In situ anchored ternary hierarchical hybrid nickel@cobaltous sulfide on poly(3,4-ethylenedioxythiophene)-reduced graphene oxide for highly efficient non-enzymatic glucose sensing.

A ternary hierarchical hybrid Ni@CoxSy/poly(3,4-ethylenedioxythiophene)-reduced graphene oxide (Ni@CoxSy/PEDOT-rGO) is rationally designed and in situ facilely synthesized as electrocatalyst to construct a binder-free sensing platform for non-enzymatic glucose monitoring through traditional electrodeposition procedure. The as-prepared Ni@CoxSy/PEDOT-rGO presents unique hierarchical structure and multiple valence states as well as strong and robust adhesion between Ni@CoxSy/PEDOT-rGO and GCE. Profiting from the aforementioned merits, the sensing platform constructed under optimal conditions achieved a wide detection range (0.2 µM ~ 2.0 mM) with high sensitivity (1546.32 µA cm-2 mM-1), a rapid response time (5 s), an ultralow detection limit (0.094 µM), superior anti-interference performance, excellent reproducibility and considerable stability. Furthermore, the sensor demonstrates an acceptable accuracy and appreciable recoveries ranging from 90.0 to 102.0% with less than 3.98% RSD in human blood serum samples, indicating the prospect of the sensor for the real samples analysis. It will provide a strategy to rationally design and fabricate ternary hierarchical hybrid as nanozyme for glucose assay.

Caprin-1 influences autophagy-induced tumor growth and immune modulation in pancreatic cancer.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is characterized by rapid progression and poor prognosis. Understanding the genetic mechanisms that affect cancer properties and reprogram tumor immune microenvironment will develop new strategies to maximize the benefits for cancer therapies. METHODS: Gene signatures and biological processes associated with advanced cancer and unfavorable outcome were profiled using bulk RNA sequencing and spatial transcriptome sequencing, Caprin-1 was identified as an oncogenesis to expedite pancreatic cancer growth by activating autophagy. The mechanism of Caprin-1 inducing autophagy activation was further explored in vitro and in vivo. In addition, higher level of Caprin-1 was found to manipulate immune responses and inflammatory-related pathways. The immune profiles associated with increased levels of Caprin-1 were identified in human PDAC samples. The roles of CD4+T cells, CD8+T cells and tumor associated macrophages (TAMs) on clinical outcomes prediction were investigated. RESULTS: Caprin-1 was significantly upregulated in advanced PDAC and correlated with poor prognosis. Caprin-1 interacted with both ULK1 and STK38, and manipulated ULK1 phosphorylation which activated autophagy and exerted pro-tumorigenic phenotypes. Additionally, the infiltrated CD4+T cells and tumor associated macrophages (TAMs) were increased in Caprin-1High tissues. The extensive CD4+T cells determined poor clinical outcome in Caprin-1high patients, arguing that highly expressed Caprin-1 may assist cancer cells to escape from immune surveillance. CONCLUSIONS: Our findings establish causal links between the upregulated expression of Caprin-1 and autophagy activation, which may manipulate immune responses in PDAC development. Our study provides insights into considering Caprin-1 as potential therapeutic target for PDAC treatment.

Gut microbiota aggravates neutrophil extracellular traps-induced pancreatic injury in hypertriglyceridemic pancreatitis.

Hypertriglyceridemic pancreatitis (HTGP) is featured by higher incidence of complications and poor clinical outcomes. Gut microbiota dysbiosis is associated with pancreatic injury in HTGP and the mechanism remains unclear. Here, we observe lower diversity of gut microbiota and absence of beneficial bacteria in HTGP patients. In a fecal microbiota transplantation mouse model, the colonization of gut microbiota from HTGP patients recruits neutrophils and increases neutrophil extracellular traps (NETs) formation that exacerbates pancreatic injury and systemic inflammation. We find that decreased abundance of Bacteroides uniformis in gut microbiota impairs taurine production and increases IL-17 release in colon that triggers NETs formation. Moreover, Bacteroides uniformis or taurine inhibits the activation of NF-κB and IL-17 signaling pathways in neutrophils which harness NETs and alleviate pancreatic injury. Our findings establish roles of endogenous Bacteroides uniformis-derived metabolic and inflammatory products on suppressing NETs release, which provides potential insights of ameliorating HTGP through gut microbiota modulation.

Gut microbiota affects pancreatic fibrotic progression through immune modulation in chronic pancreatitis.

Chronic pancreatitis (CP) is characterized by chronic progressive pancreatic inflammation, which leads to the permanent damage of exocrine and endocrine cells. CP causes irreversible morphological and functional changes, and the clinical manifestations includes abdomen pain, steatorrhea and diabetes. CP induces changes in the composition of gut microbiota that could be used as potential biomarkers for pancreatic fibrosis evaluation. Gut microbiota has emerged as key regulator of immunomodulation and gut microbiota-induced immune activation has not been explored in CP. In current study, we profiled gut microbial signatures in mouse CP model, and found that higher proportion of Streptomyces, Turicibacter, Methylobacterium, Enterococcus and Candidatus_Paenicardiniummore were positively associated with the occurrence of pancreatic fibrosis. We then identified increased CD3+T cells and macrophage infiltration in mouse and human CP tissues by transcriptome sequencing data from GEO database. Subsequently, we demonstrated that fecal microbiota transplantation (FMT) from CP mouse (FMT-CP) exacerbated pancreatic fibrosis by increasing CD4+T cells and macrophage infiltration compared to fecal samples obtained from healthy mouse donor (FMT-HC). Our study describes the link between gut microbiota dysbiosis and immune activation in pancreatic fibrotic progression, and highlights the potential therapeutic roles of FMT and CP treatment.

Fibrinogen-like Protein 1 as a Predictive Marker for the Incidence of Severe Acute Pancreatitis and Infectious Pancreatic Necrosis.

Background and Objectives: Acute pancreatitis (AP) is defined as an acute inflammatory disorder of the pancreas and is a common gastrointestinal disease. Since currently used indicators lack specifics and cannot accurately reflect the phase of disease, better diagnostic approaches need to be explored. Fibrinogen-like protein 1 (FGL-1) is a reactant in acute inflammatory diseases and is increased in the plasma of AP patients. In the current study, we aim to investigate the clinical benefits of FGL-1 in predicting the severity of AP and infected pancreatic necrosis (IPN), which can improve the diagnostic efficiency of AP. Materials and Methods: In this study, 63 patients diagnosed with AP from December 2018 to September 2019 were enrolled. Regarding the severity of AP, patients were separated into severe acute pancreatitis (SAP, n = 12) and No-SAP groups (n = 51). On the basis of infective conditions, patients were divided into IPN (n = 9) and No-IPN (n = 54) groups. The demographic data (sex and age) and blood parameters (WBC, HCT, glucose, calcium, FIB, APTT, PCT, CRP, and FGL-1) were retrospectively analyzed. Results: The plasma FGL-1 levels were increased in both SAP (p < 0.01) and IPN (p < 0.05) subgroups compared to the healthy control group. Multivariate analysis showed that elevated plasma FGL-1 (p < 0.01) and PCT levels (p < 0.05) within 72 h after the onset of AP were positively correlated with the severity of AP, while increased plasma FGL-1 (p < 0.01) and CRP (p < 0.05) levels were positively correlated with the occurrence of IPN. The combination of FGL-1 and PCT showed superiority to both individual markers in SAP prediction. However, the combination of FGL-1 and CRP showed no diagnostic advantage over CRP in IPN prediction. Conclusions: Plasma FGL-1 within 72 h after the onset could be used for the stratification of AP and its infectious complications. The combination of PCT and FGL-1 presents an enormous advantage for the early identification of SAP.

Glabridin, a bioactive component of licorice, ameliorates diabetic nephropathy by regulating ferroptosis and the VEGF/Akt/ERK pathways.

BACKGROUND: Glabridin (Glab) is a bioactive component of licorice that can ameliorate diabetes, but its role in diabetic nephropathy (DN) has seldom been reported. Herein, we explored the effect and underlying mechanism of Glab on DN. METHODS: The bioactive component-target network of licorice against DN was by a network pharmacology approach. The protective effect of Glab on the kidney was investigated by a high-fat diet with streptozotocin induced-diabetic rat model. High glucose-induced NRK-52E cells were used for in vitro studies. The effects of Glab on ferroptosis and VEGF/Akt/ERK pathways in DN were investigated in vivo and in vitro using qRT-PCR, WB, and IHC experiments. RESULTS: Bioinformatics analysis constructed a network comprising of 10 bioactive components of licorice and 40 targets for DN. 13 matching targets of Glab were mainly involved in the VEGF signaling pathway. Glab treatment ameliorated general states and reduced FBG, HOMA-ß, and HOMA-insulin index of diabetic rats. The renal pathological changes and the impaired renal function (the increased levels of Scr, BUN, UREA, KIM-1, NGAL, and TIMP-1) were also improved by Glab. Moreover, Glab repressed ferroptosis by increasing SOD and GSH activity, and GPX4, SLC7A11, and SLC3A2 expression, and decreasing MDA and iron concentrations, and TFR1 expression, in vivo and in vitro. Mechanically, Glab significantly suppressed VEGF, p-AKT, p-ERK1/2 expression in both diabetic rats and HG-induced NRK-52E cells. CONCLUSIONS: This study revealed protective effects of Glab on the kidney of diabetic rats, which might exert by suppressing ferroptosis and the VEGF/Akt/ERK pathway.

Role of Interleukin-17 in Acute Pancreatitis.

Acute pancreatitis (AP) is a leading cause of death and is commonly accompanied by systemic manifestations that are generally associated with a poor prognosis. Many cytokines contribute to pancreatic tissue damage and cause systemic injury. Interleukin-17 (IL-17) is a cytokine that may play a vital role in AP. Specifically, IL-17 has important effects on the immune response and causes interactions between different inflammatory mediators in the AP-related microenvironment. In this literature review, we will discuss the existing academic understanding of IL-17 and the impacts of IL-17 in different cells (especially in acinar cells and immune system cells) in AP pathogenesis. The clinical significance and potential mechanisms of IL-17 on AP deterioration are emphasized. The evidence suggests that inhibiting the IL-17 cytokine family could alleviate the pathogenic process of AP, and we highlight therapeutic strategies that directly or indirectly target IL-17 cytokines in acute pancreatitis.

Microwave-Assisted Chitosan-Functionalized Graphene Oxide as Controlled Intracellular Drug Delivery Nanosystem for Synergistic Antitumour Activity.

To achieve better antitumour efficacy, it is urgent to improve anticancer drug delivery efficiency in targeting cancer cells. In this work, chitosan-functionalized graphene oxide (ChrGO) nanosheets were fabricated via microwave-assisted reduction, which were employed to the intracellular delivery nanosystem for anticancer drug agent in breast cancer cells. Drug loading and release research indicated that adriamycin can be efficiently loaded on and released from the ChrGO nanosheets. Less drug release during delivery and better biocompatibility of ChrGO/adriamycin significantly improve its safety and therapeutic efficacy in HER2-overexpressing BT-474 cells. Furthermore, ChrGO/adriamycin in combination with trastuzumab exhibited synergistic antitumour activity in BT-474 cells, which demonstrated superior therapeutic efficacy compared with each drug alone. Cells treated with trastuzumab (5 µg/mL) or equivalent ChrGO/adriamycin (5 µg/mL) each elicited 54.5% and 59.5% cell death, respectively, while the combination treatment with trastuzumab and ChrGO/adriamycin resulted in a dramatic 88.5% cell death. The dual-targeted therapy displayed higher apoptosis, indicating superior therapeutic efficacy due to the presence of different mechanisms of action. The combined treatment of ChrGO/adriamycin and trastuzumab in BT-474 cells induced cell cycle arrest and apoptosis, which ultimately led to the death of augmented cancer cells. This work has provided a facile microwave-assisted fabrication of ChrGO as a controlled and targeted intracellular drug delivery nanosystem, which is expected to be a novel promising therapy for treating HER2-overexpressing breast cancer cells.

Gut microbiota patterns associated with somatostatin in patients undergoing pancreaticoduodenectomy: a prospective study.

Postoperative pancreatic fistula (POPF) is a common and dreaded complication after pancreaticoduodenectomy (PD). The gut microbiota has been considered as an crucial mediator of postoperative complications, however, the precise roles of gut microbiota in POPF are unclear. A prospective study was developed to explore the effects of somatostatin on gut microbiota and we aim to identify the microbial alterations in the process of POPF. A total of 45 patients were randomly divided into PD group or additional somatostatin therapy group. The fecal sample of each patient was collected preoperatively and postoperatively and the gut microbiota was analyzed by 16S rRNA sequencing. Our study found that somatostatin therapy was independent risk factor for the occurrence of POPF, and it reduced the microbial diversity and richness in patients. At genus level, somatostatin therapy led to a decreased abundance in Bifidobacterium, Subdoligranulum and Dubosiella, whereas the abundance of Akkermansia, Enterococcus and Enterobacter were increased. The abundance levels of certain bacteria in the gut microbiota have significantly shifted in patients with POPF. The LEfSe analysis revealed that Ruminococcaceae could be used as microbial markers for distinguishing patients with high risk of POPF. Furthermore, Verrucomicrobia and Akkermansia could be used as preoperative biomarkers for identifying patients without POPF. Our prospective study highlights the specific communities related with somatostatin therapy and discovers POPF-associated microbial marker, which suggests that gut microbiota may become a diagnostic biomarker and potential therapeutic target for POPF.

Correction: Gut microbiota patterns associated with somatostatin in patients undergoing pancreaticoduodenectomy: a prospective study.

[This corrects the article DOI: 10.1038/s41420-020-00329-4.].

Plasmonic tweezers for optical manipulation and biomedical applications.

Plasmonic tweezers are an emerging research topic because of their breakthrough in the conventional diffraction limit and precise manipulation at the nanoscale. Notably, their compatibility with analytical techniques (e.g. fluorescence, surface-enhanced Raman scattering (SERS), and laser desorption/ionization mass spectrometry (LDI MS)) opens up opportunities in optical manipulation and biomedical applications. Herein, we first introduce the structures and trapping forces, followed by a summary of the properties of plasmonic tweezers. The optical trapping of biosamples by plasmonic tweezers are then reviewed, including microorganisms and biomolecules. Finally, we highlight the integration of plasmonic tweezers with analytical techniques towards bioanalytical applications. We conclude with perspectives on the future directions for this topic. We foresee the upcoming era of biological detection by plasmonic tweezing in both academy and industry, which calls for the interest and efforts of scientists from diverse fields.

Preventive effect of ursolic acid derivative on particulate matter 2.5-induced chronic obstructive pulmonary disease involves suppression of lung inflammation.

Respiratory diseases like chronic obstructive pulmonary disease (COPD) are associated with the presence of particulate matter 2.5 (PM2.5) in the air. In the present study, the effect of synthesized ursolic acid derivatives on mice model of PM2.5-induced COPD was investigated in vivo. The mice model of COPD was established by the administration of 25 µL of PM2.5 suspension through intranasal route daily for 1 week. The levels of oxidative stress markers and inflammatory cytokines like tumor necrosis factors-α and interleukin-6 in the mice bronchoalveolar fluids increased markedly on administration with PM2.5. However, treatment with ursolic acid derivative caused a significant suppression in PM2.5-induced increase in oxidative stress markers and inflammatory cytokines in dose-dependent manner. Hematoxylin and eosin staining showed excessive inflammatory cell infiltration in pulmonary tissues in mice with COPD. The inflammatory cell infiltration was inhibited on treatment of the mice with ursolic acid derivative. The ursolic acid derivative treatment increased level of superoxide dismutase in mice with COPD. The lung injury induced by PM2.5 in mice was also prevented on treatment with ursolic acid derivative. Thus, ursolic acid derivative inhibits pulmonary tissues damage in mice through suppression of inflammatory cytokine and oxidative enzymes. Therefore, ursolic acid derivative can be of therapeutic importance for treatment of PM2.5-induced COPD.

[The clinical analysis of a step-up approach for severe acute pancreatitis: report of 121 cases].

OBJECTIVE: To investigate the feasibility and clinical value of the step-up approach for severe acute pancreatitis (SAP). METHODS: Clinical data of 121 SAP patients admitted between January 2002 and December 2011 were retrospectively analyzed. Fifty-eight patients (37 males and 21 females, aged from 20 to 72 years, mean 47.6 years) in the group of direct open necrosectomy from January 2002 to December 2006 were performed laparotomy through removal of all necrotic tissue. Sixty-three patients (42 males and 21 females, aged from 19 to 78 years, mean 46.2 years) of step-up approach from January 2007 to December 2011 underwent percutaneous catheter drainage through retroperitoneum or omental bursa guided by B-type ultrasonography for the first therapy, and then, according to the pathogenetic condition, if necessary, followed by a small incisional necrosectomy along the drainage tube. The two groups were compared for the rates of postoperative complications, death, transfusion and length of stay, medical costs. RESULTS: The rates of total postoperative complications, organ dysfunction, alimentary tract fistula and incisional hernia in step-up approach group were significantly lower than those of direct open necrosectomy group (31.7% vs. 62.1%, 14.3% vs. 37.5%, 6.3% vs. 19.0%, 9.5% vs. 29.3%; χ(2) = 4.43 to 11.17, P = 0.001 to 0.035). The other complications had no significant differences between the two groups (P > 0.05). Patients in step-up approach group had a lower rates of transfusion (44.4% vs. 70.7%, χ(2) = 8.488, P = 0.004), fewer medical costs of transfusion and hospital stay, compared with those in direct open necrosectomy group ((2525 ± 4573) yuan vs. (4770 ± 6867) yuan, t = 2.131, P = 0.035; (171 213 ± 50 917) yuan vs. (237 874 ± 67 832) yuan, t = 2.496, P = 0.014). There were no significant differences of length of stay and mortality between two groups (P > 0.05). CONCLUSION: Step-up approach for SAP which can reduce the rates of postoperative complications, transfusion and medical costs has significant feasibility and great clinical value.

Antisense hypoxia-inducible factor-1alpha augments transcatheter arterial embolization in the treatment of hepatocellular carcinomas in rats.

Transcatheter arterial embolization (TAE) is a standard treatment for unresectable hepatic malignancies. It blocks the arterial blood supply to the tumor, but blockade of the blood supply can be short-lived as collateral blood vessels develop, leading to the failure of TAE. Here we report that intraportal delivery of adeno-associated viral (AAV) vectors expressing antisense hypoxia-inducible factor-1alpha (HIF-1alpha) (AAV-ASHIF) augments TAE to combat hepatocellular carcinoma (HCC). Intraportal delivery of AAV-ASHIF led to long-term localized expression of transgenic ASHIF in rat liver, and suppressed the growth of CBRH7919 HCC tumors established in rat liver by inhibiting the formation of neovessels and tumor cell proliferation. TAE therapy caused the necrosis and shrinkage of liver tumors; however, neovessels quickly formed and the residual tumors underwent rapid expansion. TAE enhanced tumor and liver hypoxia, which in turn upregulated expression of HIF-1alpha, vascular endothelial growth factor, glucose transporter-1, lactate dehydrogenase A, and proliferating cell nuclear antigen. Intraportal injection of AAV-ASHIF augmented the therapeutic effects of TAE and diminished its undesirable effects, resulting in extensive tumor cell death and suppression of the growth of liver tumors. In conclusion, this study has revealed that HIF-1 impedes the response of liver tumors to TAE. Antisense HIF-1alpha therapy is warranted as an approach for enhancing the efficacy of TAE to treat unresectable liver cancers.

Antiangiogenic therapy enhances the efficacy of transcatheter arterial embolization for hepatocellular carcinomas.

Transcatheter arterial embolization (TAE) is a well-established technique for unresectable hepatic malignancies. However, TAE can temporally halt the growth of hepatic tumors by blocking their arterial supply, but often tumors rapidly develop collateral blood vessels via angiogenesis. We have previously demonstrated that intraportal delivery of adeno-associated viral particles expressing angiostatin leads to long-term expression of angiostatin capable of inhibiting angiogenesis and suppressing the outgrowth of tumors in the liver. Thus, we hypothesize that adeno-associated virus (AAV)-mediated antiangiogenic therapy could enhance the efficacy of TAE to combat liver cancers. To achieve this objective, we engineered a recombinant AAV vector encoding rat angiostatin. Intraportal delivery of this vector led to long term and stable transgenic expression of angiostatin locally in rat hepatocytes and suppressed the growth of CBRH7919 hepatocellular carcinomas established in rat livers by inhibiting formation of neovessels. Although TAE therapy led to necrosis of liver tumors and suppressed their growth, the neovessels of tumors were rapidly reformed 3 weeks after TAE. However, intraportal injection of AAV-angiostatin inhibited the angiogenesis stimulated by TAE, synergized with TAE in suppressing growth of tumors established in livers and prolonged the survival of rats. In conclusion, these encouraging results warrant future investigation of the use of antiangiogenic therapy for enhancing the therapeutic efficacy of TAE to treat unresectable liver cancers.

Opposite effects of donor apoptotic versus necrotic splenocytes on splenic allograft tolerance.

BACKGROUND: Apoptotic cells have immunosuppressive activity, whereas necrotic cells activate immune response, indicating they might have different effects on immune rejection against splenic allografts. The aim of this study was to determine whether administration of apoptotic or necrotic splenocytes of donor origin could impact the acute rejection of splenic allografts. MATERIALS AND METHODS: Apoptotic or necrotic splenocytes derived from donor rats were induced by irradiation or freeze thaw, respectively. Heterotopic vascularized spleen transplantation was performed from Wistar-Furth (donor) to Sprague-Dawley (recipient) rats, and splenocytes were intravenously injected into the recipients. At different time points, the recipients were sacrificed and the splenic allografts underwent histological examination. The interferon-gamma (IFN-gamma) and transforming growth factor-beta1 (TGF-beta1) in sera, spleens of recipients, and donor splenocytes before administration were measured. Mixed leukocyte reaction (MLR) was detected with recipient splenocytes as effectors and donor splenocytes as stimulators. RESULTS: Exposure to gamma-irradiation at dose of 10,000 rad caused over 80% splenocytes to become apoptotic. The levels of TGF-beta1 released by apoptotic splenocytes in vitro were significantly higher than that by untreated splenocytes, whereas there was almost no TGF-beta1 detected in necrotic splenocytes culture medium. Administration of apoptotic splenocytes significantly attenuated acute rejection of splenic allografts, evidenced by less severe splenic histological alteration and reduction of histological scores compared with control; whereas necrotic splenocytes exacerbated the acute rejection. Apoptotic splenocytes inhibited production of IFN-gamma but increased the levels of TGF-beta1, whereas necrotic splenocytes showed opposite activity in production of those cytokines. Administration of apoptotic splenocytes inhibited MLR, and necrotic splenocytes promoted MLR. CONCLUSIONS: The apoptotic and necrotic splenocytes exhibited opposite effects on acute rejection against splenic allografts, and IFN-gamma and TGF-beta1 have been involved in the effects.