Crystalline nanoxylan from hot water extracted wood xylan at multi-length scale: Molecular assembly from nanocluster hydrocolloids to submicron spheroids.

As a contribution to expand accessibility in the territory of bio-based nanomaterials, we demonstrate a novel material strategy to convert amorphous xylan preserved in wood biomass to hierarchical assemblies of crystalline nanoxylan on a multi-length scale. By reducing the end group in pressurized hot water extracted (PHWE) xylan to primary alcohol as a xylitol form with borohydride reduction, the endwise-peeling depolymerization is effectively impeded in the alkali-catalyzed hydrolytic cleavage of side substitutions in xylan. Nanoprecipitation by a gradual pH decrease resulted in a stable hydrocolloid dispersion in the form of worm-like nanoclusters assembled with primary crystallites, owing to the self-assembly of debranched xylan driven by strong intra- and inter-chain H-bonds. With evaporation-induced self-assembly, we can further construct the hydrocolloids as dry submicron spheroids of crystalline nanoxylan (CNX) with a high average elastic modulus of 47-83 GPa. Taking the advantage that the chain length and homogeneity of PHWE-xylan can be tailored, a structure-performance correlation was established between the structural order in CNX and the phosphorescent emission of this crystalline biopolymer. Rigid clusterization and high crystallinity that are constructed by strong intra- and inter-molecule interactions within the nanoxylan effectively restrict the molecular motion, thereby promoting the emission of ultralong organic phosphorescence.

CDK12 Loss Promotes Prostate Cancer Development While Exposing Vulnerabilities to Paralog-Based Synthetic Lethality.

Biallelic loss of cyclin-dependent kinase 12 (CDK12) defines a unique molecular subtype of metastatic castration-resistant prostate cancer (mCRPC). It remains unclear, however, whether CDK12 loss per se is sufficient to drive prostate cancer development-either alone, or in the context of other genetic alterations-and whether CDK12-mutant tumors exhibit sensitivity to specific pharmacotherapies. Here, we demonstrate that tissue-specific Cdk12 ablation is sufficient to induce preneoplastic lesions and robust T cell infiltration in the mouse prostate. Allograft-based CRISPR screening demonstrated that Cdk12 loss is positively associated with Trp53 inactivation but negatively associated with Pten inactivation-akin to what is observed in human mCRPC. Consistent with this, ablation of Cdk12 in prostate organoids with concurrent Trp53 loss promotes their proliferation and ability to form tumors in mice, while Cdk12 knockout in the Pten-null prostate cancer mouse model abrogates tumor growth. Bigenic Cdk12 and Trp53 loss allografts represent a new syngeneic model for the study of androgen receptor (AR)-positive, luminal prostate cancer. Notably, Cdk12/Trp53 loss prostate tumors are sensitive to immune checkpoint blockade. Cdk12-null organoids (either with or without Trp53 co-ablation) and patient-derived xenografts from tumors with CDK12 inactivation are highly sensitive to inhibition or degradation of its paralog kinase, CDK13. Together, these data identify CDK12 as a bona fide tumor suppressor gene with impact on tumor progression and lends support to paralog-based synthetic lethality as a promising strategy for treating CDK12-mutant mCRPC.

Development of high-efficiency superparamagnetic drug delivery system with MPI imaging capability.

In this study, a high-efficiency superparamagnetic drug delivery system was developed for preclinical treatment of bladder cancer in small animals. Two types of nanoparticles with magnetic particle imaging (MPI) capability, i.e., single- and multi-core superparamagnetic iron oxide nanoparticles (SPIONs), were selected and coupled with bladder anti-tumor drugs by a covalent coupling scheme. Owing to the minimal particle size, magnetic field strengths of 270 mT with a gradient of 3.2 T/m and 260 mT with a gradient of 3.7 T/m were found to be necessary to reach an average velocity of 2 mm/s for single- and multi-core SPIONs, respectively. To achieve this, a method of constructing an in vitro magnetic field for drug delivery was developed based on hollow multi-coils arranged coaxially in close rows, and magnetic field simulation was used to study the laws of the influence of the coil structure and parameters on the magnetic field. Using this method, a magnetic drug delivery system of single-core SPIONs was developed for rabbit bladder therapy. The delivery system consisted of three coaxially and equidistantly arranged coils with an inner diameter of Φ50 mm, radial height of 85 mm, and width of 15 mm that were positioned in close proximity to each other. CCK8 experimental results showed that the three types of drug-coupled SPION killed tumor cells effectively. By adjusting the axial and radial positions of the rabbit bladder within the inner hole of the delivery coil structure, the magnetic drugs injected could undergo two-dimensional delivery motions and were delivered and aggregated to the specified target location within 12 s, with an aggregation range of about 5 mm × 5 mm. In addition, the SPION distribution before and after delivery was imaged using a home-made open-bore MPI system that could realistically reflect the physical state. This study contributes to the development of local, rapid, and precise drug delivery and the visualization of this process during cancer therapy, and further research on MPI/delivery synchronization technology is planned for the future.

Stimuli-responsive thin film composites of conducting polymers and cellulose nanocrystals for tissue engineering.

Thin composite films comprising two primary representatives of conducting polymers, poly(3, 4-ethylenedioxythiophene) (PEDOT) and polypyrrole (PPy), with eco-friendly cellulose nanocrystals (CNC) were prepared through electrochemical polymerization. The combination of CNC and PEDOT (or PPy) results in the formation of films with highly different surface topography and thickness. Intriguingly, different surface conductivity of PEDOT and PPy was revealed by atomic force microscopy albeit that the electrochemical properties were rather similar. The biological properties of the composites in contact with prospective human induced pluripotent stem cells (hiPSC) and cardiomyocytes derived from hiPSC demonstrated good cytocompatibility of both composites and their potential in engineering of electro-sensitive tissues. The as-prepared conducting, eco-friendly and cytocompatible composites are thus promising candidates for biomedical applications where stimuli-responsivity is a crucial cell-instructive property.

NSD2 is a requisite subunit of the AR/FOXA1 neo-enhanceosome in promoting prostate tumorigenesis.

The androgen receptor (AR) is a ligand-responsive transcription factor that binds at enhancers to drive terminal differentiation of the prostatic luminal epithelia. By contrast, in tumors originating from these cells, AR chromatin occupancy is extensively reprogrammed to drive hyper-proliferative, metastatic, or therapy-resistant phenotypes, the molecular mechanisms of which remain poorly understood. Here, we show that the tumor-specific enhancer circuitry of AR is critically reliant on the activity of Nuclear Receptor Binding SET Domain Protein 2 (NSD2), a histone 3 lysine 36 di-methyltransferase. NSD2 expression is abnormally gained in prostate cancer cells and its functional inhibition impairs AR trans-activation potential through partial off-loading from over 40,000 genomic sites, which is greater than 65% of the AR tumor cistrome. The NSD2-dependent AR sites distinctly harbor a chimeric AR-half motif juxtaposed to a FOXA1 element. Similar chimeric motifs of AR are absent at the NSD2-independent AR enhancers and instead contain the canonical palindromic motifs. Meta-analyses of AR cistromes from patient tumors uncovered chimeric AR motifs to exclusively participate in tumor-specific enhancer circuitries, with a minimal role in the physiological activity of AR. Accordingly, NSD2 inactivation attenuated hallmark cancer phenotypes that were fully reinstated upon exogenous NSD2 re-expression. Inactivation of NSD2 also engendered increased dependency on its paralog NSD1, which independently maintained AR and MYC hyper-transcriptional programs in cancer cells. Concordantly, a dual NSD1/2 PROTAC degrader, called LLC0150, was preferentially cytotoxic in AR-dependent prostate cancer as well as NSD2-altered hematologic malignancies. Altogether, we identify NSD2 as a novel subunit of the AR neo-enhanceosome that wires prostate cancer gene expression programs, positioning NSD1/2 as viable paralog co-targets in advanced prostate cancer.

Targeting the mSWI/SNF Complex in POU2F-POU2AF Transcription Factor-Driven Malignancies.

The POU2F3-POU2AF2/3 (OCA-T1/2) transcription factor complex is the master regulator of the tuft cell lineage and tuft cell-like small cell lung cancer (SCLC). Here, we found that the POU2F3 molecular subtype of SCLC (SCLC-P) exhibits an exquisite dependence on the activity of the mammalian switch/sucrose non-fermentable (mSWI/SNF) chromatin remodeling complex. SCLC-P cell lines were sensitive to nanomolar levels of a mSWI/SNF ATPase proteolysis targeting chimera (PROTAC) degrader when compared to other molecular subtypes of SCLC. POU2F3 and its cofactors were found to interact with components of the mSWI/SNF complex. The POU2F3 transcription factor complex was evicted from chromatin upon mSWI/SNF ATPase degradation, leading to attenuation of downstream oncogenic signaling in SCLC-P cells. A novel, orally bioavailable mSWI/SNF ATPase PROTAC degrader, AU-24118, demonstrated preferential efficacy in the SCLC-P relative to the SCLC-A subtype and significantly decreased tumor growth in preclinical models. AU-24118 did not alter normal tuft cell numbers in lung or colon, nor did it exhibit toxicity in mice. B cell malignancies which displayed a dependency on the POU2F1/2 cofactor, POU2AF1 (OCA-B), were also remarkably sensitive to mSWI/SNF ATPase degradation. Mechanistically, mSWI/SNF ATPase degrader treatment in multiple myeloma cells compacted chromatin, dislodged POU2AF1 and IRF4, and decreased IRF4 signaling. In a POU2AF1-dependent, disseminated murine model of multiple myeloma, AU-24118 enhanced survival compared to pomalidomide, an approved treatment for multiple myeloma. Taken together, our studies suggest that POU2F-POU2AF-driven malignancies have an intrinsic dependence on the mSWI/SNF complex, representing a therapeutic vulnerability.

Integrating network pharmacology and bioinformatics to explore and experimentally verify the regulatory effect of Buyang Huanwu decoction on glycolysis and angiogenesis after cerebral infarction.

ETHNOPHARMACOLOGICAL RELEVANCE: Promoting the recovery of cerebral blood circulation after cerebral infarction (CI) is an important intervention. Buyang Huanwu decoction (BHD) is a classic prescription for treating CI that promotes angiogenesis. Cytoplasmic glycolysis ischaemic-region cells after CI may be highly activated to maintain metabolic activity under hypoxia. From the perspective of long-term maintenance of glycolytic metabolism in the ischaemic area after CI, it may be beneficial to promote angiogenesis and maintain glial cell activation and neuronal survival. In this context, the regulatory relationship of lncRNAs and miRNAs with mRNAs is worthy of attention. Mining the competitive binding relationships among RNAs will aid in the screening of key gene targets post-CI. In this study, network pharmacology and bioinformatics were used to construct a ceRNA network, screen key targets, and explore the effect of glycolysis on angiogenesis during BHD-mediated CI regulation. AIM OF THE STUDY: This study aimed to explore the effect of BHD on angiogenesis after glycolysis regulation in CI. MATERIALS AND METHODS: According to the 21 active BHD ingredients we identified by our research team, we conducted network pharmacology. BHD targets that can regulate glycolysis and angiogenesis after CI were screened from the GeneCards, CTD and OMIM databases. We retrieved CI-related datasets from the GEO database and screened for differentially expressed lncRNAs and miRNAs. LncRNA‒miRNA-mRNA/TF targeting relationships were screened and organized with the miRcode, miRDB, TargetScan, miRWalk, and TransmiR v2.0 databases. Cytoscape was used to construct an lncRNA‒miRNA-mRNA/TF ceRNA network. Through BioGPS, key mRNAs/TFs in the network were screened for enrichment analysis. Animal experiments were then conducted to validate some key mRNAs/TFs and enriched signalling pathways. RESULTS: PFKFB3 and other genes may help regulate glycolysis and angiogenesis through AMPK and other signalling pathways. The anti-CI effect of BHD may involve maintaining activation of genes such as AMPK and PFKFB3 in the ischaemic cortex, maintaining moderate glycolysis levels in brain tissue, and promoting angiogenesis. CONCLUSION: BHD can regulate glycolysis and promote angiogenesis after CI through multiple pathways and targets, in which AMPK signalling pathway activation may be important.

Metal Ion-controlled Growth of Different Metal-Organic Framework Micro/nanostructures for Enhanced Supercapacitor Performance.

We report a metal ion-modulated effective strategy to achieve different metal-organic framework (MOF) micro/nanostructures using different metal precursors like CoCl2 ⋅ 6H2 O, CoCl2 ⋅ 6H2 O and NiCl2 ⋅ 6H2 O, and NiCl2 ⋅ 6H2 O with pyridine-3,5-dicarboxylate (3,5-pdc). The structural characterizations confirm that different morphological structures, hollow microsphere, hierarchical nanoflower, and solid nanosphere are for Co-(3,5-pdc), Co0.19 Ni0.81 -(3,5-pdc), and Ni-(3,5-pdc), respectively. These different MOF micro/nanostructures correlate with the coordination ability of Co and Ni with 3,5-pdc. Benefitting from the synergistic effect of the alloying metal nodes of Co and Ni producing rapid and rich redox reactions and the hierarchical nanoflower with higher surface area enabling excellent ion kinetics, the Co0.19 Ni0.81 -(3,5-pdc) exhibits higher specific capacitance of 515 F g-1 /273 C g-1 at 0.5 A g-1 than that of Ni-(3,5-pdc) (290 F g-1 /153.7 C g-1 ) and Co-(3,5-pdc) (132 F g-1 /67 C g-1 ), good rate capability and cycling stability. Moreover, the asymmetric supercapacitor device (Co0.19 Ni0.81 -(3,5-pdc)//AC) assembled from Co0.19 Ni0.81 -(3,5-pdc) and activated carbon (AC) achieves a maximum energy density of 42.6 Wh kg-1 at a power density of 277.3 W kg-1 .

Photocross-Linkable and Shape-Memory Biomaterial Hydrogel Based on Methacrylated Cellulose Nanofibres.

In the context of three-dimensional (3D) cell culture and tissue engineering, 3D printing is a powerful tool for customizing in vitro 3D cell culture models that are critical for understanding the cell-matrix and cell-cell interactions. Cellulose nanofibril (CNF) hydrogels are emerging in constructing scaffolds able to imitate tissue in a microenvironment. A direct modification of the methacryloyl (MA) group onto CNF is an appealing approach to synthesize photocross-linkable building blocks in formulating CNF-based bioinks for light-assisted 3D printing; however, it faces the challenge of the low efficiency of heterogenous surface modification. Here, a multistep approach yields CNF methacrylate (CNF-MA) with a decent degree of substitution while maintaining a highly dispersible CNF hydrogel, and CNF-MA is further formulated and copolymerized with monomeric acrylamide (AA) to form a super transparent hydrogel with tuneable mechanical strength (compression modulus, approximately 5-15 kPa). The resulting photocurable hydrogel shows good printability in direct ink writing and good cytocompatibility with HeLa and human dermal fibroblast cell lines. Moreover, the hydrogel reswells in water and expands to all directions to restore its original dimension after being air-dried, with further enhanced mechanical properties, for example, Young's modulus of a 1.1% CNF-MA/1% PAA hydrogel after reswelling in water increases to 10.3 kPa from 5.5 kPa.

Aqueous Processable One-Dimensional Polypyrrole Nanostructured by Lignocellulose Nanofibril: A Conductive Interfacing Biomaterial.

One-dimensional (1D) nanomaterials of conductive polypyrrole (PPy) are competitive biomaterials for constructing bioelectronics to interface with biological systems. Synergistic synthesis using lignocellulose nanofibrils (LCNF) as a structural template in chemical oxidation of pyrrole with Fe(III) ions facilitates surface-confined polymerization of pyrrole on the nanofibril surface within a submicrometer- and micrometer-scale fibril length. It yields a core-shell nanocomposite of PPy@LCNF, wherein the surface of each individual fibril is coated with a thin nanoscale layer of PPy. A highly positive surface charge originating from protonated PPy gives this 1D nanomaterial a durable aqueous dispersity. The fibril-fibril entanglement in the PPy@LCNFs facilely supported versatile downstream processing, e.g., spray thin-coating on glass, flexible membranes with robust mechanics, or three-dimensional cryogels. A high electrical conductivity in the magnitude of several to 12 S·cm-1 was confirmed for the solid-form PPy@LCNFs. The PPy@LCNFs are electroactive and show potential cycling capacity, encompassing a large capacitance. Dynamic control of the doping/undoping process by applying an electric field combines electronic and ionic conductivity through the PPy@LCNFs. The low cytotoxicity of the material is confirmed in noncontact cell culture of human dermal fibroblasts. This study underpins the promises for this nanocomposite PPy@LCNF as a smart platform nanomaterial in constructing interfacing bioelectronics.

Personalizing oral delivery of nanoformed piroxicam by semi-solid extrusion 3D printing.

Semi-solid extrusion (SSE) 3D printing enables flexible designs and dose sizes to be printed on demand and is a suitable tool for fabricating personalized dosage forms. Controlled Expansion of Supercritical Solution (CESS®) is a particle size reduction technology, and it produces particles of a pure active pharmaceutical ingredient (API) in a dry state, suspendable in the printing ink. In the current study, as a model API of poorly water-soluble drug, nanoformed piroxicam (nanoPRX) prepared by CESS® was accommodated in hydroxypropyl methylcellulose- or hydroxypropyl cellulose-based ink formulations to warrant the printability in SSE 3D printing. Importantly, care must be taken when developing nanoPRX formulations to avoid changes in their polymorphic form or particle size. Printing inks suitable for SSE 3D printing that successfully stabilized the nanoPRX were developed. The inks were printed into films with escalating doses with exceptional accuracy. The original polymorphic form of nanoPRX in the prepared dosage forms was not affected by the manufacturing process. In addition, the conducted stability study showed that the nanoPRX in the prepared dosage form remained stable for at least three months from printing. Overall, the study rationalizes that with nanoparticle-based printing inks, superior dose control for the production of personalized dosage forms of poorly water-soluble drugs at the point-of-care can be achieved.

Template-Directed Polymerization of Binary Acrylate Monomers on Surface-Activated Lignin Nanoparticles in Toughening of Bio-Latex Films.

Fabricating bio-latex colloids with core-shell nanostructure is an effective method for obtaining films with enhanced mechanical characteristics. Nano-sized lignin is rising as a class of sustainable nanomaterials that can be incorporated into latex colloids. Fundamental knowledge of the correlation between surface chemistry of lignin nanoparticles (LNPs) and integration efficiency in latex colloids and from it thermally processed latex films are scarce. Here, an approach to integrate self-assembled nanospheres of allylated lignin as the surface-activated cores in a seeded free-radical emulsion copolymerization of butyl acrylate and methyl methacrylate is proposed. The interfacial-modulating function on allylated LNPs regulates the emulsion polymerization and it successfully produces a multi-energy dissipative latex film structure containing a lignin-dominated core (16% dry weight basis). At an optimized allyl-terminated surface functionality of 1.04 mmol g-1 , the LNPs-integrated latex film exhibits extremely high toughness value above 57.7 MJ m-3 . With multiple morphological and microstructural characterizations, the well-ordered packing of latex colloids under the nanoconfinement of LNPs in the latex films is revealed. It is concluded that the surface chemistry metrics of colloidal cores in terms of the abundance of polymerization-modulating anchors and their accessibility have a delicate control over the structural evolution of core-shell latex colloids.

Facile fabrication of AgVO3/rGO/BiVO4 hetero junction for efficient degradation and detoxification of norfloxacin.

In the recent past, the development of efficient materials for degradation and detoxification of antibiotics has gained more attention in wastewater treatment process. As a visible light active material AgVO3 has attracted much concern in environmental remediation. To improve its efficiency and stability, a novel heterojunction was prepared by combining AgVO3 with rGO and BiVO4 through a hydrothermal method. The prepared AgVO3/rGO/BiVO4 composite was further utilized for effective detoxification of Norfloxacin (NFC) antibiotic. The morphological analysis revealed the clear rod shaped AgVO3 and leaf like BiVO4 that are evenly distributed on reduced graphene oxide (rGO) layers. The visible light absorbance and the catalytic activity of AgVO3/rGO/BiVO4 was dramatically improved compared to pure AgVO3 and BiVO4. From the results it showed that the degradation efficiency of AgVO3/rGO/BiVO4 (∼96.1%, k = 0.01782 min-1) was 2.5 times higher than pure AgVO3 and 3.4 times higher than the pure BiVO4 respectively towards NFC after 90 min. The higher efficiency could be attributed to the heterojunction formation and faster charge separation. The radical trapping experiments results indicated that the •OH, and O2•- are the main species responsible for degradation. The degradation products of NFC were analysed through ESI-LC/MS and pathway was proposed. Furthermore, the toxicity assessment of pure NFC and its degradation products was studied using E. coli as the model bacteria through colony forming unit assay and the results indicated the efficient detoxification was attained during the degradation process. Thus, our study provides new insight into detoxification of antibiotics using AgVO3 based composites.

Aqueous Two-Phase Emulsion Bioresin for Facile One-Step 3D Microgel-Based Bioprinting.

Microgel assembly as void-forming bioinks in 3D bioprinting has evidenced recent success with a highlighted scaffolding performance of these bottom-up biomaterial systems in supporting the viability and function of the laden cells. Here, a ternary-component aqueous emulsion is established as a one-step strategy to integrate the methacrylated gelatin (GelMA) microgel fabrication and assembly through vat photopolymerization in situ using digital light processing (DLP)-based bioprinting. The as-proposed aqueous emulsion is featured with the partitioning of a secondary photo-crosslinkable polysaccharide, methacrylated galactoglucomannan (GGMMA) derived from plant source in both the dispersed phase of GelMA droplets and the continuous phase of dextran (Dex). As an emulgator, GGMMA renders enhanced stability of the aqueous emulsion bioresins. Strategically, the photo-crosslinkable GGMMA adheres the GelMA microgels that are conveniently converted from emulsion droplets to form hydrogel construct in layer-by-layer curing to accommodate the laden cells directly mixed in the aqueous emulsion. The spatially interconnected void space left by the removal of Dex benefits the cell growth under the guidance of the microgel surface and supports cell colonization within the macroscopic porous hydrogel. This work amends a low-concentration and cost-effective bioresin that is highly applicable for facilely fabricating microgel assembly as a porous hydrogel construct in DLP-based bioprinting.

High glucose promotes apoptosis and autophagy of MC3T3-E1 osteoblasts.

Introduction: Diabetes and osteoporosis are common metabolic diseases. Abnormal high glucose can lead to the apoptosis of osteoblasts. Autophagy is a highly conserved cellular process that degrades proteins or organelles. In the present study, we comparatively analyzed the effects of high glucose and glucose fluctuation on apoptosis and autophagy of MC3T3-E1 osteoblasts. Material and methods: MC3T3-E1 cells were respectively treated with different concentrations of D-glucose: 5.5 mM for the control group, 25 mM for the high glucose group and 5.5/25 mM for the glucose fluctuation group. Results: High glucose and glucose fluctuation decreased MC3T3-E1 proliferation and activated autophagy. Also, high glucose and glucose fluctuation might induce the production of reactive oxygen species, decline the mitochondrial membrane potential and trigger apoptosis. The differences in the glucose fluctuation treatment group were more significant. Moreover, N-acetylcysteine, an antioxidant reagent, dramatically eliminated the intracellular reactive oxygen species induced by high glucose and glucose fluctuation, and significantly inhibited the autophagy and apoptosis in MC3T3-E1 osteoblasts. Furthermore, treatment with chloroquine, an inhibitor of autophagy, significantly increased the apoptosis of MC3T3-E1 osteoblasts. Conclusions: High glucose, especially high glucose fluctuation, inhibits proliferation and promotes apoptosis and autophagy of MC3T3-E1 osteoblasts. This may occur through inducing oxidative stress and mitochondrial damage in the osteoblasts.

Effects of rTMS combined with rPMS on stroke patients with arm paralysis after contralateral seventh cervical nerve transfer: a case-series.

OBJECTIVE: We conducted this study to evaluate the effect of rTMS combined with rPMS on stroke patients with arm paralysis after CSCNTS. METHODS: A case-series of four stroke patients with arm paralysis, ages ranging from 39 to 51 years, that underwent CSCNTS was conducted. Patients were treated with 10 HZ rTMS on the contralesional primary motor cortex combined with 20 HZ rPMS on groups of elbow and wrist muscles for 15 days. RESULTS: The muscle tone of elbow flexor muscle (EFM), elbow extensor muscle (EEM), wrist flexor muscle (WFM) and flexor digitorum (FD) reduced immediately after operation followed by increasing gradually. After rehabilitation, the muscle tone of EEM and EFM reduced by 14% and 11%, respectively. There was a 13% and 45% change ratio in WFM and FD. The numeric rating scale (mean = 5.75 ± 1.71) was significantly lower (mean = 3.25 ± 1.90, t = 8.66, p = .00). Grip and pinch strength (mean = 23.65 ± 4.91; mean = 4.9 ± 0.59) were significantly higher (mean = 34.63 ± 5.23, t = -61.07, p = .00; mean = 7.1 ± 0.73, t = -13.91, p = .00). CONCLUSIONS: The rehabilitation of stroke patients with arm paralysis after CSCNTS is a long, complicated process which includes great change of neuropathic pain, muscle tone, and muscle strength. In order to enhance the neural connection between the contralesional hemisphere and the hemiplegic limb, alleviate postoperative complications, as well as accelerate the rehabilitation process, we can consider to use rTMS combined with rPMS.

Cranial electrotherapy stimulation alleviates depression-like behavior of post-stroke depression rats by upregulating GPX4-mediated BDNF expression.

To elucidate whether cranial electrotherapy stimulation (CES) improves depression-like behavior of post-stroke depression (PSD) via regulation of glutathione peroxidase 4 (GPX4)-mediated brain-derived neurotrophic factor (BDNF) expression. Middle cerebral artery occlusion (MCAO) and chronic unpredictable mild stress (CUMS) were used to develop a rat PSD model. CES was applied, and RAS-selective lethal 3 (RSL3) was injected into the hippocampus to inhibit GPX4 in PSD rats. The depression behavior was detected by sucrose preference and forced swimming tests. The structure and morphology of the hippocampus were observed and analyzed by histopathological hematoxylin-eosin (HE) staining. The mRNA and protein expressions of GPX4 and BDNF in the hippocampus were detected by qRT-PCR, western blot and immunohistochemical analysis.The degeneration and necrosis of hippocampal neurons, the depression-like behavior were severer and the expression of BDNF in the hippocampus were decreased in PSD rats than those in MCAO and control groups. CES promoted the hippocampal neuron repair, alleviated the depression-like behavior and increased the expression of BDNF in PSD rats. The inhibition of GPX4 by RSL3 exacerbated the depression-like behavior and decreased the expression of BDNF in PSD rats. In addition, we found that RSL3 disrupted the positive effects of CES on the PSD rats. Conclusion: CES improves depression-like behavior of PSD rats through upregulation of GPX4-mediated BDNF expression in the hippocampus.

Uricase sensitizes hepatocellular carcinoma cells to 5-fluorouracil through uricase-uric acid-UMP synthase axis

Conventional chemotherapy plays a key role in hepatocellular carcinoma (HCC) treatment, however, with intrinsic or acquired chemoresistance being a major constraint. Here, we aimed to identify potential target to reverse such chemoresistance. In the present study, we found significant difference in uridine monophosphate synthetase (UMPS) expression between 5-FU resistant and sensitive HCC cell lines and the overexpression or downregulation of UMPS impacted 5-FU response in HCC cells. We further found that inhibition of UMPS activity with uric acid at concentration present in human plasma decreased the 5-FU sensitivity of HCC cells, while reduction of uric acid levels with uricase improved the 5-FU sensitivity of HCC cells as well as colorectal cancer cells. In vivo studies also suggested that modulation of uric acid levels did affect 5-FU sensitivity of tumors. These data indicated that UMPS was correlated with the 5-FU resistance in HCC cells and uricase sensitized cancer cells to 5-FU through uricase-uric acid-UMP synthase axis, which provided a potential strategy to improve the efficacy of 5-FU-based chemotherapy for human cancers. (AU)