作者机构：
[Xie, Zhizhong; Zou, Wei; Wang, Jiaying] Univ South China, Hunan Prov Maternal & Child Hlth Care Hosp, Sch Pharm, Hengyang 421001, Peoples R China.;[Gao, Yinhuang; Liu, Menghua; Miao, Zhishuo] Southern Med Univ, Sch Pharmaceut Sci, Key Lab Drug Metab Res & Evaluat State Drug Adm, Guangdong Prov Key Lab New Drug Screening, Guangzhou 510515, Peoples R China.
通讯机构：
[Liu, MH ] S;[Zou, W ] U;Univ South China, Hunan Prov Maternal & Child Hlth Care Hosp, Sch Pharm, Hengyang 421001, Peoples R China.;Southern Med Univ, Sch Pharmaceut Sci, Key Lab Drug Metab Res & Evaluat State Drug Adm, Guangdong Prov Key Lab New Drug Screening, Guangzhou 510515, Peoples R China.
摘要：
Formyl peptide receptor 2 (FPR2) is a G protein-coupled receptor with seven transmembrane domains, widely distributed in human cells. It plays a crucial role in inflammation-related diseases. Known for its "double-edged sword" nature, FPR2 can bind a variety of exogenous and endogenous ligands, mediating both pro-inflammatory and anti-inflammatory responses in tissues such as eyes, liver, joints, lungs, nerves, and blood vessels. FPR2's bioactivities are regulated by a complex network of genes and signaling pathways. However, the precise regulatory mechanisms governing its functions in different inflammatory conditions are still not well understood. This review summarizes the FPR2's activities in various inflammation-related diseases and looks into its potential as a therapeutic target. This review highlights recent advances in developing exogenous agonists for FPR2 and discusses receptor expression across species to support nonclinical research. Overall, this review aims to clarify FPR2's role in inflammation and provide insights for the development of new drugs against inflammatory diseases.
期刊：
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY,2025年73(26):16011–16027 ISSN：0021-8561
通讯作者：
Bo Su
作者机构：
[Xinyi Guo; Bo Su] Institute of Pharmacy and Pharmacology, School of Pharmacy, Hengyang Medical School, University of South China, Chang Sheng Xi Avenue 28, Hengyang, Hunan 421001, China
通讯机构：
[Bo Su] I;Institute of Pharmacy and Pharmacology, School of Pharmacy, Hengyang Medical School, University of South China, Chang Sheng Xi Avenue 28, Hengyang, Hunan 421001, China
摘要：
Diallyl trisulfide (DATS), an organosulfur compound from the common food garlic, has been attracting attention by exhibiting low toxicity, tumor susceptibility, and, especially, multiple antitumor activities, despite its simple molecular structure. The mounting data suggest that the effects of DATS are related to its induction of oxidative stress cell death in various forms via reactive oxygen species (ROS), such as apoptosis, ferroptosis, autophagy, and pyroptosis. Disruption of redox equilibrium by DATS involves not only the induction of ROS generation but also the inhibition of ROS scavenging through modulation of antioxidant systems, which in turn affects the redox-dependent key molecules in the signaling pathways, consequently curbing the malignant behavior of cancers. Retracing the progress of DATS antitumor research in the past decade, we conduct an in-depth analysis of the multitarget mechanisms of DATS intervening in redox homeostasis. This review provides clues for future studies to further reveal its potential antitumor effects.
摘要：
Microcystin-LR (MC-LR) is a toxin that causes hepatic steatosis. Our previous study found that exposure to 60 μg/L MC-LR for 9 months resulted in liver lipid accumulation, but the underlying mechanisms remain elusive. Herein, for the first time, fatty acid-targeted metabolome and RNA-seq were combined to probe the effect and mechanism of chronic (12-month) MC-LR treatment on mice lipid metabolism at environmental-related levels (1, 60, and 120 μg/L). It was found that MC-LR dose-dependently raised serum and liver lipid levels. The total cholesterol (TC) levels in the liver were significantly increased following treatment with 1 μg/L MC-LR (equivalent to 0.004 μ/L in human). Treatment with 60 and 120 μg/L MC-LR significantly elevated TC and triglyceride (TG) levels in both serum and liver. Serum fatty acid-targeted metabolome analysis demonstrated that exposure to 1, 60, and 120 μg/L MC-LR caused significant alterations in the fatty acid profile. Chronic 1, 60, and 120 μg/L MC-LR treatment significantly increased serum polyunsaturated fatty acids (PUFAs), including conjugated linoleic acid and eicosapentaenoic acid, which positively correlated with serum or liver TG levels. Chronic exposure to 120 μg/L MC-LR led to a significant decrease in the accumulation of saturated fatty acids, including citramalic acid, pentadecanoic acid, and docosanoic acid, which were negatively correlated with serum or liver lipid levels. These findings suggested that 1 μg/L MC-LR exposure caused mild lipid metabolism disruption, while 60 and 120 μg/L MC-LR treatment resulted in pronounced hepatic steatosis in mice. Transcriptome analysis revealed that chronic environmental MC-LR treatment regulated the expression of genes involved in the phosphatidylinositol 3-kinase (PI3K) complex and fatty acid metabolism. Western blotting and RT-qPCR confirmed that chronic environmental MC-LR exposure activated the PI3K/AKT/mTOR signaling pathway, the downstream of fads3 gene that participates in fatty acid desaturation was upregulated, fatty acid degradation-related genes, including acsl1, acsl4, and ehhadh were inhibited, and lipid transport-related genes, including slc27a4 and apol7a, were promoted. Thus, chronic environmental MC-LR exposure boosts hepatic steatosis. Our work indicated that the limit concentration of 1 μg/L MC-LR in human drinking water for safety needs to be discussed. The study provides the first evidence of the fatty acid profile and gene changes and gains new insights into the mechanisms of chronic environmental MC-LR treatment-induced hepatic steatosis.
期刊：
Molecular and Cellular Biochemistry,2025年480(4):2143-2157 ISSN：0300-8177
通讯作者：
Wang, J
作者机构：
[Jiang, Tingting] Univ South China, Hengyang Med Sch, Affiliated Nanhua Hosp, Dept Clin Lab, Hengyang 421000, Peoples R China.;[Zeng, Qun] Univ South China, Hengyang Med Sch, Dept Biochem & Mol Biol, Hengyang 421000, Peoples R China.;[Wang, Jing] Changsha Med Univ, Hunan Prov Key Lab Tradit Chinese Med Agr Biogenom, Changsha 410219, Peoples R China.;[Wang, Jing] Changsha Med Univ, Hunan Prov Univ Key Lab Fundamental & Clin Res Fun, Changsha 410219, Peoples R China.;[Wang, Jing] Changsha Med Univ, Clin Coll 1, Changsha 410219, Peoples R China.
通讯机构：
[Wang, J ] C;Changsha Med Univ, Hunan Prov Key Lab Tradit Chinese Med Agr Biogenom, Changsha 410219, Peoples R China.;Changsha Med Univ, Hunan Prov Univ Key Lab Fundamental & Clin Res Fun, Changsha 410219, Peoples R China.;Changsha Med Univ, Clin Coll 1, Changsha 410219, Peoples R China.
摘要：
FHL2 (Four-and-a-half LIM domain protein 2) is a crucial factor involved in cardiac morphogenesis, the process by which the heart develops its complex structure. It is expressed in various tissues during embryonic development, including the developing heart, and has been shown to play important roles in cell proliferation, differentiation, and migration. FHL2 interacts with multiple proteins to regulate cardiac development as a coactivator or a corepressor. It is involved in cardiac specification and determination of cell fate, cardiomyocyte growth, cardiac remodeling, myofibrillogenesis, and the regulation of HERG channels. Targeting FHL2 has therapeutic implications as it could improve cardiac function, control arrhythmias, alleviate heart failure, and maintain cardiac integrity in various pathological conditions. The identification of FHL2 as a signature gene in atrial fibrillation suggests its potential as a diagnostic marker and therapeutic target for this common arrhythmia.
摘要：
The major facilitator superfamily (MFS) type efflux pumps of Acinetobacter baumannii play important roles in antibiotic resistance. However, the molecular mechanism of these transporters remains poorly understood. To address the molecular basis of substrate polyspecificity mediated by multidrug MFS transporters, we compared the substrate binding modes of A. baumannii CraA with its well-studied homolog, Escherichia coli MdfA. MdfA and CraA share similar structural features, including a cavity accessible to drugs from the cytoplasm when these transporters adopt the inside-out conformation. This predominantly hydrophobic cavity contains several distinct titratable and hydrophilic residues. Through substitution analysis, we demonstrate that these polar residues within the CraA drug binding cavity contribute to the transport of all tested drugs, whereas mutations of hydrophobic residues result in altered drug recognition profiles. In addition to the known titratable residues E38 and D46, we identified E338 as the only titratable residue that plays a substrate-specific role, as it is required for efficient transport of norfloxacin, but not ethidium. Substitution of E338 with asparagine or glutamine changes substrate specificity, enabling specific recognition of phenicols and mitomycin C. Furthermore, we show that the aromaticity of Y42 is crucial for phenicol recognition, while general hydrophobicity at this position is critical for mitomycin C specificity. We propose that E338 and Y42 function as key substrate selectivity determinants in CraA. IMPORTANCE Multidrug efflux transporters of the major facilitator superfamily (MFS) are key contributors to antibiotic resistance, mediating the export of structurally diverse compounds across bacterial membranes. While homologous transporters such as Escherichia coli MdfA and Acinetobacter baumannii CraA share high structural similarity and overlapping substrate profiles, the molecular basis of their substrate specificity remains poorly understood. In this study, we show that structural homology among MFS transporters does not inherently imply mechanistic conservation, as species-specific variations can give rise to distinct substrate recognition profiles. Our findings reveal that CraA utilizes unique residues Y42 and E338 for substrate selectivity, while R124 and Y73 contribute to its transport activity. These findings enhance our understanding of efflux pump specificity and underscore the need to consider organism-specific features when targeting multidrug transporters in antimicrobial therapy.
The major facilitator superfamily (MFS) type efflux pumps of Acinetobacter baumannii play important roles in antibiotic resistance. However, the molecular mechanism of these transporters remains poorly understood. To address the molecular basis of substrate polyspecificity mediated by multidrug MFS transporters, we compared the substrate binding modes of A. baumannii CraA with its well-studied homolog, Escherichia coli MdfA. MdfA and CraA share similar structural features, including a cavity accessible to drugs from the cytoplasm when these transporters adopt the inside-out conformation. This predominantly hydrophobic cavity contains several distinct titratable and hydrophilic residues. Through substitution analysis, we demonstrate that these polar residues within the CraA drug binding cavity contribute to the transport of all tested drugs, whereas mutations of hydrophobic residues result in altered drug recognition profiles. In addition to the known titratable residues E38 and D46, we identified E338 as the only titratable residue that plays a substrate-specific role, as it is required for efficient transport of norfloxacin, but not ethidium. Substitution of E338 with asparagine or glutamine changes substrate specificity, enabling specific recognition of phenicols and mitomycin C. Furthermore, we show that the aromaticity of Y42 is crucial for phenicol recognition, while general hydrophobicity at this position is critical for mitomycin C specificity. We propose that E338 and Y42 function as key substrate selectivity determinants in CraA.
IMPORTANCE
Multidrug efflux transporters of the major facilitator superfamily (MFS) are key contributors to antibiotic resistance, mediating the export of structurally diverse compounds across bacterial membranes. While homologous transporters such as Escherichia coli MdfA and Acinetobacter baumannii CraA share high structural similarity and overlapping substrate profiles, the molecular basis of their substrate specificity remains poorly understood. In this study, we show that structural homology among MFS transporters does not inherently imply mechanistic conservation, as species-specific variations can give rise to distinct substrate recognition profiles. Our findings reveal that CraA utilizes unique residues Y42 and E338 for substrate selectivity, while R124 and Y73 contribute to its transport activity. These findings enhance our understanding of efflux pump specificity and underscore the need to consider organism-specific features when targeting multidrug transporters in antimicrobial therapy.
Multidrug efflux transporters of the major facilitator superfamily (MFS) are key contributors to antibiotic resistance, mediating the export of structurally diverse compounds across bacterial membranes. While homologous transporters such as Escherichia coli MdfA and Acinetobacter baumannii CraA share high structural similarity and overlapping substrate profiles, the molecular basis of their substrate specificity remains poorly understood. In this study, we show that structural homology among MFS transporters does not inherently imply mechanistic conservation, as species-specific variations can give rise to distinct substrate recognition profiles. Our findings reveal that CraA utilizes unique residues Y42 and E338 for substrate selectivity, while R124 and Y73 contribute to its transport activity. These findings enhance our understanding of efflux pump specificity and underscore the need to consider organism-specific features when targeting multidrug transporters in antimicrobial therapy.
Multidrug efflux transporters of the major facilitator superfamily (MFS) are key contributors to antibiotic resistance, mediating the export of structurally diverse compounds across bacterial membranes. While homologous transporters such as Escherichia coli MdfA and Acinetobacter baumannii CraA share high structural similarity and overlapping substrate profiles, the molecular basis of their substrate specificity remains poorly understood. In this study, we show that structural homology among MFS transporters does not inherently imply mechanistic conservation, as species-specific variations can give rise to distinct substrate recognition profiles. Our findings reveal that CraA utilizes unique residues Y42 and E338 for substrate selectivity, while R124 and Y73 contribute to its transport activity. These findings enhance our understanding of efflux pump specificity and underscore the need to consider organism-specific features when targeting multidrug transporters in antimicrobial therapy.
摘要：
Pulmonary hypertension is a progressive vascular disease characterized by pulmonary vascular remodeling , with high mortality and poor prognosis despite advances in medical therapy. Recently, histone modification therapies for pulmonary hypertension have received more attention. Studies have shown that abnormal histone modifications and the enzymes responsible for these alterations can drive pulmonary vascular cell proliferation , migration, and anti-apoptosis by regulating chromatin structure and gene expression, thereby promoting pulmonary vascular remodeling in pulmonary hypertension. This review illustrates histone modifications, including methylation , acetylation , lactylation, and SUMOylation , and the enzymes responsible for these modifications, exploring their role and pathophysiological mechanism in pulmonary hypertension. In addition, the review summarizes the small molecule modulators currently under development and their efficacy in various preclinical models of pulmonary hypertension. Comprehending the function of histone modifications in pulmonary hypertension will help identify new biomarkers and molecular targets and facilitate personalized treatments for this severe disease.
Pulmonary hypertension is a progressive vascular disease characterized by pulmonary vascular remodeling , with high mortality and poor prognosis despite advances in medical therapy. Recently, histone modification therapies for pulmonary hypertension have received more attention. Studies have shown that abnormal histone modifications and the enzymes responsible for these alterations can drive pulmonary vascular cell proliferation , migration, and anti-apoptosis by regulating chromatin structure and gene expression, thereby promoting pulmonary vascular remodeling in pulmonary hypertension. This review illustrates histone modifications, including methylation , acetylation , lactylation, and SUMOylation , and the enzymes responsible for these modifications, exploring their role and pathophysiological mechanism in pulmonary hypertension. In addition, the review summarizes the small molecule modulators currently under development and their efficacy in various preclinical models of pulmonary hypertension. Comprehending the function of histone modifications in pulmonary hypertension will help identify new biomarkers and molecular targets and facilitate personalized treatments for this severe disease.
通讯机构：
[Tan, XF; Yang, QL ; Chen, GD; Wu, GL] U;Univ South China, Affiliated Hosp 1, Hengyang Med Sch, Dept Hepatopancreatobiliary Surg, Hengyang 421001, Hunan, Peoples R China.;Univ South China, Inst Pharm & Pharmacol, Hengyang Med Sch, Sch Pharmaceut Sci, Hengyang 421001, Hunan, Peoples R China.;Univ South China, Hengyang Med Sch, NHC Key Lab Birth Defect Res & Prevent, Hengyang 421001, Hunan, Peoples R China.;Univ South China, Hengyang Med Sch, MOE Key Lab Rare Pediat Dis, Hengyang 421001, Hunan, Peoples R China.
摘要：
The advancement of mitochondria-targeted near-infrared-II (NIR-II) excitable phototheranostics constitutes a promising strategy for improving fluorescence-image-guided cancer phototherapy. However, developing phototheranostic agents that simultaneously combine high-contrast NIR-II fluorescence imaging with effective multimodal therapeutic techniques remains a substantial challenge. Herein, we reported a shielding-donor–acceptor–donor-shielding structured NIR-II phototheranostic (FCD-T) by a molecular engineering strategy, followed by self-assembly with glutathione-responsive copolymer to form FCD-T nanoparticles. The introduction of functional bithiophene endows FCD-T with significant electron-donating properties and reduces intermolecular π-π stacking interactions. The robust π-conjugation of fluorene with good rigidity would enhance the intramolecular charge transfer capability. Therefore, FCD-T NPs exhibited an NIR-II absorption peak at 1075 nm and an emission peak at 1280 nm. Upon NIR-II light excitation, such nanoparticles could generate excellent photothermal and photodynamic performances with good biocompatibility. Moreover, the NIR-II mitochondria-targeted phototherapy further facilitated mitochondrial apoptosis-related pathways, activating antitumor immunity and inhibiting tumor growth with single irradiation at low doses.
The advancement of mitochondria-targeted near-infrared-II (NIR-II) excitable phototheranostics constitutes a promising strategy for improving fluorescence-image-guided cancer phototherapy. However, developing phototheranostic agents that simultaneously combine high-contrast NIR-II fluorescence imaging with effective multimodal therapeutic techniques remains a substantial challenge. Herein, we reported a shielding-donor–acceptor–donor-shielding structured NIR-II phototheranostic (FCD-T) by a molecular engineering strategy, followed by self-assembly with glutathione-responsive copolymer to form FCD-T nanoparticles. The introduction of functional bithiophene endows FCD-T with significant electron-donating properties and reduces intermolecular π-π stacking interactions. The robust π-conjugation of fluorene with good rigidity would enhance the intramolecular charge transfer capability. Therefore, FCD-T NPs exhibited an NIR-II absorption peak at 1075 nm and an emission peak at 1280 nm. Upon NIR-II light excitation, such nanoparticles could generate excellent photothermal and photodynamic performances with good biocompatibility. Moreover, the NIR-II mitochondria-targeted phototherapy further facilitated mitochondrial apoptosis-related pathways, activating antitumor immunity and inhibiting tumor growth with single irradiation at low doses.
Download: Download high-res image (284KB) Download: Download full-size image
Download: Download high-res image (284KB) Download: Download full-size image
摘要：
With the development of society and the economy, metabolic dysfunction-associated steatotic liver disease (MASLD) has become a major chronic disease in contemporary society. Finding a safe, effective, and economical diagnostic method is essential for the prevention of MASLD. Serum immunoglobulin is a protein produced by the B cells after the body is stimulated by an external antigen or pathogen. It is very interesting and valuable to explore the relationship between serum immunoglobulins and MASLD. Unfortunately, only a small number of studies have explored the relationship between serum immunoglobulins and MASLD. Therefore, we review the research progress of serum immunoglobulins in MASLD. At the same time, we also discuss the shortcomings of these studies. We hope this review will provide experience and reference for the prevention of MASLD in the future.
摘要：
Zinc (Zn(2+)) is an essential trace element that plays a crucial role in various biological functions. Aberrant Zn(2+) homeostasis may lead to the occurrence and development of diseases. Zinc transporters, primarily classified into two families in humans: the ZnT (SLC30A) family and the ZIP (SLC39A) family, are critical regulators of Zn(2+) homeostasis. The roles of ZnT-mediated Zn(2+) homeostasis in diseases are an active area of research. The ZnT family comprises ten members, belonging to four subfamilies, which are widely distributed in various tissues and subcellular organelles. ZnTs mediate directional Zn(2+) efflux, transporting cytoplasmic Zn(2+) into extracellular compartments or sequestering it within intracellular vesicles. Accumulating evidence has shown that ZnT dysregulation or ZnT mutations can disrupt Zn(2+) homeostasis, leading to the occurrence and development of diseases, such as cancer, cardiovascular disease, and neurodegenerative diseases. In this review, we focus on the distribution and structure of ZnTs. Furthermore, we synthesize recent advances in ZnT-mediated regulation of Zn(2+) homeostasis in disease pathogenesis to guide the development of novel diagnostic and therapeutic strategies.
关键词：
bioequivalence;healthy subject;liquid chromatography–tandem mass spectrometry;pharmacokinetics;sodium valproate
摘要：
Sodium valproate, a broad-spectrum antiseizure medication of the fatty acid derivative class, was investigated in this study. The trial was designed as a single-center, open-label, randomized, 2-treatment, 4-period, 2-sequence crossover study conducted among healthy Chinese subjects. The objective was to evaluate the pharmacokinetic properties and bioequivalence of a novel generic 0.2g sodium valproate tablet and the branded reference product under fasting (n = 28) and fed (n = 28) conditions, with a 14-day washout period between dosing periods. Blood samples were collected at predefined time points within 72 hours after dosing, and plasma valproic acid concentrations were quantified using a validated liquid chromatography-tandem mass spectrometry method. The results demonstrated comparable pharmacokinetic profiles between the formulations, with the 90% confidence intervals for both maximum plasma concentration and area under the concentration-time curve falling entirely within the 80%-125% bioequivalence acceptance range. Additionally, although food coadministration reduced maximum plasma concentration and delayed time to maximum concentration, area under the concentration-time curve remained unaffected. Regarding safety, neither formulation caused serious adverse events, and both exhibited similar safety profiles. These findings indicate that the generic sodium valproate tablet is bioequivalent to the reference product, with both formulations showing consistent bioequivalence and safety.
摘要：
Revealing changes in the tumor microenvironment is crucial for understanding cancer and developing sensitive methods for precise cancer imaging and diagnosis. Intracellular hydrogen peroxide (H(2)O(2)) and microenvironmental factors (e.g., viscosity and polarity) are closely linked to various physiological and pathological processes, making them potential biomarkers for cancer. However, a triple-response theranostic probe for precise tumor imaging and therapy has not yet been achieved due to the lack of effective tools. Herein, we present a mitochondria-targeting near-infrared (NIR) fluorescent probe, VPH-5DF, capable of simultaneously monitoring H(2)O(2), viscosity, and polarity through dual NIR channels. The probe specifically detects H(2)O(2) via NIR emission (λ(em) = 650 nm) and shows high sensitivity to microenvironmental viscosity/polarity in the deep NIR channel (λ(em) ≈ 750 nm). Furthermore, the probe not only monitors mitochondrial polarity, viscosity, and fluctuations in endogenous/exogenous H(2)O(2) levels but also distinguishes cancer cells from normal cells through multiple parameters. Additionally, VPH-5DF can be employed to monitor alterations in H(2)O(2) levels, as well as changes in viscosity and polarity, during drug-induced pyroptosis in living cells. After treatment with VPH-5DF, chemotherapy-induced oxidative damage to the mitochondria in tumor cells activated the pyroptosis pathway, leading to a robust antitumor response, as evidenced in xenograft tumor models. Thus, this triple-response theranostic prodrug offers a new platform for precise in vivo cancer diagnosis and anticancer chemotherapy.
摘要：
Circadian rhythms are 24-h oscillating variations in physiology and behavior generated by the circadian clock, enabling an individual's circadian cycle to synchronize with the external light-dark cycle. The circadian clock precisely regulates multiple aspects of the innate immune system, including immune cells and diverse immune parameters. The oscillations of innate immune cells and their effector molecules typically determine the extent of the inflammatory responses. During the onset of cardiovascular diseases, many innate immune cells accumulate at the lesion sites. Their continuously augmented recruitment and effector function typically drive the progression of pathological processes and often coincide with cardiovascular events during their peak activities. It is essential to comprehensively understand the influence of the circadian clock on the trafficking and function of innate immune cells, as this influence exerts profound impacts on the immune and inflammatory responses to specific cardiovascular diseases, such as atherosclerosis and myocardial infarction. Proposing innate immunotherapy targeting the circadian clock is anticipated to offer valuable insights for the prevention and management strategies of cardiovascular diseases.
Circadian rhythms are 24-h oscillating variations in physiology and behavior generated by the circadian clock, enabling an individual's circadian cycle to synchronize with the external light-dark cycle. The circadian clock precisely regulates multiple aspects of the innate immune system, including immune cells and diverse immune parameters. The oscillations of innate immune cells and their effector molecules typically determine the extent of the inflammatory responses. During the onset of cardiovascular diseases, many innate immune cells accumulate at the lesion sites. Their continuously augmented recruitment and effector function typically drive the progression of pathological processes and often coincide with cardiovascular events during their peak activities. It is essential to comprehensively understand the influence of the circadian clock on the trafficking and function of innate immune cells, as this influence exerts profound impacts on the immune and inflammatory responses to specific cardiovascular diseases, such as atherosclerosis and myocardial infarction. Proposing innate immunotherapy targeting the circadian clock is anticipated to offer valuable insights for the prevention and management strategies of cardiovascular diseases.
作者机构：
[Xu, Rui; Zhao, Zixuan; Xu, Xiaoding; Fang, Junyue; Zhang, Yuxuan; Lu, Yanan; Cao, Yuan; Wu, Guo] Sun Yat Sen Univ, Sun Yat Sen Mem Hosp, Med Res Ctr, Guangdong Prov Key Lab Malignant Tumor Epigenet &, Guangzhou 510120, Peoples R China.;[Xu, Rui; Xu, Xiaoding; Fang, Junyue; Zhang, Yuxuan; Cao, Yuan; Wu, Guo] Sun Yat Sen Univ, Sun Yat Sen Mem Hosp, Guangzhou Key Lab Med Nanomat, Guangzhou 510120, Peoples R China.;[Lu, Yanan] Sun Yet Sen Univ, Sun Yat Sen Mem Hosp, Dept Anesthesiol, Guangzhou 510120, Peoples R China.;[Li, Rong; Zhao, Zixuan; Xu, Xiaoding] Univ South China, Affiliated Hosp 2, Hunan Prov Key Clin Lab Basic & Clin Pharmacol Res, Hengyang Med Sch,Inst Pharm & Pharmacol, Hengyang 421001, Peoples R China.
通讯机构：
[Lu, YN ; Xu, XD ; Lu, YN] S;Sun Yat Sen Univ, Sun Yat Sen Mem Hosp, Med Res Ctr, Guangdong Prov Key Lab Malignant Tumor Epigenet &, Guangzhou 510120, Peoples R China.;Sun Yat Sen Univ, Sun Yat Sen Mem Hosp, Guangzhou Key Lab Med Nanomat, Guangzhou 510120, Peoples R China.;Sun Yet Sen Univ, Sun Yat Sen Mem Hosp, Dept Anesthesiol, Guangzhou 510120, Peoples R China.;Univ South China, Affiliated Hosp 2, Hunan Prov Key Clin Lab Basic & Clin Pharmacol Res, Hengyang Med Sch,Inst Pharm & Pharmacol, Hengyang 421001, Peoples R China.
关键词：
Cancer immunotherapy;Mitophagy;Nanoplatform;RNA interfering (RNAi);Tumor microenvironment (TME)
摘要：
Tumor microenvironment (TME) is the major obstacle in cancer immunotherapy due to its adverse effects on tumor-infiltrating immune cells. Emerging evidences have revealed that mitophagy plays an important role in regulating cell fate and immune microenvironment. Targeted regulation of mitophagy could be a promising strategy for enhanced cancer immunotherapy, which however remains unexploited due to the absence of robust therapeutic platform. We herein developed a mitophagy-induced RNA interfering (RNAi) nanoplatform composed of a hydrophilic polyethylene glycol (PEG) shell and an endosomal pH-responsive hydrophobic core encapsulating the complexes of mitophagy-inducer carbonyl cyanide 3-chlorophenylhydrazone (CCCP) and small interfering RNA (siRNA) for enhanced breast cancer (BCa) immunotherapy. Using the orthotopic and metastatic BCa tumor models, we demonstrate that this nanoplatform could effectively induce excessive mitophagy in BCa cells to suppress their proliferation and silence PD-L1 expression to block its immunosuppressive effect on CD8 + T cells. More importantly, excessive mitophagy could inhibit C C motif chemokine ligand 2 (CCL2) secretion from BCa cells and thus alleviate the immunosuppressive effect on CD8 + T cells via impairing the tumor infiltration of tumor-associated macrophages (TAMs), regulatory T cells (Tregs), and myeloid-derived suppressor cells (MDSCs), which could ultimately combine with the PD-L1 silencing to synergistically enhance the antitumor immunity and inhibit BCa tumor growth.
Tumor microenvironment (TME) is the major obstacle in cancer immunotherapy due to its adverse effects on tumor-infiltrating immune cells. Emerging evidences have revealed that mitophagy plays an important role in regulating cell fate and immune microenvironment. Targeted regulation of mitophagy could be a promising strategy for enhanced cancer immunotherapy, which however remains unexploited due to the absence of robust therapeutic platform. We herein developed a mitophagy-induced RNA interfering (RNAi) nanoplatform composed of a hydrophilic polyethylene glycol (PEG) shell and an endosomal pH-responsive hydrophobic core encapsulating the complexes of mitophagy-inducer carbonyl cyanide 3-chlorophenylhydrazone (CCCP) and small interfering RNA (siRNA) for enhanced breast cancer (BCa) immunotherapy. Using the orthotopic and metastatic BCa tumor models, we demonstrate that this nanoplatform could effectively induce excessive mitophagy in BCa cells to suppress their proliferation and silence PD-L1 expression to block its immunosuppressive effect on CD8 + T cells. More importantly, excessive mitophagy could inhibit C C motif chemokine ligand 2 (CCL2) secretion from BCa cells and thus alleviate the immunosuppressive effect on CD8 + T cells via impairing the tumor infiltration of tumor-associated macrophages (TAMs), regulatory T cells (Tregs), and myeloid-derived suppressor cells (MDSCs), which could ultimately combine with the PD-L1 silencing to synergistically enhance the antitumor immunity and inhibit BCa tumor growth.
Statement of significance Amplification of mitophagy in tumor cells has been considered as a promising strategy for effective cancer therapy due to its important role in regulating cell fate and TME. We herein developed a mitophagy-induced RNAi nanoplatform, which could effectively induce BCa cell death via amplifying mitophagy and enhance the tumoricidal ability of CD8 + T cells via silencing PD-L1 expression. More importantly, this nanoplatform-induced excessive mitophagy could inhibit tumor-derived CCL2 secretion and thus remodel the immunosuppressive TME via impairing the tumor infiltration of TAMs, Tregs, and MDSCs, leading to enhanced antitumor immunity and significant inhibition of BCa tumor growth. The nanoplatform developed herein could be used as an effective tool for enhanced cancer immunotherapy.
Amplification of mitophagy in tumor cells has been considered as a promising strategy for effective cancer therapy due to its important role in regulating cell fate and TME. We herein developed a mitophagy-induced RNAi nanoplatform, which could effectively induce BCa cell death via amplifying mitophagy and enhance the tumoricidal ability of CD8 + T cells via silencing PD-L1 expression. More importantly, this nanoplatform-induced excessive mitophagy could inhibit tumor-derived CCL2 secretion and thus remodel the immunosuppressive TME via impairing the tumor infiltration of TAMs, Tregs, and MDSCs, leading to enhanced antitumor immunity and significant inhibition of BCa tumor growth. The nanoplatform developed herein could be used as an effective tool for enhanced cancer immunotherapy.
摘要：
Peptides exhibit various biological activities, including biorecognition, cell targeting, and tumor penetration, and can stimulate immune cells to elicit immune responses for tumor immunotherapy. Peptide self-assemblies and peptide-functionalized nanocarriers can reduce the effect of various biological barriers and the degradation by peptidases, enhancing the efficiency of peptide delivery and improving antitumor immune responses. To date, the design and development of peptides with various functionalities have been extensively reviewed for enhanced chemotherapy; however, peptide-mediated tumor immunotherapy using peptides acting on different immune cells, to the knowledge, has not yet been summarized. Thus, this work provides a review of this emerging subject of research, focusing on immunomodulatory anticancer peptides. This review introduces the role of peptides in the immunomodulation of innate and adaptive immune cells, followed by a link between peptides in the innate and adaptive immune systems. The peptides are discussed in detail, following a classification according to their effects on different innate and adaptive immune cells, as well as immune checkpoints. Subsequently, two delivery strategies for peptides as drugs are presented: peptide self-assemblies and peptide-functionalized nanocarriers. The concluding remarks regarding the challenges and potential solutions of peptides for tumor immunotherapy are presented. This work introduces the role of peptides in immune regulation of innate and adaptive immune cells, as well as immune checkpoints. Then this work introduces two strategies for delivering polypeptides: peptide self-assemblies, and peptide-functionalized nanocarriers. Finally, the challenges and prospects of peptides in tumor immunotherapy are summarized. image
摘要：
Detergents are essential molecular tools for membrane protein (MP) research, yet traditional detergents with static properties often fail to address the diverse and evolving needs of MP studies. To this end, this study introduces "living detergents", an innovative class of detergents equipped with functional tags that enable bioorthogonal modifications with externally introduced structural elements. This approach allows for not only the parallel generation of new detergents, but also in situ tuning of MP samples within freshly formed detergents. The efficacy of this strategy was demonstrated through the rapid identification of optimal detergents for high-quality electron microscopy studies of A(2A)AR. Overall, this flexible and robust platform enables efficient tailoring of detergents, advancing the exploration of detergent structure-function relationships in MP research and opening pathways for more specialized solutions for diverse experimental demands.
期刊：
Journal of Colloid and Interface Science,2025年692:137529 ISSN：0021-9797
通讯作者：
Xue, FQ;Liu, Xiaolong;Wang, PY
作者机构：
[Zhang, Ziqian; Xue, Fangqin; Xu, Chao; He, Liangzhen; Xue, FQ] Fuzhou Univ, Affiliated Prov Hosp, Fujian Prov Hosp, Fujian Med Univ,Dept Gastrointestinal Surg,Shengli, Fuzhou 350001, Peoples R China.;[Ying, Yunfei; Wang, Peiyuan; Zhang, Ziqian; Liu, Xiaolong; Dang, Yongying; Li, Siyaqi; Liu, XL] Chinese Acad Sci, Fujian Inst Res Struct Matter, Fuzhou 350002, Peoples R China.;[Liu, Xiaolong; Wang, Peiyuan] Fujian Med Univ, United Innovat Mengchao Hepatobiliary Technol Key, Mengchao Hepatobiliary Hosp, Fuzhou 350025, Peoples R China.;[Ying, Yunfei] Univ South China, Sch Basic Med, Dept Biochem & Mol Biol, Hengyang 421001, Peoples R China.;[Li, Siyaqi] Fujian Agr & Forestry Univ, Coll Life Sci, Fuzhou 350002, Peoples R China.
通讯机构：
[Wang, PY ; Liu, XL] C;[Xue, FQ ] F;Fuzhou Univ, Affiliated Prov Hosp, Fujian Prov Hosp, Fujian Med Univ,Dept Gastrointestinal Surg,Shengli, Fuzhou 350001, Peoples R China.;Chinese Acad Sci, Fujian Inst Res Struct Matter, Fuzhou 350002, Peoples R China.
关键词：
Fluorescence imaging;Multi ion synergistic;PTT enhanced CDT;Tumor microenvironment;Tumor surgery
摘要：
Colon cancer, characterized by its high incidence and mortality rates, continues to present a significant challenge in cancer treatment. To address this, we present a novel ZnCe based nanocarrier featuring stacked mesopores and rough surface, indocyanine Green (ICG) is encapsulated within these mesopores (ZnCe&ICG). This innovative nanoplatform demonstrates effective accumulation in tumor regions and can be triggered to generate efficacious reactive oxygen species (ROS) in the weakly acidic and high H 2 O 2 conditions typical of tumor microenvironments. Enhanced fluorescent imaging using improved tumor-to-background ratio has proven effective in precisely delineating tumor margins from surrounding healthy tissue. With the guidance of this second near-infrared region (NIR II, 1000–1700 nm) fluorescence imaging technique, tumors are completely excised, resulting in negligible instances of in situ recurrence or metastasis observed 30 days following surgery. Notably, under 808 nm laser irradiation, the nanoplatform exhibits a high photothermal conversion efficiency, leading to localized heating that further amplifies ROS production via multi ion synergetic catalysis for tumor cell killing. These results underscore the potential of tumor microenvironment-responsive ZnCe-based nanocomposite as a fluorescence imaging contrast agent and chemodynamic agent for cancer treatment, particularly when combined with NIR light activation.
Colon cancer, characterized by its high incidence and mortality rates, continues to present a significant challenge in cancer treatment. To address this, we present a novel ZnCe based nanocarrier featuring stacked mesopores and rough surface, indocyanine Green (ICG) is encapsulated within these mesopores (ZnCe&ICG). This innovative nanoplatform demonstrates effective accumulation in tumor regions and can be triggered to generate efficacious reactive oxygen species (ROS) in the weakly acidic and high H 2 O 2 conditions typical of tumor microenvironments. Enhanced fluorescent imaging using improved tumor-to-background ratio has proven effective in precisely delineating tumor margins from surrounding healthy tissue. With the guidance of this second near-infrared region (NIR II, 1000–1700 nm) fluorescence imaging technique, tumors are completely excised, resulting in negligible instances of in situ recurrence or metastasis observed 30 days following surgery. Notably, under 808 nm laser irradiation, the nanoplatform exhibits a high photothermal conversion efficiency, leading to localized heating that further amplifies ROS production via multi ion synergetic catalysis for tumor cell killing. These results underscore the potential of tumor microenvironment-responsive ZnCe-based nanocomposite as a fluorescence imaging contrast agent and chemodynamic agent for cancer treatment, particularly when combined with NIR light activation.
作者机构：
[Yang, Liu-Pan; Yuan, Peng-Xiang; Wang, Li-Li; Wang, Yu-Ping; Du, Fangfang] Univ South China, Sch Pharmaceut Sci, Hengyang Med Sch, Hengyang 421001, Hunan, Peoples R China.;[Wang, Li-Li] Univ South China, Affiliated Hosp 1, Hengyang Med Sch, Dept Pharm, Hengyang 421001, Hunan, Peoples R China.;[Du, Fangfang] Hainan Med Univ, Affiliated Hosp 1,Minist Educ, Key Lab Haikou Trauma,Key Lab Emergency & Trauma, Key Lab Hainan Trauma & Disaster Rescue, Haikou 571199, Hainan, Peoples R China.
通讯机构：
[Yang, LP; Wang, LL ] U;Univ South China, Sch Pharmaceut Sci, Hengyang Med Sch, Hengyang 421001, Hunan, Peoples R China.
摘要：
As widely used antibiotics, tetracycline residues exist in food and environmental media, which pose certain hidden dangers and negative effects on public health. Therefore, the sensing and discrimination of tetracycline analogs (TCs) have great significance for improving food safety and preventing environmental pollution. Herein, a 7-hydroxycoumarin-3-carboxylic acid-embedded Eu-MOF (HC@Eu-MOF) material was constructed and then developed for the detection of TCs. Upon addition of TCs, the synthesized sensor displays opposite fluorescence changes at two different wavelengths due to the simultaneous presence of the inner filter effect (IFE) and the antenna effect (AE), and achieves a stable ratio signal response within 90s. In addition, six important tetracycline analogs, including chlortetracycline (CTC), oxytetracycline (OTC), tetracycline (TC), metacycline (MC), doxycycline (DC) and demeclocycline (DMC) can be discriminated with 100% accuracy through the principal component analysis even in extremely complicated mixtures. Further, a smartphone-assisted portable device was applied for visual sensing of TCs. The as-developed platform possessed the characteristics of simple synthesis, fast response, high sensitivity, and high stability, which further lays a further foundation for the on-site visual detection and discrimination of TCs in real samples.
摘要：
ZBTB (zinc finger and BTB domain) proteins are a class of evolutionarily conserved transcriptional factors (TFs) with zinc finger (ZF) and BTB (Broad-complex, Tram-track, and Bric-à-brac) domains. The ZBTB protein family has a wide range of functions in numerous biological processes, including cell cycle regulation, DNA repair, organ development, and haematopoietic stem cell fate determination. The ZBTB proteins regulate gene expression through interactions with transcriptional regulators, influencing processes such as myocardial contractility, inflammation, fibrosis, and cellular metabolism. Given the critical role of the ZBTB family in cardiac biology, the present review endeavours to comprehensively summarize the regulatory roles of seven ZBTB family members (HIC2, BCL6, PLZF, ZBTB17, ZBTB20, ZBTB7a, and ZBTB11) in cardiac development and diseases, along with their potential molecular mechanisms. Elucidating the molecular mechanisms of ZBTB proteins opens avenues for developing targeted therapies for cardiovascular diseases, including hypertrophy, fibrosis, and inflammation. This review provides a comprehensive summary of recent research on the role of ZBTB proteins in regulating cardiac transcription. Particular emphasis is placed on elucidating their functions in both cardiac development and the pathogenesis of cardiac diseases.
ZBTB (zinc finger and BTB domain) proteins are a class of evolutionarily conserved transcriptional factors (TFs) with zinc finger (ZF) and BTB (Broad-complex, Tram-track, and Bric-à-brac) domains. The ZBTB protein family has a wide range of functions in numerous biological processes, including cell cycle regulation, DNA repair, organ development, and haematopoietic stem cell fate determination. The ZBTB proteins regulate gene expression through interactions with transcriptional regulators, influencing processes such as myocardial contractility, inflammation, fibrosis, and cellular metabolism. Given the critical role of the ZBTB family in cardiac biology, the present review endeavours to comprehensively summarize the regulatory roles of seven ZBTB family members (HIC2, BCL6, PLZF, ZBTB17, ZBTB20, ZBTB7a, and ZBTB11) in cardiac development and diseases, along with their potential molecular mechanisms. Elucidating the molecular mechanisms of ZBTB proteins opens avenues for developing targeted therapies for cardiovascular diseases, including hypertrophy, fibrosis, and inflammation. This review provides a comprehensive summary of recent research on the role of ZBTB proteins in regulating cardiac transcription. Particular emphasis is placed on elucidating their functions in both cardiac development and the pathogenesis of cardiac diseases.
摘要：
There is relatively little research on cyclic amphiphilic block polymers, having both hydrophilic and hydrophobic segments placed in the ring and thus resulting in a higher degree of topological restriction, as drug vehicles. Cyclic amphiphilic binary block polymer is synthesized by the click coupling reaction of bimolecular homodifunctional precursors. The results indicate that cyclization between linear polymer precursors is successful if the trace linear by-products generated are ignored, which also suggests that the small molecule bifunctional terminating agent applied in traditional bimolecular homodifunctional ring-closure process can be extended to large molecule. Moreover, the study on the self-assembly behavior of polymers shows that, compared with linear counterparts, the stability and drug loading capacity of micelles based on the resultant cyclic polymer are not significantly improved due to the influence of topological structure and linear impurities. Nevertheless, drug loaded micelles formed by the obtained cyclic polymers still exhibit superior cellular uptake ability. It can be seen that topological effects do play an irreplaceable role in the application performance of polymers. Therefore, the construction and synthesis of cyclic and its derivative polymers with moderate topological confinement and high purity may be a key direction for future exploration of polymer drug delivery carriers.
