Exosomal miR-23b from bone marrow mesenchymal stem cells alleviates oxidative stress and pyroptosis after intracerebral hemorrhage.

Our previous studies showed that miR-23b was downregulated in patients with intracerebral hemorrhage (ICH). This indicates that miR-23b may be closely related to the patho-physiological mechanism of ICH, but this hypothesis lacks direct evidence. In this study, we established rat models of ICH by injecting collagenase VII into the right basal ganglia and treating them with an injection of bone marrow mesenchymal stem cell (BMSC)-derived exosomal miR-23b via the tail vein. We found that edema in the rat brain was markedly reduced and rat behaviors were improved after BMSC exosomal miR-23b injection compared with those in the ICH groups. Additionally, exosomal miR-23b was transported to the microglia/macrophages, thereby reducing oxidative stress and pyroptosis after ICH. We also used hemin to mimic ICH conditions in vitro. We found that phosphatase and tensin homolog deleted on chromosome 10 (PTEN) was the downstream target gene of miR-23b, and exosomal miR-23b exhibited antioxidant effects by regulating the PTEN/Nrf2 pathway. Moreover, miR-23b reduced PTEN binding to NOD-like receptor family pyrin domain containing 3 (NLRP3) and NLRP3 inflammasome activation, thereby decreasing the NLRP3-dependent pyroptosis level. These findings suggest that BMSC-derived exosomal miR-23b exhibits antioxidant effects through inhibiting PTEN and alleviating NLRP3 inflammasome-mediated pyroptosis, thereby promoting neurologic function recovery in rats with ICH.

Advances in clinical and safety studies of phosphodiesterase 4 inhibitors / 药学学报

Phosphodiesterase 4 (PDE4) is an important member of the phosphodiesterase enzyme family that specifically catalyzes the hydrolysis of cyclic adenosine monophosphate (cAMP), activates the downstream phosphorylation cascade pathway by altering cAMP concentration, and is strongly associated with multiple diseases. Inhibition of PDE4 is clinically investigated as a therapeutic strategy in a broad range of disease areas, including respiratory system diseases, autoimmune disorders, central nervous system diseases, and dermatological conditions. However, the incidence of adverse reactions such as nausea and vomiting is relatively high in the marketed PDE4 inhibitors, which has stalled their clinical development. In this review, we provide an overview of the clinical progression and safety issues of the marketed PDE4 inhibitors. We also review the main causes underlying PDE4-mediated adverse effects by combining the structural analysis of the PDE4 protein, the mechanism of action of PDE4 inhibitors, and the related side effect mechanism research, aiming to provide a reference for the development of safe and effective PDE4 inhibitors.

A multi-omics study on cutaneous and uveal melanoma.

AIM: To present the multi-omics landscape of cutaneous melanoma (CM) and uveal melanoma (UM) from The Cancer Genome Atlas (TCGA). METHODS: The differentially expressed genes (DEGs) between CM and UM were found and integrated into a gene ontology enrichment analysis. Besides, the differentially expressed miRNAs were also identified. We also compared the methylation level of CM with UM and identified the differentially methylated regions to integrate with the DEGs to display the relationship between the gene expression and DNA methylation. The differentially expressed transcription factors (TFs) were identified. RESULTS: Though CM had more mutational burden than UM, they shared several similarities such as the same rankings in diverse variant types. Except GNAQ and GNA11, the other top 18 mutated genes of the combined group were mostly detected in CM instead of UM. On the transcriptomic level, 4610 DEGs were found and integrated into a gene ontology enrichment analysis. We also identified 485 differentially expressed miRNAs. The methylation analysis showed that UM had a significantly higher methylation level than CM. The integration of differentially methylated regions and DEGs demonstrated that most DEGs were downregulated in UM and the hypo- and hypermethylation presented no obvious difference within these DEGs. Finally, 116 hypermethylated TFs and 114 hypomethylated TFs were identified as differentially expressed TFs in CM when compared with UM. CONCLUSION: This multi-omics study on comparing CM with UM confirms that they differ in all analyzed levels. Of notice, the results also offer new insights with implications for elucidating certain unclear problems such as the distinct role of epithelial mesenchymal transition in two melanomas, the different metastatic routes of CM and UM and the liver tropism of metastatic UM.

Construction of High-Nuclearity Manganese-Cluster-Organic Frameworks by Using a Tripodal Alcohol Ligand.

Two novel cluster-organic frameworks based on the 12-nuclearity manganese-cluster secondary building unit (SBU), [MnIII4MnII8(L)4(Ac)8(MeO)2(µ5-O)2(H2O)4](Ac)2·16H2O (1) and [MnIII4MnII8(L)4(Ac)8(MeO)2(µ5-O)2(H2O)4](Ac)2·12H2O (2), where Ac = CH3COO- and MeO = CH3O, have been constructed from solvothermal reactions of the 3-nuclearity manganese cluster [Mn3(µ3-O)(Ac)6(py)3](ClO4) (Mn3, where py = pyridine) with a tripodal alcohol ligand containing a 4-pyridyl group. 1 and 2 represent the first examples of metal-organic frameworks containing 12-nuclearity manganese-cluster SBUs. In addition, 1 exhibits an integration of the porosity and magnetic properties from both the framework and cluster in a porous material.

Composite Hybrid Cluster Built from the Integration of Polyoxometalate and a Metal Halide Cluster: Synthetic Strategy, Structure, and Properties.

A step-by-step synthetic strategy, setting up a bridge between the polyoxometalate (POM) and metal halide cluster (MHC) systems, is demonstrated to construct an unprecedented composite hybrid cluster built up from one high-nuclearity cationic MHC [Cu8I6](2+) and eight Anderson-type anionic POMs [HCrMo6O18(OH)6](2-) cross-linked by a tripodal alcohol derivative.

Location of the supraorbital and infraorbital foramen with references to the soft tissue landmarks in a Chinese population.

The purpose of the current study was to determine the supraorbital foramen (SOF) and infraorbital foramen (IOF) based on soft tissue landmarks, to facilitate prediction of the location of this structure during facial surgery. Forty-two hemispheres of 21 adult cadavers (16 men and 5 women; aged 30-75 years) were dissected to expose the SOF and IOF. The locations of the SOF and IOF were evaluated with direct and photographic measurements. The data gained were analyzed by statistical method. The SOF localized 23.11 ± 2.35 mm superior and 9.48 ± 3.06 mm lateral to the angulus oculi medialis (AOM). The vertical angle from AOM to SOF was 68.3 (SD, 6.44) degrees. The SOF localized 24.81 (SD, 3.39) mm inferior and 10.89 (SD, 2.78) mm lateral to the AOM on the front view. The vertical angle from AOM to IOF was 66.5 (SD, 5.18) degrees. The SOF localized 11.22 (SD, 2.01) mm inferior and 6.09 (SD, 2.32) mm lateral to the ala of the nose (AL) on the front view. The vertical angle from AL to IOF was 61.7 (SD, 7.61) degrees. These results were a little different from the results of some other populations. We found the IOFs located on the point of one-fifth proportion distant to the ALs along the vertical direction distance from AL to SOF, whereas the AOMs located on the point of three-fifths proportion distant from the AL. Our results may provide more detailed information to predict the location of the SOFs and IOFs and help to prevent nerve or vessel damage.

Sex assessment using measurements of the first lumbar vertebra.

Sex determination is a vital part of the medico-legal system but can be difficult in cases where the integrity of the body has been compromised. The purpose of this study was to develop a technique for sex assessment from measurements of the first lumber vertebrate. Twenty-nine linear measurements and five ratios were collected from 113 Chinese adult males and 97 Chinese adult females using digital three-dimensional anthropometry methods. By using discriminant analysis, we found that 23 linear measurements and two ratios identified sexual dimorphism (P<0.01), with predictive accuracy ranging from 57.1% to 86.6%. Using a stepwise method of discriminant function analysis, we found three dimensions predicted sex with 88.6% accuracy: (a) upper end-plate width (EPWu), (b) left pedicle height (PHl), and (c) middle end-plate depth (EPDm). This study shows that a single first lumber vertebra can be used for this purpose, and that the discriminant equation will help forensic determination of sex in the Chinese population.

Conformational changes of hapten-protein conjugates resulting in improved broad-specificity and sensitivity of an ELISA for organophosphorus pesticides.

The type of hapten linkage to a carrier protein can play an important role in determining the nature of the resulting antibody response. Generic haptens using three types of linkers were synthesized (a monocarboxylic acid, an unsaturated hydrocarbon and a carboxamido spacer). These haptens were conjugated to bovine serum albumin (BSA) and used as immunogens to produce broad-specificity monoclonal antibodies (MAbs) to organophosphorus pesticides (OPs). Three-dimensional (3D) structures of hapten-lysine conjugates were optimized using molecular modeling (MM) to mimic conformations of hapten-BSA conjugates. The results from MM studies revealed a change of the 3D conformation and electrostatic potential of hapten 1 when the monocarboxylic acid linker was coupled to lysine. This result was consistent with the observed high-cross-reactivity of the corresponding MAb-H1 for the OPs. The competitive indirect enzyme-linked immunosorbent assay based on MAb-H1 is ideally suited to be used as a screening method for OP contaminants.

Broad-specificity immunoassay for O,O-diethyl organophosphorus pesticides: application of molecular modeling to improve assay sensitivity and study antibody recognition.

A monoclonal antibody (mAb) against 4-(diethoxyphosphorothioyloxy)benzoic acid (hapten 1) was raised and used to develop a broad-specificity competitive indirect enzyme-linked immunosorbent assay (ciELISA) for 14 O,O-diethyl organophosphorus pesticides (OPs). Computer-assisted molecular modeling was used to model two-dimensional (2D) and three-dimensional (3D) quantitative structure-activity relationships (QSARs) to study antibody recognition. On the basis of insights obtained from the QSAR models, two heterologous coating haptens, 4-(diethoxyphosphorothioylamino)butanoic acid (hapten 2) and 4-(diethoxyphosphorothioyloxy)-2-methylbenzoic acid (hapten 3) were designed, synthesized, and used to develop heterologous ciELISAs with significantly improved sensitivity. The heterologous ciELISA using hapten 2 as the coating hapten showed good sensitivity in a broad-specific manner for eight O,O-diethyl OPs and may be used as a screening method for the determination of these OPs. Our studies demonstrated that molecular modeling can provide insights into the spatial and electronic effects of molecular structures that are important for antibody activity, which can then be used to improve immunoassay sensitivity.

Use of anthropometric data from the medial tibial and femoral condyles to design unicondylar knee prostheses in the Chinese population.

Anthropometric data on medial tibial condyles and medial femoral condyles of 172 normal knees (94 male knees, 78 female knees) were obtained using three-dimensional computer tomographic measurements. In the medial tibial condyle, we measured the anteroposterior (AP) and widest dimension (WD), and compared the measurements with the similar dimensions of five tibial unicondylar knee prostheses conventionally used in China. In the femur, we used best-fit two-circular arcs to measure the morphology of the sagittal plane of the medial femoral condyle. We found that three of the prostheses showed WD overhang for all ranges of the AP dimension, while two of them showed WD underhang. We also found a progressive decrease in the condylar aspect ratio (WD/AP%) in parallel with an increase in the AP dimension in the medial tibial condyle. However, none of the conventional tibial prosthesis showed a similar change. Furthermore, males had larger values in aspect ratio than females with the same values for AP dimension. There were definite correlations between the radius of the curvature for the posterior part (R1) and distal part (R2) in the sagittal plane of medial femoral condyle. Both of these values were smaller than in the Caucasian population. Both radiuses of curvature for the posterior and distal components showed definite correlations with the AP dimension. The results of this study may provide guidelines for designing unicondylar knee prostheses suitable for the Chinese population.

Three dimensional morphometry of the knee to design the total knee arthroplasty for Chinese population.

Anthropometric data on the proximal tibia and distal femur of 172 normal knees (94 male knees, 78 female knees) were obtained using three dimensional computer tomographic measurements. We measured the tibial mediolateral (tML) and tibial anteroposterior (tAP) dimension in resected proximal tibia surface, femoral mediolateral (fML) and femoral anteroposterior (fAP) dimension in resected distal femur surface. The measurements were compared with the similar dimensions of five total knee prostheses conventionally used in China. We found that in the smaller sized prostheses the tibial mediolateral dimension was undersized, while in the larger size prostheses the tibial mediolateral dimension was overhang. For all sizes of prostheses the femoral mediolateral dimension was overhang. We found a progressively decreased in the aspect ratio (ML/AP %) with an increasing anteroposterior dimension both in the tibia and femur, as compared to the constant aspect ratio shown by the conventional total prostheses. Male had larger values in mediolateral dimension and aspect ratio than female under a given anteroposterior dimension both in the tibia and femur. There were strong correlations between measurements of the tibia and femur. The results of this study may provide guidelines for designing suitable total knee prosthesis for the Chinese population, especially for design of gender-specific prostheses.