Multienzyme-Like Polyoxometalate-Based Single-Atom Enzymes for Cancer-Specific Therapy Through Acid-Triggered Nontoxicity-to-Toxicity Transition.

Single-atom enzymes (SAzymes) exhibit great potential for chemodynamic therapy (CDT); while, general application is still challenged by their instability and unavoidable side effects during delivery. Herein, a manganese-based polyoxometalate single-atom enzyme (Mn-POM SAE) is first introduced into tumor-specific CDT, which exhibits tumor microenvironment (TME)-activated transition of nontoxicity-to-toxicity. Different from traditional POM materials, the aggregates of low-toxic Mn-POM SAE nanospheres are obtained at neutral conditions, facilitating efficient delivery and avoiding toxicity problems in normal tissues.

The Upregulation of Leucine-Rich Repeat Containing 1 Expression Activates Hepatic Stellate Cells and Promotes Liver Fibrosis by Stabilizing Phosphorylated Smad2/3.

Liver fibrosis poses a significant global health risk due to its association with hepatocellular carcinoma (HCC) and the lack of effective treatments. Thus, the need to discover additional novel therapeutic targets to attenuate liver diseases is urgent. Leucine-rich repeat containing 1 (LRRC1) reportedly promotes HCC development.

Dysfunction of CCT3-associated network signals for the critical state during progression of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors and is a serious threat to human health; thus, early diagnosis and adequate treatment are essential. However, there are still great challenges in identifying the tipping point and detecting early warning signals of early HCC. In this study, we aimed to identify the tipping point (critical state) of and key molecules involved in hepatocarcinogenesis based on time series transcriptome expression data of HCC patients.

Subcutaneous Administration of Monoclonal Antibodies: Pharmacology, Delivery, Immunogenicity, and Learnings From Applications to Clinical Development.

Subcutaneous (s.c.) administration of monoclonal antibodies (mAbs) can reduce treatment burden for patients and healthcare systems compared with intravenous (i.

Pharmacokinetics and immunogenicity of eftozanermin alfa in subjects with previously-treated solid tumors or hematologic malignancies: results from a phase 1 first-in-human study.

Purpose: Eftozanermin alfa is a second-generation tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor agonist that enhances death receptor 4/5 clustering on tumor cells to induce apoptosis. We report the pharmacokinetics and immunogenicity of eftozanermin alfa administered intravenously to 153 adults with previously-treated solid tumors or hematologic malignancies from the first-in-human, open-label, dose-escalation and dose-optimization study.

Methods: Dose escalation evaluated eftozanermin alfa monotherapy 2.

Synergistically remodulating H/Ca gradients to induce mitochondrial depolarization for enhanced synergistic cancer therapy.

The remodulation of H/Ca gradients in the mitochondria matrix could be effective to induce mitochondria depolarization for the enhancement of cancer therapy. However, it is still challenged by H homeostasis, insufficient Ca, uncoordinated regulations, and inefficient loading/delivery strategies. Herein, a supramolecular DNA nanocomplex (Ca@DNA-MF) was prepared to synergistically remodulate H/Ca gradients for mitochondrial depolarization.

Ultrathin 2D Pd/Cu Single-Atom MOF Nanozyme to Synergistically Overcome Chemoresistance for Multienzyme Catalytic Cancer Therapy.

Single-atom nanozymes (SAzymes) have obtained increasing interest to mimic natural enzymes for efficient cancer therapy, while challenged by chemoresistance from cellular redox homeostasis and the interface of reductive species in tumor microenvironment (TME). Herein, a dual single-atomic ultrathin 2D metal organic framework (MOF) nanosheet of multienzyme (Pd/Cu SAzyme@Dzy) is prepared to synergistically overcome chemoresistance for multienzyme enhanced cancer catalytic therapy. The Pd SAzyme exhibits peroxidase (POD)-like catalytic activity for overcoming chemoresistance via disturbing cellular redox balance.

Near-Infrared Fluorescent Probe for HS Detection: Will pH Affect the Intracellular Sensing?

Near-infrared (NIR) fluorescent probe has exhibited unique advantages for and detection of hydrogen sulfide (HS), an important endogenous gasotransmitter in redox homeostasis and multiple life processes. However, both the pH-dependent emission of NIR probes and HS conversions would normally affect the accurate detection in cellular environments in different acidic conditions. Herein, both experiments and theoretical calculations were carried out to examine the effect of pH on intracellular sensing of HS by the NIR probe.

Modular and hierarchical self-assembly of siRNAs into supramolecular nanomaterials for soft and homogeneous siRNA loading and precise and visualized intracellular delivery.

siRNA therapeutics are challenged by homogeneous and efficient loading, maintenance of biological activities, and precise, dynamic and monitorable site-release. Herein, supramolecular nanomaterials of WP5⊃G-siRNA were constructed by modular and hierarchical self-assembly of siRNA with guest (3,6-di(thiophen-2-yl)pyrrolo[3,4-]pyrrole-1,4(2,5)-dione derivative, G) and host (pillar[5]arene, WP5) molecules in the same system. Demonstrated by experiments and theoretical calculations, WP5⊃G-siRNA was constructed comprehensive weak interactions including electrostatic, hydrophobic-hydrophilic, host-guest and π-π interactions.

EZH2 overexpression dampens tumor-suppressive signals via an EGR1 silencer to drive breast tumorigenesis.

The mechanism underlying EZH2 overexpression in breast cancer and its involvement in tumorigenesis remain poorly understood. In this study, we developed an approach to systematically identify the trans-acting factors regulating the EZH2 expression, and identified more than 20 such factors. We revealed reciprocal regulation of early growth response 1 (EGR1) and EZH2: EGR1 activates the expression of EZH2, and EZH2 represses EGR1 expression.

In Vitro and In Vivo Efficacy of AZD3965 and Alpha-Cyano-4-Hydroxycinnamic Acid in the Murine 4T1 Breast Tumor Model.

Monocarboxylate transporter 1 (MCT1) represents a potential therapeutic target in cancer. The objective of this study was to determine the efficacy of AZD3965 (a specific inhibitor of MCT1) and α-cyano-4-hydroxycinnamic acid (CHC, a nonspecific inhibitor of MCTs) in the murine 4T1 tumor model of triple-negative breast cancer (TNBC). Expression of MCT1 and MCT4 in 4T1 and mouse mammary epithelial cells were determined by Western blot.

Pharmacokinetics of the Monocarboxylate Transporter 1 Inhibitor AZD3965 in Mice: Potential Enterohepatic Circulation and Target-Mediated Disposition.

Purpose: To evaluate the pharmacokinetics (PK) of the monocarboxylate transporter 1 (MCT1) inhibitor AZD3965 in mice after IV and oral administration and to develop mechanistic PK models to assess the potential enterohepatic circulation (EHC) and target-mediated drug disposition (TMDD) of AZD3965.

Methods: Female BALB/c mice were administered AZD3965 by IV injection (10, 50 and 100 mg/kg) or oral gavage (100 mg/kg). Plasma samples were analyzed using LC/MS/MS, and PK parameters determined by compartmental and non-compartmental analyses.

A novel supramolecular AIE π-gel for fluorescence detection and separation of metal ions from aqueous solution.

A novel supramolecular aggregation induced emission (AIE) π-gel (ONT) was constructed by using a functionalized trimesic amide (TCP) molecule assembled with a bis-pyridine functionalized naphthalene diimide (ND) molecule using a non-covalent interaction. The ONT showed strong AIE at 468 nm. Furthermore, the ONT could detect and adsorb ferric (Fe) or cupric (Cu) ions from water.

Phosphorylation of TET2 by AMPK is indispensable in myogenic differentiation.

Background: TET-mediated oxidation of 5-mC participates in both passive and active DNA demethylation, which exerts a significant influence on diverse biological processes. Mass spectrometry has identified multiple phosphorylation sites of TET2. However, the functions of these phosphosites and their corresponding kinases are mostly unknown.

Rationally introduce AIE into chemosensor: A novel and efficient way to achieving ultrasensitive multi-guest sensing.

Recently, ultrasensitive detection and multi-guest sensing have received extensive attention due to their high sensitivity and efficiency. Herein, we report a novel approach to achieve ultrasensitive detection of multi-analyte. This approach is concluded as "rationally introduce Aggregation-Induced Emission (AIE) into chemosensor".

Pillar[5]arene-based spongy supramolecular polymer gel and its properties in multi-responsiveness, dye sorption, ultrasensitive detection and separation of Fe.

Herein, a novel way to design and construct multi-functional spongy supramolecular polymer gels through an easy to make tripodal guest (TA) and a naphthalimide functionalized-pillar[5]arene host (AP5) has been developed. According to this approach, a novel pillar[5]arene-based supramolecular polymer gel (SHG) was constructed via multi-non-covalent interactions such as host-guest inclusion, C-Hπ, ππ and hydrogen bonds and so on. Interestingly, the SHG exhibits a spongy structure and strong aggregation induced emission (AIE).

Anion induced supramolecular polymerization: a novel approach for the ultrasensitive detection and separation of F.

A novel approach for the ultrasensitive detection and separation of F- has been successfully developed. F- could induce a tripodal naphthalene imide sensor (TNA) to result in supramolecular polymerization, leading to strong AIEE. The TNA could act as an excellent recyclable material for F- detection and separation.

CBX6 is negatively regulated by EZH2 and plays a potential tumor suppressor role in breast cancer.

Chromobox 6 (CBX6) is a subunit of Polycomb Repressive Complex 1 (PRC1) that mediates epigenetic gene repression and acts as an oncogene or tumor suppressor in a cancer type-dependent manner. The specific function of CBX6 in breast cancer is currently undefined. In this study, a comprehensive analysis of The Cancer Genome Atlas (TCGA) dataset led to the identification of CBX6 as a consistently downregulated gene in breast cancer.

Cellular Uptake of MCT1 Inhibitors AR-C155858 and AZD3965 and Their Effects on MCT-Mediated Transport of L-Lactate in Murine 4T1 Breast Tumor Cancer Cells.

AR-C155858 and AZD3965, pyrrole pyrimidine derivatives, represent potent monocarboxylate transporter 1 (MCT1) inhibitors, with potential immunomodulatory and chemotherapeutic properties. Currently, there is limited information on the inhibitory properties of this new class of MCT1 inhibitors. The purpose of this study was to characterize the concentration- and time-dependent inhibition of L-lactate transport and the membrane permeability properties of AR-C155858 and AZD3965 in the murine 4T1 breast tumor cells that express MCT1.

In Vitro and In Vivo Efficacy of the Monocarboxylate Transporter 1 Inhibitor AR-C155858 in the Murine 4T1 Breast Cancer Tumor Model.

Monocarboxylate transporter 1 (MCT1), also known as a L-lactate transporter, is a potential therapeutic target in cancer. The objectives of this study were to evaluate efficacy and assess concentration-effect relationships of AR-C155858 (a selective and potent MCT1 inhibitor) in murine 4T1 breast cancer cells and in the 4T1 tumor xenograft model. Western blotting of 4T1 cells demonstrated triple negative breast cancer (TNBC) characteristics and overexpression of MCT1 and CD147 (a MCT1 accessory protein), but absence of MCT4 expression.

Acylhydrazone functionalized benzimidazole-based metallogel for the efficient detection and separation of Cr.

Chromium(iii) is a kind of microelement and can be converted to the more toxic chromium(vi), which is a carcinogen, by redox cycling. Thus, the development of novel materials for the detection and removal of Cr is a very important issue. A novel metallogel chemosensor (BMG-Fe) based on functionalized benzimidazole (BM) and Fe was constructed, which could fluorescently detect and separate Cr.

Increased megalin expression in early type 2 diabetes: role of insulin-signaling pathways.

The megalin/cubilin complex is responsible for the majority of serum protein reclamation in the proximal tubules. The current study examined if decreases in their renal expression, along with the albumin recycling protein neonatal Fc receptor (FcRn) could account for proteinuria/albuminuria in the Zucker diabetic fatty rat model of type 2 diabetes. Immunoblots of renal cortex samples obtained at worsening disease stages demonstrated no loss in megalin, cubilin, or FcRn, even when proteinuria was measured.

Development and validation of a liquid chromatography tandem mass spectrometry assay for AZD3965 in mouse plasma and tumor tissue: Application to pharmacokinetic and breast tumor xenograft studies.

AZD3965, a pyrole pyrimidine derivative, is a potent and orally bioavailable inhibitor of monocarboxylate transporter 1 (MCT1), currently in a Phase I clinical trial in UK for lymphomas and solid tumors. There is currently no published assay for AZD3965. The objectives of this study were to develop and validate a LC/MS/MS assay for quantifying AZD3965 in mouse plasma and tumor tissue.

One-pot synthesis and biological evaluation of N-(aminosulfonyl)-4-podophyllotoxin carbamates as potential anticancer agents.

A series of N-(aminosulfonyl)-4-podophyllotoxin carbamates were synthesized via the Burgess-type intermediate, and their antiproliferative activities were evaluated. Most of them possessed more potent cytotoxic effects against four human tumor cell lines (HeLa, A-549, HCT-8 and HepG2) and less toxic to normal human fetal lung fibroblast WI-38 cells than etoposide. In particular, N-(morpholinosulfonyl)-4-podophyllotoxin carbamate (9) exhibited the most potent activity towards these four tumor cells with IC values in the range of 0.