. We concluded that the protection was due to an inhibition of norepinephrine-induced renal vasoconstriction. Consistent with the conclusion that calcium channel-blocking agents exert their protective effects primarily at the level of the vasculature is the observation that marginal effects of high doses of verapamil are observed when isolated kidney tubules are exposed to anoxia (Weinberg, et al., 1984).
Influence of Altered Extent of Regional Ischemia on in Situ End-Systolic Pressure-Volume Relationships
Published in Samuel Sideman, Rafael Beyar, Analysis and Simulation of the Cardiac System — Ischemia, 2020
David A. Kass, Paolo Marino, W. Lowell Maughan
The results for a 25% ischemic injury are shown in Figure 10A. At the low values of pressure and volume, there is little apparent difference between the net ESPVR predicted by the no-interaction model (open squares) vs. the model incorporating an interaction (solid diamonds). However, as the volume is increased, net Ees with interaction was progressively lower than Ees without interaction. Figure 10B displays the predicted relationship between the percent reduction in Ees as a function of Pes for the two models. By incorporating this simple interaction assumption, the extent of Ees reduction was increased by 100% at a Pes of 80 mmHg to approximately −40% from control. Using the same model, a family of curves could be generated for varying extents of ischemia and the percent reduction in Ees could be examined in each at the same Pes (80 mmHg). This result is displayed in Figure 8 (solid diamonds) and appeared to lie closer to the experimental data than the initial noninteraction model. The precise “fit” of the model to the data depended on several model assumptions of systolic and diastolic properties, and there is sufficient scatter in the experimental data to limit the significance of this agreement. However, in a general sense, the results suggest that some form of interaction may be important and that by a very simple addition to the two-compartment model, predictions can be made that are more in concert with observed experimental data in situ.
Inorganic Chemical Pollutants
Published in William J. Rea, Kalpana D. Patel, Reversibility of Chronic Disease and Hypersensitivity, Volume 4, 2017
William J. Rea, Kalpana D. Patel
Derailed infarct healing contributes to HF: Young and healthy humans, however, rarely suffer from MI. Atherosclerosis risk factors, and comorbidities such as diabetes and obesity many of which have an inflammatory component280 typically precede ischemic injury. However, any pollutant overload such as the fumes of natural gas stoves and heaters, insecticides incidences, formaldehyde overload or CO, N2O, SO2 particulate, and mycotoxin exposure can increase inflammation. The smoldering systemic inflammation impedes infarct healing by interfering with the resolution of local inflammation and delaying the reparative phase.281 Consequently, the infarct expands and the left ventricle dilates, ultimately leading to HF. This frequent syndrome, defined by the inability to pump sufficient quantities of oxygenated blood into peripheral tissues, manifests with shortness of breath and fluid retention and carries a mortality as high as 50%.234 Data on leukocyte activity in the chronically failing myocardium are unavailable; however, inflammatory biomarkers, such a C-reactive protein and inflammatory mediators, such as the cytokines tumor necrosis factor-α (TNF-α) and IL-6, increase systemically in HF, and leukocytosis associates with disease progression.
Effects of stem cell-derived exosomes on neuronal apoptosis and inflammatory cytokines in rats with cerebral ischemia-reperfusion injury via PI3K/AKT pathway-mediated mitochondrial apoptosis
Published in Immunopharmacology and Immunotoxicology, 2021
Ying Zhang, Jun Yu, Jing Liu, Hongbiao Liu, Jing Li
Ischemic injury of the brain is one of the commonly diagnosed diseases in neurology. Cerebral ischemia can cause local brain damage, the severity of which is influenced by the duration of the ischemia. If symptoms of cerebral ischemia develop, reversible damage may be observed in the short term; however, prolonged ischemia and hypoxia can cause cerebral edema and neuronal necrosis [1]. Reperfusion injury is the tissue damage caused when the blood supply is restored in a tissue after experiencing ischemia or hypoxia. This restoration of the circulation results in inflammation and oxidative damage rather than, or along with, the restoration of normal function [2]. Clinical studies [3] have shown that free radicals, intracellular calcium overload, leukocyte adhesion and aggregation, and inadequate production of high-energy phosphate compounds are involved in the development of cerebral ischemia-reperfusion injury. In addition, a previous study [4] has shown that a large number of free radicals and inflammatory factors are often produced during cerebral ischemia-reperfusion injury and that the mitochondrial apoptotic pathway, regulated by the phosphatidylinositol-3-kinase/protein kinase B (PI3K/AKT) pathway, may participate in the induction of apoptosis [5,6] and worsen the ischemic damage.
Investigation on beneficial role of l -carnosine in neuroprotective mechanism of ischemic postconditioning in mice: possible role of histidine histamine pathway
Published in International Journal of Neuroscience, 2020
Jasleen Kaur Virdi, Amritansh Bhanot, Amteshwar Singh Jaggi, Neha Agarwal
Cerebral ischemia is a diagnostic term that encompasses a complex constellation of pathophysiological and molecular injuries to the brain induced by hypoxia, ischemia, cytotoxicity, embolus occlusion or hemorrhage due to rupture of blood vessels or combinations of these conditions. It leads to deprivation of oxygen to the tissues of the brain and results in death of brain tissue [1]. WHO defined stroke as ‘rapidly developing clinical signs of focal disturbance of cerebral function lasting more than 24hrs with no apparent cause other than vascular origin’. Ischemic injury and traumatic brain injuries are global health problems [2]. Cerebral ischemia is the third most common cause of death in most industrialized countries with estimated global mortality of 4.7 million per year. Around total number of 1 million cases has been reported in India related to stroke [3]. The symptoms characteristically pointing at this disease are: difficulty in speaking, coma, delirium, vertigo, sensory loss, nystagmus, anopia, facial numbness, ataxia, dysphagia, dysarthria, ophthalmoplegia, hemiparesis, arm and leg paralysis, amnesia, color amnesia, abulia, alexia and urinary incontinence depending on arterial territory involved [4,5]. Major disability is loss of ability to communicate, ambulate, co-ordinate and reason [6].
Probing the drug delivery strategies in ischemic stroke therapy
Published in Drug Delivery, 2020
Qiong Wu, Rong Yan, Jingjing Sun
After the onset of cerebral ischemia, a series of cascade reactions occur, including glutamate excitotoxicity, oxidative free radical accumulation, inflammation and apoptosis of nerve cells (Choi & Rothman, 1990; Dirnagl et al., 1999; Brookes et al., 2004; Kim et al., 2006). Additionally, reperfusion of the ischemic injury can cause further damage (Halestrap, 2006). As illustrated schematically in Figure 2, the neuronal damage in the penumbra around the ischemic focus is reversible for a short period if adequate measures are utilized. Neuroprotectants have been developed to prevent and treat different types of secondary damage (Dobkin & Carmichael, 2016; Bernhardt et al., 2017). These medications can fall into several classes: glutamate antagonists, calcium channel blockers, antioxidants, free radical scavengers, and anti-inflammatory and immune factors (Neuhaus et al., 2017). Unfortunately, no country has recommended neuroprotective agents in clinical treatment (Neuroprotection: the end of an era?, 2006; Shi et al., 2018). Disodium 2,4-disulphophenyl-N-tert-butylnitrone (NXY-059) is a novel free radical-trapping agent that showed promising neuroprotective actions in preclinical studies, yet failed in clinical trials (Maples et al., 2001; Lapchak et al., 2002). Several reasons may be responsible for the inadequate clinical translation, including inappropriate animal modeling, individual variation, narrow treatment windows, in effective doses for the brain, and side effects.