Cichoric acid ameliorates sepsis-induced acute kidney injury by inhibiting M1 macrophage polarization.

Cichoric acid (CA), a widely utilized polyphenolic compound in medicine, has garnered significant attention due to its potential health benefits. Sepsis-induced acute kidney disease (AKI) is related with an elevated risk of end-stage kidney disease (ESKD). However, it remains unclear whether CA provides protection against septic AKI. The aim of this study is to investigated the protective effect and possible mechanisms of CA against LPS-induced septic AKI. Sepsis-induced AKI was induced in mice through intraperitoneal injection of lipopolysaccharide (LPS), and RAW264.7 macrophages were incubated with LPS. LPS exposure significantly increased the levels of M1 macrophage biomarkers while reducing the levels of M2 macrophage indicators. This was accompanied by the release of inflammatory factors, superoxide anion production, mitochondrial dysfunction, activation of succinate dehydrogenase (SDH), and subsequent succinate formation. Conversely, pretreatment with CA mitigated these abnormalities. CA attenuated hypoxia-inducible factor-1α (HIF-1α)-induced glycolysis by lifting the NAD+/NADH ratio in macrophages. Additionally, CA disrupted the K (lysine) acetyltransferase 2A (KAT2A)/α-tubulin complex, thereby reducing α-tubulin acetylation and subsequently inactivating the NLRP3 inflammasome. Importantly, administration of CA ameliorated LPS-induced renal pathological damage, apoptosis, inflammation, oxidative stress, and disturbances in mitochondrial function in mice. Overall, CA restrained HIF-1α-mediated glycolysis via inactivation of SDH, leading to NLRP3 inflammasome inactivation and the amelioration of sepsis-induced AKI.

Chicoric acid ameliorates sepsis-induced cardiomyopathy via regulating macrophage metabolism reprogramming.

BACKGROUND: Sepsis-related cardiac dysfunction is believed to be a primary cause of high morbidity and mortality. Metabolic reprogramming is closely linked to NLRP3 inflammasome activation and dysregulated glycolysis in activated macrophages, leading to inflammatory responses in septic cardiomyopathy. Succinate dehydrogenase (SDH) and succinate play critical roles in the progression of metabolic reprogramming in macrophages. Inhibition of SDH may be postulated as an effective strategy to attenuate macrophage activation and sepsis-induced cardiac injury. PURPOSE: This investigation was designed to examine the role of potential compounds that target SDH in septic cardiomyopathy and the underlying mechanisms involved. METHODS/RESULTS: From a small molecule pool containing about 179 phenolic compounds, we found that chicoric acid (CA) had the strongest ability to inhibit SDH activity in macrophages. Lipopolysaccharide (LPS) exposure stimulated SDH activity, succinate accumulation and superoxide anion production, promoted mitochondrial dysfunction, and induced the expression of hypoxia-inducible factor-1α (HIF-1α) in macrophages, while CA ameliorated these changes. CA pretreatment reduced glycolysis by elevating the NAD+/NADH ratio in activated macrophages. In addition, CA promoted the dissociation of K(lysine) acetyltransferase 2A (KAT2A) from α-tubulin, and thus reducing α-tubulin acetylation, a critical event in the assembly and activation of NLRP3 inflammasome. Overexpression of KAT2A neutralized the effects of CA, indicating that CA inactivated NLRP3 inflammasome in a specific manner that depended on KAT2A inhibition. Importantly, CA protected the heart against endotoxin insult and improved sepsis-induced cardiac mitochondrial structure and function disruption. Collectively, CA downregulated HIF-1α expression via SDH inactivation and glycolysis downregulation in macrophages, leading to NLRP3 inflammasome inactivation and the improvement of sepsis-induced myocardial injury. CONCLUSION: These results highlight the therapeutic role of CA in the resolution of sepsis-induced cardiac inflammation.

Epigenetic repression of THBD transcription by BRG1 contributes to deep vein thrombosis.

BACKGROUND: Deep vein thrombosis (DVT) with its major complication, pulmonary embolism, is a global health problem. Endothelial dysfunction is involved in the pathogenesis of DVT. We have previously demonstrated that endothelial specific deletion of Brahma-related gene 1 (BRG1) ameliorates atherosclerosis and aneurysm in animal models. Whether endothelial BRG1 contributes to DVT development remains undetermined. METHODS: DVT was induced in mice by ligation of inferior vena cava. Deletion of BRG1 in endothelial cells was achieved by crossing the Cdh5-ERT-Cre mice with the Brg1loxp/loxp mice. RESULTS: Here we report that compared to the wild type mice, BRG1 conditional knockout (CKO) mice displayed substantially decreased DVT susceptibility characterized by decreased weight and size of thrombus and reduced immune infiltration. In endothelial cells, thrombomodulin (THBD) expression was significantly decreased by TNF-α stimulation, while BRG1 knockdown or inhibition recovered THBD expression. Further analysis revealed that BRG1 deficiency decreased the CpG methylation levels of the THBD promoter induced by TNF-α. Mechanistically, BRG1 directly upregulated DNMT1 expression after TNF-α treatment in endothelial cells. More importantly, administration of a small-molecule BRG1 inhibitor PFI-3 displayed potent preventive and therapeutic potentials in the DVT model. CONCLUSIONS: Our findings implicate BRG1 as an important regulator of DVT pathogenesis likely through epigenetic regulation of THBD expression in endothelial cells and provide translational proof-of-concept for targeting BRG1 in DVT intervention.

Subclavian steal syndrome associated with Sjogren's syndrome: A case report.

BACKGROUND: Subclavian steal syndrome (SSS) caused by Sjogren's syndrome is rare, especially for elderly patients with risk factors for atherosclerosis. The current report presents the uncommon etiology and treatment of SSS, aiming to improve doctor's clinical experience. CASE SUMMARY: A 69-year-old man was diagnosed with hypertension and acute cerebral infarction presenting with left upper limb weakness and pain even gradually aggravating to left limb hemiplegia 30 years ago. He was managed with antihypertensive and antithrombotic therapy; however, his condition was recurrent, and he never had any further examination. It was found that the difference of the bilateral upper arm systolic pressure was over 20 mmHg, and Doppler examination showed that the blood flow of the left vertebral artery was reversed, suggesting SSS. Further tests revealed a benign lymphoepithelial lesion in salivary gland tissue, confirming the Sjogren's syndrome. CONCLUSION: The patient was found to have hypertension when he was 33 years old, and the blood pressure of both sides was asymmetric, which was ignored. The patient's symptoms of dizziness and upper limb weakness were misdiagnosed as general cerebral infarction. It is necessary to test the aorta computed tomography angiography to prove secondary hypertension factors such as Sjogren's syndrome.

Comparison of one-month versus twelve-month dual antiplatelet therapy after implantation of drug-eluting stents guided by either intravascular ultrasound or angiography in patients with acute coronary syndrome: rationale and design of prospective, multicenter, randomized, controlled IVUS-ACS and ULTIMATE-DAPT trial.

BACKGROUND: Current guidelines recommend administering dual antiplatelet therapy (DAPT) for 12 months to patients with acute coronary syndromes (ACS) and without contraindications after drug-eluting stent (DES) implantation. A recent study reported that 3 months of DAPT followed by ticagrelor monotherapy is effective and safe in ACS patients undergoing DES implantation compared with the standard duration of DAPT. However, it is unclear whether antiplatelet monotherapy with ticagrelor alone versus ticagrelor plus aspirin reduces the incidence of clinically relevant bleeding without increasing the risk of major adverse cardiovascular and cerebrovascular events (MACCEs) in ACS patients undergoing percutaneous coronary intervention (PCI) with DES implantation guided by either intravascular ultrasound (IVUS) or angiography who have completed a 1-month course of DAPT with aspirin plus ticagrelor. METHODS: The IVUS-ACS and ULTIMATE-DAPT is a prospective, multicenter, randomized, controlled trial designed to determine (1) whether IVUS-guided versus angiography-guided DES implantation in patients with ACS reduces the risk of target vessel failure (TVF) at 12 months and (2) whether ticagrelor alone versus ticagrelor plus aspirin reduces the risk of clinically relevant bleeding without increasing the risk of MACCE 1-12 months after the index PCI in ACS patients undergoing DES implantation guided by either IVUS or angiography. This study will enroll 3486 ACS patients eligible for DES implantation, as confirmed by angiographic studies. The patients who meet the inclusion criteria and none of the exclusion criteria will be randomly assigned in a 1:1 fashion to the IVUS- or angiography-guided group (first randomization). All enrolled patients will complete a 1-month course of DAPT with aspirin plus ticagrelor after the index PCI. Patients with no MACCEs or major bleeding (≥Bleeding Academic Research Consortium (BARC) 3b) within 30 days will be randomized in a 1:1 fashion to either the ticagrelor plus matching placebo (SAPT)group or ticagrelor plus aspirin (DAPT)group for an additional 11 months (second randomization). The primary endpoint of the IVUS-ACS trial is TVF at 12 months, including cardiac death, target vessel myocardial infarction (TVMI), or clinically driven target vessel revascularization (CD-TVR). The primary superiority endpoint of the ULTIMATE-DAPT trial is clinically relevant bleeding, defined as BARC Types 2, 3, or 5 bleeding, and the primary non-inferiority endpoint of the ULTIMATE-DAPT trial is MACCE, defined as cardiac death, myocardial infarction, ischemic stroke, CD-TVR, or definite stent thrombosis occurring 1-12 months in the second randomized population. CONCLUSION: The IVUS-ACS and ULTIMATE-DAPT trial is designed to test the efficacy and safety of 2 different antiplatelet strategies in ACS patients undergoing PCI with DES implantation guided by either IVUS or angiography. This study will provide novel insights into the optimal DAPT duration in ACS patients undergoing PCI and provide evidence on the clinical benefits of IVUS-guided PCI in ACS patients.

Obstructive sleep apnea affects the clinical outcomes of patients undergoing percutaneous coronary intervention.

BACKGROUND: There is a paucity of evidence regarding the association between obstructive sleep apnea (OSA) and patients undergoing percutaneous coronary intervention (PCI) for coronary artery disease. We sought to investigate whether OSA affects the clinical outcomes of patients undergoing PCI. PATIENTS AND METHODS: All enrolled individuals treated with PCI were evaluated for OSA by polysomnography. The primary end point was defined as major adverse cardiac events (MACEs) at 2 years, including cardiac death, myocardial infarction (MI), and/or target vessel revascularization. RESULTS: A total of 340 consecutive patients undergoing PCI were assigned to the OSA (n=152, apnea-hypopnea index ≥15) and non-OSA (n=188, apnea-hypopnea index <15) groups. The incidence of OSA in patients with coronary artery disease undergoing PCI was 44.7%. Patients in the OSA group had more three-vessel disease (34.9%), increased number of total implanted stents (3.3±2.0), and longer total stent length (83.8±53.1 mm) when compared to the non-OSA group (23.4%, P=0.020; 2.8±1.9, P=0.007; 68.7±48.4, P=0.010). After a median follow-up of 2 years, the incidence of MACEs was significantly higher in patients with OSA (25.0% vs 16.0%, P=0.038), mainly driven by the increased periprocedural MI (19.2% vs 11.2%, P=0.038) in the OSA group. By Cox regression multivariable analysis, the independent predictor of MACEs was OSA (hazard ratio: 1.962, 95% confidence interval: 1.036-3.717, P=0.039). CONCLUSION: There was a high prevalence of moderate-to-severe OSA in patients undergoing PCI, and OSA was associated with significantly increased MACE rate, mainly due to the increase in periprocedural MI rate.

Comparison of one-year clinical outcomes between intravascular ultrasound-guided versus angiography-guided implantation of drug-eluting stents for left main lesions: a single-center analysis of a 1,016-patient cohort.

BACKGROUND: The importance of intravascular ultrasound (IVUS)-guided stenting of the unprotected left main coronary artery (ULMCA) remains controversial and has not been fully studied in the subset of patients with ULMCA. This study evaluated the clinical outcome of IVUS-guided stenting using a drug-eluting stent for ULMCA. METHODS: A total of 1,016 consecutive patients with ULMCA stenosis who underwent drug-eluting stent implantation from January 2006 to December 2011 were prospectively registered. The primary endpoint of this nonrandomized registry was the rate of one-year major adverse cardiac events (MACE, including cardiac death, myocardial infarction, and target vessel revascularization). Stent thrombosis served as the safety endpoint. Propensity score matching was used to calculate the adjusted event rate. RESULTS: The unadjusted one-year MACE rate was 14.8% in the IVUS-guided group (n=337, 33.2%), significantly different from the 27.7% (P<0.001) in the angiography-guided group (n=679, 66.8%). After propensity score matching, 291 paired patients were matched between the two groups, and the difference in one-year MACE between IVUS-guided (16.2%) versus angiography-guided (24.4%) groups was still significant (P=0.014), mainly driven by decreased rates of cardiac death (1.7%) and target vessel revascularization (3.4%) in the IVUS-guided group when compared with 5.2% (P=0.023) and 10.0% (P=0.002) in the angiography-guided group, respectively. Although it did not reach significance (P=0.075), the adjusted one-year rate of stent thrombosis in the angiography-guided group was higher than in the IVUS-guided group. CONCLUSION: Compared with angiography guidance, IVUS-guided treatment of ULMCA using a drug-eluting stent was associated with a significant reduction of one-year cardiac death and target vessel revascularization, resulting in less frequent one-year MACE after propensity score matching.