Dynamically changing antineutrophil cytoplasmic antibodies in granulomatosis with polyangiitis: A case report.

BACKGROUND: Granulomatosis with polyangiitis (GPA) is one of the most prevalent forms of the antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. GPA is characterized histologically by necrotizing granulomatous inflammation in addition to vasculitis. The diagnosis of GPA depends on clinical presentation, serological evidence of a positive ANCA, and/or histological evidence of necrotizing vasculitis or granulomatous destructive parenchymal inflammation. Cytoplasmic ANCA (c-ANCA) is positive in 65%-75% of GPA patients, accompanied by proteinase 3 (PR3), the main target antigen of c-ANCA, another 5% of GPA patients had negative ANCA. CASE SUMMARY: The patient, a 52-year-old male, presented with unexplained nasal congestion, tinnitus, and hearing loss. After a duration of 4 months experiencing these symptoms, the patient subsequently developed fever and headache. The imaging examination revealed the presence of bilateral auricular mastoiditis and partial paranasal sinusitis, and the ANCA results were negative. The anti-infective therapy proved to be ineffective, but the patient's symptoms and fever were quickly relieved after 1 wk of treatment with methylprednisolone 40 mg once a day. However, after continuous use of methylprednisolone tablets for 3 months, the patient experienced a recurrence of fever accompanied by right-sided migraine, positive c-ANCA and PR3, and increased total protein in cerebrospinal fluid. The patient was diagnosed with GPA. After receiving a treatment regimen of intravenous methylprednisolone 40 mg/d and cyclophosphamide 0.8 g monthly, the patient experienced alleviation of fever and headache. Additionally, the ANCA levels became negative and there has been no recurrence. CONCLUSION: For GPA patients with negative ANCA, there is a potential for early missed diagnosis. The integration of histopathological results and multidisciplinary communication plays a crucial role in facilitating ANCA-negative GPA.

Targeting pro-inflammatory T cells as a novel therapeutic approach to potentially resolve atherosclerosis in humans.

Atherosclerosis (AS), a leading cause of cardio-cerebrovascular disease worldwide, is driven by the accumulation of lipid contents and chronic inflammation. Traditional strategies primarily focus on lipid reduction to control AS progression, leaving residual inflammatory risks for major adverse cardiovascular events (MACEs). While anti-inflammatory therapies targeting innate immunity have reduced MACEs, many patients continue to face significant risks. Another key component in AS progression is adaptive immunity, but its potential role in preventing AS remains unclear. To investigate this, we conducted a retrospective cohort study on tumor patients with AS plaques. We found that anti-programmed cell death protein 1 (PD-1) monoclonal antibody (mAb) significantly reduces AS plaque size. With multi-omics single-cell analyses, we comprehensively characterized AS plaque-specific PD-1+ T cells, which are activated and pro-inflammatory. We demonstrated that anti-PD-1 mAb, when captured by myeloid-expressed Fc gamma receptors (FcγRs), interacts with PD-1 expressed on T cells. This interaction turns the anti-PD-1 mAb into a substitute PD-1 ligand, suppressing T-cell functions in the PD-1 ligands-deficient context of AS plaques. Further, we conducted a prospective cohort study on tumor patients treated with anti-PD-1 mAb with or without Fc-binding capability. Our analysis shows that anti-PD-1 mAb with Fc-binding capability effectively reduces AS plaque size, while anti-PD-1 mAb without Fc-binding capability does not. Our work suggests that T cell-targeting immunotherapy can be an effective strategy to resolve AS in humans.

Efficacy and safety of olmesartan medoxomil­amlodipine besylate tablets (Sevikar®) in older patients with essential hypertension: Subgroup analysis from the Sevikar study.

Essential hypertension is a notable threat for the older (age, ≥65 years) population. However, to the best of our knowledge, a real-world study assessing olmesartan medoxomil-amlodipine besylate (OM-AML) tablets in older Chinese patients with essential hypertension has not been performed. Therefore, the present study aimed to evaluate the efficacy and safety of OM-AML tablets in these patients. A total of 463 older Chinese patients with essential hypertension treated with OM-AML (20/5 mg) tablets (Sevikar®) were analyzed in a prospective, single-arm, multi-center, real-world study. Seated systolic blood pressure (SeSBP) and seated diastolic blood pressure (SeDBP) at baseline, and at week (W)4 and W8 after OM-AML tablet administration were measured. The mean ± standard error change of SeSBP/SeDBP was -10.3±0.8/-4.6±0.5 and -12.5±0.8/-5.6±0.5 mmHg at W4 and W8, respectively. At W4, 74.1 and 26.8% of patients achieved BP target according to the China and American Heart Association (AHA) criteria, while at W8, 78.0 and 38.7% of patients reached these BP targets accordingly. Finally, 76.5 and 80.5% of patients achieved BP response at W4 and W8, respectively. Furthermore, home-measured SeSBP and SeDBP were significantly decreased from W1 to W8 (both P<0.001). Additionally, the satisfaction of both patients and physicians was elevated at W8 compared with at W0 (both P<0.001). The medication possession rate from baseline to W4 and W8 was 95.5 and 92.5%. The most common drug-associated adverse events by system organ classes were nervous system disorder (4.5%), vascular disorder (2.8%), and general disorder and administration site conditions (2.6%), which were generally mild. In conclusion, OM-AML tablets may be considered effective and safe in lowering BP, enabling the achievement of guideline-recommended BP targets in older Chinese patients with essential hypertension.

Enhancing aortic valve drug delivery with PAR2-targeting magnetic nano-cargoes for calcification alleviation.

Calcific aortic valve disease is a prevalent cardiovascular disease with no available drugs capable of effectively preventing its progression. Hence, an efficient drug delivery system could serve as a valuable tool in drug screening and potentially enhance therapeutic efficacy. However, due to the rapid blood flow rate associated with aortic valve stenosis and the lack of specific markers, achieving targeted drug delivery for calcific aortic valve disease has proved to be challenging. Here we find that protease-activated-receptor 2 (PAR2) expression is up-regulated on the plasma membrane of osteogenically differentiated valvular interstitial cells. Accordingly, we develop a magnetic nanocarrier functionalized with PAR2-targeting hexapeptide for dual-active targeting drug delivery. We show that the nanocarriers effectively deliver XCT790-an anti-calcification drug-to the calcified aortic valve under extra magnetic field navigation. We demonstrate that the nano-cargoes consequently inhibit the osteogenic differentiation of valvular interstitial cells, and alleviate aortic valve calcification and stenosis in a high-fat diet-fed low-density lipoprotein receptor-deficient (Ldlr-/-) mouse model. This work combining PAR2- and magnetic-targeting presents an effective targeted drug delivery system for treating calcific aortic valve disease in a murine model, promising future clinical translation.

Efficacy and safety of olmesartan medoxomil-amlodipine besylate tablet in Chinese patients with essential hypertension: A prospective, single-arm, multi-center, real-world study.

There lacks real-world study with a large sample size assessing olmesartan medoxomil-amlodipine besylate (OM-AML) tablet. Therefore, this study aimed to evaluate the efficacy and safety of OM-AML tablet in patients with essential hypertension. Totally, 1341 patients from 36 medical centers with essential hypertension who took OM-AML (20/5 mg) tablet were analyzed in the current prospective, single-arm, multi-center, real-world study (SVK study). Seated systolic blood pressure (SeSBP) and seated diastolic blood pressure (SeDBP) at baseline, week (W)4 and W8 were measured. The mean (±SE) change of SeSBP/SeDBP was -10.8 ± 0.4/-6.6 ± 0.3 mmHg at W4 and -12.7 ± 0.5/-7.6 ± 0.3 mmHg at W8, respectively. At W4, 78.8% and 29.0% patients achieved BP target by China and American Heart Association (AHA) criteria; at W8, 84.7% and 36.5% patients reached blood pressure (BP) target by China and AHA criteria, accordingly. Meanwhile, 80.2% and 86.4% patients achieved BP response at W4 and W8, respectively. Home-measured SeSBP and SeDBP decreased from W1 to W8 (both p < .001). Besides, patients' and physicians' satisfaction were elevated at W8 compared with W0 (both p < .001). The medication possession rate was 94.8% from baseline to W4 and 91.3% from baseline to W8. The most common drug-related adverse events were nervous system disorders (4.6%), vascular disorders (2.6%), and general disorders and administration site conditions (2.3%) by system organ class, which were generally mild and manageable. In conclusion, OM-AML tablet is one of the best antihypertensive agents in patients with essential hypertension.

Dynamics of Endothelial Cell Generation and Turnover in Arteries During Homeostasis and Diseases.

BACKGROUND: Endothelial cell (EC) generation and turnover by self-proliferation contributes to vascular repair and regeneration. The ability to accurately measure the dynamics of EC generation would advance our understanding of cellular mechanisms of vascular homeostasis and diseases. However, it is currently challenging to evaluate the dynamics of EC generation in large vessels such as arteries because of their infrequent proliferation. METHODS: By using dual recombination systems based on Cre-loxP and Dre-rox, we developed a genetic system for temporally seamless recording of EC proliferation in vivo. We combined genetic recording of EC proliferation with single-cell RNA sequencing and gene knockout to uncover cellular and molecular mechanisms underlying EC generation in arteries during homeostasis and disease. RESULTS: Genetic proliferation tracing reveals that ≈3% of aortic ECs undergo proliferation per month in adult mice during homeostasis. The orientation of aortic EC division is generally parallel to blood flow in the aorta, which is regulated by the mechanosensing protein Piezo1. Single-cell RNA sequencing analysis reveals 4 heterogeneous aortic EC subpopulations with distinct proliferative activity. EC cluster 1 exhibits transit-amplifying cell features with preferential proliferative capacity and enriched expression of stem cell markers such as Sca1 and Sox18. EC proliferation increases in hypertension but decreases in type 2 diabetes, coinciding with changes in the extent of EC cluster 1 proliferation. Combined gene knockout and proliferation tracing reveals that Hippo/vascular endothelial growth factor receptor 2 signaling pathways regulate EC proliferation in large vessels. CONCLUSIONS: Genetic proliferation tracing quantitatively delineates the dynamics of EC generation and turnover, as well as EC division orientation, in large vessels during homeostasis and disease. An EC subpopulation in the aorta exhibits more robust cell proliferation during homeostasis and type 2 diabetes, identifying it as a potential therapeutic target for vascular repair and regeneration.

Semisynthesis and in Vitro Anti-cancer Effect of New Magnolol Derivatives on the Cell Proliferation, Apoptosis, Migration, and Invasion of Human Hepatocellular Carcinoma SMMC-7721 Cells.

Four new magnolol derivatives were synthesized and evaluated for their in vitro anti-cancer properties. Among these, compound 3 showed the most potent cytotoxic activity against the SMMC-7721, SUN-449, and HepG2 human hepatocellular carcinoma cell lines, with IC50 values of 3.39, 4.11, and 6.88 µM, respectively. Compound 3 also induced apoptosis of SMMC-7721 cells by down-regulating Bcl-2 and Akt protein levels, up-regulating of Bax protein level, and cleaving caspase-9 and -3. In addition, transwell assays showed that compound 3 significantly suppressed the migration and invasion of SMMC-7721 cells, which was confirmed based on the down-regulation of hypoxia inducible factor-1α (HIF-1α), matrix metalloproteinase-2 and -9 (MMP-2, and MMP-9) protein levels.

Current optimized strategies for stem cell-derived extracellular vesicle/exosomes in cardiac repair.

Ischemic heart diseases remain the leading cause of death globally, and stem cell-based therapy has been investigated as a potential approach for cardiac repair. Due to poor survival and engraftment in the cardiac ischemic milieu post transplantation, the predominant therapeutic effects of stem cells act via paracrine actions, by secreting extracellular vesicles (EVs) and/or other factors. Exosomes are nano-sized EVs of endosomal origin, and now viewed as a major contributor in facilitating myocardial repair and regeneration. However, EV/exosome therapy has major obstacles before entering clinical settings, such as limited production yield, unstable biological activity, poor homing efficiency, and low tissue retention. This review aims to provide an overview of the biogenesis and mechanisms of stem cell-derived EV/exosomes in the process of cardiac repair and discuss the current advancements in different optimized strategies to produce high-yield EV/exosomes with higher bioactivity, or engineer them with improved homing efficiency and therapeutic potency. In particular, we outline recent findings toward preclinical and clinical translation of EV/exosome therapy in ischemic heart diseases, and discuss the potential barriers in regard to clinical translation of EV/exosome therapy.

Reduced Mitochondrial Protein Translation Promotes Cardiomyocyte Proliferation and Heart Regeneration.

BACKGROUND: The importance of mitochondria in normal heart function are well recognized and recent studies have implicated changes in mitochondrial metabolism with some forms of heart disease. Previous studies demonstrated that knockdown of the mitochondrial ribosomal protein S5 (MRPS5) by small interfering RNA (siRNA) inhibits mitochondrial translation and thereby causes a mitonuclear protein imbalance. Therefore, we decided to examine the effects of MRPS5 loss and the role of these processes on cardiomyocyte proliferation. METHODS: We deleted a single allele of MRPS5 in mice and used left anterior descending coronary artery ligation surgery to induce myocardial damage in these animals. We examined cardiomyocyte proliferation and cardiac regeneration both in vivo and in vitro. Doxycycline treatment was used to inhibit protein translation. Heart function in mice was assessed by echocardiography. Quantitative real-time polymerase chain reaction and RNA sequencing were used to assess changes in transcription and chromatin immunoprecipitation (ChIP) and BioChIP were used to assess chromatin effects. Protein levels were assessed by Western blotting and cell proliferation or death by histology and terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assays. Adeno-associated virus was used to overexpress genes. The luciferase reporter assay was used to assess promoter activity. Mitochondrial oxygen consumption rate, ATP levels, and reactive oxygen species were also analyzed. RESULTS: We determined that deletion of a single allele of MRPS5 in mice results in elevated cardiomyocyte proliferation and cardiac regeneration; this observation correlates with improved cardiac function after induction of myocardial infarction. We identified ATF4 (activating transcription factor 4) as a key regulator of the mitochondrial stress response in cardiomyocytes from Mrps5+/- mice; furthermore, ATF4 regulates Knl1 (kinetochore scaffold 1) leading to an increase in cytokinesis during cardiomyocyte proliferation. The increased cardiomyocyte proliferation observed in Mrps5+/- mice was attenuated when one allele of Atf4 was deleted genetically (Mrps5+/-/Atf4+/-), resulting in the loss in the capacity for cardiac regeneration. Either MRPS5 inhibition (or as we also demonstrate, doxycycline treatment) activate a conserved regulatory mechanism that increases the proliferation of human induced pluripotent stem cell-derived cardiomyocytes. CONCLUSIONS: These data highlight a critical role for MRPS5/ATF4 in cardiomyocytes and an exciting new avenue of study for therapies to treat myocardial injury.

Programing Cell Assembly via Ink-Free, Label-Free Magneto-Archimedes Based Strategy.

Tissue engineering raised a high requirement to control cell distribution in defined materials and structures. In "ink"-based bioprintings, such as 3D printing and photolithography, cells were associated with inks for spatial orientation; the conditions suitable for one ink are hard to apply on other inks, which increases the obstacle in their universalization. The Magneto-Archimedes effect based (Mag-Arch) strategy can modulate cell locomotion directly without impelling inks. In a paramagnetic medium, cells were repelled from high magnetic strength zones due to their innate diamagnetism, which is independent of substrate properties. However, Mag-Arch has not been developed into a powerful bioprinting strategy as its precision, complexity, and throughput are limited by magnetic field distribution. By controlling the paramagnetic reagent concentration in the medium and the gaps between magnets, which decide the cell repelling scope of magnets, we created simultaneously more than a hundred micrometer scale identical assemblies into designed patterns (such as alphabets) with single/multiple cell types. Cell patterning models for cell migration and immune cell adhesion studies were conveniently created by Mag-Arch. As a proof of concept, we patterned a tumor/endothelial coculture model within a covered microfluidic channel to mimic epithelial-mesenchymal transition (EMT) under shear stress in a cancer pathological environment, which gave a potential solution to pattern multiple cell types in a confined space without any premodification. Overall, our Mag-Arch patterning presents an alternative strategy for the biofabrication and biohybrid assembly of cells with biomaterials featured in controlled distribution and organization, which can be broadly employed in tissue engineering, regenerative medicine, and cell biology research.

Human antigen R regulates autophagic flux by stabilizing autophagy-associated mRNA in calcific aortic valve disease.

AIMS: The incidence of calcific aortic valve disease (CAVD) has risen over the last decade and is expected to continue rising; however, pharmacological approaches have proven ineffective. In this study, we evaluated the role and underlying mechanisms of human antigen R (HuR)-mediated post-transcriptional regulation in CAVD. METHODS AND RESULTS: We found that HuR was significantly upregulated in human calcified aortic valves and primary aortic valvular interstitial cells (VICs) following osteogenic stimulation. Subsequent functional studies revealed that HuR silencing ameliorated calcification both in vitro and in vivo. For the first time, we demonstrated that HuR directly interacted with the transcript of phosphatidylinositol-5-phosphate 4-kinase, type II, alpha (PIP4K2A), which mediates phosphatidylinositol signalling, facilitates autophagy, and acts as an mRNA stabilizer. HuR positively modulated PIP4K2A expression at the post-transcriptional level and consequently influenced the AKT/mTOR/ATG13 pathway to regulate autophagy and CAVD progression. CONCLUSION: Our study provides new insights into the post-transcriptional regulatory role of HuR in modulating autophagy-positive factors to regulate the pathogenesis of CAVD. Our findings highlight the potential of HuR as an innovative therapeutic target in CAVD treatment.

Diagnostic performance of computational fluid dynamics (CFD)-based fractional flow reserve (FFR) derived from coronary computed tomographic angiography (CCTA) for assessing functional severity of coronary lesions.

Background: Fractional flow reserve (FFR) is the gatekeeper for lesion-specific revascularization decision-making in patients with stable coronary artery disease (CAD). The potential of noninvasive calculation of FFR from coronary computed tomographic angiography (CCTA) to identify ischemia-causing lesions has not been sufficiently assessed. The objective of this study was to evaluate the feasibility and diagnostic accuracy of a novel computational fluid dynamics (CFD)-based technology, termed as AccuFFRct, for the diagnosis of functionally significant lesions from CCTA, using wire-based FFR as a reference standard. Methods: A total of 191 consecutive patients who underwent CCTA and FFR measurement for suspected or known CAD were retrospectively enrolled at 2 medical centers. Three-dimensional anatomic model of coronary tree was extracted from CCTA data, CFD was applied subsequently with a novel strategy for the computation of FFR in a blinded fashion by professionals. Results were compared to invasive FFR, a threshold of ≤0.80 was used to indicate the hemodynamically relevant stenosis. Results: On a per-patient basis, the overall accuracy, sensitivity, specificity of AccuFFRct for detecting ischemia were 91.78% (95% CI: 86.08% to 95.68%), 92.31% (95% CI: 81.46% to 97.86%) and 91.49% (95% CI: 83.92% to 96.25%), respectively; those for per-vessel basis were 91.05% (95% CI: 86.06% to 94.70%), 92.73% (95% CI: 82.41% to 97.98%) and 90.37% (95% CI: 84.10% to 94.77%), respectively. The AccuFFRct and FFR was well correlated on per-patient (r=0.709, P<0.001) and per-vessel basis (r=0.655, P<0.001). The AUC of AccuFFRct determination was 0.935 (95% CI: 0.881 to 0.969) and 0.927 (95% CI: 0.880 to 0.960) on per-patient and per-vessel basis. Conclusions: This novel CFD-based CCTA-derived FFR shows good diagnostic performance for detecting hemodynamic significance of coronary stenoses and may potentially become a new gatekeeper for invasive coronary angiography (ICA).

Lipocalin-2 in neutrophils induces ferroptosis in septic cardiac dysfunction via increasing labile iron pool of cardiomyocytes.

Cardiac dysfunction is a common complication of sepsis with high mortality. The present study was designed to identify the effect of neutrophil-derived lipocalin-2 (LCN2) in septic cardiac dysfunction (SCD) and its potential mechanism. Wild-type (WT) and LCN2-knockout (LCN2 KO) mice were peritoneally injected with lipopolysaccharide (LPS) to induce SCD. The cardiac function was assessed 12 h after LPS injection by echocardiography. Cardiac tissue was harvested for the evaluation of malonaldehyde (MDA) and prostaglandin E synthase 2 (PTGS2) mRNA levels. LPS induced ferroptosis and SCD in mice. LCN2 deficiency attenuated cardiac injury post-LPS administration. In vitro, LCN2 expression in neutrophils increased in response to LPS. Ferroptosis of cardiomyocytes induced by conditioned medium (CM) from LPS-induced neutrophils of WT mice could be attenuated in CM from LPS-induced neutrophils of LCN2 KO mice. Exogenous LCN2 induced H9C2 cell ferroptosis via increasing labile iron pool (LIP). In conclusion, our results showed that LCN2 deficiency prevented heart dysfunction and ferroptosis in SCD mice and suggested that neutrophil-derived LCN2 might be a promising therapeutic target for SCD.

Clinical efficacy of microwave in the treatment of axillary osmidrosis and primary hyperhidrosis.

Axillary osmidrosis (AO) and primary hyperhidrosis (PH) are common diseases, but there are still difficulties in treatment. Microwave therapy may become a new method. In order to evaluate long-time efficacy of patients with AO or PH treated by microwave and to discuss possible mechanism of microwave therapy by combining results of clinical and pathological, the study was carried out. Ten AO or PH patients with moderate or severe level were selected as subjects, and each subject received microwave treatment of bilateral armpits. The follow-up period lasted 2 years, and the changes of perspiration and odor were evaluated in subjective and objective ways. Each subject took skin biopsy in the treatment area before and after treatment or each follow-up. Hematoxylin-eosin and immunohistochemical staining were performed. Both subjective and objective index reflected the significant improvement of AO and PH after treatment (p < 0.05). Dermatology life quality index score decreased by 10.4 ± 4.6 (p < 0.05). The number of apocrine glands decreased significantly after treatment, and most of them changed from secretory phase to quiescent phase. In conclusion, microwave therapy can destroy apocrine sweat glands, reduce number of functional glands, so as to improve symptoms of AO and PH and elevate quality of life, which is safe, effective, and stable.

Transcatheter mitral valve repair in patient with atrial functional mitral regurgitation using novel DragonFly™ device.

We report the first case of transcatheter mitral valve repair with the novel DragonFly™ device, a transcatheter edge-to-edge mitral regurgitation (MR) repair device, in a patient with severe, symptomatic MR due to annular dilation from atrial functional disease (Carpentier type I). The patient had experienced multiple heart failure events and was unsuitable for surgery due to pulmonary dysfunction and obesity.

Diagnostic performance of AccuFFRangio in the functional assessment of coronary stenosis compared with pressure wire-derived fractional flow reserve.

BACKGROUND: Non-invasive fractional flow reserve (FFR) has been increasingly used in the clinical workflow to assist clinical decision-making for percutaneous coronary intervention (PCI). This clinical study evaluates the diagnostic accuracy of coronary stenosis assessed by a non-invasive FFR analysis method (termed AccuFFRangio) based on invasive coronary angiography (ICA). It is a blinded, self-controlled, retrospective, and dual-center clinical investigation study. METHODS: Coronary angiography data and the related information of 320 patients with 320 vessels were collected, and AccuFFRangio was used to assess the FFR for these patients. Compared with the wire-measured FFR values, we evaluated AccuFFRangio performance by its accuracy, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). RESULTS: The diagnostic accuracy, sensitivity, specificity, PPV, and NPV for AccuFFRangio in identifying hemodynamically significant coronary stenosis were 93.3%, 92.6%, 93.5%, 84.3%, and 97.1%, respectively. The direct correlation between computed AccuFFRangio and measured FFR was 0.812 (P<0.001), and the area under the receiver operating characteristic curve (AUC) value of AccuFFRangio was 0.96. CONCLUSIONS: This clinical study demonstrates the efficiency and accuracy of AccuFFRangio for clinical implementation when using invasive wire-measured FFR as a reference. Further validation is required in a large prospective multicenter study.

Long noncoding RNA LUCAT1 enhances the survival and therapeutic effects of mesenchymal stromal cells post-myocardial infarction.

Mesenchymal stromal cell (MSC) transplantation has been a promising therapeutic strategy for repairing heart tissues post-myocardial infarction (MI). Nevertheless, its therapeutic efficacy remains low, which is mainly ascribed to the low viability of transplanted MSCs. Recently, long noncoding RNAs (lncRNAs) have been reported to participate in diverse physiological and pathological processes, but little is known about their role in MSC survival. Using unbiased transcriptome profiling of hypoxia-preconditioned MSCs (HP-MSCs) and normoxic MSCs (N-MSCs), we identified a lncRNA named lung cancer-associated transcript 1 (LUCAT1) under hypoxia. LUCAT1 knockdown reduced the survival of engrafted MSCs and decreased the MSC-based therapeutic potency, as shown by impaired cardiac function, reduced cardiomyocyte survival, and increased fibrosis post-MI. Conversely, LUCAT1 overexpression had the opposite results. Mechanistically, LUCAT1 bound with and recruited jumonji domain-containing 6 (JMJD6) to the promoter of forkhead box Q1 (FOXQ1), which demethylated FOXQ1 at H4R3me2(s) and H3R2me2(a), thus downregulating Bax expression and upregulating Bcl-2 expression to attenuate MSC apoptosis. Therefore, our findings revealed the protective effects of LUCAT1 on MSC apoptosis and demonstrated that the LUCAT1-mediated JMJD6-FOXQ1 pathway might represent a novel target to potentiate the therapeutic effect of MSC-based therapy for ischemic cardiovascular diseases.

Hair Growth-Promoting Effect of Resveratrol in Mice, Human Hair Follicles and Dermal Papilla Cells.

BACKGROUND: Oxidative damage has been found in various types of hair loss. As a polyphenolic phytoalexin, resveratrol (RSV) is known as an antioxidant, anti-inflammatory and anti-apoptotic agent. OBJECTIVE: Thus, we aim to examine the effects of RSV on hair growth. METHODS: In vivo C57BL/6 mice were used to evaluate the effects of RSV on hair cycle, hair length, skin thickness, hair follicle diameter, hair cycle score and the percentage of hair cycle stage. Then hair shaft length and hair cycle were evaluated by human hair follicles (HFs) ex vivo. The proliferative activities of human dermal papilla cells (hDPCs) cultured in vitro with RSV were assessed using RTCA. The ability of RSV to protect hDPCs against H2O2-induced oxidative damage is examined by a ROS assay kit. RESULTS: Topical application of RSV significantly promoted hair growth and stimulated the transition of hair cycle from telogen into the anagen phase on shaved C57BL/6 mice. Ex vivo experiments showed that RSV increased the hair shaft length of HFs and delayed the entry into catagen. In vitro experiments indicated that RSV proliferated hDPCs and prevented hDPCs from oxidative damage caused by H2O2. CONCLUSION: RSV can promote hair growth and may be a potential candidate for the treatment of hair loss.

Fractional flow reserve for coronary stenosis assessment derived from fusion of intravascular ultrasound and X-ray angiography.

BACKGROUND: Intravascular ultrasound (IVUS) provides good insight into lumen boundary and plaques; however, it is still difficult to detect functionally significant stenosis from IVUS images for the guidance of coronary percutaneous intervention (PCI). This study aimed to develop a novel method to estimate fractional flow reserve (FFR) value for determining the functional significance of coronary artery disease through the fusion of IVUS and X-ray angiographic images. METHODS: We developed a novel approach to 3D vessel reconstruction by integrating IVUS with X-ray angiographic images. Based on the reconstructed geometry and the inlet flow derived from the thrombolysis in myocardial infarction (TIMI) frame count, a simplified fluid dynamics equation was established to compute the pressure drop and IVUS-derived FFR (AccuFFRivus) was subsequently obtained. To validate the feasibility and performance of this IVUS-based FFR method, we performed AccuFFRivus calculations on 32 coronary vessels with invasive FFR as the reference standard. RESULTS: Great correlation (r=0.86, P<0.001) was observed between AccuFFRivus and FFR. The area under the receiver-operating characteristic curve (AUC) was higher for AccuFFRivus than minimal lumen area (MLA, <4 mm2) and diameter stenosis rate (DS% ≥50%) [0.98 (95% CI: 0.86 to 1.0) vs. 0.78 (95% CI: 0.60 to 0.91) and 0.66 (95% CI: 0.47 to 0.82)]. Bland-Altman plot showed a mean difference value of -0.011 (limits of agreement: -0.156 to 0.134). CONCLUSIONS: AccuFFRivus is a novel method for hybridizing IVUS and X-ray angiographic images to identify functionally significant stenosis with FFR ≤0.80. The good diagnostic performance from the initial validation study demonstrates the potential for clinical utilization of physiologically guided decision-making. Further validation is required in future studies with a large number of cases.