FSTL1-USP10-Notch1 Signaling Axis Protects Against Cardiac Dysfunction Through Inhibition of Myocardial Fibrosis in Diabetic Mice.

The incidence of type 2 diabetes mellitus (T2DM) has been increasing globally, and T2DM patients are at an increased risk of major cardiac events such as myocardial infarction (MI). Nevertheless, the molecular mechanisms underlying MI injury in T2DM remain elusive. Ubiquitin-specific protease 10 (USP10) functions as a NICD1 (Notch1 receptor) deubiquitinase that fine-tunes the essential myocardial fibrosis regulator Notch signaling. Follistatin-like protein 1 (FSTL1) is a cardiokine with proven benefits in multiple pathological processes including cardiac fibrosis and insulin resistance. This study was designed to examine the roles of FSTL1/USP10/Notch1 signaling in MI-induced cardiac dysfunction in T2DM. High-fat-diet-treated, 8-week-old C57BL/6J mice and db/db T2DM mice were used. Intracardiac delivery of AAV9-FSTL1 was performed in T2DM mice following MI surgery with or without intraperitoneal injection of crenigacestat (LY3039478) and spautin-1. Our results demonstrated that FSTL1 improved cardiac function following MI under T2DM by reducing serum lactate dehydrogenase (LDH) and myocardial apoptosis as well as cardiac fibrosis. Further in vivo studies revealed that the protective role of FSTL1 against MI injury in T2DM was mediated by the activation of USP10/Notch1. FSTL1 protected cardiac fibroblasts (CFs) against DM-MI-induced cardiofibroblasts injury by suppressing the levels of fibrosis markers, and reducing LDH and MDA concentrations in a USP10/Notch1-dependent manner. In conclusion, FSTL1 treatment ameliorated cardiac dysfunction in MI with co-existent T2DM, possibly through inhibition of myocardial fibrosis and apoptosis by upregulating USP10/Notch1 signaling. This finding suggests the clinical relevance and therapeutic potential of FSTL1 in T2DM-associated MI and other cardiovascular diseases.

Vitiligo Skin Biomarkers Associated With Favorable Therapeutic Response.

Vitiligo is an acquired depigmentation skin disease caused by immune-mediated death of melanocytes. The most common treatment for vitiligo is narrow band ultraviolet B phototherapy, which often is combined with topical therapies such as tacrolimus. However, patients' responses to these treatments show large variations. To date, the mechanism for this heterogeneity is unknown, and there are no molecular indicators that can predict an individual patient's response to therapy. The goal of this study is to identify clinical parameters and gene expression biomarkers associated with vitiligo response to therapy. Six patients with segmental vitiligo and 30 patients with non-segmental vitiligo underwent transcriptome sequencing of lesional and nonlesional skin at baseline before receiving combined UBUVB and tacrolimus therapy for 6 month, and were separated into good response and bad response groups based on target lesion achieving > 10% repigmentation or not. Our study revealed that treatment-responsive vitiligo lesions had significantly shorter disease duration compared with non-responsive vitiligo lesions (2.5 years vs 11.5 years, p=0.046, t-Test), while showing no significant differences in the age, gender, ethnicity, vitiligo subtype, or disease severity. Transcriptomic analyses identified a panel of 68 genes separating the good response from bad response lesions including upregulation of immune active genes, such as CXCL10, FCRL3, and TCR, Further, compared with vitiligo lesions with long disease duration, the lesions with short duration also have much higher level of expression of immune-active genes, including some (such as FCRL3 and TCR genes) that are associated with favorable therapeutic response. In conclusion, our study has identified clinical parameters such as short disease duration and a panel of immune active and other gene expression biomarkers that are associated with favorable response to immune suppressive NBUVB + tacrolimus therapy. These markers may be useful clinically for individualized therapeutic management of vitiligo patients in the future.

Predictors of cardiac involvement and survival in patients with primary systemic light-chain amyloidosis: roles of the clinical, chemical, and 3-D speckle tracking echocardiography parameters.

BACKGROUND: Light-chain (AL) amyloidosis is the most common type of systemic amyloidosis with poor prognosis. Currently, the predictors of cardiac involvement and prognostic staging systems are primarily based on conventional echocardiography and serological biomarkers. We used three-dimensional speckle tracking echocardiography (STE-3D) measurements of strain, hypothesizing that it could detect cardiac involvement and aid in prediction of mortality. METHODS: We retrospectively analysed 74 consecutive patients with biopsy-proven AL amyloidosis. Among them, 42 showed possible cardiac involvement and 32 without cardiac involvement. LV global longitudinal strain (GLS), global radial strain, global circumferential strain and global area strain (GAS) measurements were obtained. RESULTS: The GLS and GAS were considered significant predictors of cardiac involvement. The cut-off values discriminating cardiac involvement were 16.10% for GLS, 32.95% for GAS. During the median follow-up of 12.5 months (interquartile range 4-25 months), 20 (27%) patients died. For the Cox proportional model survival analysis, heart rate, cardiac troponin T, NT-proBNP levels, E/e', GLS, and GAS were univariate predictors of death. Multivariate Cox model showed that GLS ≤ 14.78% and cardiac troponin T ≥ 0.049 mg/l levels were independent predictors of survival. CONCLUSIONS: STE-3D measurements of LV myocardial mechanics could detect cardiac involvement in patients with AL amyloidosis; GLS and cardiac biomarkers can provided prognostic information for mortality prediction.

A Peptide-Functionalized Magnetic Nanoplatform-Loaded Melatonin for Targeted Amelioration of Fibrosis in Pressure Overload-Induced Cardiac Hypertrophy.

INTRODUCTION: Currently, the unsatisfactory treatment of cardiac hypertrophy is due to the unbridled myocardial fibrosis. Melatonin has been demonstrated to ameliorate cardiac hypertrophy and its accompanied fibrosis in previous studies. But it is not clinically appealing due to its short-lasting time against the hostile microenvironment when administered orally. METHODS: Herein, to address this, poly (lactide) polycarboxybetaine (PLGA-COOH) accompanied by cardiac homing peptide (CHP) and superparamagnetic iron oxide nanoparticles (SPIONs) were used to establish a novel drug delivery and transportation strategy for melatonin via a facile two-step emulsion method. This study characterized these nanoparticles (CHP-mel@SPIONs) and tested their delivery to the hypertrophied heart and their effect on myocardial hypertrophy and fibrosis in an animal model of pressure overload-induced cardiac hypertrophy. RESULTS: The engineered magnetic nanoparticles of CHP-mel@SPIONs were spherical (diameter = 221 ± 13 nm) and had a negative zeta potential of -19.18 ± 3.27 mV. The CHP-mel@SPIONs displayed excellent drug encapsulation capacities of SPIONs (75.27 ± 3.1%) and melatonin (77.69 ± 6.04%) separately, and their magnetic properties were characterized by constructing magnetic hysteresis curves and exhibited no remnant magnetization or coercivity. The animal experiments showed that compared with mel@SPIONs, CHP-mel@SPIONs accumulated more in the heart, especially in the presence of an external magnetic field, with in vivo echocardiography and RT-PCR and histological assessments confirming the amelioration of the myocardial hypertrophy and fibrosis with low drug doses. CONCLUSION: This simple biocompatible dual-targeting nanoagent may be a potential candidate for the guided clinical therapy of heart disease.

Novel phenotype-genotype correlations of hypertrophic cardiomyopathy caused by mutation in α-actin and myosin-binding protein genes in three unrelated Chinese families.

BACKGROUND: The correlations between genotype and phenotype in hypertrophic cardiomyopathy (HCM) have not been established. Mutation of α-actin gene (ACTC1) is a rare cause of HCM. This study aimed to explore novel genotype-phenotype correlations in HCM patients with the variants in ACTC1 and myosin-binding protein (MYBPC3) genes in three unrelated Chinese families. METHODS: Clinical, electrocardiographic, and echocardiographic examinations were performed in three Han pedigrees. Exon and boarding intron analysis of 96 cardio-disease-related genes was performed using second-generation sequencing on three probands. The candidate variants were validated in 14 available family members and 300 unrelated healthy controls by bi-directional Sanger sequencing. The pathogenicity and conservation were calculated using MutationTaster, PolyPhen-2, SIFT, and Clustal X. Pathogenicity classification of the variants was based on American College of Medical Genetics and Genomics (ACMG) guidelines. RESULTS: Nine members fulfilled diagnostic criteria for HCM with clinical characteristics, electrocardiographic, and echocardiographic findings. Two candidate variants in ACTC1 p.Asp26Asn (ACTC1-D26N) and MYBPC3 p.Arg215Cys (MYBPC3-R215C) were identified in patients. Only ACTC1-D26N strongly co-segregated with the HCM phenotype. Seven patients who harbored variant ACTC-D26N only were diagnosed with non-obstructive HCM, and four of these patients exhibited a triphasic left ventricular (LV) filling pattern. Two patients carrying both ACTC1-D26N and MYBPC3-R215C variants showed a higher LV outflow tract pressure gradient. Bioinformatics analysis revealed that the two variants were deleterious and highly conserved across species. According to ACMG guidelines, ACTC1-D26N is classified as a likely pathogenic mutation. The second variation MYBPC3-R215C may function as a genetic modifier, which remains uncertain here. CONCLUSIONS: Novel p.(Asp26Asn) mutation of ACTC1 was associated with HCM phenotype, and the penetrance is extremely high (∼81.8%) in adults. The second variation, MYBPC3-R215C may function as a genetic modifier, which remains uncertain here.

[Analysis of genotype-phenotype correlation for a novel MYH7-D554Y mutation identified in an ethnic Han Chinese pedigree affected with hypertrophic cardiomyopathy].

OBJECTIVE: To explore the genotype-phenotype correlation of a MYH7-D554Y mutation identified in an ethnic Han Chinese pedigree affected with hypertrophic cardiomyopathy. METHODS: Ninety six cardiovascular disease-related genes were detected in the proband by exonic amplification and high-throughput sequencing. Suspected mutations were verified by Sanger sequencing among 300 healthy controls as well as family members of the proband. The pathogenicity and conservation of the detected mutations were analyzed with ClustalX, MutationTaster, PolyPhen-2, Provean and SIFT software. RESULTS: Four of the 5 first-degree relatives of the proband were diagnosed with hypertrophic cardiomyopathy. The proband has featured extremely hypertrophic left ventricular wall with a maximal thickness of 35 mm. Genetic testing showed that four of them have carried a heterozygous c.1660G>T (p.Asp554Tyr) mutation of the MYH7 gene, who the remaining one was phenotypically normal and did not carry the mutation. The mutation has not been recorded by the Human Gene Mutation Database (HGMD) and other databases. Bioinformatics analysis suggested that the mutation site is highly conserved and that the mutation is pathogenic. CONCLUSION: The p.Asp554Tyr mutation of the MYH7 gene probably underlies the hypertrophic cardiomyopathy in this pedigree.

Efficacy and safety of fractional Q-switched 1064-nm neodymium-doped yttrium aluminum garnet laser in the treatment of melasma in Chinese patients.

Melasma is an acquired disorder of symmetrical hyperpigmentation commonly seen in patients with Fitzpatrick skin types III and IV. Various novel therapeutic modalities have emerged to treat melasma. The large-spot low-fluence QS Nd:YAG laser has been widely used in Asia; however, the modality needs to be optimized because of the high recurrence rate. The objective of this study is to explore the clinical efficacy and safety of fractional-mode (Pixel) Q-switched neodymium-doped yttrium aluminum garnet (Nd:YAG) 1064-nm laser for treatment of melasma in Chinese patients. Twenty-seven patients were enrolled and completed all the treatment sessions and the 12-week follow-up. All were treated using the fractional-mode Pixel QS Nd:YAG (1064 nm) laser for eight sessions at a 2-3-week interval. Clinical photographs were taken using the Visia skin analysis imaging system. Two blinded assessors evaluated melasma area and severity index (MASI) scores before and 4 weeks after the final session. Melanin index (MI) and erythema index (EI) was measured before each treatment visit and after the final treatment. The degree of pigmentation and erythema was assessed using a tristimulus color analyzer. Physicians' global assessment (PGA) and patients' self-assessment were taken as the subjective assessments. Wilcoxon signed-rank test was performed to evaluate clinical response. Recurrence rate were also evaluated. Mean MASI scores decreased from 12.84 ± 6.89 to 7.29 ± 4.15 after treatment (p = 0.000). Seventy percent of patients got moderate to good improvements after all the treatment. Mean MI decreased significantly from 56.52 ± 23.35 to 32.75 ± 12.91 (p = 0.000). L value increased from 59.21 ± 2.22 before treatment to 61.60 ± 2.40 (p = 0.000) after therapy. The mean score of PGA was 3.76 ± 0.71, indicating a "moderate" clearance of the lesion. In patients' self-evaluations, 70 % of the patients rated the result as "good" to "remarkable." Partial recurrence was seen in 40 % patients at the 3-month follow-up. No severe adverse events were observed during the study, and the treatment was well tolerated. The fractional mode (Pixel) QS Nd:YAG 1064-nm laser is an effective and safe treatment for melasma. The recurrence rate was relatively lower than that reported in studies treating with large-spot low-fluence QS Nd:YAG laser.

Efficacy and safety of 1550-nm fractional laser in the treatment of acne scars in Chinese patients: A split-face comparative study.

OBJECTIVE: To evaluate the efficacy and side effects of 1550-nm fractional Er:Glass laser in treating atrophic acne scar. MATERIALS AND METHODS: Thirty Chinese patients aged 18-65 with atrophic acne scars on both cheeks received a split-face treatment, one side with four sessions of treatment with fractional 1550-nm Er:Glass laser at 20-day interval and the other with topical asiaticoside cream application three times daily as control. Clinical response and side effects were evaluated by a dermatologist three weeks after each treatment and again 12 weeks after the last laser treatment. In addition, self-evaluation of satisfaction by the patients was done at the end of treatment. RESULTS: The study found that mean scores decrease after treatment was 5.65 ± 4.34 for the treated side and 1.23 ± 3.41 for the control side. The improvement in acne scars after the fractional Er:Glass laser 1550-nm treatment was more significant than the control side (p = 0.0001). The side effects were mainly local skin irritation and erythema, which disappeared within one week. CONCLUSION: The research results show that the fractional 1550-nm Er:Glass laser is an effective and safe treatment device for atrophic acne scars.