SENP1 regulates intermittent hypoxia-induced microglia mediated inflammation and cognitive dysfunction via wnt/ß-catenin pathway.

Obstructive sleep apnea syndrome (OSAS), characterized by repeated narrow or collapse of the upper airway during sleep, resulting in periodic reductions or cessations in ventilation, consequent hypoxia, hypercapnia, increased sympathetic activity and sleep fragmentation, places a serious burden on society and health care. Intermittent hypoxia (IH), which cause central nervous system (CNS) inflammation, and ultimately lead to neuropathy, is thought to be a crucial contributor to cognitive impairment in OSAS. Wnt signaling pathway exerts an important role in the regulation of CNS disorders. Particularly, it may be involved in the regulation of neuroinflammation and cognitive dysfunction. However, its underlying mechanism remains poorly understood. Accumulating evidence demonstrated that Wnt signaling pathway may inhibited in a variety of neurological disorders. Recently studies revealed that SUMOylation was participated in the regulation of neuroinflammation. Members of Wnt/ß-catenin pathway may be targets of SUMOylation. In vitro and in vivo molecular biology experiments explored the regulatory mechanism of SUMOylation on Wnt/ß-catenin in IH-induced neuroinflammation and neuronal injury, which demonstrated that IH induced the SUMOylation of ß-catenin, microglia mediated inflammation and neuronal damage. Moreover, SENP1 regulated the de-SUMOylation of ß-catenin, triggered Wnt/ß-catenin pathway, and alleviated neuroinflammation and neuronal injury, thus improving IH-related mice cognitive dysfunction.

Sleep disordered breathing and neurobehavioral deficits in children and adolescents: a systematic review and meta-analysis.

BACKGROUND: Sleep disordered breathing (SDB) is broadly recognized to be associated with neurobehavioral deficits, which have significant impacts on developing-aged children and adolescents. Therefore, our study aimed to quantify the proportion of neurobehavioral impairments attributed to SDB in general children and adolescents by population attributable fraction (PAF). METHODS: The study was registered at PROSPERO (ID: CRD42023388143). We collected two types of literature on the prevalence of SDB and the risk of SDB-related neurobehavioral deficits from ten electronic databases and registers, respectively. The pooled effect sizes (Pe, Pc, RR) by random-effects meta-analysis were separately substituted into Levin's formula and Miettinen's formula to calculate PAFs. RESULTS: Three prevalence literature and 2 risk literature, all with moderate/high quality, were included in the quantitative analysis individually. The prevalence of SDB was 11% (95%CI 2%-20%) in children and adolescents (Pe), while the SDB prevalence was 25% (95%CI 7%-42%) in neurobehavioral patients (Pc). SDB diagnosis at baseline was probably associated with about threefold subsequent incidence of neurobehavioral deficits (pooled RR 3.24, 95%CI 1.25-8.41), after multi-adjustment for key confounders. Up to 19.8% or 17.3% of neurobehavioral consequences may be attributed to SDB from Levin's formula and Miettinen's formula, respectively. CONCLUSIONS: A certain number of neurobehavioral consequences may be attributable to SDB. It is essential for clinicians to identify and treat SDB timely, as well as screen for SDB in patients with neurobehavioral impairments. More longitudinal studies of SDB and neurobehavioral deficits are needed in the future to further certify the association between them.

How is Obstructive Sleep Apnea Associated with High Blood Pressure and Diabetes Mellitus Type 2? Clues from a Two-Step Mendelian Randomized Study.

Background: Obstructive sleep apnea (OSA), high blood pressure (HBP), and type 2 diabetes mellitus (T2DM) have a close clinical relationship, but whether and how OSA affects HBP and T2DM is unclear. Study Design and Methods: Two-step, two-sample Mendelian randomization techniques were applied using single-nucleotide polymorphisms as genetic instruments for exposure and mediators, thus minimizing bias due to confounding factors and reverse causality. The total effect of OSA on HBP and T2DM was categorized into direct and mediating effects based on the mediating factors. Results: Two-sample MR analysis showed that OSA increased the risk of HBP (odds ratio [OR] = 1.010, 95% confidence interval [CI], 1.002-1.018; P = 0.0121) and T2DM (OR = 1.140, 95% CI, 1.059-1.228; P = 0.0005). In the process of OSA caused by HBP, sex hormone-binding globulin (SHBG) (female, 4.47% mediation; male, 2.76% mediation), total testosterone (TT) (male, 3.72% mediation), bioavailable testosterone (BioT) (female, 7.74% mediation), high-density lipoprotein cholesterol (HDL-C) (3.25% mediation), and apolipoprotein A1 (ApoA1) (1.31% mediation) were individual contributors. SHBG (female, 4.10% mediation; male, 1.58% mediation), TT (male, 3.69% mediation), BioT (female, 2.58% mediation), HDL-C (3.32% mediation), ApoA1 (2.14% mediation), and omega-6 fatty acids (2.33% mediation) may have mediating roles to varying degrees in the process of OSA caused by T2DM. Interpretation: This MR study showed that OSA is a risk factor for HBP and T2DM, and the evaluation of mediators may help further reveal the specific mechanism by which OSA causes HBP and T2DM.

A rapid screening platform for antibiotic susceptibility testing based on a simple colorimetric method.

Rapid screening platforms for antibiotic susceptibility testing (AST) are important in inhibiting bacterial resistance in clinical practice. Herein, a rapid screening platform is reported for AST, which is based on nanofiber membrane enrichment bacteria-assisted cell counting Kit-8 (CCK8) colorimetry. The absorbance of CCK8 formazan has a linear relationship with the number of bacteria. The interference of antibiotics in the absorbance of CCK8 formazan could be eliminated by separating planktonic bacteria from the culture medium using nanofiber membranes. The total detection time is 7-9 h, using the new screening platform, which is significantly shorter than that with the traditional method, and the limit of detection of this method is 10 CFU mL-1. The evaluation results of antibiotic susceptibility are identical when using the new screening method and traditional methods. This method meets the definition of "rapid testing" for antibiotic susceptibility by most microbiologists. Furthermore, the new screening platform for antibiotic susceptibility testing ability in vitro was proved using E. coli in urine and blood, and S. aureus in wound fluid as practical samples. All the results showed that the new screening platform is a promising method for rapid antibiotic susceptibility testing in vitro.

SENP1 modulates chronic intermittent hypoxia-induced inflammation of microglia and neuronal injury by inhibiting TOM1 pathway.

Chronic intermittent hypoxia (CIH) is a characteristic pathophysiological change of obstructive sleep apnea syndrome (OSAS). Inflammation of microglia induced by CIH, plays a vital role in OSAS-associated cognitive dysfunction. SUMO-specific proteases 1 (SENP1) has been implicated in tumor inflammatory microenvironment and cells migration. However, the role of SENP1 in CIH-induced neuroinflammation remains unknown. We aimed to investigate the effect of SENP1 on neuroinflammation and neuronal injury. After the preparation of SENP1 overexpression microglia and SENP1 knockout mouse, CIH microglia and mice were established using an intermittent hypoxia device. Results showed that CIH reduced the level of SENP1 and TOM1, induced the SUMOylation of TOM1, and promoted microglial migration, neuroinflammation, neuronal amyloid-beta 42 (Aß42) deposition and apoptosis in vitro and in vivo. After SENP1 overexpression in vitro, the enhanced SUMOylation of TOM1 was inhibited; the level of TOM1 and microglial migration were enhanced; neuroinflammation, neuronal Aß42 deposition and apoptosis were significantly reduced. However, the administration of siRNA-TOM1 suppressed microglial migration, neuroinflammation, neuronal Aß42 deposition and apoptosis. After SENP1 knockout in vivo, the SUMOylation enhancement of TOM1 was accelerated, microglial migration was inhibited. Neuroinflammation, neuronal Aß42 deposition and apoptosis, cognitive impairment was significantly exacerbated. Overall, the results demonstrated that SENP1 promoted microglial migration by alleviating the de-SUMOylation of TOM1, thus contributing to attenuate neuroinflammation, neuronal Aß42 deposition and neuronal apoptosis induced by CIH.

Cultivating China's Cinchona: The Local Developmental State, Global Botanic Networks and Cinchona Cultivation in Yunnan, 1930s-1940s.

This article reconstructs the history of China's first successful cinchona cultivation programme in Hekou, Yunnan province from the 1930s to 1940s during the Nationalist era (1928-49). I argue that the Hekou programme was initiated by the Yunnan 'local developmental state' to control endemic malaria and achieve quinine self-sufficiency. It was expanded during the Sino-Japanese War (1937-45) as part of the national defence project in order to develop Yunnan's malaria-ridden southwest frontier to provide more resources for the war, as well as to solve broader wartime epidemic crises in southwest China. A closer examination also indicates that the development of the Hekou programme was closely intertwined with global networks of cinchona cultivation and international politics.

Formulation of insulin-loaded N-trimethyl chitosan microparticles with improved efficacy for inhalation by supercritical fluid assisted atomization.

Supercritical fluid assisted atomization introduced by a hydrodynamic cavitation mixer (SAA-HCM) was proposed as a green technique to fabricate insulin-loaded dry powders for inhalation administration. N-trimethyl chitosan (TMC), a polymeric mucoadhesive absorption enhancer, was synthesized and successfully micronized from aqueous solution using SAA-HCM. The prepared well-defined spherical TMC microparticles with preserved structure and thermal stability were potential carriers for delivery of proteins. Then, insulin-loaded TMC microparticles with high loading efficiency were coprecipitated from aqueous solutions using SAA-HCM without use of any organic solvents. The polymer/protein ratio revealed to be a factor influencing the particle morphology, and non-coalescing composite microparticles in amorphous state mainly ranging from 1µm to 5µm could be obtained in this work. Aerodynamic properties were assessed by next generation impactor (NGI) and the mass median aerodynamic diameter (MMAD) lied inside the inhalable range of 1-5µm, while fine particle fraction (FPF) reached above 60%. The structural integrity of encapsulated insulin was confirmed by HPLC, circular dichroism and fluorescence spectroscopy. In vivo study demonstrated that TMC could enhance the absorption and bioavailability of the pulmonarily administered insulin formulation for SD rats. These results suggest that TMC microparticles could be efficiently prepared as a promising vehicle for drug delivery, and SAA-HCM is a promising technique to prepare inhalable polymer/protein composite dry powders.

Supercritical fluid assisted production of micrometric powders of the labile trypsin and chitosan/trypsin composite microparticles.

Supercritical fluid assisted atomization introduced by a hydrodynamic cavitation mixer (SAA-HCM) was used to prepare micrometric particles of a labile protein, i.e., trypsin from aqueous solution without use of any organic solvents. The trypsin particles precipitated had various morphologies under different process conditions, with particle diameters ranging from 0.2 to 4 µm. FTIR, SDS-PAGE, CD and fluorescence spectra were performed to analyze the structural stability of the protein, and trypsin retained above 70% of the biological activity. Besides, chitosan was selected as the polymer carrier in an effort to prepare trypsin composite microparticles via SAA-HCM process. The influences of chitosan molecular weight, polymer/protein ratio and solution concentration on the particle morphology and size distribution were investigated in detail. Non-coalescing spherical composite microparticles with a narrow particle distribution (0.2-3 µm) could be obtained. The SAA-HCM prepared particles were amorphous as demonstrated by XRD and had a loading efficiency about 90%. The protein release profiles of the composite microparticles were evaluated using both the immersion condition and a Franz diffusion cell. Finally, the distribution of the protein within the particles was characterized through CLSM analysis of FITC-labeled trypsin-loaded chitosan microparticles. The SAA-HCM process is demonstrated to be a protein-friendly and promising technique for production of protein and polymer/protein composite particles formulations from aqueous solutions for drug delivery systems.

Supercritical fluid assisted production of chitosan oligomers micrometric powders.

Chitosan oligomers (O-chitosan) micrometric particles were produced from aqueous solution using a novel process, i.e. supercritical fluid assisted atomization introduced by hydrodynamic cavitation mixer (SAA-HCM). Hydrodynamic cavitation was introduced to enhance mass transfer and facilitate the mixing between SC-CO2 and liquid solution for fine particles formation. Well defined, separated and spherical microparticles were obtained, and the particles size could be well controlled with narrow distribution ranging from 0.5 µm to 3 µm. XRD patterns showed amorphous structure of O-chitosan microparticles. FTIR, TGA and DSC analyses confirmed that no change in molecular structure and thermal stability after SAA-HCM processing, while the water content was between 5.8% and 8.4%. Finally, tap densities were determined to be below 0.45 g/cm(3) indicating hollow or porous structures of microparticles. By tuning process parameters, theoretical mass median aerodynamic sizes lied inside respirable range of 1-2 µm, which presented the potential of the O-chitosan microparticles in application as inhaled dry powders. SAA-HCM was demonstrated to be very useful in particle size engineering.