Academic literature on the topic 'Ischemic-like damage'

Critical limb ischemia (CLI) is associated with skeletal muscle damage. However, the pathophysiology of the muscle damage is poorly understood. Toll-like receptors (TLR) have been attributed to play a role in ischemia-induced tissue damage but their role in skeletal muscle damage in CLI is unknown. TLR2 and TLR6 expression was found to be upregulated in skeletal muscle of patients with CLI. In vitro, ischemia led to upregulation of TLR2 and TLR6 by myotubes, and activation of the downstream TLR signaling pathway. Ischemia-induced activation of the TLR signaling pathway led to secretion of the pro-inflammatory cytokine interleukin-6 and muscle apoptosis, which were abrogated by neutralising TLR2 and TLR6 antibodies. Our study demonstrates that TLR2 and TLR6 are upregulated in ischemic muscle and play a role in ischemia-induced muscle damage. Thus, manipulating the TLR pathway locally may be of potential therapeutic benefit.

Preconditioning induces ischemic tolerance, which confers robust protection against ischemic damage. We show marked protection with polyinosinic polycytidylic acid (poly-IC) preconditioning in three models of murine ischemia-reperfusion injury. Poly-IC preconditioning induced protection against ischemia modeled in vitro in brain cortical cells and in vivo in models of brain ischemia and renal ischemia. Further, unlike other Toll-like receptor (TLR) ligands, which generally induce significant inflammatory responses, poly-IC elicits only modest systemic inflammation. Results show that poly-IC is a new powerful prophylactic treatment that offers promise as a clinical therapeutic strategy to minimize damage in patient populations at risk of ischemic injury.

Preconditioning with lipopolysaccharide (LPS), a toll-like receptor 4 (TLR4) ligand, provides neuroprotection against subsequent cerebral ischemic brain injury, through a tumor necrosis factor (TNF)α-dependent process. Here, we report the first evidence that another TLR, TLR9, can induce neuroprotection. We show that the TLR9 ligand CpG oligodeoxynucleotide (ODN) can serve as a potent preconditioning stimulus and provide protection against ischemic brain injury. Our studies show that systemic administration of CpG ODN 1826 in advance of brain ischemia (middle cerebral artery occlusion (MCAO)) reduces ischemic damage up to 60% in a dose- and time-dependent manner. We also offer evidence that CpG ODN preconditioning can provide direct protection to cells of the central nervous system, as we have found marked neuroprotection in modeled ischemia in vitro. Finally, we show that CpG preconditioning significantly increases serum TNFα levels before MCAO and that TNFα is required for subsequent reduction in damage, as mice lacking TNFα are not protected against ischemic injury by CpG preconditioning. Our studies show that preconditioning with a TLR9 ligand induces neuroprotection against ischemic injury through a mechanism that shares common elements with LPS preconditioning via TLR4.

Membrane-free stem cell extract (MFSCE) of human adipose tissues possesses various biological activities. However, the effects of MFSCE on blood–brain barrier dysfunction and brain damage are unknown. In this study, we determined the role of MFSCE in an ischemic stroke mouse model. Mice were treated with MFSCE once daily for 4 days and 1 h before ischemic damage. Experimental ischemia was induced by photothrombosis. Pretreatment with MFSCE reduced infarct volume and edema and improved neurological, as well as motor functions. Evans blue leakage and water content in the brain tissue were reduced by MFSCE pretreatment relative to those in the vehicle group. MFSCE increased the expression of the tight junction proteins zonula occludens 1 and claudin-5, as well as vascular endothelial-cadherin, but decreased that of matrix metalloproteinase 9. Notably, MFSCE treatment decreased cell death and the level of NOD-like receptor protein 3 inflammasome, consistent with the downregulated expression of the pro-inflammatory cytokines interleukin (IL)-1β and IL-18 in the ischemic brain. These effects might have occurred via the suppression of the expression of Toll-like receptor 4 and activation of nuclear factor-κB. The results highlighted the potential of MFSCE treatment as a novel and preventive strategy for patients at a high risk of ischemic stroke.

Inflammatory damage plays an important role in cerebral ischemic pathogenesis and may represent a target for treatment. Toll-like receptor-4 (TLR4), toll-like receptor-2 (TLR2), myeloid differentiation factor 88 (MyD88), and nuclear factor kappa-B (NF-κB) have been linked to inflammatory reactions. Our previous studies have proved that oxymatrine (OMT) protected ischemic brain injury and this effect may be through the decreasing of NF-κB expression. However, little is known regarding the mechanism of OMT in the acute phase of ischemic stroke. We therefore investigated the OMT's potential neuroprotective role and the underlying mechanisms. Male, Sprague-Dawley rats were randomly divided into sham, saline and OMT treatment groups. We used a middle cerebral artery occlusion (MCAO) model and administered OMT intraperitoneally immediately after cerebral ischemia and once daily on the following days. At time points after MCAO, brain water content and infarct size were measured. Immunohistochemistry and RT-PCR were used to analyse the expression of TLR4, TLR2, MyD88, and NF-κB at gene and protein level in ischemic brain tissue. The result indicated that OMT protected the brain from damage caused by MCAO; this effect may be through downregulation of the TLR4, TLR2, MyD88, and NF-κB.

High-mobility group protein box-1 (HMGB1) has recently been recognized as a novel candidate in a specific upstream pathway promoting inflammation after brain ischemia. However, its downstream pathway and underlying mechanism have yet to be elucidated. The HMGB1 level in the acute cerebral infarct (ACI) group was significantly increased compared with that of control group, and correlated with the severity of neurologic impairment of ACI patients. Further, recombinant human HMGB1 (rhHMGB1) had no effect on microglia derived from mice lacking the Toll-like receptor 4 (TLR4−/–). Intracerebroventricular injection of rhHMGB1 in TLR4+/+ mice cause significantly more injury after cerebral ischemia–reperfusion than control group. But, TLR4−/– mice administered with rhHMGB1 showed moderate impairment after ischemia–reperfusion than TLR4+/+ mice. To determine the potential downstream signaling of HMGB1/TLR4 in cerebral ischemic injury, we used the ischemic–reperfusion model with Toll/interleukin-1 receptor domain-containing adaptor-inducing interferon-β knockout mice (TRIF−/–) and evaluated the activity and expression of TRIF pathway-related kinases. The results suggest that the TRIF pathway is not likely to be involved in TLR4-mediated ischemia brain injury. Finally, we found that TLR4 expressed by immigrant macrophages was involved in the development of ischemic brain damage. These results suggest that HMBG1 mediates ischemia–reperfusion injury by TRIF-adaptor independent Toll-like receptor 4 signaling. The TLR4 expressed by immigrant macrophages may be involved in the development of ischemic brain damage.

Oligodendrocytes, myelin-forming glial cells of the central nervous system, are vulnerable to damage in a variety of neurologic diseases. Much is known of primary myelin injury, which occurs in settings of genetic dysmyelination or demyelinating disease. There is growing awareness that oligodendrocytes are also targets of injury in acute ischemia. Recognition of oligodendrocyte damage in animal models of ischemia requires attention to their distinct histologic features or use of specific immunocytochemical markers. Like neurons, oligodendrocytes are highly sensitive to injury by oxidative stress, excitatory amino acids, trophic factor deprivation, and activation of apoptotic pathways. Understanding mechanisms of oligodendrocyte death may suggest new therapeutic strategies to preserve or restore white matter function and structure after ischemic insults.

Ischemic colitis (IC) results from reduced colonic vascular perfusion, accounting for 50-60% of all gastrointestinal ischemic episodes. IC leads to mucosal damage with clinical symptom severity developing based on the duration and extent of colonic injury. In rare cases IC may form a mass-like lesion mimicking malignancy. Here we present the case of a 55-year-old female with hematochezia and diarrhea, who on workup was found to have a mass-like lesion at the ileocecal valve. Multiple biopsies demonstrated ischemic change and mucosal injury without evidence of dysplasia or carcinoma. Two months later on follow-up imaging, after supportive treatment the lesion was completely resolved. It is critical for gastroenterologists and pathologists to be aware of this variant of IC to avoid unnecessary surgical procedures and treatment of patients.

Nowadays, new spinal cord injury (SCI) cases are frequently due to non traumatic causes, especially vascular disorders. A prerequisite to developing mechanism-based neuroprotective strategies for acute SCI is a full understanding of the early pathophysiological changes to prevent later disability and paralysis. The immediate damage spreads from the initial site through excitotoxicity and metabolic dysfunction (ischemia, free radicals and neuroinflammation) to surrounding tissue (secondary damage). Using an in vitro neonatal rat spinal cord model, an experimental protocol (pathological medium, PM) has been developed to mimic the profound metabolic perturbation (hypoxia, aglycemia, oxidative stress, acidosis, toxic free radicals) occurring in vivo after ischemic SCI, a condition surprisingly worsened by extracellular Mg2+ (1 mM). The current study sought to identify the cells affected by PM (with Mg2+), and the associated molecular death pathways in the spinal lumbar region which contains the locomotor networks. The results indicated that 1 h PM+Mg2+ application induced delayed pyknosis chiefly in the spinal white matter via overactivation of poly (ADP-ribose) polymerase 1 (PARP1), suggesting cell death mediated by the process of parthanatos and also via caspase 3-dependent apoptosis. Grey matter damage was less intense and concentrated in dorsal horn neurons and motoneurons which became nuclearimmunoreactive for the mitochondrial apoptosis-inducing factor. Moreover, TRPM2 channel expression was enhanced 24 h later in dorsal horn and motoneurons, while TRPM7 channel expression concomitantly decreased. Conversely, TRPM7 expression grew earlier (3 h) in white matter cells, while TRPM2 remained undetectable. Our results show that extracellular Mg2+ amplified the white matter cell death via parthanatos and apoptosis, and motoneuronal degeneration via PARP1-dependent pathways with distinct changes in their TRPM expression. In fact, the PARP-1 inhibitor PJ34, when applied 30 min after the moderate excitotoxic insult, could protect spinal networks controlling locomotion in more than 50 % of preparations. Interestingly, the drug per se strongly increased spontaneous network discharges without cell damage. Glutamate ionotropic receptor blockers suppressed this phenomenon reversibly. Our results suggest that pharmacological inhibition of PARP-1 could prevent damage to the locomotor networks if this procedure had been implemented early after the initial lesion and when the lesion was limited. PJ34 had also a positive effect on PM+Mg2+ treated spinal cords, especially in the white matter after 24 h, both alone or administered together with caspase-3 inhibitor. The neonatal rat in vitro SCI model was also useful to study the activation of endogenous spinal stem cells. We identified the ATF3 transcription factor as a novel dynamic marker for ependymal stem/progenitor cells (nestin, vimentin and SOX2 positive) located around the central canal of the neonatal or adult rat spinal cord. While quiescent ependymal cells showed cytoplasmic ATF3 expression, over 6-24 h in vitro these cells mobilized and acquired intense nuclear ATF3 staining. The migration of ATF3-nuclear positive cells preceded the strong proliferation of ependymal cells occurring after 24 h in vitro. Pharmacological inhibition of MAPK-p38 and JNK/c-Jun, upstream effectors of ATF3 activation, prevented the mobilization of ATF3 nuclear-positive cells. Excitotoxicity or ischemia-like conditions did not enhance migration of ependymal cells at 24 h. ATF3 is, therefore, suggested as a new biomarker of activated migrating stem cells in the rat spinal cord in vitro that represents an advantageous tool to study basic properties of endogenous stem cells.

Abstract: The consequences of the transferred new coronavirus infection are currently not well understood, but the neurotropicity of SARS-CoV-2 is beyond doubt. In the manifestations of postcoid syndrome, damage to the central nervous system is dominant and requires timely diagnosis and correction, incl. at the rehabilitation stage of medical care. The introduction of highly effective non-drug methods of treatment with a small number of side effects is an urgent task of modern medicine. Such methods of treatment can include ozone therapy - the use of an ozone-oxygen mixture (ACS) for therapeutic purposes, which significantly improves blood microcirculation and oxygenation of ischemic tissues due to its fibrinolytic activity and antiaggregatory properties, and therapeutic doses of ozone are able to correct the lipid profile of patients due to reducing atherogenic lipoproteins, triglycerides and cholesterol. In the range of therapeutic concentrations, ozone exhibits immunomodulatory, anti-inflammatory, bactericidal, antiviral, and detoxification effects. This article presents the experience of using ozone therapy in patients who have undergone covid-associated pneumonia (CT1-CT4) with postcoid syndrome and a predominant lesion of the central nervous system. The analysis of the dynamics of symptoms in a group of patients who underwent a course of ozone therapy in comparison with a group where ozone therapy was contraindicated is presented. The defeat of the central nervous system was represented by the following syndromes and symptoms, both individually and in combination: - cerebrasthenic syndrome, incl. anxiety, insomnia, decreased or lack of appetite, unstable mood background, weakness, fatigue - 94% - cerebral syndrome (headaches, constant "fog in the head", less often dizziness, decreased memory and attention, impaired sensitivity like anosmia, hyposmia) - 62%, incl. loss of memory and attention was observed in 42%, anosmia and hyposmia occurred in 11% of cases. The severity of certain symptoms was manifested depending on the age, the severity of the disease, the timing of the beginning of rehabilitation measures and the comorbid background. Diagnostics of the lesion of the central nervous system by coronavirus in patients was carried out by the methods of questioning complaints, dynamic observation, using the questionnaire for assessing the quality of life EQ-5D. In addition, in both groups of patients, the assessment of the severity of the main syndromes in points from 0 to 10 was carried out using a questionnaire at the beginning of the rehabilitation course and at the end of it. Evaluation of the results at discharge was carried out using the Pearson correlation coefficient. The use of an ozone-oxygen gas mixture in a comprehensive rehabilitation program for patients with postcoid syndrome and a predominant CNS lesion can reduce the intensity or completely stop cerebroasthenic and cerebral syndromes, completely restore taste and smell, and improve certain cognitive functions. This will improve the quality of life of patients, their social adaptation and reduce the drug load. The syndromic complex of CNS lesions, which remains in a certain volume, even after a comprehensive rehabilitation program with ozone therapy, indicates the need for long-term follow-up, clinical examination and medical rehabilitation of patients after a new coronavirus infection.