A5100733992- Chronic Lymphocytic Leukemia Research
- Immunodeficiency and Autoimmune Disorders
- Endoplasmic Reticulum Stress and Disease
- Sphingolipid Metabolism and Signaling
- Chronic Myeloid Leukemia Treatments
- Parasitic infections in humans and animals
- Connective tissue disorders research
- Cell death mechanisms and regulation
- Cancer-related gene regulation
- Carbon dioxide utilization in catalysis
- Chemical Synthesis and Reactions
- Fibroblast Growth Factor Research
- Skin and Cellular Biology Research
- Lymphoma Diagnosis and Treatment
- Congenital Anomalies and Fetal Surgery
- Wnt/β-catenin signaling in development and cancer
- RNA regulation and disease
- Biosimilars and Bioanalytical Methods
- Glioma Diagnosis and Treatment
- Coronary Artery Anomalies
- Protein Tyrosine Phosphatases
- Genomics, phytochemicals, and oxidative stress
- Spine and Intervertebral Disc Pathology
- Marine Sponges and Natural Products
- Protein Kinase Regulation and GTPase Signaling
Luoyang Central Hospital Affiliated to Zhengzhou University
2024
Sunesis (United States)
2024
Gansu Provincial Maternal and Child Health Hospital
2024
Biogen (United States)
2009-2024
Peking University
2024
Lanzhou University Second Hospital
2023
Xi'an Jiaotong University
2023
Lanzhou University
2022-2023
Dalian University of Technology
2023
Zhejiang Sci-Tech University
2022
Multiple sclerosis (MS) is a chronic disease with an underlying pathology characterized by inflammation-driven neuronal loss, axonal injury, and demyelination. Bruton's tyrosine kinase (BTK), nonreceptor member of the TEC family kinases, involved in regulation, migration, functional activation B cells myeloid periphery central nervous system (CNS), cell types which are deemed to contributing progression MS patients. Herein, we describe discovery BIIB129 (25), structurally distinct...
Multiple Sclerosis is a chronic autoimmune neurodegenerative disorder of the central nervous system (CNS) that characterized by inflammation, demyelination, and axonal injury leading to permeant disability. In early stage MS, inflammation primary driver disease progression. There remains an unmet need develop high efficacy therapies with superior safety profiles prevent processes Herein, we describe discovery BIIB091, structurally distinct orthosteric ATP competitive, reversible inhibitor...
Poly(β-amino ester)s (PAEs) have been widely developed for gene delivery, and hydrophobic modification can further enhance their transfection efficiency. However, systematic manipulation of amphiphilicity PAEs through copolymerization with monomers is time-consuming and, to some extent, uncontrollable. Here, a modular strategy manipulate the PAE/DNA polyplexes. A polymer (DD-C12-122) hydrophilic (DD-90-122) are synthesized separately used as module module, respectively. The polyplexes could...
Autoreactive B cell-derived antibodies form immune complexes that likely play a pathogenic role in autoimmune diseases. In systemic lupus erythematosus (SLE), these bind Fc receptors on myeloid cells and induce proinflammatory cytokine production by monocytes NETosis neutrophils. Bruton's tyrosine kinase (BTK) is non-receptor signals downstream of plays transduction antibody expression following cell activation. Given the roles BTK both sensing autoreactive antibodies, inhibitors activity...
Abstract Fibroblast growth factor 18 (FGF18) emerges as a promising therapeutic target for osteoarthritis (OA). In this study, novel articular cavity‐localized lipid nanoparticle (LNP) named WG‐PL14 is developed. This optimized formulation has nearly 30‐fold increase in mRNA expression well better cavity enrichment compared to commercial lipids MC3 when performing intra‐articular injection. Then, sequence encoding recombinant human FGF18 (rhFGF18) potential therapy OA optimized. vitro assays...
MLKL is a pore forming pseudokinase involved in the final stage of necroptosis, form programmed cell death. Its phosphorylation by RIPK3 necessary for triggering necroptosis but not apoptosis, which makes it unique target pharmacological inhibition to block necroptotic This mechanism has been described as playing role disease progression neurodegenerative and inflammatory diseases. A type II kinase inhibitor (cpd 1) that reportedly binds domain prevents necroptosis. Here we describe five...
Bruton's tyrosine kinase (BTK) plays a non-redundant signaling role downstream of the B-cell receptor (BCR) in B cells and receptors for Fc region immunoglobulins (FcR) myeloid cells. Here, we characterise BIIB091, novel, potent, selective reversible small-molecule inhibitor BTK.BIIB091 was evaluated vitro vivo preclinical models phase 1 clinical trial.In vitro, BIIB091 potently inhibited BTK-dependent proximal distal functional responses both with IC50s ranging from 3 to 106 nm, including...
Glycogen synthase kinase 3 (GSK3) remains a therapeutic target of interest for diverse clinical indications. However, one hurdle in the development small molecule GSK3 inhibitors has been safety concerns related to pan-inhibition both paralogs, leading activation Wnt/β-catenin pathway and potential aberrant cell proliferation. Development GSK3α or GSK3β paralog-selective that could offer an improved profile reported but further advancement hampered by lack structural information GSK3α. Here...
Cystic echinococcosis is a severe parasitic disease that commonly affects the liver and causes abscesses or rupture into surrounding tissues, leading to multiple complications, such as shock, abdominal pain, post-treatment abscess recurrence. Currently, there are no efficient measures prevent these complications. We previously confirmed arsenic trioxide (As2O3) exhibited in vitro cytotoxicity against Echinococcus granulosus protoscoleces. In present study, we aimed explore mechanism of...
Echinococcosis is a global enzootic disease influenced by different biological and environmental factors causes heavy financial burden on sick families governments. Currently, government subsidies for the treatment of patients with echinococcosis are only fixed number despite patients' finical income or cost treatment, health authorities demanded to supply an annual summary endemic data. The risk people in urban areas non-endemic increasing climate, landscape, lifestyle changes.We conducted...
Background: Glutathione (GSH) is an important endogenous antioxidant protecting cells from oxidative injury. Cysteine (Cys), the substrate limiting production of GSH, mainly generated trans-sulfuration pathway. S-adenosylmethionine (SAM) a critical molecule produced in methionine cycle and can be utilized by Reductions GSH SAM as well dysfunction pathway have been documented brains Alzheimer’s disease (AD) patients. Our previous vivo study revealed that administration attenuated stress...
In Brief Study Design. To conform the 3 media way of apoptosis for degenerative lumbar disc with DR5 (TRAIL-R2) and DcR2 (TRAIL-R4), as one tumor necrosis factors family. Objective. detect expression (TRAIL-R4) protein mRNA in human herniated normal intervertebral discs (IVD). Summary Background Data. The pathogenesis lumber herniation degeneration is still unclear. A series reports have suggested that may play a key role degeneration. There are apoptosis-inducing factors: FasL, TNF-α,...
Chemical process development efforts leading to multikilogram production of BIIB068 hemiadipate are discussed. Process optimization resulted in (1) removal transition metal from the process, (2) a streamlined with significantly improved overall yield, and (3) appropriate impurity control (including potential mutagenic impurities), which enabled delivery quality material for toxicology studies clinical trials.
Mitochondrial dysfunction has been attributed to many disease indications, including metabolic, cardiovascular, neoplastic, and neurodegenerative diseases. Dynamin related protein 1 (DRP1) is crucial in regulating mitochondrial fission maintaining homeostasis. MiD49 a dynamic peripheral receptor on the surface of membrane that recruits DRP1 induce binary fission. By targeting protein-protein interaction DRP1/MiD49, we have discovered novel potent allosteric inhibitor inhibits mitochondria...
S1P5 is one of the five sphingosine-1-phosphate (S1P) receptors which play important roles in immune and CNS cell homeostasis, growth, differentiation. Little known about effect modulation due to lack specific modulators with suitable druglike properties. Here we describe discovery optimization a novel series potent selective antagonists identification an orally active brain-penetrant tool compound 15.
Route evaluation, process development, and large-scale manufacturing of 4-chloro-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine (1) are described. The improved route consists two linear chemical steps: oxidation 4-chloro-2-(methylthio)pyrimidine (11) to 4-chloro-2-(methylsulfonyl)pyrimidine (7) displacement the sulfonyl with N-(1-methyl-1H-pyrazol-4-yl)formamide (10) under basic conditions followed by in situ hydrolysis N-formyl intermediate deliver compound 1....
Embedded within the field of drug metabolism and pharmacokinetics (DMPK), biotransformation is a discipline that studies origins, disposition, structural identity metabolites to provide comprehensive safety assessment, including assessment exposure coverage in toxicological species. Spanning discovery development, metabolite identification (metID) scientists employ various strategies tools address stage-specific questions aimed at guiding maturation early chemical matter into candidates....
ABSTRACT Dilated cardiomyopathy (DCM), a form of non‐ischaemic myocardial disease, is characterised by structural and functional cardiac abnormalities. As defined the World Health Organisation, DCM constitutes significant pathology, leading to increased morbidity mortality due complications such as heart failure arrhythmias. The diagnostic process for predominantly employs echocardiography MRI, with biomarkers like NT‐pro BNP troponin providing supportive, yet non‐specific, evidence....