Materials Today Bio
·
2025
·
IF 10.2
Li Chen,Mengyi Zhan,Li Zhang,Zhuohang Xiong,Chi Zhang,Xuanxuan Zhang,Zhengyang Yang,Lixin Ma,Yibin Cheng,Huanhuan Chen
Diabetic foot ulcers (DFU) are a refractory form of chronic wound characterized by persistent infection and impaired healing. Distinct from other hard-to-treat infections, DFU are aggravated by neuropathy, vasculopathy, and immune dysfunction, which hinder microbial clearance and tissue repair. Their management is further challenged by antibiotic overuse, rising resistance, and the limited efficacy of current therapies. To address these issues, we developed the dual-layer microneedles (IGR MNs) platform that integrated a nitroreductase (NTR)-responsive fluorescent probe for real-time infection monitoring with near-infrared (NIR)-triggered photothermal therapy. The microneedle tips were loaded with liposome-encapsulated antibacterial and immunomodulatory agents for controlled, on-demand release, while the base layer incorporated the infection-responsive probe for spatially precise detection. The IGR MNs overcame the limitations of conventional single-layer microneedles by simultaneously enabling diagnosis and therapy. In vivo evaluations in diabetic wound models demonstrated efficient infection detection, reduced local inflammation, enhanced collagen deposition and neovascularization, and significantly accelerated wound closure. This antibiotic-free strategy enables targeted biofilm disruption and immunomodulation, providing a clinically translatable approach for managing refractory, infected diabetic wounds.
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BIOCHEMICAL PHARMACOLOGY
·
2026
·
IF 5.6
Shaoqin Cen,Zhenxing Hou,Yuan Zhang,Nan Wang,Zihe Zhao,Ao Li,Guoqiang Wan,Tianhong Zhang,Xia Gao
Cisplatin, a widely used antitumor agent, is limited in clinical application due to its ototoxicity. This study investigates the protective effects of obacunone, an active compound from Phellodendron bark, against cisplatin-induced hearing loss. Obacunone significantly improved the survival of cisplatin-treated House Ear Institute-Organ of Corti 1 (HEI-OC1) cells, preserved the cochlear explant, and enhanced auditory function in mice upon cisplatin treatment. Mechanistically, obacunone inhibited cisplatin-induced apoptosis by activating autophagy. Transcriptome profiling revealed that the expression of corticotropin-releasing hormone-binding protein (CRHBP) was increased in the cisplatin and obacunone co-treated group compared to the cisplatin-only group. Overexpression of CRHBP significantly enhanced autophagy and inhibited apoptosis, mirroring the effects of obacunone. Our findings demonstrate that obacunone promotes autophagy by upregulating CRHBP, thereby reducing cisplatin-induced hair cell apoptosis. This study provides a novel therapeutic strategy using the natural product obacunone for preventing cisplatin-induced hearing loss and highlights the potential of CRHBP as a target for otoprotective interventions.
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ACS Applied Materials & Interfaces
·
2026
·
IF 8.2
Yanfang Cheng,Yebi Qin,Wenhui Zhu,Weirong Yao,Hang Zou,Bairong He,Lizhi Yan,Lei Zheng
Photoimmunotherapy is limited by inadequate dendritic cells (DCs) antigen presentation and cytotoxic T lymphocytes (CTLs) dysfunction. Innate immune activation can potentiate DCs maturation and restore CTLs function, augmenting photoimmunotherapy efficiency. Herein, we developed a biomimetic gold nanorod-core/mesoporous manganese dioxide (MnO2)-shell nanoagonist (denoted as m@AMCR) loaded with chlorin e6 and rapamycin (Rap) to synergize photodynamic therapy (PDT)/photothermal therapy (PTT) with cGAS-STING pathway activation for enhanced tumor treatment. Tumor cell membrane biomimetic camouflage conferred m@AMCR with self-targeting ability toward homologous cancer cells. Subsequently, intratumoral glutathione triggered MnO2 decomposition to release Rap. Rap augmented PDT/PTT by suppressing hypoxia-inducible factor-1α and heat shock protein 70 expression while downregulating matrix metalloproteinase-2 to inhibit tumor metastasis. Concurrently, the released Mn2+ activated the cGAS-STING pathway, promoting DCs maturation and CTLs infiltration. Finally, the combination of photoimmunotherapy-induced immunogenic cell death and cGAS-STING activation potently suppressed primary tumor growth and lung metastases. Overall, this biomimetic self-augmenting nanoagonist established a paradigm for tumor immunotherapy by integrating photoimmunotherapy with cGAS-STING-mediated innate immune activation.
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Journal of Pharmaceutical Analysis
·
2026
·
IF 8.9
Xiaohui Hu,Yingxia Tian,Qianping Chen,Yanan Guo,Pengfei Ji,Yixiao Tian,Shuangxi Qian,Guolin Chai,Fangdi Hu,Rong Shen,Degui Wang
Senescence is widely recognized as a key driving factor in the onset and progression of many chronic diseases. Although numerous animal studies have demonstrated that various drugs can delay senescence, their clinical application is severely limited due to significant toxic side effects. As a result, developing safer, natural anti-senescence agents has become an urgent priority. In this study, we identified mitochondrial dysfunction as a critical contributor to cellular senescence. In addition, we identified Shenrong Guben Huanshao Pill (SRW) as an effective agent that alleviates mitochondrial dysfunction and consequently delays cellular senescence by regulating mitochondrial metabolism. Mechanistically, SRW enhances mitochondrial function by upregulating the expression of NADH:ubiquinone oxidoreductase subunit V2 (NDUFV2), a core component of mitochondrial respiratory chain complex I. Simultaneously, SRW reduces lactate-induced mitochondrial dysfunction by regulating the glycolytic enzyme lactate dehydrogenase B (LDHB), thereby decreasing lactate accumulation. Collectively, our findings indicate that SRW alleviates cellular senescence by coordinately regulating NDUFV2 expression and LDHB-mediated lactate metabolism to improve mitochondrial function. In addition, several flavonoids in SRW were identified to possess potential anti-senescence activity. Molecular docking and cellular experiments confirmed that myricetin, luteolin, and gamma-mangostin effectively alleviate cellular senescence.
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JOURNAL OF ETHNOPHARMACOLOGY
·
2026
·
IF 6.8
Yangdi Chen,Fanggang Bi,Zhong Hua,Jianshe Chen,Chenxi Li,Mingsan Miao,Zixue Sun
Ethnopharmacological relevance Yishen Tongluo Formula (YSTLF) is a modern compound formula derived from the traditional Chinese medicine (TCM) theory of “kidney deficiency and collateral obstruction”, and consists of seven Chinese medicinal herbs. It has been used clinically to treat oligoasthenozoospermia (OAS) for more than two decades, with proven efficacy and a favorable safety profile. However, its precise molecular mechanism has yet to be fully elucidated. Aim of the study The aim was to investigate the therapeutic efficacy and the underlying mechanism of YSTLF in treating OAS associated with the kidney deficiency and collateral obstruction pattern. Materials and methods The chemical constituents of YSTLF were identified by UHPLC-Q-Orbitrap HRMS, and molecular docking was performed between the ten most abundant compounds and AMPK/mTOR. Rat OAS models were established by combined GTW, adrenaline, and ice-water immersion. Pharmacodynamic effects were evaluated through general status, reproductive organ weights, sperm quality, coagulation parameters, and serum sex hormones. Testicular histopathology, ultrastructure, and autolysosomes were examined by HE staining and TEM. Apoptosis was detected by TUNEL staining, and autophagy/apoptosis-related protein expression by IHC. Integrated metabolomics and proteomics with KEGG enrichment were conducted. In GTW-injured GC-1spg cells treated with Compound C or rapamycin, CCK-8 assay assessed viability, flow cytometry evaluated apoptosis, immunofluorescence examined LC3B/cleaved caspase-3 expression and colocalization, and Western blotting/RT-qPCR validated AMPK/mTOR pathway key molecules. Results Among 307 identified compounds (mostly flavonoids), YSTLF improved general status, organ weights, and sperm quality in model rats. The ten most abundant compounds showed binding energies < −7.0 kcal/mol for AMPK/mTOR. Sperm concentration and motility increased dose-dependently. PT and TT were prolonged, FIB decreased, and FSH, LH, T, PRL, and Inh-B were restored. H&E, TEM, and TUNEL revealed alleviated testicular pathology, improved ultrastructure, reduced autolysosomes, and decreased apoptosis. IHC showed downregulated Beclin1 and Bax, and upregulated p62 and Bcl-2. Multi-omics revealed co-enrichment of differential proteins/metabolites in autophagy and mTOR pathways. Western blot/RT-qPCR validated downregulated p-AMPK/AMPK, AMPK mRNA, LC3II, Beclin1, Bax, cleaved caspase-3, and cleaved caspase-3/caspase-3 ratio, alongside upregulated p-mTOR/mTOR, mTOR mRNA, p62, and Bcl-2. In vitro , GTW reduced viability concentration-/time-dependently (stable model: 10%/24 h); YSTLF reversed this (optimal: 15%/24 h), restored viability, reduced apoptosis, and decreased LC3B/cleaved caspase-3 fluorescence/colocalization, while downregulating p-AMPK, LC3II, Bax and upregulating p-mTOR, p62, Bcl-2. Compound C alone mimicked YSTLF's effects without additivity, whereas rapamycin aggravated GTW-induced viability loss, apoptosis, and autophagy/apoptosis co-activation. Conclusion YSTLF improved spermatogenic function in rats with OAS (kidney deficiency and collateral obstruction pattern). Its mechanism of action involves regulation of the AMPK/mTOR signaling pathway and restoration of the balance between autophagy and apoptosis.
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JOURNAL OF PHARMACEUTICAL SCIENCES
·
2026
·
IF 3.9
Xinyi He,Xu Jiang,Huazhong Lin,Kexin Zhang,Xuewen Yu,Jiaxin Bi,Lu Zhang,Yingying Liang,Lijuan Chen,Mumin Shao
Breast malignant phyllodes tumor (MPT) is a fibroepithelial neoplasm characterized by high recurrence rates. Currently, no effective therapeutic agents are available, and surgery remains the mainstay of treatment for MPT. Niclosamide ethanolamine (NEN), an antiparasitic agent, has recently demonstrated broad-spectrum antitumor activity against various solid malignancies. This study aimed to evaluate the antitumor efficacy of NEN against MPT and elucidate the underlying molecular mechanisms. The effects of NEN on MPT cell proliferation and migration were assessed using CCK-8, wound healing, and Transwell migration assays. Ultrastructural alterations following NEN treatment were examined by transmission electron microscopy. Bioinformatics analyses, quantitative real-time PCR (qPCR), Western blotting, and immunofluorescence staining were employed to investigate the molecular mechanisms underlying NEN-mediated modulation of autophagy and lysosomal function. NEN significantly inhibited MPT cell proliferation and migration. Transmission electron microscopy revealed the accumulation of numerous autolysosomal structures in NEN-treated cells. Mechanistically, NEN suppressed mTOR phosphorylation, promoted nuclear translocation of transcription factor EB (TFEB), and induced lysosomal biogenesis. However, lysosomal function was compromised, as evidenced by elevated luminal pH, impaired cathepsin D maturation, and lysosomal membrane permeabilization, ultimately resulting in autophagic flux blockade at the degradation stage. Furthermore, lysosomal cathepsin leakage activated the mitochondrial apoptotic pathway, culminating in caspase-3-dependent apoptosis. NEN effectively kills MPT cells by inducing "lysosomal biogenesis–function uncoupling." This study is the first to reveal a novel anti-MPT mechanism that targets the mTOR-TFEB-lysosome axis and disrupts lysosomal homeostasis, providing a potential drug candidate for the treatment of MPT.
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Biology-Basel
·
2026
·Vol. 15
·期 14
·1124
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IF 4.3
Zhe Wang,Zhenguo Liu,Ge Zhang,Hongfang Wang,Xuepeng Chi,Ying Wang,Baohua Xu
Simple SummaryHoneybees are essential for crop pollination and ecological balance, yet their health is increasingly compromised by environmental stressors such as heavy metals and pesticides. These stressors induce oxidative stress, a cellular imbalance that damages tissues and impairs bee survival. This study investigated whether leucine, a common amino acid in pollen, can enhance the natural antioxidant defenses of honeybees. Our experiments showed that supplementing bees with leucine significantly increased their capacity to counteract oxidative stress, reduced cellular damage, and improved survival under stress conditions. Further analysis revealed that leucine acts by activatingsestrin, which serves as a key regulator of antioxidant responses. Notably, the protective effect of leucine did not primarily depend on the previously recognized TOR pathway. Whensestrinwas experimentally silenced, bees became highly susceptible to stress and developed gut damage, confirming its essential role. Importantly, leucine partially restored resilience even whensestrinwas absent, suggesting additional protective mechanisms. These findings demonstrated that dietary leucine supplementation offers a feasible nutritional strategy to strengthen honeybee health and stress resistance.Environmental stressors such as heavy metals and pesticides pose significant threats to honeybee health by inducing oxidative stress. Enhancing nutritional supply has emerged as a potential strategy for honeybees to enhance stress resistance. However, the underlying molecular mechanisms remain poorly understood. This study investigated the role of leucine (Leu) in regulating antioxidant responses in honeybees (Apis melliferaL.), with a focus on the involvement ofsestrinand the Target of Rapamycin (TOR) signaling pathway. The results showed that Leu supplementation activated the TOR signaling pathway and upregulatedsestrinexpression, leading to enhanced antioxidant capacity and reduced reactive oxygen species (ROS) levels. Silencingsestrindisrupted antioxidant homeostasis, increased stress susceptibility, and caused midgut damage, confirming its essential role in oxidative stress resistance. Notably, inhibition of TOR did not prohibit the protective effects of Leu, suggesting thatsestrin, rather than TOR, serves as a key mediator. Furthermore, Leu fine-tuned antioxidant responses under different stress conditions throughsestrin. Overall, this study demonstrates that Leu andsestrinplay a central role in maintaining antioxidant homeostasis and provide a theoretical basis for nutritional strategies to improve honeybee health and stress resilience.
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CHEMICO-BIOLOGICAL INTERACTIONS
·
2026
·
IF 5.2
Xuguang Mi,Jianhua Fu,Lei Liu,Lingshan Wang,Shiling Chen,Mengxue Wu,Chunxue Niu,Yan Wang,Lixin Cao,Lin Wang,Ling Deng,Xiaodan Lu,Xiuying Lin
Bisphenol S (BPS), as an environmental pollutant, poses a potential threat to reproductive system health. In this study, we added BPS to primary human endometrial stromal cells (hEnSCs) to detect the acute injury it causes and its long-term effects on the endometrium. The results showed that short-term treatment with BPS can significantly promote oxidative stress and apoptosis of hEnSCs, while long-term treatment can cause excessive senescence of hEnSCs and reduced receptivity. In addition, the culture medium of senescent cells treated with BPS can induce senescence of young hEnSCs. Studies have reported that secondary senescence can be alleviated, and we utilised the autophagy activator Rapa to treat secondary senescence of hEnSCs. We found that Rapa can inhibit the senescence of young cells induced by the culture medium of senescent cells treated with BPS. Therefore, autophagy activated by Rapa can attenuate the secondary senescence of hEnSCs induced by BPS-treated culture medium.
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ANALYTICA CHIMICA ACTA
·
2026
·
IF 6.1
Jiaqin Chen,Guangxu Hu,Jie Song,Lin Huang,Xumin Zhang
Deciphering protein-ligand binding events is essential for unraveling biological pathways and advancing drug development. The recently developed peptide-centric local stability assay (PELSA) has demonstrated superior performance compared to other mainstream approaches. However, the conventional PELSA approach relies on filter-based peptide recovery, which results in prolonged processing times and relatively low yields, particularly when operating with limited starting material. To address these limitations, we present an optimized PELSA approach termed SP3-PELSA, which leverages the simple and efficient peptide recovery of the Single-Pot, Solid-Phase-enhanced Sample Preparation (SP3) method. Through a systematic evaluation of protein precipitation and trypsin inactivation conditions, we identified 1% formic acid and 80% acetonitrile as the optimal parameters. A comparative analysis of SP3-PELSA with conventional PELSA revealed that SP3-PELSA reduces the processing time by fivefold and significantly increases the peptide recovery rate, especially for hydrophobic peptides. Consequently, SP3-PELSA outperformed other mainstream approaches in the identification of established drug targets. Owing to its high recovery efficiency and potential for automation, SP3-PELSA holds great promise for large-scale drug target discovery, especially in the context of scarce clinical samples. Furthermore, its exceptional recovery of hydrophobic peptides positions this approach as a powerful tool for analyzing highly hydrophobic proteins in drug target screening.
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Nature Communications
·
2026
·
IF 18.1
Zhao Lei,Gao Zhongqiang,Yuan Ze,Yang Xiaodie,Li Duxin,Ren Qian,Yu Yunli,Pan Jie,Zheng Yiran,Zhang Xinyun
Inducing antigen-specific regulatory T (T reg ) cells is a promising strategy for treating autoimmune diseases (AID). Here, we present dendritic cells-CD4⁺ T cells (DC-CD4) bispecific tolerogenic nanovesicles (NV) co-loaded with an antigenic peptide and rapamycin. We show that these NVs bring DCs and CD4⁺ T cells into close spatial proximity through CTLA4-CD80/86 and anti-CD4 (aCD4)-CD4 interactions, thereby promoting antigen-specific T reg cell generation. In a collagen-induced arthritis mouse model, the bispecific NVs display enhanced lymph node (LN) tropism and increase antigen-specific T reg cells in LNs and spleen, when administered in both therapeutic and prophylactic settings, resulting in robust efficacy against CIA. Furthermore, arthritogenic cell transfer and adoptive transfer of T reg cells into T reg -ablated mice confirm the pivotal role of bispecific NV-induced antigen-specific T reg cells in mediating the anti-inflammatory efficacy. Collectively, our data support DC-CD4 bispecific tolerogenic NVs as a platform to induce antigen-specific T reg cells for precise immune tolerance in AIDs.
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CARBOHYDRATE POLYMERS
·
2026
·
IF 13.2
Zheng Jia,Yadong Gao,Husile Han,Chaonan Wang,Jiaqing Wang,Junjie Guo,Shuhe Zhang,Yifan Li,Junwei Ge,Fang Wang,Mingchun Gao
Subunit vaccines represent a leading platform in modern vaccinology due to their defined antigenicity and favorable safety profiles. However, their efficacy requires advanced adjuvants to overcome limited immunogenicity. While plant-derived polysaccharides are widely recognized for their immunostimulatory properties, their capacity to induce trained immunity remains largely unexplored. This study demonstrates, for the first time, that a Konjac glucomannan (KGM)-based hydrogel can induce trained immunity. Specifically, we developed an injectable hydrogel composed of KGM and carboxymethyl cellulose (CMC) that confers protection against Staphylococcus aureus infection via trained immunity. Mechanistically, peritoneal macrophages from KGM/CMC-trained mice exhibited a metabolic shift toward oxidative phosphorylation, accompanied by the significant accumulation of key metabolites such as succinate and palmitate. This KGM/CMC-induced trained immunity provided rapid protection within 3 days and broad-spectrum defense against Gram-positive bacteria. Furthermore, the hydrogel synergized with specific antigens and aluminum adjuvants to significantly potentiate single-dose subunit vaccines, increasing the survival rate of challenged mice to 50%. These findings identify the KGM/CMC as a promising delivery vehicle for vaccines leveraging trained immunity and establish a proof-of-concept for adapting plant-derived bioactive polysaccharides into next-generation immunomodulatory tools.
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mBio
·
2025
·
IF 4.7
Bolin Fan,Biyun Qin,Mingjun Li,Yuchao Zhu,Fuqiang Fan,Hao Xu,Lilan Xue,Yukun Chen,Ming Pan,Bang Shen
Toxoplasma gondii is an obligate intracellular pathogen that infects humans and many animals. It harbors unique secretory organelles to facilitate its parasitic lifestyle, including dense granules that secrete diverse proteins to different destinations. Yet the biological functions of these secretory proteins are mostly unknown. Here, we examined the roles of GRA1, the first dense granule protein discovered. GRA1 is secreted to the parasitophorous vacuole (PV), and its conditional depletion led to growth arrest of tachyzoites, suggesting a crucial role of GRA1 for parasite propagation during acute infection. Furthermore, GRA1 inactivation resulted in severe metabolic defects, including reduced glycolysis and tricarboxylic acid cycle activities and a drop in cellular ATP levels. GRA1 depletion also disrupted the integrity of the mitochondrion and apicoplasts. Mechanistically, disruption of GRA1 altered the structures of membranous tubules in the PV, called the intravacuolar network (IVN), which are thought to mediate the transport of molecules in and out of the parasites. Consistently, GRA1 inactivation impaired the secretion of various GRA proteins to the PV membrane (PVM) or host cells, including GRA17 that is involved in nutrient uptake from host cells. In agreement with the mislocalization of GRA proteins, mutants lacking GRA1 had a strong defect in absorbing nutrients like glucose and pantothenate from host cells. Consequently, the parasites displayed slower growth and a higher tendency to differentiate into bradyzoites. Together, these results suggest that GRA1 plays a vital role in maintaining the structural integrity of the IVN, thus contributing to the scavenging of host nutrients.
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