JOURNAL OF MOLECULAR STRUCTURE
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2025
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IF 4.7
Kaikai Xu,Lulu Kong,Zhikang Song,Xingchen Mu,Dongxin Wang,Zhou Lin,Wei Wang,Shaohua Wei
Photodynamic therapy (PDT), a non-invasive treatment, has attracted significant attention in the field of cancer therapy. However, its clinical efficacy is largely restricted by the targeted retention ability of photosensitizers (PSs) in tumor tissues. Currently, a well-recognized strategy to enhance drug targeting is to conjugate targeting molecules to anti-cancer drugs. Due to the high demand for rapid proliferation, cancer cells take up D-Glucose at a much higher rate than normal cells. This characteristic has made D-Glucose a widely used targeting molecule in clinical applications. In recent years, the field of mirror-image biology has witnessed a surge in research. Studies have shown that mirror-image molecules are resistant to decomposition by natural enzymes. Mirror-image drugs developed based on this principle are expected to have longer half-lives, enabling more desirable lesion enrichment. To date, there has been limited research on the effects of L-Glucose modification on drug properties. Therefore, in this paper, we synthesized D-glucose and L-Glucose modified mirror-image zinc phthalocyanine PSs, D-GluPc and L-GluPc. Preliminary investigations indicated that the modification of D-GluPc and L-GluPc improved the targeting ability of zinc phthalocyanine. Moreover, changing the chirality of glucose did not affect the spectral, photophysical, and photochemical properties, sub-organelle distribution, or in vitro anti-tumor activity of phthalocyanine. Nevertheless, compared with D-GluPc, L-GluPc exhibited a significantly enhanced targeted retention ability in in-vivo tumor tissues, leading to superior anti-tumor activity in PDT. This may be attributed to the unique advantages of the mirror-image drug L-GluPc.
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INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
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2025
·
IF 8.5
Mingxiao Feng,Qianyu Wang,Minzhen Lei,Dawei Zhang,Qian Yu,Chunyan Yan
Neuroinflammation is closely linked to Alzheimer's disease, where the deposition of amyloid-beta activates microglia, triggering multiple processes that lead to neuronal damage and cognitive decline. However, studies have shown that water extract of Pinellia ternata can improve cognitive function and reduce inflammatory response in the brain injury of mice. Herein, a water-soluble polysaccharide, PTTBP-2-2. with a molecular weight of 11.7 kDa, consisting of D-Glc, D-Gal, D-Xyl, and L-Ara, was isolated from P. ternata . Methylation analysis, partial acid hydrolysis, and nuclear magnetic resonance revealed that the of PTTBP-2-2 backbone consisted of →4)- α -D-Glc p -(1→, →4,6)- α -D-Glc p -(1→, and →6)- α -D-Gal p -(1 → residues, with side chains substituted at O -2, O -3, and O -6 positions of →4)- α -D-Glc p -(1→. In vitro experiments demonstrated that PTTBP-2-2 significantly reduced nitrous oxide levels in BV2 microglia cells and suppressed the expression of pro-inflammatory genes, including COX2 , iNOS , TNF-α , IL-1β , and IL-6 . These factors are key mediators of neuroinflammation. Mechanistic investigations revealed that the anti-neuroinflammatory activity of PTTBP-2-2 was mediated through the regulation of NF-κB and Nrf2/HO-1 signaling pathways. Overall, PTTBP-2-2 shows potential as a therapeutic agent for the treatment of neuroinflammation.
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JOURNAL OF ETHNOPHARMACOLOGY
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2025
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IF 5.4
Dongju Lin,Guangyao Li,Haoran Deng,Shuo Wang
Ethnopharmacological relevance Dictamnine (DIC) is the predominant pharmacological and hepatotoxic component of Cortex Dictamni (CD). CYP3A-mediated metabolic activation plays an important role in DIC-induced hepatotoxicity. Schisandra lignans (SCLs) are the major hepatoprotective ingredients of Schisandra chinensis (SC). CD and SC are frequently used as herb pairs in traditional Chinese medical formulas particularly for the treatment of eczema and urticarial. Our preliminary studies have shown that SC can protect against CD-induced liver injury. However, the underlying protective mechanism of SC against CD-induced liver injury has remained unknown. Aim of the study : This study aims to investigate the effects of SCLs on the hepatotoxicity and metabolic activation of DIC and elucidate the underlying hepatoprotective mechanism from the perspective of the inhibition of CYP3A-mediated metabolic activation. Material and methods The protective effect of SCLs against DIC-induced hepatotoxicity was evaluated by biochemical analysis and liver histological observation. The effect of SCLs on the in vitro metabolic activation of DIC was assessed by detecting the level of DIC-N-acetylcysteine (NAC) conjugates in mouse liver microsomal incubations. The effect of SCLs on the metabolic activation in vivo of DIC was examined by monitoring the toxicokinetic behaviors of DIC, DIC-induced hepatic GSH depletion, the cumulative urine excretion of DIC, the levels of DIC-NAC conjugates in urine and liver of mice, and the formation of DIC-derived cysteine-protein adducts. Results Our findings indicated that SCLs protected against DIC-induced hepatotoxicity in a dose-dependent manner. SCLs exhibited dose-dependent inhibitory effect on the formation of DIC-NAC conjugates in liver microsomal incubations, indicating SCLs inhibited the metabolic activation of DIC in vitro . SCLs increased C max and AUC s of DIC in the blood and liver of mice, leading to the enhancive accumulation of DIC in the circulation. Pretreatment with SCLs relieved hepatic GSH depletion induced by DIC, promoted the urinary excretion of DIC, inhibited the formation of reactive metabolite of DIC in urine and liver of mice, and reduced the production of DIC-derived cysteine-protein adducts, suggesting that SCLs influenced absorption, distribution, metabolism, and excretion (ADME) of DIC by suppressing the metabolic activation of DIC in vivo . Conclusions The study demonstrated the protective effect of SCLs against hepatotoxicity induced by DIC was related to the inhibition of CYP3A-mediated metabolic activation of DIC. Therefore, the study demonstrated that SCLs may serve as the candidate drugs for the intoxication of DIC. Moreover, our findings may interpret the protective mechanism of SC against CD-induced liver injury.
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Acta Biomaterialia
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2025
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IF 9.6
Zhihao Zhao,Ke Ling,Jun Yan,Zhexiang Wang,Chuntao Chen,Dongping Sun,Jian Liu
Calcium ions (Ca²⁺) and reactive oxygen species (ROS) play pivotal roles in cellular signaling and the regulation of diverse biological processes. Complex and dynamic interactions between Ca²⁺ and ROS signaling pathways are often exploited by tumor cells to resist therapeutic interventions. In this study, we present a strategy of cancer treatment based on the reciprocally reinforcing interplay between ROS burst and mitochondrial calcium overload. The major components of our nano carriers integrate CaCO 3 nanoparticles loaded with glucose oxidase (GOx), and copper peroxide nanodots (CPDs) in a DSPE-S-S-PEG-modified liposomal format (abbr. GCCL,). This hybrid nanosystem is designed to facilitate controlled and accelerated release of Ca²⁺ and ROS, thereby establishing dual positive feedback loops that amplify both mitochondrial calcium accumulation and oxidative stress. By harnessing this synergistic cycle, our platform enhances the efficacy of chemodynamic therapy and calcium-induced mitochondrial damage, offering a promising strategy for translational cancer treatment. Statement of significance Here we report a strategy of antitumor therapeutic by designing a dual positive feedback loop of pH-driven self-accelerated Ca 2+ and H 2 O 2 release, thus reciprocally promoting ROS production and mitochondrial calcium overload for tumor eradication. After cellular uptake of GCCL, releasing of the cargos inside the liposomes can introduce a cascade of chemical reactions and biochemical cues, leading to calcium overload and ROS burst. These two major effects are mutually linked with each other, which is utilized by our GCCL design to fuel the positive feedback loops for tumor cell apoptosis in vitro and effective cancer ablation in vivo . Our nano therapy stands out with improved tumor suppression, with a lower dosage of copper element in the treatments of 4T1 xenograft tumor-bearing BALB/c mice model.
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JOURNAL OF DRUG DELIVERY SCIENCE AND TECHNOLOGY
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2025
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IF 4.9
Yuling Wang,Jun Deng,Xi Wang,Dan Luo,Shujing Ren,Xueping Guo,Dan Chen,Rui Liu,Siyuan Chen,Wei Liu
Adjuvant skincare formulations possessing anti-inflammatory and antibacterial properties can alleviate treatment-related side effects and enhance patient adherence in acne management. Paeonol (PAE), totarol (TOT), and ergothioneine (ERG) demonstrate promising anti-acne activity. However, their clinical translation is hindered by poor solubility, limited stability, and insufficient skin permeation. To address these limitations, we co-encapsulated PAE, TOT, and ERG into hyaluronic acid (HA)-modified nanoliposomes (NLPs). Compared to the NLPs modified with HA with high molecular weights, those formulated with miniHA (3-10 kD a ) exhibited superior skin penetration capability and cellular uptake efficiency. The miniHA modified NLPs co-encapsulated PAE, TOT, and ERG (PTE-NLPs) exhibited excellent biocompatibility in both in vitro cytotoxicity assay and chicken embryo chorionic allantoic membrane irritation assays. Compared to free functional ingredients, PTE-NLPs demonstrated significantly enhanced anti-inflammatory and antibacterial efficacy in cellular assays. Furthermore, in 3D skin models, PTE-NLPs suppressed Transient Receptor Potential Vanilloid 1 (TRPV1) expression, indicating a potential mechanism for attenuating neuronal hyperreactivity. The anti-inflammatory activity was subsequently validated in vivo. These findings collectively demonstrate that miniHA-modified NLPs provide a safe and efficient platform for co-delivering synergistic anti-acne actives, highlighting their strong potential as an adjuvant therapy for acne management.
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BIOMACROMOLECULES
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2025
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IF 5.4
Hao Liao,Yuyue Xiong,Jinghang Li,Dongdong Wang,Jinglong Yang,Dong Xie,Lesan Yan
Sonodynamic therapy (SDT) emerges as a promising noninvasive modality for deep tumors but is hindered by the hypoxic tumor microenvironment and glutathione (GSH)-mediated reactive oxygen species (ROS) scavenging. Herein, we report a GSH-responsive nanoplatform fabricated from an mPEG-b-PMNC copolymer, enabling spatiotemporal codelivery of nitric oxide (NO) donors and the sonosensitizer chlorin e6 (Ce6) via self-assembled micelles. Upon exposure to elevated intracellular GSH, the micelles disintegrate to release NO and Ce6 selectively. The released NO attenuates hypoxia through downregulation of hypoxia-inducible factor-1α (HIF-1α) and synergizes with ultrasound-triggered Ce6-generated ROS to yield highly cytotoxic peroxynitrite (ONOO–). This integrated synergy substantially potentiates SDT outcomes, as evidenced by an IC50 of 1.935 μg/mL for mPEG-b-PMNC@Ce6 micelles under ultrasound, outperforming free Ce6 (4.808 μg/mL) and control mPEG-b-PCL@Ce6 (2.736 μg/mL). This polycarbonate-based strategy provides a novel approach for synergistic gas-sonosensitizer delivery, overcoming key limitations of conventional SDT for treating hypoxic tumors.
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Journal for ImmunoTherapy of Cancer
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2025
·Vol. 13
·期 9
·e011893
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IF 10.6
Zhengning Yang,Zhongxuan Meng,Shangyuan Liu,Yuxin Chen,Xuhong Gan,Zi‑Mei Zhang,Xiaoshan Luo,Jiahong Yan,Huijin Chen,Danqing Huang,Lihong Huang,Xiaomin Zeng,Wenyu Ma,Jun Liu,Linlin Wang,Haotian Huang,Xinyi Yang,Mei Hu,Lin Chen,Hongli Du,Qibin Leng,Li Qiu,Xiaoling Wang
Background Nonsense-mediated messenger RNA decay (NMD) is a highly conserved surveillance system that degrades mRNAs with premature termination codons (PTCs), and regulates the mRNA quantity. Cancer cells hijack NMD to compensate for the imbalanced DNA levels and modulate their antigenicity. We identified the LTO1/YAE1 complex as NMD factors regulating ribosome biogenesis. Our study aimed to investigate their roles in modulating NMD and major histocompatibility complex class I (MHC-I) antigen presentation, which is vital for cancer immunotherapy. Methods Clustered regularly interspaced short palindromic repeats (CRISPR) and the CRISPR-associated protein 9 (Cas9)-mediated gene knockouts, overexpression, and mutational analysis were used to explore the role of LTO1 and YAE1 in NMD and MHC-I expression across various tumor cell lines, assayed by fluorescent reporter-based assays, fluorescence-activated cell sorting analysis, reverse transcription-quantitative PCR, mRNA decay assay, and polysome profiling. Transcriptomic analyses were used to assess the expression of LTO1/YAE1 and their correlation with MHC-I molecules in human cancers. T cell receptor (TCR)-T cells and tumor cells coculture were employed to monitor the effect of LTO1 and YAE1 loss on T cell activation. Iron chelators were further tested as NMD inhibitors to enhance cancer immunotherapy using in vitro coculture assay and a mouse tumor model for immune checkpoint blockade (ICB) therapy. Results We demonstrate that deficiency in LTO1, YAE1, or their downstream target ABCE1 impairs NMD, causes the overexpression of key regulators of MHC-I, including NLR family CARD domain containing 5 (NLRC5), interferon regulatory factor 1 (IRF1), and nuclear factor-kappa B (NFκB), which results in enhanced T cell activation and tumor cell killing in TCR-T models. Transcriptomic analyses reveal that the LTO1/YAE1 complex is frequently overexpressed in human cancers, where it negatively regulates MHC-I. Moreover, low doses of iron chelators inhibit NMD and enhance MHC-I expression, leading to improved recognition and activation of CD8 + T cells, thereby promoting antigen-specific killing and increasing the efficacy of TCR-T and ICB therapy. Conclusions Collectively, our findings establish novel roles for the LTO1/YAE1 complex in regulating MHC-I expression via NMD. As MHC-I is crucial for antigen presentation and T cell activation, these results reveal a previously unappreciated link between NMD and tumor immunogenicity, with potential implications for cancer immunotherapies.
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SPECTROCHIMICA ACTA PART A-MOLECULAR AND BIOMOLECULAR SPECTROSCOPY
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2025
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IF 4.6
Yuting Liu,Yi Zhou,Dawei Yin,Zixu Zhang,Ruilin Zheng,Jiabao Chen,Chi Dang,Yawen Yang,Ziqi Gao
Arginine (Arg) and ascorbic acid (AA) are biologically essential compounds that play a key role in human development and disease resistance. Consequently, it is imperative to detect these molecules expeditiously and efficiently. In the present study, 5-phenyl-1,3,4-thiadizole-2-amine and 2-((5-phenyl-1,3,4-thiadizole-2-yl)imino) methyl) phenol (henceforth designated Probe L) were synthesised catalytically by low eutectic solvent. Subsequently, probe L was utilised as a fluorescence sensor for the detection of Arg and AA. Specifically, the solution of probe L undergoes a colour change from yellow to orange-red in the presence of Arg, and fades when interacting with AA. However, under the fluorescence spectrum, the fluorescence intensity of the probe L solution significantly increases after the addition of Arg and AA. The experiments on the influence of time on the recognition of probe L demonstrated that Arg and AA could be recognised at different times. In the experiments on the influence of pH on the recognition of probe L, it was shown that Arg and AA could be effectively detected within the pH range of 4–12. The curve analysis of Job indicates that 2:3 (probe L: Arg) and 3:2 (probe L: AA) are combined with the stoichiometric ratio. The binding constants of Arg and AA were determined to be 7.43 × 10 3 M −1 and 14.11 × 10 4 M −1 , respectively. The detection limits (LOD) were calculated to be 1.05 × 10 −5 M and 9.37 × 10 −6 M, respectively. In conclusion, this work presents the synthesis of probe L, promoted by DES, and establishes its practicality as a highly selective and stable optical sensor for Arg and AA, which is of great significance for biomedical and environmental monitoring.
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CELLULAR SIGNALLING
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2025
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IF 3.7
YaoNan Han,XingTong Wang,DeShui Yu
Spinal cord injury (SCI) is a serious central nervous system disease. Ferroptosis is one of the major causes of spinal cord neurological loss, and targeting ferroptosis is a promising therapeutic strategy. Roflumilast has shown promising applications in the treatment of neurological diseases due to its potent anti-inflammatory and anti-oxidative stress effects. This study aimed to investigate whether roflumilast could inhibit neuronal ferroptosis to improve motor function after SCI in rats. In vitro experiments, we found that roflumilast significantly increased cell survival in an in vitro ferroptosis model, improved mitochondrial function, reduced intracellular iron, reactive oxygen species (ROS), and lipid peroxides accumulation as well as the expression of the pro-ferroptosis proteins, long-chain acyl-coenzyme A synthase 4 (ACSL4), and prostaglandin-endoperoxide synthase 2 (PTGS2), and increased the expression of ferroptosis-inhibitory protein glutathione peroxidase 4 (GPX4), and ferritin heavy chain 1 (FTH1) expression. Mechanistically, these protective effects were achieved by activating AMP-dependent protein kinase (AMPK)/nuclear factor E2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) signaling and were attenuated when AMPK signaling was blocked. In vivo experiments, roflumilast attenuated spinal cord tissue damage, increased the number of motor neuron survivors, and improved motor function after SCI in rats. Overall, activation of AMPK/Nrf2/HO-1 signaling by roflumilast attenuated neuronal ferroptosis and improved motor function after SCI in rats.
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FOOD CHEMISTRY
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2024
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IF 8.5
Rui Hu,Da-Wen Sun,You Tian,Liang Xu,Libin Sun
Natural deep eutectic solvents (NADESs) showing higher cryoprotective effects are attracting concerns, because during the storage, system browning always occurs in aldose/amino acid-based NADESs, which generated brown substances remarkably weaken the cryoprotective effects. In this study, proline/glucose-based (PG) and proline/sorbitol-based (PS) NADESs were prepared, of which storage stability, browning profile, brown substance, and cryoprotective effects were investigated. Results showed that PG at molar ratios of 1:1, 2:1, and 3:1, as well as PS at 1:1, and 2:1 can form NADESs, among which only the PG-based ones could get browning after storage. The predominant brown substance was identified as 1-deoxy-1-L-proline- d -fructose (C 11 H 19 O 7 N, 278 m / z ), which was subsequently verified to show cytotoxicity and decrease Saccharomyces cerevisiae cells viability after cryopreservation, suggesting that the brown substance could take a negative effect on cryopreservation. This study may help to attract more concerns to the storage and cryopreservation stabilities of the NADESs in food-related applications.
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JOURNAL OF MOLECULAR LIQUIDS
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2024
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IF 5.3
Xiuxiu Huang,Wenqing Dong,Xiao Luo,Lu Xu,Dongzhi Yang,Yinan Wang
Presently, a significant number of pharmaceutical drugs exhibit poor solubility in water and fall within categories II and IV of the biopharmaceutical classification system. This predicament has prompted the exploration for novel solvents or excipients to enhance the solubility and bioavailability of the active compounds in aqueous environments. Low-melting mixture solvents (LoMMSs) have gained recognition as potential solvents for active pharmaceutical ingredients to improve therapeutic efficacy and delivery. This study focuses on the preparation of a eutectic mixture composed of betaine, malic acid, proline, and water (BE-MA-PR-WA) to enhance the formulation options for tolvaptan, an FDA-approved medication used to treat acute congestive heart failure, which has limited solubility in aqueous solutions. The findings presented in this article represent the first reported results on the administration of LoMMS-solubilized tolvaptan. Furthermore, an examination of the solubility and bioavailability of tolvaptan utilizing this mixture was conducted, alongside an assessment of its toxicity. The solubility of tolvaptan in BE-MA-PR-WA (1:1:1:7) increased 483 times compared to solubility in water. Toxicity studies indicated that the LoMMS formulation BE-MA-PR-WA was safe for oral administration. The oral bioavailability of tolvaptan was significantly increased by 1.9-fold in the BE-MA-PR-WA than that in water. In addition, the 5-hour urine volume of rats indicated that BE-MA-PR-WA also enhanced the diuretic effects of tolvaptan in rats. The findings suggest that BE-MA-PR-WA enhance the solubility and bioavailability of tolvaptan, and are deemed non-toxic. Consequently, LoMMS may be deemed promising solubilizing agents, potentially facilitating the absorption of poorly bioavailable medications.
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ACS Applied Materials & Interfaces
·
2026
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IF 7.8
Yanjiao Ding,Daogong Zhang,Jinye Li,Lei Xu,Haibo Wang
Hearing loss is a widespread global disability, commonly treated using dexamethasone (Dex). However, targeted delivery of Dex to the inner ear remains a significant challenge due to the blood-perilymph barrier (BLB), which limits its therapeutic efficacy. In this study, we aimed to develop a strategy to enhance Dex delivery to the inner ear and improve its treatment outcome by the noninvasive intranasal approach. Also, poly(ethylene glycol) (PEG)─liposomal nanoparticles were used as a drug carrier and loaded with Dex (PLN-Dex). For intranasal delivery, a thermosensitive hydrogel was fabricated by methylcellulose. The PLN-Dex nanocomposite was incorporated into the hydrogel to obtain PLN-Dex@Gel. PLN-Dex@Gel could be administrated intranasally and their transport pathway from olfactory mucosa to the cochlea was explored. In vivo magnetic resonance and fluorescence microscopy showed that drugs delivery into the olfactory mucosa reached the inner ear by dispersive transport via the brain. Interestingly, we found that beyond the cochlear duct, the cochlear axis may serve as a crucial pathway for the transportation of drugs from the brain to the inner ear. In guinea pig models of LPS-induced and noise-induced hearing loss, intranasal PLN-Dex@Gel treatment significantly reduced auditory brainstem response thresholds, ameliorated cochlear blood flow, and protected hair cells and synapses. Our findings underscore the potential of intranasal Dex delivery as a noninvasive and effective strategy for treating hearing loss. The target drug delivery to the inner ear, combined with the enhanced formulation of Dex-loaded liposomal hydrogels, offers promising prospects for future research in the treatment of inner ear disorders, with potential for clinical translation. This study expands the understanding of delivery route from nose to inner ear and suggests a method for utilizing intranasal administration as a strategy for treating hearing loss.
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