Transcriptomic Analysis of Type 2 Diabetes Mellitus Combined with Lower Extremity Atherosclerotic Occlusive Disease.

Background: The pathological damage mechanism of type 2 diabetes (T2D) and macroangiopathy is extremely complex, and T2D and arteriosclerosis obliterans have different biological behaviors and clinical features. To explore the mechanism of lower extremity arteriosclerosis occlusion (LEAOD) in T2D patients, we utilized RNA-seq to identify unique gene expression signatures of T2D and LEAOD through transcriptomic analysis. Methods: We obtained blood samples and performed RNA sequencing from four patients with T2D, five of whom had LEAOD. Another six age- and gender-matched blood samples from healthy volunteers were used for control. By exploring the general and specific differential expression analysis after transcriptome sequencing, specific gene expression patterns of T2D and LEAOD were verified. Results: Transcriptome analysis found differentially expressed genes in T2D, and T2D + LEAOD (vs normal) separately, of which 35/486 (T2D/T2D + LEAOD) were up-regulated and 1290/2970 (T2D/T2D + LEAOD) were down-regulated. A strong overlap of 571 genes across T2D, LEAOD, and coexisting conditions was mainly involved in extracellular exosomes and the transcription process. By exploring the sex difference gene expression features between T2D, T2D + LEAOD, and healthy controls, we noticed that sex chromosome-associated genes do not participate in the sexual dimorphism gene expression profiles of T2D and LEAOD. Protein-Protein Interaction Network analysis and drug target prediction provided the drug candidates to treat T2D and LEAOD. Conclusion: This study provides some evidence at the transcript level to uncover the association of T2D with LEAOD. The screened hub genes and predicted target drugs may be therapeutic targets.

Novel Multitarget ACE Inhibitory Peptides from Bovine Colostrum Immunoglobulin G: Cellular Transport, Efficacy in Regulating Endothelial Dysfunction, and Network Pharmacology Studies.

In this study, we used traditional laboratory methods, bioinformatics, and cellular models to screen novel ACE inhibitory (ACEI) peptides with strong ACEI activity, moderate absorption rates, and multiple targets from bovine colostrum immunoglobulin G (IgG). The purified fraction of the compound proteinase hydrolysate of IgG showed good ACEI activity. After nano-UPLC-MS/MS identification and in silico analysis, eight peptides were synthesized and verified. Among them, SFYPDY, TSFYPDY, FSWF, WYQQVPGSGL, and GVHTFP were identified as ACEI peptides, as they exhibited strong ACEI activity (with IC50 values of 104.7, 80.0, 121.2, 39.8, and 86.3 µM, respectively). They displayed good stability in an in vitro simulated gastrointestinal digestion assay. In a Caco-2 monolayer model, SFYPDY, FSWF, and WYQQVPGSGL exhibited better absorption rates and lower IC50 values than the other peptides and were thereby identified as novel ACEI peptides. Subsequently, in a H2O2-induced endothelial dysfunction (ED) model based on HUVECs, SFYPDY, FSWF, and WYQQVPGSGL regulated ED by reducing apoptosis and ROS accumulation while upregulating NOS3 mRNA expression. Network pharmacology analysis and RT-qPCR confirmed that they regulated multiple targets. Overall, our results suggest that SFYPDY, FSWF, and WYQQVPGSGL can serve as novel multitarget ACEI peptides.

Millettia speciosa Champ cellulose-based hydrogel as a novel delivery system for Lactobacillus paracasei: Its relationship to structure, encapsulation and controlled release.

We report for the first time the usage of Millettia speciosa Champ cellulose (MSCC) and carboxymethylcellulose (MSCCMC) for the fabrication of 3D-network hydrogel as delivery system for probiotics. The structural features, swelling behavior and pH-responsiveness of MSCC-MSCCMC hydrogels and their encapsulation and controlled-release behavior for Lactobacillus paracasei BY2 (L. paracasei BY2) were mainly studied. Structural analyses demonstrated that MSCC-MSCCMC hydrogels with porous and network structures were successfully synthesized through the crosslinking of -OH groups between MSCC and MSCCMC molecules. An increasing concentration of MSCCMC significantly improved the pH-responsiveness and swelling ability of the MSCC-MSCCMC hydrogel toward neutral solvent. Besides, the encapsulation efficiency (50.38-88.91 %) and release (42.88-92.86 %) of L. paracasei BY2 were positively correlated with the concentration of MSCCMC. The higher the encapsulation efficiency was, the higher the release in the target intestine. However, due to the existence of bile salts, controlled-release behavior decreased the survivor rate and physiological state (degrading cholesterol) of encapsulating L. paracasei BY2. Even so, the number of viable cells encapsulated by hydrogels still reached the minimum effective concentration in the target intestine. This study provides an available reference for the practical application of hydrogels fabricated from the cellulose of the Millettia speciosa Champ plant for probiotic delivery.

Lewis Acid-Catalyzed Remote Site-Selective Ring Deconstruction of Cyclobuteno[a]naphthalene-4-ones to Access Unsymmetric 1,1-Diarylated Olefins.

A catalytic site-selective ring deconstruction of cyclobuteno[a]naphthalene-4-ones with alcohols is reported, enabling the direct production of a wide range of unsymmetric 1,1-diarylated olefins with good yields and complete regioselectivity. The late-stage application of these resulting terminal olefins demonstrates great possibilities to apply this strategy to complex molecules. The protocol features good functional group compatibility, broad substrate scope, and controllable site selectivity.

Complement activation mainly mediates the association of heart rate variability and cognitive impairment in adults with obstructive sleep apnea without dementia.

STUDY OBJECTIVES: The relationship between autonomic nervous system dysfunction measured by heart rate variability (HRV) and cognitive impairment in obstructive sleep apnea (OSA) patients is complex and still not well understood. We aimed to analyze the role of complement activation, Alzheimer's disease (AD) biomarkers, and white matter hyperintensity (WMH) in modulating the association of HRV with cognitive performance. METHODS: There were 199 subjects without dementia, including 42 healthy controls, 80 OSA patients with mild cognitive impairment (MCI), and 77 OSA patients without cognitive impairment. All participants who completed polysomnography, cognition, WMH volume, and 5-min HRV analysis were recorded during wakefulness and sleep periods. Neuron-derived exosome and astrocyte-derived exosome proteins were measured by ELISA kits. RESULTS: The OSA with MCI group were associated with a lower mean of standard deviations of R-R intervals for 5-min intervals (SDANN index) during wakefulness, standard deviation of the R-R interval (SDNN) during sleep stage and percentage of adjacent R-R intervals differing by more than 50 ms (PNN50) in each stage compared with OSA without MCI. The influence of HRV on cognition was partially mediated by complement activation (C5b-9 mediated a maximum of 51.21%), AD biomarkers, and WMH. CONCLUSIONS: Lower SDANN index and PNN50 during wakefulness and SDNN and PNN50 during sleep periods were found in OSA patients with MCI, suggesting potential vulnerability to autonomic and parasympathetic dysfunction. Complement activation, AD biomarkers, and WMH might partially mediate and interact with the influence of HRV on cognitive impairment in OSA patients. CLINICAL TRIAL REGISTRATION: ChiCTR1900021544.

Mitofusin-2 mediates cannabidiol-induced neuroprotection against cerebral ischemia in rats.

Cannabidiol (CBD) reportedly exerts protective effects against many psychiatric disorders and neurodegenerative diseases, but the mechanisms are poorly understood. In this study, we explored the molecular mechanism of CBD against cerebral ischemia. HT-22 cells or primary cortical neurons were subjected to oxygen-glucose deprivation insult followed by reoxygenation (OGD/R). In both HT-22 cells and primary cortical neurons, CBD pretreatment (0.1, 0.3, 1 µM) dose-dependently attenuated OGD/R-induced cell death and mitochondrial dysfunction, ameliorated OGD/R-induced endoplasmic reticulum (ER) stress, and increased the mitofusin-2 (MFN2) protein level in HT-22 cells and primary cortical neurons. Knockdown of MFN2 abolished the protective effects of CBD. CBD pretreatment also suppressed OGD/R-induced binding of Parkin to MFN2 and subsequent ubiquitination of MFN2. Overexpression of Parkin blocked the effects of CBD in reducing MFN2 ubiquitination and reduced cell viability, whereas overexpressing MFN2 abolished Parkin's detrimental effects. In vivo experiments were conducted on male rats subjected to middle cerebral artery occlusion (MCAO) insult, and administration of CBD (2.5, 5 mg · kg-1, i.p.) dose-dependently reduced the infarct volume and ER stress in the brains. Moreover, the level of MFN2 within the ischemic penumbra of rats was increased by CBD treatment, while the binding of Parkin to MFN2 and the ubiquitination of MFN2 was decreased. Finally, short hairpin RNA against MFN2 reversed CBD's protective effects. Together, these results demonstrate that CBD protects brain neurons against cerebral ischemia by reducing MFN2 degradation via disrupting Parkin's binding to MFN2, indicating that MFN2 is a potential target for the treatment of cerebral ischemia.

Regulation of Hepatocellular Cholesterol Metabolism By Lactobacillus Paracasei BY2 and Its Embedding Delivery.

In this study, five strains of lactic acid bacteria (LAB) with excellent cholesterol-lowering ability were screened from fermented foods. The gastrointestinal stress resistance, intestinal adhesion, and bacteriostasis abilities were evaluated to obtain the best LAB. And then, high-cholesterol HepG2 cell model was further prepared to explore the cholesterol-lowering mechanism of the LAB. Finally, pH-sensitive hydrogel prepared by Millettia speciosa Champ. carboxymethyl cellulose and Millettia speciosa Champ. cellulose was first applied to the microencapsulation of LAB. As a result, Lactobacillus paracasei BY2 (LP-BY2) exhibited higher cholesterol-lowering activity, intestinal adhesion, and bacteriostasis abilities compared with other LAB. Furthermore, it was found that LP-BY2 could reduce the cholesterol level by regulating the expression of key genes that involved in cholesterol synthesis (HMGCR and SREBP-2), uptake (LDLR), and outflow (LXR-α, ABCA1, ABCG5, ABCG8, and CYP7A1) in liver. At the same time, microencapsulation significantly enhanced the survival rate and cholesterol-lowering ability of LP-BY2 after gastrointestinal digestion. This study will provide an available reference for the application of Lactobacillus in prevention and treatment of hypercholesterolemia.

Development of Millettia speciosa champ polysaccharide conjugate stabilized oil-in-water emulsion for oral delivery of ß-carotene: Protection effect and in vitro digestion fate.

In this study, a natural antioxidant emulsifier, Millettia speciosa Champ polysaccharide conjugates (MSC-PC), was used for fabricating oil-in-water emulsion, and the influences of MSC-PC on ß-carotene stability and bioaccessibility were studied. Results suggested that MSC-PC stabilized emulsion exhibited excellent resistance to a wide range of salt levels (0-500 mM of Na+), thermal treatments (50-90 °C) and pH values (3.0-11.0). MSC-PC also exhibited an outstanding inhibition capacity on lipid oxidation. Besides, MSC-PC stabilized emulsion had a better protective effect on ß-carotene than other systems. Interestingly, in spite of similar lipolysis extent, ß-carotene bioaccessibility in MSC-PC fabricated emulsion (14.75 %) was markedly higher than that in commercial Tween 80 fabricated emulsion (10.08 %), likely due to the steric-hindrance effect and antioxidant ability of MSC-PC, building interfacial layers that prevented ß-carotene from degradation. This work supplied a deep insight into elucidating the mechanisms of emulsifying performance and ß-carotene protection effect of MSC-PC fabricated emulsion.

Treatment of Preschool Children With Autism Spectrum Disorder: A Trial to Evaluate a Learning Style Profile Intervention Program in China.

Objective: To investigate whether the provision of learning style profile (LSP) training improves development in preschool children with autism spectrum disorder (ASD) in China and to describe the characteristics of children who benefit from the intervention. Methods: Eighty-one children aged 36 to 72 months who were diagnosed with ASD for the first time were recruited for the intervention group. All of them received 24 weeks of LSP training, consisting of hospital- and home-based training. Twenty-one children with ASD of the same age in the control group had never received any intervention after diagnosis but underwent an assessment. Assessments were conducted at baseline and 24 weeks later. Differences in the developmental level and severity of ASD symptoms over time and between groups were analyzed by repeated standardized measures. Secondary analyses examined age effects among the 36- 48-, 48- 60-, and 60-72-month age groups. Results: Within-group comparison of the intervention group revealed significant treatment effects after the intervention, according to: language, social and adaptive developmental quotients (DQs) of the China Developmental Scale; total Childhood Autism Rating Scale (CARS) score; and hyperactivity, peer problems, total difficulties, and prosocial behavior scores of the Strengths and Difficulties Questionnaire (SDQ). Similar gains were observed in gross and fine motor DQs of the China Developmental Scale and emotional symptoms and conduct problems scores of the SDQ; however, the differences between these pre- and postintervention scores did not reach statistical significance. Comparisons among the three age groups in the intervention groups demonstrated a significant age effect on adaptive DQs of the China Developmental Scale; total CARS score; hyperactivity, peer problems and total difficulties scores of the SDQ. Comparison between the intervention and control groups revealed significant treatment effects on language, social and adaptive DQs of the China Developmental Scale; total CARS score; and emotional symptoms, conduct problems, hyperactivity, peer problems, total difficulties, and prosocial behavior scores of the SDQ after the intervention. Similar gains were observed in gross and fine motor DQs of the China Developmental Scale, although differences between the two groups did not reach statistical significance. Conclusion: Our findings suggest that LSP training can effectively improve social behavior and reduce the severity of ASD symptoms in children with ASD. Our data also highlight the importance of early intervention.

Novel Antioxidative Wall Materials for Lactobacillus casei Microencapsulation via the Maillard Reaction between the Soy Protein Isolate and Prebiotic Oligosaccharides.

In this study, three kinds of Maillard reaction products (MRPs) have been, for the first time, successfully prepared by conjugating soy protein isolate (SPI) with isomaltooligosaccharide, xylooligosaccharide, or galactooligosaccharide at 80 °C for 30 or 60 min and applied for the construction of Lactobacillus casei (L. casei) microcapsules. The results showed that MRPs exhibited enhanced antioxidative activities compared with their physically mixed counterparts. The digested MRPs displayed excellent resistance to pathogenic bacteria and promoted the growth of L. casei. Moreover, MRP-encapsulated L. casei showed a higher survival rate than free L. casei under tested adverse conditions including heat treatment, storage, and mechanical forces. Under simulated digestion conditions, the viability of L. casei decreased from 8.8 log cfu/mL to 1.6 log cfu/mL, while that of MRP-encapsulated L. casei was maintained at 7.4 log cfu/mL. Thus, MRP-based SPI-oligosaccharide conjugates exhibited great potential for microencapsulation of probiotics.

Multiarchitecture-Based Plasmonic-Coupled Emission Employing Gold Nanoparticles: An Efficient Fluorescence Modulation and Biosensing Platform.

Surface plasmon-coupled emission (SPCE) is an efficient surface-enhanced fluorescence method based on the near-field coupling process of surface plasmons and fluorophores. Based on this, we developed multiple coupling structures for an SPCE system by introducing gold nanoparticles (AuNPs) with different architectures by adjusting different modification methods and configurations. By assembling AuNPs on a gold substrate through electrostatic adsorption and spin-coating, 40- and 55-fold enhancements were obtained compared to free space (FS) emission, respectively. After theoretical simulations and the optimization of experimental conditions, a novel "hot-spot" plasmonic structure, an intense electromagnetic field within the system, plasmonic properties, and the coupled process were found to be mainly responsible for the diverse enhancement effects observed. For the spin-coating deposition method, new enhancing systems with high efficiency can be easily built without complex modification. Additionally, the subsequent detection system based on the uniform modification of AuNPs through electrostatic adsorption is convenient to establish with high sensitivity and stability, which can broaden the application of SPCE in both fluorescence-based sensing and imaging. This AuNP-enhanced SPCE using an electrostatic adsorption method was designed as an immunosensor to prove feasibility.

Roflupram protects against rotenone-induced neurotoxicity and facilitates α-synuclein degradation in Parkinson's disease models.

We have previously shown that roflupram (ROF) protects against MPP+-induced neuronal damage in models of Parkinson's disease (PD). Since impaired degradation of α-synuclein (α-syn) is one of the key factors that lead to PD, here we investigated whether and how ROF affects the degradation of α-syn in rotenone (ROT)-induced PD models in vivo and in vitro. We showed that pretreatment with ROF (10 µM) significantly attenuated cell apoptosis and reduced the level of α-syn in ROT-treated SH-SY5Y cells. Furthermore, ROF significantly enhanced the lysosomal function, as evidenced by the increased levels of mature cathepsin D (CTSD) and lysosomal-associated membrane protein 1 (LAMP1) through increasing NAD+/NADH and the expression of sirtuin 1 (SIRT1). Pretreatment with an SIRT1 inhibitor selisistat (SELI, 10 µM) attenuated the neuroprotection of ROF, ROF-reduced expression of α-syn, and ROF-increased expression levels of LAMP1 and mature CTSD. Moreover, inhibition of CTSD by pepstatin A (20 µM) attenuated ROF-reduced expression of α-syn. In vivo study was conducted in mice exposed to ROT (10 mg·kg-1·d-1, i.g.) for 6 weeks; then, ROT-treated mice received ROF (0.5, 1, or 2 mg·kg-1·d-1; i.g.) for four weeks. ROF significantly ameliorated motor deficits, which was accompanied by increased expression levels of tyrosine hydroxylase, SIRT1, mature CTSD, and LAMP1, and a reduced level of α-syn in the substantia nigra pars compacta. Taken together, these results demonstrate that ROF exerts a neuroprotective action and reduces the α-syn level in PD models. The mechanisms underlying ROF neuroprotective effects appear to be associated with NAD+/SIRT1-dependent activation of lysosomal function.

How Do Location-Based Augmented Reality Games Improve Physical and Mental Health? Evaluating the Meanings and Values of Pokémon Go Users' Experiences through the Means-End Chain Theory.

New technology has dramatically changed online games and blurred the boundary between active and passive activities. This study aims to explore the meanings and values of augmented reality online games by examining users' Pokémon Go experiences through the means-end chain theory. Using data from interviews with 34 Pokémon Go users, this study adopts the soft laddering method to identify Pokémon Go's potential attributes, consequences, and values, and to construct a hierarchical value map. The results indicated that Pokémon Go users pursue social relationships through play, and these relationships are triggered by the benefits of making new friends, maintaining current relationships with friends and family, and the attributes of prevalence, childhood memory, game design, and augmented reality. Subsequently, this study describes how Pokémon Go can be considered an active leisure activity because of its social, mental, and physical benefits and assesses the implications of its findings.

Palladium/N,N'-Disulfonyl Bisimidazoline-Catalyzed Enantioselective Addition of Arylboronic Acids to Cyclic N-Sulfonyl Ketimines.

The combination of Pd(TFA)2 and an N,N'-disulfonyl bisimidazoline ligand shows high catalytic activity and excellent asymmetric induction in the addition of arylboronic acids to cyclic N-sulfonyl ketimines including benzo[d]isothiazole-1,1-dioxides, benzo[e][1,2,3]oxathiazine-2,2-dioxides, and 1,2,5-thiadiazole-1,1-dioxides, by which three types of chiral quaternary carbon-containing sultams with substantial substitution diversity were synthesized with high yields and excellent enantioselectivities (up to >99% ee). The current catalysis demonstrated a remarkable tolerance to oxygen and thus provided an operationally simple approach for constructing enantioenriched cyclic quaternary stereocenters.

Synthesis of polycyclic indoles via organocatalytic bicyclization of α-alkynylnaphthalen-2-ols with nitrones.

A new organocatalytic bicyclization of α-alkynylnaphthalen-2-ols with nitrones was first reported, leading to the convergent synthesis of polycyclic indoles with substantial substitution diversity in generally good yields through scission of the N-O bond of nitrones via [3,3]-sigmatropic rearrangement. This transformation showcases the use of a quinine catalyst in a complicated cascade system that has been shown to effectively construct polycyclic heterocycles via alkyne difunctionalization.

Hybrid Fullerene-Based Electron Transport Layers Improving the Thermal Stability of Perovskite Solar Cells.

The structure-dependent thermal stability of fullerene electron transport layers (ETLs) and its impact on device stability have been underrated for years. Based on cocrystallographic understanding, herein, we develop a thermally stable ETL comprising a hybrid layer of [6,6]-phenyl-C61-butyric acid methyl ester (PCBM) and [6,6]-phenyl-C61-propylbenzene (PCPB). By tuning the weight ratios of PCBM and PCPB to influence the noncovalent intermolecular interactions and packing of fullerene derivatives, we obtained a champion device based on the 20PCPB (20 wt % addition of PCPB into the mixture of PCBM/PCPB) ETL and excellent thermal stability of 500 h under 85 °C thermal aging in a N2 atmosphere in the dark. The present work exemplifies that cocrystallography can be a precise tool to probe the interaction and aggregation of fullerene derivatives in ETLs, and mixed fullerene derivatives can be sought as promising ETLs to enhance the long-term stability of perovskite solar cells under high-temperature working environments.

N-Sulfonyl Bisimidazoline Ligands and Their Applications in Pd(II)-Catalyzed Asymmetric Addition toward α-Tertiary Amines.

A new class of chiral N-sulfonyl bisimidazoline (Bim) ligands have been designed, prepared, and applied in Pd(II)-catalyzed asymmetric addition of arylboronic acids to isatin-derived N-Boc ketimines. The combination of Pd(OCOCF3)2 and N-tosyl Bim ligand shows high catalytic activity and excellent asymmetric induction, enabling asymmetric addition to offer α-tertiary amines with generally good to high yields and excellent enantioselectivity (up to 96% yield, 96% ee). This asymmetric Pd(II) catalysis can tolerate air conditions, providing a practical and operationally simple protocol toward the construction of an enantioenriched α-tertiary stereocenter.

The formation of zein-chitosan complex coacervated particles: Relationship to encapsulation and controlled release properties.

The complex coacervation between zein and chitosan (CS) as well as the relationship with the controlled release properties of their complex nanoparticles were studied. The factors influencing the nanoparticle formation between zein and CS, including solid to liquid ratio, zein to CS ratio and pH, were systematically investigated. The isothermal titration calorimetry (ITC) showed that zein-CS interaction was spontaneous exothermic process. The pH the higher was, the stronger the interaction between zein and CS. The mean particle sizes of ZCNPs were increased by enhanced turbidity between zein and CS (from 90.89 nm to 1368.77 nm). The morphology study showed that spherical particles and coacervate were obtained with the increased interaction between zein and CS. The release profiles of curcumin in vitro indicated that slight burst effect followed by slow release was observed after interacting CS. The ZCNPs at pH 4.0 exhibited smaller particle size (162.07 nm), more stable ζ-potential (49.7 mV), higher encapsulation efficiency (94.67%) and slower release rate. In conclusion, the stronger the interaction was, the lower the curcumin released from the nanoparticles in vitro, and the ZCNPs at pH 4.0 had better potential in oral delivery application.