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Drug Design, Development and Therapy 2024Insulin attaches insulin receptor to activate the PI3-kinase/Akt signaling to maintain glucose homeostasis and inhibit apoptosis. This study determined whether...
Short-Term Preconditioning with Insulin and Glucose Efficiently Protected the Kidney Against Ischemia-Reperfusion Injury via the P-AKT-Bax-Caspase-3 Signaling Pathway in Mice.
OBJECTIVE
Insulin attaches insulin receptor to activate the PI3-kinase/Akt signaling to maintain glucose homeostasis and inhibit apoptosis. This study determined whether preconditioning with insulin and glucose protects the kidney against ischemia-reperfusion injury (IRI).
METHODS
Kidney IRI was performed in C57BL/6 mice by clamping the renal vessels for 30 min, followed by reperfusion for 24 h. A total subcutaneous 0.1 unit of insulin along with 10% glucose in drinking water was treated on the mice for 24 h before kidney IRI. The kidney function and injuries were investigated through the determination of BUN and Cr in blood plasma, as well as the apoptosis and the expression of P-AKT, BAX, and caspase-3 in the kidneys. The role of P-AKT in insulin-treated IRI kidneys was tested using an AKT inhibitor. The effects of the preconditional duration of insulin and glucose on IRI kidneys were investigated by expanding the treatment duration to 1, 3, and 6 days.
RESULTS
Preconditioning with insulin and glucose protected the kidney against IRI as manifested by a decrease in creatinine and BUN and a reduction of kidney tubular injury. The protection effect was mediated by P-AKT-BAX-caspase-3 signaling pathway resulting in suppression of apoptotic cell death. An AKT inhibitor partially reversed the protective effects of preconditional insulin. The preconditional duration for 1, 3, and 6 days had no differences in improving kidney functions and pathology.
CONCLUSION
A short-term preconditioning with insulin and glucose protected the kidney from IRI through the activation of p-AKT and subsequent reduction of BAX-caspase-3-induced apoptosis. The short-term precondition provides a practicable strategy for protecting the kidney against predictable IRI, such as kidney transplant and major surgical operations with high risk of hypotension.
Topics: Animals; Reperfusion Injury; Proto-Oncogene Proteins c-akt; Mice; Mice, Inbred C57BL; Signal Transduction; Insulin; Male; Caspase 3; Glucose; bcl-2-Associated X Protein; Kidney; Apoptosis
PubMed: 38915866
DOI: 10.2147/DDDT.S465836 -
Frontiers in Nutrition 2024Cardiovascular disease (CVD) is the leading cause of death in women, with increased risk following menopause. Dietary intake of beetroot juice and other plant-based...
Seven-day dietary nitrate supplementation clinically significantly improves basal macrovascular function in postmenopausal women: a randomized, placebo-controlled, double-blind, crossover clinical trial.
INTRODUCTION
Cardiovascular disease (CVD) is the leading cause of death in women, with increased risk following menopause. Dietary intake of beetroot juice and other plant-based nitrate-rich foods is a promising non-pharmacological strategy for increasing systemic nitric oxide and improving endothelial function in elderly populations. The purpose of this randomized, placebo-controlled, double-blind, crossover clinical trial was to determine the effects of short-term dietary nitrate (NO ) supplementation, in the form of beetroot juice, on resting macrovascular endothelial function and endothelial resistance to whole-arm ischemia-reperfusion (IR) injury in postmenopausal women at two distinct stages of menopause.
METHODS
Early-postmenopausal [1-6 years following their final menstrual period (FMP), = 12] and late-postmenopausal (6+ years FMP, = 12) women consumed nitrate-rich (400 mg NO /70 mL) and nitrate-depleted beetroot juice (approximately 40 mg NO /70 mL, placebo) daily for 7 days. Brachial artery flow-mediated dilation (FMD) was measured pre-supplementation (Day 0), and approximately 24 h after the last beetroot juice (BR) dose (Day 8, post-7-day BR). Consequently, FMD was measured immediately post-IR injury and 15 min later (recovery).
RESULTS
Results of the linear mixed-effects model revealed a significantly greater increase in resting FMD with 7 days of BR compared to BR (mean difference of 2.21, 95% CI [0.082, 4.34], = 0.042); however, neither treatment blunted the decline in post-IR injury FMD in either postmenopausal group. Our results suggest that 7-day BR-mediated endothelial protection is lost within the 24-h period following the final dose of BR.
CONCLUSION
Our findings demonstrate that nitrate-mediated postmenopausal endothelial protection is dependent on the timing of supplementation in relation to IR injury and chronobiological variations in dietary nitrate metabolism.
CLINICAL TRIAL REGISTRATION
https://classic.clinicaltrials.gov/ct2/show/NCT03644472.
PubMed: 38915856
DOI: 10.3389/fnut.2024.1359671 -
Frontiers in Neurology 2024In central retinal artery occlusion (CRAO) or retinal stroke, which is usually a vision-threatening condition, timely diagnosis is imperative to improve the chances of...
In central retinal artery occlusion (CRAO) or retinal stroke, which is usually a vision-threatening condition, timely diagnosis is imperative to improve the chances of retinal preservation and to establish adequate secondary prevention measures. Even though retinal strokes have been traditionally assigned to the field of ophthalmology, while considering reperfusion therapy as the only way to avoid permanent vision loss, we suggest prompt evaluation of CRAO causes (primarily related to cardiovascular risk factors) performed by a well-organized interdisciplinary team (ophthalmologist and neurologist) in a neurovascular center with stroke expertise. Therefore, the most suitable adjunct method for rapidly diagnosing non-arteritic CRAO could be target transorbital ultrasound, performed by an experienced neurologist/neurosonologist in the stroke unit. Consequently, after an ophthalmological assessment, a final decision on thrombolytic therapy could be made. We accept that further research is obviously needed to determine whether transorbital ultrasound could replace ophthalmological investigation in the case of a suspected acute retinal stroke. We assert that retinal stroke requires interdisciplinary treatment in cooperation with neurologists and ophthalmologists, with an additive value for each to achieve the best results for the patient.
PubMed: 38915799
DOI: 10.3389/fneur.2024.1397751 -
BioRxiv : the Preprint Server For... Jun 2024Experimental stroke models in rodents are essential for mechanistic studies and therapeutic development. However, these models have several limitations negatively...
Experimental stroke models in rodents are essential for mechanistic studies and therapeutic development. However, these models have several limitations negatively impacting their translational relevance. Here we aimed to develop a minimally invasive thrombotic stroke model through magnetic particle delivery that does not require craniotomy, is amenable to reperfusion therapy, can be combined with in vivo imaging modalities, and can be performed in awake mice. We found that the model results in reproducible cortical infarcts within the middle cerebral artery (MCA) with cytologic and immune changes similar to that observed with more invasive distal MCA occlusion models. Importantly, the injury produced by the model was ameliorated by tissue plasminogen activator (tPA) administration. We also show that MCA occlusion in awake animals results in bigger ischemic lesions independent of day/night cycle. Magnetic particle delivery had no overt effects on physiologic parameters and systemic immune biomarkers. In conclusion, we developed a novel stroke model in mice that fulfills many requirements for modeling human stroke.
PubMed: 38915621
DOI: 10.1101/2024.06.10.598243 -
Frontiers in Cell and Developmental... 2024This comprehensive review inspects the therapeutic potential of mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) across multiple organ systems. Examining... (Review)
Review
This comprehensive review inspects the therapeutic potential of mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) across multiple organ systems. Examining their impact on the integumentary, respiratory, cardiovascular, urinary, and skeletal systems, the study highlights the versatility of MSC-EVs in addressing diverse medical conditions. Key pathways, such as Nrf2/HO-1, consistently emerge as central mediators of their antioxidative and anti-inflammatory effects. From expediting diabetic wound healing to mitigating oxidative stress-induced skin injuries, alleviating acute lung injuries, and even offering solutions for conditions like myocardial infarction and renal ischemia-reperfusion injury, MSC-EVs demonstrate promising therapeutic efficacy. Their adaptability to different administration routes and identifying specific factors opens avenues for innovative regenerative strategies. This review positions MSC-EVs as promising candidates for future clinical applications, providing a comprehensive overview of their potential impact on regenerative medicine.
PubMed: 38915448
DOI: 10.3389/fcell.2024.1397954 -
Cell Death Discovery Jun 2024Neuroinflammation caused by microglia and other immune cells plays pivotal role in cerebral ischemia/reperfusion injury and recovery. Modulating microglial polarization...
Curcumol ameliorates neuroinflammation after cerebral ischemia-reperfusion injury via affecting microglial polarization and Treg/Th17 balance through Nrf2/HO-1 and NF-κB signaling.
Neuroinflammation caused by microglia and other immune cells plays pivotal role in cerebral ischemia/reperfusion injury and recovery. Modulating microglial polarization or Treg/Th17 balance from pro-inflammatory phenotype to anti-inflammatory phenotype are promising strategies for the treatment of cerebral ischemia. Curcumol has potential to fight against oxidative stress and inflammation, but whether it has protective effect in cerebral ischemia is uncertain. In the present study, cerebral ischemia was induced in C57BL/6 mice via middle cerebral artery occlusion (MCAO). MCAO mice were treated with curcumol for 7 days, then post-stroke ischemic injury, neurological deficits, microglial polarization and brain leukocyte infiltration were evaluated by TTC staining, behavioural tests, flow cytometry, western blot and immunofluorescence. We found that poststroke administration of curcumol reduced infarct volume, attenuated neuronal damage and inflammation, and improved motor function recovery of MCAO mice. Curcumol skewed microglial polarization toward anti-inflammatory phenotype in MCAO mice in vivo or after oxygen-glucose deprivation and reoxygenation (OGD/R) in vitro. In addition, curcumol reduced local T cell infiltration in ischemic brain of MCAO mice and impaired Treg/Th17 balance. Curcumol inhibited ROS production and regulated Nrf2/HO-1 and NF-κB signaling in microglia. Finally, inhibiting Nrf2/HO-1 signaling or activating NF-κB signaling abrogated the influence of curcumol on microglial polarization. In conclusion, curcumol treatment reduced brain damage and neuroinflammation via modulating anti-inflammatory microglial polarization and Treg/Th17 balance through Nrf2/HO-1 and NF-κB signaling. Curcumol might be a promising treatment strategy for stroke patients.
PubMed: 38914581
DOI: 10.1038/s41420-024-02067-3 -
International Journal of Applied &... 2024Aerobic glycolysis has recently demonstrated promising potential in mitigating the effects of ischemia-reperfusion (IR) injury. Scutellarin (Scu) possesses various...
BACKGROUND
Aerobic glycolysis has recently demonstrated promising potential in mitigating the effects of ischemia-reperfusion (IR) injury. Scutellarin (Scu) possesses various cardioprotective properties that warrant investigation. To mimic IR injury , this study employed hypoxia/reoxygenation (H/R) injury.
METHODS AND RESULTS
First, we conducted an assessment of the protective properties of Scu against HR in H9c2 cells, encompassing inflammation damage, apoptosis injury, and oxidative stress. Then, we verified the effects of Scu on the Warburg effect in H9c2 cells during HR injury. The findings indicated that Scu augmented aerobic glycolysis by upregulating p-PKM2/PKM2 levels. Following, we built a panel of six long noncoding RNAs and seventeen microRNAs that were reported to mediate the Warburg effect. Based on the results, miR-34c-5p was selected for further experiments. Then, we observed Scu could mitigate the HR-induced elevation of miR-34c-5p. Upregulation of miR-34c-5p could weaken the beneficial impacts of Scu in cellular viability, inflammatory damage, oxidative stress, and the facilitation of the Warburg effect. Subsequently, our investigation revealed a decrease in both ALDOA mRNA and protein levels following HR injury, which could be restored by Scu administration. Downregulation of ALDOA or Mimic of miR-34c-5p could reduce these effects induced by Scu.
CONCLUSIONS
Scu provides cardioprotective effects against IR injury by upregulating the Warburg effect via miR-34c-5p/ALDOA.
PubMed: 38912363
DOI: 10.4103/ijabmr.ijabmr_415_23 -
The Indian Journal of Radiology &... Jul 2024Regardless of the number of vessels involved endovascular recanalization of mesenteric vessels is the treatment of choice for chronic mesenteric ischemia. Reperfusion...
Regardless of the number of vessels involved endovascular recanalization of mesenteric vessels is the treatment of choice for chronic mesenteric ischemia. Reperfusion injury post-endovascular recanalization in chronic mesenteric ischemia is a rare clinical scenario as it is mostly encountered in cases of acute mesenteric ischemia. Here in, we describe a case with characteristic clinical and imaging findings of reperfusion syndrome, post-endovascular recanalization of chronically occluded superior mesenteric artery and severely stenosed celiac trunk in a patient with chronic mesenteric ischemia.
PubMed: 38912233
DOI: 10.1055/s-0043-1778058 -
Research progress on the role of mitochondria in the process of hepatic ischemia-reperfusion injury.Gastroenterology Report 2024During liver ischemia-reperfusion injury, existing mechanisms involved oxidative stress, calcium overload, and the activation of inflammatory responses involve... (Review)
Review
During liver ischemia-reperfusion injury, existing mechanisms involved oxidative stress, calcium overload, and the activation of inflammatory responses involve mitochondrial injury. Mitochondrial autophagy, a process that maintains the normal physiological activity of mitochondria, promotes cellular metabolism, improves cellular function, and facilitates organelle renewal. Mitochondrial autophagy is involved in oxidative stress and apoptosis, of which the PINK1-Parkin pathway is a major regulatory pathway, and the deletion of PINK1 and Parkin increases mitochondrial damage, reactive oxygen species production, and inflammatory response, playing an important role in mitochondrial quality regulation. In addition, proper mitochondrial permeability translational cycle regulation can help maintain mitochondrial stability and mitigate hepatocyte death during ischemia-reperfusion injury. This mechanism is also closely related to oxidative stress, calcium overload, and the aforementioned autophagy pathway, all of which leads to the augmentation of the mitochondrial membrane permeability transition pore opening and cause apoptosis. Moreover, the release of mitochondrial DNA (mtDNA) due to oxidative stress further aggravates mitochondrial function impairment. Mitochondrial fission and fusion are non-negligible processes required to maintain the dynamic renewal of mitochondria and are essential to the dynamic stability of these organelles. The Bcl-2 protein family also plays an important regulatory role in the mitochondrial apoptosis signaling pathway. A series of complex mechanisms work together to cause hepatic ischemia-reperfusion injury (HIRI). This article reviews the role of mitochondria in HIRI, hoping to provide new therapeutic clues for alleviating HIRI in clinical practice.
PubMed: 38912038
DOI: 10.1093/gastro/goae066 -
Annals of Surgery Open : Perspectives... Jun 2024The adverse effects of ischemia-reperfusion injury (IRI) remain a principal barrier to a successful outcome after lifesaving orthotopic liver transplantation (OLT). Gene...
OBJECTIVE
The adverse effects of ischemia-reperfusion injury (IRI) remain a principal barrier to a successful outcome after lifesaving orthotopic liver transplantation (OLT). Gene expression during different phases of IRI is dynamic and modified by individual exposures, making it attractive for identifying potential therapeutic targets for improving the number of suitable organs for transplantation and patient outcomes. However, data remain limited on the functional landscape of gene expression during liver graft IRI, spanning procurement to reperfusion and recovery. Therefore, we sought to characterize transcriptomic profiles of IRI during multiple phases in human OLT.
METHODS
We conducted clinical data analyses, histologic evaluation, and RNA sequencing of 17 consecutive human primary OLT. We performed liver allograft biopsies at 4 time points: baseline (B, before donor cross-clamp), at the end of cold ischemia (CI), during early reperfusion (ER, after revascularization), and during late reperfusion (LR). Data were generated and then recipients grouped by post-OLT outcomes categories: immediate allograft function (IAF; n = 11) versus early allograft dysfunction (EAD; n = 6) groups.
RESULTS
We observed that CI (vs B) modified a transcriptomic landscape enriched for a metabolic and immune process. Expression levels of hallmark inflammatory response genes were higher transitioning from CI to ER and decreased from ER to LR. IAF group predominantly showed higher bile and fatty acid metabolism activity during LR compared with EAD group, while EAD group maintained more immunomodulatory activities. Throughout all time points, EAD specimens exhibited decreased metabolic activity in both bile and fatty acid pathways.
CONCLUSIONS
We report transcriptomic profiles of human liver allograft IRI from prepreservation in the donor to posttransplantation in the recipient. Immunomodulatory and metabolic landscapes across ER and LR phases were different between IAF and EAD allografts. Our study also highlights marker genes for these biological processes that we plan to explore as novel therapeutic targets or surrogate markers for severe allograft injury in clinical OLT.
PubMed: 38911661
DOI: 10.1097/AS9.0000000000000444