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Background. The revascularization of small vessels using drug-eluting stents remains challenging. The use of the drug-coated balloon is an attractive therapeutic strategy in de novo lesions in small coronary vessels, particularly in the diabetic group. This study aimed to assess the outcomes of DCB-only angioplasty in small vessel disease. Methods. A total of 1198 patients with small vessel disease treated with DCB-only strategy were followed. Patients were divided into the diabetic and nondiabetic groups. Clinical and angiographical follow-up were organized at 12 months. The primary endpoints were target lesion failure and secondary major adverse cardiac events. Results. There was a significantly higher rate of target lesion failure among diabetic patients compared to nondiabetic [17 (3.9%) vs. 11 (1.4%), P = 0.006 ], taken separately, the rate of target lesion revascularization significantly differed between groups with a higher rate observed in the diabetic group [9 (2%) vs. 4 (0.5%), P = 0.014 ]. Diabetes mellitus remained an independent predictor for TLF (HR: 2.712, CI: 1.254–5.864, P = 0.011 ) and target lesion revascularization (HR: 3.698, CI: 1.112–12.298, P = 0.033 ) after adjustment. However, no significant differences were observed between groups regarding the target vessel myocardial infarction (0.6% vs. 0.1%, P = 0.110 ) and MACE [19 (4.4%) vs. 21 (2.7%), P = 0.120 ]. Conclusion. Drug-coated balloon-only treatment achieved lower incidence rates of TLF and MACE. Diabetes is an independent predictor for target lesion failure and target lesion revascularization at one year following DCB treatment in small coronary vessels. We observed no significant differences between groups regarding MACE in one year.

Aberrant expression of the zinc finger protein (ZIC) family has been extensively reported to contribute to progression and metastasis in multiple human cancers. However, the functional roles and underlying mechanisms of ZIC2 in non-small cell lung cancer (NSCLC) are largely unknown. In this study, ZIC2 expression was evaluated using qRT-PCR, western blot, and immunohistochemistry, respectively. Animal experiments in vivo and functional assays in vitro were performed to investigate the role of ZIC2 in NSCLC. Luciferase assays and chromatin immunoprecipitation (ChIP) were carried out to explore the underlying target involved in the roles of ZIC2 in NSCLC. Here, we reported that ZIC2 was upregulated in NSCLC tissues, and high expression of ZIC2 predicted worse overall and progression-free survival of NSCLC patients. Silencing ZIC2 repressed tumorigenesis and reduced the anoikis resistance of NSCLC cells. Mechanical investigation further revealed that silencing ZIC2 transcriptionally inhibited Src expression and inactivated steroid receptor coactivator/focal adhesion kinase signaling, which further attenuated the anoikis resistance of NSCLC cells. Importantly, our results showed that the number of circulating tumor cells (CTCs) was positively correlated with ZIC2 expression in NSCLC patients. Collectively, our findings unravel a novel mechanism implicating ZIC2 in NSCLC, which will facilitate the development of anti-tumor strategies in NSCLC., Graphical abstract, We pinpointed the oncogenic role of ZIC2 in NSCLC. Silencing ZIC2 abrogates tumorigenesis and anoikis resistance of non-small cell lung carcinoma cells (NSCLCs) by transcriptionally inhibiting Src/FAK signaling. Summarily, ZIC2 may hold the potential biomarker for early diagnosis and anti-tumor strategy in NSCLC.

Although drug-eluting stents are the most common interventional devices for patients with coronary disease, drug-coated balloons (DCBs) represent a novel therapeutic alternative in certain scenarios. This prospective, observational all-comers study explored the clinical outcomes of DCB use in patients with coronary lesions. All patients treated with DCBs were enrolled in this study, including patients with in-stent restenosis (ISR) or de novo lesions. The primary outcome was the target lesion revascularization (TLR) rate at one year. We enrolled 2306 patients with 2660 lesions and performed DCB angioplasty in 399 patients (17.3%) with ISR and 1907 patients (82.7%) with de novo lesions. During follow-up (366 ± 46 days), the TLR rate was lower in the de novo lesion group (1.31%) compared to the ISR group (7.02%) [odds ratio (OR) 0.176, 95% confidence interval (CI) 0.101–0.305, p

Background Cryoballoon ablation (CBA) and radiofrequency ablation (RFA) are the most common procedures used to treat refractory atrial fibrillation (AF) and are performed through pulmonary vein isolation (PVI). Studies have shown that CBA can approximately match the therapeutic effects of RFA against AF. However, few studies have investigated the difference between CBA and RFA of the effects on left atrial remodeling for paroxysmal AF. Objective Atrial remodeling is considered pivotal to the occurrence and development of AF, therefore we sought to assess the influence of atrial remodeling in patients with paroxysmal AF after CBA and RFA in this study. Methods In this nonrandomized retrospective observational study, we enrolled 328 consecutive patients who underwent CBA or RFA for refractory paroxysmal AF in May 2014 to May 2017 in our hospital. After propensity score matching, 96 patients were included in the CBA group, and 96 were included in the RFA group. Patients were asked to undergo a 12‐lead electrocardiogram, a 24‐h Holter monitor, and an echocardiogram and to provide their clinical history and symptoms at 6 months and 1, 2, and 3 years postprocedurally. Electrical remodeling of the left atrium was assessed by P wave dispersion (Pdis); structural remodeling was assessed by the left atrium diameter (LAD) and left atrial volume index (LAVI) during scheduled visits. Results As of January 2020, compared with baseline, at 1 year, 2 years, and 3 years after ablation, the average changes in Pdis (∆Pdis), LAD (∆LAD), and LAVI (∆LAVI) were significant in both the CBA and RFA groups. Six months after ablation, ∆Pdis, ∆LAD, and ∆LAVI were greater in the CBA group than in the RFA group. There was no significant difference between the two groups in AF/flutter recurrence, but the AF/flutter‐free survival time of CBA group may be longer than RFA group after 2 years after ablation. A higher ∆Pdis, ∆LAD, or ∆LAVI at 1 year after ablation may increase AF/flutter‐free survival. Conclusions Although CBA and RFA are both effective in left atrial electrical and structural reverse‐remodeling in paroxysmal AF, CBA may outperform RFA for both purposes 6 months after ablation. However, during long‐term follow‐up, there was no significant intergroup difference.

Background Mitochondrial fission regulator 2 (MTFR2) has been reported to promote proliferation, migration and invasion in tumors; however, little is known about its function in breast cancer. Thus, we investigated the effect of MTFR2 expression on prognosis of breast cancer. Methods The expression of MTFR2 in breast cancer tissues was detected by immunohistochemistry, and overall survival (OS) and recurrence free survival (RFS) were evaluated by the Log rank test and Cox model. Results We found that MTFR2 expression was significantly associated with clinical stage (P

Potential underlying molecular mechanisms for uric acid-induced lipid metabolic disturbances had not been elucidated clearly. This study investigated the effects and underlying mechanisms of uric acid on the development of lipid metabolic disorders. We collected blood samples from 100 healthy people and 100 patients with hyperuricemia for whom serum lipid analysis was performed. Meanwhile, a mouse model of hyperuricemia was generated, and lipidomics was performed on liver tissues, comparing control and hyperuricemia groups, to analyze lipid profiles and key metabolic enzymes. Uric acid directly induced serum lipid metabolic disorders in both humans and mice based on triglycerides, total cholesterol, and low-density lipoprotein cholesterol. Through lipidomic analysis, 46 lipids were differentially expressed in hyperuricemic mouse livers, and the phosphatidylcholine composition was altered, which was mediated by LPCAT3 upregulation. High-uric acid levels-induced p-STAT3 inhibition and SREBP-1c activation in vivo and in vitro. Moreover, LPCAT3-knockdown significantly attenuated uric acid-induced p-STAT3 inhibition, SREBP-1c activation, and lipid metabolic disorders in L02 cells. In conclusion, uric acid induces lipid metabolic disturbances through LPCAT3-mediated p-STAT3 inhibition and SREBP-1c activation. LPCAT3 could be a key regulatory factor linking hyperuricemia and lipid metabolic disorders. These results might provide novel insights into the clinical treatment of hyperuricemia.

Random flaps are widely used in tissue reconstruction, attributed to the lack of vascular axial limitation. Nevertheless, the distal end of the flap is prone to necrosis due to the lack of blood supply. Notoginseng triterpenes (NTs) are the active components extracted from Panax notoginseng, reducing oxygen consumption and improving the body’s tolerance to hypoxia. However, their role in random flap survival has not been elucidated. In this study, we used a mouse random skin flap model to verify that NT can promote cell proliferation and migration and that increasing blood perfusion can effectively improve the survival area of a skin flap. Our study also showed that the autophagy of random flaps after NT treatment was activated through the Beclin-1/VPS34/LC3 signaling pathway, and the therapeutic effect of NT significantly decreased after VPS34 IN inhibited autophagy. In conclusion, we have demonstrated that NT can significantly improve the survival rate of random flaps through the Beclin-1/VPS34/LC3 signaling pathway, suggesting that it might be a promising clinical treatment option.

Background Aberrant expression of m6A-related proteins contributes to the occurrence and progression of non-small cell lung cancer (NSCLC). Current studies mainly focus on single m6A regulatory genes and their underlying mechanisms, and the expression of multiple m6A regulatory proteins in NSCLC remains unclear. Therefore, it is necessary to systematically examine these proteins, particularly in clinical specimens. Methods Bioinformatic analysis was used to determine the expression of m6A regulatory genes and their correlation with common gene mutations, such as TP53, EGFR, and KRAS, using The Cancer Genome Atlas (TCGA) and the AE-meta databases. Immunohistochemistry was employed to analyze the protein expression of m6A regulatory proteins in 61 benign lung tissues and 316 NSCLC tissues. Statistical analysis was performed to calculate the correlation between the expression of m6A regulatory proteins and clinicopathological features, survival, and common gene mutations in lung carcinoma patients. Results Analysis of the mRNA levels of 13 core m6A regulators, using information from TCGA and the AE-meta databases, revealed that YTHDF1 levels were upregulated in NSCLC compared with those in adjacent normal tissues. Immunohistochemical staining showed that the expression of METTL3, ALKBH5, YTHDC2, and YTHDF1 was significantly upregulated in NSCLC tissues. Further analyses demonstrated a positive correlation between differentially expressed m6A regulatory proteins, including METTL3, ALKBH5, YTHDC2, and YTHDF1, and the poor clinicopathological features and survival of NSCLC patients. According to the statistics of NSCLC patients enrolled in this study, the protein levels of METTL3 in patients with EGFR exon-19 mutation were higher than those in patients with wild-type EGFR. Conclusion Our results indicate that m6A regulators, including METTL3, ALKBH5, YTHDC2, and YTHDF1, could serve as predictive markers of NSCLC, which will facilitate early detection and diagnosis of NSCLC.

Dysregulation of microRNAs (miRNAs) is frequently found in the tumorigenesis of osteosarcoma (OS). miR-376a was found to play tumor suppressive roles in human cancers. However, the role of miR-376a in OS remains unclear. The expression of miR-376a was analyzed by quantitative real-time PCR (qRT-PCR) in OS cell lines. Cell proliferation assay, cell invasion assay, and cell apoptosis assay were performed to detect the biological function of miR-376a after synthetic miRNA transfection. The target of miR-376a was predicted by TargetScan and miRDB, and further validated by luciferase activity reporter assay and western blot. miR-376a expression was revealed to be decreased in OS cell lines. In vitro experiments showed that overexpression of miR-376a inhibits OS cell proliferation and invasion but promotes apoptosis. Luciferase activity reporter assay and western blot assay showed F-box protein 11 (FBXO11) was a direct target of miR-376a. Furthermore, FBXO11 mediated the role of miR-376a on the proliferation, invasion, and apoptosis of OS cells. Collectively, these results revealed miR-376a functions as a tumor suppressor by targeting FBXO11 in OS. It may be developed as a therapeutic target for OS patients.

Background A drug-coated balloon (DCB) has been designed as a new device for the treatment of coronary artery disease. The data regarding DCB-treated lesions in large coronary artery are limited. The purpose of our study was to explore the effectiveness and safety of DCB in large coronary artery. Methods We prospectively analyzed all patients treated with DCB in de novo lesions consistent with inclusion criteria between May 2015 and April 2017. The observed outcomes included target lesion revascularization (TLR), myocardial infarction, cardiac death and non-cardiac death, and major adverse cardiac events (MACE). Results There were 92 patients including 94 coronary de novo lesions treated in all. The most often utilized DCB diameters were 3.0 mm (41.5%) and 3.5 mm (39.4%). Two acute closures occurred in hospital. Six bailout drug-eluting stents were used in the percutaneous coronary interventions (6.4%). Quantitative coronary angiography measurement at follow-up showed late lumen loss was -0.02 ± 0.49 mm. The TLR rate and overall MACE rates were 4.3% and 4.3% during the follow-up period in the whole patient population, respectively. Conclusions Our study showed that the “DCB only” strategy is safe and efficient in large vessel lesions of patients whose predilation achieved an acceptable result.

Cathelicidin-related antimicrobial peptide (CRAMP), antimicrobial peptide, was reported to protect against myocardial ischemia/reperfusion injury. In the pathology of diabetic cardiomyopathy, endothelial-to-mesenchymal transition (EndMT) results from hyperglycemia-induced endothelial injury, leading to cardiac fibrosis. This study aims to evaluate the effect of CRAMP on EndMT and cardiac fibrosis on diabetic mice heart. Mice were subjected to streptozotocin to induce diabetes. CRAMP was administered by intraperitoneal injection (1 or 8 mg/kg/d) for 4 weeks from 12 weeks till 16 weeks after final streptozotocin injection. Cardiac dysfunction was observed in diabetic mice. Only 8 mg/kg/d CRAMP treatment proved cardiac function. Increased EndMT and fibrosis level were also observed in diabetic mice heart. 8mg/kg CRAMP inhibited EndMT and fibrosis level in diabetic mice. Mouse heart endothelial cells (MHECs) were treated with CRAMP and exposed to high glucose. Hyperglycemia-induced EndMT in MHECs was also attenuated by CRAMP treatment. Activation of TGFβ/Smad signalling was increased in diabetic mice heart tissue and hyperglycemia stimulated MHECs, which was prevented following CRAMP treatment. Activation of AMPKa1/mTOR showed similar changes. AMPKa1 siRNA abrogated the effects of CRAMP in MHECs. TGFβ/Smad inhibitor LY2109761 and AMPKa agonist AIRCA mimic the effect of CRAMP. In summary, CRAMP can inhibit EndMT, cardiac fibrosis and protect against diabetic cardiomyopathy by regulating AMPKa1/TGFβ signalling.

Transplantation of oligodendrocyte progenitor cells (OPCs) is a promising way for treating demyelinating diseases. However, generation of scalable and autologous sources of OPCs has proven difficult. We previously established a chemical condition M9 that could specifically initiate neural program in mouse embryonic fibroblasts. Here we found that M9 could induce the formation of colonies that undergo mesenchymal-to-epithelial transition at the early stage of reprogramming. These colonies may represent unstable and neural lineage-restricted intermediates that have not established a neural stem cell identity. By modulating the culture signaling recapitulating the principle of OPC development, these intermediate cells could be reprogrammed towards OPC fate. The chemical-induced OPC-like cells (ciOPLCs) resemble primary neural stem cell-derived OPCs in terms of their morphology, gene expression, and the ability of self-renewal. Upon differentiation, ciOPLCs could produce functional oligodendrocytes and myelinate the neuron axons in vitro, validating their OPC identity molecularly and functionally. Therefore, our study provides a non-integrating approach to OPC reprogramming that may ultimately provide an avenue to patient-specific cell-based or in situ regenerative therapy.

Aromatase (CYP19) catalyzes the last biosynthetic step of estrogens in mammals and is a primary drug target for hormone-related breast cancer. However, treatment with aromatase inhibitors is often associated with adverse effects and drug resistance. In this study, we used virtual screening targeting a predicted cytochrome P450 reductase binding site on aromatase to discover four novel non-steroidal aromatase inhibitors. The inhibitors have potencies comparable to the noncompetitive tamoxifen metabolite, endoxifen. Our two most potent inhibitors, AR11 and AR13, exhibit both mixed-type and competitive-type inhibition. The cytochrome P450 reductase-CYP19 coupling interface likely acts as a transient binding site. Our modeling shows that our inhibitors bind better at different sites near the catalytic site. Our results predict the location of multiple ligand binding sites on aromatase. The combination of modeling and experimental results supports the important role of the reductase binding interface as a low affinity, promiscuous ligand binding site. Our new inhibitors may be useful as alternative chemical scaffolds that may show different adverse effects profiles than current clinically used aromatase inhibitors., Identification of multiple ligand binding sites in aromatase.

Uric acid is the end product of purine metabolism in humans. Hyperuricemia is a metabolic disease caused by the increased formation or reduced excretion of serum uric acid (SUA). Alterations in SUA homeostasis have been linked to a number of diseases, and hyperuricemia is the major etiologic factor of gout and has been correlated with metabolic syndrome, cardiovascular disease, diabetes, hypertension, and renal disease. Oxidative stress is usually defined as an imbalance between free radicals and antioxidants in our body and is considered to be one of the main causes of cell damage and the development of disease. Studies have demonstrated that hyperuricemia is closely related to the generation of reactive oxygen species (ROS). In the human body, xanthine oxidoreductase (XOR) catalyzes the oxidative hydroxylation of hypoxanthine to xanthine to uric acid, with the accompanying production of ROS. Therefore, XOR is considered a drug target for the treatment of hyperuricemia and gout. In this review, we discuss the mechanisms of uric acid transport and the development of hyperuricemia, emphasizing the role of oxidative stress in the occurrence and development of hyperuricemia. We also summarize recent advances and new discoveries in XOR inhibitors.

Hyperactivated glycolysis, favoring uncontrolled growth and metastasis by producing essential metabolic intermediates engaging bioenergetics and biosynthesis, is a metabolic hallmark of most cancer cells. Although sporadic information has revealed glycolytic metabolites also possess non-metabolic function as signaling molecules, it remains largely elusive how these metabolites interact with and functionally regulate their binding targets. Here we introduce a Target Responsive Accessibility Profiling (TRAP) approach that measures ligand binding-induced steric hindrance in protein targets via global profiling accessibility changes in reactive lysines, and mapped 913 target candidates and 2,487 interactions for 10 major glycolytic metabolites in cancer cells via TRAP. The elucidated targetome uncovers diverse regulatory modalities of glycolytic metabolites involving the direct perturbation of carbohydrate metabolism enzymes, intervention of transcriptional control, modulation of proteome-level acetylation and protein complex assemblies. The advantages gained from glycolysis by cancer cells are expanded by discovering lactate as a ligand for an orphan transcriptional regulator TRIM 28 that promotes p53 degradation, and by identifying pyruvate acting against a cell apoptosis inducer trichostatin A via attenuating protein acetylation. Lastly, the inhibition of glycolytic key enzymes led to identify an intrinsically active glycolytic intermediate glyceraldehyde 3-phosphate that elicits its cytotoxicity by engaging with ENO1 and MTHFD1. Collectively, the glycolytic targetome depicted by TRAP constitutes a fertile resource for understanding how glycolysis finely tunes metabolism and signaling in support of cancer cells, and fostering the exploitation of glycolytic targetome as promising nodes for anti-cancer therapeutics development.

Cancer cells exhibit different metabolic patterns compared to their normal counterparts. Although the reprogrammed metabolism has been indicated as strong biomarkers of cancer initiation and progression, increasing evidences suggest that metabolic alteration tuned by oncogenic drivers contributes to the occurrence and development of cancers rather than just being a hallmark of cancer. With this notion, targeting cancer metabolism holds promise as a novel anticancer strategy and is embracing its renaissance during the past two decades. Herein we have summarized the most recent developments in omics technology, including both metabolomics and proteomics, and how the combined use of these analytical tools significantly impacts this field by comprehensively and systematically recording the metabolic changes in cancer and hence reveals potential therapeutic targets that function by modulating the disrupted metabolic pathways.

Background. Diabetes is an independent risk factor for coronary artery disease and portends adverse prognosis in diabetic patients undergoing percutaneous coronary intervention (PCI) compared to nondiabetic patients. Few studies are currently available regarding the relationship between diabetes duration and major adverse cardiac events (MACEs) post-PCI. This study is aimed at assessing the association between diabetes duration and major adverse cardiac events after PCI. Methods. A total of 302 cases of diabetic patients undergoing an elective PCI with drug-eluting stent (DES) deployment and or percutaneous transluminal coronary angioplasty (PTCA) using a drug-coated balloon (DCB) were prospectively studied. We divided patients into three groups based on diabetes duration: n = 165 ), 5–10 years’ group ( n = 72 ), and ≥10 years’ group ( n = 65 ). Angiographic and clinical follow-up were conducted 12 months after the procedures for all the patients and at any given time during the study when needed. Results. A significantly higher rate of myocardial infarction (MI) in diabetic patients with the longest diabetes duration (7.7% vs. 0% and 0.6%, P = 0.001 ) was observed compared with groups of shorter duration. Repeat coronary revascularization was found to be significantly higher in the >10-year group than was it in groups with shorter duration of diabetes (23.1% vs. 19.4% and 9.10%, P = 0.03 ). After adjustment for confounding risk factors, longer diabetes duration remained an independent predictor of MI (hazard ratio (HR): 5.525, confidence interval (CI): 1.273-23.978, P = 0.022 ) and repeat revascularization (HR: 1.608, CI: 1.058-2.443, P = 0.026 ). Repeat revascularization was significantly related to the progression of nontreated lesions (De novo lesions 20% vs. 18% and 7.3%, P = 0.009 ) compared to previously treated lesions (target lesion revascularization (TLR) 3% vs. 1.3% and 2%, P = 0.774 ). However, all-cause mortality was not significantly different among the groups (3.1% vs. 5.6% and 0.6%, P = 0.06 , HR: 2.403, CI: 0.464-12.436, P = 0.293 ). Conclusion. Diabetes duration was associated with significant differences in major adverse cardiac events after the percutaneous coronary intervention; the longest diabetes duration portended higher rates of MACEs than shorter duration at the 12-month follow-up.

Background. Relative to nondiabetic patients, percutaneous coronary intervention (PCI) in patients with diabetes mellitus (DM) is associated with inferior clinical outcomes. We aimed to evaluate the outcomes of drug-coated balloon (DCB) in diabetic versus nondiabetic patients. Methods and Results. In this observational, prospective, multicenter study, we compared the outcomes of patients with and without DM after undergoing PCI with DCBs. Target lesion failure (TLF) was analyzed as primary endpoint. Secondary endpoints were the rates of target lesion revascularization (TLR), major adverse cardiovascular events (MACE), cardiac death, myocardial infarction (MI), and any revascularization. Propensity score matching was used to assemble a cohort of patients with similar baseline characteristics. Among 2,306 eligible patients, 578 with DM and 578 without DM had similar propensity scores and were included in the analyses. During follow-up ( 366 ± 46 days), compared with DM patients, patients without DM were associated with a lower yearly incidence of TLF (2.77% vs. 5.36%; OR, 1.991; 95% CI, 1.077 to 3.681; P = 0.025 ) and TLR (1.90% vs. 4.15%; OR, 2.233; 95% CI, 1.083 to 4.602; P = 0.026 ). No significant differences were observed with regards to rates of MACE (OR: 1.580, 95% CI: 0.912-2.735; P = 0.100 ), cardiac death (OR: 1.608, 95% CI: 0.523-4.946; P = 0.403 ), MI (OR: 4.042, 95% CI: 0.855-19.117; P = 0.057 ), and any revascularization (OR: 1.534, 95% CI: 0.983-2.393; P = 0.058 ). Conclusions. Diabetic patients experience higher TLF and TLR rates following DCB angioplasty without substantial increase in the risk of MACE, cardiac death, MI, or revascularization.

Systemic chemotherapy and radiotherapy have been widely used in clinics for several decades, but their disadvantages, such as systemic cytotoxicity and severe side effects, are the biggest obstacle to maximum therapeutic efficacy. In recent years, the impact of extracellular matrix components in tumor progression has gained the attention of researchers, and with the rapid development of nanomaterials, extracellular matrix targeted nanomaterials have become a promising strategy in tumor theranostics. In this review, we will outline the recent and relevant examples of various tumor extracellular matrix targeted nanomaterials applied in tumor therapy and imaging. And we will discuss the challenges and prospects of nanomaterials for future tumor therapy.

The aim of this study was to develop the Metformin Hydrochloride and Gliclazide (MH-GZ) sandwiched osmotic pump capsule which could overcome the problems associated with short half-life and burst release. The system could deliver drugs with different solubility simultaneously at zero-order rate, in which MH-GZ were filled in both sides of the push layer respectively. The single factor and orthogonal test were employed to obtain the optimized formulation with the evaluation index of similarity factor (ƒ

NADPH is a pivotal cofactor that maintains redox homeostasis and lipogenesis in cancer cells and interference with NADPH production is a promising approach for treating cancer. However, how normal and cancer cells differentially exploit NADPH-producing pathways is unclear, and selective approaches to targeting NADPH are lacking. Here, we show that the assayed cancer cell lines preferentially depend on ME1-mediated NADPH production. ME1 knockdown increases intracellular ROS levels and impairs lipogenesis in cancer cells, leading to retarded proliferation and increased anoikis, while sparing normal cells. Notably, ME1 interference ultimately resulted in adaptive upregulation of mitochondrial IDH2 dependent of AMPK-FoxO1 activation to replenish the NADPH pool and mitigate cytosolic ROS. Combining ME1 ablation and IDH2 inhibition drastically reduces intracellular NADPH and prevents resistance to ME1 interference, resulting in increased apoptosis and impeded tumor growth and metastasis. This study demonstrates that cytosolic ME1 integrated with mitochondrial IDH2 is essential for tumor growth and metastasis, thereby highlighting the blockade of metabolic compensation by disrupting mitochondrial-cytosol NADPH transport as a promising approach to selectively targeting NADPH in cancer cells that rely on NADPH-driven antioxidant systems., Graphical abstract Image 1, Highlights • NADPH is vital in mitigating ROS stress and supporting lipogenesis in cancer cells. • Certain cancer cells preferentially depend on ME1-mediated NADPH production route. • ME1 knockdown adaptively upregulates IDH2 dependent of AMPK-FoxO1 axis. • Compensatory IDH2 contributes to replenish the NADPH pool and mitigates ROS. • Combined targeting ME1 and IDH2 depletes NADPH and inhibits tumor growth and metastasis.

Purpose Aggressively growing tumors are characterized by significant variations in metabolites, including lipids, and can involve the elevated synthesis ofde novo fatty acids. Methods Ultra-performance liquid chromatography–tandem mass spectrometry (UPLC-MS/MS)-based metabolomics and lipidomics were performed to compare human gastric cancer tissues and adjacent normal tissues from clinical patients. A series of cellular and molecular biological methods were applied to validate the lipidomics results. Results Palmitic acid (PA) was found to be significantly downregulated in gastric cancer tissues, and it was found that a high concentration of PA specifically inhibited cell proliferation and impaired cell invasiveness and migrationin vitro in AGS, SGC-7901, and MGC-803 gastric cancer cell lines. Moreover, sterol regulatory element-binding protein 1 (SREBP-1c) was activated in human gastric cancer tissues, and it promoted the expression of a series of genes associated with the synthesis of fatty acids, such as SCD1 and FASN. SREBP-1c knockdown rescued the migration and invasion defects in AGS and SGC-7901 gastric cancer cells. Conclusion Taken together, our findings confirmed the variation in fatty acid synthesis in gastric cancer and identified SREBP-1c as a promising target for gastric cancer treatment.

Background Anti-angiogenic therapy represents a promising strategy for non-small-cell lung cancer (NSCLC) but its application in lung squamous cell carcinoma (SQC) is limited due to the high-risk adverse effects. Accumulating evidence indicates that long noncoding RNAs (lncRNAs) mediate in tumor progression by participating in the regulation of VEGF in NSCLC, which might guide the development of new antiangiogenic strategies. Methods Differential lncRNA expression in SQC was analyzed in AE-meta and TCGA datasets, and further confirmed in lung cancer tissues and adjacent normal tissues with RT-qPCR and in-situ hybridization. Statistical analysis was performed to evaluate the clinical correlation between LINC00173.v1 expression and survival characteristics. A tube formation assay, chick embryo chorioallantoic membrane assay and animal experiments were conducted to detect the effect of LINC00173.v1 on the proliferation and migration of vascular endothelial cells and tumorigenesis of SQC in vivo. Bioinformatics analysis, RNA immunoprecipitation and luciferase reporter assays were performed to elucidate the downstream target of LINC00173.v1. The therapeutic efficacy of antisense oligonucleotide (ASO) against LINC00173.v1 was further investigated in vivo. Chromatin immunoprecipitation and high throughput data processing and visualization were performed to identify the cause of LINC00173.v1 overexpression in SQC. Results LINC00173.v1 was specifically upregulated in SQC tissues, which predicted poorer overall and progression-free survival in SQC patients. Overexpression of LINC00173.v1 promoted, while silencing LINC00173.v1 inhibited the proliferation and migration of vascular endothelial cells and the tumorigenesis of SQC cells in vitro and in vivo. Our results further revealed that LINC00173.v1 promoted the proliferation and migration of vascular endothelial cells and the tumorigenesis of SQC cells by upregulating VEGFA expression by sponging miR-511-5p. Importantly, inhibition of LINC00173.v1 via the ASO strategy reduced the tumor growth of SQC cells, and enhanced the therapeutic sensitivity of SQC cells to cisplatin in vivo. Moreover, our results showed that squamous cell carcinoma-specific factor ΔNp63α contributed to LINC00173.v1 overexpression in SQC. Conclusion Our findings clarify the underlying mechanism by which LINC00173.v1 promotes the proliferation and migration of vascular endothelial cells and the tumorigenesis of SQC, demonstrating that LINC00173.v1-targeted drug in combination with cisplatin may serve as a rational regimen against SQC.

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death due to its early recurrence and widespread metastatic potential. Accumulating studies have reported that dysregulation of circadian rhythms-associated regulators is implicated in the recurrence and metastasis of NSCLC. Therefore, identification of metastasis-associated circadian rhythm genes is clinically necessary. Here we report that the circadian gene hepatic leukemia factor (HLF), which was dramatically reduced in early-relapsed NSCLC tissues, was significantly correlated with early progression and distant metastasis in NSCLC patients. Upregulating HLF inhibited, while silencing HLF promoted lung colonization, as well as metastasis of NSCLC cells to bone, liver and brain in vivo. Importantly, downexpression of HLF promoted anaerobic metabolism to support anchorage-independent growth of NSCLC cells under low nutritional condition by activating NF-κB/p65 signaling through disrupting translocation of PPARα and PPARγ. Further investigations revealed that both genetic deletion and methylation contribute to downexpression of HLF in NSCLC tissues. In conclusion, our results shed light on a plausible mechanism by which HLF inhibits distant metastasis in NSCLC, suggesting that HLF may serve as a novel target for clinical intervention in NSCLC.

The study was performed aiming to enhance the solubility and oral bioavailability of poorly water-soluble drug osthole by formulating solid self-microemulsifying drug delivery system (S-SMEDDS) via spherical crystallization technique. Firstly, the liquid self-microemulsifying drug delivery system (L-SMEDDS) of osthole was formulated with castor oil, Cremophor RH40, and 1,2-propylene glycol after screening various lipids and emulsifiers. The type and amount of polymeric materials, good solvents, bridging agents, and poor solvents in S-SMEDDS formulations were further determined by single-factor study. The optimal formulation contained 1:2 of ethyl cellulose (EC) and Eudragit S100, which served as matrix forming and enteric coating polymers respectively. Anhydrous ethanol and dichloromethane with a ratio of 5:3 are required to perform as good solvent and bridging agent, respectively, with the addition of 0.08% SDS aqueous solution as poor solvent. The optimized osthole S-SMEDDS had a high yield (83.91 ± 3.31%) and encapsulation efficiency (78.39 ± 2.25%). Secondly, osthole L-SMEDDS was solidified to osthole S-SMEDDS with no significant changes in terms of morphology, particle size, and zeta potential. In vitro release study demonstrated a sustained release of the drug from osthole S-SMEDDS. Moreover, in vivo pharmacokinetic study showed that the Tmax and mean residence time (MRT(0-t)) of osthole were significantly prolonged and further confirmed that osthole S-SMEDDS exhibited sustained release effect in rabbits. Comparing with osthole aqueous suspension and L-SMEDDS, osthole S-SMEDDS increased bioavailability by 205 and 152%, respectively. The results suggested that S-SMEDDS was an effective oral solid dosage form, which can improve the solubility and oral bioavailability of poorly water-soluble drug osthole.

An electrochemical immunosensor was developed for sensitive assay of E. coli in urban sludge, in which electron mediator-mediated enzymatic catalysis and gold nanoparticles(AuNPs) were utilized for signal amplification. The immnuosensing platform chitosan-thionine(chit-thio)/poly(amidoamine) dendrimer-encapsulated AuNPs [PAMAM(Au)] composites were first prepared from chit-thio and PAMAM(Au) using the layer-by-layer method to provide a matrix for high-stability and high-bioactivity bindings of the capture antibody(cAb). Moreover, the {dAb-AuNPs-HRP} nanoprobes were designed to exploit the amplification effect of the carrier AuNPs due to the loading amounts of horseradish peroxidase(HRP) and the detection antibody(dAb). The sandwich-type immunoassay was then successfully used to assay E. coli based on the oxidation of thionine as a result of H2O2-induced enzymatic catalytic reaction by HRP. This study presents a powerful tool in electrochemical immunoassay for E. coli detection with rapid response, high-sensitivity and high-specificity, providing a potential new tool for feasibility assessment of sludge recycle.

Butyrate is a typical short chain fatty acid produced by gut microbiota of which the dysmetabolism has been consistently associated with colorectal diseases. However, whether butyrate affects metastatic colorectal cancer is not clear. In this study we investigated in vitro the effect of butyrate on motility, a significant metastatic factor of colorectal cancer cells and explored the potential mechanism. By using wound healing and transwell-based invasion models, we demonstrated that pretreatment of butyrate significantly inhibited motility of HCT116, HT29, LOVO and HCT8 cells, this activity was further attributed to deactivation of Akt1 and ERK1/2. Suberanilohydroxamic acid (SAHA), another HDAC inhibitor, mimicked the inhibitory effect of butyrate on cell motility and deactivation of Akt/ERK. Furthermore, by silencing of HDAC3 with siRNA, we confirmed dependence of butyrate's effect on HDAC3, the similar reduced cell motility observed under HDAC3 silencing also indicates the significance of HDAC itself in cell motility. In conclusion, we confirmed the HDAC3-relied activity of butyrate on inhibiting motility of colorectal cancer cells via deactivating Akt/ERK signaling. Our data indicate that modulating butyrate metabolism is an effective therapeutic strategy of metastatic colorectal cancer; and HDAC3 might be a novel target for management of colorectal cancer metastasis.

Objective: The aim of this study was to evaluate the safety and efficiency of enucleation (EU) for proximal pancreatic non-invasive neoplasms. Methods: Patients with solitary non-invasive neoplasms in the proximal pancreas from January 1998 to April 2014 at the Second Affiliated Hospital of Zhejiang University, Hangzhou, China were included. Different operations and outcomes were analyzed. Results: A total of 123 patients were enrolled. Forty patients (32.5%) underwent EU including 18 patients who had tumors close to the main pancreatic duct (MPD). Sixty-one patients (49.6%) had pancreaticoduodenectomy (PD) performed and 22 (17.9%) underwent central pancreatectomy (CP). Pathological outcomes included neuroendocrine tumors, cystic lesions, and solid pseudopapillary tumors. Operation time, intra-operative blood loss, and duration of hospital stay were significantly reduced in the EU group. PD was associated with the greatest complication rate (55.7%), followed by EU (50%) and CP (40.9%), though the pancreatic fistula rate after EU was the highest (50%), especially in patients with tumors larger than 3 cm and tumors close to the MPD. EU had advantages in the preservation of pancreatic parenchyma and endocrine and exocrine function. Conclusions: EU can be carried out safely and effectively for tumors in the proximal pancreas with improved outcomes compared with standard resections, even if the tumor is larger than 3 cm and close to the MPD.

Uric acid (UA) is a purine metabolite that in most mammals is degraded by the hepatic enzyme uricase to allantoin. Epidemiological studies have shown that an elevated UA level predicts the development of cognition and memory deficits; however, there is no direct evidence of this relationship, and the underlying mechanism is largely undefined. Here, we show that a high-UA diet triggers the expression of proinflammatory cytokines, activates the Toll-like receptor 4 (TLR4)/nuclear factor (NF)-κB pathway, and increases gliosis in the hippocampus of Wistar rats. We, subsequently, identify a specific inhibitor of NF-κB, BAY11-7085, and show that stereotactic injections of the inhibitor markedly ameliorate UA-induced hippocampal inflammation and memory deficits in C57BL/6 mice. We also found that NF-κB is activated in the primary cultured hippocampal cells after UA administration. Additionally, C57BL/6 mice that lack TLR4 are substantially protected against UA-induced cognitive dysfunction, possibly due to a decrease in inflammatory gene expression in the hippocampus. Importantly, magnetic resonance imaging confirms that hyperuricemia in rats and humans is associated with gliosis in the hippocampus. Together, these results suggest that UA can cause hippocampal inflammation via the TLR4/NF-κB pathway, resulting in cognitive dysfunction. Our findings provide a potential therapeutic strategy for counteracting UA-induced neurodegeneration.SIGNIFICANCE STATEMENTThis work demonstrates that a high-uric acid (UA) diet triggers the expression of proinflammatory cytokines, activates the Toll-like receptor 4 (TLR4)/nuclear factor (NF)-κB pathway, and increases gliosis in the hippocampus of Wistar rats. Inhibition of the NF-κB signaling pathway markedly ameliorates UA-induced hippocampal inflammation and cognitive dysfunction in C57BL/6 mice. TLR4-knock-out mice are substantially protected against UA-induced cognitive dysfunction, possibly due to a decrease in inflammatory gene expression in the hippocampus. Moreover, magnetic resonance imaging confirms that hyperuricemia in rats and humans are associated with gliosis in the hippocampus. Together, this study suggests that there is an important link between UA-induced cognitive dysfunction and hippocampal inflammation in rodents and humans, which may have remarkable implications in the treatment of UA-induced neurodegeneration.

Metronomic chemotherapy, a relatively new dosing paradigm for anticancer therapy, is an alternative to traditional chemotherapy that uses maximal tolerated dose (MTD). Although these two dosing regimens both lead to tumor cell death, how cell metabolism is differentially affected during apoptosis remains elusive. Herein, we employed metabolomics to monitor the metabolic profiles of MCF-7 cells in response to the two dosing regimens that mimic MTD and MN treatments using a model chemotherapeutic drug, doxorubicin (Dox), and correlated the changes of metabolic genes examined by PCR array to integratively describe the reprogrammed metabolic patterns. We found glycolysis, amino acid, and nucleotide synthesis-associated metabolic pathways were activated in response to the MN treatment, whereas these pathways were inhibited in a pronounced way in response to the MTD treatment. Direct supplementation of key metabolites and pharmacological modulation of targeted metabolic enzymes can both regulate cell fates. Subsequently, we tested the combined use of MN dosing with targeted metabolic intervention using a normal cell line and found the combined treatment hardly affected its apoptotic rate. Our in vitro findings using MCF-7 and MCF-10A cells thus suggest the promising perspective of combining MN dosing of chemotherapeutic agents with metabolic modulation to selectively kill cancer cells rather than normal cells.

Huperzine A (hup A), extracted from the Chinese medicinal plant Huperzia serrata, is a reversible and highly selective second-generation acetylcholine esterase (AchE) inhibitor for treating Alzheimer’s disease (AD), but it suffers from low bioavailability in the brain. This study aimed to develop a nasal temperature and pH dual-responsive in situ gel delivery system based on microemulsion of hup A (hup A-M-TPISG). The optimal formulation was obtained by central composite design and response surface methodology. The optimized mucoadhesive formulation, hup A-M-TPISG, was composed of pluronic F127 (20.80%), pluronic F68 (2.8%), and chitosan (0.88%) as the gel matrix, which could gelatinize under physiological conditions (29–34°C, pH 6.5) because of its temperature and pH responsiveness. The optimized hup A-M-TPISG formulation was further evaluated by in vitro release and in vivo pharmacokinetic studies via microdialysis. The in vitro release study showed continuous and steady drug release from hup A-M-TPISG, which was in accordance with the first-order model. Moreover, the pharmacokinetic results revealed that the optimized formulation for nasal administration, with convenient administration and improved patient compliance, could achieve similar brain-targeting properties as intravenous administration. In conclusion, the hup A-M-TPISG for intranasal administration, as an effective and safe vehicle, could enhance the absorption of hup A in vivo and would be a promising noninvasive alternative for partially improving brain-targeting therapy.

Although drug-coated balloon (DCB) angioplasty is an effective therapy for drug-eluting stent- in stent restenosis (DES-ISR) after coronary stenting, recurrent ISR after DCB angioplasty still occurs. Different patterns of DES-ISR responding to DCB are largely unknown. This study sought to assess outcomes of different patterns of DES-ISR treated with DCB. From December 2014 to December 2016, a total of 160 DES-ISR lesions treated with DCB were retrospectively evaluated. Restenosis patterns were classified into two groups according to Mehran classification: focal, defined as

This paper demonstrated that a novel enteric osmotic pump capsule (EOPC) could effectively deliver metformin hydrochloride (MH) into the small intestine and keep releasing in a sustained manner consistently. The MH EOPC was composed of enteric semipermeable capsule shell and the core prescription fillers. Using a single factor tests, formulation and process factors were investigated and optimized based on the in vitro drug dissolution results. The optimized results were MH (250 mg), fructose (60 mg), mannitol (30 mg), polyethylene oxide-N60K (9 mg), ludipress® (49.5 mg), magnesium stearate (1.5 mg), and an orifice diameter of 0.8 mm. And, in vitro release studies showed sustained and stable drug release from the optimal MH EOPC, which was in line with the zero-order model. A higher bioavailability of MH was achieved from EOPC in comparison with commercial enteric capsules and sustained release tablets. Finally, using the technology of multislice computed tomography, as a visual means, further confirmed that EOPC achieved MH release specifically in the small intestine. In summary, the current study showed that the MH EOPC could potentially reduce MH adverse reactions and improve patient compliance which serves as an additional option for the treatment of type 2 diabetes.

Homeobox C8 (HOXC8) has been implicated in cell growth, migration, and metastasis of various cancers, yet its role in osteosarcoma remains to be explored. In the present study, resected osteosarcoma specimens from 50 patients were enrolled to evaluate the expression of HOXC8 protein by immunohistochemistry (IHC). In vitro and in vivo assays were used to determine the effect of HOXC8 on cell growth, migration, and tumor growth. HOXC8 expression was observed in 31 (62.0 %) of the 50 primary tumors and significantly associated with poorly or un-differentiated specimens (P = 0.031) and larger tumor size (P = 0.049). Survival analysis demonstrated that HOXC8 is a candidate predictive factor in predicting patients' outcome and chemotherapeutic effect. HOXC8 knockdown led to inhibition of tumor cell proliferation and migration in vitro by inhibiting MMP-9 expression and tumor growth in vivo. Our results strongly suggest that HOXC8 is involved in the tumorigenesis of osteosarcoma and might serve as a novel predictor for patients' outcome.

Accurate and highly sensitive detection of glycan expression on cell surface is extremely important for cancer diagnosis and therapy. Herein, a carbohydrate derivative-functionalized biosensor was developed for electrochemical detection of the expression level of cell surface glycan (mannose used as model). Thiomannosyl dimer was synthesized to design the thiomannosyl-functionalized biosensor by direct and rapid one-step protocols. The biosensing surface-confined mannose could effectively mimic the presentation of cell surface mannose and was responsible for competing with mannose on cancer cells in incubation solution. Greatly enhanced sensitivity was achieved by exploiting the excellent conductivity of multiwalled carbon nanotube/Au nanoparticle (MWNT/AuNP), the amplification effect of MWNTs, and the favorable catalytic ability of horseradish peroxidase (HRP). Using competitive strategy, the developed biosensor exhibits attractive performances for the analysis of mannose expression with rapid response, high sensitivity and accuracy, and possesses great promise for evaluation of cell surface glycan expression by using a greater variety of lectins.

This article has been retracted by the editors because the data are unreliable. It appears that the images in Figure 4c have been re-used but labelled as different conditions. The authors were asked to provide raw data for this figure, but were unable to do so. Author Jianyang Chen stated on behalf of all co-authors that they agree to this retraction.

The use of small molecule compounds to inhibit cell proliferation is one of the most promising approaches in cancer therapy. In the present study, a cell viability assay, flow cytometry analysis, western blotting and mouse xenograft models were used to investigate the anticancer activities of #2714 and its underlying mechanisms in lung cancer. The present in vitro results suggested that #2714 significantly inhibited the viability of the human non‑small cell lung cancer line SPC‑A1 in a concentration‑ and time‑dependent manner, with a half‑maximal inhibitory concentration value of 5.54 µM after 48 h of treatment. Additionally, #2714 inhibited SPC‑A1 cell proliferation via the Wnt/β‑catenin pathway and by impairing mitochondrial membrane potential. The protein expression levels of Wnt 3a, Wnt 5a/b, phosphorylated (p)‑β‑catenin, p‑glycogen synthase kinase 3β, and p‑mitogen‑activated protein kinase 14 were downregulated following treatment with #2714. Furthermore, using a mouse xenograft model, #2714 was identified to significantly inhibit tumor growth and to decrease cancer cell proliferation in vivo. #2714 may represent a novel effective anticancer compound targeting lung cancer cells. Additionally, #2714 was able to induce apoptosis and decrease cell proliferation in SPC‑A1 cells via the Wnt/β‑catenin pathway.

Butyrate is a short chain fatty acid present in a high concentration in the gut lumen. It has been well documented that butyrate, by serving as an energetic metabolite, promotes the proliferation of normal colonocytes while, by serving as a histone deacetylase inhibitor, epigenetically suppressing the proliferation of cancerous counterparts undergoing the Warburg effect. However, how butyrate interrupts the metabolism of colorectal cancer cells and ultimately leads to the suppression of cell proliferation remains unclear. Here, we employed a metabolomics-proteomics combined approach to explore the link between butyrate-mediated proliferation arrest and cell metabolism. A metabolomics study revealed a remodeled metabolic profile with pronounced accumulation of pyruvate, decreased glycolytic intermediates upstream of pyruvate and reduced levels of nucleotides in butyrate-treated HCT-116 cells. Supplementation of key metabolite intermediates directly affected cancer-cell metabolism and modulated the suppressive effect of butyrate in HCT-116 cells. By a Drug Affinity Responsive Target Stability (DARTS)-based quantitative proteomics approach, we revealed the M2 isoform of a pyruvate kinase, PKM2, as a direct binding target of butyrate. Butyrate activates PKM2 via promoting its dephosphorylation and tetramerization and thereby reprograms the metabolism of colorectal cancer cells, inhibiting the Warburg effect while favoring energetic metabolism. Our study thus provides a mechanistic link between PKM2-induced metabolic remodeling and the antitumorigenic function of butyrate and demonstrates a widely applicable approach to uncovering unknown protein targets for small molecules with biological functions.

Gastric cancer (GC) is one of the most common malignancies worldwide. Previous studies have focused on long non‑coding RNAs (lncRNAs), which have important roles in the development and progression of GC. The present study aimed to clarify the expression and function of lncRNA small nucleolar RNA host gene 12 (SNHG12) in GC. The expression and the clinical characteristics of GC were analyzed in the samples from patients with GC and matched adjacent normal tissues. The present study determined that SNHG12 was significantly overexpressed in GC and its expression level was highly associated with tumor size, tumor‑node‑metastasis stage, distant metastasis, lymphatic metastasis. Patients with high SNHG12 expression had a short survival period. Additionally, inhibition of SNHG12 in GC cell lines SGC‑7901 and AGS suppressed cell growth, colony formation, proliferation and invasion. MicroRNA (miR)‑320, a putative target gene of SNHG12, was inversely correlated with SNHG12 expression in GC tissues and cell lines. In addition, the present study determined that miR‑320 was directly regulated by SNHG12 and suppression of miR‑320 expression reversed the inhibitory effects of SNHG12 siRNA on GC cell proliferation and invasion. These findings revealed that SNHG12 acts as a tumor promoter by directly targeting miR‑320 in GC, suggesting a potential novel biomarker for the diagnosis and prognosis of GC.

Effective assay of Escherichia coli ( E. coli ) as indicator bacteria is critical for evaluating the recycling of urban sludge. In this work, we utilized multiwalled carbon nanotube/gold nanoparticle (CNT/AuNP) hybrid nanostructures as sensing electrode to design a novel electrochemical immunosensor for E. coli analysis. Herein, the hybrid nanostructures were fabricated by electrodepositing AuNPs on CNTs surface via multi-potential step technique. The CNT/AuNP hybrids were proved to facilitate the improvement of electrochemical performance for signal amplification, as well as the immobilization of E. coli capture antibody ( c Ab). The sandwich-type system was formed by specific recognition of the immobilized c Ab on CNT/AuNP hybrids to E. coli , followed by the attachment of horseradish peroxidase-conjugated E. coli detection antibody ( d Ab-HRP) to produce the electrochemical immunosensor. On the basis of the dual signal amplification of CNT/AuNP hybrid nanostructures and enzymatic catalysis, the electrochemical immunosensor exhibits an excellent performance for E. coli assay ranging from 2.0 × 10 2 to 2.0 × 10 6 cfu mL −1 . The electrochemical method was also successfully used to evaluate E. coli in urban sludge. The proposed strategy provides a convenient and effective method for E. coli detection, and could become a promising technique for estimating the feasibility of sludge recycling.

The stubborn chemoresistance of pancreatic ductal adenocarcinoma (PDA) is simultaneously influenced by tumor parenchymal and stromal factors, and the ctritical role of Notch ligand Delta-like 4 (DLL4) in the regulation of tumor malignancies has been observed. DLL4 positive expression ratio between duct cells from clinical tumor and adjacent tissues was statistically significant, and the overactivation of DLL4/Notch pathway enhanced the phenotype of EMT and cancer stem cell, even can induce multi-chemoresistance in vitro. Notably, the accompanied defective angiogenesis directly induced inefficient chemo-drug delivery in vivo. Collectively, overexpressed DLL4 on neoplastic cells can enhance chemoresistance through angiogenesis-dependent/independent mechanisms in PDA.

Methamphetamine (METH), a commonly abused psychostimulant, has been shown to induce neuronal damage by causing reactive oxygen species (ROS) formation, apoptosis and autophagy. Taurine (2-aminoethanesulfonic acid) is involved in several physiological actions in the brain, including neuroprotection, osmoregulation and neurotransmission. In this study, we investigate the protective effect of taurine against METH-induced neurotoxicity in PC12 cells and the underlying mechanism. The results showed that taurine significantly increased the cell viability inhibited by METH. LC3-II expression was elevated by METH treatment, whereas such increase was obviously attenuated by taurine. Co-treatment of taurine strongly reversed the decline of antioxidase activities induced by METH. Moreover, phosphorylated mammalian target of rapamycin (p-mTOR) was significantly inhibited by METH, whereas complementation of taurine markedly increased the expression of p-mTOR in PC12 cells, rather than phosphorylated Erk. Interestingly, taurine-induced decreasing expression of LC3-II was partially blocked by pretreatment of RAD001, an mTOR inhibitor. These results indicated that taurine inhibits METH-induced autophagic process through activating mTOR rather than Erk signaling. Collectively, our study shows that taurine protects METH-induced PC12 cells damage by attenuating ROS production, apoptosis and autophagy, at least in part, via mTOR signaling pathway.

The findings of clinical studies concerning the association between anthocyanins supplementation and blood pressure (BP) are inconsistent. In order to provide a more precise estimate of the overall effect of anthocyanins on systolic blood pressure (SBP) and diastolic blood pressure (DBP), we conducted a meta-analysis of clinical trials about anthocyanins supplementation and BP. PubMed, Web of Science, Wanfang Database, and China National Knowledge Infrastructure (CNKI) (until October 2015) were searched to identify potential studies with information on anthocyanins extract supplementation and arterial BP. The weighted mean difference (WMD) and 95% confidence interval (CI) were used as a summary statistic. Net changes in SBP and DBP between anthocyanins supplementation and placebo groups were calculated by subtracting the values at end of follow-up from those at baseline. Meta regression was used to explore the potential moderators of effect size. The publication bias was assessed using Begger's Funnel plots and Egger's tests; P

It has been suggested that the newly identified metastasis-associated in colon cancer-1 (MACC1) oncogene is involved in the progression and metastasis of cancer. Several studies have indicated that MACC1 has potential as a novel biomarker. In this study, we aimed to investigate the functions and serum expression levels of MACC1 in pancreatic cancer patients. Blood serum samples from 60 cancer patients and 49 controls were analyzed for serum MACC1 by ELISA. The results revealed that high expression levels of MACC1 were correlated with lymph node metastasis, distant metastasis and a later TNM stage. Inhibition of MACC1 by siRNAs significantly suppressed pancreatic cancer cell proliferation and migration. Furthermore, it was found that the downregulation of MACC1 sensitized pancreatic cancer cells to gemcitabine treatment through the inhibition of the Ras/ERK signaling pathway. Our findings suggest that MACC1 may aid in the diagnosis of pancreatic cancer and serve as a potential therapeutic target.

Aberrant expression of DJ-1 has been proven to be associated with tumorigenesis in many carcinomas. However, its role in pancreatic cancer is unknown. The aims of this study were to investigate whether the serum DJ-1 might be a potential biomarker for pancreatic cancer and to determine the biologic function of DJ-1 expression in gemcitabine-induced chemoresistance of pancreatic cancer. The serum level of DJ-1 was higher in 128 pancreatic cancer patients compared with 62 healthy controls by ELISA. To determine the effect of DJ-1 on pancreatic tumor chemoresistance, a siRNA-targeting DJ-1 was synthesized and a stably transfected cell line with DJ-1 over-expression was constructed. The mechanism of tumor chemoresistance was assessed by multiple methods, such as MTT assay, real-time PCR, Western blot and flow cytometry. The serum level of DJ-1 was higher in pancreatic cancer patients than healthy controls, and it has the relationship with tumor differentiation in pancreatic cancer. Down-regulation of DJ-1 enhanced gemcitabine-induced apoptosis in three pancreatic cancer cell lines. On the contrary, over-expression of DJ-1 desensitized the MIA PaCa-2 to the induction of apoptosis by gemcitabine. Our results suggest that the serum level of DJ-1 may be a potential biomarker for pancreatic cancer, and that DJ-1 plays critical roles in the pancreatic tumor chemoresistance, supporting the development of chemotherapeutic approaches targeting this oncogene.