Puerarin-Loaded Electrospun Patches with Anti-Inflammatory and Pro-Collagen Synthesis Properties for Pelvic Floor Reconstruction.

Pelvic organ prolapse (POP) is one of the most common pelvic floor dysfunction disorders worldwide. The weakening of pelvic connective tissues initiated by excessive collagen degradation is a leading cause of POP. However, the patches currently used in the clinic trigger an unfavorable inflammatory response, which often leads to implantation failure and the inability to simultaneously reverse progressive collagen degradation. Therefore, to overcome the present challenges, a new strategy is applied by introducing puerarin (Pue) into poly(l-lactic acid) (PLLA) using electrospinning technology. PLLA improves the mechanical properties of the patch, while Pue offers intrinsic anti-inflammatory and pro-collagen synthesis effects. The results show that Pue is released from PLLA@Pue in a sustained manner for more than 20 days, with a total release rate exceeding 80%. The PLLA@Pue electrospun patches also show good biocompatibility and low cytotoxicity. The excellent anti-inflammatory and pro-collagen synthesis properties of the PLLA@Pue patch are demonstrated both in vitro in H2O2-stimulated mouse fibroblasts and in vivo in rat abdominal wall muscle defects. Therefore, it is believed that this multifunctional electrospun patch integrating anti-inflammatory and pro-collagen synthesis properties can overcome the limitations of traditional patches and has great prospects for efficient pelvic floor reconstruction.

Disruption of RBMS3 suppresses PD-L1 and enhances antitumor immune activities and therapeutic effects of auranofin against triple-negative breast cancer.

Programmed cell death protein-1 (PD-1)/programmed cell death ligand-1 (PD-L1) interaction exerts a vital role in tumor-associated immune evasion. While strategies disrupting PD-1/PD-L1 axis have shown clinical benefits in various cancers, the limited response rate prompts us to investigate the complex mechanisms underlying the molecular regulation of PD-L1. Here, we identify the RNA binding protein RBMS3 as a crucial PD-L1 regulator in triple-negative breast cancer (TNBC). Correlation analysis shows that Rbms3 significantly correlates with immunosuppressive CD274, Rbms1, NT5E and ENTPD1. RBMS3 protein binds to CD274 mRNA specifically in TNBC cells to increase PD-L1 levels. Mechanistically, RBMS3 stabilizes CD274 mRNA by interacting with its 3'UTR, which represents as an intrinsic cancer cell mechanism for driving PL-D1 upregulation in TNBC. RBMS3 depletion not only destabilizes the mRNA stability and protein expression of PD-L1, but also suppresses the migratory abilities of TNBC MDA-MB-231 cells. Importantly, combination of RBMS3 ablation with auranofin (AUF), an FDA-approved thioredoxin reductase inhibitor, facilitates anti-tumor T-cell immunity in vivo and improves AUF-mediated anti-cancer effect. Taken together, our findings reveal RBMS3 as a key post-transcriptional regulator of PD-L1 and how they contribute to immune escape in TNBC, which could lead to novel combinatorial therapeutic strategies to enhance the efficacy of cancer immunotherapy.

P38 MAPK/AKT signalling is involved in IL-33-mediated anti-apoptosis in childhood acute lymphoblastic leukaemia blast cells.

BACKGROUND: Acute lymphoblastic leukaemia (ALL) is often characterized by broad clinical and biological heterogeneity, as well as recurrent genetic aberrations. Despite remarkable improvements in the treatment outcome in paediatric ALL over the past several decades, it remains a leading cause of morbidity and mortality among children. Cytokines have been extensively studied in haematologic diseases; however, the mechanisms by which cytokines contribute to ALL pathogenesis remain poorly understood. METHODS: IL-33 levels were measured by enzyme-linked immunosorbent assay (ELISA). IL1RL1 expression on ALL cell surface was accessed by flow cytometry. Expression of phosphorylated p38 MAPK, p38, pAKT, AKT and GAPDH were quantified by western blot. Cell survival signals were evaluated by apoptosis using flow cytometry. RESULTS: BM samples from ALL patients at diagnosis upregulated their cell surface expression of IL1RL1, and a higher interleukin (IL)-33 level in the serum was observed as compared to the healthy individuals. Moreover, exogenous IL-33 treatment significantly inhibited apoptosis by activating p38 mitogen-activated protein kinase (MAPK) and AKT pathway, while the inhibitor for p38 MAPK, SB203580, counteracted IL-33-induced anti-apoptosis via inactivation of p38 MAPK and AKT. Furthermore, IL-33 negatively regulates cyclin B1 protein level while increasing the expression of CDK1, with SB203580 inhibiting the effect. CONCLUSION: Our study reveals an important role for IL-33/IL1RL1 axis in supporting ALL which may represent a novel treatment for paediatric patients.KEY MESSAGESBoth IL-33 and IL1RL1 levels are upregulated in primary ALL samples.IL-33 increased both p38 MAPK and AKT activation in ALL.IL-33 promotes survival and cell cycle progression of ALL cells via activating p38 MAPK.

miR-9-5p regulates immunometabolic and epigenetic pathways in ß-glucan-trained immunity via IDH3α.

Trained immunity, induced by ß-glucan in monocytes, is mediated by activating metabolic pathways that result in epigenetic rewiring of cellular functional programs; however, molecular mechanisms underlying these changes remain unclear. Here, we report a key immunometabolic and epigenetic pathway mediated by the miR-9-5p-isocitrate dehydrogenase 3α (IDH3α) axis in trained immunity. We found that ß-glucan-trained miR-9-5p-/- monocytes showed decreased IL-1ß, IL-6, and TNF-α production after LPS stimulation. Trained miR-9-5p-/- mice produced decreased levels of proinflammatory cytokines upon rechallenge in vivo and had worse protection against Candida albicans infection. miR-9-5p targeted IDH3α and reduced α-ketoglutarate (α-KG) levels to stabilize HIF-1α, which promoted glycolysis. Accumulating succinate and fumarate via miR-9-5p action integrated immunometabolic circuits to induce histone modifications by inhibiting KDM5 demethylases. ß-Glucan-trained monocytes exhibited low IDH3α levels, and IDH3α overexpression blocked the induction of trained immunity by monocytes. Monocytes with IDH3α variants from autosomal recessive retinitis pigmentosa patients showed a trained immunity phenotype at immunometabolic and epigenetic levels. These findings suggest that miR-9-5p and IDH3α act as critical metabolic and epigenetic switches in trained immunity.

Epidemic situation of the complex seasonality of imported influenza A and B virus transmission in Guangxi ports of China

Background/aim: Analysis of the characteristics of influenza virus in imported cases in Guangxi province of China. Materials and methods: Throat swabs of imported cases with influenza-like symptoms were detected by real-time PCR from July 2016 to December 2019. Results: 1292 laboratory detections of influenza were reported in 3974 influenza-like cases, of which 71.67% (926) were influenza A. The ratio of test positive was 32.82%. The proportion of detections of influenza B was 28.33% (366). A total of 70.51% of the cases mostly came from Vietnam (911). A total of 86.76% (1121) of the cases were imported from Dongxing Port, Nanning Airport, and Pingxiang Port. There was no statistical difference in all age groups. At the same time, 3 of the untyped A-type specimens were sequenced by next- generation sequencing. Among them, the sequences of 2 specimens from Vietnam had high homology with the influenza strain H3N2 in Hong Kong in 2017. The specimen sequence from Thailand is highly homologous to the influenza pandemic strain H1N1 in Brisbane, Australia in 2018. Conclusion: Imported influenza cases in Guangxi have occurred throughout the year, with higher numbers in winter and spring. The cases mostly came from Vietnam with influenza A. Relevant measures should be taken to control the further spread of the virus.

An easy-to-prepare microshotgun for efficient transmembrane delivery by powering nanoparticles.

Biological barriers are the first line of defense against pathogen invasions, but they can also present as critical obstacles to drug delivery. Despite a variety of strategies have been developed recently to overcome them, significant efforts are still needed to achieve safer and more effective drug delivery. Herein, we constructed a metal-free, "slim waist" shaped microshotgun delivery device, which was able to cross the tympanic membrane and round window membrane. The efficient penetration was powered by the gas generating reactions of self-contained chemicals. This device is advantageous in several aspects. First, the device could be prepared using simple procedures, common equipment and affordable materials. Second, the device is deemed biocompatible, revealed by low cytotoxicity, normal blood cell parameters and histological morphology after single/repeated administration. Third, the nanoparticles loaded in the microshotgun were able to actively penetrate the epithelial layer of the membrane after the first acceleration, and can penetrate the endothelial layer of tympanic membrane using external magnetic field as the secondary power to align and accelerate the nanoparticles. In addition, the micro-penetration of membrane induced by microshotgun could recover in a short time as observed in high-resolution scanning electron microscopy. This easy-to-get, efficient and safe micro device provides a new delivery platform for the treatment of diseases in the middle ear and inner ear, and holds potential to overcome the physiologic barrier in the body.

A novel vehicle for local protein delivery to the inner ear: injectable and biodegradable thermosensitive hydrogel loaded with PLGA nanoparticles.

Delivery of biomacromolecular drugs into the inner ear is challenging, mainly because of their inherent instability as well as physiological and anatomical barriers. Therefore, protein-friendly, hydrogel-based delivery systems following local administration are being developed for inner ear therapy. Herein, biodegradable poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) containing interferon α-2 b (IFN α-2 b) were loaded in chitosan/glycerophosphate (CS/GP)-based thermosensitive hydrogel for IFN delivery by intratympanic injection. The injectable hydrogel possessed a physiological pH and formed semi-solid gel at 37 °C, with good swelling and deswelling properties. The CS/GP hydrogel could slowly degrade as visualized by scanning electron microscopy (SEM). The presence of NPs in CS/GP gel largely influenced in vitro drug release. In the guinea pig cochlea, a 1.5- to 3-fold increase in the drug exposure time of NPs-CS/GP was found than those of the solution, NPs and IFN-loaded hydrogel. Most importantly, a prolonged residence time was attained without obvious histological changes in the inner ear. This biodegradable, injectable, and thermosensitive NPs-CS/GP system may allow longer delivery of protein drugs to the inner ear, thus may be a potential novel vehicle for inner ear therapy.

Engineering PLGA nano-based systems through understanding the influence of nanoparticle properties and cell-penetrating peptides for cochlear drug delivery.

The properties of poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) and penetration enhancers play a deciding role in the inner ear drug delivery of NPs across the round window membrane (RWM). Thus, PLGA nano-based systems with a variety of particle sizes and surface chemistries and those combined with cell-penetrating peptides (CPPs) as penetration enhancers were devised to explore their impact on the cochlear drug delivery in vivo. First, we demonstrated that the properties of NPs dictated the extent of NP cochlear entry by near-infrared fluorescence imaging. NPs with the sizes of 150 and 300nm had faster entry than that of 80nm NPs. At 0.5h, among the NPs unmodified and modified with chitosan (CS), poloxamer 407 (P407) and methoxy polyethylene glycol, CS-PLGA-NPs (positive surface charge) carried payload to the cochlea fastest, whereas P407-PLGA-NPs (surface hydrophilicity) showed the greatest distribution in the cochlea at 24h. Compared to other CPPs (TAT, penetratin and poly(arginine)8), low molecular weight protamine (LMWP) performed an outstanding enhanced NP cellular uptake in HEI-OC1 cells and cochlear entry. More importantly, NPs with optimized properties and CPPs may be combined to improve RWM penetration. For the first time, we confirmed that the combination of P407-PLGA-NPs (mean diameter: 100-200nm) and LMWP provided a synergistic enhancement in NP entry to the organ of Corti and stria vascularis without inducing pathological alteration of cochlear tissues and RWM. Taken together, we propose an effective PLGA nano-based strategy for enhanced drug delivery to the inner ear tissues that combines hydrophilic molecule-modified NPs and CPPs, ultimately opening an avenue for superior inner ear therapy.

[Comprehensive chemical pattern recognition of atractylodis rhizoma].

A method of comprehensive chemical pattern recognition of Atractylodis Rhizoma was established by GC-MS fingerprint, principal component analysis, cluster analysis and discriminant analysis. A DB-wax column (0.25 mm x 60 m, 0.25 microm) with El ion source and 70 V electron multiplier were used for GC-MS analysis. Using principal component analysis, cluster analysis, and discriminant analysis, 15 common peaks of sample fingerprints for chemical pattern recognition research were analysed. The same results were obtained from the fingerprint, principal component analysis and cluster analysis, which could use to distinguish genuine Atractylodes lancea, ungenuine A. lancea and A. chinensis. Thus, this method could be used for the quality control and comprehensive evaluation of Atractylodis Rhizoma.

[A clinical study of tension-free inguinal hernioplasty in patients with different ages].

OBJECTIVE: To study the application of mesh and hernia ring for tension-free hernia repair in inguinal hernioplasty in patients with different ages. METHODS: A total of 190 patients with inguinal hernia undergoing tension-free hernia repair were divided into two groups with age above and below 60 years, and the surgical effect and complications were compared. RESULTS: Tension-free hernia repair with mesh and hernia ring was superior to conventional hernia repair in terms of operative time, mean time for exercise and pain in patients above 60 years, but not in patients below 60 years. CONCLUSION: Surgical repair of inguinal hernia should be performed with individualized surgical plans.