Structure-Based Rational Design and Evaluation of BET-Aurora Kinase Dual-Inhibitors for Treatment of Cancers.

Simultaneous inhibition of the bromodomain and extra-terminal domain and Aurora kinases is a promising anticancer therapeutic strategy. Based on our previous study on BET-kinase dual inhibitors, we employed the molecular docking approach to design novel dual BET-Aurora kinase A inhibitors. Through several rounds of optimization and with the guidance of the solved cocrystal structure of BRD4 bound to inhibitor , we finally obtained a series of highly potent dual BET-Aurora kinase A inhibitors.

Mechanism of HJ11 Decoction in the Treatment of Atherosclerosis Based on Network Pharmacology and Experimental Validation.

Background: HJ11 (HJ11 decoction), which is based on the traditional prescription Si-Miao-Yong-An decoction, has exerted a remarkable effect on atherosclerosis (AS). Nevertheless, the main components and underlying mechanisms of HJ11 for treating AS remain unclear.

Aim Of The Study: This study was designed to elucidate the mechanism of HJ11 in the treatment of AS through network pharmacology and in vivo experimental validation.

Deep learning-based synthetic CT for dosimetric monitoring of combined conventional radiotherapy and lattice boost in large lung tumors.

Purpose: Conventional radiotherapy (CRT) has limited local control and poses a high risk of severe toxicity in large lung tumors. This study aimed to develop an integrated treatment plan that combines CRT with lattice boost radiotherapy (LRT) and monitors its dosimetric characteristics.

Methods: This study employed cone-beam computed tomography from 115 lung cancer patients to develop a U-Net +  + deep learning model for generating synthetic CT (sCT).

N-acetylcysteine and chitosan conjugate modified dexamethasone nanostructured lipid carriers: Enhanced permeability, precorneal retention and lower inflammation for the treatment of dry eye syndrome.

Dexamethasone (Dex) is a primary medication for treating dry eye syndrome, and tobramycin-dexamethasone eye drops are commercially available. However, the eye's complex physiological environment reduces its bioavailability, and repeated use can lead to significant systemic toxicity and side effects. This study introduces a novel conjugate of chitosan (CS) and N-acetylcysteine (NAC), a bioadhesive material, which was grafted onto the surface of a Dex-supported nanostructured lipid carrier (NLC) to develop an innovative nanoparticle lipid ocular drug delivery system (CS-NAC@Dex-NLC).

Analysis of partly bio-derived nonionic polyethylene glycol-based rheology modifiers by comprehensive two-dimensional liquid chromatography.

Rheology modifiers (RMs) are polymeric molecules providing rheological control of formulations, which are important in product application, shelf-life, and aesthetic perception. Bio-derived polyethylene glycol (PEG)-based RMs thicken formulations through nonionic-associative thickening where at least two hydrophobic end groups from a RM molecule interact with other hydrophobic groups of other RM molecules or ingredients in the formulation to form an associative network. We report a comprehensive two-dimensional liquid chromatography (2D-LC) separation of partly bio-derived PEG-based RMs in size exclusion chromatography (SEC) × reversed-phase liquid chromatography (RPLC) mode for the separation of RM components based on both molecular weight distribution and end group hydrophobe distribution.

Stimuli-Responsive Nano Drug Delivery Systems for the Treatment of Neurological Diseases.

Nanomaterials with unparalleled physical and chemical attributes have become a cornerstone in the field of nanomedicine delivery. These materials can be engineered into various functionalized nanocarriers, which have become the focus of research. Stimulus-responsive nanodrug delivery systems (SRDDS) stand out as a sophisticated class of nanocarriers that can release drugs in response to environmental cues.

Functional genomic imaging (FGI), a virtual tool for visualization of functional gene expression modules in heterogeneous tumor samples.

Advances in sequencing technologies are reshaping clinical diagnostics, prompting the development of new software tools to decipher big data. To this end, we developed functional genomic imaging (FGI), a visualization tool designed to assist clinicians in interpreting RNA-Seq results from patient samples. FGI uses weighted gene co-expression network analysis (WGCNA), followed by a modified Phenograph clustering algorithm to identify co-expression gene clusters.

CD133PD-L1 cancer cells confer resistance to adoptively transferred engineered macrophage-based therapy in melanoma.

Adoptive transfer of genetically or nanoparticle-engineered macrophages represents a promising cell therapy modality for treatment of solid tumor. However, the therapeutic efficacy is suboptimal without achieving a complete tumor regression, and the underlying mechanism remains elusive. Here, we discover a subpopulation of cancer cells with upregulated CD133 and programmed death-ligand 1 in mouse melanoma, resistant to the phagocytosis by the transferred macrophages.

Fibroblast activation protein peptide-targeted NIR-I/II fluorescence imaging for stable and functional detection of hepatocellular carcinoma.

Purpose: Cancer-associated fibroblasts (CAFs) are the primary stromal component of the tumor microenvironment in hepatocellular carcinoma (HCC), affecting tumor progression and post-resection recurrence. Fibroblast activation protein (FAP) is a key biomarker of CAFs. However, there is limited evidence on using FAP as a target in near-infrared (NIR) fluorescence imaging for HCC.

Discovery of Novel Spirocyclic MAT2A Inhibitors Demonstrating High In Vivo Efficacy in MTAP-Null Xenograft Models.

Synthetic lethality offers a robust strategy for discovering the next generation of precision medicine therapies tailored for molecularly defined patient populations. MAT2A inhibition is synthetically lethal in several cancers that exhibit a homozygous deletion of -methyl-5'-thioadenosine phosphorylase (MTAP). Herein, we report the identification of novel MAT2A inhibitors featuring a spiral ring to circumvent the C-N atropisomeric chirality utilizing structure-based drug design.

Effects of non-pharmacological interventions on biochemical hyperandrogenism in women with polycystic ovary syndrome: a systematic review and network meta-analysis.

Objective: To systematically evaluate the effectiveness of non-pharmacological interventions (NPIs), including electroacupuncture, exercise, diet, and lifestyle changes, in reducing androgen levels in women with polycystic ovary syndrome (PCOS) through a systematic review and network meta-analysis.

Methods: Comprehensive searches were conducted in PubMed, Embase, Cochrane Library, Web of Science, CNKI, and Wanfang up to June 2024. Randomized controlled trials (RCTs) comparing NPIs with other NPIs or placebo treatments in adult women with PCOS were included.

Identifying a non-conserved site for achieving allosteric covalent inhibition of CECR2.

The bromodomain (BRD) represents a highly conserved structural module that provides BRD proteins with fundamental functionality in modulating protein-protein interactions involved in diverse biological processes such as chromatin-mediated gene transcription, DNA recombination, replication and repair. Consequently, dysregulation of BRD proteins has been implicated in the pathogenesis of numerous human diseases. In recent years, considerable scientific endeavors have focused on unraveling the molecular mechanisms underlying BRDs and developing inhibitors that target these domains.

Peptidoglycan isolated from the fruit of Lycium barbarum alleviates liver fibrosis in mice by regulating the TGF-β/Smad7 signaling and gut microbiota.

The hepatoprotective effect of the fruit of Lycium barbarum has been documented in China over millennia. Lycium barbarum polysaccharides (LBPs) were the first macromolecules reported to mitigate liver fibrosis in carbon tetrachloride (CCl)-treated mice. Herein, a neutral peptidoglycan, named as LBPW, was extracted from the fruit of Lycium barbarum.

PEGylation of Dipeptide Linker Improves Therapeutic Index and Pharmacokinetics of Antibody-Drug Conjugates.

Hydrophobic payloads incorporated into antibody-drug conjugates (ADCs) typically are superior to hydrophilic ones in tumor penetration and "bystander killing" upon release from ADCs. However, they are prone to aggregation and accelerated plasma clearance, which lead to reduced efficacies and increased toxicities of ADC molecules. Shielding the hydrophobicity of payloads by incorporating polyethylene glycol (PEG) elements or sugar groups into the ADC linkers has emerged as a viable alternative to directly adopting hydrophilic payloads.

Preparation of protein and its preventive effect on nonalcoholic fatty liver disease in mice.

is a valuable edible fungus with multidimensional bioactivities; however, research on protein and its beneficial effects on nonalcoholic fatty liver disease (NAFLD) have been limited. In this study, protein (MEP) with 80.59% protein content was prepared, isolated, and characterized by the complete amino acid composition.

Eleutherlenes A-D, Diverse Types of Naphthalene Derivatives with Anti-inflammatory Activity from .

Eleutherlene A (), an unprecedented carbon skeleton featuring an aryl-fused 6-methyl-2,7-dioxabicyclo[3.2.1]octane unit, and eleutherlene B (), a naphthoquinone derivative with interesting ring fusion of an α,β-unsaturated γ-lactam and a tetrahydropyran moiety, along with two novel naphthoquinone alkaloids, eleutherlenes C () and D (), were isolated from and identified.

The protective effects of active ingredients from acrorus tatarinowii on sperm and their molecular mechanisms.

Purpose: To investigate the therapeutic potential of Acrorus tatarinowii in oligoasthenozoospermia and its related mechanism through modulation of the BCL2/Bax/Caspase3 signaling pathway.

Methods: Initially, using the TCMSP and Disgenet databases, active ingredients of Acrorus tatarinowii were identified and their target genes associated with sperm-related diseases were elucidated.Subsequently, an oligoasthenozoospermia mouse model was induced and treated with Acrorus tatarinowii.

Creating Single Atomic Coordination for Hypoxia-Resistant Pyroptosis Nano-Inducer to Boost Anti-Tumor Immunotherapy.

General synthesis and mechanical understanding of type I nano-photosensitizers are of great importance for hypoxia-resistant pyroptosis inducers. Herein, a simple solvothermal treatment is developed to convert non-photosensitive small molecules (hemin) into uniform carbon nanodots (HNCDs) with strong type I photodynamic activity and red fluorescence emission. These HNCDs inherit the single atomic Fe-N center of hemin while creating sp-hybridized carbon surroundings, which synergistically modulated the energy level and electron transfer for converting the type II photodynamic process to type I.

Computer-Aided Design of Self-Assembled Nanoparticles to Enhance Cancer Chemoimmunotherapy via Dual-Modulation Strategy.

The rational design of self-assembled compounds is crucial for the highly efficient development of carrier-free nanomedicines. Herein, based on computer-aided strategies, important physicochemical properties are identified to guide the rational design of self-assembled compounds. Then, the pharmacophore hybridization strategy is used to design self-assemble nanoparticles by preparing new chemical structures by combining pharmacophore groups of different bioactive compounds.

A novel and practical strategy for comprehensive differentiation and profiling of eight Curcumae varieties and their counterfeit from the Chinese market.

The Curcuma genus is extensively used in food, traditional medicine, and spice, however, nine closely related varieties are frequently misidentified, leading to mislabeling and adulteration. This study presents an innovative and practical strategy for precise differentiation of nine Curcumae varieties-eight authentic and one counterfeit. For the first time, comprehensive characterizations were conducted using LC-Orbitrap MS, and 702 non-volatiles were annotated, laying a groundwork for marker selection and identification.

Lymphatic platelet thrombosis limits bone repair by precluding lymphatic transporting DAMPs.

In the musculoskeletal system, lymphatic vessels (LVs), which are interdigitated with blood vessels, travel and form an extensive transport network. Blood vessels in bone regulate osteogenesis and hematopoiesis, however, whether LVs in bone affect fracture healing is unclear. Here, we investigate the lymphatic draining function at the tibial fracture sites using near-infrared indocyanine green lymphatic imaging (NIR-ICG) and discover that lymphatic drainage insufficiency (LDI) starts on day one and persists for up to two weeks following the fracture in male mice.

Therapeutic potential and pharmacological mechanisms of Traditional Chinese Medicine in gout treatment.

Gout is a systemic metabolic disorder caused by elevated uric acid (UA) levels, affecting over 1% of the population. The most common complication of gout is gouty arthritis (GA), characterized by swelling, pain or tenderness in peripheral joints or bursae, which can lead to the formation of tophi. At present, western medicines like colchicine, febuxostat and allopurinol are the primary treatment strategy to alleviate pain and prevent flare-ups in patients with GA, but they have significant side effects and increased mortality risks.

Ether bond-modified lipid nanoparticles for enhancing the treatment effect of hepatic fibrosis.

Lipid nanoparticle (LNP)-mediated RNA delivery holds significant potential for the treatment of various liver diseases. Ionizable lipids play a crucial role in the formulation of LNPs and directly influence their delivery efficiency. In this study, we introduced an innovative concept by incorporating an ether bond into the hydrophobic tail of ionizable lipids for the first time.

Computational Methods for Predicting Chemical Reactivity of Covalent Compounds.

In recent decades, covalent inhibitors have emerged as a promising strategy for therapeutic development, leveraging their unique mechanism of forming covalent bonds with target proteins. This approach offers advantages such as prolonged drug efficacy, precise targeting, and the potential to overcome resistance. However, the inherent reactivity of covalent compounds presents significant challenges, leading to off-target effects and toxicities.

Synthesis of Unprotected Racemic Tryptophan Derivatives Using Gramine via Nickel(II) Complex.

A chemical method for the preparation of nonprotected tryptophan via nickel(II) complexes under simple operating conditions was established. The carefully designed nickel(II) glycinates are inexpensive and can be quantitatively recovered releasing the target tryptophans in high yield. The method has a wide range of synthesis generality, allowing the preparation of various substituted tryptophans.