Attenuation of binuclear hepatocytes in the paracancerous liver tissue is associated with short-term recurrence of hepatocellular carcinoma post-radical surgery.

Short-term recurrence of hepatocellular carcinoma (HCC) after radical resection leads to dismal outcomes. To screen high-recurrence risk patients to provide adjuvant treatment is necessary. Herein, based on our previous research, we further focused on the changes in the abundance of binuclear hepatocytes (ABH) in the paracancerous liver tissue to discuss the relationship between the attenuation of binuclear hepatocytes and postoperative short-term recurrence, by combining with the assessment of the value of a reported independent early recurrence risk factor in HCC, protein induced by vitamin K absence or antagonist-II (PIVKA-II). A cohort of 142 paracancerous liver tissues from HCC patients who received radical resection was collected. Binuclear hepatocytes were reduced in the paracancerous liver tissues, compared with the liver tissues from normal donors. ABH was negatively correlated with clinical features such as tumor size, TNM stages, tumor microsatellite formation, venous invasion, and Alpha-fetoprotein (AFP) level, as well as the expression of E2F7 and Anillin, which are two critical regulators concerning the hepatocyte polyploidization. According to the short-term recurrence information, ABH value was laminated, and univariate and multivariate logistic regression was performed to analyze the relationship between paracancerous ABH and short-term tumor relapse. Simultaneously, the predictive effectiveness of the ABH value was compared with the preoperative PIVKA-II value. As observed, the paracancerous ABH value below 1.5% was found to be an independent risk factor for recurrence. In conclusion, the paracancerous ABH is a credible indicator of short-term recurrence of HCC patients after radical resection, and regular assessment of ABH might help to prevent short-term HCC recurrence.

Bone marrow mesenchymal stem cells combined with Atractylodes macrocephala polysaccharide attenuate ulcerative colitis.

The aim of the present study was to explore the effects of bone marrow mesenchymal stem cells (BMSCs), combined with Atractylodes macrocephala polysaccharide (AMP), in an experimental model of ulcerative colitis. BMSCs were first isolated, cultured, and identified by flow cytometry. A rat model of colitis was established by trinitrobenzene sulfonic acid (TNBS) injection. Rats were treated with BMSCs with or without AMP for 1 or 2 weeks. H&E staining was performed to assess the extent of histological injury. IEC-6 and BMSCs were co-cultured and treated with AMP. Cell migration was measured using the Transwell assay, whilst the levels of cytokines in the rat blood samples were detected using ELISA. In addition, cytokine levels in the cell supernatant were measured by microarray. The results showed that BMSCs were successfully isolated. BMSCs treatment could markedly alleviate injury according to histological analysis and regulate inflammatory cytokine production in this rat model of TNBS-induced colitis, where a higher number of BMSCs was found in the intestinal tract, compared to the model. AMP not only potentiated the effects of BMSCs on preventing TNBS-induced colitis but also promoted BMSC homing to the injured tissue and regulated cytokines. Furthermore, BMSCs and AMP promoted the migration of IEC in vitro and influenced multiple genes. In conclusion, AMP treatment improved the therapeutic effects of BMSCs on ulcerative colitis, potentially providing a novel clinical treatment strategy for colitis.

The study on the clinical effectiveness and safety of traditional Chinese medicine acupoint catgut embedding guided by musculoskeletal ultrasound in the treatment of nerve root sciatica: A protocol for systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Nerve root sciatica (NRS) is a common orthopedic disease, which usually occurs between 20 and 40 years of age, and the incidence rate is increasing year by year and is being younger. The disease has no special effect of treatment, clinically generally taking the symptomatic treatment, such as taking short-term glucocorticoids, sedatives, analgesics, and so on. Long-term use of drugs will adversely affect the patient's gastrointestinal tract, liver, and kidney function. The surgical treatment has a high risk of surgery, high cost, side effects, and other problems, so the choice of treatment method has always been a difficult problem in clinical and scientific research. The study shows that 90% of patients with sciatica can be cured by non-surgical treatment, so conservative therapy is often used in the treatment of sciatica, traditional Chinese medicine treatment methods in the treatment of NRS has been widely used, which has achieved good results, but there is no evidence of evidence-based medicine. Therefore, this study uses systematic evaluation to conduct the scientific evaluation of the clinical effectiveness and safety of traditional Chinese medicine acupoint catgut embedding guided by musculoskeletal ultrasound in the treatment of NRS, and provide evidence-based medical evidence support for the treatment of NRS. METHODS: Using the computer to retrieve the PubMed, ScienceDirect, Web of Science, Embase, Cochrane Library, CNKI, VIP, WANFANG Database, and CBM. Using the subject words and terminology words to retrieve the Chinese-English database and retrieve a randomized controlled study on the clinical effectiveness and safety of traditional Chinese medicine acupoint catgut embedding guided by musculoskeletal ultrasound in the treatment of NRS, and the range of search time is January 1990 to January 2021. The searched literature is screened and evaluated by two researchers respectively according to the inclusion and exclusion criteria. If there is disagreement, discussing it with the third researcher to determine the final inclusion of the literature. Using the RevMan 5.3 software to conduct the meta-analysis. RESULTS: This study will compare the effectiveness and safety of traditional Chinese medicine acupoint catgut embedding guided by musculoskeletal ultrasound in the treatment of NRS. CONCLUSION: The results of this study will be published in internationally influential academic journals to provide evidence-based medical evidence for the clinical effectiveness and safety of traditional Chinese medicine acupoint catgut embedding in the treatment of NRS. ETHICS AND DISSEMINATION: This study does not involve specific patients, and all research data comes from publicly available professional literature, so an ethics committee is not required to conduct an ethical review and approval of the study. OSF REGISTRATION NUMBER: DOI 10.17605/OSF.IO/Q492E.

In situ sprayed NIR-responsive, analgesic black phosphorus-based gel for diabetic ulcer treatment.

The treatment of diabetic ulcer (DU) remains a major clinical challenge due to the complex wound-healing milieu that features chronic wounds, impaired angiogenesis, persistent pain, bacterial infection, and exacerbated inflammation. A strategy that effectively targets all these issues has proven elusive. Herein, we use a smart black phosphorus (BP)-based gel with the characteristics of rapid formation and near-infrared light (NIR) responsiveness to address these problems. The in situ sprayed BP-based gel could act as 1) a temporary, biomimetic "skin" to temporarily shield the tissue from the external environment and accelerate chronic wound healing by promoting the proliferation of endothelial cells, vascularization, and angiogenesis and 2) a drug "reservoir" to store therapeutic BP and pain-relieving lidocaine hydrochloride (Lid). Within several minutes of NIR laser irradiation, the BP-based gel generates local heat to accelerate microcirculatory blood flow, mediate the release of loaded Lid for "on-demand" pain relief, eliminate bacteria, and reduce inflammation. Therefore, our study not only introduces a concept of in situ sprayed, NIR-responsive pain relief gel targeting the challenging wound-healing milieu in diabetes but also provides a proof-of-concept application of BP-based materials in DU treatment.

Enhancement of Production of D-Glucosamine in Escherichia coli by Blocking Three Pathways Involved in the Consumption of GlcN and GlcNAc.

D-Glucosamine is a commonly used dietary supplement that promotes cartilage health in humans. Metabolic flux analysis showed that D-glucosamine production could be increased by blocking three pathways involved in the consumption of glucosamine-6-phosphate and acetylglucosamine-6-phosphate. By homologous single-exchange, two key genes (nanE and murQ) of Escherichia coli BL21 were knocked out, respectively. The D-glucosamine yields of the engineered strains E. coli BL21ΔmurQ and E. coli BL21ΔnanE represented increases by factors of 2.14 and 1.79, respectively. Meanwhile, for bifunctional gene glmU, we only knocked out its glucosamine-1-phosphate acetyltransferase domain by 3D structural analysis to keep the engineered strain E. coli BL21glmU-Δgpa survival, which resulted in an increase in the production of D-glucosamine by a factor of 2.16. Moreover, for further increasing D-glucosamine production, two genes encoding rate-limiting enzymes, named glmS and gna1, were coexpressed by an RBS sequence in those engineered strains. The total concentrations of D-glucosamine in E. coli BL21 glmU-Δgpa', E. coli BL21ΔmurQ', and E. coli BL21ΔnanE' were 2.65 g/L, 1.73 g/L, and 1.38 g/L, which represented increases by factors of 8.83, 5.76, and 3.3, respectively.

ROS-Mediated Selective Killing Effect of Black Phosphorus: Mechanistic Understanding and Its Guidance for Safe Biomedical Applications.

Black phosphorus (BP)-based nanomaterials have distinguished advantages and potential applications in various biomedical fields. However, their biological effects in physiological systems remain largely unexplored. Here, we systematically revealed a reactive oxygen species (ROS)-mediated mechanism for the selective killing of cancer cells by BP-based nanosheets. The treatment with BP-based materials can induce higher levels of ROS in cancer cells than in normal cells, leading to significant changes in the cytoskeleton, cell cycle arrest, DNA damage, and apoptosis in tumor cell lines. We revealed that the decreased superoxide dismutase activity by lipid peroxides could be an essential mechanism of the selectively higher ROS generation induced by BP-based nanosheets in cancer cells. In addition, the selective killing effect only occurred within a certain dosage range (named "SK range" in this study). Once exceeding the SK range, BP-based materials could also induce a high ROS production in normal tissues, leading to detectable DNA damage and pathological characteristics in normal organs and raising safety concerns. These findings not only shed light on a new mechanism for the selective killing of cancer cells by BP-based materials but also provide deep insights into the safe use of BP-based therapies.

Development of mazF-based markerless genome editing system and metabolic pathway engineering in Candida tropicalis for producing long-chain dicarboxylic acids.

Candida tropicalis can grow with alkanes or plant oils as the sole carbon source, and its industrial application thus has great potential. However, the choice of a suitable genetic operating system can effectively increase the speed of metabolic engineering. MazF functions as an mRNA interferase that preferentially cleaves single-stranded mRNAs at ACA sequences to inhibit protein synthesis, leading to cell growth arrest. Here, we constructed a suicide plasmid named pPICPJ-mazF that uses the mazF gene of Escherichia coli as a counterselectable marker for the markerless editing of C. tropicalis genes to increase the rate of conversion of oils into long-chain dicarboxylic acids. To reduce the ß-oxidation of fatty acids, the carnitine acetyltransferase gene (CART) was deleted using the gene editing system, and the yield of long-chain acids from the strain was increased to 8.27 g/L. By two homologous single exchanges, the promoters of both the cytochrome P450 gene and the NADPH-cytochrome P450 reductase gene were subsequently replaced by the constitutively expressed promoter pGAP, and the production of long-chain dicarboxylic acids by the generated strain (C. tropicalis PJPP1702) reached 11.39 g/L. The results of fed-batch fermentation showed that the yield of long-chain acids from the strain was further increased to 32.84 g/L, which was 11.4 times higher than that from the original strain. The results also showed that the pPICPJ-mazF-based markerless editing system may be more suited for completing the genetic editing of C. tropicalis.

Integrative bioinformatics analysis identifies ROBO1 as a potential therapeutic target modified by miR-218 in hepatocellular carcinoma.

Patients diagnosed with advanced hepatocellular carcinoma (HCC) presented poor prognosis and short survival time. Althouth accumulating contribution of continuous research has gradually revealed complex tumorigenesis mechanism of HCC with numerous and jumbled biomarkers, those specific ones for HCC diagnose and therapeutic treatment are required illustration. Multiple genes over-expressed in HCC specimens with at least 1.5 fold change were cohorted, compared with the non-cancerous tissues through integrative bioinformatics analysis from Gene Expression Omnibus (GEO) datasets GSE14520 and GSE6764, including 445 and 45 cases of samples spearatly, along with intensive exploration on the Cancer Genome Altas (TCGA) dataset of liver cancer. Thirteen genes significantly highly expressed, overlapping in the datasets above. The Database for Annotation Visualization and Integrated Discovery (DAVID) program was utilized for functional pathway enrichment analysis. Protein-protein Interaction (PPI) analysis was conducted through the Search Tool for the Retrieval of Interacting Genes (STRING) database. ROBO1 was highlighted as one of the most probable molecules among the 13 candidates participating in cancer process. Cancer Cell Line Encycolopedia (CCLE) database was utilized exploring ROBO1 expression in cell lines. Immunochemistry analysis and qRT-PCR assay were performed in our medical center, which indicates significant over-expression status in either HCC tumor specimens and 3 HCC cell lines. Furtherly, we recognized that miR-218, a tumor suppressor, might be an upstream regulator for ROBO1 directly binding to the mRNA 3'UTR and potentially modifying the expression and function of ROBO1. Herein, we conclude that ROBO1 is a mighty therapeutic targets modified by miR-218 in HCC deserving further investigation.

Tumor Microenvironment-Triggered Supramolecular System as an In Situ Nanotheranostic Generator for Cancer Phototherapy.

The efficacy of photosensitizers in cancer phototherapy is often limited by photobleaching, low tumor selectivity, and tumor hypoxia. Assembling photosensitizers into nanostructures can improve photodynamic therapy efficacy and the safety profile of photosensitizers. Herein by employing supramolecular assembly, enhanced theranostic capability of Mn2+ -assisted assembly of a photosensitizer (sinoporphyrin sodium, DVDMS) is demonstrated. A tumor environment-triggered coassembly strategy is further developed to form Mn/DVDMS nanotheranostics (nanoDVD) for cancer phototherapy. MnO2 nanosheets serve as a highly effective DVDMS carrier and in situ oxygen and nanoDVD generator. In MCF-7 cells and xenograft tumors, MnO2 /DVDMS is reduced by glutathione (GSH) and H2 O2 and reassembled into nanoDVD, which can be monitored by activated magnetic resonance/fluorescence/photoacoustic signals. Intriguingly, the decrease of GSH, the production of O2 , and the formation of nanoDVD are shown to be synergistic with phototherapy to improve antitumor efficacy in vitro and in vivo, offering a new avenue for cancer theranostics.

Engineering Phototheranostic Nanoscale Metal-Organic Frameworks for Multimodal Imaging-Guided Cancer Therapy.

Many photoresponsive dyes have been utilized as imaging and photodynamic/photothermal therapy agents. Indocyanine green (ICG) is the only near-infrared region (NIR) organic dye for clinical applications approved by the United States Food and Drug Administration; however, the clinical application of ICG is limited by its poor aqueous solubility, low cancer specificity, and low sensitivity in cancer theranostics. To overcome these issues, a multifunctional nanoplatform based on hyaluronic acid (HA) and ICG-engineered metal-organic framework MIL-100(Fe) nanoparticles (MOF@HA@ICG NPs) was successfully developed for imaging-guided, anticancer photothermal therapy (PTT). The synthesized NPs showed a high loading content of ICG (40%), strong NIR absorbance, and photostability. The in vitro and in vivo imaging showed that the MOF@HA@ICG NPs exhibited greater cellular uptake in CD44-positive MCF-7 cells and enhanced tumor accumulation in xenograft tumors due to their targeting capability, compared to MOF@ICG NPs (non-HA-targeted) and free ICG. The in vitro photothermal toxicity and in vivo PTT treatments demonstrated that MOF@HA@ICG NPs could effectively inhibit the growth of MCF-7 cells/xenograft tumors. These results suggest that MOF@HA@ICG NPs could be served as a new promising theranostic nanoplatform for improved anticancer PTT through cancer-specific and image-guided drug delivery.

Upregulation of adenosine A2A receptors induced by atypical antipsychotics and its correlation with sensory gating in schizophrenia patients.

Sensory gating deficits have been found in patients with schizophrenia and their unaffected relatives. However, the underlying neurobiological mechanism of this deficit remains unclear. Pre-clinical studies have implicated adenosine in sensory gating deficits in schizophrenia. Therefore, the current study investigated a possible relationship between peripheral adenosine A2A receptor (ADORA2A) and sensory gating indices (P50 measures) in medication-free schizophrenia (n=31) and healthy (n=21) groups. The effects of six-week antipsychotic treatment were examined. At baseline, schizophrenia patients showed impaired sensory gating compared to healthy controls. However, there was no significant difference in ADORA2A gene expression among groups. In addition, ADORA2A expression was not correlated with sensory gating at any time point. Following treatment, we found a significant upregulation of ADORA2A expression. Intriguingly, we observed a significant positive association between ADORA2A upregulation and baseline P50 amplitudes in the schizophrenia group. A main finding of the current pilot study is the upregulation of ADORA2A expression following treatment with antipsychotics. In addition, this upregulation was predicted by baseline P50 amplitude, an observation that awaits replication in an expanded sample.

[Simultaneous determination of 7 alkaloid in herba Sophorae Alopecuroidis by HPLC].

OBJECTIVE: To establish a method for determination of 7 alkaloid in Herba Sophorae Alopecuroidis by HPLC. METHOD: X-Brige C18 (4.6 mm x 200 mm, 5 microm) column was used with acetonitriles-0.05 mol x L(-1) KH2PO4 solution (2.0 mL x L(-1) triethylamine) with gradient elution as the mobile phase and 1.0 mL x min(-1) as the flow rate. The detection wavelength was 205 nm. RESULT: Aloperin curve was linear in the range from 20.66 to 103.32 microg (r = 0.998 8) and the average recovery was 97.12% (RSD 7. 3%); sophoridine curve was linear in the range from 22.82 to 114.12 microg (r = 0.999 7) and the average recovery was 97.47% (RSD 3.0%); oxymatrine curve was linear in the range from 25.10 to 125.52 microg (r = 0.999 1) and the average recovery was 96.21% (RSD 4.5%); oxysophocarpine curve was linear in the range from 23.88 to 119.40 microg (r = 0.997 5) and the average recovery was 94. 64% (RSD 5.2%); matrine curve was linear in the range from 5.00 to 24.99 microg (r = 0.998 6) and the average recovery was 98.04% (RSD 5.4%); sophocarping curve was linear in the range from 4.69 to 23.46 microg (r = 0.999 6) and the average recovery was 96.24 (RSD 5.8%); lehmannine curve was linear in the range from 4.60 to 23.01 microg (r = 0.997 8) and the average recovery was 101.31% (RSD 4.3%). CONCLUSION: The method is accurate, simple and feasible. It can be used as a quality evaluation in Herba S. Alopecuroidis.

Neuroleptic effects on P50 sensory gating in patients with first-episode never-medicated schizophrenia.

Sensory gating deficit, as reflected by P50 suppression, has been demonstrated in schizophrenia. Despite extensive evidence of the irreversible effects of typical neuroleptics on this deficit, recent studies of atypical neuroleptics have produced inconsistent findings on the reversibility of P50 suppression in schizophrenia. As the majority of these studies were limited by either their cross-sectional design or the recruitment of patients on multiple medications, the current study was designed to examine the effects of different neuroleptic medications on the P50 sensory gating index in patients with first-episode, never-medicated schizophrenia. P50-evoked potential recordings were obtained from 62 normal controls when they entered the study and from 65 patients with first-episode, never-medicated schizophrenia at baseline and after six weeks of different neuroleptic treatments (sulpiride [n=24], risperidone [n=24] and clozapine [n=17]). The first-episode, never-medicated schizophrenia patients had impaired sensory gating relative to the normal controls (mean=94.19% [SD=61.31%] versus mean=41.22% [SD=33.82%]). The test amplitude S2 was significantly higher in the schizophrenia patients than in the normal controls. The conditioning amplitude S1 and the positive symptom scores were related to the P50 gating ratios in schizophrenia at baseline. There was no change in P50 sensory gating (P>0.10) and a significant improvement in the clinical ratings (P>0.10) after six-week neuroleptic treatment for schizophrenia. P50 sensory gating was not significant for the patients who received sulpiride, risperidone or clozapine at baseline (F=1.074, df=2, 62, P=0.348) or at endpoint (F=0.441, df=2, 62, p=0.646). Our findings indicate that there is P50 sensory gating impairment in first-episode, never-medicated schizophrenia and that treatment with typical and atypical antipsychotics has no significant impact on such gating in this illness.