Latest ArticlesThe clinical application of photodynamic therapy (PDT) is usually limited by the low penetration depth of light and the hypoxic condition of tumor microenvironment. Therefore, it is urgent to develop a drug system that can activate photosensitizers (PSs) in deeply seated tumors and spontaneously generate O2 to enhance the efficacy of PDT. Herein, we design a liquid polyethylene glycol (PEG) 200 (PEG200)-based drug depot containing calcium peroxide (CaO2) nanoparticles, bis[2,4,5-trichloro-6-(pentyloxycarbonyl)phenyl]oxalate (CPPO, a high-energy compound), and chlorin e6 (Ce6, a PS) for achieving O2/H2O2 self-supplied chemiexcited (light irradiation-free) PDT and immunotherapy. By injecting the drug depot into the tumor, CaO2 can react with water to produce H2O2, which can activate CPPO to generate chemical energy, further stimulating Ce6 to produce 1O2. Meanwhile, CaO2 can also generate O2 to enhance PDT. Besides, CaO2 can neutralize the acidic tumor microenvironment by the formation of Ca(OH)2, cause calcium overload in tumor cells, and lead to tumor calcification. Further experiments show that CaO2, CPPO, and Ce6 can cause mitochondrial damage, trigger immunogenic cell death, and significantly improve the therapeutic effect of programmed death-1 (PD-1) monoclonal antibody. This work highlights the application potential of the rational combination of CaO2, CPPO, and Ce6 for realizing light irradiation-free PDT and immunotherapy.
Accumulating evidence highlights the therapeutic potential of soluble epoxide hydrolase (sEH) inhibitors with anti-inflammatory and neuroprotective properties for Alzheimer’s disease (AD). In this work, an ent–atisane diterpenoid J12 was identified as a hit compound against sEH with moderate inhibitory activity from five distinct series of compounds (J1–J44) isolated from Excoecaria agallocha L. After rational structural modification, a novel sEH inhibitor HXY14 with improved sEH inhibitory activity (half maximal inhibitory concentration (IC50) = 1.6 µmol/L, 10-fold compared to J12) was obtained. The cellular thermal shift assay (CETSA) demonstrated direct binding of HXY14 to sEH. In an Aβ-induced neuroinflammation cell model, treatment with HXY14 increased epoxyeicosatrienoic acids (EETs) levels, leading to reduced neuroinflammation and concomitant neuroprotection. HXY14 could ameliorate memory impairment and exhibited cognitive improvement in Aβ1–42-induced AD model and exhibited preferable safety in vivo. Treatment with HXY14 significantly decreased the expression levels of inflammatory factors and attenuated microglia activation, thereby inhibiting neuroinflammation. Furthermore, HXY14 could promote neuroprotection and alleviate synaptic dysfunction in AD model mice. This study expands the discovery of novel naturally derived sEH inhibitors and provides evidence for the utility of sEH inhibitors for AD therapy.
Two novel anthrone–macrolide hybrids, neonectones A and B (1 and 2), one new 10-membered macrolide neonectone C (3), and one new oxaphenalenone derivative, (±)-neonectone D (4), together with five known compounds (5–9) were isolated from the crude extract of the ascomycete fungus Neonectria sp. Compounds 1 and 2 represent the first example of anthrone–ten-membered lactone heterodimers, possessing an unprecedented 5-(10-oxo-9,10-dihydroanthracen-9-yl)oxecane-2,7-dione skeleton. Their structures and absolute configurations were established by a combination of extensive spectroscopic analysis, 13C nuclear magnetic resonance spectroscopy (NMR) chemical shifts calculations with DP4+ probability analysis and electronic circular dichroism (ECD) calculations. Bioactivity evaluation revealed that compounds 1, 2 and 9 exhibited anti-methicillin-resistant Staphylococcus aureus (MRSA) activity. Compound 9 exhibited anti-MRSA activity through disrupting membrane integrity, suppressing energy and nucleotide metabolism, modulating membrane transport and transcription/translation regulatory factors, as well as inhibiting quorum sensing and biofilm formation.
Inhibiting the contraction of cardiac myosin is an important strategy for treating hypertrophic cardiomyopathy (HCM). However, currently only MYK-461 has been approved for market, and its safety and pharmacokinetic (PK) properties still have deficiencies. Herein, we reported the discovery of a novel and potent cardiac myosin inhibitor Z5–11 through rational structural optimization of MYK-461. Compared with MYK-461, Z5–11 exhibited stronger inhibitory activity against myosin ATPase and could significantly inhibit myocardial cell contraction, as well as alleviate Ang Ⅱ-induced cardiac hypertrophy. The cytotoxicity assessment on rat myocardial cells showed that Z5–11 exhibited better safety than MYK-461. The PK study revealed that Z5–11 had reasonable half-life time (t1/2 = 2.74 h), and excellent oral bioavailability (F = 105.2%). More importantly, Z5–11 can effectively ameliorate transverse aortic constriction (TAC)-induced cardiac dysfunction and cardiac hypertrophy and remodeling in mice. These findings suggest that Z5–11 can be developed as a promising drug candidate for treating HCM.
Methamphetamine (METH) addiction represents a severe global public health crisis with currently limited therapeutic options, highlighting an urgent need for innovative approaches. Emerging evidence indicates that neuroinflammation, particularly microglial activation and subsequent cytokine release, significantly contributes to the neuropathology associated with METH use. Cannabidiol (CBD), a phytocannabinoid with promising anti-inflammatory and neuroprotective properties, has demonstrated therapeutic potential in mitigating METH-related neuroimmune responses. However, its clinical translation is severely restricted due to low bioavailability, rapid hepatic metabolism, and limited blood-brain barrier (BBB) penetration. To address these challenges, we developed a novel therapeutic platform utilizing exosomes derived from hypoxia-preconditioned human umbilical vein endothelial cells. These exosomes were loaded with CBD and surface-functionalized with the transcriptional activator protein (TAT) peptide, generating HP-Exo-CBD-TAT, to enhance brain targeting. Intranasal administration of HP-Exo-CBD-TAT significantly improved BBB penetration and brain accumulation compared to unmodified CBD-loaded exosomes (HP-Exo-CBD). In mouse models of METH addiction, treatment with HP-Exo-CBD-TAT markedly attenuated behavioral sensitization and conditioned place preference (CPP), two key indicators of addiction-like behaviors. The observed therapeutic effects correlated strongly with reductions in microglial activation and pro-inflammatory cytokine expression (interleukin-1β (IL-1β), IL-6, tumor necrosis factor-α (TNF-α)) in critical addiction-associated brain regions, such as the medial prefrontal cortex and ventral tegmental area. Importantly, even the carrier alone (HP-Exo-TAT) exhibited intrinsic immunomodulatory effects, underscoring the dual therapeutic action of this delivery system. Our findings highlight HP-Exo-CBD-TAT as a highly efficient, biocompatible, and non-invasive strategy that effectively targets neuroinflammation and addictive behaviors. This intranasal exosomal platform demonstrates significant translational promise for the clinical management of METH addiction.
Breast cancer is the most prevalent cancer in women worldwide and a major contributor to cancer-related death. It has been established for decades that natural bioactive compounds are a crucial source for developing novel anticancer drugs. However, their poor targeting, limited solubility and bioavailability, and instability hinder the effectiveness of treatment. With advancements in nanotechnology, nanomedicine delivery systems have emerged as viable approaches to enhance drug bioavailability and therapeutic effectiveness, with natural polymer-based drug carriers gaining significant attention for breast cancer treatment. Chitosan's distinct physicochemical characteristics, biocompatibility, and low immunogenicity make it a popular choice for carrier materials in nanomedicine delivery systems. Their desired qualities include the extent of chemical modification, controlled drug release, surface flexibility, non-toxicity, enhanced stability, cellular uptake, anticancer drug solubility, modulation of release kinetics, and biodistribution. This review aims to illustrate current concerns regarding breast cancer treatment, highlighting the untapped potential of natural bioactive compounds while promoting the latest developments of using chitosan-based nanocarriers to deliver natural bioactive compounds. Finally, this review spotlights the limitations of existing research and the futuristic prospects in this emerging field.
Prostate cancer poses a severe threat to the health of middle-aged and elderly males. In recent years, the development and clinical utilization of prostate-specific membrane antigen (PSMA)-targeted agents have significantly expanded diagnostic options for this malignancy. However, tumor heterogeneity substantially compromises the efficacy of radionuclide therapy, necessitating the exploration of multi-target strategies as potential solutions. This study presents a novel heterodimeric construct engineered for prostate cancer management, labeled with both diagnostic and therapeutic radionuclides to enable concurrent application in positron emission computed tomography (PET) imaging and radionuclide therapy. Our investigation primarily evaluates the therapeutic efficacy of ultra-low-dose (3.7 MBq) radionuclide therapy combined with anti-programmed cell death protein-1 (PD-1) antibody immunotherapy. In the RM-1 prostate cancer model with elevated PSMA expression, we have validated that the combination of ultra-low-dose radionuclide treatment and anti-PD-1 antibody immunotherapy yields superior therapeutic outcomes. Notably, compared to the immunotherapy-only group, the combination regimen elicited a significant increase in dendritic cells (DCs) and natural killer (NK) cells populations, with enhancements ranging from 32% to 103%. This ultra-low-dose radioimmunotherapy strategy offers a valuable theoretical framework for clinical translation, holding promise for further enhancing therapeutic efficacy in prostate cancer treatment.
Hydrogen sulfide (H2S), a gaseous signaling molecule with diverse biological functions, exhibits abnormal concentrations that are closely associated with arthritic pathogenesis and serve as a characteristic indicator of protein-rich food spoilage. To address the need for reliable H2S detection, this study developed a novel fluorescent probe, BHP-PC, by rationally integrating methylene blue and benzothiazole fluorophores. The probe demonstrates remarkable spectral separation (215 nm) and high selectivity, enabling simultaneous monitoring of fluorescence signals in both blue (detection limit: 12.5 nmol/L) and red (detection limit: 22.6 nmol/L) channels for highly sensitive H2S quantification. BHP-PC exhibits excellent dual-color imaging capabilities in both cellular and zebrafish models. The distinct colorimetric response facilitated the successful development of test strips for practical H2S detection in spoiled proteinaceous samples. Furthermore, the probe’s application in a λ-carrageenan-induced murine arthritis model enabled real-time H2S visualization, demonstrating its potential as an analytical tool for arthritis diagnosis and therapeutic monitoring.
Hydrogen evolution reaction (HER) is the critical process of hydrogen production through water electrolysis. However, the dependence on precious metal catalysts limits its large-scale application. Transition metal phosphides (TMPs) are promising alternatives due to their metal-like conductivity, adjustable electronic structure and low cost. Yet they still show some shortcomings such as insufficient intrinsic activity and poor surface stability. This review first systematically summarizes the HER reaction mechanism and its implications for TMPs catalyst design. Subsequently, it details the characteristics, limitations, and performance optimization strategies for monometallic TMPs. Furthermore, it discusses advances in polymetallic TMPs and composite structures for overcoming the activity limitations of monometallic TMPs. Finally, we propose key obstacles limiting TMPs in HER and their research directions and development prospects in the future.
Ovarian cancer (OC) manifests the second deadliest gynecologic malignancy and shows severe conventional therapies-resistance, underscoring the urgent need for new therapeutic interventions. Disulfidptosis, caused in solute carrier family 7 member 11 (SLC7A11)-overexpressing (SLC7A11high) cancer cells under glucose deficiency, has emerged as an appealing alternative approach. Herein we identified the significantly high expression of SLC7A11 in OC, and demonstrated that disulfidptosis induced by 6-aminonicotinamide (6-AN) effectively kill SLC7A11high OC cells. Hence, to enhance the therapeutic effect of 6-AN, we engineered a novel nanodrug, FA-L@AI, utilizing folic acid (FA)-modified liposome, and also illustrated the detailed therapeutic mechanism. Upon exposed to FA-L@AI, SLC7A11high OC cells endured internal nicotinamide adenine dinucleotide phosphate (NADPH) pools deleting, which leads to cystine accumulations. The elevated cystine levels resulted in disulfide bonds formation in actin cytoskeletal protein, ultimately triggering disulfidptosis. FA-L@AI nanoparticles exhibited an impactful suppression of tumor cells growth through 6-AN-induced disulfidptosis both in vitro and in vivo. Consistently, mRNA transcriptomic analysis further elucidated the underlying mechanism of disulfidptosis. Altogether, our work displays a unique strategy mediating disulfidptosis for OC specific therapy.
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