Investigation of the toxic mechanism of aspartame on female infertility using network toxicology and molecular docking approaches.

Aspartame is a nonnutritive sweetener derived from phenylalanine and is widely used in food and beverages globally. In recent years, its safety, particularly the potential carcinogenic risks, has garnered significant attention; however, there has been relatively less focus on its potential infertility risks. This study employed network toxicology methods to construct an interaction network of aspartame and infertility-related targets and identify key targets and pathways.

Lipid Isobaric Mass Tagging for Enhanced Relative Quantification of Unsaturated -Positional Isomers.

Changes in the levels of lipid -positional isomers are associated with perturbation of the physiological environment within the biological system. Consequently, knowing the concentrations of these lipids holds significant importance for unraveling their involvement in disease diagnosis and pathological mechanisms. However, existing methods for lipid quantification often fall short in accuracy due to the structural diversity and isomeric forms of lipids.

BRD4354 Is a Potent Covalent Inhibitor against the SARS-CoV-2 Main Protease.

Numerous organic molecules are known to inhibit the main protease (M) of SARS-CoV-2, the pathogen of Coronavirus Disease 2019 (COVID-19). Guided by previous research on zinc-ligand inhibitors of M and zinc-dependent histone deacetylases (HDACs), we identified BRD4354 as a potent inhibitor of M. The protease activity assays show that BRD4354 displays time-dependent inhibition against M with an IC (concentration that inhibits activity by 50%) of 0.

Targeting DHODH reveals therapeutic opportunities in ATRA-resistant acute promyelocytic leukemia.

Although all-trans retinoic acid (ATRA)-induced differentiation has transformed acute promyelocytic leukemia (APL) from the most fatal to the most curable hematological disease, resistance to ATRA in high-risk APL patients remains a clinical challenge. In this paper, we discovered that dihydroorotate dehydrogenase (DHODH) inhibition overcame ATRA resistance. 416, a potent DHODH inhibitor previously obtained in our group, inhibited the occurrence of APL in cells and model mice.

Discovery and optimization of 4-anilinoquinazoline derivatives spanning ATP binding site and allosteric site as effective EGFR-C797S inhibitors.

Epidermal growth factor receptor (EGFR) is an effective drug target for the treatment of non-small cell lung cancer (NSCLC). However, a tertiary point mutation (C797S) at the ATP binding pocket of the EGFR induces resistance to the third-generation EGFR inhibitors, due to the loss of covalent interaction with Cys797. Here, we designed a series of 4-anilinoquinazoline derivatives that simultaneously occupied the ATP binding pocket and the allosteric site.

Lipid Mass Tags via Aziridination for Probing Unsaturated Lipid Isomers and Accurate Relative Quantification.

Knowing concentrations of lipids is essential for understanding their physiological functions and discovering new disease biomarkers. However, it is highly challenging to accurately quantify lipids due to structural diversity and multiple isomeric forms of lipids. To address these critical gaps, we have developed a novel aziridine-based isobaric tag labelling strategy that allows (i) determination of lipid double-bond positional isomers, (ii) accurate relative quantification of unsaturated lipids, and (iii) improvement of ionization efficiencies of nonpolar lipids.

P2RX7 Enhances Tumor Control by CD8+ T Cells in Adoptive Cell Therapy.

Expression of the purinergic receptor P2RX7 by CD8+ T cells promotes the generation of memory populations following acute infections. However, data suggest that P2RX7 may limit the efficacy of antitumor responses. Herein, we show that P2RX7 is beneficial for optimal melanoma control in a mouse CD8+ T-cell adoptive transfer model.

Picomole-Scale Transition Metal Electrocatalysis Screening Platform for Discovery of Mild C-C Coupling and C-H Arylation through Anodically Generated Cationic Pd.

Development of new transition-metal-catalyzed electrochemistry promises to improve overall synthetic efficiency. Here, we describe the first integrated platform for online screening of electrochemical transition-metal catalysis. It utilizes the intrinsic electrochemical capabilities of nanoelectrospray ionization mass spectrometry (nano-ESI-MS) and picomole-scale anodic corrosion of a Pd electrode to generate and evaluate highly efficient cationic catalysts for mild electrocatalysis.

Phosphatase PHLPP2 regulates the cellular response to metabolic stress through AMPK.

PHLPP2 is a member of the PHLPP family of phosphatases, known to suppress cell growth by inhibiting proliferation or promoting apoptosis. Oncogenic kinases Akt, S6K, and PKC, and pro-apoptotic kinase Mst1, have been recognized as functional targets of the PHLPP family. However, we observed that, in T-leukemia cells subjected to metabolic stress from glucose limitation, PHLPP2 specifically targets the energy-sensing AMP-activated protein kinase, pAMPK, rather than Akt or S6K.

Reversing Hypoxia with PLGA-Encapsulated Manganese Dioxide Nanoparticles Improves Natural Killer Cell Response to Tumor Spheroids.

The adoptive transfer of natural killer (NK) cells, which can recognize and obliterate cancer cells, provides a practical alternative to current treatment modalities to improve cancer patients' survival. However, translating NK cell therapies to treat solid tumors has proven challenging due to the tumor microenvironment (TME). Hypoxia in the TME induces immunosuppression that inhibits the cytotoxic function of NK cells.

Tumor microenvironment remodeling and tumor therapy based on M2-like tumor associated macrophage-targeting nano-complexes.

Among the many immunosuppressive cells in the tumor microenvironment, tumor-associated-macrophages (TAMs) are well known to contribute to tumor development. TAMs can be conditioned (polarized) to transition between classical M1-like macrophages, or alternatively to M2-like macrophages. Both are regulated by signaling molecules in the microenvironment.

Design, synthesis, molecular modeling, and biological evaluation of acrylamide derivatives as potent inhibitors of human dihydroorotate dehydrogenase for the treatment of rheumatoid arthritis.

Human dihydroorotate dehydrogenase (DHODH) is a viable target for the development of therapeutics to treat cancer and immunological diseases, such as rheumatoid arthritis (RA), psoriasis and multiple sclerosis (MS). Herein, a series of acrylamide-based novel DHODH inhibitors as potential RA treatment agents were designed and synthesized. 2-Acrylamidobenzoic acid analog was identified as the lead compound for structure-activity relationship (SAR) studies.

Accelerating Electrochemical Reactions in a Voltage-Controlled Interfacial Microreactor.

Microdroplet chemistry is attracting increasing attention for accelerated reactions at the solution-air interface. We report herein a voltage-controlled interfacial microreactor that enables acceleration of electrochemical reactions which are not observed in bulk or conventional electrochemical cells. The microreactor is formed at the interface of the Taylor cone in an electrospray emitter with a large orifice, thus allowing continuous contact of the electrode and the reactants at/near the interface.

Design, synthesis and biological evaluation of potent EGFR kinase inhibitors against 19D/T790M/C797S mutation.

The efficacy of EGFR inhibitors is frequently affected by acquired resistance. EGFR mutation is one of the primary reasons for the emergence of resistance after treatment with the third-generation EGFR inhibitors such as AZD9291, CO1686 and Olmutinib. To overcome the resistance mutation 19D/T790M/C797S, we designed and prepared a series of indole derivatives with the terminal hydroxyl of alkyl chain to increase extra interaction with the Asp855 in the conservative DFG site.

The incorporation of cationic property and immunopotentiator in poly (lactic acid) microparticles promoted the immune response against chronic hepatitis B.

Biodegradable microparticles (MPs) as vaccine adjuvants have sparked the passion of researchers in recent decades. However, it is still a huge challenge to develop an efficient vaccine delivery system to reverse chronic hepatitis B (CHB). Herein, we integrated a physiochemical merit and an immunopotentiator property in poly (lactic acid) (PLA) MPs and verified the therapeutic effect on CHB model mice.

Multifunctional biomimetic nanoparticles loading baicalin for polarizing tumor-associated macrophages.

Immunosuppression and immune tolerance lead tumor cells to evade immune system surveillance and weaken drug efficacy. The presence of various immunosuppressive cells in the tumor microenvironment, especially tumor-associated macrophages (TAMs), has been shown to be a driving force in tumor initiation and development. Reversion of the TAM phenotype is an effective way to induce a subsequent antitumor immune response.

Design, synthesis and structure-activity relationship study of aminopyridine derivatives as novel inhibitors of Janus kinase 2.

Janus Kinase 2 (JAK2) is a kind of intracellular non-receptor protein tyrosine kinase and has been certified as an important target for the treatment of myeloproliferative neoplasms and rheumatoid arthritis. However, the low selectivity and potential safety issues restrict the clinical applications of JAK2 inhibitors. Here we found that crizotinib showed good inhibitory activity against JAK2 by enzymatic assays (IC = 27 nM).

New thiophene-based C fullerene derivatives as efficient electron transporting materials for perovskite solar cells.

The synthesis of new C fullerene derivatives functionalized with thiophene moieties as well as with electron donating or electron withdrawing groups, bromine (Br) or cyano (CN), respectively, using Bingel reactions is reported. The synthesized derivatives were used as the electron transporting materials (ETMs) in inverted perovskite solar cells (PSCs). Compared to devices fabricated with [6,6]-phenyl-C-butyric acid methyl ester (PCBM), the new derivatives showed similar electrochemical properties and electron mobilities.

Self-Assembly of a Monochromophore-Based Polymer Enables Unprecedented Ratiometric Tracing of Hypoxia.

The accuracy of traditional bischromophore-based ratiometric probes is always compromised by undesirable energy/charge transferring interactions between the internal reference moiety and the sensing chromophore. In this regard, ratiometric sensing with a monochromophore system is highly desirable. Herein, an unprecedented monochromophore-based ratiometric probe, which consists of a hydrophilic backbone poly(N-vinylpyrrolidone) (PVP) and single chromophore of platinum(II) tetraphenylporphyrin (Pt-TPP) is reported.

A Novel Human Papillomavirus 16 L1 Pentamer-Loaded Hybrid Particles Vaccine System: Influence of Size on Immune Responses.

Cervical cancer remains the second-most prevalent female malignancy around the world, leading to a great majority of cancer-related mortality that occurs mainly in developing countries. Developing an effective and low-cost vaccine against human papillomavirus (HPV) infection, especially in medically underfunded areas, is urgent. Compared with vaccines based on HPV L1 viruslike particles (VLPs) in the market, recombinant HPV L1 pentamer expressed in Escherichia coli represents a promising and potentially cost-effective vaccine for preventing HPV infection.

Potential Hepatitis B Vaccine Formulation Prepared by Uniform-Sized Lipid Hybrid PLA Microparticles with Adsorbed Hepatitis B Surface Antigen.

For the purpose of strengthening the immunogenicity of the hepatitis B vaccine, which contains hepatitis B surface antigen (HBsAg), the development of biodegradable poly(lactic acid) (PLA) microparticles (MPs) modified with the cationic surfactant didodecyldimethylammonium bromide (DDAB) was attempted. DDAB-PLA MPs with an uniform size of about 1 μm were prepared in a simple and mild way. DDAB-PLA MPs with increased surface charge enhanced antigen adsorption capacity compared to plain PLA MPs.

Design, Synthesis, and Biological Evaluation of Pyrimido[4,5- d]pyrimidine-2,4(1 H,3 H)-diones as Potent and Selective Epidermal Growth Factor Receptor (EGFR) Inhibitors against L858R/T790M Resistance Mutation.

First-generation epidermal growth factor receptor (EGFR) inhibitors, gefitinib and erlotinib, have achieved initially marked clinical efficacy for nonsmall cell lung cancer (NSCLC) patients with EGFR activating mutations. However, their clinical benefit was limited by the emergence of acquired resistance mutations. In most cases (approximately 60%), the resistance was caused by the secondary EGFR T790M gatekeeper mutation.

Fabrication and characterization of DDAB/PLA-alginate composite microcapsules as single-shot vaccine.

The most effective method to reduce chronic hepatitis B virus infection is the universal implementation of vaccination. The commercial aluminum-based vaccines need multiple-injection protocols for complete protection resulting in poor compliance in developing countries. It is necessary to develop single-shot vaccine formulations.

Engineering Multifunctional RNAi Nanomedicine To Concurrently Target Cancer Hallmarks for Combinatorial Therapy.

Cancer hallmarks allow the complexity and heterogeneity of tumor biology to be better understood, leading to the discovery of various promising targets for cancer therapy. An amorphous iron oxide nanoparticle (NP)-based RNAi strategy is developed to co-target two cancer hallmarks. The NP technology can modulate the glycolysis pathway by silencing MCT4 to induce tumor cell acidosis, and concurrently exacerbate oxidative stress in tumor cells via the Fenton-like reaction.

Porous Nanohydroxyapatite/Collagen Scaffolds Loading Insulin PLGA Particles for Restoration of Critical Size Bone Defect.

Insulin is considered to be a classical central regulator of energy homeostasis. Recently, the effect of insulin on bone has gained a lot of attention, but little attention has been paid to the application in bone tissue engineering. In this study, porous nanohydroxyapatite/collagen (nHAC) scaffolds incorporating poly lactic-co-glycolic acid (PLGA) particles were successfully developed as an insulin delivery platform for bone regeneration.