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.

Fine-tuned calcium homeostasis is crucial for murine erythropoiesis.

Intracellular calcium (Ca) is a crucial signaling molecule involved in multiple cellular processes. However, the functional role of Ca in terminal erythropoiesis remains unclear. Here, we uncovered the dynamics of intracellular Ca levels during mouse erythroid development.

Tools for Intersectional Optical and Chemical Tagging on Cell Surfaces.

We present versatile tools for intersectional optical and chemical tagging of live cells. Photocaged tetrazines serve as "photo-click" adapters between recognition groups on the cell surface and diverse chemical payloads. We describe two new functionalized photocaged tetrazine structures which add a light-gating step to three common cell-targeting chemical methods: HaloTag/chloroalkane labeling, nonspecific primary amine labeling, and antibody labeling.

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.

The role of phospholipid transfer protein in sepsis-associated acute kidney injury.

Background: Phospholipid transfer protein (PLTP), a glycoprotein widely expressed in the body, is primarily involved in plasma lipoprotein metabolism. Previous research has demonstrated that PLTP can exert anti-inflammatory effects and improve individual survival in patients with sepsis and endotoxemia by neutralizing LPS and facilitating LPS clearance. However, the role of PLTP in sepsis-associated acute kidney injury (SA-AKI) and the specific mechanism of its protective effects are unclear.

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.

Spatiotemporal transcriptome and metabolome landscapes of cotton fiber during initiation and early development.

Cotton fibers are single cells that develop from the epidermal cells in the outer integument of developing seeds. The processes regulating fiber cell development have been extensively studied; however, the spatiotemporal transcriptome and metabolome profiles during the early stages of fiber development remain largely unknown. In this study, we profile the dynamics of transcriptome and metabolome during the early stages of cotton fiber cell development using a combination of spatial transcriptomic, single-cell transcriptomic, and spatial metabolomic analyses.

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.

Development of Off-On Near-Infrared Fluorescent Probes for Sensitive In Vivo Imaging of Amyloid-β Species with Enhanced Pharmacokinetic.

The fluorescent imaging of pathologically accumulated β-amyloid (Aβ) proteins is of significant importance to the diagnosis of Alzheimer's disease (AD). In the paper, we prepared two new NIR probes, NIR-1 and NIR-2, through hydrophilic modification of introducing water-soluble bioactive groups such as polyethylene glycol (PEG) and morpholine to tune in vivo pharmacokinetics for specific detection of soluble and insoluble Aβ species. The in vitro assessments confirm that both NIR-1 and NIR-2 display strong near-infrared (NIR) fluorescence (FL) enhancement upon association with Aβ42 monomers, oligomers or aggregates (λem > 670 nm) and show high sensitive, rapid and selective response towards Aβ42 species.

Study on the absorption characteristics of euscaphic acid and tiliroside in fruits of Retz.

The fruits of Retz. (FRL) have a long history of medicinal use, known for their rich composition of flavonoids, polyphenols, amino acids, sugars, and other bioactive compounds. FRL exhibits pharmacological effects such as antioxidant, antiviral, antibacterial, and antitumor activities, making it a valuable resource with significant development potential in both the food and pharmaceutical industries.

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.

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.

Oral barriers to food-derived active peptides and nano-delivery strategies.

Food-derived bioactive peptides are a class of peptides from natural protein. It may have biological effects on the human body and play a significant role in protecting human physiological health and regulating physiological metabolism, such as lowering blood pressure, lowering cholesterol, antioxidant, antibacterial, regulating immune activity, and so on. However, most of the natural food-derived functional peptides need to overcome a variety of barriers in the body to enter the blood circulation system and target to specific tissues to generate physiological activity.

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.

DNA logic nanomachine for the accurate identification of multiple microRNAs in tumor cells.

The use of dynamic DNA logic circuits for disease diagnosis at the molecular level plays a considerable role in biomedical fields. Nevertheless, how to create programmable nanomachines based on molecular logical gates to accurately identify multiple biomarkers from tumor cells remains a pivotal challenge. Herein, we developed a DNA-based nanomachine for analyzing and imaging multiple microRNAs (miRNAs) in cancerous cells with a logical AND operation.

A novel supramolecular nanodrugs for improving the cognitive function of schizophrenia by protecting active lactone of arecoline.

Over 30 % of patients with schizophrenia experience treatment resistance and severe side effects. The limited efficacy of antipsychotic therapies poses a challenge, partly due to the blood-brain barrier (BBB) and the non-selective targeting of these drugs. Herein, we report on arecoline (ARE), a water soluble natural small molecule, which was successfully constructed a phospholipid complex by noncovalent interactions.

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.

A nanobody-enzyme fusion protein targeting PD-L1 and sialic acid exerts anti-tumor effects by C-type lectin pathway-mediated tumor associated macrophages repolarizing.

Aberrant sialylated glycosylation in the tumor microenvironment is a novel immune suppression pathway, which has garnered significant attention as a targetable glycoimmune checkpoint for cancer immunotherapy to address the dilemma of existing therapies. However, rational drug design and in-depth mechanistic studies are urgently required for tumor sialic acid to become valuable glycoimmune targets. In this study, we explored the positive correlation of PD-L1 and sialyltransferase expression in clinical colorectal cancer tissues and identified their mutual regulation effects in macrophages.

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.

An expanding universe of mutational signatures and its rapid evolution in single-stranded RNA viruses.

The study of mutational processes in somatic genomes has gained recent momentum, uncovering a wide array of endogenous and exogenous factors associated with somatic changes. However, the overall landscape of mutational processes in germline mutations across the tree of life and associated evolutionary driving forces are rather unclear. In this study, we analyzed mutational processes in single-stranded RNA (ssRNA) viruses which are known to jump between different hosts with divergent exogenous environments.

26-Week Repeated-Dose Toxicity Study of a Novel Antiarrhythmic Drug Sulcardine Sulfate in Sprague-Dawley Rats.

Sulcardine sulfate (Sul) is a novel antiarrhythmic agent blocking multiple channels and exhibits unique pharmacological properties such as lower APD-dependent prolongation and reduced arrhythmia risk. Sul is currently in Phase III clinical trials, yet studies on its long-term toxicological profile and potential target organs remain unexplored. This study investigated the related toxicity of Sul in Sprague Dawley (SD) rats through repeated oral administration for 26 weeks, followed by a 4-week recovery period.

Discovery of Novel RNA Demethylase FTO Inhibitors Featuring an Acylhydrazone Scaffold with Potent Antileukemia Activity.

Fat mass obesity-associated protein (FTO) has been emerging as a potential therapeutic target for drug discovery in RNA epigenetics. In this work, a series of novel FTO inhibitors featuring an acylhydrazone scaffold were identified, and the optimized compounds - showed potent FTO inhibitory activities with IC values ranging from 7.1 to 9.

Design, synthesis and activity evaluation of novel quinazolinone compounds as TRPC5 inhibitors.

The TRPC5 channel plays an important role in regulating various physiological processes, which is related to various human diseases, especially psychiatric and kidney diseases. Although the TRPC5 channel is one of the essential potential target, no drugs against TRPC5 channels have been granted in the market to date. In this study, based on the structure of hit compound ph1, we further synthesied 49 compounds of novel quinazolinone and heterocyclic fusion pyrimidinone derivatives, and their activities were evaluated by electrophysiological assays.

Small molecule inhibits KCNQ channels with a non-blocking mechanism.

Voltage-gated ion channels (VGICs) are crucial targets for neuropsychiatric therapeutics owing to their role in controlling neuronal excitability and the established link between their dysfunction and neurological diseases, highlighting the importance of identifying modulators with distinct mechanisms. Here we report two small-molecule modulators with the same chemical scaffold, Ebio2 and Ebio3, targeting a potassium channel KCNQ2, with opposite effects: Ebio2 acts as a potent activator, whereas Ebio3 serves as a potent and selective inhibitor. Guided by cryogenic electron microscopy, patch-clamp recordings and molecular dynamics simulations, we reveal that Ebio3 attaches to the outside of the inner gate, employing a unique non-blocking inhibitory mechanism that directly squeezes the S6 pore helix to inactivate the KCNQ2 channel.