Bioinformatics Identification of angiogenesis-related biomarkers and therapeutic targets in cerebral ischemia-reperfusion.

Promoting vascular endothelial cell regeneration can enhance recovery from cerebral ischemia reperfusion injury (CIRI), but there is a lack of bioinformatic studies on angiogenesis-related biomarkers in CIRI. In this study, we utilized the GSE97537 and GSE61616 datasets from GEO to identify 181 angiogenesis-related genes (ARGs) and analyzed differentially expressed genes (DEGs) between CIRI and control groups. We converted ARGs to 169 rat homologues and intersected them with DEGs to find DE-ARGs.

A patent review of small molecular inhibitors targeting EGFR exon 20 insertion (Ex20ins) (2019-present).

Introduction: Mutations in epidermal growth factor receptor (EGFR) kinase domain consistently activate downstream signaling pathways, such as the PI3K/AKT/mTOR and RAS/RAF/MEK, thereby promoting tumor growth. Although the majority of non-small cell lung cancer (NSCLC) patients harboring EGFR mutations are sensitive to existing EGFR tyrosine kinase inhibitors (EGFR-TKIs), there remains an unmet clinical need for effective therapies targeting EGFR Ex20ins mutations, making direct targeting EGFR Ex20ins mutations a promising therapeutic strategy.

Areas Covered: This review covers the progress of clinical studies targeting EGFR Ex20ins inhibitors and summarizes recent (1 January 2019 - 30 April 2024) patents disclosing EGFR Ex20ins inhibitors available in the Espacenet and CAS SciFinder databases.

A Self-Assembled Nano-Molecular Glue (Nano-mGlu) Enables GSH/HO-Triggered Targeted Protein Degradation in Cancer Therapy.

Molecular glues are promising protein-degrading agents that hold great therapeutic potential but face significant challenges in rational design, effective synthesis, and precise targeting of tumor sites. In this study, we first overcame some of these limitations by introducing a fumarate-based molecular glue handle onto specific ligands of therapeutic kinases (TBK1, FGFR, and Bcr-Abl), resulting in the effective degradation of these important cancer targets. Despite the broad applicability of the strategy, we unexpectedly discovered potent and widespread cytotoxicity across various cell lines, including noncancerous ones, rendering it less effective in cancer therapy.

Transcriptomic Analysis of Blood Collagen-Induced Arthritis Mice Exposed to 0.1 THz Reveals Inhibition of Genes and Pathways Involved in Rheumatoid Arthritis.

Inflammation plays an essential role in the phases of rheumatoid arthritis (RA) as the joints secrete a range of molecules that modulate the inflammatory process. While therapies based on physical properties have shown effectiveness in a range of animal experimental models, the understanding of their biological mechanisms remains unclear. The aim of this study was to investigate the immunomodulatory effects of a 0.

Pharmacological targeting of casein kinase 1δ suppresses oncogenic NRAS-driven melanoma.

Activating mutations in NRAS account for 15-20% of melanoma, yet effective anti-NRAS therapies are still lacking. In this study, we unveil the casein kinase 1δ (CK1δ) as an uncharacterized regulator of oncogenic NRAS mutations, specifically Q61R and Q61K, which are the most prevalent NRAS mutations in melanoma. The genetic ablation or pharmacological inhibition of CK1δ markedly destabilizes NRAS mutants and suppresses their oncogenic functions.

Design, Synthesis, and Biological Evaluation of Novel Diaminopyrimidine Macrocycles as Fourth Generation Reversible EGFR Inhibitors That Overcome Clinical Resistance to Osimertinib Mediated by C797S Mutation.

Overcoming clinical resistance to osimertinib mediated by the tertiary C797S mutation remains an unmet medical need. To date, there are no effective drugs that have been approved for patients who harbor EGFR mutations. Herein, we applied a structure-based drug design strategy to discover a series of potent and selective diaminopyrimidine macrocycles as novel EGFR inhibitors.

NeoaPred: a deep-learning framework for predicting immunogenic neoantigen based on surface and structural features of peptide-human leukocyte antigen complexes.

Motivation: Neoantigens, derived from somatic mutations in cancer cells, can elicit anti-tumor immune responses when presented to autologous T cells by human leukocyte antigen. Identifying immunogenic neoantigens is crucial for cancer immunotherapy development. However, the accuracy of current bioinformatic methods remains unsatisfactory.

Non-Thermal Effects of Terahertz Radiation on Gene Expression: Systematic Review and Meta-Analysis.

With the advancement of terahertz technology, unveiling the mysteries of terahertz has had a profound impact on the field of biomedicine. However, the lack of systematic comparisons for gene expression signatures may diminish the effectiveness and efficiency of identifying common mechanisms underlying terahertz effects across diverse research findings. We performed a comprehensive review and meta-analysis to compile patterns of gene expression profiles associated with THz radiation.

Propyl acetate protects intestinal barrier during parenteral nutrition in mice and Caco-2 cells.

Background: Gut microbiota dysbiosis induces intestinal barrier damage during parenteral nutrition (PN). However, the underlying mechanisms remain unclear. This study aimed to investigate gut microbiota dysbiosis, luminal short-chain fatty acids, and autophagy in a mouse model and how these short-chain fatty acids regulate autophagy.

β-Hydroxybutyrate enhances astrocyte glutamate uptake through EAAT1 expression regulation.

β-Hydroxybutyrate (BHB) has been reported to exert neuroprotective functions and is considered a promising treatment for neurodegenerative diseases such as Parkinson's and Alzheimer's. Numerous studies have revealed BHB's multifaceted roles, including anti-senescence, anti-oxidative, and anti-inflammatory activities. However, the underlying mechanisms warrant further investigation.

Structure-Based Drug Design of 2-Amino-[1,1'-biphenyl]-3-carboxamide Derivatives as Selective PKMYT1 Inhibitors for the Treatment of -Amplified Breast Cancer.

amplification occurs in breast cancer and currently lacks effective therapies. PKMYT1 as a synthetic lethal target for amplification holds promise for the treatment of -amplified breast cancer. Herein, we discover a series of 2-amino-[1,1'-biphenyl]-3-carboxamide derivatives as potent and selective PKMYT1 inhibitors using structure-based drug design.

Small Molecule-Induced Post-Translational Acetylation of Catalytic Lysine of Kinases in Mammalian Cells.

Reversible lysine acetylation is an important post-translational modification (PTM). This process in cells is typically carried out enzymatically by lysine acetyltransferases and deacetylases. The catalytic lysine in the human kinome is highly conserved and ligandable.

DNA-DISK: Automated end-to-end data storage via enzymatic single-nucleotide DNA synthesis and sequencing on digital microfluidics.

In the age of information explosion, the exponential growth of digital data far exceeds the capacity of current mainstream storage media. DNA is emerging as a promising alternative due to its higher storage density, longer retention time, and lower power consumption. To date, commercially mature DNA synthesis and sequencing technologies allow for writing and reading of information on DNA with customization and convenience at the research level.

Targeting Solvent-Front Mutations for Kinase Drug Discovery: From Structural Basis to Design Strategies.

Solvent-front mutations have emerged as a common mechanism leading to acquired resistance to kinase inhibitors, representing a major challenge in the clinic. Several new-generation kinase inhibitors targeting solvent-front mutations have either been approved or advanced to clinical trials. However, there remains a need to discover effective, new-generation inhibitors.

Therapeutic targeting ERRγ suppresses metastasis via extracellular matrix remodeling in small cell lung cancer.

Small-cell lung cancer (SCLC) is the most aggressive and lethal type of lung cancer, characterized by limited treatment options, early and frequent metastasis. However, the determinants of metastasis in SCLC are poorly defined. Here, we show that estrogen-related receptor gamma (ERRγ) is overexpressed in metastatic SCLC tumors, and is positively associated with SCLC progression.

Dynamics Playing a Key Role in the Covalent Binding of Inhibitors to Focal Adhesion Kinase.

Covalent kinase inhibitors (CKIs) have recently garnered considerable attention, yet the rational design of CKIs continues to pose a great challenge. In the discovery of CKIs targeting focal adhesion kinase (FAK), it has been observed that the chemical structure of the linkers plays a key role in achieving covalent targeting of FAK. However, the mechanism behind the observation remains elusive.

Membrane-mediated modulation of mitochondrial physiology by terahertz waves.

Extensive studies have demonstrated the diverse impacts of electromagnetic waves at gigahertz and terahertz (THz) frequencies on cytoplasmic membrane properties. However, there is little evidence of these impacts on intracellular membranes, particularly mitochondrial membranes crucial for mitochondrial physiology. In this study, human neuroblast-like cells were exposed to continuous 0.

Anti-Inflammatory and Immunomodulatory Effects of 0.1 Sub-Terahertz Irradiation in Collagen-Induced Arthritis Mice.

The primary emphasis of photoimmunology is the impact of nonionizing radiation on the immune system. With the development of terahertz (THz) and sub-terahertz (sub-THz) technology, the biological effects of this emerging nonionizing radiation, particularly its influence on immune function, remain insufficiently explored but are progressively attracting attention. Here, we demonstrated that 0.

Design, synthesis and biological evaluation of 5-amino-1H-pyrazole-4-carboxamide derivatives as pan-FGFR covalent inhibitors.

The aberrant activation of FGFRs plays a critical role in various cancers, leading to the development of several FGFR inhibitors in clinic. However, the emergence of drug resistance, primarily due to gatekeeper mutations in FGFRs, has limited their clinical efficacy. To address the unmet medical need, a series of 5-amino-1H-pyrazole-4-carboxamide derivatives were designed and synthesized as novel pan-FGFR covalent inhibitors targeting both wild-type and the gatekeeper mutants.

Increased expression of REG3A promotes tumorigenic behavior in triple negative breast cancer cells.

Background: Identifying new targets in triple negative breast cancer (TNBC) remains critical. REG3A (regenerating islet-derived protein 3 A), a calcium-dependent lectin protein, was thoroughly investigated for its expression and functions in breast cancer.

Methods: Bioinformatics and local tissue analyses were employed to identify REG3A expression in breast cancer.

Structure-Based Optimization of Pyrazinamide-Containing Macrocyclic Derivatives as Fms-like Tyrosine Kinase 3 (FLT3) Inhibitors to Overcome Clinical Mutations.

Secondary mutations in Fms-like tyrosine kinase 3-tyrosine kinase domain (FLT3-TKD) (e.g., D835Y and F691L) have become a major on-target resistance mechanism of FLT3 inhibitors, which present a significant clinical challenge.