Late-Stage Stitching Enabled by Palladium-Catalyzed Tryptophan C4 Amination: Peptide Ligation and Cyclodimerization.

Here, we report on methods for late-stage peptide diversification through palladium-catalyzed site-selective C(sp)-H amination of tryptophan residues at the C4 position, utilizing tryptophan-amine cross-links. Our strategy enables practical access to C-N bonds, facilitating the construction of cyclopeptides via late-stage cyclodimerization of structurally complex peptides, which poses significant challenges for organic synthesis. The synthetic utility of this protocol is demonstrated through the synthesis of 30- to 38-membered macrocyclic peptides.

A reactive oxygen species-responsive hydrogel loaded with Apelin-13 promotes the repair of spinal cord injury by regulating macrophage M1/M2 polarization and neuroinflammation.

Spinal cord injury (SCI) is a chronic condition whereby persistent aberrant macrophage activation hinders the repair process. During acute trauma, dominant M1 macrophages produce high levels of reactive oxygen species (ROS), leading to increased apoptosis in neurons, glial cells, and oligodendrocytes. This study investigated the specific effects of a ROS-responsive hydrogel loaded with Apelin-13 (Apelin-13@ROS-hydrogel) on macrophage polarization and neuroinflammation, thereby exploring its role in boosting SCI repair.

Advancements in Transdermal Drug Delivery Systems: Harnessing the Potential of Macromolecular Assisted Permeation Enhancement and Novel Techniques.

Transdermal drug delivery (TDD) represents a transformative paradigm in drug administration, offering advantages such as controlled drug release, enhanced patient adherence, and circumvention of hepatic first-pass metabolism. Despite these benefits, the inherent barrier function of the skin, primarily attributed to the stratum corneum, remains a significant impediment to the efficient permeation of therapeutic agents. Recent advancements have focused on macromolecular-assisted permeation enhancers, including carbohydrates, lipids, amino acids, nucleic acids, and cell-penetrating peptides, which modulate skin permeability by transiently altering its structural integrity.

Prediction of Proteolysis-Targeting Chimeras Retention Time Using XGBoost Model Incorporated with Chromatographic Conditions.

Proteolysis-targeting chimeras (PROTACs) are heterobifunctional molecules that target undruggable proteins, enhance selectivity and prevent target accumulation through catalytic activity. The unique structure of PROTACs presents challenges in structural identification and drug design. Liquid chromatography (LC), combined with mass spectrometry (MS), enhances compound annotation by providing essential retention time (RT) data, especially when MS alone is insufficient.

Gentiopicroside ameliorates psoriasis-like skin lesions in mice via regulating the Keap1-Nrf2 pathway and inhibiting keratinocyte activation.

Psoriasis is a chronic, systemic immune-mediated skin disease. Although many new strategies for psoriasis treatment have been developed, there is great need in clinic for treating psoriasis. Gentiopicroside (GPS), derived from Gentiana manshurica Kitagawa, has multiple pharmacological activities including anti-inflammatory, anti-oxidative and antiviral activities.

Mechanistic Insights Underlying the Drug Release and Skin Permeation of Guanfacine Transdermal Patch with Various Acrylic Pressure-Sensitive Adhesives.

Acrylic pressure-sensitive adhesives (PSAs) are widely applied in transdermal drug delivery systems (TDDS). However, the molecular mechanisms underlying the effect of functional groups of PSAs on drug release and transdermal permeation properties remain insufficiently clear. In this study, we investigated the effect of acrylic PSAs' functional groups on the in vitro release and transdermal permeation properties of a model drug guanfacine (GFC).

Polysialic acid-based nanoparticles for enhanced targeting and controlled dexamethasone release in pulmonary inflammation treatment.

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are life-threatening conditions characterized by severe inflammation and respiratory failure. Despite the use of dexamethasone (Dex) in treatment, challenges such as poor solubility and systemic side effects persist, highlighting the need for novel therapeutic approaches. This study introduces an innovative nanoparticle delivery system based on chitosan (CS) and polysialic acid (PSA), engineered via electrostatic assembly, to improve the targeted delivery of Dex to inflamed lung tissues.

Aqueous extract of Cornus officinalis alleviate NAFLD via protecting hepatocytes proliferation through regulation of the tricarboxylic acid cycle.

Ethnopharmacological Relevance: Cornus officinalis (CO) has been widely used as Chinese herbal medicine and has a good clinical efficacy in liver disease. In particular, it has a significant therapeutic effect on metabolic liver disease. However, systematic pharmacological studies on its hepatoprotective effect on non-alcoholic fatty liver disease (NAFLD) are lacking.

The bioinformatics analysis and experimental validation of the carcinogenic role of EXO1 in lung adenocarcinoma.

Background: Exonuclease 1 (EXO1), a protein involved in mismatch repair and recombination processes, has been identified as a prognostic biomarker in lung adenocarcinoma (LUAD). Nevertheless, its role in LUAD progression remains elusive. This study seeks to elucidate the functional significance of EXO1 in LUAD and evaluate its potential as a therapeutic target.

The Function of Poly (U) Binding Splicing Factor 60 (PUF60) in Disease Regulation.

The alternative splicing (AS) of pre-mRNA is an important process in controlling the expression of human genes, which can enrich the diversity of the proteome and regulate gene function. On the contrary, aberrant splicing contributes significantly to numerous human diseases progression, including tumors, neurological diseases, metabolic diseases, infections, and immune diseases. The PUF60, a protein related to RNA splicing, plays critical functions in RNA splicing and gene transcription regulation.

Concomitant Statin Use and Survival in Patients With Cancer on Immune Checkpoint Inhibitors: A Meta-Analysis.

Purpose: The prognostic significance of concomitant statin use in cancer treatment with immune checkpoint inhibitors (ICIs) remains a subject of ongoing investigation. This study aims to clarify the prognostic value of statin use in this patient population and to provide a robust, evidence-based foundation to guide therapeutic decisions.

Methods: A systematic search strategy was used across a multitude of digital archives to exhaustively identify all relevant academic literature published up until June 20, 2024.

Structure-Guided Discovery of Novel -(Substituted Thiazol-2-yl)--(4-Substituted phenyl)pyrimidine-2,4-Diamines as Potent CDK2 and CDK9 Dual Inhibitors with High Oral Bioavailability.

CDK2 and CDK9 play pivotal roles in cell cycle progression and gene transcription, respectively, making them promising targets for cancer treatment. Herein, we discovered a series of -(substituted thiazol-2-yl)--(4-substituted phenyl)pyrimidine-2,4-diamines as highly potent CDK2/9 dual inhibitors. Especially, compound significantly inhibited CDK2 (IC = 0.

Precisely Tailoring Molecular Structure of Doxorubicin Prodrugs to Enable Stable Nanoassembly, Rapid Activation, and Potent Antitumor Effect.

Background: Achieving a balance between stable drug loading/delivery and on-demand drug activation/release at the target sites remains a significant challenge for nanomedicines. Carrier-free prodrug nanoassemblies, which rely on the design of prodrug molecules, offer a promising strategy to optimize both drug delivery efficiency and controlled drug release profiles.

Methods: A library of doxorubicin (DOX) prodrugs was created by linking DOX to fatty alcohols of varying chain lengths via a tumor-responsive disulfide bond.

Vitamin C and MEK Inhibitor PD0325901 Synergistically Promote Oligodendrocytes Generation by Promoting DNA Demethylation.

DNA methylation and demethylation are key epigenetic events that regulate gene expression and cell fate. DNA demethylation via oxidation of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) is typically mediated by TET (ten-eleven translocation) enzymes. The 5hmC modification is considered an intermediate state of DNA demethylation; it is particularly prevalent in the brain and is believed to play a role in the development of many cell types in the brain.

Comparison of Interactions Between Soy Protein Isolate and Three Folate Molecules: Effect on the Stabilization, Degradation, and Oxidization of Folates and Protein.

This study selected three approved folate sources-folic acid (FA), L-5-methyltetrahydrofolate (MTFA), and calcium 5-methyltetrahydrofolate (CMTFA)-to explore their interaction mechanisms with soy protein isolate (SPI) through spectrofluorometric analysis and molecular docking simulations. We investigated how these interactions influence the structural and physicochemical stability of folates and SPI. Three folates spontaneously bound to SPI, forming complexes, resulting in a decrease of approximately 30 kJ·mol in Gibbs free energy and an association constant (K) of 10 L·mol.

Current Progress and Future Directions in Non-Alzheimer's Disease Tau PET Tracers.

Alzheimer's disease (AD) and non-AD tauopathies are dominant public health issues driven by several factors, especially in the aging population. The discovery of first-generation radiotracers, including [F]FDDNP, [C]PBB3, [F]flortaucipir, and the [F]THK series, for the in vivo detection of tauopathies has marked a significant breakthrough in the fields of neuroscience and radiopharmaceuticals, creating a robust new category of labeled compounds: tau positron emission tomography (PET) tracers. Subsequently, other tau PET tracers with improved binding properties have been developed using various chemical scaffolds to target the three-repeat/four-repeat (3R/4R) tau folds in AD.

Structure-Guided Development of ClpP Agonists with Potent Therapeutic Activities against Infection.

Peritonitis caused by poses a severe threat to patients with end-stage renal failure. Treating multidrug-resistant infections requires the use of antibiotics with diverse mechanisms of action. Caseinolytic protease P (ClpP) is a promising antibacterial target; however, selective activation of (ClpP) over human ClpP (ClpP) remains challenging.

Single-cell RNA sequencing reveals the changes of the pulmonary immune environment in rat after L. treatment.

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HepG2 spheroids cultured in alginate microcapsules as a model for exploring mitochondrial and glycolytic metabolism using the Seahorse XFe24 Analyzer.

Mitochondria are affected by chemical substances and play a critical role in drug-induced liver injury (DILI). Chemical substances can have a significant impact on various cellular processes, such as the disruption of oxidative phosphorylation, oxidative stress, and alteration of glucose metabolism. Given the consequences of these effects, it is crucial to understand the molecular pathways of chemical substances in the context of hepatotoxicity to prevent and treat DILI.

Harnessing acylhydrazone-oxime exchange reaction to achieve diverse synthesis of glycosite-specific antibody-drug conjugates.

Glycosite-specific antibody-drug conjugates (gsADCs), which carry cytotoxic payloads at the conserved -glycosylation site, N297, of an IgG, have emerged as a promising ADC format with better therapeutic index. Conjugating the payloads aldehyde-based chemistry is more friendly to IgGs, and has been widely investigated. However, the efficiency of introducing an aldehyde tag at the N297 site is poor due to the complicated procedures required, such as the multiple-enzyme-catalyzed IgG glycoengineering process and the successive oxidation step, which always results in heterogeneous products and poor stability.

[Cardiotoxicity risk assessment of anticancer drugs by focusing on mitochondrial quality of human iPS cell-derived cardiomyocytes].

Currently, a variety of anticancer agents are used in the treatment of cancer. Since anticancer agents are used continuously over a long time, they carry the risk of side effects. One of the major side effects is cardiac dysfunction.

Punicalagin inhibits excessive autophagy and improves cerebral function in neonatal rats with hypoxia-ischemia brain injury by regulating AKT-FOXO4.

Background: Neonatal hypoxic-ischemic encephalopathy (HIE) has a high incidence and mortality rate, representing a significant patient burden. Therefore, treatment strategies that work synergistically with hypothermic therapies are urgently required. Punicalagin (PUN) is a natural and safe polyphenol with anti-inflammatory functions whose excellent water solubility and safety make it an advantageous perinatal medication.

Xinnaoxin capsule alleviates neuropathological changes and cognitive deficits in Alzheimer's disease mouse model induced by D-galactose and aluminum chloride via reducing neuroinflammation and protecting synaptic proteins.

Ethnopharmacological Relevance: Originally formulated to mitigate high-altitude sickness, Xinnaoxin capsules (XNX) are composed of three traditional Chinese medicines (Rhodiola rosea L., Lycium barbarum L. and Hippophae rhamnoides) with properties of anti-hypoxia, anti-fatigue, and anti-aging.