Platelet-derived microvesicles regulate vascular smooth muscle cell energy metabolism via PRKAA after intimal injury.

Vascular intimal injury initiates various cardiovascular disease processes. Exposure to subendothelial collagen can cause platelet activation, leading to collagen-activated platelet-derived microvesicles (aPMVs) secretion. In addition, vascular smooth muscle cells (VSMCs) exposed to large amounts of aPMVs undergo abnormal energy metabolism; they proliferate excessively and migrate after the loss of endothelium, eventually contributing to neointimal hyperplasia. However, the roles of aPMVs in VSMC energy metabolism are still unknown. Our carotid artery intimal injury model indicated that platelets adhered to injured blood vessels. In vitro, phosphorylated Pka (cAMP-dependent protein kinase) content was increased in aPMVs. We also found that aPMVs significantly reduced VSMC glycolysis and increased oxidative phosphorylation, and promoted VSMC migration and proliferation by upregulating phosphorylated PRKAA (α catalytic subunit of AMP-activated protein kinase) and phosphorylated FoxO1. Compound C, an inhibitor of PRKAA, effectively reversed the enhancement of cellular function and energy metabolism triggered by aPMVs in vitro and neointimal formation in vivo. We show that aPMVs can affect VSMC energy metabolism through the Pka-PRKAA-FoxO1 signaling pathway and this ultimately affects VSMC function, indicating that the shift in VSMC metabolic phenotype by aPMVs can be considered a potential target for the inhibition of hyperplasia. This provides a new perspective for regulating the abnormal activity of VSMCs after injury.

Shikonin potentiates skin wound healing in Sprague-Dawley rats by stimulating fibroblast and endothelial cell proliferation and angiogenesis.

BACKGROUND: Shikonin, a major component of Lithospermum erythrorhizon, exerts anti-inflammatory and antibacterial effects and expedites wound healing. This study aims to evaluate the anti-inflammatory and antioxidant activities of shikonin in a Sprague-Dawley rat model and cell models using fibroblast and endothelial cells. METHODS: The impact of shikonin on the activity of endothelial cells and fibroblasts was examined by cell counting kit 8 and wound-healing assays. A diabetic rat model was constructed, followed by wound creation for treatment with shikonin. Hematoxylin-eosin staining was used to assess pathological changes, and Masson's trichrome method to detect collagen deposition. Immunohistochemistry using antibodies against proliferating cell nuclear antigen and CD31 was conducted to detect proliferation and vascular density. Enzyme-linked immunosorbent assay and immunohistochemistry were carried out to assess pro-inflammatory and anti-inflammatory factor concentrations. Western blot and immunofluorescence were implemented to analyze oxidative stress-related protein expression. RESULTS: Shikonin induced the activity of both fibroblasts and endothelial cells. Shikonin treatment contributed to facilitated wound healing and higher healing rates in rats. It also resulted in faster lesion debulking in tissues, reduced inflammatory infiltration, increased collagen deposition, and enhanced angiogenesis. Detection of markers at the wounds showed that shikonin accelerated cell proliferation, enhanced tissue remodeling, and inhibited oxidative stress. CONCLUSION: Shikonin stimulates the proliferation and migration of fibroblasts and endothelial cells to promote angiogenesis and tissue remodeling, resulting in faster wound healing.

A multicenter, randomized, double-blinded, placebo-controlled, phase â ¢ study evaluating the efficacy and safety of Xeligekimab (GR1501) in patients with moderate-to-severe plaque psoriasis.

BACKGROUND: Xeligekimab is a fully human monoclonal antibody that selectively neutralizes IL-17A and had shown potential efficacy in preliminary trials. OBJECTIVE: To evaluate the efficacy and safety of Xeligekimab in Chinese patients with moderate-to-severe psoriasis. METHODS: A total of 420 Chinese patients were randomized to 200 mg Xeligekimab every 2 weeks (n = 281) or placebo (n = 139) for the first 12 weeks, followed by extending the treatment schedule to GR1501 every 4 weeks for further 40 weeks. Efficacy was assessed by evaluating the Physician's Global Assessment (PGA) 0/1 and Psoriasis Area and Severity Index (PASI) 75/90/100 improvement. The safety profile was also evaluated. RESULTS: At week 12, The PASI 75/90/100 were achieved in 90.7%/74.4%/30.2%% patients in GR1501 group compared with 8.6%/1.4%/0% patients in placebo group, respectively. The PGA 0/1 were achieved in 74.4% patients of GR1501 group and 3.6% patients in placebo group, respectively. The PASI 75 and PGA 0/1 maintained until week 52. No unexpected adverse events were observed. CONCLUSION: Xeligekimab showed high efficacy and is well tolerated in Chinese patients with moderate-to-severe plaque psoriasis.

CdSe/TiO2NTs Heterojunction-Based Nonenzymatic Photoelectrochemical Sensor for Glucose Detection.

Compared with a single semiconductor, the heterojunction formed by two different semiconductors usually has higher light utilization and better photoelectric performance. By using stable TiO2 nanotubes as the main subject, CdSe/TiO2NTs heterojunctions were synthesized by a hydrothermal method. XRD, TEM, SEM, PL, UV-vis, and EIS were used to characterize the fabricated CdSe/TiO2NTs. Under visible light irradiation, CdSe/TiO2NTs heterojunctions exhibited a higher absorption intensity and lower degree of photogenerated carrier recombination than TiO2. The electrons and holes were proven to be effectively separated in this heterojunction via theoretical calculation. Under CdSe/TiO2NTs' optimal conditions, the glucose concentrations (10-90 µM) had a linear relationship with the photocurrent value, and the detection limit was 3.1 µM. Moreover, the CdSe/TiO2NTs sensor exhibited good selectivity and stability. Based on the experimental data and theoretical calculations, its PEC sensing mechanism was also illuminated.

A randomized, double-blind, placebo-controlled phase II study to evaluate the efficacy and safety of ivarmacitinib (SHR0302) in adult patients with moderate-to-severe alopecia areata.

BACKGROUND: Alopecia areata (AA) is a CD8+ T cell-mediated autoimmune disease characterized by nonscarring hair loss. Ivarmacitinib, which is a selective oral Janus kinase 1 inhibitor, may interrupt certain cytokine signaling implicated in the pathogenesis of AA. OBJECTIVE: To evaluate the efficacy and safety of ivarmacitinib in adult patients with AA who have ≥25% scalp hair loss. METHODS: Eligible patients were randomized 1:1:1:1 to receive ivarmacitinib 2, 4, or 8 mg once daily or placebo for 24 weeks. The primary end point was the percentage change from baseline in the Severity of Alopecia Tool score at week 24. RESULTS: A total of 94 patients were randomized. At week 24, the least squares mean difference in the percentage change from baseline in the Severity of Alopecia Tool score for ivarmacitinib 2, 4, and 8 mg and placebo groups were -30.51% (90% CI, -45.25, -15.76), -56.11% (90% CI, -70.28, -41.95), -51.01% (90% CI, -65.20, -36.82), and -19.87% (90% CI, -33.99, -5.75), respectively. Two serious adverse events-follicular lymphoma and COVID-19 pneumonia-were reported. LIMITATIONS: A small sample size limits the generalizability of the results. CONCLUSION: Treatment with ivarmacitinib 4 and 8 mg doses in patients with moderate and severe AA for 24 weeks was efficacious and generally tolerated.

Defective autophagy triggered by arterial cyclic stretch promotes neointimal hyperplasia in vein grafts via the p62/nrf2/slc7a11 signaling pathway.

Autophagy is an adaptation mechanism to keep cellular homeostasis, and its deregulation is implicated in various cardiovascular diseases. After vein grafting, hemodynamic factors play crucial roles in neointimal hyperplasia, but the mechanisms are poorly understood. Here, we investigated the impacts of arterial cyclic stretch on autophagy of venous smooth muscle cells (SMCs) and its role in neointima formation after vein grafting. Rat jugular vein graft were generated via the 'cuff' technique. Autophagic flux in venous SMCs is impaired in 3-day, 1-week and 2-week grafted veins. 10%-1.25 Hz cyclic stretch (arterial stretch) loaded with FX5000 stretch system on venous SMCs blocks cellular autophagic flux in vitro and shows no significant impact on activity of mTORC1 and AMPK. Microtubule depolymerization but not lysosome dysfunction nor autophagosome/amphisome-lysosomal membrane fusion blockade is involved in the impairment of autophagic flux. Microtubule stabilization, induced by paclitaxel treatment and external stents intervention respectively, restores venous SMC autophagy and ameliorates neointimal hyperplasia in vivo. Moreover, autophagy impairment causes accumulation of the cargo receptor p62, which sequesters keap1 to p62 aggregates and results in the stabilization and nuclear translocation of nrf2 to modulate its target antioxidative gene SLC7A11. p62 silencing abrogates the increases of nrf2 and slc7a11 protein expression, glutathione level and venous SMC proliferation triggered by arterial cyclic stretch in vitro, and further hinders nrf2 nuclear translocation, reduces neointimal thickness after vein grafting in vivo. p62 (T349A) mutation also inhibited venous SMC proliferation and alleviated neointimal formation in vivo. These findings suggest that stabilization of microtubules to rescue autophagic flux or direct silencing of p62 are potential therapeutic strategies for neointimal hyperplasia.

[Variation of COL7A1 gene in dystrophic epidermolysis bullosa pruriginosa].

OBJECTIVE: To perform gene mutation analysis in a Chinese pedigree with dystrophic epidermolysis bullosa pruriginosa (DEB-Pr), and explore phetotype, genotype, and genotypes-phenotypes relationship of DEB-Pr. METHODS: Potential variants of the COL7A1 gene were detected by skin targeted sequencing panel and verified by Sanger sequencing. The pathogenicity of the variation was analyzed. RESULTS: Compound heterozygous variants, c.4128delT and c.8234G>A, were detected in the COL7A1 gene of the two patients. The c.4128delT(p.Pro1376fs) variant was derived from their mother and unreported previously. According to the American College of Medical Genetics and Genomics Standards and Guidelines, it was suggested to be a pathogenic mutation. The c.8234G>A(p.Arg2745Gln) variant was derived from their father, and possibly is a pathogenic variation. CONCLUSION: In this study, the compound heterozygous variants of c.4128delT(p.Pro1376fs) and c.8234G>A(p.Arg2745Gln) of the COL7A1 gene probably underlies the disease in this patient and his sister. And our study expands the database on mutations of DEB-Pr.

[Genetic testing and genotype-phenotype analysis for a child with X-linked hypohidrotic ectodermal dysplasia].

OBJECTIVE: To carry out genetic testing for a Chinese patient with X-linked hypohidrotic ectodermal dysplasia (XLHED) and explore its genotype-phenotype correlation. METHODS: Clinical data of the patient was collected. Peripheral blood samples were taken from the patient, his parents and 100 unrelated healthy controls. Genetic variants were detected by using next-generation sequencing using a skin-disease panel through targeted capture and next generation sequencing. Candidate variant was verified by Sanger sequencing. All literature related to genetic testing of XLHED patients in China was searched in the database, and the genotypes and phenotypes of patients in the literature and the correlation between them were statistically analyzed. RESULTS: A novel splice site variant c.655_689del was detected in the patient but not among his parents and the 100 unrelated healthy controls. So far 61 variants of the EDA gene have been identified among Chinese patients with XLHED, which suggested certain degree of genotype-phenotype correlation. CONCLUSION: A novel c.655_689del variant has been identified in the EDA gene, which has expanded the spectrum of EDA gene variant and facilitated delineation of the genotype-phenotype correlation of XLHED.

3D Hydrogen Titanate Nanotubes on Ti Foil: A Carrier for Enzymatic Glucose Biosensor.

Glucose oxidase (GOx) based biosensors are commercialized and marketed for the high selectivity of GOx. Incorporation nanomaterials with GOx can increase the sensitivity performance. In this work, an enzyme glucose biosensor based on nanotubes was fabricated. By using Ti foil as a carrier, hydrogen titanate nanotubes (HTNTs), which present fine 3D structure with vast pores, were fabricated in-situ by the hydrothermal treatment. The multilayer nanotubes are open-ended with a diameter of 10 nm. Then glucose oxidase (GOx) was loaded on the nanotubes by cross-linking to form an electrode of the amperometric glucose biosensor (GOx/HTNTs/Ti electrode). The fabricated GOx/HTNTs/Ti electrode had a linear response to 1-10 mM glucose, and the response time was 1.5 s. The sensitivity of the biosensor was 1.541 µA·mM-1·cm-2, and the detection limit (S/N = 3) was 59 µM. Obtained results indicate that the in-situ fabrication and unique 3D structure of GOx/HTNTs/Ti electrode are beneficial for its sensitivity.

lncRNA TINCR participates in ALA-PDT-induced apoptosis and autophagy in cutaneous squamous cell carcinoma.

This study aims to investigate whether terminal differentiation-induced ncRNA (TINCR) has an effect on apoptosis and autophagy induced by ALA-PDT in cutaneous squamous cell carcinoma (CSCC). A431 cells were treated with 5-aminolevulinic acid (ALA) solution at different concentrations and for different duration time. A431 cell viability was detected by Cell Counting Kit-8 (CCK-8) assay, relative TINCR messenger RNA expression was detected by quantitative reverse-transcription polymerase chain reaction (qRT-PCR). A431 cell apoptosis was examined by flow cytometry. Relative apoptosis/autophagy-related protein expression was analyzed by Western blot analysis. The effect of TINCR on cell autophagy was detected by RFP-LC3 immunofluorescence assay. Reactive oxygen species concentration was detected by 2',7'-dichlorodihydrofluorescein diacetate (DCFH-DA) fluorescent probe. Relative expressions of ERK1/2 and specificity protein 3 (Sp3) in A43 cells were detected by Western blot analysis and qRT-PCR. Sp3 binding sites were analyzed by ChIP-qPCR. The relative transcription activity was measured with luciferase reporter assay. ALA-PDT treatment at 3.2 mmol/L for 120 minutes significantly promoted TINCR expression in CSCC A431 cells, and TINCR promoted ALA-PDT-induced apoptosis and cell autophagy. Furthermore, ALA-PDT promoted TINCR expression through ERK1/2-SP3 pathway. Sp3 promoted TINCR transcription by binding TINCR promoters. Our data indicated that TINCR involves in ALA-PDT-induced apoptosis and autophagy in CSCC.

Facile Preparation of Magnetically Separable Fe3O4/ZnO Nanocomposite with Enhanced Photocatalytic Activity for Degradation of Rhodamine B.

Magnetic separation of photocatalysts holds great promise for water treatment. A magnetic separation method has a positive effect on the recovery of catalysts after degradation. In this paper, an efficient and reusable catalytic system is developed based on coating magnetic Fe3O4 by depositing Fe2+ on the surface of ZnO. The Fe3O4/ZnO nanocomposite exhibits enhanced performance for organic pollutant degradation. The Fe3O4/ZnO system demonstrates a high photocatalytic activity of 100% degradation efficiency in Rhodamine B (RhB) degradation under UV light irradiation for 50 min. The excellent photocatalytic activity is primarily due to the separation of photogenerated electron-hole pairs being facilitated by the strong interaction between Fe3O4 and ZnO. The induction of the magnetic Fe3O4 endows the Fe3O4/ZnO composite with superior magnetic separation capability from water. Experiments with different radical scavengers revealed that the hydroxyl radical (·OH) is the key reactive radical for the effective degradation of RhB. This work innovatively affords a common interfacial dopant deposition strategy for catalytic application in the degradation of organic dye pollutants and catalyst separation from wastewater efficiently.

Case Report: Successful Treatment of Alopecia Universalis With Tofacitinib and Increased Cytokine Levels: Normal Therapeutic Reaction or Danger Signal?

Alopecia universalis (AU) is an autoimmune disorder characterized by non-scarring hair loss in the scalp, eyebrows, beard, and nearly the entire body, negatively affecting patient prognosis. Available treatments are usually unsatisfactory. The autoimmune attacks of hair follicles induced by CD8+ T cells and the collapse of hair follicle immune privilege are believed to be the leading causes of AU. Additionally, interferon (IFN)-γ plays an important role in triggering the collapse of hair follicle immune privilege and impairing hair follicle stem cells. Furthermore, the upregulation of Janus kinase (JAK)3 and phospho-signal transducer and activator of transcription (pSTAT)3/STAT1 in alopecia areata patients suggest that JAK inhibitors can be a potentially promising choice for AU patients for the reason that JAK inhibitors can interfere with JAK-STAT signaling pathways and inhibit IFN-γ. Herein, we report a case of AU successfully treated with tofacitinib. However, this beneficial response in the patient was accompanied by a remarkable increase in peripheral blood cytokine levels during tofacitinib treatment.

Amine-Functionalized Natural Halloysite Nanotubes Supported Metallic (Pd, Au, Ag) Nanoparticles and Their Catalytic Performance for Dehydrogenation of Formic Acid.

In today's age of resource scarcity, the low-cost development and utilization of renewable energy, e.g., hydrogen energy, have attracted much attention in the world. In this work, cheap natural halloysite nanotubes (HNTs) were modified with γ-aminopropyltriethoxysilane (APTES), and the functionalized HNTs were used as to support metal (Pd, Au, Ag) catalysts for dehydrogenation of formic acid (DFA). The supports and fabricated catalysts were characterized with ICP, FT-IR, XRD, XPS and TEM. The functional groups facilitate the anchoring of metal particles to the supports, which brings about the high dispersion of metallic particles in catalysts. The catalysts show high activity against DFA and exhibit selectivity of 100% toward H2 at room temperature or less. The interactions between active centers and supports were investigated by evaluation and comparison of the catalytic performances of Pd/NH2-HNTs, PdAg/NH2-HNTs and PdAu/NH2-HNTs for DFA.

Successful treatment of Netherton syndrome with dupilumab: A case report and review of the literature.

Netherton syndrome (NS) is a rare autosomal recessive genetic disease caused by SPINK5 gene mutation without specific effective therapies available. We report a case of NS confirmed by whole exome sequencing of DNA using peripheral blood, and Sanger sequencing found two new mutations associated with her clinical presentation located at SPINK5 gene c.1220+5G>A from her father and c.1870delA from her mother. The patient was treated with dupilumab (600 mg at week 0, then 300 mg every 2 weeks, s.c.). The clinical manifestation and dermoscopic images of the patient's hair showed remarkable improvement after dupilumab treatment with no adverse effects. We also reviewed previous reports to learn more about the therapeutic effect and adverse reactions of NS treated with dupilumab.

Surface Plasmon-Enhanced Photoelectrochemical Sensor Based on Au Modified TiO2 Nanotubes.

Based on the enhanced charge separation efficiency of the one-dimensional structure and strong surface plasmon resonance (SPR) of gold, a gold modified TiO2 nanotube (Au/TiO2NTs) glucose photoelectrochemical (PEC) sensor was prepared. It could be activated by visible red light (625 nm). Under optimal conditions, the Au/TiO2NTs sensor exhibited a good sensitivity of 170.37 µA·mM-1·cm-2 in the range of 1-90 µM (R2 = 0.9993), and a detection limit of 1.3 µM (S/N = 3). Due to its high selectivity, good anti-interference ability, and long-term stability, the fabricated Au/TiO2NTs sensor provides practical detection of glucose. It is expected to be used in the construction of non-invasive PEC biosensors.

CdS-Modified TiO2 Nanotubes with Heterojunction Structure: A Photoelectrochemical Sensor for Glutathione.

The formation of heterojunction structures can effectively prevent the recombination of photogenerated electron-hole pairs in semiconductors and result in the enhancement of photoelectric properties. Using TiO2 nanotubes (prepared using the hydrothermal-impregnation method) as carriers, CdS-TiO2NTs were fabricated as a photoelectrochemical (PEC) sensor, which can be used under visible light and can exhibit good PEC performance due to the existence of the heterojunction structure. The experimental results show that the prepared CdS-TiO2NTs electrode had a linear response to 2-16 mM glutathione (GSH). The sensor's sensitivity and detection limit (LOD) were 102.9 µA·mM-1 cm-2 and 27.7 µM, respectively. Moreover, the biosensor had good stability, indicating the potential application of this kind of heterojunction PEC biosensor.