High Reactivity of Dimethyl Ether Activated by Zeolite Ferrierite within a Fer Cage: A Prediction Study.

The zeolite-catalyzed conversion of DME into chemicals is considered environmentally friendly in industry. The periodic density functional theory, statistical thermodynamics, and the transition state theory are used to study some possible parallel reactions about the hydrogen-bonded DME over zeolite ferrierite. The following are the key findings: (1) the charge separation probably leads to the conversion of a hydrogen-bonded DME into a dimethyl oxonium ion (i.e., DMO+ or (CH3)2OH+) with a positive charge of about 0.804 e; (2) the methylation of DME, CH3OH, H2O, and CO by DMO+ at the T2O6 site of zeolite ferrierite shows the different activated internal energy (∆E≠) ranging from 18.47 to 30.06 kcal/mol, implying the strong methylation ability of DMO+; (3) H-abstraction by DMO+ is about 3.94-15.53 or 6.57-18.16 kcal/mol higher than DMO+ methylation in the activation internal energy; (4) six DMO+-mediated reactions are more likely to occur due to the lower barriers, compared to the experimental barrier (i.e., 39.87 kcal/mol) for methyl acetate synthesis; (5) active intermediates, such as (CH3)3O+, (CH3)2OH+, CH3CO+, CH3OH2+, and CH2=OH+, are expected to appear; (6) DMO+ is slightly weaker than the well-known surface methoxy species (ZO-CH3) in methylation; and (7) the methylated activity declines in the order of DME, CH3OH, H2O, and CO, with corresponding rate constants at 463.15 K of about 3.4 × 104, 1.1 × 102, 0.18, and 8.2 × 10-2 s-1, respectively.

Mechanic study based on untargeted metabolomics of Pi-pa-run-fei-tang on pepper combined with ammonia induced chronic cough model mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Pi-pa-run-fei-tang (PPRFT), a traditional Chinese medicine formula with long-standing history, demonstrated beneficial effect on chronic cough. However, the mechanism underlying efficacy unclear. In current research, we explored the impact and molecular mechanism of chronic cough mouse stimulating with capsaicin combined with ammonia. AIM OF THE STUDY: To investigate the metabolic modulating effects, and potential mechanisms underlying the therapeutic effect of PPRFT in chronic cough. MATERIALS AND METHODS: Chronic cough mouse models were created by stimulating mice by capsaicin combined with ammonia. Number of coughs and cough latency within 2 min were recorded. With lung tissue and serum samples collected for histopathology, metabolomics, RT-qPCR, immunohistochemistry, and WB analysis. Lymphocytes were isolated and flow cytometric assays were conducted to evaluate the differentiation between Th17 and Treg cell among CD4+ cells. RESULTS: Results indicated that PPRFT obviously reduced the number of coughs, prolonged cough latency, reduced inflammatory cell infiltration and lung tissues damage, and decreased the serum level of IL-6, IL-1ß, TNF-α, and IL-17 while increasing IL-10 levels. Notably, PPRFT suppressed Th17 cell divergence and promoted Treg cell divergence. Furthermore, serum metabolomic assays showed that 46 metabolites differed significantly between group, with 35 pathways involved. Moreover, mRNA levels of IL-6, NF-κB, IL-17, RORγT, JAK2, STAT3, PI3K and AKT in lung tissues remarkably reduced and mRNA levels of IL-10 and FOXP3 were elevated after PPRFT pretreatment. Additionally, PPRFT treatments decreased the protein levels of IL-6, NF-κB, IL-17, RORγT, p-JAK2, p-STAT3, p-PI3K, and p-AKT and increased the protein levels of IL-10 and FOXP3, but no significantly effects to the levels on JAK2, STAT3, PI3K, and AKT in the lungs. CONCLUSION: Conclusively, our result suggested the effect with PPRFT on chronic cough may be mediated through IL-6/JAK2/STAT3 and PI3K/AKT/NF-κB pathway, which regulate the differentiation between Th17 and Treg cell. This beneficial effect of PPRFT in capsaicin and ammonia-stimulated chronic cough mice indicates its potential application in treating chronic cough.

Plasma trimethylamine N-oxide metabolites in the second trimester predict the risk of hypertensive disorders of pregnancy: a nested case-control study.

The relationship between gut microbiota products trimethylamine oxide (TMAO) and related metabolites including betaine, choline and L-carnitine and hypertensive disorders of pregnancy (HDP) is unclear. In order to examine whether plasma TMAO and related metabolites predict the risk of HDP, a nested case-control study was conducted in Chinese women based on a prospective cohort including 9447 participants. 387 pairs of pregnant women (n = 774) were matched and their plasma TMAO, betaine, choline, and L-carnitine at 16-20 gestational weeks were measured by liquid chromatography-mass spectrometry. Odds ratio (OR) and the 95% confidence interval (95% CI) were calculated using the conditional logistic regression, to examine the association between TMAO metabolites and HDP. The findings showed that higher plasma betaine (≥24.94 µmol/L) was associated with a decreased risk of HDP and its subtype gestational hypertension (GH), with adjusted ORs of 0.404 (95% CI: 0.226-0.721) and 0.293 (95% CI: 0.134-0.642), respectively. Higher betaine/choline ratio (>2.64) was associated with a lower risk of HDP and its subtype preeclampsia or chronic hypertension with superimposed preeclampsia (PE/CH-PE), with adjusted ORs of 0.554 (95% CI: 0.354-0.866) and 0.226 (95% CI: 0.080-0.634). Moreover, compared with traditional factors (TFs) model, the TMAO metabolites+ TFs model had a higher predictive ability for PE/CH-PE (all indexes P values < 0.0001). Therefore, it suggests that the detection of plasma betaine and choline in the early second trimester of pregnancy can better assess the risk of HDP.

Enhancer-mediated FOXO3 expression promotes MSC adipogenic differentiation by activating autophagy.

BACKGROUND: Mesenchymal stem cells (MSCs) are pluripotent stem cells capable of differentiating into osteocytes, adipocytes and chondrocytes. However, in osteoporosis, the balance of differentiation is tipped toward adipogenesis and the key mechanism is controversial. Researches have shown that, as upstream regulatory elements of gene expression, enhancers ar involved in the expression of identity genes. In this study, we identified enhancers-mediated gene FOXO3 promoting MSC adipogenic differentiation by activating autophagy. METHODS: We integrated data of RNA sequencing (RNA-seq), chromatin immunoprecipitation sequencing (ChIP-seq) and ATAC-sequencing (ATAC-seq) to find the identity gene FOXO3. The expression of FOXO3 protein, adipogenic transcription factors and the substrate of autophagy were measured by western blotting. The Oil Red O (ORO) staining was used to visualize the adipogenesis of MSCs. Immunohistochemistry was used to visualize the FOXO3 expression in adipocytes in bone marrow. Immunofluorescence was used to detect the expression of PPARγ and LC3B. RESULTS: During adipogenesis, enhancers redistribute to genes associated with adipogenic differentiation, among which we identified the pivotal identity gene FOXO3. FOXO3 could promote the expression of the adipogenic transcription factors PPARγ, CEBPα, and CEBPß during adipogenic differentiation, while PPARγ, CEBPα, and CEBPß could in turn bind to FOXO3 and continue to promote FOXO3 expression to form a positive feedback loop. Consistently elevated FOXO3 expression promotes autophagy by activating the PI3K-AKT pathway which mediates adipogenic differentiation. CONCLUSIONS: Pivotal identity gene FOXO3 promotes autophagy by activating PI3K-AKT pathway, which provokes adipogenic differentiation of MSCs. Enhancer-regulated adipogenic identity gene FOXO3 could be an attractive treatment for osteoporosis.

Laser additive manufacturing of shape memory biopolymer bone scaffold: 3D conductive network construction and electrically driven mechanism.

INTRODUCTION: The electro-actuated shape memory polymer scaffold has gained increasing attentions on the utilization of minimally invasive surgery for bone defect repair, which requires to construct an efficient conductive network to accomplish electrical-to-thermal conversion from conductive fillers to the entire matrix evenly. OBJECTIVES: In this study, multiwall carbon nanotube (MWCNT) was convective self-assembled on the ZnO tetrapod (t-ZnO) template, where MWCNT was controlled to disperse uniformly and regulated to contact with each other effectively due to the immersion capillary force during the evaporation loss of the convective self-assembly process, leading to an interwoven layer on the t-ZnO surface. METHODS: The prepared t-ZnO@MWCNT assembly was embedded in the poly(L-lactic acid)/thermoplastic polyurethane (PLLA/TPU) scaffold fabricated via selective laser sintering to construct a 3D conductive MWCNT network for improving the electro-actuated shape memory properties. RESULTS: It was observed that the interconnected MWCNT formed a 3D conductive network in the matrix without significant aggregation, which boosted the electrical-to-thermal properties of the scaffold, and the scaffold containing t-ZnO@MWCNT assembly possessed better electro-actuated shape memory properties with shape fixity of 98.0% and shape recovery of 98.8%. CONCLUSION: The scaffold exhibited improved electro-actuated shape memory properties and mechanical properties and the osteogenic inductivity was promoted with the combined effect of t-ZnO and electrical stimulation.

Silencing circSERPINE2 restrains mesenchymal stem cell senescence via the YBX3/PCNA/p21 axis.

Increasing evidence indicates that circular RNAs (circRNAs) accumulate in aging tissues and nonproliferating cells due to their high stability. However, whether upregulation of circRNA expression mediates stem cell senescence and whether circRNAs can be targeted to alleviate aging-related disorders remain unclear. Here, RNA sequencing analysis of differentially expressed circRNAs in long-term-cultured mesenchymal stem cells (MSCs) revealed that circSERPINE2 expression was significantly increased in late passages. CircSERPINE2 small interfering RNA delayed MSC senescence and rejuvenated MSCs, while circSERPINE2 overexpression had the opposite effect. RNA pulldown followed by mass spectrometry revealed an interaction between circSERPINE2 and YBX3. CircSERPINE2 increased the affinity of YBX3 for ZO-1 through the CCAUC motif, resulting in the sequestration of YBX3 in the cytoplasm, inhibiting the association of YBX3 with the PCNA promoter and eventually affecting p21 ubiquitin-mediated degradation. In addition, our results demonstrated that senescence-related downregulation of EIF4A3 gave rise to circSERPINE2. In vivo, intra-articular injection of si-circSerpine2 restrained native joint-resident MSC senescence and cartilage degeneration in mice with aging-related osteoarthritis. Taken together, our findings provide strong evidence for a regulatory role for the circSERPINE2/YBX3/PCNA/p21 axis in MSC senescence and the therapeutic potential of si-circSERPINE2 in alleviating aging-associated syndromes, such as osteoarthritis.

Targeting macrophage M1 polarization suppression through PCAF inhibition alleviates autoimmune arthritis via synergistic NF-κB and H3K9Ac blockade.

Sustained inflammatory invasion leads to joint damage and progressive disability in several autoimmune rheumatic diseases. In recent decades, targeting M1 macrophage polarization has been suggested as a promising therapeutic strategy for autoimmune arthritis. P300/CBP-associated factor (PCAF) is a histone acetyltransferase (HAT) that exhibits a strong positive relationship with the proinflammatory microenvironment. However, whether PCAF mediates M1 macrophage polarization remains poorly studied, and whether targeting PCAF can protect against autoimmune arthritis in vivo remains unclear. Commonly used drugs can cause serious side effects in patients because of their extensive and nonspecific distribution in the human body. One strategy for overcoming this challenge is to develop drug nanocarriers that target the drug to desirable regions and reduce the fraction of drug that reaches undesirable targets. In this study, we demonstrated that PCAF inhibition could effectively inhibit M1 polarization and alleviate arthritis in mice with collagen-induced arthritis (CIA) via synergistic NF-κB and H3K9Ac blockade. We further designed dextran sulfate (DS)-based nanoparticles (DSNPs) carrying garcinol (a PCAF inhibitor) to specifically target M1 macrophages in inflamed joints of the CIA mouse model via SR-A-SR-A ligand interactions. Compared to free garcinol, garcinol-loaded DSNPs selectively targeted M1 macrophages in inflamed joints and significantly improved therapeutic efficacy in vivo. In summary, our study indicates that targeted PCAF inhibition with nanoparticles might be a promising strategy for treating autoimmune arthritis via M1 macrophage polarization inhibition.

Pi-Pa-Run-Fei-Tang alleviates lung injury by modulating IL-6/JAK2/STAT3/IL-17 and PI3K/AKT/NF-κB signaling pathway and balancing Th17 and Treg in murine model of OVA-induced asthma.

ETHNOPHARMACOLOGICAL RELEVANCE: Pi-Pa-Run-Fei-Tang (PPRFT) is an empirical TCM prescription for treating asthma. However, the underlying mechanisms of PPRFT in asthma treatment have yet to be elucidated. Recent advances have revealed that some natural components could ameliorate asthma injury by affecting host metabolism. Untargeted metabolomics can be used to better understand the biological mechanisms underlying asthma development and identify early biomarkers that can help advance treatment. AIM OF THE STUDY: The aim of this study was to verification the efficacy of PPRFT in the treatment of asthma and to preliminarily explore its mechanism. MATERIALS AND METHODS: A mouse asthma model was built by OVA induction. Inflammatory cell in BALF was counted. The level of IL-6, IL-1ß, and TNF-α in BALF were measured. The levels of IgE in the serum and EPO, NO, SOD, GSH-Px, and MDA in the lung tissue were measured. Furthermore, pathological damage to the lung tissues was detected to evaluate the protective effects of PPRFT. The serum metabolomic profiles of PPRFT in asthmatic mice were determined by GC-MS. The regulatory effects on mechanism pathways of PPRFT in asthmatic mice were explored via immunohistochemical staining and western blotting analysis. RESULTS: PPRFT displayed lung-protective effects through decreasing oxidative stress, airway inflammation, and lung tissue damage in OVA-induced mice, which was demonstrated by decreasing inflammatory cell levels, IL-6, IL-1ß, and TNF-α levels in BALF, and IgE levels in serum, decreasing EPO, NO, and MDA levels in lung tissue, elevating SOD and GSH-Px levels in lung tissue and lung histopathological changes. In addition, PPRFT could regulate the imbalance in Th17/Treg cell ratios, suppress RORγt, and increase the expression of IL-10 and Foxp3 in the lung. Moreover, PPRFT treatment led to decreased expression of IL-6, p-JAK2/Jak2, p-STAT3/STAT3, IL-17, NF-κB, p-AKT/AKT, and p-PI3K/PI3K. Serum metabolomics analysis revealed that 35 metabolites were significantly different among different groups. Pathway enrichment analysis indicated that 31 pathways were involved. Moreover, correlation analysis and metabolic pathway analysis identified three key metabolic pathways: galactose metabolism; tricarboxylic acid cycle; and glycine, serine, and threonine metabolism. CONCLUSION: This research indicated that PPRFT treatment not only attenuates the clinical symptoms of asthma but is also involved in regulating serum metabolism. The anti-asthmatic activity of PPRFT may be associated with the regulatory effects of IL-6/JAK2/STAT3/IL-17 and PI3K/AKT/NF-κB mechanistic pathways.

Reduced APPL1 impairs osteogenic differentiation of mesenchymal stem cells by facilitating MGP expression to disrupt the BMP2 pathway in osteoporosis.

An imbalance of human mesenchymal stem cells (MSCs) adipogenic and osteogenic differentiation plays an important role in the pathogenesis of osteoporosis. Our previous study verified that Adaptor protein, phosphotyrosine interacting with PH domain and leucine zipper 1 (APPL1)/myoferlin deficiency promotes adipogenic differentiation of MSCs by blocking autophagic flux in osteoporosis. However, the function of APPL1 in the osteogenic differentiation of MSCs remains unclear. This study aimed to investigate the role of APPL1 in the osteogenic differentiation of MSCs in osteoporosis and the underlying regulatory mechanism. In this study, we demonstrated the downregulation of APPL1 expression in patients with osteoporosis and osteoporosis mice. The severity of clinical osteoporosis was negatively correlated with the expression of APPL1 in bone marrow MSCs. We found that APPL1 positively regulates the osteogenic differentiation of MSCs in vitro and in vivo. Moreover, RNA sequencing showed that the expression of MGP, an osteocalcin/matrix Gla family member, was significantly upregulated after APPL1 knockdown. Mechanistically, our study showed that reduced APPL1 impaired the osteogenic differentiation of mesenchymal stem cells by facilitating Matrix Gla protein expression to disrupt the BMP2 pathway in osteoporosis. We also evaluated the significance of APPL1 in promoting osteogenesis in a mouse model of osteoporosis. These results suggest that APPL1 may be an important target for the diagnosis and treatment of osteoporosis.

The safety of digestive tract cancer surgery during COVID-19: A living systematic review and meta-analysis.

Surgery is the primary curative treatment of solid cancers. However, its safety has been compromised by the outbreak of COVID-19. Therefore, it is necessary to evaluate the safety of digestive tract cancer surgery in the context of COVID-19. We used the Review Manager software (v.5.4) and Stata software (version 16.0) for meta-analysis and statistical analysis. Sixteen retrospective studies involving 17,077 patients met the inclusion criteria. The data indicates that performing digestive tract cancer surgery during the COVID-19 pandemic led to increased blood loss(MD = -11.31, 95%CI:-21.43 to -1.20, P = 0.03), but did not increase postoperative complications(OR = 1.03, 95%CI:0.78 to1.35, P = 0 0.86), anastomotic leakage (OR = 0.96, 95%CI:0.52 to1.77, P = 0 0.89), postoperative mortality (OR = 0.65, 95%CI:0.40 to1.07, P = 0 0.09), number of transfusions (OR = 0.74, 95%CI:0.30 to 1.80, P = 0.51), number of patients requiring ICU care(OR = 1.37, 95%CI:0.90 to 2.07, P = 0.14), postoperative 30-d readmission (OR = 0.94, 95%CI:0.82 to 1.07, P = 0 0.33), total hospital stay (MD = 0.11, 95%CI:-2.37 to 2.59, P = 0.93), preoperative waiting time(MD = - 0.78, 95%CI:-2.34 to 0.79, P = 0.33), postoperative hospital stay(MD = - 0.44, 95%CI:-1.61 to 0.74, P = 0.47), total operation time(MD = -12.99, 95%CI:-28.00 to 2.02, P = 0.09) and postoperative ICU stay (MD = - 0.02, 95%CI:-0.62 to 0.57, P = 0.94). Digestive tract cancer surgery can be safely performed during the COVID-19.

BTA Deep Hole Vibration Drilling for Nickel-Based Alloys: Cooling Patterns and Cutter Tooth Wear Mechanisms.

The high cutting temperature and poor thermal diffusion efficiency of nickel-based alloys during deep hole machining have become technical challenges in the hole machining field. In this paper, a finite element simulation model of Inconel-718 BTA ordinary drilling and vibration drilling processes was established by using Deform-3D finite element simulation software. The variations in the temperatures of the tool teeth and the workpiece at different positions of the nickel-based alloy under ordinary drilling and vibration drilling were investigated. Additionally, the wear pattern of each tool tooth under the two drilling methods was further analyzed by building an experimental platform for workpiece temperature detection, which reveals the wear and cooling mechanism of nickel-based alloy BTA deep hole drilling. The results show that the average temperatures of the external, intermediate, and central teeth were reduced by 18.1%, 21.1%, and 17.8%, respectively, during vibration drilling. In addition, the workpiece hole wall and hole bottom temperatures were reduced by 5.7% and 4.6%, respectively. To conclude, the experimental tests were consistent with the simulated temperature trends. BTA vibration drilling optimizes the heat exchange conditions between the cutter teeth and the workpiece during the drilling of nickel-based alloys, which effectively reduces the cutting temperature and, thus, improves the wear resistance of the cutter teeth.

Impairment of APPL1/Myoferlin facilitates adipogenic differentiation of mesenchymal stem cells by blocking autophagy flux in osteoporosis.

An imbalance of human mesenchymal stem cells (hMSCs) adipogenic and osteogenic differentiation is crucial in the pathogenesis of osteoporosis, and elucidation of the underlying mechanism is urgently needed. APPL1, an adaptor protein of the adiponectin receptor, was recently shown to be closely related to bone mass. However, the role of APPL1 in the imbalance of hMSC differentiation in osteoporosis is unclear. Therefore, we aimed to explore the mechanisms by which APPL1 alters hMSCs adipogenic differentiation in osteoporosis. Here, we found that APPL1 expression was downregulated in elderly patients with osteoporosis and in mouse osteoporosis model. APPL1 negatively regulated hMSC adipogenic differentiation in vivo and in vitro. Mechanistically, by enhancing ubiquitination-mediated Myoferlin degradation, downregulated APPL1 expression increased the risk of lysosome dysfunction during hMSCs adipogenic differentiation. Lysosomal dysfunction inhibited autophagy flux by suppressing autophagosome degradation and promoted hMSC differentiation towards the adipocyte lineage. Our findings suggest that APPL1/Myoferlin downregulation promoted hMSCs adipogenic differentiation by inhibiting autophagy flux, further impairing the balance of hMSCs adipogenic and osteogenic differentiation in osteoporosis; the APPL1/ Myoferlin axis may be a promising diagnostic and therapeutic target for osteoporosis.

Preparation and Analysis of Sheath-Core Intelligent Thermo-Regulating Fiber.

In this work, a skin-core composite intelligent temperature-adjusting fiber was prepared using the composite melt spinning method, with polypropylene as the skin layer and T28-type paraffin as the core layer, in order to obtain clothing fibers with a bidirectional temperature adjustment function. A differential scanning calorimeter was used to test the phase-change latent heat of fibers with different amounts of paraffin injections, and an infrared thermal imager was used to monitor the skin-core composite intelligent temperature-adjusting fiber bundles and ordinary polypropylene fiber bundles under the same heating and cooling conditions. The temperature of the fiber bundle was considered to be a function of time. The results showed that with the increase in the amount of the paraffin injections, the proportion of the paraffin component in the fiber and the latent heat of the fiber phase transition also increased. When the paraffin injection amount was 1.5 mL/min, the melting enthalpy and the crystallization enthalpy reached 65.93 J/g and 66.15 J/g, respectively. Under the same conditions, the heating speed of the intelligent temperature-adjusting fiber bundle was found to be slower than that of the ordinary polypropylene fibers, and the maximum temperature difference between the two reached 8.0 °C. Further, the cooling speed of the former was also observed to be slower than that of the latter, and the maximum temperature difference between the two reached 6.7 °C.

Acupuncture inhibits mammalian target of rapamycin, promotes autophagy and attenuates neurological deficits in a rat model of hemorrhagic stroke.

BACKGROUND: Intracerebral hemorrhage (ICH) accounts for approximately 15% of all stroke cases. Previous studies suggested that acupuncture may improve ICH-induced neurological deficits. Therefore, we investigated the effects of acupuncture on neurological deficits in an animal model of ICH. METHODS: Adult male Sprague-Dawley rats were injected with autologous blood (50 µL) into the right caudate nucleus. Additional rats underwent sham surgery as controls. ICH rats either received acupuncture (GV20 through GB7 on the side of the lesion) or sham acupuncture (1 cm to the right side of the traditional acupuncture point locations). Some ICH rats received acupuncture plus rapamycin injection into the right lateral ventricle. Neurological deficits in the various groups were assessed based on composite neurological score. The perihemorrhagic penumbra was analyzed by histopathology following hematoxylin-eosin staining. Levels of autophagy-related proteins light chain (LC)3 and p62 as well as of mammalian target of rapamycin (mTOR)-related proteins, and phosphorylated (p)-mTOR and p-S6K1 (ribosomal protein S6 kinase beta-1), were assessed by Western blotting. RESULTS: Acupuncture significantly improved composite neurological scores 7 days after ICH (17.7 ± 1.49 vs 14.8 ± 1.32, p < 0.01). Acupuncture augmented autophagosome and autolysosome accumulation based on transmission electron microscopy. Acupuncture significantly increased expression of LC3 (p < 0.01) but decreased expression of p62 (p < 0.01). Acupuncture also reduced levels of p-mTOR and p-S6K1 (both p < 0.01). CONCLUSION: Acupuncture improved neurological deficits in a rat model of ICH, possibly by inhibiting the mTOR pathway and activating autophagy.

Application and progress of medical imaging in total mesopancreas excision for pancreatic head carcinoma.

Pancreatic head carcinoma (PHC) is one of the common gastrointestinal malignancies with a high morbidity and poor prognosis. At present, radical surgery is still the curative treatment for PHC. However, in clinical practice, the actual R0 resection rate, the local recurrence rate, and the prognosis of PHC are unsatisfactory. Therefore, the concept of total mesopancreas excision (TMpE) is proposed to achieve R0 resection. Although there have various controversies and discussions on the definition, the range of excision, and clinical prognosis of TMpE, the concept of TMpE can effectively increase the R0 resection rate, reduce the local recurrence rate, and improve the prognosis of PHC. Imaging is of importance in preoperative examination for PHC; however, traditional imaging assessment of PHC does not focus on mesopancreas. This review discusses the application of medical imaging in TMpE for PHC, to provide more accurate preoperative evaluation, range of excision, and more valuable postoperative follow-up evaluation for TMpE through imaging. It is believed that with further extensive research and exploratory application of TMpE for PHC, large-sample and multicenter studies will be realized, thus providing reliable evidence for imaging evaluation.

Effects of long-term culture on the biological characteristics and RNA profiles of human bone-marrow-derived mesenchymal stem cells.

Expansion in vitro prior to mesenchymal stem cells (MSCs) application is a necessary process. Functional and genomic stability has a crucial role in stem-cell-based therapies. However, the exact expression and co-expressed profiles of coding and non-coding RNAs in human bone marrow (BM)-MSCs in vitro aging are still lacking. In the present studies, the change of morphology, immunophenotype, and capacity of proliferation, differentiation, and immunoregulation of MSCs at passage (P) 4, P6, P8, P10, and P12 were investigated. RNA sequencing identified that 439 mRNAs, 65 long noncoding RNAs (lncRNAs), 59 microRNAs (miRNAs), and 229 circular RNAs (circRNAs) were differentially expressed (DE) in P12 compared with P4, with a similar trend in P6. Gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and gene set enrichment analysis (GSEA) identified several significant biological processes and pathways, including binding, ossification, and Wnt and PPAR signaling pathways. Interaction and co-expression/localization analyses were performed for DE mRNAs and lncRNAs, and several key lncRNAs, circRNAs, and important pathways like autophagy and mitophagy were identified in the competing endogenous RNA (ceRNA) network. Some key RNAs found in the bioinformatics analysis were validated. Our studies indicate that replicative senescence of MSCs is a continuous process, including widespread alterations in biological characteristics and global gene expression patterns that need to be considered before therapeutic applications of MSCs.

A sequentially responsive nanogel via Pt(IV) crosslinking for overcoming GSH-mediated platinum resistance.

Chemotherapy efficiency of platinum(II) (Pt(II)) is often attenuated owing to the low intracellular drugs concentration and glutathione (GSH)-mediated detoxification. To address these problems, we fabricated a step-by-step responsive nanogel (~160 nm) by copolymerization between four functional monomers. Hydrophilic methoxypolyethylene glycols (mPEG) distributedrandomly on the surface of particles endowed the nanogel with "stealth" property in blood circulation, while the chemical crosslinking inside particles by platinum(IV) (Pt(IV)) linker remarkably increased the stability of nanogel in vivo. These advantages of nanogels leaded to higher accumulation at tumor region (6.4% ID/g), followed by triggering the dePEGylation effect by the cleavage of ortho ester at tumoral extracellular pH. Meanwhile, the exposed phenylboric acid (PBA) could significantly increase cellular uptake and intracellular drugs levels by targteing sialic acid residues on the cells membrane. More importantly, this nanogels could further deplete intracellular glutathione (GSH) by the dual-regulation of platinum(IV) and arylboronic ester, resulting in enhanced platinum(II) toxicity both in vitro and in vivo, eventually achieving superior inhibition rate (79.14%) in A549/DDP tumor. Thus, the sequentially responsive nanogel could be considered as an effective strategy for cancer treatment.

Dual-functional scaffolds of poly(L-lactic acid)/nanohydroxyapatite encapsulated with metformin: Simultaneous enhancement of bone repair and bone tumor inhibition.

Bone defects caused by tumors are difficult to repair clinically because of their poor morphology and residual tumor cell-induced recurrence. Scaffolds with the dual function of bone repair and bone tumor treatment are urgently needed to resolve this problem. In this study, a poly(L-lactic acid) (PLLA)/nanoscale hydroxyapatite (nHA)/metformin (MET) nanocomposite scaffold was constructed via selective laser sintering. The scaffolds were expected to combine the excellent mechanical strength and biodegradability of PLLA, the good bioactivity of nHA, and the water solubility and antitumor properties of MET. The PLLA/nHA/MET scaffolds showed improved cell adhesion, appropriate porosity, good biocompatibility and osteogenic-induced ability in vitro because metformin improves water solubility and promotes the osteogenic differentiation of cells within the scaffold. The PLLA/nHA/MET scaffold had an extended drug release time because the MET particles were wrapped in the biodegradable polymer PLLA and the wrapped MET particles were slowly released into body fluids as the PLLA was degraded. Moreover, the scaffold induced osteosarcoma (OS) cell apoptosis by upregulating apoptosis-related gene expression and showed excellent tumor inhibition characteristics in vitro. In addition, the scaffold induced osteogenic differentiation of bone marrow mesenchymal cells (BMSCs) by promoting osteogenic gene expression. The results suggest that the PLLA/nHA/MET composite scaffold has the dual function of tumor inhibition and bone repair and therefore it provides a promising new approach for the treatment of tumor-induced bone defects.

In Situ Generation of Hydroxyapatite on Biopolymer Particles for Fabrication of Bone Scaffolds Owning Bioactivity.

Hydroxyapatite (HAP) can endow a biopolymer scaffold with good bioactivity and osteoconductive ability, while the interfacial bonding is fairly weak between HAP and biopolymers. In this study, HAP was in situ generated on poly(l-lactic acid) (PLLA) particles, and then they were used to fabricate a scaffold by selective laser sintering. Detailedly, PLLA particles were first functionalized by dopamine oxide polymerization, which introduced abundance active catechol groups on the particle surface, and subsequently, the catechol groups concentrated Ca2+ ions by chelation in a simulated body fluid solution, and then, Ca2+ ions absorbed PO43- ions through electrostatic interactions for in situ nucleation of HAP. The results indicated that HAP was homogeneously generated on the PLLA particle surface, and HAP and PLLA exhibited good interfacial bonding in the HAP/PLLA scaffolds. Meanwhile, the scaffolds displayed excellent bioactivity by inducing apatite precipitation and provided a good environment for human bone mesenchymal stem cell attachment, proliferation, and osteogenic differentiation. More importantly, the ingrowth of blood vessel and the formation of new bone could be stimulated by the scaffolds in vivo, and the bone volume fraction and bone mineral density increased by 44.44 and 41.73% compared with the pure PLLA scaffolds, respectively. Serum biochemical indexes fell within the normal range, which indicated that there was no harmful effect on the normal functioning of the body after implanting the scaffold.

Electromagnetized-Nanoparticle-Modulated Neural Plasticity and Recovery of Degenerative Dopaminergic Neurons in the Mid-Brain.

The degeneration of dopaminergic neurons is a major contributor to the pathogenesis of mid-brain disorders. Clinically, cell therapeutic solutions, by increasing the neurotransmitter dopamine levels in the patients, are hindered by low efficiency and/or side effects. Here, a strategy using electromagnetized nanoparticles to modulate neural plasticity and recover degenerative dopamine neurons in vivo is reported. Remarkably, electromagnetic fields generated by the nanoparticles under ultrasound stimulation modulate intracellular calcium signaling to influence synaptic plasticity and control neural behavior. Dopaminergic neuronal functions are reversed by upregulating the expression tyrosine hydroxylase, thus resulting in ameliorating the neural behavioral disorders in zebrafish. This wireless tool can serve as a viable and safe strategy for the regenerative therapy of the neurodegenerative disorders.