Influenza A virus infection activates caspase-8 to enhance innate antiviral immunity by cleaving CYLD and blocking TAK1 and RIG-I deubiquitination.

Caspase-8, an aspartate-specific cysteine protease that primarily functions as an initiator caspase to induce apoptosis, can downregulate innate immunity in part by cleaving RIPK1 and IRF3. However, patients with caspase-8 mutations or deficiency develop immunodeficiency and are prone to viral infections. The molecular mechanism underlying this controversy remains unknown. Whether caspase-8 enhances or suppresses antiviral responses against influenza A virus (IAV) infection remains to be determined. Here, we report that caspase-8 is readily activated in A549 and NL20 cells infected with the H5N1, H5N6, and H1N1 subtypes of IAV. Surprisingly, caspase-8 deficiency and two caspase-8 inhibitors, Z-VAD and Z-IETD, do not enhance but rather downregulate antiviral innate immunity, as evidenced by decreased TBK1, IRF3, IκBα, and p65 phosphorylation, decreased IL-6, IFN-ß, MX1, and ISG15 gene expression; and decreased IFN-ß production but increased virus replication. Mechanistically, caspase-8 cleaves and inactivates CYLD, a tumor suppressor that functions as a deubiquitinase. Caspase-8 inhibition suppresses CYLD cleavage, RIG-I and TAK1 ubiquitination, and innate immune signaling. In contrast, CYLD deficiency enhances IAV-induced RIG-I and TAK1 ubiquitination and innate antiviral immunity. Neither caspase-3 deficiency nor treatment with its inhibitor Z-DEVD affects CYLD cleavage or antiviral innate immunity. Our study provides evidence that caspase-8 activation in two human airway epithelial cell lines does not silence but rather enhances innate immunity by inactivating CYLD.

Influenza virus infection activates TAK1 to suppress RIPK3-independent apoptosis and RIPK1-dependent necroptosis.

Many DNA viruses develop various strategies to inhibit cell death to facilitate their replication. However, whether influenza A virus (IAV), a fast-replicating RNA virus, attenuates cell death remains unknown. Here, we report that IAV infection induces TAK1 phosphorylation in a murine alveolar epithelial cell line (LET1) and a murine fibroblastoma cell line (L929). The TAK1-specific inhibitor 5Z-7-Oxzeneonal (5Z) and TAK1 knockout significantly enhance IAV-induced apoptosis, as evidenced by increased PARP, caspase-8, and caspase-3 cleavage. TAK1 inhibition also increases necroptosis as evidenced by increased RIPK1S166, RIPK3T231/S232, and MLKLS345 phosphorylation. Mechanistically, TAK1 activates IKK, which phosphorylates RIPK1S25 and inhibits its activation. TAK1 also activates p38 and its downstream kinase MK2, which phosphorylates RIPK1S321 but does not affect RIPK1 activation. Further investigation revealed that the RIPK1 inhibitor Nec-1 and RIPK1 knockout abrogate IAV-induced apoptosis and necroptosis; re-expression of wild-type but not kinase-dead (KD)-RIPK1 restores IAV-induced cell death. ZBP1 knockout abrogates IAV-induced cell death, whereas RIPK3 knockout inhibits IAV-induced necroptosis but not apoptosis. 5Z treatment enhances IAV-induced cell death and slightly reduces the inflammatory response in the lungs of H1N1 virus-infected mice and prolongs the survival of IAV-infected mice. Our study provides evidence that IAV activates TAK1 to suppress RIPK1-dependent apoptosis and necroptosis, and that RIPK3 is required for IAV-induced necroptosis but not apoptosis in epithelial cells.

Acute suppurative terminal cholangitis: Clinical characteristics of a new subtype of acute cholangitis.

BACKGROUND: Acute suppurative terminal cholangitis (ASTC) is rarer than acute obstructive cholangitis and is not well studied. To explore this subtype of acute cholangitis, we described our clinical experience with ASTC. METHODS: We performed a retrospective review of patients with ASTC admitted to our center from September 2014 to August 2020. We analyzed their clinical characteristics, including etiology, clinical manifestations, imaging features, treatment and prognosis. RESULTS: A total of 32 ASTC patients were included in the analysis. The majority of the patients had a history of biliary operations, and clinical manifestations were occult and atypical. The positive rate of bacterial culture was 46.9%. All the patients had typical imaging features on computed tomography and magnetic resonance imaging. Treatment with effective antibiotics was provided as soon as diagnosis was established. After treatment, most patients had a good outcome. Elevated levels of total bilirubin, aspartate aminotransferase, procalcitonin and gamma-glutamyltransferase were the characteristics of critically ill patients and were associated with relatively poor prognosis. CONCLUSIONS: Our results demonstrated that ASTC should be recognized as a new subtype of acute cholangitis, and that earlier diagnosis and more personalized treatments are needed.

Covalent Organic Framework Nanohydrogels.

Nanohydrogelation of covalent organic frameworks (COFs) will undoubtedly open up new applications for them in water, such as aqueous catalysis and biomedicine. It is currently a great challenge to achieve water dispersion of COFs through either bottom-up construction strategies or top-down exfoliating technologies. Herein, poly(N-isopropylacrylamide) (PNIPAM)-postmodified COF nanohydrogels (COF-NHGs) are successfully designed and synthesized via in situ atom-transfer radical polymerization (ATRP) on a scaffold of COFs. During the polymer growth process, the bulk COFs are exfoliated into nanosheets with a lateral size of ∼500 nm and a thickness of ∼6.5 nm. Moreover, their size can be precisely controlled by the degree of polymerization of PNIPAMs. In aqueous solution, the obtained COF-NHGs are assembled into nanohydrogels retaining intra-plane crystallinity and exhibit a temperature-sensitive sol-gel phase transition. With excellent solubility in organic solvents, the COF-NHGs' intrinsic physical properties in the solution state can be characterized through their solution nuclear magnetic resonance and ultraviolet absorption spectra. These results put forward new opportunities for regulating the solution processability of COFs and building an intelligent, stimuli-response platform of COF-polymer composite nanohydrogels for device applications.

Dysregulated PD-L2 is correlated with disease activity and inflammation in rheumatoid arthritis.

The programmed death-1 (PD-1) pathway has been shown to deliver an inhibitory signal, and aberrant expression of the PD-1 molecule and/or its ligand programmed death ligand 1 (PD-L1) has been demonstrated in human diseases, while its other ligand, programmed death ligand 2 (PD-L2), has rarely been studied. Here, we investigated the expression of PD-L2 in synovial tissue and blood from patients with rheumatoid arthritis (RA). Soluble PD-L2 and inflammatory cytokine levels in serum among healthy controls and patients with RA were compared via enzyme-linked immunosorbent assay (ELISA). Membrane PD-L2 on monocytes in blood was analyzed through flow cytometry (FCM). The different expression levels of PD-L2 between the RA and non-RA synovium were semi-quantified by immunohistochemical (IHC) staining. The soluble PD-L2 levels in serum from patients with RA were significantly lower than those in healthy subjects, correlating with active parameters (rheumatoid factor) and inflammatory cytokine secretion. The FCM results showed that patients with RA had significantly increased percentages of PD-L2-expressing CD14+ monocytes and correlated with inflammatory cytokines. PD-L2 expression on macrophages in the synovium from patients with RA was recorded by IHC staining with a higher score, and its correlation with pathological scores and clinical features was determined. Together, our results revealed aberrant expression of PD-L2 in RA, which may be a promising biomarker and therapeutic target associated with the pathogenesis of RA.

Urolithin A ameliorates obesity-induced metabolic cardiomyopathy in mice via mitophagy activation.

Metabolic cardiomyopathy (MC) is characterized by intracellular lipid accumulation and utilizing fatty acids as a foremost energy source, thereby leading to excess oxidative stress and mitochondrial dysfunction. There is no effective therapy available yet. In this study we investigated whether defective mitophagy contributed to MC and whether urolithin A (UA), a naturally occurring microflora-derived metabolite, could protect against MC in experimental obese mice. Mice were fed high fat diet for 20 weeks to establish a diet-induced obese model. We showed that mitochondrial autophagy or mitophagy was significantly downregulated in the heart of experimental obese mice. UA (50 mg·kg-1·d-1, for 4 weeks) markedly activated mitophagy and ameliorated MC in obese mice by gavage. In PA-challenged H9C2 cardiomyocytes, UA (5 µM) significantly increased autophagosomes and decreased autolysosomes. Furthermore, UA administration rescued PINK1/Parkin-dependent mitophagy and relieved mitochondrial defects in the heart of obese mice, which led to improving cardiac diastolic function and ameliorating cardiac remodelling. In PA-challenged primarily isolated cardiomyocytes, both application of mitophagy inhibitor Mdivi-1 (15 µM) and silencing of mitophagy gene Parkin blunted the myocardial protective effect of UA. In summary, our data suggest that restoration of mitophagy with UA ameliorates symptoms of MC, which highlights a therapeutic potential of UA in the treatment of MC.

FEN1 inhibitor synergizes with low-dose camptothecin to induce increased cell killing via the mitochondria mediated apoptotic pathway.

Camptothecin has been used in tumor therapy for a long time but its antitumor effect is rather limited due to the side effect and the drug resistance. FEN1, a major component of DNA repair systems, plays important roles in maintaining genomic stability via DNA replication and repair. Here we found that FEN1 inhibitor greatly sensitizes cancer cells to low-dose camptothecin. The combinative treatment of FEN1 inhibitor and 1 nM camptothecin induced a synthetic lethal effect, which synergistically suppressed cancer cell proliferation and significantly mediated apoptosis both in vitro and in vivo. Our study suggested that targeting FEN1 could be a potent strategy for tumor-targeting cancer therapy.

Ubiquitin-specific protease 3 facilitates cell proliferation by deubiquitinating pyruvate kinase L/R in gallbladder cancer.

Ubiquitin-specific protease 3 (USP3), a kind of cysteine protease, is a crucial family member of deubiquitinating enzymes. USP3 is aberrantly expressed in several tumors, which may contribute to cancer progression. However, the role of USP3 in gallbladder cancer (GBC) is still unknown. In the current study, we detected the expression of USP3 in GBC tissues, measured its contribution to the cell proliferation in GBC progression, and further studied the underlying mechanism of USP3 in GBC through pyruvate kinase L/R (PKLR; a kind of glycolytic enzyme). We found that the expression of USP3 in GBC tissues were higher than that of adjacent tissues, and the protein levels of USP3 and PKLR were positively correlated. Additionally, overexpressed USP3 significantly promoted cell proliferation in vitro and tumor growth in vivo, while the silencing of USP3 inhibited proliferation and tumor growth. Glycolysis in GBC cells ws promoted by the USP3 overexpression and inhibited bye USP3 downregulation. Moreover, the loss of USP3 promoted the ubiquitination and weakened the stability of PKLR. Results of the rescue assay confirmed that PKLR knockdown suppressed USP3-induced oncogenic activity in USP3 overexpressed GBC cells. These findings imply that USP3 is an essential positive regulator in GBC progression, and USP3-PKLR plays a vital role in the progression and metabolism of GBC.

Mechanically Robust and Flame-Retardant Superhydrophobic Textiles with Anti-Biofouling Performance.

The attachment of bio-fluids to surfaces promotes the transmission of diseases. Superhydrophobic textiles may offer significant advantages for reducing the adhesion of bio-fluids. However, they have not yet found widespread use because dried remnants adhere strongly and have poor mechanical or chemical robustness. In addition, with the massive use of polymer textiles, features such as fire and heat resistance can reduce the injuries and losses suffered by people in a fire accident. We developed a superhydrophobic textile covered with a hybrid coating of titanium dioxide and polydimethylsiloxane (TiO2/PDMS). Such a textile exhibits low adhesion to not only bio-fluids but also dry blood. Compared to a hydrophilic textile, the peeling force of the coated textile on dried blood is 20 times lower. The textile's superhydrophobicity survives severe treatment by sandpaper (400 mesh) at high pressure (8 kPa) even if some of its microstructures break. Furthermore, the textile shows excellent heat resistance (350 °C) and flame-retardant properties as compared to those of the untreated textile. These benefits can greatly inhibit the flame spread and reduce severe burns caused by polymer textiles adhering to the skin when melted at high temperatures.

Ice Recrystallization Inhibition Is Insufficient to Explain Cryopreservation Abilities of Antifreeze Proteins.

Antifreeze proteins (AFPs) and glycoproteins (AFGPs) are exemplary at modifying ice crystal growth and at inhibiting ice recrystallization (IRI) in frozen solutions. These properties make them highly attractive for cold storage and cryopreservation applications of biological tissue, food, and other water-based materials. The specific requirements for optimal cryostorage remain unknown, but high IRI activity has been proposed to be crucial. Here, we show that high IRI activity alone is insufficient to explain the beneficial effects of AF(G)Ps on human red blood cell (hRBC) survival. We show that AF(G)Ps with different IRI activities cause similar cell recoveries of hRBCs and that a modified AFGP variant with decreased IRI activity shows increased cell recovery. The AFGP variant was found to have enhanced interactions with a hRBC model membrane, indicating that the capability to stabilize cell membranes is another important factor for increasing the survival of cells after cryostorage. This information should be considered when designing novel synthetic cryoprotectants.

Clinical characteristic and pathogenesis of tumor-induced acute pancreatitis: a predictive model.

BACKGROUND: The aim of our study was to investigate the clinical characteristics and pathogenesis of tumor-induced acute pancreatitis (AP), and to develop a reliable prediction model of the clinical features to guide the diagnosis and treatment. METHODS: Patients with AP between January 2013 and December 2021 were enrolled in the study and were subdivided into the tumor group and the non-tumor group. The tumor group was subdivided into three groups based on the primary sites. Characteristic parameters, laboratory and imaging results were compared between groups. Least absolute shrinkage and selection operator regression model, XGBoost and random forest model were used to select the predictors associated with tumor-induced AP. Logistic regression analysis was used to validate the performance of the selected predictors and a nomogram was established to provide individualized probability of a tumor origin for AP. RESULTS: A total amount of 8970 patients were admitted for AP during the study period, and 8637 AP patients were enrolled in the study. Of these, 100 cases (1.16%) were tumor-induced AP. The tumor group was significantly older than the non-tumor group (t = 6.050, p = 0.000). Mild AP was observed in 90 cases, moderate AP in 9 cases and severe AP in one case. Tumors respectively originated from distal bile duct (14 cases), ampulla (13 cases) and pancreas (73 cases). The median time from initial AP to tumor diagnosis was 8.57 weeks and the median number of episode was 2 in the tumor group, which significantly surpassed the non-tumor group (p = 0.000). Age, white blood cell count, percentage of neutrophils, pancreatic or bile duct dilation and recurrent attacks were selected independent predictors for tumor origin. A nomogram model based on these factors was established. CONCLUSION: For patients with agnogenic AP, elderly man, recurrent attacks, pancreatic or bile duct dilatation and continuous no significant increase of inflammatory markers prompt to further screening of pancreatic biliary and ampulla.

CELF2 is a candidate prognostic and immunotherapy biomarker in triple-negative breast cancer and lung squamous cell carcinoma: A pan-cancer analysis.

CUGBP Elav-like family member 2(CELF2) plays crucial roles in the development and activation of T cell. However, the impacts of CELF2 on tumour-infiltrating immune cells (TIICs) and clinical outcomes of tumours remain unclear. In this study, we found that elevated CELF2 expression was markedly correlated with prolonged survival in multiple tumours, particularly in breast and lung cancers. Notably, CELF2 only impacted the prognosis of triple-negative breast cancer (TNBC) with lymph node metastasis. Further investigation showed CELF2 expression was positively correlated with the infiltration abundance of dendritic cells (DCs), CD8+ T cells and neutrophils in breast invasive carcinoma (BRCA) and DCs in lung squamous cell carcinoma (LUSC). CELF2 also had strong correlations with markers of diverse TIICs such as T cells, tumour-associated macrophages and DCs in BRCA and LUSC. Importantly, CELF2 was significantly associated with plenty of immune checkpoint molecules (ICMs) and outperformed five prevalent biomarkers including PD-1, PD-L1, CTLA-4, CD8 and tumour mutation burden in predicting immunotherapeutic responses. Immunohistochemistry also revealed lower protein levels of CELF2 in TNBC and LUSC compared to normal tissues, and patients with high expression showed significantly prolonged prognosis. In conclusion, we demonstrated that increased CELF2 expression was closely related to better prognosis and superior TIIC infiltration and ICM expression, particularly in BRCA and LUSC. CELF2 also performed well in evaluating the immunotherapeutic efficacy, suggesting CELF2 might be a promising biomarker.

SOD3 deficiency induces liver fibrosis by promoting hepatic stellate cell activation and epithelial-mesenchymal transition.

Hepatic stellate cell (HSC) activation plays an important role in the pathogenesis of liver fibrosis, and epithelial-mesenchymal transition (EMT) is suggested to potentially promote HSC activation. Superoxide dismutase 3 (SOD3) is an extracellular antioxidant defense against oxidative damage. Here, we found downregulation of SOD3 in a mouse model of liver fibrosis induced by carbon tetrachloride (CCl4 ). SOD3 deficiency induced spontaneous liver injury and fibrosis with increased collagen deposition, and further aggravated CCl4 -induced liver injury in mice. Depletion of SOD3 enhanced HSC activation marked by increased α-smooth muscle actin and subsequent collagen synthesis primarily collagen type I in vivo, and promoted transforming growth factor-ß1 (TGF-ß1)-induced HSC activation in vitro. SOD3 deficiency accelerated EMT process in the liver and TGF-ß1-induced EMT of AML12 hepatocytes, as evidenced by loss of E-cadherin and gain of N-cadherin and vimentin. Notably, SOD3 expression and its pro-fibrogenic effect were positively associated with sirtuin 1 (SIRT1) expression. SOD3 deficiency inhibited adenosine monophosphate-activated protein kinase (AMPK) signaling to downregulate SIRT1 expression and thus involving in liver fibrosis. Enforced expression of SIRT1 inhibited SOD3 deficiency-induced HSC activation and EMT, whereas depletion of SIRT1 counteracted the inhibitory effect of SOD3 in vitro. These findings demonstrate that SOD3 deficiency contributes to liver fibrogenesis by promoting HSC activation and EMT process, and suggest a possibility that SOD3 may function through modulating SIRT1 via the AMPK pathway in liver fibrosis.

Disaccharide Residues are Required for Native Antifreeze Glycoprotein Activity.

Antifreeze glycoproteins (AFGPs) are able to bind to ice, halt its growth, and are the most potent inhibitors of ice recrystallization known. The structural basis for AFGP's unique properties remains largely elusive. Here we determined the antifreeze activities of AFGP variants that we constructed by chemically modifying the hydroxyl groups of the disaccharide of natural AFGPs. Using nuclear magnetic resonance, two-dimensional infrared spectroscopy, and circular dichroism, the expected modifications were confirmed as well as their effect on AFGPs solution structure. We find that the presence of all the hydroxyls on the disaccharides is a requirement for the native AFGP hysteresis as well as the maximal inhibition of ice recrystallization. The saccharide hydroxyls are apparently as important as the acetyl group on the galactosamine, the α-linkage between the disaccharide and threonine, and the methyl groups on the threonine and alanine. We conclude that the use of hydrogen-bonding through the hydroxyl groups of the disaccharide and hydrophobic interactions through the polypeptide backbone are equally important in promoting the antifreeze activities observed in the native AFGPs. These important criteria should be considered when designing synthetic mimics.

Complete resection of the gastric antrum decreased incidence and severity of delayed gastric emptying after pancreaticoduodenectomy.

BACKGROUND: Delayed gastric emptying (DGE) is the main complication after pancreaticoduodenectomy (PD), but the mechanism is still unclear. The aim of this study was to elucidate the role of complete resection of the gastric antrum in decreasing incidence and severity of DGE after PD. METHODS: Sprague-Dawley rats were divided into three groups: expanded resection (ER group), complete resection (CR group), and incomplete resection (IR group) of the gastric antrum. The tension (g) of remnant stomach contraction was observed. We analyzed the histological morphology of the gastric wall by different excisional methods after distal gastrectomy. Moreover, patients underwent PD at our department between January 2012 and May 2016 were included in the study. These cases were divided into IR group and CR group of the gastric antrum, and the clinical data were retrospectively analyzed. RESULTS: The ex vivo remnant stomachs of CR group exhibited much greater contraction tension than others (P < 0.05). The contraction tension of the remnant stomach increased with increasing acetylcholine concentration, while remained stable at the concentration of 10 × 10-5 mol/L. Furthermore, 174 consecutive patients were included and retrospectively analyzed in the study. The incidence of DGE was significantly lower (3.5% vs. 21.3%, P < 0.01) in CR group than in IR group. In addition, hematoxylin-eosin staining analyses of the gastric wall confirmed that the number of transected circular smooth muscle bundles were higher in IR group than in CR group (8.24 ± 0.65 vs. 3.76 ± 0.70, P < 0.05). CONCLUSIONS: The complete resection of the gastric antrum is associated with decreased incidence and severity of DGE after PD. Gastric electrophysiological and physiopathological disorders caused by damage to gastric smooth muscles might be the mechanism underlying DGE.

MicroRNA-214-3p enhances erastin-induced ferroptosis by targeting ATF4 in hepatoma cells.

Primary liver cancer is the second most frequent cause of cancer-related deaths. Ferroptosis, a recognized form of regulated cell death, recently gains attention. MicroRNA-214-3p (miR-214) plays a regulatory role in hepatocarcinogenesis. However, the role of miR-214 in cellular ferroptosis is unclear. This study aimed at elucidating whether miR-214 could regulate ferroptosis of liver cancer. In vitro, HepG2 and Hep3B cancer cells were treated with erastin, a ferroptosis inducer, and then erastin was demonstrated to suppress the cell viability. Moreover, pre-miR-214 overexpression caused that HepG2 and Hep3B cells were more susceptible to erastin, whereas anti-miR-214 sponge showed the opposite effect. Additionally, pre-miR-214 overexpression increased the malondialdehyde and reactive oxygen species levels, upregulated Fe2+ concentration, and decreased glutathione levels in cancer cells exposed to erastin. Further, erastin enhanced the activation of transcription factor 4 (ATF4) in HepG2 and Hep3B cells, and pre-miR-214 overexpression inhibited ATF4 expression. The luciferase reporter data validated ATF4 as a direct target of miR-214. Cancer cells transfected with ATF4 overexpression plasmid rendered lower susceptible to miR-214-induced ferroptotic death. In vivo, erastin significantly reduced the size and weight of xenografted tumors, and miR-214 elevated the ferroptosis-promoting effects of erastin and decreased ATF4 expression. In summary, our study demonstrates that the ferroptosis-promoting effects of miR-214 in hepatoma cells are attributed at least to its inhibitory effects on ATF4, which may provide a new target for therapy of hepatoma regarding ferroptosis.

Sigma-1 receptor protects against ferroptosis in hepatocellular carcinoma cells.

Sigma-1 receptor (S1R) regulates reactive oxygen species (ROS) accumulation via nuclear factor erythroid 2-related factor 2 (NRF2), which plays a vital role in ferroptosis. Sorafenib is a strong inducer of ferroptosis but not of apoptosis. However, the mechanism of sorafenib-induced ferroptosis in hepatocellular carcinoma (HCC) remains unclear. In this study, we found for the first time that sorafenib induced most of S1Rs away from nucleus compared to control groups in Huh-7 cells, and ferrostatin-1 completely blocked the translocation. S1R protein expression, but not mRNA expression, in HCC cells was significantly up-regulated by sorafenib. Knockdown of NRF2, but not of p53 or hypoxia-inducible factor 1-alpha (HIF1α), markedly induced S1R mRNA expression in HCC cells. Inhibition of S1R (by RNAi or antagonists) increased sorafenib-induced HCC cell death in vitro and in vivo. Knockdown of S1R blocked the expression of glutathione peroxidase 4 (GPX4), one of the core targets of ferroptosis, in vitro and in vivo. Iron metabolism and lipid peroxidation increased in the S1R knockdown groups treated with sorafenib compared to the control counterpart. Ferritin heavy chain 1 (FTH1) and transferrin receotor protein 1 (TFR1), both of which are critical for iron metabolism, were markedly up-regulated in HCC cells treated with erastin and sorafenib, whereas knockdown of S1R inhibited these increases. In conclusion, we demonstrate that S1R protects HCC cells against sorafenib and subsequent ferroptosis. A better understanding of the role of S1R in ferroptosis may provide novel insight into this biological process.

Signal-On Electrochemiluminescence of Self-Ordered Molybdenum Oxynitride Nanotube Arrays for Label-Free Cytosensing.

In this paper, a signal-on electrochemiluminescence (ECL) cytosensing platform was developed based on nitrogen doped molybdenum oxynitride nanotube arrays (MoO xN y NTs) for the first time. The MoO xN y NTs exhibited excellent cathodic ECL behavior with 2-(dibutylamino)-ethanol (DBAE) as a coreactant. Owing to the surface plasmon resonance (SPR) of Au triggered by the ECL emission, the generation of "hot electrons" on AuNPs hampered DBAE to give off electrons and leads to the ECL quenching. This process could be hindered via adding "barriers" on the surface of AuNPs, such as antibody molecules and cells, to achieve the signal recovery. Based on the quenching-recovering mechanism, a facile label-free ECL cytosensor was constructed. The linear response of HepG2 cells was in the range of 50-13800 cells mL-1 with a low detection limit of 47 cells mL-1 (S/N = 3). Moreover, the proposed ECL cytosensor exhibits a satisfying performance in the practical application. Due to the anodic formation from a Mo metal substrate, the valuable feature is that the MoO xN y NTs-based ECL cytosensor can be used directly, thereby providing a stable and simplified ECL cytosensing platform for future clinical applications.

Haloperidol, a sigma receptor 1 antagonist, promotes ferroptosis in hepatocellular carcinoma cells.

Ferroptosis is a novel form of cell death, which is characterized by accumulation of reactive oxygen species (ROS). Sigma 1 receptor (S1R) has been suggested to function in oxidative stress metabolism. Both erastin and sorafenib significantly induced S1R protein expression. Haloperidol strongly promoted erastin- and sorafenib-induced cell death, which was blocked by ferrostatin-1 but not ZVAD-FMK or necrosulfonamide. During ferroptosis, haloperidol substantially increased the cellular levels of Fe2+, GSH and lipid peroxidation. Furthermore, several ferroptosis-related protein targets were up-regulated in the absence of haloperidol. Thus, Our study identified an association between haloperidol and ferroptosis for the first time. Our analyses of a combination of drugs may provide a novel strategy of hepatocellular carcinoma (HCC) therapy.

Structural Phase Transitions and Dielectric Switching in a Series of Organic-Inorganic Hybrid Perovskites ABX3 (X=ClO4- or BF4- ).

A series of organic-inorganic hybrid perovskites ABX3 (A=diprotonated 1,4-diazabicyclo[2.2.2]octane or piperazine; B=Na+ or K+ ; X=ClO4- or BF4- ) has been synthesized. They feature a cubic cage-like host-guest structures of which A is the cationic guest residing in the anionic cage B8 X12 , B is the vertex of the cage with variable coordination numbers between six and twelve, and X is the bridging ligand with mono- and/or bidentate coordination modes. The extended Goldschmidt tolerance factor t is used to describe the phase stability of the compounds. Differential scanning calorimetry, variable-temperature structural analyses, and dielectric measurements reveal that order-disorder transitions of the A guest and/or X bridging ligand are supposed to be responsible for structural phase transitions and dielectric switching in the compounds.