Structure-Guided Optimization and Preclinical Evaluation of 6--Benzylguanine-Based Pin1 Inhibitor for Hepatocellular Carcinoma Treatment.

Hepatocellular carcinoma (HCC) is a major cause of cancer-related deaths globally, and the need for effective systemic therapies for HCC is urgent. Our previous work reveals that Pin1 is a potential anti-HCC target, which regulates miRNA biogenesis and identifies as a novel Pin1 inhibitor to suppresses HCC. However, a great demand in HCC therapy as well as the limited chemical stability and pharmacokinetic feature of motivated us to find improved Pin1 inhibitors.

Manganese dioxide-based in situ vaccine boosts antitumor immunity via simultaneous activation of immunogenic cell death and the STING pathway.

In situ vaccine (ISV) can activate the anti-tumor immune system by inducing immunogenic cell death (ICD) at the tumor site. However, the development of tumor ISV still faces challenges due to insufficient tumor antigens released by tumor cells and the existence of tumor immunosuppressive microenvironment (TIME). Targeting the STING pathway has been reported to enhance the adjuvant effects of in situ tumor vaccines by initiating innate immunity.

Cryo-EM reveals cholesterol binding in the lysosomal GPCR-like protein LYCHOS.

Cholesterol plays a pivotal role in modulating the activity of mechanistic target of rapamycin complex 1 (mTOR1), thereby regulating cell growth and metabolic homeostasis. LYCHOS, a lysosome-localized G-protein-coupled receptor-like protein, emerges as a cholesterol sensor and is capable of transducing the cholesterol signal to affect the mTORC1 function. However, the precise mechanism by which LYCHOS recognizes cholesterol remains unknown.

Targeting FOXM1 condensates reduces breast tumour growth and metastasis.

Identifying phase-separated structures remains challenging, and effective intervention methods are currently lacking. Here we screened for phase-separated proteins in breast tumour cells and identified forkhead (FKH) box protein M1 (FOXM1) as the most prominent candidate. Oncogenic FOXM1 underwent liquid-liquid phase separation (LLPS) with FKH consensus DNA element, and compartmentalized the transcription apparatus in the nucleus, thereby sustaining chromatin accessibility and super-enhancer landscapes crucial for tumour metastatic outgrowth.

Low-input redoxomics facilitates global identification of metabolic regulators of oxidative stress in the gut.

Oxidative stress plays a crucial role in organ aging and related diseases, yet the endogenous regulators involved remain largely unknown. This work highlights the importance of metabolic homeostasis in protecting against oxidative stress in the large intestine. By developing a low-input and user-friendly pipeline for the simultaneous profiling of five distinct cysteine (Cys) states, including free SH, total Cys oxidation (Sto), sulfenic acid (SOH), S-nitrosylation (SNO), and S-glutathionylation (SSG), we shed light on Cys redox modification stoichiometries and signaling with regional resolution in the aging gut of monkeys.

Current and Emerging Approaches Targeting G9a for the Treatment of Various Diseases.

G9a, a histone lysine methyltransferase, is instrumental in regulating gene expression through epigenetic modifications. Its overexpression is closely linked to the progression of various human diseases, including cancers. Therefore, targeting G9a enzyme is a promising strategy for treating various diseases.

Copper-coordination driven brain-targeting nanoassembly for efficient glioblastoma multiforme immunotherapy by cuproptosis-mediated tumor immune microenvironment reprogramming.

Limited drug accumulation and an immunosuppressive microenvironment are the major bottlenecks in the treatment of glioblastoma multiforme (GBM). Herein, we report a copper-coordination driven brain-targeting nanoassembly (TCe6@Cu/TP5 NPs) for site-specific delivery of therapeutic agents and efficient immunotherapy by activating the cGAS-STING pathway and downregulating the expression of PD-L1. To achieve this, the mitochondria-targeting triphenylphosphorus (TPP) was linked to photosensitizer Chlorin e6 (Ce6) to form TPP-Ce6 (TCe6), which was then self-assembled with copper ions and thymopentin (TP5) to obtain TCe6@Cu/TP5 NPs.

Deciphering the molecular basis of lipoprotein recognition and transport by LolCDE.

Outer membrane (OM) lipoproteins serve vital roles in Gram-negative bacteria, contributing to their pathogenicity and drug resistance. For these lipoproteins to function, they must be transported from the inner membrane (IM), where they are assembled, to the OM by the ABC transporter LolCDE. We have previously captured structural snapshots of LolCDE in multiple states, revealing its dynamic conformational changes.

Advances in Microfluidic Cochlea-On-A-Chip.

The current understanding of the human auditory system has been primarily based on studies using animal and cellular models. Organoids have been used to simulate cochlear structures and replicate cochlear functions. However, the physical and chemical cues required to control the development of cochlear organoids accurately remain poorly understood, limiting research advances on cochlea-on-a-chip systems.

Peptide Nanocarriers for Targeted Delivery of Nucleic Acids for Cancer Therapy.

Peptides have been extensively studied in nanomedicine with great bioactivity and biocompatibility; however, their poor cell-membrane-penetrating properties and nonselectivity greatly limit their clinical applications. In this study, tumor-targeting therapy was achieved by modifying our previously developed efficient peptide vector with the cancer-targeting peptide RGD, enabling it to specifically target tumor cells with a high expression of RGD-binding receptors. B-cell lymphoma-2 antisense oligonucleotides were selected as the target model to validate the effectiveness of the delivery carriers.

Design, synthesis, and antitumor evaluation of quinazoline-4-tetrahydroquinoline chemotypes as novel tubulin polymerization inhibitors targeting the colchicine site.

We designed, synthesized, and evaluated the antitumor activity of a series of novel quinazoline-4-(6-methoxytetrahydroquinoline) analogues. Among the tested compounds, 4a4 exhibited the most potent antiproliferative activities across four human cancer cell lines with half-maximal inhibitory concentration (IC) values ranging from 0.4 to 2.

Acquired resistance to tyrosine kinase targeted therapy: mechanism and tackling strategies.

Over the past two decades, tyrosine kinase inhibitors (TKIs) have rapidly emerged as pivotal targeted agents, offering promising therapeutic prospects for patients. However, as the cornerstone of targeted therapies, an increasing number of TKIs have been found to develop acquired resistance during treatment, making the challenge of overcoming this resistance a primary focus of current research. This review comprehensively examines the evolution of TKIs from multiple perspectives, with particular emphasis on the mechanisms underlying acquired resistance, innovative drug design strategies, inherent challenges, and future directions.

Insights on exploring the therapeutic potential and structural modification of Tetrandrine.

Tetrandrine (Tet), a bisbenzylisoquinoline alkaloid from , is noted for its diverse pharmacological effects but faces limitations in clinical use due to toxicity, poor solubility, and low bioavailability. Researchers are working to address these issues by developing Tet derivatives with greater therapeutic potential through structural modification. Generally, key modifications include: 1) introducing an aromatic heterocycle or a hydrophobic alkyne unit at the -5 position can enhance its antitumor activity; 2) adding an amide, sulfonamide, or electron-withdrawing group at the -14 position can enhance its antitumor activity; 3) changing its structure to a quaternary ammonium salt can alter its solubility and greatly boost its antibacterial activity; 4) structural modification of the -12-methoxybenzyl motif can enhance its metabolic stability and thus change the activity of the analogs; 5) Tet structural simplification may result in the identification of anticancer lead compounds with novel mechanisms of action.

The pathophysiological functions and therapeutic potential of GPR39: Focus on agonists and antagonists.

G protein-coupled receptor 39 (GPR39), a member of the growth hormone-releasing peptide family, exhibits widespread expression across various tissues and demonstrates high constitutive activity, primarily activated by zinc ions. It plays critical roles in cell proliferation, differentiation, survival, apoptosis, and ion transport through the recruitment of Gq/11, Gs, G12/13, and β-arrestin proteins. GPR39 is involved in anti-inflammatory and antioxidant responses, highlighting its diverse pathophysiological functions.

A platform of functional studies of ESCC-associated gene mutations identifies the roles of TGFBR2 in ESCC progression and metastasis.

Genomics studies have detected numerous genetic alterations in esophageal squamous cell carcinoma (ESCC). However, the functions of these mutations largely remain elusive, partially due to a lack of feasible animal models. Here, we report a convenient platform with CRISPR-Cas9-mediated introduction of genetic alterations and orthotopic transplantation to generate a series of primary ESCC models in mice.

Dual-payload antibody-drug conjugates: Taking a dual shot.

Antibody-drug conjugates (ADCs) enable the precise delivery of cytotoxic agents by conjugating small-molecule drugs with monoclonal antibodies (mAbs). Over recent decades, ADCs have demonstrated substantial clinical efficacy. However, conventional ADCs often encounter various clinical challenges, including suboptimal efficacy, significant adverse effects, and the development of drug resistance, limiting their broader clinical application.

A pH and glutathione-responsive carbon monoxide-driven nano-herb delivery system for enhanced immunotherapy in colorectal cancer.

Dihydroartemisinin (DHA), a compound extracted from the herbal medicine Artemisia annua, has shown promise as a clinical treatment strategy for colorectal cancer. However, its clinical use is hindered by its low water solubility and bioavailability. A pH/glutathione (GSH) dual-responsive nano-herb delivery system (PMDC NPs) has been developed for the targeted delivery of DHA, accompanied by abundant carbon monoxide (CO) release.

Structural insights into the mechanotransducing mechanism of FtsEX in cell division.

The filamentous temperature-sensitive (Fts) protein FtsEX plays a pivotal role in () cell division by facilitating the activation of peptidoglycan hydrolysis through the adaptor EnvC. FtsEX belongs to the type VII ATP-binding cassette (ABC) transporter superfamily, which harnesses ATP energy to induce mechanical force, triggering a cascade of conformational changes that activate the pathway. However, the precise mechanism by which FtsEX initiates mechanotransmission remains elusive.

Causal association of epigenetic age acceleration and risk of subacute thyroiditis: a bidirectional Mendelian randomization study.

Background: Epigenetic age accelerations (EAAs) are a promising new avenue of research, yet their investigation in subacute thyroiditis (SAT) remains scarce. Our study endeavors to fill this void by exploring the potential causal association between EAAs and SAT.

Methods: Our study utilized publicly available genome-wide association study (GWAS) data of European ancestry to conduct a bidirectional Mendelian randomization (MR) study.

Data-driven risk stratification and precision management of pulmonary nodules detected on chest computed tomography.

The widespread implementation of low-dose computed tomography (LDCT) in lung cancer screening has led to the increasing detection of pulmonary nodules. However, precisely evaluating the malignancy risk of pulmonary nodules remains a formidable challenge. Here we propose a triage-driven Chinese Lung Nodules Reporting and Data System (C-Lung-RADS) utilizing a medical checkup cohort of 45,064 cases.

Integrative residue-intuitive machine learning and MD Approach to Unveil Allosteric Site and Mechanism for β2AR.

Allosteric drugs offer a new avenue for modern drug design. However, the identification of cryptic allosteric sites presents a formidable challenge. Following the allostery nature of residue-driven conformation transition, we propose a state-of-the-art computational pipeline by developing a residue-intuitive hybrid machine learning (RHML) model coupled with molecular dynamics (MD) simulation, through which we can efficiently identify the allosteric site and allosteric modulator as well as reveal their regulation mechanism.

Targeting HSP90 for Cancer Therapy: Current Progress and Emerging Prospects.

Heat shock protein 90 (HSP90), a highly conserved member of the heat shock protein family, regulates various proteins and signaling pathways involved in cancer, making it a promising target for cancer therapy. Traditional HSP90 inhibitors have demonstrated significant antitumor potential in preclinical trials, with over 20 compounds advancing to clinical trials and showing promising results. However, the limited clinical efficacy and shared toxicity of these inhibitors restrict their further clinical use.