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International Journal of Biological... 2024Acute kidney injury (AKI) transformed to chronic kidney disease (CKD) is a critical clinical issue characterized by tubulointerstitial inflammation (TII) and fibrosis....
Acute kidney injury (AKI) transformed to chronic kidney disease (CKD) is a critical clinical issue characterized by tubulointerstitial inflammation (TII) and fibrosis. However, the exact mechanism remains largely unclear. In this study, we used single-cell RNA sequencing (scRNA-seq) to obtain a high-resolution profile of T cells in AKI to CKD transition with a mice model of unilateral ischemia-reperfusion injury (uIRI). We found that T cells accumulated increasingly with the progression of AKI to CKD, which was categorized into 9 clusters. A notably increased proportion of CD8 T cells via self-proliferation occurred in the early stage of AKI was identified. Further study revealed that the CD8 T cells were recruited through CXCL16-CXCR6 pathway mediated by macrophages. Notably, CD8 T cells induced endothelial cell apoptosis via Fas ligand-Fas signaling. Consistently, increased CD8 T cell infiltration accompanied with peritubular capillaries (PTCs) rarefaction was observed in uIRI mice. More impressively, the loss of PTCs and renal fibrosis was remarkably ameliorated after the elimination of CD8 T cells. In summary, our study provides a novel insight into the role of CD8 T cells in the transition from AKI to CKD via induction of PTCs rarefaction, which could suggest a promising therapeutic target for AKI.
Topics: Animals; CD8-Positive T-Lymphocytes; Acute Kidney Injury; Mice; Renal Insufficiency, Chronic; Male; Mice, Inbred C57BL; Disease Models, Animal; Receptors, CXCR6; Chemokine CXCL16; Reperfusion Injury; Apoptosis
PubMed: 38904017
DOI: 10.7150/ijbs.96812 -
Frontiers in Cardiovascular Medicine 2024Using a pig model of cardiopulmonary bypass, we compared outcomes after cardioplegia either with our in-house "Huaxi-1" solution containing natural blood and crystalloid...
BACKGROUND
Using a pig model of cardiopulmonary bypass, we compared outcomes after cardioplegia either with our in-house "Huaxi-1" solution containing natural blood and crystalloid or with the entirely crystalloid, commercially available "histidine-tryptophan-ketoglutarate" solution.
METHODS
Cardiopulmonary bypass was established in 12 healthy male pigs, who were randomized to receive a single dose of either Huaxi-1 or entirely crystalloid. All animals were then subjected to whole-heart ischemia for 90 min, followed by 2 h of reperfusion, after which myocardial injury was assessed in terms of cardiac function, myocardial pathology and levels of biomarkers in plasma, while levels of high-energy phosphate in myocardium were assayed using liquid chromatography.
RESULTS
Animals given Huaxi-1 cardioplegia required significantly less time to be weaned off bypass, they received significantly lower doses of norepinephrine, and they showed significantly higher levels (mean ± SD) of adenosine triphosphate (14 ± 4 vs. 8 ± 2 µg/mg, = 0.005), adenosine diphosphate (16 ± 2 vs. 13 ± 2 µg/mg, = 0.046), and total adenine nucleotide (37 ± 4 vs. 30 ± 3 µg/mg, = 0.006) in myocardium after 2 h of reperfusion. They also showed less severe bleeding, edema and injury to mitochondria and myofibers in myocardium. The two groups did not differ significantly in doses of inotropic drugs received, cardiac output or levels of biomarkers in plasma.
CONCLUSIONS
In this animal model of healthy hearts subjected to 90 min of ischemia, Huaxi-1 cardioplegia may be superior to entirely crystalloid cardioplegia for promoting energy generation and attenuating ischemia/reperfusion injury in myocardium.
PubMed: 38903973
DOI: 10.3389/fcvm.2024.1385253 -
Cureus May 2024The efficacy of mechanical thrombectomy (MT) for acute ischemic stroke has been established, but there are few reports on the effectiveness of MT for stroke patients...
The efficacy of mechanical thrombectomy (MT) for acute ischemic stroke has been established, but there are few reports on the effectiveness of MT for stroke patients with collagen disease. We report the case of a systemic lupus erythematosus (SLE) patient with cerebral infarction who underwent MT. A 48-year-old woman had been diagnosed with SLE for 30 years. She visited our hospital because of dizziness from the day before, but when she arrived at the hospital parking lot, she developed vomiting and impaired consciousness. An MRI revealed increased cerebellar hemisphere infarction and magnetic resonance angiography (MRA) did not visualize the right vertebral artery or basilar artery. Urgent cerebral angiography was performed, and angiography of the right vertebral artery revealed occlusion of the V4 segment of the vertebral artery. In addition to these angiographic findings, the patient also had impaired consciousness and was judged to be in need of emergency revascularization treatment. We performed an MT using a stent retriever. Immediately after the angiography examination, reperfusion to the basilar artery and severe stenosis of the right vertebral artery were noted. Therefore, percutaneous transluminal angioplasty (PTA) and stent placement for vertebral artery stenosis were done. This procedure successfully maintained the patency of the vertebral artery and blood flow to the basilar artery. Her consciousness improved; she only had mild nausea and no remarkable neurological findings.
PubMed: 38903344
DOI: 10.7759/cureus.60733 -
BioRxiv : the Preprint Server For... Apr 2024The cannabinoid CB2 receptor (CB2R) is a potential therapeutic target for distinct forms of tissue injury and inflammatory diseases. To thoroughly investigate the role...
The cannabinoid CB2 receptor (CB2R) is a potential therapeutic target for distinct forms of tissue injury and inflammatory diseases. To thoroughly investigate the role of CB2R in pathophysiological conditions and for target validation , optimal pharmacological tool compounds are essential. Despite the sizable progress in the generation of potent and selective CB2R ligands, pharmacokinetic parameters are often neglected for studies. Here, we report the generation and characterization of a tetra-substituted pyrazole CB2R full agonist named RNB-61 with high potency ( 0.13-1.81 nM, depending on species) and a peripherally restricted action due to P-glycoprotein mediated efflux from the brain. H and C labelled RNB-61 showed apparent values < 4 nM towards human CB2R in both cell and tissue experiments. The >6000-fold selectivity over CB1 receptors and negligible off-targets , combined with high oral bioavailability and suitable systemic pharmacokinetic (PK) properties, prompted the assessment of RNB-61 in a mouse ischemia-reperfusion model of acute kidney injury (AKI) and in a rat model of chronic kidney injury/inflammation and fibrosis (CKI) induced by unilateral ureteral obstruction. RNB-61 exerted dose-dependent nephroprotective and/or antifibrotic effects in the AKI/CKI models. Thus, RNB-61 is an optimal CB2R tool compound for preclinical studies with superior biophysical and PK properties over generally used CB2R ligands.
PubMed: 38903103
DOI: 10.1101/2024.04.26.591311 -
Journal of Physiological Investigation May 2024Ischemia-reperfusion (IR) injury remains a pivotal contributor to myocardial damage following acute coronary events and revascularization procedures. Phosphoinositide...
Ischemia-reperfusion (IR) injury remains a pivotal contributor to myocardial damage following acute coronary events and revascularization procedures. Phosphoinositide 3-kinase (PI3K), a key mediator of cell survival signaling, plays a central role in regulating inflammatory responses and cell death mechanisms. Trans-chalcone (Tch), a natural compound known for its anti-inflammatory activities, has shown promise in various disease models. The aim of the current study was to investigate the potential protective effects of Tch against myocardial injury induced by ischemia and reperfusion challenges by targeting the PI3K-inflammasome interaction. Experimental models utilizing male rats subjected to an in vivo model of IR injury and myocardial infarction were employed. Administration of Tch (100 μg/kg, intraperitoneally) significantly reduced myocardial injury, as indicated by limited infarct size and decreased levels of the myocardial enzyme troponin. Mechanistically, Tch upregulated PI3K expression, thereby inhibiting the activity of the NOD-like receptor protein 3 inflammasome followed by the activation of pro-inflammatory cytokines interleukin-1β (IL-1β) and IL-18. Moreover, it mitigated oxidative stress and suppressed vascular-intercellular adhesion molecules, contributing to its cardioprotective effects. The PI3K/Akt pathway inhibitor LY294002 considerably attenuated the beneficial effects of Tch. These findings highlight the therapeutic potential of Tch in ameliorating myocardial injury associated with IR insults through its modulation of the PI3K/Akt-inflammasome axis. The multifaceted mechanisms underlying its protective effects signify Tch as a promising candidate for further exploration in developing targeted therapies aimed at mitigating ischemic heart injury and improving clinical outcomes in cardiovascular diseases characterized by IR injury.
Topics: Animals; Male; Myocardial Reperfusion Injury; Proto-Oncogene Proteins c-akt; Rats; Phosphatidylinositol 3-Kinases; Rats, Sprague-Dawley; Inflammasomes; Chalcone; Signal Transduction; NLR Family, Pyrin Domain-Containing 3 Protein
PubMed: 38902960
DOI: 10.4103/ejpi.EJPI-D-24-00006 -
Molecular Biomedicine Jun 2024Hepatic ischemia-reperfusion injury (HIRI) is a critical pathophysiological process during liver transplantation (LT). Multiple genes and signal pathways are...
Hepatic ischemia-reperfusion injury (HIRI) is a critical pathophysiological process during liver transplantation (LT). Multiple genes and signal pathways are dysregulated during HIRI. This study aims to identify genes as potential therapeutic targets for ameliorating HIRI. Datasets containing samples from the human donor liver (GSE151648) and mouse HIRI model (GSE117066) were analyzed to determine differentially expressed genes (DEGs). The selected DEGs were confirmed by real-time PCR and western blot in the hepatocyte hypoxia-reoxygenation (HR) model, mouse HIRI model, and human liver samples after transplantation. Genetic inhibition was used to further clarify the underlying mechanism of the gene in vitro and in vivo. Among the DEGs, CSRNP1 was significantly upregulated (|log FC|= 2.08, P < 0.001), and was positively correlated with the MAPK signal pathway (R = 0.67, P < 0.001). CSRNP1 inhibition by siRNA significantly suppressed apoptosis in the AML-12 cell line after HR (mean Annexin ratio = 60.62% vs 42.47%, P = 0.0019), but the protective effect was eliminated with an additional MAPK activator. Knocking down CSRNP1 gene expression by intravenous injection of AAV-shRNA markedly reduced liver injury in mouse HIRI model (ALT: AAV-NC vs AAV-shCsrnp1 = 26,673.5 ± 2761.2 vs 3839.7 ± 1432.8, P < 0.001; AST: AAV-NC vs AAV-shCsrnp1 = 8640.5 ± 1450.3 vs 1786.8 ± 518.3, P < 0.001). Liver-targeted delivery of siRNA by nanoparticles effectively inhibited intra-hepatic genetic expression of Csrnp1 and alleviated IRI by reducing tissue inflammation and hepatocyte apoptosis. Furthermore, CSRNP1 inhibition was associated with reduced activation of the MAPK pathway both in vitro and in vivo. In conclusion, our results demonstrated that CSRNP1 could be a potential therapeutic target to ameliorate HIRI in an MAPK-dependent manner.
Topics: Reperfusion Injury; Animals; Liver Transplantation; Humans; Mice; Apoptosis; MAP Kinase Signaling System; Male; Cell Line; Liver; Hepatocytes; Disease Models, Animal; Mice, Inbred C57BL
PubMed: 38902590
DOI: 10.1186/s43556-024-00185-z -
Clinical Neurology and Neurosurgery Jun 2024Futile reperfusion (FR) is becoming a major challenge in the treatment of patients with acute ischaemic stroke (AIS) undergoing endovascular thrombectomy. This study...
U-shaped association between low-density lipoprotein cholesterol levels and risk of futile reperfusion mediated by stroke-associated pneumonia in acute ischemic stroke after endovascular thrombectomy.
OBJECTIVE
Futile reperfusion (FR) is becoming a major challenge in the treatment of patients with acute ischaemic stroke (AIS) undergoing endovascular thrombectomy. This study aims to determine the dose-response relationship between low-density lipoprotein cholesterol (LDL-C) levels and the risk of FR in patients with AIS undergoing endovascular thrombectomy and to investigate potential mediators.
METHODS
A total of 614 patients with AIS undergoing endovascular thrombectomy were enrolled and divided into five groups according to quintiles of LDL-C levels: Q1(≤2.27 mmol/l), Q2 (2.27-2.5 mmol/l), Q3 (2.5-2.59 mmol/l), Q4 (2.59-2.97 mmol/l) and Q5 (≥2.97 mmol/l). Associations between LDL-C levels and the risk of FR and stroke-associated pneumonia (SAP) were estimated using multivariate logistic regression models. Restricted cubic spline curves were used to describe the dose-response relationship between LDL-C levels and the risk of FR and SAP. Mediation effect analysis was performed in R software with 100 bootstrap samples.
RESULTS
After adjustment for confounders, both low and high LDL-C levels were significantly associated with a higher risk of FR compared with the reference group (Q3). We observed a U-shaped association between LDL-C levels and the risk of FR (P for nonlinear =0.012). Mediation analysis showed that the association between LDL-C levels and the risk of FR was 29.7 % (95 % CI: 2.96 %-75.0 %, P=0.02) mediated by SAP.
CONCLUSIONS
We found a U-shaped association between LDL-C levels and the risk of FR that was mediated by SAP. Clinicians should note that in AIS patients undergoing endovascular thrombectomy, lower LDL-C levels are not always better.
PubMed: 38901376
DOI: 10.1016/j.clineuro.2024.108399 -
Clinics (Sao Paulo, Brazil) 2024Cuproptosis is known to regulate diverse physiological functions in many diseases, but its role in regulating Myocardial Ischemia-Reperfusion Injury (MI/RI) remains...
BACKGROUND
Cuproptosis is known to regulate diverse physiological functions in many diseases, but its role in regulating Myocardial Ischemia-Reperfusion Injury (MI/RI) remains unclear.
METHODS
For this purpose, the MI/RI microarray datasets GSE61592 were downloaded from the Gene Expression Omnibus (GEO) database, and the Differently Expressed Genes (DEGs) in MI/RI were identified using R software. Moreover, the MI/RI mice model was established to confirm further the diagnostic value of Pyruvate Dehydrogenase B (Pdhb), Dihydrolipoamide S-acetyltransferase (Dlat), and Pyruvate dehydrogenase E1 subunit alpha 1 (Pdhα1).
RESULTS
The analysis of microarray datasets GSE61592 revealed that 798 genes were upregulated and 768 were downregulated in the myocardial tissue of the ischemia-reperfusion injury mice. Furthermore, Dlat, Pdhb, Pdhα1, and cuproptosis-related genes belonged to the downregulated genes. The receiver operating characteristics curve analysis results indicated that the Dlat, Pdhb, and Pdhα1 levels were downregulated in MI/RI and were found to be potential biomarkers for MI/RI diagnosis and prognosis. Similarly, analysis of Dlat, Pdhb, and Pdhα1 levels in the MI/RI mice revealed Pdhb being the key diagnostic marker.
CONCLUSIONS
This study demonstrated the prognostic value of cuproptosis-related genes (Dlat, Pdhb, and Pdhα1), especially Pdhb, MI/RI, providing new insight into the MI/RI treatment.
Topics: Animals; Myocardial Reperfusion Injury; Computational Biology; Mice; Down-Regulation; Male; Disease Models, Animal; Up-Regulation; Mice, Inbred C57BL; Gene Expression Profiling; Pyruvate Dehydrogenase (Lipoamide); Biomarkers; Acetyltransferases
PubMed: 38901133
DOI: 10.1016/j.clinsp.2024.100410 -
Kidney International Reports Jun 2024Beta-carotene (BC) protects the body against free radicals that may damage the kidney and lead to the development of acute kidney injury and chronic kidney disease...
INTRODUCTION
Beta-carotene (BC) protects the body against free radicals that may damage the kidney and lead to the development of acute kidney injury and chronic kidney disease (CKD). Previous studies in animal models have demonstrated a potential protective effect of 30 mg/kg BC supplementation on renal ischemia or reperfusion injury and subsequently improved kidney function. The extension of these findings to humans, however, remains unclear.
METHODS
Our study leverages previously collected data from the Physicians' Health Study I (PHS I), a large-scale, long-term, randomized trial of middle-aged and older US male physicians testing 50 mg BC every other day for primary prevention of cardiovascular disease and cancer. We examined the impact of randomized BC supplementation on self-reported incident CKD identified by self-reports stating "yes" to kidney disease from annual follow-up questionnaires from randomization in 1982 through the end of the randomized BC intervention at the end of 1995, and on CKD defined as an estimated glomerular filtration rate (eGFR) < 60 ml/min per 1.73 m at the end of 1995. Analyses compared incident CKD between BC supplementation and placebo using Cox proportional hazards regression models and logistic regression. We also examined whether smoking status (current vs. former or never smoker) or other factors modified the effect of randomized BC supplementation on CKD.
RESULTS
A total of 10,966 participants were randomized to BC, and 10,952 participants were randomized to a placebo group. Baseline characteristics between randomized BC groups were similar. There was no significant benefit between BC supplementation and self-reported incident CKD after adjusting for age and randomized aspirin treatment (hazard ratio [HR] = 0.97, 95% confidence interval [CI]: 0.86-1.08, -value = 0.56). Stratified by smoking status, there was no significant benefit of BC supplementation and self-reported incident CKD either among former or never smokers (HR = 0.95, 95% CI: 0.84-1.07, -value = 0.41) or current smokers (HR = 1.08, 95% CI: 0.78-1.50, -value = 0.64). Smoking status did not modify the association between BC supplementation and incident CKD (-interaction = 0.47). In subgroup analysis among those with available serum creatinine at the study end (5480 with BC and 5496 with placebo), there was no significant benefit between BC supplementation and CKD based on eGFR < 60 ml/min per 1.73 m (odds ratio [OR] = 0.96, 95% CI: 0.85-1.08, -value = 0.49).
CONCLUSION
Long-term randomized BC supplementation did not affect the risk of incident CKD in middle-aged and older male physicians.
PubMed: 38899218
DOI: 10.1016/j.ekir.2024.04.001 -
Vascular Pharmacology Jun 2024Several factors contribute to ischemia/reperfusion injury (IRI), including activation of the NLRP3 inflammasome and its byproducts, such as interleukin-1β (IL-1β) and...
BACKGROUND
Several factors contribute to ischemia/reperfusion injury (IRI), including activation of the NLRP3 inflammasome and its byproducts, such as interleukin-1β (IL-1β) and caspase-1. However, NLRP3 may paradoxically exhibit cardioprotective properties. This study aimed to assess the protective effects of the novel NLRP3 inhibitor, INF195, both in vitro and ex vivo.
METHODS
To investigate the relationship between NLRP3 and myocardial IRI, we synthetized a series of novel NLRP3 inhibitors, and investigated their putative binding mode via docking studies. Through in vitro studies we identified INF195 as optimal for NLRP3 inhibition. We measured infarct-size in isolated mouse hearts subjected to 30-min global ischemia/one-hour reperfusion in the presence of three different doses of INF195 (5, 10, or 20-μM). We analyzed caspase-1 and IL-1β concentration in cardiac tissue homogenates by ELISA. Statistical significance was determined using one-way ANOVA followed by Tukey's test.
RESULTS AND CONCLUSION
INF195 reduces NLRP3-induced pyroptosis in human macrophages. Heart pre-treatment with 5 and 10-μM INF195 significantly reduces both infarct size and IL-1β levels. Data suggest that intracardiac NLRP3 activation contributes to IRI and that low doses of INF195 exert cardioprotective effects by reducing infarct size. However, at 20-μM, INF195 efficacy declines, leading to a lack of cardioprotection. Research is required to determine if high doses of INF195 have off-target effects or dual roles, potentially eliminating both harmful and cardioprotective functions of NLRP3. Our findings highlight the potential of a new chemical scaffold, amenable to further optimization, to provide NLRP3 inhibition and cardioprotection in the ischemia/reperfusion setting.
PubMed: 38897555
DOI: 10.1016/j.vph.2024.107397