Discovery of Novel 1-Phenylpiperidine Urea-Containing Derivatives Inhibiting β-Catenin/BCL9 Interaction and Exerting Antitumor Efficacy through the Activation of Antigen Presentation of cDC1 Cells.

Aberrant activation of the Wnt/β-catenin signaling is associated with tumor development, and blocking β-catenin/BCL9 is a novel strategy for oncogenic Wnt/β-catenin signaling. Herein, we presented two novel β-catenin variations and exposed conformational dynamics in several β-catenin crystal structures at the BCL9 binding site. Furthermore, we identified a class of novel urea-containing compounds targeting β-catenin/BCL9 interaction.

Clinical efficacy and biomarker analysis of neoadjuvant camrelizumab plus chemotherapy for early-stage triple-negative breast cancer: a experimental single-arm phase II clinical trial pilot study.

Background: Triple-negative breast cancer (TNBC) is associated with a dismal prognosis. Immune checkpoint inhibitors have shown promising antitumor activity in neoadjuvant settings. This single-arm, phase II trial aimed to evaluate the efficacy and safety of camrelizumab plus chemotherapy as the neoadjuvant therapy (NAT) in early TNBC.

HMGB1 inhibition reduces TDI-induced occupational asthma through ROS/AMPK/autophagy pathway.

Exposure to toluene diisocyanate (TDI) can cause pulmonary diseases such as asthma. Inhibition of high mobility group box 1 protein (HMGB1) has been found to be protective against the toxic effects of TDI on human bronchial epithelial (HBE) cells. Here, we evaluated the in vivo positive roles of HMGB1 in the TDI-caused asthma mice and explored its underlying mechanisms in HBE cells.

Fermented cordyceps powder alleviates silica-induced pulmonary inflammation and fibrosis in rats by regulating the Th immune response.

Background: Silicosis is an important occupational disease caused by inhalation of free silica and is characterized by persistent pulmonary inflammation, subsequent fibrosis and lung dysfunction. Until now, there has been no effective treatment for the disease due to the complexity of pathogenesis. Fermented cordyceps powder (FCP) has a similar effect to natural cordyceps in tonifying the lung and kidney.

Abnormality of mussel in the early developmental stages induced by graphene and triphenyl phosphate: In silico toxicogenomic data-mining, in vivo, and toxicity pathway-oriented approach.

Increasing number of complex mixtures of organic pollutants in coastal area (especially for nanomaterials and micro/nanoplastics associated chemicals) threaten aquatic ecosystems and their joint hazards are complex and demanding tasks. Mussels are the most sensitive marine faunal groups in the world, and their early developmental stages (embryo and larvae) are particularly susceptible to environmental contaminants, which can distinguish the probable mechanisms of mixture-induced growth toxicity. In this study, the potential critical target and biological processes affected by graphene and triphenyl phosphate (TPP) were developed by mining public toxicogenomic data.

Structure basis of two nanobodies neutralizing SARS-CoV-2 Omicron variant by targeting ultra-conservative epitopes.

The evolving SARS-CoV-2 Omicron strain has repeatedly caused widespread disease epidemics, and effective antibody drugs continue to be in short supply. Here, we identified a batch of nanobodies with high affinity for receptor binding domain (RBD) of SARS-CoV-2 spike protein, separated them into three classes using high performance liquid chromatography (HPLC), and then resolved the crystal structure of the ternary complexes of two non-competing nanobodies (NB1C6 and NB1B5) with RBD using X-ray crystallography. The structures showed that NB1B5 and NB1C6 bind to the left and right flank of the RBD, respectively, and that the binding epitopes are highly conserved cryptic sites in all SARS-CoV-2 mutant strains, as well as that NB1B5 can effectively block the ACE2.

Preparation and characterization of nanobodies targeting SARS-CoV-2 papain-like protease.

Coronavirus Papain-like protease (PLpro) mediates the cleavage of viral polyproteins and assists the virus escaping from innate immune response. Thus, PLpro is an attractive target for the development of broad-spectrum drugs as it has a conserved structure across different coronaviruses. In this study, we purified SARS-CoV-2 PLpro as an immune antigen, constructed a nanobody phage display library, and identified a set of nanobodies with high affinity for SARS-CoV-2.

A procedure for producing an anti-AXL nanobody in E. coli.

As one of the receptors of the TAM family, AXL plays a vital role in stem cell maintenance, angiogenesis, immune escape of viruses and drug resistance against tumors. In this study, the truncated extracellular segment containing two immunoglobulin-like domains of human AXL (AXL-IG), which has been confirmed to bind growth arrest specific 6 (GAS6) by structural studies [1], was expressed in a prokaryotic expression system and then purified. Immunizing camelid with the purified AXL-IG as antigen could lead to the production of unique nanobodies composed of only variable domain of heavy chain of heavy-chain antibody (VHH), which are around 15 kD and stable.

Synthesis and Biological Evaluation of Sclareolide-Indole Conjugates and Their Derivatives.

Sclareolide is a sesquiterpene lactone isolated from various plant sources in tons every year and is commercially used as a flavor ingredient in the cosmetic and food industries. Antitumor and antiviral activities of sclareolide have been previously reported. However, biological studies of sclareolide synthetic analogous are few.

Particulate Matter and Its Components Induce Alteration on the T-Cell Response: A Population Biomarker Study.

Compared with the T-cell potential of particulate matter (PM) in animal studies, comprehensive evaluation on the impairments of T-cell response and exposure-response from PM and its components in human population is limited. There were 768 participants in this study. We measured environmental PM and its polycyclic aromatic hydrocarbons (PAHs) and metals and urinary metabolite levels of PAHs and metals among population.

Bile acids-gut microbiota crosstalk contributes to the improvement of type 2 diabetes mellitus.

Type 2 diabetes mellitus (T2DM) occurs that cannot effectively use the insulin. Insulin Resistance (IR) is a significant characteristic of T2DM which is also an essential treatment target in blood glucose regulation to prevent T2DM and its complications. Bile acids (BAs) are one group of bioactive metabolites synthesized from cholesterol in liver.

The mitochondrial complex I proteins of Candida albicans moderate phagocytosis and the production of pro-inflammatory cytokines in murine macrophages and dendritic cells.

Loss of respiratory functions impairs Candida albicans colonization of host tissues and virulence in a murine model of candidiasis. Furthermore, it is known that respiratory inhibitors decrease mannan synthesis and glucan exposure and thereby promotes phagocytosis. To understand the impact of respiratory proteins of C.

Individualized CT image-guided free-hand catheter technique: A new and reliable method for minimally invasive evacuation of basal ganglia hematoma.

Objective: To validate the clinical reliability of an individualized CT image-guided' free-hand catheter technique (CTGFC) for basal ganglia hematoma (BGH) evacuation.

Methods: From January 2017 to December 2020, 58 cases of patients with BGH who underwent catheter evacuation were enrolled. The surgery was conducted using the CTGFC ( = 31) or stereotactic catheter technique (STC, = 27).

A chemical perspective on the modulation of TEAD transcriptional activities: Recent progress, challenges, and opportunities.

TEADs are transcription factors and core downstream components of the Hippo pathway. Mutations of the Hippo pathway and/or dysregulation of YAP/TAZ culminate in aberrant transcriptional activities of TEADs, which were considered as key contributing factors of mesotheliomas, fibrotic diseases, Alzheimer's diseases, Huntington's diseases, suppressive immune response, and drug resistance, among others. To modulate transcriptional activities of TEADs, several pharmacological approaches have been pursued, including TEAD/YAP protein-protein interaction inhibitors, TEAD PBP inhibitors, and TEAD activators.

Identification of key pathways and genes in the progression of silicosis based on WGCNA.

Silicosis, induced by inhaling silica particles in workplaces, is one of the most common occupational diseases. The prognosis of silicosis and its consequent fibrosis is extremely poor due to limited treatment modalities and lack of understanding of the disease mechanisms. In this study, a Wistar rat model for silicosis fibrosis was established by intratracheal instillation of silica (0, 50, 100 and 200 mg/mL, 1 mL) with the evidence of Hematoxylin and Eosin (HE) and Masson staining and the expressions of inflammatory and fibrotic proteins of rats' lung tissues.

Structure-Based Discovery of MDM2/4 Dual Inhibitors that Exert Antitumor Activities against MDM4-Overexpressing Cancer Cells.

Despite recent clinical progress in peptide-based dual inhibitors of MDM2/4, small-molecule ones with robust antitumor activities remain challenging. To tackle this issue, () was structure-based designed and synthesized, which had MDM2/4 binding values of 1.1 and 642 nM, respectively.

Targeting Wnt Signaling in the Tumor Immune Microenvironment to Enhancing EpCAM CAR T-Cell therapy.

Colorectal cancer (CRC) patients are still lacking viable treatments. Chimeric antigen receptor (CAR) T cells have shown promise in hematologic malignancies, but their efficacy in solid tumors has been limited due to the immunosuppressive tumor microenvironment. We found that cancer antigen- EpCAM expression increased in the metastatic stage compared with the primary stage in cancers and the activation of Wnt and TGFβ pathways was positively correlated with EpCAM expression in multiple cancers, including colorectal cancer.

Wnt signaling pathway in cancer immunotherapy.

Wnt/β-catenin signaling is a highly conserved pathway that regulates cell proliferation, differentiation, apoptosis, stem cell self-renewal, tissue homeostasis, and wound healing. Dysregulation of the Wnt pathway is intricately involved in almost all stages of tumorigenesis in various cancers. Through direct and/or indirect effects on effector T cells, T-regulatory cells, T-helper cells, dendritic cells, and other cytokine-expressing immune cells, abnormal activation of Wnt/β-catenin signaling benefits immune exclusion and hinders T-cell-mediated antitumor immune responses.

Graphene-triphenyl phosphate (TPP) co-exposure in the marine environment: Interference with metabolism and immune regulation in mussel Mytilus galloprovincialis.

Both immune regulation and endocrine systems are great challenges to marine organisms, and effective protocols for determining these adverse outcome pathways are limited, especially in vivo. The increasing usage of graphene nanomaterials can lead to the frequent exposure to marine organisms. Triphenyl phosphate (TPP), an organophosphate flame retardant, is frequently detected in natural environments.

Similarities and Differences: A Comparative Review of the Molecular Mechanisms and Effectors of NAFLD and AFLD.

Non-alcoholic fatty liver disease (NAFLD) and alcoholic fatty liver disease (AFLD) are the most prevalent metabolic liver diseases globally. Due to the complex pathogenic mechanisms of NAFLD and AFLD, no specific drugs were approved at present. Lipid accumulation, oxidative stress, insulin resistance, inflammation, and dietary habits are all closely related to the pathogenesis of NAFLD and AFLD.

Toxicological effects of graphene on mussel Mytilus galloprovincialis hemocytes after individual and combined exposure with triphenyl phosphate.

Graphene nanoparticles are increasingly released into the aquatic environment with the growth of production. However, there are rare investigations focusing on the interaction of nanoparticles with other contaminants. Triphenyl phosphate (TPP) is a frequently detected organophosphate flame retardant in the environment.

Combinatorial immune and stress response, cytoskeleton and signal transduction effects of graphene and triphenyl phosphate (TPP) in mussel Mytilus galloprovincialis.

Owing to its unique surface properties, graphene can absorb environmental pollutants, thereby affecting their environmental behavior. Triphenyl phosphate (TPP) is a highly produced flame retardant. However, the toxicities of graphene and its combinations with contaminants remain largely unexplored.

The critical factors affecting typical organophosphate flame retardants to mimetic biomembrane: An integrated in vitro and in silico study.

Organophosphate flame retardants (OPFRs) have been reported to induce cytotoxicity in a structure-dependent manner. The toxic effects may be due to the damage of biomembrane integrity and/or the interference of membrane signal pathway. In this study, the damages of fifteen typical OPFRs (chlorinated phosphates, alkyl phosphates, aryl phosphates, and alkoxy phosphates) to mimetic biomembrane were determined by the electrochemical impedance spectroscopy (EIS).