Synergic effects and possible mechanism of emodin and stilbene glycosides on colorectal cancer.

BACKGROUND: Polygonum multiflorum (PM) is a core herb that enhances immunity. It can also detoxify, reduce swelling, and intercept malaria. Its main components, emodin (EMD) and 2,3,5,4'-Tetrahydroxy stilbene-2-O-ß-D-glucoside (stilbene glycoside, TSG), have good anti-cancer potential. PURPOSE: The study aims to investigate synergic effects of EMD and TSG on CRC and its possible mechanism. METHODS: Network pharmacology and bioinformatics were used to identify targets. HPLC was used to analyze the effective ingredients in PM and to determine the content of the main ingredients. HT-29 cells were used for in vitro experiments. Cell Counting Kit-8 (CCK8) and scratch test were used to detect the effects of various chemical components of PM on the proliferation and migration of HT-29 cells, and Western Bolt (WB) test was used to evaluate the effects of EMD and TSG on P53 pathway. In vivo experiments, the effects of EMD and TSG were evaluated by measuring tumor weight and tumor volume in CRC mice model and histological analysis were carried out with HE staining. The expressions of HSP90, P53, COX2, and ROS were detected by quantitative reverse transcription polymerase chain reaction (PCR), and IL-1ß, IL-4, IL-6, IL-10, TGF-ß and IFN-γ were detected by enzyme linked immunosorbent assay (ELISA). WB and Immunohistochemistry (IHC) were used to detect the expression of P53 related proteins. RESULTS: Network pharmacology showed PM closely related to colorectal cancer pathway and the core targets included STAT3 and P53; bioinformatics indicated P53 played an important role in the development and prognosis of CRC; chemical analysis showed identified and quantified gallic acid (GA), cis-TSG, trans-TSG, Emodin glucoside(EMDG), physcion glucoside (PHYG), EMD in PM; EMD induced apoptosis and TSG inhibited migration of HT-29 cells; EMD and TSG could coordinately shrink tumor size of CRC mice, elevate expressions of F4/80, decrease the content of IL-6 and TGF-ß, promote tumor oxidized and reduce expression of P53 and STAT3 in the tumor. CONCLUSIONS: In vitro experiments showed that TSG inhibited cancer cell migration and EMD induced apoptosis. EMD and TSG had synergic effects on CRC, whose possible mechanism might be to regulate the expression of cytokines and inhibit P53 pathway.

Structure and pharmacokinetics/pharmacodynamics of the anticoagulant tetradecasaccharide oHG-14 as an intrinsic tenase inhibitor.

The intrinsic tenase complex (iXase) is an attractive antithrombotic target to treat or prevent pathological thrombosis with negligible bleeding risk. Fucosylated glycosaminoglycan (FG) is a promising anticoagulant by inhibiting iXase. A depolymerized FG (dHG-5) as an anticoagulant has been approved for clinical trials. Given that dHG-5 is a multi-component drug candidate consisting of a homologous series of oligosaccharides, it is difficult to predict a clear pharmacokinetics. Here, as a major oligosaccharide component, the tetradecasaccharide (oHG-14) was purified from dHG-5 and its structure was defined as L-Fuc3S4S-α(1,3)-L-Δ4,5GlcA-α(1,3)-{D-GalNAc4S6S-ß(1,4)-[L-Fuc3S4S-α(1,]3)-D-GlcA-ß(1,3)-}3-D-GalNAc4S6S-ß(1,4)-[L-Fuc3S4S-α(1,]3)-D-GlcA-ol. oHG-14 showed potent iXase inhibitory activity in vitro and antithrombotic effect in vivo comparable to dHG-5. After single subcutaneous administration of oHG-14 at 8, 14.4 and 32.4 mg/kg to rats, the absolute bioavailability was 71.6 %-80.9 % determined by the validated bioanalytical methods. The maximum concentration (Cmax) was 3.73, 8.07, and 11.95 µg/mL, respectively, and the time reaching Cmax (Tmax) was about 1 h. oHG-14 was mainly excreted by kidney as the parent compound with the elimination kinetics of first-order linear model. Anticoagulant activity of oHG-14 was positively correlated with its concentration in rat plasma. The pharmacokinetics/pharmacodynamics (PK/PD) of oHG-14 is similar to that of dHG-5. This study could provide supportive data for the clinical trial of dHG-5 and further development of pure oligosaccharide as an antithrombotic drug candidate.

Targeting epidermal growth factor receptor signalling pathway: A promising therapeutic option for COVID-19.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is continuously producing new variants, necessitating effective therapeutics. Patients are not only confronted by the immediate symptoms of infection but also by the long-term health issues linked to long COVID-19. Activation of epidermal growth factor receptor (EGFR) signalling during SARS-CoV-2 infection promotes virus propagation, mucus hyperproduction, and pulmonary fibrosis, and suppresses the host's antiviral response. Over the long term, EGFR activation in COVID-19, particularly in COVID-19-induced pulmonary fibrosis, may be linked to the development of lung cancer. In this review, we have summarised the significance of EGFR signalling in the context of SARS-CoV-2 infection. We also discussed the targeting of EGFR signalling as a promising strategy for COVID-19 treatment and highlighted erlotinib as a superior option among EGFR inhibitors. Erlotinib effectively blocks EGFR and AAK1, thereby preventing SARS-CoV-2 replication, reducing mucus hyperproduction, TNF-α expression, and enhancing the host's antiviral response. Nevertheless, to evaluate the antiviral efficacy of erlotinib, relevant clinical trials involving an appropriate patient population should be designed.

Gallic acid ameliorates dextran sulfate sodium-induced ulcerative colitis in mice via inhibiting NLRP3 inflammasome.

Background: Ulcerative colitis (UC) is a chronic recurrent inflammatory bowel disease (IBD). The conventional drugs for UC may induce severe side effects. Herbal medicine is considered as a complementary and alternative choice for UC. Purpose: This study aims to estimate the effect of natural polyphenol gallic acid (GA) on the NLRP3 inflammasome with dextran sulfate sodium (DSS)-induced colitis in mice. Study design: The body weights and symptoms of BALB/c mice were recorded. Histological evaluation, ELISA, q-PCR, immunohistochemistry, and western blotting were carried out to observe the morphology, cytokine contents, mRNA expressions, and protein expressions, respectively. Lipopolysaccharide (LPS)-induced RAW264.7 macrophage was used to probe GA's effect on relative protein expression. Results: GA attenuated weight loss (p < 0.05), relieved symptoms, and ameliorated colonic morphological injury (p < 0.05) in mice with colitis induced by DSS. GA also lowered the contents of TNF-α, IL-1ß, IL-18, IL-33, and IFN-γ in the serum and colon of mice, which were elevated by DSS, downregulated protein, and mRNA expressions of the NLRP3 pathway in the colon tissue. Furthermore, GA downregulated the expressions of NLRP3 (p < 0.05), iNOS (p < 0.01), COX2 (p < 0.01), and P-p65 (p < 0.05), and suppressed NO release (p < 0.001) in LPS-induced RAW264.7 cells. Conclusion: GA ameliorated DSS-induced UC in mice via inhibiting the NLRP3 inflammasome. These findings furnish evidence for the anti-inflammatory effect of herbal medicines containing GA on UC.

Total Hip Arthroplasty in the Nonparalytic Limb of Residual Poliomyelitis Patients: A Propensity Score Matched Study.

OBJECTIVE: Poliomyelitis is a rare neuromuscular disease that can cause hip osteoarthritis on the contralateral side due to an abnormal mechanical weight-bearing state, making some residual poliomyelitis patients candidates for total hip arthroplasty (THA). The aim of this study was to investigate the clinical outcome of THA in the nonparalytic limbs of these patients compared with those of non-poliomyelitis patients. METHODS: Patients treated between January 2007 and May 2021 were retrospectively identified in a single center arthroplasty database. Eight residual poliomyelitis cases that met the inclusion criteria were matched to non-poliomyelitis cases in a ratio of 1:2 based on age, sex, body mass index (BMI), age-adjusted Charlson comorbidity index (aCCI), surgeon, and operation date. The hip function, health-related quality of life, radiographic outcomes, and complications were analyzed with unpaired Student's t test, Mann-Whitney test, Fisher's exact test or analysis of covariance (ANCOVA). Survivorship analysis was determined using the Kaplan-Meier estimator analysis and Gehan-Breslow-Wilcoxon test. RESULTS: After a mean follow-up of about 5 years, patients with residual poliomyelitis had worse postoperative mobility outcomes(P < 0.05), but there was no difference in total modified Harris hip score (mHHS) or European quality of life-visual analogue scale (EQ-VAS) between the two groups (P > 0.05). There was no difference in radiographic outcomes or complications between the two groups, and patients had similar postoperative satisfaction (P > 0.05). No readmission or reoperation occurred in the poliomyelitis group (P > 0.05), but the postoperative limb length discrepancy (LLD) in the residual poliomyelitis group was greater than that in the control group (P < 0.05). CONCLUSION: Functional outcomes, health-related quality of life improvement were similarly significantly improved in the nonparalytic limb of residual poliomyelitis patients after THA compared with conventional osteoarthritis patients. However, the residual LLD and weak muscle strength of the affected side will still influence mobility, so residual poliomyelitis patients should be fully informed of this outcome before surgery.

Computer Navigation Assisted Restricted Kinematic Alignment Improves Short-Term Outcomes in Total Knee Arthroplasty: An Ambispective Cohort Study.

OBJECTIVES: Mechanical alignment (MA)-total knee arthroplasty (TKA) has been challenged due to the excessive soft tissue release and the evidence of the clinical outcomes of computer assisted navigation is still limited. The aim of this ambispective cohort study was to: (i) investigate whether computer assisted navigation is capable to achieve restricted kinematic alignment (rKA)-TKA; and (ii) compare the short-term outcomes between rKA-TKA and MA-TKA. METHODS: We retrospectively included 41 patients diagnosed with osteoarthritis who received MA-TKA between April 2019 and January 2021 and 43 patients diagnosed with osteoarthritis who received rKA-TKA were included in the prospective cohort from January 2021 to September 2021. Demographical, peri-operative, and radiological data were collected and compared. Unpaired two-sample t-test for continuous variables and χ2 test for categorical variables were used to compare various measurements in two groups. The patient-reported outcome measures at baseline, 10 days (T1), and 6 months (T6) after surgery were statistically analyzed by generalized estimating equation (GEE) models. RESULTS: Fourty-one patients (45 knees) and 43 patients (48 knees) were included in the MA and the rKA group respectively. Three constitutional knee phenotypes (II, I, IV) were the commonest in our population. Navigation improved the surgical accuracy (1.5° vs 3.5°, p < 0.001) and precision (interquartile range 4.0 vs 2.0, p < 0.001) in the rKA group than the MA group. The changes in Knee Injury and Osteoarthritis Outcome Score 12 (KOOS12), EuroQol five-dimension questionnaire (EQ5D) from baseline to T1 and T6 for patients with on-target rKA were larger than on-target MA counterparts (26.053 vs 18.607, P < 0.001(KOOS12, T1) , 0.457 vs 0.367 p < 0.001(EQ5D, T1) ; 51.017 vs 46.896, P = 0.023(KOOS12, T6) , 0.606 vs 0.565, P = 0.01(EQ5D, T6) ). Patients with on-target rKA had better Forgotten Joint Score (FJS) at T1 (54.126 vs 40.965, P = 0.002) compared with on-target MA counterparts. CONCLUSIONS: Computer assisted navigation achieved the level of accuracy required by rKA-TKA. rKA-TKA offered significantly better short-term outcomes than MA-TKA.

Total Knee Arthroplasty in Patients with Primary Sjögren's Syndrome: A Retrospective Case-Control Study Matched Patients without Rheumatic Diseases.

Background: The number of patients with primary Sjögren's syndrome (pSS) who require total knee arthroplasty (TKA) is expected to increase, and there are few studies describing their outcomes. This research was focused on the evaluation of a TKA cohort in pSS patients and to compare outcomes with those of matched individuals from the general population. Methods: From 2004 to 2020, we found 36 TKAs in 30 patients with pSS from the single-institution arthroplasty registry, and they were matched for age, gender, bilateral or unilateral surgery, American Society of Anesthesiologists (ASA) score, and year of surgery with 72 TKAs in 60 osteoarthritis patients without rheumatic diseases (1:2 ratio). Perioperative outcomes were obtained, and clinical evaluations were performed at the last follow-up. Results: After a mean six-year follow-up, both cohorts had similar knee function and health-related quality of life outcomes. The pSS group had more patients with post-operative anemia and hypoalbuminemia and more patients needing platelet transfusion. There were no significant differences in other complications, the rates of 90-day readmission, or overall revision. By multivariate analysis, the influencing factor for anemia in pSS patients was lower preoperative hemoglobin (OR = 0.334, 95% CI (0.125−0.889), p < 0.05). Conclusions: Our study demonstrated that pSS patients who received TKA could achieve comparable clinical outcomes to the general population. However, more attention should be paid to the perioperative hematological management of pSS patients who underwent TKA.

Recent Advances in Detection for Breast-Cancer-Derived Exosomes.

Breast cancer is the most common malignant tumor in women, its incidence is secret, and more than half of the patients are diagnosed in the middle and advanced stages, so it is necessary to develop simple and efficient detection methods for breast cancer diagnosis to improve the survival rate and quality of life of breast cancer patients. Exosomes are extracellular vesicles secreted by all kinds of living cells, and play an important role in the occurrence and development of breast cancer and the formation of the tumor microenvironment. Exosomes, as biomarkers, are an important part of breast cancer fluid biopsy and have become ideal targets for the early diagnosis, curative effect evaluation, and clinical treatment of breast cancer. In this paper, several traditional exosome detection methods, including differential centrifugation and immunoaffinity capture, were summarized, focusing on the latest research progress in breast cancer exosome detection. It was summarized from the aspects of optics, electrochemistry, electrochemiluminescence and other aspects. This review is expected to provide valuable guidance for exosome detection of clinical breast cancer and the establishment of more reliable, efficient, simple and innovative methods for exosome detection of breast cancer in the future.

M6A-mediated upregulation of circMDK promotes tumorigenesis and acts as a nanotherapeutic target in hepatocellular carcinoma.

BACKGROUND: Emerging evidence suggest the critical role of circular RNAs (circRNAs) in disease development especially in various cancers. However, the oncogenic role of circRNAs in hepatocellular carcinoma (HCC) is still largely unknown. METHODS: RNA sequencing was performed to identify significantly upregulated circRNAs in paired HCC tissues and non-tumor tissues. CCK-8 assay, colony formation, transwell, and xenograft mouse models were used to investigate the role of circRNAs in HCC proliferation and metastasis. Small interfering RNA (siRNA) was used to silence gene expression. RNA immunoprecipitation, biotin pull-down, RNA pull-down, luciferase reporter assay and western blot were used to explore the underlying molecular mechanisms. RESULTS: Hsa_circ_0095868, derived from exon 5 of the MDK gene (named circMDK), was identified as a new oncogenic circRNA that was significantly upregulated in HCC. The upregulation of circMDK was associated with the modification of N6-methyladenosine (m6A) and poor survival in HCC patients. Mechanistically, circMDK sponged miR-346 and miR-874-3p to upregulate ATG16L1 (Autophagy Related 16 Like 1), resulting to the activation of PI3K/AKT/mTOR signaling pathway to promote cell proliferation, migration and invasion. Poly (ß-amino esters) (PAEs) were synthesized to assist the delivery of circMDK siRNA (PAE-siRNA), which effectively inhibited tumor progression without obvious adverse effects in four liver tumor models including subcutaneous, metastatic, orthotopic and patient-derived xenograft (PDX) models. CONCLUSIONS: CircMDK could serve as a potential tumor biomarker that promotes the progression of HCC via the miR-346/874-3p-ATG16L1 axis. The PAE-based delivery of siRNA improved the stability and efficiency of siRNA targeting circMDK. The PAE-siRNA nanoparticles effectively inhibited HCC proliferation and metastasis in vivo. Our current findings offer a promising nanotherapeutic strategy for the treatment of HCC.

Validation of CT-Based Three-Dimensional Preoperative Planning in Comparison with Acetate Templating for Primary Total Hip Arthroplasty.

OBJECTIVE: This study aims to compare the accuracy of CT-based preoperative planning with that of acetate templating in predicting implant size, neck length, and neck cut length, and to evaluate the reproducibility of the two methods. METHODS: This prospective study was conducted between August 2020 and March 2021. Patients who underwent elective primary total hip arthroplasty by a single surgeon were assessed for eligibility. The included patients underwent both acetate templating and CT-based planning by two observers after the operation. Each observer conducted both acetate templating and CT-based planning twice for each case. The outcome measures included the following: (1) the accuracy of surgical planning in predicting implant size, calcar length, and neck length, which was defined as the difference between the planned size and length and the actual size and length; (2) reproducibility of the two planning techniques, which were assessed by inter-observer and intra-observer reliability analysis; (3) the influence of potential confounding factors on planning accuracy, which was evaluated using generalized estimating equations. RESULTS: A total of 57 cases were included in the study. CT-based planning was more accurate than acetate templating for predicting cup size (93% vs 79%, p < 0.001) and stem size (93% vs 75%, p < 0.001). When assessed by mean absolute difference, the comparison between acetate templating and CT-based planning was 4.28 mm vs 3.74 mm (p = 0.122) in predicting neck length and 3.05 mm vs 2.93 mm (p = 0.731) in predicting neck cut length. In the inter-observer reliability analysis, an intraclass correlation coefficient (ICC) of 0.790 was achieved for predicting cup size, and an ICC of 0.966 was achieved for predicting stem size using CT-based planning. In terms of intra-observer reliability, Observer 1 achieved an ICC of 0.803 for predicting cup size and 0.965 for predicting stem size in CT-based planning. Observer 2 achieved ICC values of 0.727 and 0.959 for predicting cup and stem sizes, respectively. The average planning time was 6.48 ± 1.55 min for CT-based planning and 6.12 ± 1.40 min for acetate templating (p = 0.015). CONCLUSION: The CT-based planning system is more accurate than acetate templating for predicting implant size and has good reproducibility in total hip arthroplasty.

Host E3 ligase HUWE1 attenuates the proapoptotic activity of the MERS-CoV accessory protein ORF3 by promoting its ubiquitin-dependent degradation.

With the outbreak of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), coronaviruses have begun to attract great attention across the world. Of the known human coronaviruses, however, Middle East respiratory syndrome coronavirus (MERS-CoV) is the most lethal. Coronavirus proteins can be divided into three groups: nonstructural proteins, structural proteins, and accessory proteins. While the number of each of these proteins varies greatly among different coronaviruses, accessory proteins are most closely related to the pathogenicity of the virus. We found for the first time that the ORF3 accessory protein of MERS-CoV, which closely resembles the ORF3a proteins of severe acute respiratory syndrome coronavirus and SARS-CoV-2, has the ability to induce apoptosis in cells in a dose-dependent manner. Through bioinformatics analysis and validation, we revealed that ORF3 is an unstable protein and has a shorter half-life in cells compared to that of severe acute respiratory syndrome coronavirus and SARS-CoV-2 ORF3a proteins. After screening, we identified a host E3 ligase, HUWE1, that specifically induces MERS-CoV ORF3 protein ubiquitination and degradation through the ubiquitin-proteasome system. This results in the diminished ability of ORF3 to induce apoptosis, which might partially explain the lower spread of MERS-CoV compared to other coronaviruses. In summary, this study reveals a pathological function of MERS-CoV ORF3 protein and identifies a potential host antiviral protein, HUWE1, with an ability to antagonize MERS-CoV pathogenesis by inducing ORF3 degradation, thus enriching our knowledge of the pathogenesis of MERS-CoV and suggesting new targets and strategies for clinical development of drugs for MERS-CoV treatment.

Wnt/ß-catenin signaling in colorectal cancer: Is therapeutic targeting even possible?

The Wnt/ß-catenin signaling pathway has been implicated as the central mechanism that drives colorectal carcinogenesis. Its activation is historically due to mutation on APC (adenomatous polyposis coli), resulting to nuclear localization of ß-catenin and expression of Wnt target genes that promote tumor progression. Although this pathway seems to be a pivotal therapeutic target because of its critical role in colorectal cancer, there has been no clinically approved therapies targeting Wnt/ß-catenin signaling pathway to this date. Here, we reviewed the recent progress of this signal transduction pathway in colorectal tumorigenesis. Apart from their roles in cancer initiation, the new pathway modulators (activators and repressors) also participate in chemoresistance, epithelial-mesenchymal transition and cancer stem cell renewal. Of the proteins reported to modulate this pathway, CDX2 (Caudal-related homeobox transcription factor 2) showed potentials as promising molecular target. CDX2 warrants further studies to determine its significance as molecular target for colorectal cancer therapeutics. Overall, the regulation of Wnt/ß-catenin signaling pathway remains intriguingly complex and is not fully understood in spite of the widespread research efforts. Its intricacy remains a major barrier in the development of chemotherapeutic agent that specifically targets it.

Degree of coronal alignment correction can't predict knee function in total knee replacement.

BACKGROUND: Whether neutral alignment brings better clinical outcomes is controversial. Consideration of the preoperative knee condition of patients and some limitations of previous studies, we suggested that other index may be more important than a generic target of 0° ± 3° of a neutral axis to reflect changes in coronal alignment after total knee replacement (TKR). The purpose of this study was to explore the relationship between alignment and functional outcome with a new grouping method and the concept of correction rate. METHODS: The study included 358 knees, the mean follow-up period was 3.62 years. A new grouping method was adopted to divide patients into three groups based on the degree of correction of mechanical femoral-tibial angle (MFTA): under-correction (n = 128), neutral (n = 209) and over-correction (n = 21). Hospital for Special Surgery (HSS) score were compared among the 3 groups (ANOVA with or without LSD t-test). In addition, we also attempt to further explore whether the concept of correction rate can predict postoperative functional score (Simple linear correlation analysis). RESULTS: HSS score showed significant improvement in all groups. There was no difference in HSS score (88.27 vs 88 vs 85.62) (p = 0.88) or incremental scores (26.23 vs 25.22 vs 22.88) (p = 0.25) based on the postoperative alignment category for the degree of correction of MFTA at the last follow-up. The correlational analyses also didn't show any positive results (r = -0.01 p = 0.95, r = -0.01 p = 0.97, r = 0.11 p = 0.15, r = 0.01 p = 0.90). CONCLUSION: Categorization of optimal coronal alignment after TKR may be impractical. But we still believe that the concept of correction rate and new grouping method are worthy of research which can reflects the preoperative knee condition and the change of coronal alignment. Perhaps it can be better used in TKR in the future. LEVEL OF EVIDENCE: III.

Capecitabine Can Induce T Cell Apoptosis: A Potential Immunosuppressive Agent With Anti-Cancer Effect.

Capecitabine (CAP) is now widely used in the comprehensive treatment of digestive system tumors. Some clinical observations have shown that CAP may have immunosuppressive effects, but there is still a lack of clear experimental verification. In this study, different doses of CAP were administered to normal mice by gavage. Our results confirmed that CAP did not cause myelosuppression in bone marrow tissue; CAP selectively reduced the proportion of T cells and the concentration of related pro-inflammatory cytokines, while it increased the concentration of anti-inflammatory cytokines. Thymidylate phosphorylase (TP) is the key enzyme for the transformation of CAP in vivo; this study confirmed that T cells express TP, but the bone marrow tissue lacks TP expression, which explains the selectivity in pharmacodynamic effects of CAP. In addition, it was confirmed that CAP can induce T cell apoptosis in vivo and in vitro. In vitro experiments showed that CAP-induced T cell apoptosis was related to TP expression, endoplasmic reticulum stress (ERS) induction, reactive oxygen species (ROS) production, and mitochondria-mediated apoptosis activation. Therefore, this study confirmed that the differential expression of TP in cells and tissues explains why CAP avoids the toxic effects of myelosuppression while inducing T cell apoptosis to exert the immunosuppressive effect. Therefore, CAP may become an immunosuppressive agent with a simultaneous anti-cancer effect, which is worthy of further studies.

Structural characterization and anticoagulant analysis of the novel branched fucosylated glycosaminoglycan from sea cucumber Holothuria nobilis.

Glycosaminoglycan HnFG was extracted from sea cucumber Holothuria nobilis. Its chemical structure was characterized by analyzing the physicochemical properties, oligosaccharides from its mild acid hydrolysates and depolymerized products. The disaccharide d-GalNAc4S6S-α1,2-l-Fuc3S-ol found in its mild acid hydrolysates provided a clue for the presence of a unique disaccharide-branch in HnFG. Furthermore, it was confirmed by a series of oligosaccharides from the low-molecular weight HnFG prepared by ß-eliminative depolymerization. Combining with the analysis of its peroxide depolymerized products, the precise structure of HnFG was determined: A chondroitin sulfate E (CS-E)-like backbone branched with sulfated monofucoses (~67%) and disaccharides d-GalNAcS-α1,2-l-Fuc3S (~33%) at O-3 position of each GlcUA. This is the first report on the novel branches in glycosaminoglycan. Biologically, the native and depolymerized HnFG showed potent activities in prolonging the activated partial thrombin time (APTT) and inhibiting intrinsic coagulation Xase (iXase), whereas the oligosaccharides (degree of polymerization ≤6) had no obvious effects.

A new fucosylated glycosaminoglycan containing disaccharide branches from Acaudina molpadioides: Unusual structure and anti-intrinsic tenase activity.

A fucosylated glycosaminoglycan (AmFG) was extracted from the sea cucumber Acaudina molpadioides. And a series of oligosaccharides were purified from the size-homogeneous fractions, which were prepared from the ß-eliminative depolymerized AmFG. According to "bottom-up" strategy, the precise structure of AmFG was elucidated by analyzing the structures of these purified oligosaccharides, combining with NMR analysis of its free-radical depolymerized product. It contained a CS-E-like backbone, and each GlcUA was branched with a mono- or di-sulfated fucose (Fuc) at O-3. Intriguingly, besides two types of monosaccharide branches, Fuc2S4S (60 %) and Fuc4S (25 %), that were common in FG, AmFG also contained an unusual disaccharide branch GalNAc-α1,2-Fuc3S4S (15 %); this is the first report of such a structure in a glycosaminoglycan. Biological assays indicated that native AmFG and its oligosaccharides had potent anticoagulant and intrinsic tenase (iXase) inhibitory activities in a chain length-dependent manner. For these oligosaccharides, octasaccharide was the minimum structural fragment for potent anti-iXase activity, and the disaccharide branch might enhance this activity.

Risk factors of hepatic artery thrombosis in pediatric deceased donor liver transplantation.

PURPOSE: Hepatic artery thrombosis (HAT) remains a life-threatening complication in liver transplantation. We aim to investigate the risk factors of HAT in deceased donor pediatric liver transplantation. METHODS: 104 recipients from 2014 to 2016 were enrolled; donor and recipient characteristics, surgical variables, graft and recipient survival rate were compared between recipients with or without HAT. Univariate and multivariate analysis were applied to identify the risk factors of HAT. RESULTS: The recipient survival rate was 87.0% and 96.3% at 1 year, and 87.0% and 96.3% at 3 years in HAT and non-HAT groups without significant difference. The graft survival rate was 73.9% and 96.3% at 1 year, and 73.9% and 95.1% at 3 years in HAT and non-HAT groups; significant difference was observed between two groups at both 1 and 3 years. Donor age less than 8.5 months, graft weight less than 190 g and GRWR less than 2.2% were identified as independent risk factors for HAT. Recipients with HAT were associated with higher incidence of post-operative biliary complications. CONCLUSIONS: Young donor age and small liver graft are risk factors for HAT in deceased donor pediatric liver transplantation.

Feasibility and safety of using low-body-weight donors in pediatric liver transplantation.

BACKGROUND: Donors with low-body-weight were previously reported to be related to inferior recipient outcomes in pediatric liver transplantation. However, the scarce availability of age and size-matched organs has encouraged us to re-evaluate the feasibility and safety of using low-body-weight donors. METHODS: We retrospectively analyzed 91 deceased donor pediatric liver transplantation between January 2014 and December 2016, donor weight less than 5 kg was defined as low-body-weight donors. The recipients were divided into two groups according to donor weight. (≤5 kg and 5 kg < to ≤20 kg). Donor and recipient characteristics, perioperative data, postoperative complications as well as graft and recipient survival rate were compared RESULTS: The recipients and grafts recovery after transplantation were comparable between two groups. The recipients receiving low-body-weight donors showed higher risk of hepatic artery thrombosis and small-for-size syndrome, however, these complications can effectively be treated by our strategies. The 2-year patient survival rates were 92.9% and 95.2%, 2-year graft survival rates were 92.9% and 93.7% in Groups 1 and 2, without significant difference. CONCLUSIONS: Our finding suggested that the utility of livers from low-body-weight donors is a potential strategy to increase donor availability in well-selected pediatric recipients. LEVEL OF EVIDENCE: III.

The effects of Kasai procedure on living donor liver transplantation for children with biliary atresia.

OBJECTIVE: To evaluate the effects of Kasai procedure (hepatic portoenterostomy) on living donor liver transplantation (LDLT) for children with biliary atresia (BA). METHODS: From January 2006 to January 2014, 150 children with BA were treated with LDLT in China. The children were categorized into pre-Kasai and non-Kasai groups, based on whether they had previously undergone Kasai procedure. Clinical data were retrospectively analyzed, and the difference in postoperative survival was compared between the groups. Preoperative data, including height, weight, serum bilirubin, and pediatric end-stage liver disease score, and perioperative blood loss, operation duration, incidence of postoperative surgical complications including vascular complications, bile duct complications, lymphatic fluid leakage, and digestive tract fistula were compared between the groups. RESULTS: In total, 89 and 61 children were categorized in the pre-Kasai and non-Kasai groups, respectively. The 1-, 6-, and 12-month survival was 97.8%, 95.4%, and 95.4% for the Kasai group, and 98.4%, 96.7%, and 96.7% for the non-Kasai group, respectively (P > 0.05). The differences in mean operation duration and mean blood loss, and the incidences of outflow tract obstruction, portal vein stenosis, hepatic artery thrombosis, bile duct complications, lymphatic fluid leakage, and digestive tract fistula were not statistically significant between the groups (P > 0.05). CONCLUSION: Kasai procedure could effectively delay the requirement of liver transplantation. In light of previous findings that Kasai procedure could significantly improve the liver transplantation-free survival of children with BA, we suggest that Kasai procedure should be used as a first-line treatment method for this condition. TYPE OF STUDY: Treatment Study. LEVEL OF EVIDENCE: Level III.

Cellular prion protein is involved in decidualization of mouse uterus.

Prion protein (PrP) is encoded by a single copy gene Prnp in many cell and tissue types. PrP is very famous for its infectious conformers (PrPSC) resulting in transmissible spongiform encephalopathies. At present, physiological functions of its cellular isoform (PrPC) remain ambiguous. Although PrPC expression has been found in uterus, whether it functions in maternal-fetal dialogue during early pregnant is unknown. In this study, we examined PrPC mRNA and protein in the uterus of peri-implantation mice, and found that they were expressed with a spatiotemporal dynamic pattern. Interestingly, PrPC was significantly increased in the decidual zones around the implanting embryos at the implantation window stage. To further demonstrate that PrPC is involved in the decidualization of mouse uterus during embryo implantation, we constructed the artificial decidualization models and the delayed implantation models. Once the pseudopregnant mice were artificially induced to decidualization, the PrPC expression then increased significantly in the decidua zone. And also, if the delayed implantation embryos were allowed to implant, PrPC protein was also simultaneously improved in stromal cells surrounding the implanting embryos. Moreover, PrPC expression can be inhibited by progesterone but upregulated by estrogen in mouse uterus. These results suggest that PrPC may play an important role in embryo implantation and decidualization.