Synthesis and biological evaluation of aminobenzamides containing purine moiety as class I histone deacetylases inhibitors.

The aminobenzamide is selective to class I histone deacetylases (HDACs) and displays unique tight-binding/slow-off HDAC-binding mechanism. Herein, we report a series of 9-substituted purine aminobenzamides that selectively inhibit class I HDACs. The activities in vitro showed compound 9d exhibited 12 folds more potent than MS-275 against HDAC1 isoform and showed excellent inhibitory activity on cancer cells, including HCT-116, MDA-MB-231, K562 cell lines. The metabolic stability of 9d was much better than that of the well-known HDAC inhibitor SAHA. Pulse exposure test of western blot assay demonstrated that 9a, 9d induced histone acetylation in a similar manner to MS-275. Further biological validation demonstrated that 9d prevented cell transition from G1 phase to S phase by reducing Cyclin D1, CDK2 and lifting p21, induced early apoptosis by upregulating BAX and downregulating Bcl-2 in HCT-116 cells.

Decompression plus fusion versus decompression alone for degenerative lumbar spondylolisthesis: a systematic review and meta-analysis.

PURPOSE: To compare the clinical effectiveness of decompression plus fusion and decompression alone for patients with degenerative lumbar spondylolisthesis, a systematic review and meta-analysis of all available evidence was performed. METHODS: A search of the literature was conducted on PubMed/MEDLINE, EMBASE, and the Cochrane Collaboration Library. Relevant studies comparing decompression plus fusion and decompression alone were selected according to eligibility criteria. Predefined endpoints were extracted and meta-analyzed from the identified studies. RESULTS: Four randomized controlled trials and 13 observational studies were eligible. The pooled data revealed that fusion was associated with significantly higher rates of satisfaction and lower leg pain scores when compared with decompression alone. However, fusion significantly increased the intraoperative blood loss, operative time and hospital stay. Both techniques had similar ODI, back pain scores, complication rate, and reoperation rate. CONCLUSIONS: Based on the available evidence, decompression plus fusion maybe be better than decompression alone in the treatment of degenerative spondylolisthesis. Fusion had advantages of improvement of clinical satisfaction, as well as reduction of postoperative leg pain, with similar complication rate to decompression alone.

Targeting NAD metabolism regulates extracellular adenosine levels to improve the cytotoxicity of CD8+ effector T cells in the tumor microenvironment of gastric cancer.

PURPOSE: Nicotinamide adenine dinucleotide (NAD+) is closely related to the pathogenesis of tumors. However, the effect of NAD+ metabolism of gastric cancer (GC) cells on immune cells remains unexplained. We targeted nicotinamide phosphoribosyltransferase (NAMPT), a rate-limiting enzyme in the NAD+ synthesis salvage pathway, to observe its effect in the immune microenvironment. METHODS: NAMPT of GC cell lines was inhibited by using the small molecule inhibitor (FK866) and short hairpin RNA (shRNA). CCK-8 test and flow cytometry were performed to detect cell viability and apoptosis. Immunofluorescence was used to observe changes in mitochondrial membrane potential (MMP).The transfected GC cells (AGS) and patient-derived organoids (PDOs) were cocultured with activated PBMCs, followed by flow cytometric analysis (FCA) for cytokines and inhibitory marker. The level of NAD and ATP of GC cells (AGS & MKN45) was tested combined with NMN and CD39 inhibitor. RESULTS: Targeting NAD+ by FK866 obviously reduced MMP, which ultimately inhibited proliferation and increased the apoptosis of GC cells. NAMPT silencing reduced intracellular NAD and ATP，further decreased extracellular adenosine. Meawhile, the cytokines of CD8+T cells were significantly increased after cocultured with transfected AGS, and the expression of PD-1 was distinctly decreased. NMN reversed the effect of shNAMPT and enhanced the immunosuppression. Consistent results were obtained by coculturing PBMCs with PDOs. CONCLUSION: Restraining the function of NAMPT resulted in the functional improvement of effector CD8+ T cells by decreasing extracellular adenosine levels and inducing apoptosis of GC cells simultaneously. Therefore, this study demonstrates that NAMPT can be an effective target for gastric cancer immunotherapy.

Rotatable diffractive gratings based on hybrid-aligned cholesteric liquid crystals.

This work proposes a thermally rotatable grating that is based on hybrid-aligned cholesteric liquid crystals (HBA-cholesteric LCs). Experiments reveal that the HBA-cholesteric texture has a uniformly striped domain, which forms a grating, when the ratio of the cell gap to the helical pitch (d/p) is in the range of 2≤d/p≤3. The stripe direction of the HBA-cholesteric grating is predicted by the proposed vertically aligned LC layer model. The stripe direction of the HBA-cholesteric grating rotates continuously under thermal and electrical effects. Furthermore, the HBA-cholesteric grating has a larger rotational angle under the thermal effect (~101°) than under the electrical effect (~48°). Potential applications of the proposed thermally rotatable cholesteric grating for beam steering devices are emphasized.

Correction: PCL NGCs integrated with urolithin-A-loaded hydrogels for nerve regeneration.

Correction for 'PCL NGCs integrated with urolithin-A-loaded hydrogels for nerve regeneration' by Xue-Han Jin et al., J. Mater. Chem. B, 2022, https://doi.org/10.1039/D2TB01624A.

PCL NGCs integrated with urolithin-A-loaded hydrogels for nerve regeneration.

Inflammation and oxidative stress are among the leading causes of poor prognosis after peripheral nerve injury (PNI). Urolithin-A (UA), an intermediate product produced by the catabolism of ellagitannins in the gastrointestinal tract, has anti-inflammatory, antioxidant, and immunomodulatory properties for inflammation, oxidative damage, and aging-related diseases. Hence, we prepared UA-loaded hydrogels and embedded them in the lumen of PCL nerve guide conduits (NGCs). The hydrogels continuously released appropriate doses of UA into the microenvironment. Based on in vitro studies, UA facilitates cell proliferation and reduces oxidative damage. Besides, the experimental evaluation revealed good biocompatibility of the materials involved. We implanted NGCs into rat models to bridge the sciatic nerve defects in an in vivo study. The sciatic functional index of the PCL/collagen/UA group was comparable to that of the autograft group. Additionally, the consequences of electrophysiological, gastrocnemius muscle and nerve histology assessment of the PCL/collagen/UA group were better than those in the PCL and PCL/collagen groups and close to those in the autograft group. In this study, UA sustained release via the PCL/collagen/UA NGC was found to be an effective alternative treatment for PNI, validating our hypothesis that UA could promote regeneration of nerve tissue.

Ti3C2Tx MXene-Coated Electrospun PCL Conduits for Enhancing Neurite Regeneration and Angiogenesis.

An electrical signal is the key basis of normal physiological function of the nerve, and the stimulation of the electric signal also plays a very special role in the repair process of nerve injury. Electric stimulation is shown to be effective in promoting axonal regeneration and myelination, thereby promoting nerve injury repair. At present, it is considered that electric conduction recovery is a key aspect of regeneration and repair of long nerve defects. Conductive neural scaffolds have attracted more and more attention due to their similar electrical properties and good biocompatibility with normal nerves. Herein, PCL and MXene-PCL nerve guidance conduits (NGCs) were prepared; their effect on nerve regeneration was evaluated in vitro and in vivo. The results show that the NGCs have good biocompatibility in vitro. Furthermore, a sciatic nerve defect model (15 mm) of SD rats was made, and then the fabricated NGCs were implanted. MXene-PCL NGCs show similar results with the autograft in the sciatic function index, electrophysiological examination, angiogenesis, and morphological nerve regeneration. It is possible that the conductive MXene-PCL NGC could transmit physiological neural electric signals, induce angiogenesis, and stimulate nerve regeneration. This paper presents a novel design of MXene-PCL NGC that could transmit self-originated electric stimulation. In the future, it can be combined with other features to promote nerve regeneration.

Dynamic limited axial compression yields favorable functional outcomes in the fixation of Pauwels type-3 femoral neck fractures: A retrospective cohort study.

PURPOSE: Pauwels type-3 femoral neck fractures are challenging injuries to manage with high rates of complications after internal fixation and no consensus has been reached regarding the optimal fixation construct. The current study aims to evaluate the effect of dynamic limited axial compression in parallel screws combined with medial buttress plate (SMBP) or lateral compression plate (LCP) fixation of Pauwels type-3 femoral neck fractures. METHODS: We performed a retrospective analysis of 51 cases of Pauwels type-3 femoral neck fractures who were fixed by SMBP or LCP. Specifically, the screw fixing the femoral head in the buttress plate was omitted. Postoperative complications and functional outcomes were mainly studied. RESULTS: With a mean follow-up of 19.9 months, the rate of neck shortening was higher in the LCP group than that in SMBP group (32.1% vs. 8.7%, p = 0.04). Neither nonunion nor avascular necrosis was observed in both groups. Good-to-excellent Harris hip score accounts for 95.2% in SMBP group and 89.3% in LCP group (p = 0.40). Moreover, older age, fracture comminution and compression plate fixation predispose to neck shortening. CONCLUSION: Dynamic limited axial compression by SMBP or LCP fixation was effective to improve the functional outcome of patients with Pauwels type-3 femoral neck fractures.

Deep neural network-assisted computed tomography diagnosis of metastatic lymph nodes from gastric cancer.

BACKGROUND: Artificial intelligence-assisted image recognition technology is currently able to detect the target area of an image and fetch information to make classifications according to target features. This study aimed to use deep neural networks for computed tomography (CT) diagnosis of perigastric metastatic lymph nodes (PGMLNs) to simulate the recognition of lymph nodes by radiologists, and to acquire more accurate identification results. METHODS: A total of 1371 images of suspected lymph node metastasis from enhanced abdominal CT scans were identified and labeled by radiologists and were used with 18,780 original images for faster region-based convolutional neural networks (FR-CNN) deep learning. The identification results of 6000 random CT images from 100 gastric cancer patients by the FR-CNN were compared with results obtained from radiologists in terms of their identification accuracy. Similarly, 1004 CT images with metastatic lymph nodes that had been post-operatively confirmed by pathological examination and 11,340 original images were used in the identification and learning processes described above. The same 6000 gastric cancer CT images were used for the verification, according to which the diagnosis results were analyzed. RESULTS: In the initial group, precision-recall curves were generated based on the precision rates, the recall rates of nodule classes of the training set and the validation set; the mean average precision (mAP) value was 0.5019. To verify the results of the initial learning group, the receiver operating characteristic curves was generated, and the corresponding area under the curve (AUC) value was calculated as 0.8995. After the second phase of precise learning, all the indicators were improved, and the mAP and AUC values were 0.7801 and 0.9541, respectively. CONCLUSION: Through deep learning, FR-CNN achieved high judgment effectiveness and recognition accuracy for CT diagnosis of PGMLNs. TRIAL REGISTRATION: Chinese Clinical Trial Registry, No. ChiCTR1800016787; http://www.chictr.org.cn/showproj.aspx?proj=28515.

Evolutionary-Optimized Photonic Network Structure in White Beetle Wing Scales.

Most studies of structural color in nature concern periodic arrays, which through the interference of light create color. The "color" white however relies on the multiple scattering of light within a randomly structured medium, which randomizes the direction and phase of incident light. Opaque white materials therefore must be much thicker than periodic structures. It is known that flying insects create "white" in extremely thin layers. This raises the question, whether evolution has optimized the wing scale morphology for white reflection at a minimum material use. This hypothesis is difficult to prove, since this requires the detailed knowledge of the scattering morphology combined with a suitable theoretical model. Here, a cryoptychographic X-ray tomography method is employed to obtain a full 3D structural dataset of the network morphology within a white beetle wing scale. By digitally manipulating this 3D representation, this study demonstrates that this morphology indeed provides the highest white retroreflection at the minimum use of material, and hence weight for the organism. Changing any of the network parameters (within the parameter space accessible by biological materials) either increases the weight, increases the thickness, or reduces reflectivity, providing clear evidence for the evolutionary optimization of this morphology.

Dihydroartemisinin inhibits catabolism in rat chondrocytes by activating autophagy via inhibition of the NF-κB pathway.

Osteoarthritis is a disease with inflammatory and catabolic imbalance in cartilage. Dihydroartemisinin (DHA), a natural and safe anti-malarial agent, has been reported to inhibit inflammation, but its effects on chondrocytes have yet to be elucidated. We investigated the effects of DHA on catabolism in chondrocytes. Viability of SD rats chondrocytes was analyzed. Autophagy levels were determined via expression of autophagic markers LC3 and ATG5, GFP-LC3 analysis, acridine orange staining, and electron microscopy. ATG5 siRNA induced autophagic inhibition. Catabolic gene and chemokine expression was evaluated using qPCR. The NF-κB inhibitor SM7368 and p65 over-expression were used to analyze the role of NF-κB pathway in autophagic activation. A concentration of 1 µM DHA without cytotoxicity increased LC3-II and ATG5 levels as well as autophagosomal numbers in chondrocytes. DHA inhibited TNF-α-induced expression of MMP-3 and -9, ADAMTS5, CCL-2 and -5, and CXCL1, which was reversed by autophagic inhibition. TNF-α-stimulated nuclear translocation and degradation of the p65 and IκBα proteins, respectively, were attenuated in DHA-treated chondrocytes. NF-κB inhibition activated autophagy in TNF-α-treated chondrocytes, but p65 over-expression reduced the autophagic response to DHA. These results indicate that DHA might suppress the levels of catabolic and inflammatory factors in chondrocytes by promoting autophagy via NF-κB pathway inhibition.

Protective effects of total saponins of panax notoginseng on steroid-induced avascular necrosis of the femoral head in vivo and in vitro.

This research was designed to investigate the protective effects of TSPN on steroid-induced avascular necrosis of the femoral head (ANFH) and the likely mechanisms of those effects. As an in vivo study, TSPN was shown to be protective against steroid-induced ANFH due to the upregulation of VEGF-A. Furthermore, TSPN attenuated the apoptosis of osteocytes and reduced the expression of Caspase-3 relative to the model group. As an in vitro study, TSPN exerted a concentration-dependent protective effect against apoptosis in MC3T3-E1 cells. Moreover, TSPN (at a dose of 100 µg/mL) significantly reversed the dexamethasone-induced augmentation of Caspase-3 expression and activity. Therefore, our study demonstrated that TSPN had a protective effect against steroid-induced ANFH that was related to the upregulation of VEGF-A and the inhibition of apoptosis and Caspase-3 activation.