Macrophage migration inhibitory factor (MIF) suppresses mitophagy through disturbing the protein interaction of PINK1-Parkin in sepsis-associated acute kidney injury.

Damage to renal tubular epithelial cells (RTECs) signaled the onset and progression of sepsis-associated acute kidney injury (SA-AKI). Recent research on mitochondria has revealed that mitophagy plays a crucial physiological role in alleviating injury to RTECs and it is suppressed progressively by the inflammation response in SA-AKI. However, the mechanism by which inflammation influences mitophagy remains poorly understood. We examined how macrophage migration inhibitory factor (MIF), a pro-inflammatory protein, influences the PINK1-Parkin pathway of mitophagy by studying protein-protein interactions when MIF was inhibited or overexpressed. Surprisingly, elevated levels of MIF were found to directly bind to PINK1, disrupting its interaction with Parkin. This interference hindered the recruitment of Parkin to mitochondria and impeded the initiation of mitophagy. Furthermore, this outcome led to significant apoptosis of RTECs, which could, however, be reversed by an MIF inhibitor ISO-1 and/or a new mitophagy activator T0467. These findings highlight the detrimental impact of MIF on renal damage through its disruption of the interaction between PINK1 and Parkin, and the therapeutic potential of ISO-1 and T0467 in mitigating SA-AKI. This study offers a fresh perspective on treating SA-AKI by targeting MIF and mitophagy.

TIMP2 protects against sepsis-associated acute kidney injury by cAMP/NLRP3 axis-mediated pyroptosis.

The tissue inhibitor of metalloproteinases 2 (TIMP2) has emerged as a promising biomarker for predicting the risk of sepsis-associated acute kidney injury (SA-AKI). However, its exact role in SA-AKI and the underlying mechanism remains unclear. In this study, we investigated the impact of kidney tubule-specific Timp2 knockout mice on kidney injury and inflammation. Our findings demonstrated that Timp2-knockout mice exhibited more severe kidney injury than wild-type mice, along with elevated levels of pyroptosis markers NOD-like receptor protein 3 (NLRP3), Caspase1, and gasdermin D (GSDMD) in the early stage of SA-AKI. Conversely, the expression of exogenous TIMP2 in TIMP2-knockout mice still protected against kidney damage and inflammation. In in vitro experiments, using recombinant TIMP2 protein, TIMP2 knockdown demonstrated that exogenous TIMP2 inhibited pyroptosis of renal tubular cells stimulated by lipopolysaccharide (LPS). Mechanistically, TIMP2 promoted the ubiquitination and autophagy-dependent degradation of NLRP3 by increasing intracellular cyclic adenosine monophosphate (cAMP), which mediated NLRP3 degradation through recruiting the E3 ligase MARCH7, attenuating downstream pyroptosis, and thus alleviating primary tubular cell damage. These results revealed the renoprotective role of extracellular TIMP2 in SA-AKI by attenuating tubular pyroptosis, and suggested that exogenous administration of TIMP2 could be a promising therapeutic intervention for SA-AKI treatment.NEW & NOTEWORTHY Tissue inhibitor of metalloproteinase 2 (TIMP-2) has been found to be the best biomarker for predicting the risk of sepsis-associated acute kidney injury (SA-AKI). However, its role and the underlying mechanism in SA-AKI remain elusive. The authors demonstrated in this study using kidney tubule-specific knockout mice model of SA-AKI and primary renal tubule cells stimulated with lipopolysaccharide (LPS) that extracellular TIMP-2 promoted NOD-like receptor protein 3 (NLRP3) ubiquitination and autophagy-dependent degradation by increasing intracellular cyclic adenosine monophosphate (cAMP), thus attenuated pyroptosis and alleviated renal damage.

Cryo-electron microscopy structures of capsids and in situ portals of DNA-devoid capsids of human cytomegalovirus.

The portal-scaffold complex is believed to nucleate the assembly of herpesvirus procapsids. During capsid maturation, two events occur: scaffold expulsion and DNA incorporation. The portal-scaffold interaction and the conformational changes that occur to the portal during the different stages of capsid formation have yet to be elucidated structurally. Here we present high-resolution structures of the A- and B-capsids and in-situ portals of human cytomegalovirus. We show that scaffolds bind to the hydrophobic cavities formed by the dimerization and Johnson-fold domains of the major capsid proteins. We further show that 12 loop-helix-loop fragments-presumably from the scaffold domain-insert into the hydrophobic pocket of the portal crown domain. The portal also undergoes significant changes both positionally and conformationally as it accompanies DNA packaging. These findings unravel the mechanism by which the portal interacts with the scaffold to nucleate capsid assembly and further our understanding of scaffold expulsion and DNA incorporation.

Autophagy-Related Gene WD Repeat Domain 45B Promotes Tumor Proliferation and Migration of Hepatocellular Carcinoma through the Akt/mTOR Signaling Pathway.

Hepatocellular carcinoma (HCC) is a highly aggressive malignant tumor. It has been found that autophagy plays a role both as a tumor promoter and inhibitor in HCC carcinogenesis. However, the mechanism behind is still unveiled. This study aims to explore the functions and mechanism of the key autophagy-related proteins, to shed light on novel clinical diagnoses and treatment targets of HCC. Bioinformation analyses were performed by using data from public databases including TCGA, ICGC, and UCSC Xena. The upregulated autophagy-related gene WDR45B was identified and validated in human liver cell line LO2, human HCC cell line HepG2 and Huh-7. Immunohistochemical assay (IHC) was also performed on formalin-fixed paraffin-embedded (FFPE) tissues of 56 HCC patients from our pathology archives. By using qRT-PCR and Western blots we found that high expression of WDR45B influenced the Akt/mTOR signaling pathway. Autophagy marker LC3- II/LC3-I was downregulated, and p62/SQSTM1 was upregulated after knockdown of WDR45B. The effects of WDR45B knockdown on autophagy and Akt/mTOR signaling pathways can be reversed by the autophagy inducer rapamycin. Moreover, proliferation and migration of HCC can be inhibited after the knockdown of WDR45B through the CCK8 assay, wound-healing assay and Transwell cell migration and invasion assay. Therefore, WDR45B may become a novel biomarker for HCC prognosis assessment and potential target for molecular therapy.

Real-Time In Situ Volatile Organic Compound Sensing by a Dual-Emissive Polynuclear Ln-MOF with Pronounced LnIII Luminescence Response.

Lanthanide metal-organic frameworks (Ln-MOFs) are promising for luminescence detection of volatile organic compound (VOC) vapors, but usually suffer from the silent or quenched Ln3+ emission. Herein, we report a new dual-emissive Eu-MOF composed of the coordinatively unsaturated Eu9 clusters that afford abundant open metal sites to form a confined "binding pocket" to facilitate the preconcentration and recognition of VOCs. Single-crystal structural analyses reveal that specific analytes can replace the OH oscillators in the first coordination sphere of Eu3+ and form a unique hydrogen-bonding second-sphere adduct tying adjacent Eu9 clusters together to minimize their nonradiative vibrational decay. With the promoted Eu3+ luminescence, the MOF realizes real-time in situ visual sensing of THF vapor (<1 s) and shows a quantitative ratiometric response to the vapor pressure with a limit of detection down to 17.33 Pa. Also, it represents a top-performing ratiometric luminescent thermometer.

Dynamic Full-Color Tuning of Organic Chromophore in a Multi-Stimuli-Responsive 2D Flexible MOF.

Developing universal stimuli-responsive materials capable of emitting a broad spectrum of colors is highly desirable. Herein, we deliberately grafted a conformation-adaptable organic chromophore into the established coordination space of a flexible metal-organic framework (MOF). In terms of the coupled structural transformations and the space confinement, the chromophore in the MOF matrix underwent well-regulated conformational changes under physical and chemical stimuli, simultaneously displaying thermo-, piezo-, and solvato-fluoro-chromism with color tunability over the visible range. Owing to the resilient nature and the reduced dimensionality of the selected coordination space, all three color modulations behaved in a sensitive and self-reversible manner, each following a linear correlation of the emission maximum with stimulus. Single-crystal X-ray diffraction of the variable-temperature structures and solvent-inclusion crystals elucidated the intricate color varying mechanisms.

Successful startup of the single-stage PN-A (partial nitrification-anammox) process by controlling the oxygen supply.

The single PN-A (partial nitrification-anammox) reactor offers a cost-effective solution for nitrogen removal. However, optimal control of the PN-A reactor is challenging due to the interactive mechanisms among the oxygen supply, bulk liquid DO (dissolved oxygen) concentration, and the balance of various functional bacterial species. In this study, a mathematical model was used to derive the optimal control variable for the maximum nitrogen removal, and an experimental PN-A reactor was operated to verify the model simulation results. The model simulation results indicate that the oxygen supply to the ammonium load ratio is the key factor to control the single-stage PN-A reactor for optimal TN removal. For optimal TN removal, the oxygen supply to the ammonium load ratio should be 1.9 mg O2/mg N. The DO concentration is not the key control parameter to get the maximum TN removal as the optimal TN removal could be achieved under a wide range of DO concentration. The model simulation results were verified in the experimental PN-A reactor under oxygen transfer rate ([Formula: see text]) at 52 day-1, HRT at 24 h, and ammonium load ratio of 0.55 kg N/(m3∙day).

Pharmacokinetics, oral bioavailability and metabolic analysis of solasodine in mice by dried blood spot LC-MS/MS and UHPLC-Q-Exactive MS.

Solasodine, a major ingredient in Solanaceae family, has various biological functions such as inducing neurogenesis, anticonvulsant and anti-tumor. Its risk assessment has also drawn public attention. However, little is known about its oral bioavailability and metabolic process. In this study, an liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed for the quantification of solasodine in mice dried blood spot (DBS) samples. To block nonspecific adsorption, DBS samples were pretreated with bovine serum albumin (BSA) and then extracted with ethyl acetate. This method was applied to a pharmacokinetic and bioavailability study of solasodine. The absolute bioavailability was only 1.28%. Thereafter, its metabolites in mice were characterized using an ultra-performance liquid chromatography Q-Exactive high-resolution mass spectrometer (UHPLC-QE-HRMS). Several isomeric metabolites were well separated and differentiated using their retention time, fragmentation pathways and correspondingly fragmentation rules of solasodine. As a result, 21 metabolites were characterized including 16 phase I and 5 phase II metabolites. The proposed metabolic pathways showed that solasodine mainly experienced oxidation, dehydration, dehydrogenation and sulfation. These results could help us to better understand the efficacy and safety of solasodine.

Experiment and simulation of flexible CNT/SA/PDMS electromagnetic shielding composite.

Flexible electromagnetic shielding composites have a great potential for wide range applications. In this study, two flexible composites were produced by plating Ni nanoparticles on carbon nanotubes (CNTs) or infiltrating carbon nanofibers/polydimethylsiloxane (CNF/PDMS) polymer into CNT/sodium alginate (CNT/SA) sponge skeleton (CNT/SA/CNF/PDMS composites). The composites are tested under the X band in the frequency range of 8.2 - 12.4 GHz, the electromagnetic interference shielding effectiveness (EMI-SE) values of the above two composites are almost as twice as that of CNT/SA/PDMS composite at a same CNT loading. Introducing nano-sized Ni particles on CNT improved the microwave absorption capacity of the composite, while adding CNF on the PDMS matrix enhanced the conductivity of these composites. Under 10% strain, both flexible composites show stable conductivity. Simulation and calculation results shown that increasing the cladding rate of Ni nanoparticles on the surface of CNT, reducing the average size of Ni particles, and increasing the loading of CNF in PDMS matrix can significantly improve conductivity and then EMI performance of the materials. All of these could benefit for the design of flexible electromagnetic shielding composites.

Prognostic Value of Immune-Related Multi-IncRNA Signatures Associated With Tumor Microenvironment in Esophageal Cancer.

Esophageal cancer is the eighth most common cancer and the sixth leading cause of cancer death worldwide. Hence, for a better understanding of tumor microenvironment and to seek for novel molecular targets for esophageal cancer, we performed related studies on two histopathological subtypes of esophageal cancer: esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC). Bioinformatic analyses were conducted based on the RNA-seq, genomic mutation, and clinical data from TCGA and GEO cohorts. We clustered patients into high-immunity and low-immunity groups through the ssGSEA results. The ESTIMATE algorithm was used to evaluate the tumor microenvironment. Patients with high immunity in both ESCC and EAC had lower tumor purity and poor survival. Subsequently, CIBERSORT was performed to learn about the detailed difference of tumor-infiltrating lymphocytes (TILs) between high- and low-immunity patients. Specific increase of M2 macrophages and decrease of activated dendric cells can be observed in ESCC and EAC, respectively. The most enriched functions and pathways of high-immunity patients were immunoglobulin complex, MHC class II protein complex, and allograft rejection according to the GO terms and KEGG. Two prognostic immune-related multi-lncRNA risk models were constructed and validated by ROC curve and PCA in ESCC and EAC. High-risk patients in both subtypes had poor survival, advanced clinical characteristics, and higher drug susceptibility except cisplatin and sorafenib. In addition, the tumor mutation burden (TMB) was positively correlated with the risk level in the ESCC and EAC and showed distinct differences between the two subtypes. In summary, we comprehensively analyzed the tumor microenvironment for two subtypes of esophageal cancer, identified two multi-lncRNA signatures predictive for the prognosis, and explored the possibility of the signatures to forecast drug susceptibility as well as TMB for the first time. The findings may serve as a conceptual basis for innovative strategy of individualized immunotherapy for esophageal cancer.

Structural basis for genome packaging, retention, and ejection in human cytomegalovirus.

How the human cytomegalovirus (HCMV) genome-the largest among human herpesviruses-is packaged, retained, and ejected remains unclear. We present the in situ structures of the symmetry-mismatched portal and the capsid vertex-specific components (CVSCs) of HCMV. The 5-fold symmetric 10-helix anchor-uncommon among known portals-contacts the portal-encircling DNA, which is presumed to squeeze the portal as the genome packaging proceeds. We surmise that the 10-helix anchor dampens this action to delay the portal reaching a "head-full" packaging state, thus facilitating the large genome to be packaged. The 6-fold symmetric turret, latched via a coiled coil to a helix from a major capsid protein, supports the portal to retain the packaged genome. CVSCs at the penton vertices-presumed to increase inner capsid pressure-display a low stoichiometry, which would aid genome retention. We also demonstrate that the portal and capsid undergo conformational changes to facilitate genome ejection after viral cell entry.

LRRK2 is a candidate prognostic biomarker for clear cell renal cell carcinoma.

BACKGROUND: Clear cell renal cell carcinoma (ccRCC), derived from renal tubular epithelial cells, is the most common malignant tumor of the kidney. The study of key genes related to the pathogenesis of ccRCC has become important for gene target therapy. METHODS: Bioinformatics analysis of The Cancer Genome Atlas (TCGA), the NCBI Gene Expression Omnibus (GEO) database, USUC Xena database, cBioPortal for Cancer Genomics, and MethSurv were performed to examine the aberrant genetic pattern and prognostic significance of leucine-rich repeat kinase 2 (LRRK2) expression and its relationship to clinical parameters. Immunohistochemistry and Western blot were performed to verify LRRK2 expression. The regulation of ccRCC tumor cell lines proliferation by LRRK2 was examined by CCK8 assay. RESULTS: Bioinformatics analysis showed that LRRK2 expression was up-regulated and largely correlated with DNA methylation in ccRCC. The up-regulation of LRRK2 was confirmed in ccRCC tissue immunohistochemically and by protein analysis. The level of expression was related to gender, pathological grade, stage, and metastatic status of ccRCC patients. Meanwhile, Kaplan-Meier analysis showed that high expression of LRRK2 correlates to a better prognosis; knockdown of LRRK2 expression attenuated the proliferation ability of ccRCC tumor cell lines; protein-protein interaction network analysis showed that LRRK2 interacts with HIF1A and EGFR. CONCLUSION: We found that LRRK2 may play an important role in the tumorigenesis and progression of ccRCC. Our findings provided a potential predictor and therapeutic target in ccRCC.

Galactosylated Chitosan Modified Magnetic Mesoporous Silica Nanoparticles Loaded with Nedaplatin for the Targeted Chemo-Photothermal Synergistic Therapy of Cancer.

The use of chemotherapy combined with photothermal therapy (PTT) is getting a focus topic for cancer treatment. Duing this research, the double targeting drug delivery system of nedaplatin (NDP)-carboxyl-functionalized magnetic mesoporous silica (MMSN-COOH)-galactosylated chitosan (GC) nanoparticles (NPs) was constructed. Because MMSNs have special physical properties, it can target to the specific area. In addition, it's able to convert absorbed near-infrared (NIR) light into heat energy for photothermal therapy (PTT). Furthermore, the thermal energy generated by MMSNs under NIR lasers can accelerate the release of drug from preparations. Moreover, GC modified MMSNs-COOH as a carrier can increase the drug uptake of cancer cells that highly express galectins in vitro, resulting in cancer cell apoptosis, and thus increasing the targeting of cancerous tissue in vivo. The experimental consequences in vitro and in vivo revealed that the NDP@MMSNCOOH-GC NPs combined with PTT could avoid systemic toxicity and improve biosecurity while having good anticancer effect.

Organic-Inorganic Two-Dimensional Hybrid Networks Constructed from Pyridine-4-Carboxylate-Decorated Organotin-Lanthanide Heterometallic Antimotungstates.

Six organic-inorganic hybrid pyridine-4-carboxylate-decorated organotin (OT)-lanthanide (Ln) heterometallic antimotungstates [Ln(H2O)6(pca)]H[Sn(CH3)2(H2O)]3[B-ß-SbW9O33]·12H2O [Ln = La3+ (1), Ce3+ (2), Pr3+ (3), Nd3+ (4), Sm3+ (5), Eu3+ (6); Hpca = isonicotinic acid] have been prepared with the help of the structure-directing effect of the trivacant [B-α-SbW9O33]9- segment toward [(CH3)2Sn]2+ and Ln3+ ions in an acidic water medium. The prominent architecture characteristic is that their structural units consist of a trivacant [B-ß-SbW9O33]9- segment stabilized by three [Sn(CH3)2(H2O)]2+ groups and a [Ln(H2O)6(pca)]2+ cation, which are interconnected to propagate an intriguing two-dimensional (2D) network. For all we know, 1-6 stand for the first 2D OT-Ln heterometallic polyoxometalates. Furthermore, luminescence performances of solid-state 3-6 were deeply surveyed at ambient temperature. Energy migration from [B-ß-SbW9O33]9- and pca- to Sm3+ centers in 5 was also studied. Comparative studies demonstrate that the contribution of [B-ß-SbW9O33]9- sensitizing the emission of Sm3+ is prominently larger than that of pca- sensitizing the emission of Sm3+ in the emission process of 5. Most interestingly, 6 as a fluorescence probe exhibits high selectability and sensitivity for recognizing Zn2+ and Cu2+ in water.

CryoEM structure of the tegumented capsid of Epstein-Barr virus.

Epstein-Barr virus (EBV) is the primary cause of infectious mononucleosis and has been shown to be closely associated with various malignancies. Here, we present a complete atomic model of EBV, including the icosahedral capsid, the dodecameric portal and the capsid-associated tegument complex (CATC). Our in situ portal from the tegumented capsid adopts a closed conformation with its channel valve holding the terminal viral DNA and with its crown region firmly engaged by three layers of ring-like dsDNA, which, together with the penton flexibility, effectively alleviates the capsid inner pressure placed on the portal cap. In contrast, the CATCs, through binding to the flexible penton vertices in a stoichiometric manner, accurately increase the inner capsid pressure to facilitate the pressure-driven genome delivery. Together, our results provide important insights into the mechanism by which the EBV capsid, portal, packaged genome and the CATCs coordinately achieve a pressure balance to simultaneously benefit both viral genome retention and ejection.

Bovine Lactoferrin Quantification in Dairy Products by a Simple Immunoaffinity Magnetic Purification Method Coupled with High-Performance Liquid Chromatography with Fluorescence Detection.

This study described a simple, specific, and sensitive method using immunoaffinity magnetic purification coupled with high-performance liquid chromatography-fluorescence (HPLC-FL) detection for determination of bovine lactoferrin (bLf) in dairy products. BLf was selectively extracted from dairy products using immunoaffinity beads and then detected by HPLC-FL with its intrinsic fluorescence. During the analysis, standard solutions of bLf were pretreated with Tween 20, an anti-adsorptive agent, for blocking the nonspecific binding of bLf to polypropylene tubes. The calibration curve was linear over the range of 0.8-30 µg mL-1. The validated method was successfully applied to measure bLf at the intact level in dairy products.

Organic-inorganic hybrid 1-D double chain heteropolymolybdates constructed from plenary Keggin germanomolybdate anions and hepta-nuclear Cu-RE-pic heterometallic clusters.

Two unprecedented organic-inorganic hybrid 1-D double chain germanomolybdates containing hepta-nuclear Cu-RE-pic heterometallic clusters [NH4]2[RE(H2O)5]2[Cu(pic)2]2[Cu(pic)2(H2O)2]3[α-GeMo12O40]2·22H2O [RE = La3+ (1), Ce3+ (2), and Hpic = 2-picolinic acid] were successfully obtained by the stepwise self-assembly strategy via the conventional solution method. The most striking structural feature of 1 and 2 is that the two plenary Keggin [α-GeMo12O40]4- polyoxoanions are joined by an organic-inorganic hybrid hepta-nuclear Cu-RE-pic {[RE(H2O)5]2[Cu(pic)2(H2O)2]3[Cu(pic)2]2}6+ heterometallic moiety. What is more interesting is that their adjacent structural units are connected together by {Cu(pic)2} bridges, forming a 1-D extended double chain architecture. Furthermore, the adsorption capacity of 1 toward dyes in aqueous solutions was deeply investigated. It is fascinating that 1 shows a good adsorption capacity toward basic violet 3 (BV 3) in aqueous solutions and the adsorption kinetics conforms to the second-order kinetic model.

Two Penta-REIII Encapsulated Tetravacant Dawson Selenotungstates and Nanoscale Derivatives and Their Luminescence Properties.

Two penta-REIII encapsulated tetravacant Dawson selenotungstates [H2N(CH3)2]10H3[SeO4RE5(H2O)7(Se2W14O52)2]·40H2O (RE = Dy3+ (1), Gd3+ (2)) were prepared by a one-step assembly strategy under bench conditions. Notably, the penta-REIII-substituted [SeO4RE5(H2O)7(Se2W14O52)2]12- polyoxoanion consists of two equivalent tetravacant Dawson [Se2W14O52]12- fragments linked by a central penta-REIII {SeO4RE5(H2O)7} cluster through 16 lacunary oxygen atoms and four bridging oxygen atoms from two [Se2W14O52]12- fragments. Furthermore, a series of cetyltrimethylammonium bromide (CTABr) encapsulated 1@CTA nanomaterials were prepared by the microwave method by controlling different reaction times and temperatures. The effects of time and temperature on the morphologies of 1@CTA nanomaterials were characterized by SEM images, and 1@CTA-5min prepared at 80 °C has a relatively uniform size of about 190 nm. Moreover, the photoluminescence properties of 1 and 1@CTA nanomaterials were investigated systematically, indicating that 1@CTA-5min prepared at 80 °C exhibits the strongest emission due to its smallest size and high dispersion. The energy transfer from the ST fragments to Dy3+ ions in 1 and 1@CTA-5min were proved by time-resolved emission spectra (TRES) and the change in CIE coordinates with increasing time, and their energy transfer mechanism diagram was demonstrated.

Organic-inorganic hybrids assembled from plenary Keggin-type germanotungstate units and 3d-4f heterometal clusters.

Two kinds of organic-inorganic 3d-4f heterometal hybrids based on plenary α-Keggin-type germanotungstates [Cu2(H2O)3(PA)3] [Ln0.5Na0.5Cu2(H2O)12(PA)3][α-GeW12O40]·5H2O [Ln = La3+ (1), Ce3+ (2)] and [Cu2(H2O)2(PA)3][Cu(PA)2][Ln(H2O)7][α-GeW12O40]·7H2O [Ln = Tb3+ (3), Dy3+ (4), HPA = 2-picolinic acid] were prepared via the strategy of combining an in situ assembly reaction and stepwise synthesis in the aqueous solution. The most remarkable structural characteristic of 1-2 is that neighboring structural units are connected into a 1-D chain alignment by the bridging di-copper [Cu2(H2O)3(PA)3]+ subunits, whereas the most outstanding structural feature of 3-4 is that neighboring structural units are interconnected to generate a zigzag 1-D chain alignment by the bimetallic bridging [Cu2(H2O)3(PA)3]+ subunits, and then adjacent zigzag 1-D chains are integrated into a fascinating 2-D sheet structure by heterobimetallic bridging {Tb(H2O)7[Cu(PA)2]0.5}3+ subunits and [Cu(PA)2] groups. As far as we know, 1-4 represent the first examples of plenary Keggin heterometal germanotungstates including organic 3d-4f heterometal subunits so far. The electrochemical sensing properties towards the detection of Acetaminophen of 1/3@CMWCNT-Nafion/GCE electrochemical sensors were investigated, showing that 1/3@CMWCNT-Nafion/GCE electrochemical sensors exhibit good stability and good sensing performance towards AC detection.

Galactosylated Chitosan-Functionalized Mesoporous Silica Nanoparticle Loading by Calcium Leucovorin for Colon Cancer Cell-Targeted Drug Delivery.

Targeted drug delivery to colon cancer cells can significantly improve the efficiency of treatment. We firstly synthesized carboxyl-modified mesoporous silica nanoparticles (MSN⁻COOH) via two-step synthesis, and then developed calcium leucovorin (LV)-loaded carboxyl-modified mesoporous silica nanoparticles based on galactosylated chitosan (GC), which are galectin receptor-mediated materials for colon-specific drug delivery systems. Both unmodified and functionalized nanoparticles were characterized by scanning electron microscopy (SEM), transmission electron microscope (TEM), X-ray diffraction (XRD), Fourier transform infrared (FT-IR), nitrogen sorption, and dynamic light scattering (DLS). Drug release properties and drug loading capacity were determined by ultraviolet spectrophotometry (UV). LV@MSN⁻COOH/GC had a high LV loading and a drug loading of 18.07%. In vitro, its release, mainly by diffusion, was sustained release. Cell experiments showed that in SW620 cells with the galectin receptor, the LV@MSN⁻COOH/GC metabolized into methyl tetrahydrofolic acid (MTHF) and 5-fluorouracil (5-FU)@MSN⁻NH2/GC metabolized into FdUMP in vivo. MTHF and 5-fluoro-2'-deoxyuridine 5'-monophosphate (FdUMP) had combined inhibition and significantly downregulated the expression of thymidylate synthase (TS). Fluorescence microscopy and flow cytometry experiments show that MSN⁻COOH/GC has tumor cell targeting, which specifically recognizes and binds to the galectin receptor in tumor cells. The results show that the nano-dosing system based on GC can increase the concentrations of LV and 5-FU tumor cells and enhance their combined effect against colon cancer.