BACKGROUND FAVOR III China (Comparison of Quantitative Flow Ratio Guided and Angiography Guided Percutaneous Intervention in Patients with Coronary Artery Disease) reported improved clinical outcomes in quantitative flow ratio (QFR) relative to angiography-guided percutaneous coronary intervention (PCI), but the clinical impact of QFR-guided PCI according to sex remains unknown. OBJECTIVES The authors sought to compare sex differences in the 2-year clinical benefits of a QFR-guided PCI strategy and to evaluate the differences in outcomes between men and women undergoing contemporary PCI. METHODS This study involved a prespecified subgroup analysis of the FAVOR III China trial, in which women and men were randomized to a QFR-guided strategy or a standard angiography-guided strategy. Sex differences in clinical benefit of the QFR guidance were analyzed for major adverse cardiac events (MACE), a composite of all-cause death, myocardial infarction, or ischemia-driven revascularization within 2 years. RESULTS A total of 1,126 women and 2,699 men were eligible and the occurrence of 2-year MACE was similar between women and men (10.3% vs 10.5%; P = 0.96). Compared with an angiography-guided strategy, a QFR-guided strategy resulted in a 7.9% and 9.7% reduction in PCI rates in men and women, respectively. A QFR-guided strategy resulted in similar relative risk reductions for 2-year MACE in women (8.0% vs 12.7%; HR: 0.62; 95% CI: 0.42-0.90) and men (8.7% vs 12.4%; HR: 0.69; 95% CI: 0.54-0.87) (Pinteraction = 0.61). Furthermore, QFR values were not significantly different between men and women with various angiographic stenosis categories. CONCLUSIONS A QFR-guided PCI strategy resulted in improved MACE in both men and women at 2 years compared with an angiography-guided PCI strategy. The FAVOR III China Study [FAVOR III China]; (NCT03656848) (JACC: Asia 2024;4:201-212) (c) 2024 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

BACKGROUND:Adipose-derived stem cells (ADSCs) and their extracellular vesicles (EVs) have therapeutic potential in ischemic brain injury, but the underlying mechanism is poorly understood. The current study aimed to explore the contribution of miRNAs in ADSC-EVs to the treatment of cerebral ischemia.METHODS:After the intravenous injection of ADSC-EVs, therapeutic efficacy was evaluated by neurobehavioral tests and brain atrophy volume. The polarization of microglia was assessed by immunostaining and qPCR. We further performed miRNA sequencing of ADSC-EVs and analyzed the relationship between the upregulated miRNAs in ADSC-EVs and microglial polarization-related proteins using Ingenuity Pathway Analysis (IPA).RESULTS:The results showed that ADSC-EVs reduced brain atrophy volume, improved neuromotor and cognitive functions after mouse ischemic stroke. The loss of oligodendrocytes was attenuated after ADSC-EVs injection. The number of blood vessels, as well as newly proliferated endothelial cells in the peri-ischemia area were higher in the ADSC-EVs treated group than that in the PBS group. In addition, ADSC-EVs regulated the polarization of microglia, resulting in increased repair-promoting M2 phenotype and decreased pro-inflammatory M1 phenotype. Finally, STAT1 and PTEN were highlighted as two downstream targets of up-regulated miRNAs in ADSC-EVs among 85 microglia/macrophage polarization related proteins by IPA. The inhibition of STAT1 and PTEN by ADSC-EVs were confirmed in cultured microglia.CONCLUSIONS:In summary, ADSC-EVs reduced ischemic brain injury, which was associated with the regulation of microglial polarization. miRNAs in ADSC-EVs partly contributed to their function in regulating microglial polarization by targeting PTEN and STAT1.

Astrocytes play an essential role in the modulation of blood-brain barrier function. Neurological diseases induce the transformation of astrocytes into a neurotoxic A1 phenotype, exacerbating brain injury. However, the effect of A1 astrocytes on the BBB dysfunction after stroke is unknown. Adult male ICR mice (n=97) were subjected to 90-minute transient middle cerebral artery occlusion (tMCAO). Immunohistochemical staining of A1 (C3d) and A2 (S100A10) was performed to characterize phenotypic changes in astrocytes over time after tMCAO. The glucagon-like peptide-1 receptor agonist semaglutide was intraperitoneally injected into mice to inhibit A1 astrocytes. Infarct volume, atrophy volume, neurobehavioral outcomes, and BBB permeability were evaluated. RNA-seq was adopted to explore the potential targets and signaling pathways of A1 astrocyte-induced BBB dysfunction. Astrocytic C3d expression was increased, while expression of S100A10 was decreased in the first two weeks after tMCAO, reflecting a shift in the astrocytic phenotype. Semaglutide treatment reduced the expression of CD16/32 in microglia and C3d in astrocytes after ischemic stroke (p<0.05). Ischemia-induced brain infarct volume, atrophy volume and neuroinflammation were reduced in the semaglutide-treated mice, and neurobehavioral outcomes were improved compared to control mice (p<0.05). We further demonstrated that semaglutide treatment reduced the gap formation of tight junction proteins ZO-1, claudin-5 and occludin, as well as IgG leakage three days following tMCAO (p<0.05). In vitro experiments revealed that A1 astrocyte-conditioned medium disrupted BBB integrity. RNA-seq showed that A1 astrocytes were enriched in inflammatory factors and chemokines and significantly modulated the TNF and chemokine signaling pathways, which are closely related to barrier damage. We concluded that astrocytes undergo a phenotypic shift over time after ischemic stroke. C3d+/GFAP+ astrocytes aggravate BBB disruption, suggesting that inhibiting C3d+/GFAP+ astrocyte formation represents a novel strategy for the treatment of ischemic stroke.

OBJECTIVES The aim of the present study was to evaluate the safety and efficacy of thinner strut Firesorb (100/125 mm) sirolimus-eluting bioresorbable scaffolds (BRS) versus cobalt-chromium everolimus-eluting stents (CoCr-EES) in patients with coronary artery disease. BACKGROUND First-generation thicker strut BRS were associated with unexpected device-related adverse outcomes at long-term follow-up. METHODS Eligible patients with 1 or 2 de novo noncomplex coronary lesions were randomized to the Firesorb BRS group or CoCr-EES group in a 1:1 ratio. The primary endpoint was 1-year angiographic in-segment late loss (LL), powered for noninferiority testing. The key secondary endpoint was the 1-year proportion of covered struts assessed on optical coherence tomography, powered for noninferiority and subsequent superiority testing. RESULTS A total of 433 participants from 28 Chinese centers were randomized to the Firesorb BRS group (n = 215) or CoCr-EES group (n = 218). Patient-level 1-year in-segment LL was 0.17 +/- 0.27 mm in the Firesorb BRS group and 0.18 +/- 0.37 mm in the CoCr-EES group (difference -0.01 mm; 95% confidence interval [CI]: -0.07 to 0.06; p(noninferiority) < 0.0001) in the intention-to-treat population and was 0.17 +/- 0.27 mm in the Firesorb BRS group and 0.19 +/- 0.37 mm in the CoCr-EES group (difference -0.005 mm; 95% CI: -0.07 to 0.06; p(noninferiority) < 0.0001) in the per-protocol set. The proportion of covered struts was 99.3% in the Firesorb BRS group and 98.8% in the CoCr-EES group (difference 0.8%; 95% CI: -0.5% to 2.1%; p(noninferiority) < 0.0001; p(superiority) = 0.21). One-year clinical outcomes were similar between groups. CONCLUSIONS The thinner strut Firesorb BRS was noninferior to the CoCr-EES for the primary endpoint of 1-year angiographic in-segment LL and the key secondary endpoint of 1-year proportion of covered struts by optical coherence tomography. (C) 2021 by the American College of Cardiology Foundation.

BACKGROUND:Farnesoid X receptor (FXR) is a nuclear receptor that plays a critical role in controlling cell apoptosis in diverse diseases. Previous studies have shown that knocking out FXR improved cardiac function by reducing cardiomyocyte apoptosis in myocardial ischemic mice. However, the role of FXR after cerebral ischemia remains unknown. In this study, we explored the effects and mechanisms of FXR knockout (KO) on the functional recovery of mice post cerebral ischemia-reperfusion.METHODS:Adult male C57BL/6 wild type and FXR KO mice were subjected to 90-min transient middle cerebral artery occlusion (tMCAO). The mice were divided into five groups: sham, wild-type tMCAO, FXR KO tMCAO, wild-type tMCAO treated with calcium agonist Bayk8644, and FXR KO tMCAO treated with Bayk8644. FXR expression was examined using immunohistochemistry and Western blot. Brain infarct and brain atrophy volume were examined at 3 and 14 days after stroke respectively. Neurobehavioral tests were conducted up to 14 days after stroke. The protein levels of apoptotic factors (Bcl-2, Bax, and Cleaved caspase-3) and mRNA levels of pro-inflammatory factors (TNF-α, IL-6, IL-1β, IL-17, and IL-18) were examined using Western blot and RT-PCR. TUNEL staining and calcium imaging were obtained using confocal and two-photon microscopy.RESULTS:The expression of FXR was upregulated after ischemic stroke, which is located in the nucleus of the neurons. FXR KO was found to reduce infarct volume and promote neurobehavioral recovery following tMCAO compared to the vehicle. The expression of apoptotic and pro-inflammatory factors decreased in FXR KO mice compared to the control. The number of NeuN+/TUNEL+ cells declined in the peri-infarct area of FXR KO mice compared to the vehicle. We further demonstrated that inhibition of FXR reduced calcium overload and addition of ionomycin could reverse this neuroprotective effect in vitro. What is more, in vivo results showed that enhancement of intracellular calcium concentrations could aggravate ischemic injury and reverse the neuroprotective effect of FXR KO in mice.CONCLUSIONS:FXR KO can promote neurobehavioral recovery and attenuate ischemic brain injury, inflammatory release, and neuronal apoptosis via reducing calcium influx, suggesting its role as a therapeutic target for stroke treatments.

OBJECTIVES To investigate the association of sarcopenia and its components (muscle mass, muscle strength, and physical performance) with dependency in activities of daily living (ADLs) in maintaining patients on hemodialysis. DESIGN AND METHODS This is a cross-sectional study. Sarcopenia was identified according to the Asian Working Group for Sarcopenia 2019 criteria. Basic ADLs (BADLs) and instrumental ADLs (IADLs) were assessed. Logistic regression was used to estimate the association of sarcopenia and its components with dependency. Area under the receiver-operating characteristic curve of gait speed corresponding with dependency was calculated. RESULTS A total of 238 patients on hemodialysis were included. The proportion of enrolled male candidates was 67.6%, and the average age was 60.9 years. In all, 49.2% (n = 117) and 30.7% (n = 73) of patients on dialysis were diagnosed with sarcopenia and severe sarcopenia, respectively. Dependency in BADLs was 21.0% (n = 50), and dependency in IADLs was 41.2% (n = 98). Severe sarcopenia was significantly associated with dependency in BADLs and IADLs after adjustment of clinical covariables (odds ratio [OR], 4.68 [95% confidence interval (CI): 2.11-10.40]; OR, 3.24 [95% CI: 1.61-6.53], respectively), whereas those effects for sarcopenia were not significant. With all three sarcopenia components in the analysis model, high gait speed remained strongly associated with low function dependency in BADLs and IADLs (per 0.1 m/s increase of gait speed: OR, 0.52 [95% CI: 0.41-0.66]; and 0.46 [95% CI: 0.35-0.59], respectively). Area under the receiver-operating characteristic curve of gait speed corresponding with dependency in BADLs and IADLs was 0.827 (0.759, 0.896) and 0.878 (0.832, 0.925), respectively. CONCLUSIONS Severe sarcopenia was closely related to dependency in ADL in patients on hemodialysis. Gait speed was the most important factor affecting dependency in sarcopenia and had good diagnostic accuracy for screening dependency in ADL.

Background A woven coronary artery is a rare congenital coronary anomaly and incidentally found in coronary angiogram. Coronary angiography is the major diagnostic modality, which shows the main trunk of coronary divides into several channels which later reconnect with normal blood flow (J Int Cardiol 113:121-123 2006). However, some cases and reviews inferred that this characteristic might be mimicked by recanalized coronary thrombus, which occurs following thrombotic occlusion. In some case, the multiple intraluminal channels have a ‘Swiss cheese’, a ‘Spider web-like’, a ‘Honeycomb’ or a ‘Lotus root’ appearance and most of them appear in local segment (Int J Cardiol 186: 239–240, 2015). As these images are nonspecific findings, there is no angiographic uniform definition of intracoronary thrombus. More information about the characteristics and the development of this woven-like structure is needed. Case presentation A 67-year-old male patient was admitted to our hospital because of chest pain. Coronary artery angiogram revealed that the right coronary artery (RCA) divided into multiple thin channels from proximal to distal, which was similar to the so-called woven coronary artery. Compared with his prior coronary angiograms which showed a tiny hazy lesion in distal segment of RCA, we found the woven-like phenomena should be caused by a late-stage recanalized coronary thrombus. Percutaneous coronary intervention (PCI) was performed to restore the RCA flow, and the angina symptom was extremely improved during clinical follow-up. Conclusions The diagnostic criteria of woven coronary artery was based on angiographic image. However, some cases and reviews inferred that thrombotic recanalization might also share the same characteristic. In this case, we collected the baseline angiograms and intracoronary images then successfully diagnosed the woven-like RCA as thrombotic recanalization. For this kind of woven-like coronary artery, PCI could be a better treatment strategy. Detailed history collection and intracoronary image techniques should be emphasized in future clinical practice in the differentiating and treatment of woven-like phenomena.

Fibroblast growth factor 21 (FGF21), a hormone-like protein mainly derived from liver, exhibits multiple beneficial effect on energy metabolism. Similar to FGF21, berberine exerts anti-hyperglycemic and anti-dyslipidemic properties. Previous studies revealed that the beneficial metabolic effect of berberine was attributed to the activation of AMP-activated protein kinase (AMPK). Here we investigated the effect of berberine on FGF21 expression in primary mouse hepatocytes. As expected, berberine induced hepatic FGF21 expression in a dose-dependent and time-dependent manner, along with the increased expression of NUR77, a proved transcription factor of FGF21. Berberine stimulated the phosphorylations of AMPK and acetyl-CoA carboxylase in primary mouse hepatocytes. Adenovirus-mediated overexpression of constitutively active AMPK triggered hepatic FGF21 and NUR77 expressions. The inhibition of AMPK by compound C abolished berberine-stimulated FGF21 and NUR77 expressions. These results suggest that berberine-induced activation of AMPK may contribute to hepatic FGF21 expression via NUR77.

Figure S1. SCD1 promotes migration and invasion of SW116 cells. (A) Quantification results of SCD1 in HCT116 cells transfected with shRNAs for SCD1 (sh1 and sh2) or Caco2 cells ectopically expressing SCD1. (B) Representative Western blot and quantified results of SCD1 in SW116 cells transfected with shRNAs for SCD1 (sh1 and sh2). (C) Transwell assay of SW116 cells after SCD1 knockdown. The scale bar is 100Â Iźm. (D, E) Histograms show the numbers of migrated (D) and invasive (E) SW116 cells. (TIFF 1383Â kb)

Glucose promotes insulin secretion primarily via its metabolism and the production of metabolic coupling factors in beta-cells. The activation of AMP-activated protein kinase (AMPK), an energy sensor, results in a decrease in insulin secretion from beta-cells, but its mechanism remains largely unknown. Berberine, an oral anti-diabetic drug, has been shown to activate AMPK in multiple peripheral tissues. Here, we examined the effects of berberine and AMPK activation on insulin secretion and glucose oxidation in rat islets. Our results showed that berberine inhibited glucose-stimulated insulin secretion from rat islets with AMPK activation. When glucose concentration was elevated to 25 mmol/L, the inhibitory action of berberine on insulin secretion disappeared. Furthermore, berberine significantly decreased oxygen consumption rate (OCR) and ATP production induced by high glucose in rat islets. Although adenovirus-mediated overexpression of constituent-activated AMPK markedly decreased GSIS and OCR in rat islets, the inhibition of AMPK by compound C did not reverse berberine-suppressed OCR. In addition, berberine attenuated glucose-stimulated expression of fatty acid synthase. These results indicate that berberine-mediated deceleration of glucose oxidation is tightly link to the decreased insulin secretion in islets independent of AMPK activation and inhibition of fatty acid synthesis may also contribute to the effect of berberine on insulin secretion.

Background: Diabetic patients have a higher risk factor for colorectal cancer (CRC) metastasis. Stearoyl-CoA desaturase 1 (SCD1), the main enzyme responsible for producing monounsaturated fatty acids(MUFA) from saturated fatty acids, is frequently deregulated in both diabetes and CRC. The function and mechanism of SCD1 in metastasis of CRC and its relevance to glucose remains largely unknown. Methods: SCD1 expression levels were analyzed in human CRC tissues and the Cancer Browser database : (https://genome-cancer.ucsc.edu/). CRC cell lines stably transfected with SCD1 shRNAs or vector were established to investigate the role of SCD1 in modulating migration and invasion of CRC cells. A glucose concentration gradient was set to investigate regulation of SCD1 in CRC relevant to diabetic conditions. Results: The clinical data analysis showed high expression of SCD1 in CRC tissues with a negative correlation with the prognosis of CRC. In vitro experiments revealed that SCD1 increased CRC progression through promoting epithelial-mesenchymal transition (EMT). Lipidomic analysis demonstrated that SCD1 increased MUFA levels and MUFA administration could rescue migration and invasion defect of CRC cells induced by SCD1 knockdown. Furthermore, SCD1-mediated progression of CRC was promoted by carbohydrate response-element binding protein (ChREBP) in response to high glucose. Mechanistically, hyperglycemia-SCD1-MUFA induced CRC cell migration and invasion by regulating PTEN. Conclusions: Our findings show that SCD1 promotes metastasis of CRC cells through MUFA production and suppressing PTEN in response to glucose, which may be a novel mechanism for diabetes-induced CRC metastasis.

Diabetes mellitus (DM) is an important risk factor for erectile dysfunction. Adipose-derived stem cells (ADSCs) are essential for maintaining erectile function but their function is impaired during hyperglycemia. To evaluate the effects of pigment epithelium-derived factor (PEDF)-transfected ADSCs on the restoration of erectile function ADSCs and PEDF-transfected ADSCs were exposed to normal or high glucose levels for 72 h and the effects on cell survival and protein expression were determined. For in vivo studies, rats with streptozocin-induced DM were intravenously injected with ADSCs or PEDF-transfected ADSCs. Two weeks later, the intracavernosal pressure (ICP) and mean arterial pressure (MAP) were measured to assess erectile function, and penile tissues were harvested for further evaluation. PEDF overexpression in ADSCs protected cells against hyperglycemia-induced apoptosis (as determined by a TUNEL assay), increasing the expression of neurotrophic factors and decreasing the expression of inflammatory cytokines and oxidative stress-related proteins (as determined by western blotting and ELISA). In DM rats, transplantation with PEDF-transfected ADSCs effectively restored erectile function, as determined by the ICP/MAP ratio, compared with untreated ADSCs. PEDF overexpression also resulted in higher survival rates and decreased apoptosis of ADSCs. Promotion of neurotrophic factor expression and suppression of inflammatory cytokines and oxidative stress-related proteins were also observed after transplantation of PEDF-transfected ADSCs. Thus, our results demonstrate that transplantation of ADSCs restored erectile function in a rat model of DM, attenuating the negative effects of hyperglycemia. These findings indicate the therapeutic potential of ADSCs for treating erectile dysfunction and the additional benefits of PEDF overexpression.

The present study investigated whether serum levels of soluble vascular endothelial growth factor receptor (sVEGFR)-1, -2 and -3 are related to low coronary collateralization in patients with stable coronary artery disease. Serum levels of sVEGFR-1, -2, -3, VEGF and high-sensitivity C-reactive

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Deficiency in the TGF-β-induced regulatory T (iTreg) cell differentiation is associated with compromised immune homeostasis and plays a key role in many autoimmune diseases. Therapeutic intervention to enhance in situ iTreg differentiation has become a promising treatment modality for autoimmune diseases. Here we describe that the development of autoimmune inflammation in experimental autoimmune encephalomyelitis (EAE) is associated with selective impairment of iTreg differentiation largely due to the increased production of TNF-α. The neutralization of TNF-α markedly increases iTreg differentiation, leading to the amelioration of EAE, whereas the depletion of iTreg cells abolishes the therapeutic effect of an anti-TNF-α antibody. The inhibition of iTreg differentiation by TNF-α is mediated through a signaling cascade involving the induction of TNF receptor II (TNFR2) expression and the activation of Akt. The activated Akt in turn interacts with Smad3, resulting in the inhibition of TGF-β-induced Smad3 phosphorylation and consequently the reduction of p-Smad3 results in the decreased binding to the specific binding site of the foxp3 promoter, and finally foxp3 transcription itself. Interestingly, this regulatory pathway is iTreg cell specific as TNF-α does not activate Akt in naturally occurring regulatory T cells, therefore conferring a selective effect of TNF-α and its antagonism on iTreg cells. The study sheds new light on the critical role and underlying mechanism of TNF-α in the regulation of iTreg differentiation and provides a novel rationale for TNF-α antagonistic therapy for autoimmune diseases.