USP15 inhibits hypoxia-induced IL-6 signaling by deubiquitinating and stabilizing MeCP2.

Methyl-CpG binding protein 2 (MeCP2) is an important X-linked DNA methylation reader and a key heterochromatin organizer. The expression level of MeCP2 is crucial, as indicated by the observation that loss-of-function mutations of MECP2 cause Rett syndrome, whereas an extra copy spanning the MECP2 locus results in MECP2 duplication syndrome, both being progressive neurodevelopmental disorders. Our previous study demonstrated that MeCP2 protein expression is rapidly induced by renal ischemia-reperfusion injury (IRI) and protects the kidney from IRI through transcriptionally repressing the interleukin-6 (IL-6)/signal transducer and activator of transcription 3 signaling pathway. However, the mechanisms underlying the upregulation of MeCP2 have remained elusive. Here, by using two hypoxia cell models, hypoxia and reoxygenation and cobalt chloride stimulation, we confirmed that the removal of lysine 48-linked ubiquitination from MeCP2 prevented its proteasome-dependent degradation under hypoxic conditions. Through unbiased screening based on a deubiquitinating enzymes library, we identified ubiquitin-specific protease 15 (USP15) as a stabilizer of MeCP2. Further studies revealed that USP15 could attenuate hypoxia-induced MeCP2 degradation by cleaving lysine 48-linked ubiquitin chains from MeCP2, primarily targeting its C-terminal domain. Consistently, USP15 inhibited hypoxia-induced signal transducer and activator of transcription 3 activation, resulting in reduced transcription of IL-6 downstream genes. In summary, our study reveals an important role for USP15 in the maintenance of MeCP2 stability and the regulation of IL-6 signaling.

Dyslipidemia, inflammation, calcification, and adiposity in aortic stenosis: a genome-wide study.

AIMS: Although highly heritable, the genetic etiology of calcific aortic stenosis (AS) remains incompletely understood. The aim of this study was to discover novel genetic contributors to AS and to integrate functional, expression, and cross-phenotype data to identify mechanisms of AS. METHODS AND RESULTS: A genome-wide meta-analysis of 11.6 million variants in 10 cohorts involving 653 867 European ancestry participants (13 765 cases) was performed. Seventeen loci were associated with AS at P ≤ 5 × 10-8, of which 15 replicated in an independent cohort of 90 828 participants (7111 cases), including CELSR2-SORT1, NLRP6, and SMC2. A genetic risk score comprised of the index variants was associated with AS [odds ratio (OR) per standard deviation, 1.31; 95% confidence interval (CI), 1.26-1.35; P = 2.7 × 10-51] and aortic valve calcium (OR per standard deviation, 1.22; 95% CI, 1.08-1.37; P = 1.4 × 10-3), after adjustment for known risk factors. A phenome-wide association study indicated multiple associations with coronary artery disease, apolipoprotein B, and triglycerides. Mendelian randomization supported a causal role for apolipoprotein B-containing lipoprotein particles in AS (OR per g/L of apolipoprotein B, 3.85; 95% CI, 2.90-5.12; P = 2.1 × 10-20) and replicated previous findings of causality for lipoprotein(a) (OR per natural logarithm, 1.20; 95% CI, 1.17-1.23; P = 4.8 × 10-73) and body mass index (OR per kg/m2, 1.07; 95% CI, 1.05-1.9; P = 1.9 × 10-12). Colocalization analyses using the GTEx database identified a role for differential expression of the genes LPA, SORT1, ACTR2, NOTCH4, IL6R, and FADS. CONCLUSION: Dyslipidemia, inflammation, calcification, and adiposity play important roles in the etiology of AS, implicating novel treatments and prevention strategies.

Nanomaterials-based photosensitizers and delivery systems for photodynamic cancer therapy.

The increasing cancer morbidity and mortality requires the development of high-efficiency and low-toxicity anticancer approaches. In recent years, photodynamic therapy (PDT) has attracted much attention in cancer therapy due to its non-invasive features and low side effects. Photosensitizer (PS) is one of the key factors of PDT, and its successful delivery largely determines the outcome of PDT. Although a few PS molecules have been approved for clinical use, PDT is still limited by the low stability and poor tumor targeting capacity of PSs. Various nanomaterial systems have shown great potentials in improving PDT, such as metal nanoparticles, graphene-based nanomaterials, liposomes, ROS-sensitive nanocarriers and supramolecular nanomaterials. The small molecular PSs can be loaded in functional nanomaterials to enhance the PS stability and tumor targeted delivery, and some functionalized nanomaterials themselves can be directly used as PSs. Herein, we aim to provide a comprehensive understanding of PDT, and summarize the recent progress of nanomaterials-based PSs and delivery systems in anticancer PDT. In addition, the concerns of nanomaterials-based PDT including low tumor targeting capacity, limited light penetration, hypoxia and nonspecific protein corona formation are discussed. The possible solutions to these concerns are also discussed.

Drug-free and non-crosslinked chitosan scaffolds with efficient antibacterial activity against both Gram-negative and Gram-positive bacteria.

Treatment of oral pathogens is important for both oral and systemic health. The antimicrobial activity of chitosan (CS)-based scaffolds either loading antibiotics or compositing with other agents are well documented. However, the intrinsic antibacterial activity of CS scaffolds alone has never been reported. Herein, we fabricated the non-crosslinked CS scaffold and investigated its antibacterial activity against typical oral pathogens, Gram-negative Porphyromonas gingivalis and Gram-positive Streptococcus mutans. We found both pathogens were completely killed by 1 mg CS scaffolds at 6 h, due largely to the CS-induced time-dependent bacteria clustering. Interestingly, ß-glycerophosphate crosslinked scaffolds showed no antibacterial activity. In conclusion, the bactericidal activity of CS scaffolds alone is reported for the first time. Together with the biodegradability, physical stability, biocompatibility and great antibacterial activity, the non-crosslinked CS scaffolds may have great potentials not only in treating oral diseases but also in wound healing and tissue engineering.

[Establishment and application of mandarin cleft palate speech database].

OBJECTIVE: This research aims to collect speech samples from patients with cleft palate, establish a mandarin-based database of cleft palate speech after sample analysis and classification, and provide a reference for the diagnosis of hypernasal or cleft palate, clinical education, and standard training for professional speech therapists and related research. METHODS: A total of 768 speech samples were collected from patients and volunteers from the Speech Therapy Center, West China Hospital of Stomatology, between May 2016 and March 2018. These samples were edited and categoried before being saved into the cleft lip and palate biologic information database. RESULTS: A mandarin-based database of cleft palate speech was established from 768 subjects, including 456 children (male 227, female 229), 312 adults (male 178, female 134), 369 normal speech voices, 155 low-level hypernasal samples, 102 moderate-level hypernasal samples, 142 high-level hypernasal samples, and 64 512 words, 24 576 phonemes, and 7 680 numbers. CONCLUSIONS: This study first established a mandarin-based database of cleft palate speech, which has enormous value for the education of speech pathology of cleft palate in mandarin and further research.

Understanding the sheet size-antibacterial activity relationship of graphene oxide and the nano-bio interaction-based physical mechanisms.

The antibiotics-independent antimicrobial activity of graphene oxide (GO) is of great importance since antibiotic therapy is facing great challenges from drug resistance. However, the relations of GO size with its antimicrobial activity and how the size regulates the antibacterial mechanisms are still unknown. Herein, we fabricated four GO suspensions with different sizes and demonstrated the parabolic relationship between GO size and its antibacterial activity against the Gram-positive cariogenic bacterium Streptococcus mutans. More interestingly, we found out how GO size regulated the nano-bio interaction-based physical antibacterial mechanisms. Increasing the size reduced the cutting effect but enhanced the cell entrapment effect, and vice versa. In conclusion, GO size affects its edge density and lateral dimension, further regulates its physical antibacterial mechanisms in different orientations and ultimately determines its activity. These findings provide a deep understanding of GO antibacterial property and may guide the design and development of GO for clinical use.

Graphene-based nanomaterials: the promising active agents for antibiotics-independent antibacterial applications.

Graphene-based nanomaterials, such as graphene oxide (GO) and reduced graphene oxide (rGO), have shown great potentials in drug delivery and photodynamic/photothermal therapy due to their featured structure and physicochemical properties. In recent years, their antibacterial potentials have also been exploited. The commonly recognized antibacterial mechanisms include sharp edge-mediated cutting effect, oxidative stress and cell entrapment. This antibacterial activity is very important for human health. As we know, infection with the pathogenic bacteria, especially the drug-resistant ones, is a great threat to human lives. Thus, the development of the antibiotics-independent and drug-free antibacterial agents is of great importance and significance. Graphene-based nanomaterials are a kind of such antibacterial agents. An insight into their properties and antibacterial mechanisms is necessary before they are developed into real products. Herein, we provide a comprehensive understanding of the antibacterial application of graphene-based nanomaterials via summarizing their antibacterial activities against some typical microbial species and discussing their unique mechanisms. In addition, the side-effects and problems in using these nanomaterials are also discussed.

The UV absorption of graphene oxide is size-dependent: possible calibration pitfalls.

Graphene oxide (GO) is often quantified via its UV absorption, typically at around 230 nm. This is convenient but the effect of the size of GO on the accuracy of this method has been ignored so far. The authors report that the molar absorbance of GO is size-dependent. Data are presented on the absorbance of small (hydrodynamic diameter 1 µm), medium sized (1.5 µm), and large (2.2 µm) GO particles at wavelengths of 210, 230 and 250 nm. In general, linear relationship and good regression fits are obtained, but with different slope depending on size even at the same wavelength. This implies that using the UV absorption-based calibration may cause significant errors in GO quantification. Ultimately, this leads to incorrect dosages and faulty conclusions. This may also explain a variety of inconsistent results obtained in previous biological applications of GO. Graphical abstract The size of graphene oxide (GO) determines its UV absorption and the UV absorption-based calibration (GO-s, GO-m and GO-l represent the GO with small, medium and large size).

Functional Nanomaterials and Their Potential Applications in Antibacterial Therapy.

In the past decades, nanomaterials have shown great potential in biomedical fields, especially in drug delivery, imaging and targeted therapy. Recently, the development of novel functional nanomaterials for antibacterial application has attracted much attention. Compared to the traditional direct use of antibiotics, antibacterial nanomaterials either as drug delivery systems or active agents have a higher efficacy and lower side effects. Herein, we will focus on the antibacterial applications of four commonly used nanomaterials, including metal-based nanomaterials, polymeric nanoparticles, graphene oxides or carbon-based nanomaterials and nanogels.