Alleviating Recombinant Tissue Plasminogen Activator-induced Hemorrhagic Transformation in Ischemic Stroke via Targeted Delivery of a Ferroptosis Inhibitor.

Intravenous thrombolysis with recombinant tissue plasminogen activator (rtPA) is the primary treatment for ischemic stroke. However, rtPA treatment can substantially increase blood-brain barrier (BBB) permeability and susceptibility to hemorrhagic transformation. Herein, the mechanism underlying the side effects of rtPA treatment is investigated and demonstrated that ferroptosis plays an important role. The ferroptosis inhibitor, liproxstatin-1 (Lip) is proposed to alleviate the side effects. A well-designed macrocyclic carrier, glucose-modified azocalix[4]arene (GluAC4A), is prepared to deliver Lip to the ischemic site. GluAC4A bound tightly to Lip and markedly improved its solubility. Glucose, modified at the upper rim of GluAC4A, imparts BBB targeting to the drug delivery system owing to the presence of glucose transporter 1 on the BBB surface. The responsiveness of GluAC4A to hypoxia due to the presence of azo groups enabled the targeted release of Lip at the ischemic site. GluAC4A successfully improved drug accumulation in the brain, and Lip@GluAC4A significantly reduced ferroptosis, BBB leakage, and neurological deficits induced by rtPA in vivo. These findings deepen the understanding of the side effects of rtPA treatment and provide a novel strategy for their effective mitigation, which is of great significance for the treatment and prognosis of patients with ischemic stroke.

Genomic risk variants at 3q22.3 are associated with keloids in a Chinese Han population.

A keloid is the process of skin healing, collagen synthesis and metabolism of the loss of normal control in a sustained hyperactive state, resulting in excessive proliferation of collagen fibers. A large-scale genome-wide association study (GWAS) has identified multiple single nucleotide polymorphisms (SNPs) in the 3q22.3 loci that are associated with keloids in a Japanese population. However, the associations of SNPs in 3q22.3 with keloids were not confirmed in a selected Chinese population by a replication study. Thus, in the present study, the relationships between keloids and 3q22.3 were assessed in another independent Chinese Han population, including 309 keloid patients and 1080 control subjects. The results displayed that rs940187 was associated with keloids (OR=1.88, 95% CI 1.27-2.78, P=1.35E-3) and remained significant after Bonferroni's correction for multiple testing, while rs1511412 showed only a trend association (OR=2.23, 95% CI 1.09-4.55, P=0.02) with keloids. In addition, we subsequently checked the annotation datasets for rs940187 with eQTLs and obtained two hits, trans-proteins SLC7A9 and LEMD3, with significant P values less than 1e-4. In summary, genomic risk variants at 3q22.3 are associated with keloids in a Chinese Han population and contribute to the development and deterioration of the keloids, together with environmental factors.

Analysis of quality of life and influencing factors in 197 Chinese patients with port-wine stains.

Port-wine stains (PWS) are congenital capillary malformations, usually occurring on the face, neck, and other exposed parts of the skin, that have serious psychological and social impact on the patient. Most researchers focus on the treatment of PWS, but the quality of life (QoL) of PWS patients is seldom researched. The objective of this study is to evaluate the QoL of patients with PWS on exposed parts and explore the factors influencing the QoL of PWS patients. The QoL of 197 cases with PWS on exposed parts were prospectively studied using the Dermatology Life Quality Index questionnaire (DLQI), and the factors influencing the patients' QoL were analyzed by single-factor analysis and multiple-factor logistic regression analysis. The reliability and validity of the QoL of PWS patients were then assessed by DLQI. A total of 197 valid questionnaires were collected. The DLQI scores in PWS cases ranged from 2 to 16, with 2 to 5 in 52.29% (103/197), 6 to 10 in 42.13% (83/197), and 11 to 20 in 5.58% (11/197). The main score elements of the DLQI focused on symptoms and feelings, daily activities, and social entertainment. Single-factor analysis and multiple-factor logistic regression analysis showed that the main influencing factors were female sex, skin hypertrophy, and lesion area >30 cm. The inter-item correlation averaged 47.46% and the Cronbach α was 0.740, indicating high internal consistency. Correlation of the 6 dimensions of the DLQI questionnaires with the total scores showed that the Spearman correlation coefficient r ranged from 0.550 to 0.782 (P < .001), with symptoms and feelings having a correlation coefficient of 0.782 and a high correlation with total scores. This study shows that PWS has mild to moderate influence on the QoL of most patients, mainly on daily activities, social entertainment, and feelings.

NEDD4 single nucleotide polymorphism rs2271289 is associated with keloids in Chinese Han population.

Keloids are abnormally raised fibroproliferative lesions that usually occur following cutaneous traumas. Recently, a large-scale genome-wide association study (GWAS) has identified multiple single nucleotide polymorphisms (SNPs) in three genetic loci that are associated with keloids in Japanese population. Subsequently, two reported loci 1q41 (rs873549 and rs1442440) and 15q21.3 (rs2271289) for keloids were confirmed in selected Chinese population. The association of these SNPs with clinical features of keloids, has not yet been studied. To explore the role of these SNPs in the pathogenesis of keloids, we performed a case-controlled study in another independent Chinese Han population to analyze the correlation between 4 SNPs (rs873549, rs2118610, rs1511412, rs2271289) and keloids phenotypes. 309 keloids patients and 1080 control subjects were included. The results showed that, in the dominant mode of inheritance, the minor allele T of SNP rs2271289 had significantly higher odd ratios (ORs) in the severe keloid group compared with both the controls and the mild keloid group. The ORs were maintained after Bonferroni's correction (OR: 4.09, 95% CI: 1.78-9.37, P-value 3.25E-04). The ratio of the severe: mild OR for rs2271289 (dominant model) is (4.73/1.84=2.57). Similar associations in SNP rs2271289 were seen for groups with no family history and multiplesite compared with the control groups. No associations between keloid number, family history or severity relative to the controls were observed for the other three SNPs. Our data support that rs2271289 is strongly associated with severe keloids and might contribute to the complexity of clinical features of keloids.

Clinical and epidemiological analysis of keloids in Chinese patients.

Keloids are common abnormally raised fibroproliferative lesions that can occur following even minor cutaneous trauma. There are limited data on Chinese patients with keloids, and the purpose of our study was to investigate the clinical and epidemiological features of keloids in Chinese patients. Assessment was performed by unified, designed questionnaires. A total of 715 patients were enrolled and statistical analysis and heritability were performed using EPI INFO 6.0, SPSS13.0 and Falconer's method. Keloids occurred typically between the ages of 10 and 30 years, and the mean age of initial onset was 21.14 ± 13.45 years in females and 22.55 ± 11.36 years in males. The difference in the mean age of onset was not significant between males and females (p > 0.05). A greater severity of keloids was observed in the positive history family group than in the negative history family group, and this difference was statistically significant (χ (2) = 10.889, p < 0.05). The formation of keloids in multiple anatomical sites was found to be significant in the positive family history group. This difference was statistically significant (χ (2) = 15.47, p < 0.001). The prevalence of keloids in first-, second- and third-degree relatives of the proband with keloids was 7.62, 0.38 and 0.035 %, respectively. These results were higher than those in controls and the difference of the prevalence rates of first- and second-degree relatives between probands and controls was significant (χ (2) = 224.63 and 12.078, respectively, p < 0.001). The heritability of keloids in first-, second- and third-degree relatives was 72.45, 40.55 and 17.07 %, respectively. Our findings revealed that the most severe forms of keloids were observed in the probands with positive family history, and the heritability in first-degree relatives of probands was 72.45 %. It is certain, therefore, that genetic factors play a role in the hereditary composition of keloids.

A novel MVK missense mutation in one Chinese family with disseminated superficial actinic porokeratosis.

Disseminated superficial actinic porokeratosis (DSAP) is a severe chronic autosomal dominant cutaneous disorder with high genetic heterogeneity. mevalonate kinase, (MVK) a gene know to play an important role in regulation of calcium-induced keratinocyte differentiation and proliferation, has recently been suggested as the disease-causing gene for DSAP. Here we report a direct sequencing analysis of this gene in 3 DSAP families, 6 sporadic cases, and 100 unrelated healthy controls. We detected a heterozygous T to A transition at nucleotide 205 in exon 3 of MVK gene in one familial case. This mutation will result in an amino acid change at codon 69 (P.Ser69Thr), which is from a serine codon (TCA) to a threonine codon (ACA). No such mutation was detected in the unaffected family members or the 100 unrelated healthy controls. Our results demonstrated a novel missense mutation in MVK gene. This will be valuable for the diagnosis of DSAP as well as for genetic counseling and prenatal diagnosis of affected families.

Detection of a novel missense mutation in the mevalonate kinase gene in one Chinese family with DSAP.

Disseminated superficial actinic porokeratosis (DSAP) is the most common form of porokeratosis and a severe chronic autosomal dominant cutaneous disorder with high genetic heterogeneity. Recently, the mevalonate kinase (MVK) gene has been identified as a candidate gene responsible for DSAP and multiple mutations have been reported. Here, we report identification of a novel missense mutation in the MVK gene in a Chinese family with DSAP. A 50-year-old male was diagnosed as proband of DSAP based on the clinical and histological findings, which show numerous hyperpigmented macules by physical examination and cornoid lamella by skin biopsy. Similar skin symptoms were also observed in his father, who died many years ago. We prepared genomic DNA from the proband, unaffected individuals from his family members, as well as 100 unrelated healthy controls. PCR was then conducted using the above genomic DNA as template and the MVK gene-specific primers. The PCR product was subjected to direct sequencing and the sequence was compared to that of MVK gene within the NCBI database. We detected a heterozygous C to G transition at nucleotide 643 in exon 7 of MVK gene of the proband. This will result in an amino acid change at codon 215 (P.Arg215Gly.), which is from an arginine codon (CGA) to a Glycine codon (GGA). We did not detect any mutation in the unaffected family members or the 100 unrelated healthy controls, demonstrating that this is a novel missense mutation in MVK gene and therefore, contributes to the molecular diagnosis of DSAP.