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.
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：
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
作者机构：
[Yi, Wenbin; Zheng, Xing; Deng, Jiawen; Yi, WB; Yao, Xu; Zheng, X] Univ South China, Inst Pharm & Pharmacol, Hengyang Med Sch, Hengyang 421001, Hunan, Peoples R China.;[Lin, Jin-Hong; Lin, JH; Xiao, Ji-Chang; Zhang, Yahan] Univ Chinese Acad Sci, Chinese Acad Sci, Shanghai Inst Organ Chem, State Key Lab Fluorine & Nitrogen Chem & Adv Mat, 345 Lingling Lu, Shanghai 200032, Peoples R China.;[Zheng, Xing; Zhang, Jun; Zheng, X] Hunan Vocat Coll Sci & Technol, Dept Pharm, Third Zhongyi Shan Rd, Changsha 410004, Hunan, Peoples R China.;[Yi, WB; Yi, Wenbin; Lin, Lukang] Nanjing Univ Sci & Technol, Coll Chem Engn, 200 Xiaolingwei, Nanjing 210094, Peoples R China.
通讯机构：
[Yi, WB ] N;[Yi, WB; Xiao, JC ; Lin, JH; Zheng, X ] U;Univ South China, Inst Pharm & Pharmacol, Hengyang Med Sch, Hengyang 421001, Hunan, Peoples R China.;Univ Chinese Acad Sci, Chinese Acad Sci, Shanghai Inst Organ Chem, State Key Lab Fluorine & Nitrogen Chem & Adv Mat, 345 Lingling Lu, Shanghai 200032, Peoples R China.;Hunan Vocat Coll Sci & Technol, Dept Pharm, Third Zhongyi Shan Rd, Changsha 410004, Hunan, Peoples R China.
关键词：
Energetic salts;Insensitive;Trifluoromethyl
摘要：
Two types of 5-trifluoromethyl tetrazole-based energetic salts were successfully synthesized from trifluoroacetamide and sodium azide. The synthetic approach is characterized by its simplicity and safety. The X-ray diffraction analysis reveals the presence of both intermolecular and intramolecular hydrogen bonding within the crystal lattice of energetic salts. The synthesized compound 4 demonstrated notable physical properties, including high densities (1.64 g cm -3 ), great thermal stability (with decomposition temperatures of 167 °C), and excellent insensitivity (impact sensitivity exceeding 40 J). These attributes suggest that the compound 4 possess promising energetic performance and is potential candidates for use as insensitive high-energy materials.
Two types of 5-trifluoromethyl tetrazole-based energetic salts were successfully synthesized from trifluoroacetamide and sodium azide. The synthetic approach is characterized by its simplicity and safety. The X-ray diffraction analysis reveals the presence of both intermolecular and intramolecular hydrogen bonding within the crystal lattice of energetic salts. The synthesized compound 4 demonstrated notable physical properties, including high densities (1.64 g cm -3 ), great thermal stability (with decomposition temperatures of 167 °C), and excellent insensitivity (impact sensitivity exceeding 40 J). These attributes suggest that the compound 4 possess promising energetic performance and is potential candidates for use as insensitive high-energy materials.
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：
This study systematically investigated the antioxidant activities and phytochemical profiles of petroleum ether (PE), ethyl acetate (EtOAc), n-butanol (n-BuOH) and aqueous fractions of edible (tubers) and non-edible portions (peels) of Pachyrhizus erosus. The results showed that both the tubers and peels from P. erosus were rich in polyphenols and flavonoids, whereas the EtOAc fraction of peels had the highest polyphenol content, and the PE fraction of peels had the highest total flavonoid content. ABTS, DPPH, and FRAP assays revealed that both the EtOAc fraction of tubers and peels from P. erosus showed significant antioxidant activity, whereas the EtOAc fraction of peels possessed better antioxidant activity than that of tubers. UPLC-Orbitrap-MS/MS analysis indicated that thirty compounds were identified from the EtOAc fractions of peels and tubers, including twenty-one flavonoids, six phenolics, two coumarins, and one lignan, some of which have previously been revealed to display significant antioxidant and anti-inflammatory effects via the Nrf2-Keap1 and NF-kappa B signaling pathways. These findings provide robust scientific evidence for the health-promoting properties and pharmaceutical potential of P. erosus, and its non-edible portion (peels) has great potential for use as a natural antioxidant in the food, cosmetic, and pharmaceutical industries.
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.
作者机构：
[Liu, Ying; Deng, Min; Zhai, Zibo; He, Longwei; Wang, Peipei; Li, Songjiao; Cheng, Dan; He, LW] Univ South China, Hunan Prov Cooperat Innovat Ctr Mol Target New Dru, Hengyang Med Sch, Dept Pharm & Pharmacol, Hengyang 421002, Peoples R China.;[Cheng, Dan] Univ South China, Affiliated Nanhua Hosp, Clin Res Inst, Hengyang Med Sch,Dept Gastroenterol, Hengyang 421002, Peoples R China.;[He, LW; He, Longwei] Henan Normal Univ, Sch Chem & Chem Engn, Xinxiang 453007, Peoples R China.
通讯机构：
[He, LW ] H;[Li, SJ ; He, LW] U;Univ South China, Hunan Prov Cooperat Innovat Ctr Mol Target New Dru, Hengyang Med Sch, Dept Pharm & Pharmacol, Hengyang 421002, Peoples R China.;Henan Normal Univ, Sch Chem & Chem Engn, Xinxiang 453007, Peoples R China.
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.
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.
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.
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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.
摘要：
The monocyte adhesion to vascular endothelial cells constitutes a key step in atherosclerosis pathogenesis. We previously found that ROS-autophagy pathway participated in the monocyte-endothelial cell adhesion induced by angiotensin domain type 1 receptor-associated proteins (APJ) and its endogenous ligand apelin-13. In this study, we investigated what specific type of autophagy apelin-13 regulated in this process. By conducting full-scale transcriptomic analysis in apelin-13-treated human umbilical vein endothelial cells (HUVECs), we found that the transcription levels of ER-phagy receptor protein SEC62 were significantly elevated. Importantly, SEC62 was also upregulated in human atherosclerotic lesions. Thus, we investigated the effects of SEC62-dependent ER-phagy on apelin-13-induced monocyte-endothelial cell adhesion and atherosclerosis pathogenesis. We demonstrated that Apelin-13 (0.001-1 μM) dose-dependently upregulated SEC62 expression thereby inducing ER-phagy in HUVECs. This effect was reversed by autophagy inhibitor 3MA (10 mM) and endoplasmic reticulum stress inhibitor salubrinal (10 μM). The siRNA-Sec62, 3MA (10 mM), and salubrinal (10 μM) all inhibited apelin-13-induced monocyte-endothelial cells adhesion, whereas vascular endothelial cells specific SEC62 deletion alleviated atherosclerotic plaques area, intercellular adhesion molecules expression and lesional macrophages in apelin-13-treated APOE(-/-) mice with high-fat and high-cholesterol diet. Moreover, we demonstrated that ubiquitin-like modification of ALDH1L1 was involved in SEC62-dependent ER-phagy in apelin-13-treated HUVECs: apelin-13 upregulated small ubiquitin-like protein UBL4A, which mediated the ubiquitination-like modification of ALDH1L1 at 812-lysine site. This, in turn, promoted insertion of ALDH1L1 into ER membrane and led to SEC62-dependent ER-phagy. We showed that siRNA-UBL4A, siRNA-ALDH1L1, siRNA-ASNA1, and the mutant of 812 lysine site of ALDH1L1 all decreased apelin-13-induced monocyte-endothelial cell adhesion. We conclude that apelin-13 induces SEC62-dependent ER-phagy to promote monocyte-endothelial cell adhesion and atherosclerosis. This study reveals new mechanisms underlying atherosclerosis and identifies a potential therapeutic target.
摘要：
Empagliflozin is a highly selective sodium-glucose cotransporter 2 inhibitor and an effective medication for treating diabetes. This study aimed to assess the pharmacokinetics and bioequivalence of two 10-mg empagliflozin tablets in healthy Chinese subjects and examine food's effect on absorption. The research was conducted as a single-center, randomized, open-label, single-dose, 2-way crossover study involving 47 subjects (fasting: n = 23, fed: n = 24). Subjects received either the test or reference drug and switched to the alternative after a 7-day washout period. Blood samples were collected before administration and up to 48 hours after dosing, analyzed using validated liquid chromatography-tandem mass spectrometry techniques to determine empagliflozin levels. In both studies, all 23 subjects completed the study phases under fasting and fed conditions. In both scenarios, when comparing the test and reference formulations, the 90% confidence intervals for the geometric mean ratios of maximum plasma concentration, area under the concentration-time curve from time 0 to the last measurable concentration, and area under the concentration-time curve from time 0 to infinity fell within the bioequivalence threshold of 80%-125%, confirming their acceptability. The study found that a high-fat meal slightly reduced drug exposure and slightly accelerated absorption. No serious adverse events were observed. This research confirmed the pharmacokinetic similarity of the 2 empagliflozin formulations and demonstrated their good tolerance under fasting and fed conditions.
作者机构：
[Su, Bo; Jiang, Jinhuan; Liu, Jiyuan; Jiang, JH; Fan, Hui; Hu, Xiangyan] Univ South China, Inst Pharm & Pharmacol, Sch Pharmaceut Sci, Hengyang Med Sch, Hengyang, Hunan, Peoples R China.;[Su, Bo; Jiang, Jinhuan; Jiang, JH] Univ South China, Sch Pharmaceut Sci, Hengyang Med Sch, Hunan Prov Key Lab Tumor Microenvironm Respons Dru, Hengyang, Hunan, Peoples R China.;[Cai, Jiye] Jinan Univ, Dept Chem, Guangzhou 510632, Peoples R China.
通讯机构：
[Jiang, JH ] U;Univ South China, Inst Pharm & Pharmacol, Sch Pharmaceut Sci, Hengyang Med Sch, Hengyang, Hunan, Peoples R China.;Univ South China, Sch Pharmaceut Sci, Hengyang Med Sch, Hunan Prov Key Lab Tumor Microenvironm Respons Dru, Hengyang, Hunan, Peoples R China.
关键词：
XIAP;Tumor;XIAP inhibitor;Apoptotic
摘要：
X-linked inhibitor of apoptosis protein (XIAP) is the most potent endogenous member of the inhibitor of apoptosis protein family. XIAP exerts its anti-apoptotic effects by inhibiting both the death receptor pathway and mitochondrial pathway of apoptosis through various mechanisms such as directly binding to caspases, activating the nuclear factor kappa B (NF-κB) pathway, and other signaling pathways. These processes are closely related to tumor development and progression, making XIAP a therapeutic target for various types of cancer. This article will first review the structural characteristics and biological functions of XIAP, followed by its effects on tumors and an overview of XIAP-targeted inhibitors.
期刊：
JOURNAL OF ORGANIC CHEMISTRY,2025年90(4):1656-1662 ISSN：0022-3263
通讯作者：
Lei, Zhengwen;Wang, Zhen;Zeng, YF;Wang, Z
作者机构：
[Shen, Lixian] Univ South China, Affiliated Hosp 2, Hengyang Med Sch, Dept Pharm,Hunan Prov Key Lab Basic & Clin Pharmac, Hengyang 421001, Hunan, Peoples R China.;[Shen, Lixian; Liu, Jie; Wang, Zhen; Peng, Xue; Lei, Zhengwen; Zeng, Yao-Fu; Lei, ZW] Univ South China, Affiliated Hosp 1, Sch Pharmaceut Sci, Hengyang Med Sch, Hengyang 421001, Hunan, Peoples R China.;[Wang, Zhen] Univ South China, MOE Key Lab Rare Pediat Dis, Hengyang 421001, Hunan, Peoples R China.;[Wang, Zhen] Chinese Acad Sci, Northwest Inst Plateau Biol, Qinghai Prov Key Lab Tibetan Med Res, Xining 810008, Qinghai, Peoples R China.
通讯机构：
[Wang, Z; Zeng, YF ; Wang, Z ; Lei, ZW] U;Univ South China, Affiliated Hosp 1, Sch Pharmaceut Sci, Hengyang Med Sch, Hengyang 421001, Hunan, Peoples R China.;Univ South China, MOE Key Lab Rare Pediat Dis, Hengyang 421001, Hunan, Peoples R China.;Chinese Acad Sci, Northwest Inst Plateau Biol, Qinghai Prov Key Lab Tibetan Med Res, Xining 810008, Qinghai, Peoples R China.
摘要：
We report a photoredox-catalyzed three-component sulfonaminoalkynylation of alkenes with N -aminopyridine salts and potassium alkynyltrifluoroborate salts. This aminoalkylation reaction underwent a radial/polar crossover mechanism, which was distinguished from the previous reports. A variety of β-alkynylated sulfonamides were obtained in moderate to excellent yields. The versatility of this method was further evidenced by its successful application in modifying biological molecules in advanced stages of development.
We report a photoredox-catalyzed three-component sulfonaminoalkynylation of alkenes with N -aminopyridine salts and potassium alkynyltrifluoroborate salts. This aminoalkylation reaction underwent a radial/polar crossover mechanism, which was distinguished from the previous reports. A variety of β-alkynylated sulfonamides were obtained in moderate to excellent yields. The versatility of this method was further evidenced by its successful application in modifying biological molecules in advanced stages of development.
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Download: Download high-res image (72KB) Download: Download full-size image
摘要：
BACKGROUND: Proteus spp. have long been recognized for their role in urinary tract infections, while recent evidence disclosed their implications in gastrointestinal diseases. Despite this, the taxonomy of clinically-derived Proteus spp., particularly those from gastrointestinal samples, remains understudied and is frequently mis-assigned, which limits our understanding of infections caused by these species. RESULTS: Four Proteus strains (i.e., DFP240708, LHD240705, TSJ240517 and WDL240414) were isolated from the appendiceal pus of patients with acute appendicitis, whole-genome average nucleotide identity (ANI) analysis identified all of them as Proteus genomosp. 6, different from that identified using the automated bacterial identification instrument (VITEK(®)-32). Based on ANI and the core-genomic phylogenetic tree, we found that 87.5% of clinically-related strains previously identified as P. columbae should be re-classified as Proteus genomosp. 6. Additionally, the Proteus genomosp. 6 genomes all carry one or more beta-lactam resistance genes, but none carry aminoglycoside resistance genes, and antibiotic susceptibility testing conducted on the four strains isolated in this study confirmed these findings. Among the genomes analyzed, only four (two from this study (TSJ240517 and WDL240414)) carried virulence genes, specifically the hlyA, hlyB, and hlyD genes encoding hemolysin. CONCLUSION: Our study highlights inaccuracies in the taxa classification of Proteus species under clinical settings, underscoring the necessity of using genomic-based taxonomic assignment methods. We revealed that the prevalence of Proteus genomosp. 6 in clinical infections has likely been underestimated. Furthermore, given the resistance-gene absence and their sensitivity to aminoglycosides, aminoglycosides may serve as a promising first-line treatment option for infections caused by this species.
作者机构：
[Zhang, Yuexin; Li, Ye; Yin, Mingxue; Li, Chunquan; Wang, Xuan; Song, Chao; Yu, Zhengmin] Univ South China, Affiliated Hosp 1, Hengyang Med Sch, Hengyang 421001, Peoples R China.;[Zhang, Yuexin; Li, Ye; Yin, Mingxue; Li, Chunquan; Wang, Xuan; Song, Chao; Yu, Zhengmin] Univ South China, Hengyang Med Sch, Key Lab Birth Defect Res & Prevent, Natl Hlth Commiss, Hengyang 421001, Peoples R China.;[Zhang, Yuexin; Li, Ye; Yin, Mingxue; Li, Chunquan; Yu, Zhengmin] Univ South China, Hengyang Med Coll, Inst Biochem & Mol Biol, Hengyang 421001, Peoples R China.;[Zhang, Yuexin; Li, Ye; Yin, Mingxue; Li, Chunquan; Wang, Xuan; Song, Chao; Yu, Zhengmin] Univ South China, Affiliated Hosp 1, Hengyang Med Sch, Cardiovasc Lab Big Data & Imaging Artificial Intel, Hengyang 421001, Hunan, Peoples R China.;[Zhang, Yuexin; Li, Ye; Yin, Mingxue; Li, Chunquan; Wang, Xuan; Song, Chao; Yu, Zhengmin] Univ South China, Hengyang Med Sch, Hengyang 421001, Peoples R China.
通讯机构：
[Li, CQ ] U;[Guo, MZ ] B;Univ South China, Affiliated Hosp 1, Hengyang Med Sch, Hengyang 421001, Peoples R China.;Univ South China, Hengyang Med Sch, Key Lab Birth Defect Res & Prevent, Natl Hlth Commiss, Hengyang 421001, Peoples R China.;Univ South China, Hengyang Med Coll, Inst Biochem & Mol Biol, Hengyang 421001, Peoples R China.
关键词：
genes;genome-wide association study;rna, small cytoplasmic;datasets
摘要：
Identifying cell populations associated with risk variants is essential for uncovering cell-specific mechanisms that drive disease development and progression. Integrating genome-wide association studies (GWAS) with single-cell RNA sequencing (scRNA-seq) has become an effective strategy for detecting trait-cell relationships. The accumulation of trait-related single cell data has led to an urgent need for its comprehensively processing. To address this, we developed sc2GWAS (https://bio.liclab.net/sc2GWAS/), which aims to document large-scale GWAS trait-cell regulatory pairs at single-cell resolution and provide comprehensive annotations and enrichment analyses for these related pairs. The current version of sc2GWAS curates a total of 15 078 310 candidate trait-cell pairs from > 6 300 000 individual cells, offering a valuable resource for exploring complex regulatory relationships between traits and cells. We applied strict quality control measures on both scRNA-seq data and GWAS data, ensuring the reliability and accuracy of the datasets for the identification of trait-relevant cells and genes. In addition, sc2GWAS provides ranked lists of trait-relevant genes and extensive (epi) genetic annotations, making it a valuable resource for downstream analyses. We demonstrate the utility of the platform by investigating Alzheimer's disease, where we identified significant associations between the disease and microglial cells, with the APOE gene emerging as particularly significant. This platform facilitates detailed research into complex trait-cell and trait-gene interactions, we anticipate that sc2GWAS will become a comprehensive and valuable platform for exploring GWAS trait-cell regulatory mechanisms.<br /> [GRAPHICS] .
