Numb family proteins play roles in Desmin and Vimentin localization at the Z-disc.

Desmin and Vimentin are major intermediate filaments at the Z-disc and play significant roles in sarcomere architecture and signaling transduction. Abnormal expression of sarcomeric Desmin and Vimentin (SDV) results in severe dysfunctions of striated muscles. In this study, it was found that paired Numb family proteins (NFPs), including Numb and its homolog Numblike, determined the range for the recruitment of SDV to the primitive Z-disc.

Ring Size Effects on the Structures of Sandwich Compounds with a Stoichiometry of CHM (M = Ti-Ni).

Ring size effects on geometries and electronic structures were investigated for the (C H )M(C H ) ( = 4, 5, or 6; = 8, 7, or 6; + = 12; M = Ti-Ni) systems using density functional theory. The lowest-energy CHM structures for the early transition metals titanium, vanadium, and chromium are the experimentally known singlet (η-CH)Ti(η-CH), doublet (η-CH)V(η-CH), and singlet (η-CH)Cr, respectively. The likewise experimentally known singlet (η-CH)Ti, doublet (η-CH)V, and singlet (η-CH)Cr(η-CH) are the second-lowest-energy structures with only a small energy difference between the two vanadium structures.

Iron Carbonyl Complexes of [2.2.2]Hericene as a Rigid Tris(1,3-diene) Ligand.

Hericene is an unusual hexaolefin consisting of three 1,3-diene units located on a rigid bicyclo [2.2.2]octane framework that restricts the geometrical relationships of metal atoms bonded to these olefinic units.

LRRC8A drives NADPH oxidase-mediated mitochondrial dysfunction and inflammation in allergic rhinitis.

Objectives: Allergic rhinitis (AR) is a complex disorder with variable pathogenesis. Increasing evidence suggests that the LRRC8A is involved in maintaining cellular stability, regulating immune cell activation and function, and playing significant roles in inflammation. However, the involvement of LRRC8A in AR inflammation and its underlying mechanisms remain unclear.

Lipid levels and low back pain risk: A two-sample mendelian randomization study.

Background: Previous observational studies have shown controversial results about the relationship between lipid levels and low back pain (LBP). Herein, we aimed to explore the potential causal relationship between lipid levels and LBP by using the mendelian randomization (MR) analysis.

Methods: In this two-sample MR study, data were extracted from publicly available MRC Integrative Epidemiology Unit database.

Difference of Antrochoanal Polyps Between Children and Adults in the Chinese Population.

Objective: This study aims to find the difference in clinical and immunopathological characteristics between children and adults with antrochoanal polyps (ACPs) in the Chinese population.

Methods: The clinical data of 69 patients diagnosed with ACPs were retrospectively analyzed. Cytokine levels in 16 controls and 40 ACPs tissues were determined by quantitative real-time polymerase chain reaction (qPCR).

Hepatocyte CD36 protects mice from NASH diet-induced liver injury and fibrosis via blocking N1ICD production.

Background & Aims: Fatty acid translocase CD36 (CD36/FAT) is a widely expressed membrane protein with multiple immuno-metabolic functions. Genetic CD36 deficiency is associated with increased risk of metabolic dysfunction-associated fatty liver disease (MAFLD) in patients. Liver fibrosis severity mainly affects the prognosis in patients with MAFLD, but the role of hepatocyte CD36 in liver fibrosis of MAFLD remains unclear.

Exogenous plant growth regulator and foliar fertilizers for phytoextraction of cadmium with Boehmeria nivea [L.] Gaudich from contaminated field soil.

As a enrichment plant, ramie can be used for the phytoremediation of cadmium (Cd)-contaminated soil. However, it is worth exploring the role of plant growth regulators and foliar fertilizers in the process of plant growth and development and Cd adsorption. By measuring the agronomic traits, Cd content of aboveground and underground ramie, calculating the Cd transfer coefficient (TF) and Cd bioconcentration factors (BCF), and the correlation between various indicators.

Anti-Inflammatory Polyketide Derivatives from the Sponge-Derived Fungus sp. SWMU-WZ04-2.

Five undescribed polyketide derivatives, pestaloketides A-E (-), along with eleven known analogues (-), were isolated from the sponge-derived fungus sp. Their structures, including absolute configurations, were elucidated by analyses of NMR spectroscopic HRESIMS data and electronic circular dichroism (ECD) calculations. Compounds , , , and exhibited weak cytotoxicities against four human cancer cell lines, with IC values ranging from 22.

Expression of DOG1 in peripheral blood cells of patients with gastrointestinal stromal tumor.

Background And Study Aims: The diagnosis and surveillance of gastrointestinal stromal tumor (GIST) rely on pathology and immunochemistry (IHC), making it complicated and invasive. Noninvasive and convenient biomarkers of this disease need to be explored. The high specificity and sensitivity of IHC in detecting GIST 1 (DOG1) in biopsy indicate that it is also expressed in circulating tumor cells of the blood and may be an ideal biomarker for GIST.

Pyrido[2, 3-d]pyrimidin-7(8H)-ones as new selective orally bioavailable Threonine Tyrosine Kinase (TTK) inhibitors.

A series of pyrido [2, 3-d]pyrimidin-7(8H)-ones were designed and synthesized as new selective orally bioavailable Threonine Tyrosine Kinase (TTK) inhibitors. One of the representative compounds, 5o, exhibited strong binding affinity with a K value of 0.15 nM, but was significantly less potent against a panel of 402 wild-type kinases at 100 nM.

Inhibition of ELF3 confers synthetic lethality of PARP inhibitor in non-small cell lung cancer.

Background: E74 Like ETS Transcription Factor 3 (ELF3) functions as a transcriptional factor to regulate non-small cell lung cancer (NSCLC) differentiation and progression. Poly(ADP-ribose) polymerase (PARP) inhibitors demonstrate anti-tumor effect in NSCLC. This study aimed to investigate whether ELF3 confers synthetic lethal with PARP inhibitor in NSCLC.

GZD824 as a FLT3, FGFR1 and PDGFRα Inhibitor Against Leukemia In Vitro and In Vivo.

GZD824 is a novel third-generation BCR-ABL inhibitor. It entered Phase II clinical trials in China and Phase Ib clinical trials in USA in 2019 for treatment of patients with resistant chronic myeloid leukemia (CML). We found that at concentrations below 10 nM, GZD824 significantly suppresses FLT3, FGFR1 and PDGFRα kinase activities and inhibits their signal pathways in MV4-11, KG-1 and EOL-1 leukemia cells.

Design and Optimization of 3'-(Imidazo[1,2-]pyrazin-3-yl)-[1,1'-biphenyl]-3-carboxamides as Selective DDR1 Inhibitors.

DDR1 is considered as a promising target for cancer therapy, and selective inhibitors against DDR1 over other kinases may be considered as promising therapeutic agents. Herein, we have identified a series of 3'-(imidazo[1,2-]pyrazin-3-yl)-[1,1'-biphenyl]-3-carboxamides as novel selective DDR1 inhibitors. Among these, compound potently inhibited DDR1 with an IC of 23.

2-Amino-2,3-dihydro-1-indene-5-carboxamide-Based Discoidin Domain Receptor 1 (DDR1) Inhibitors: Design, Synthesis, and in Vivo Antipancreatic Cancer Efficacy.

A series of 2-amino-2,3-dihydro-1-indene-5-carboxamides were designed and synthesized as new selective discoidin domain receptor 1 (DDR1) inhibitors. One of the representative compounds, , bound with DDR1 with a value of 5.9 nM and suppressed the kinase activity with an half-maximal (50%) inhibitory concentration value of 14.

Design, Synthesis, and Structure-Activity Relationships of 1,2,3-Triazole Benzenesulfonamides as New Selective Leucine-Zipper and Sterile-α Motif Kinase (ZAK) Inhibitors.

ZAK is a new promising target for discovery of drugs with activity against antihypertrophic cardiomyopathy (HCM). A series of 1,2,3-triazole benzenesulfonamides were designed and synthesized as selective ZAK inhibitors. One of these compounds, binds tightly to ZAK protein ( = 8.

Rational design, synthesis and biological evaluation of ubiquinone derivatives as IDO1 inhibitors.

Indoleamine 2,3-dioxygenase 1 (IDO1) is an attractive therapeutic target for the treatment of cancer, chronic viral infections and neurological disorders characterized by pathological immune stimulation. Herein, a series of known metal-chelating ubiquinone derivatives were designed, synthesized and evaluated for the IDO1 inhibiting activities. The docking studies showed that the compounds 11, 16, 18 and coenzyme-Q1 exhibited different binding modes to IDO1 protein.

Quinolone antibiotic derivatives as new selective Axl kinase inhibitors.

Axl is a new promising molecular target for antineoplastic therapies. A series of quinolone antibiotic derivatives were designed and synthesized as new selective Axl inhibitors. One of the most promising compound 8i bound tightly to Axl with a K value of 1.

GZD2202, a novel TrkB inhibitor, suppresses BDNF-mediated proliferation and metastasis in neuroblastoma models.

Collective data suggest tropomyosin-related kinase B (TrkB), which is correlated with the growth, migration and poor prognosis of neuroblastoma (NB), is a potential target for NB target therapy. Several Phase I/II pan-Trk inhibitors display impressive clinical outcomes but still no drug has been approved for general use. In this paper, we report a novel structural TrkB inhibitor GZD2202, a structural derivative of our previously identified DDR1 antagonists.

Dual targeting delivery of miR-328 by functionalized mesoporous silica nanoparticles for colorectal cancer therapy.

We aim to explore the regulatory mechanism of miR-328 and further develop miR-328-loaded mesoporous silica nanoparticles (MSNs) and surface-decorated with polymerized dopamine, epithelial cell adhesion molecule aptamer and bevacizumab for the dual-targeting treatment of colorectal cancer (CRC). The relationship between miR-328 and CPTP and the mechanism and antitumor effect of MSNs-miR-328@PDA-PEG-Apt-Bev were evaluated. We found CPTP is a direct target of miR-328.

Design, Synthesis, and Biological Evaluation of 3-(Imidazo[1,2- a]pyrazin-3-ylethynyl)-4-isopropyl- N-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)benzamide as a Dual Inhibitor of Discoidin Domain Receptors 1 and 2.

Discoidin-domain receptors 1 and 2 (DDR1 and DDR2) are new potential targets for anti-inflammatory-drug discovery. A series of heterocycloalkynylbenzimides were designed and optimized to coinhibit DDR1 and DDR2. One of the most promising compounds, 5n, tightly bound to DDR1 and DDR2 proteins with K values of 7.

YL143, a novel mutant selective irreversible EGFR inhibitor, overcomes EGFR -mutant resistance in vitro and in vivo.

YL143 was identified as a novel wild-type sparing EGFR inhibitor with good pharmacokinetic properties. It potently suppresses EGFR with an 50% inhibitory concentration (IC ) value of 2.0 ± 0.

Design, Synthesis, and Structure-Activity Relationship Study of 2-Oxo-3,4-dihydropyrimido[4,5- d]pyrimidines as New Colony Stimulating Factor 1 Receptor (CSF1R) Kinase Inhibitors.

Colony stimulating factor 1 receptor kinase (CSF1R) is a well validated molecular target for anticancer drug discovery. Herein, we report the design, synthesis, and structure-activity relationship study of 2-oxo-3,4-dihydropyrimido[4,5- d]pyrimidines as new orally bioavailable CSF1R inhibitors. One of the most promising compounds, 3bw, potently inhibits CSF1R kinase with an IC value of 3.

Design, synthesis, and biological evaluation of novel highly selective polo-like kinase 2 inhibitors based on the tetrahydropteridin chemical scaffold.

Polo-like kinase 2 (Plk2) is a potential target for the treatment of cancer, which displays an important role in tumor cell proliferation and survival. In this report, according to the analysis of critical amino acid residue differences among Plk1, Plk2 and Plk3, and structure-based drug design strategies, two novel series of selective Plk2 inhibitors based on tetrahydropteridin chemical scaffold were designed and synthesized to target two specific residues, Lys86 and Tyr161 of Plk2. All compounds were evaluated for their inhibitory activity against Plk1-Plk3 and the cellular inhibition activity on six different human cancer cell lines.

EpCAM aptamer-functionalized polydopamine-coated mesoporous silica nanoparticles loaded with DM1 for targeted therapy in colorectal cancer.

DM1, a maytansine derivative, is a highly potential cytotoxic agent but with severe side effects; therefore, its application in clinical cancer therapy is limited. Here, in order to mitigate this intrinsic drawback of DM1, we developed mesoporous silica nanoparticles (MSNs) loaded with DM1 and surface-decorated with hydrochloride dopamine (PDA), polyethylene glycol (PEG), and epithelial cell adhesion molecule (EpCAM) aptamer (APt) for the targeted treatment of colorectal cancer (CRC). In this system, the PDA coating could be used as pH-sensitive gatekeepers to control the release of DM1 from MSNs in response to the pH stimulus and EpCAM APt-guided active targeting enables the increased delivery of DM1 to CRC as well as a reduction in toxicity and side effects by minimizing the exposure of normal tissues to DM1.