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1.
Anal Chim Acta ; 1308: 342611, 2024 Jun 15.
Article in English | MEDLINE | ID: mdl-38740450

ABSTRACT

BACKGROUND: Acute kidney injury (AKI) poses a severe risk to public health, mostly manifested by damage and death of renal tubular epithelial cells. However, routine blood examination, a conventional approach for clinical detection of AKI, is not available for identifying early-stage AKI. Plenty of reported methods were lack of early biomarkers and real time evaluation tools, which resulted in a vital challenge for early diagnosis of AKI. Therefore, developing novel probes for early detection and assessment of AKI is exceedingly crucial. RESULTS: Based on ESIPT mechanism, a new fluorescent probe (MEO-NO) with 2-(2'-hydroxyphenyl) benzothiazole (HBT) derivatives as fluorophore has been synthesized for dynamic imaging peroxynitrite (ONOO-) levels in ferroptosis-mediated AKI. Upon the addition of ONOO-, MEO-NO exhibited obvious fluorescence changes, a significant Stokes shift (130 nm) and rapid response (approximately 45 s), and featured exceptional sensitivity (LOD = 7.28 nM) as well as high selectivity from the competitive species at physiological pH. In addition, MEO-NO was conducive to the biological depth imaging ONOO- in cells, zebrafish, and mice. Importantly, MEO-NO could monitor ONOO- levels during sorafenib-induced ferroptosis and CP-induced AKI. With the assistance of MEO-NO, we successfully visualized and tracked ONOO- variations for early detection and assessment of ferroptosis-mediated AKI in cells, zebrafish and mice models. SIGNIFICANCE AND NOVELTY: Benefiting from the superior performance of MEO-NO, experimental results further demonstrated that the levels of ONOO- was overexpressed during ferroptosis-mediated AKI in cells, zebrafish, and mice models. The developed novel probe MEO-NO provided a strong visualization tool for imagining ONOO-, which might be a potential method for the prevention, diagnosis, and treatment of ferroptosis-mediated AKI.


Subject(s)
Acute Kidney Injury , Ferroptosis , Fluorescent Dyes , Peroxynitrous Acid , Zebrafish , Ferroptosis/drug effects , Fluorescent Dyes/chemistry , Fluorescent Dyes/chemical synthesis , Peroxynitrous Acid/metabolism , Acute Kidney Injury/chemically induced , Animals , Mice , Humans , Optical Imaging , Molecular Structure , Early Diagnosis
2.
Mol Carcinog ; 2024 Apr 24.
Article in English | MEDLINE | ID: mdl-38656551

ABSTRACT

Acetyl-CoAacyltransferase2 (ACAA2) is a key enzyme in the fatty acid oxidation pathway that catalyzes the final step of mitochondrial ß oxidation, which plays an important role in fatty acid metabolism. The expression of ACAA2 is closely related to the occurrence and malignant progression of tumors. However, the function of ACAA2 in ovarian cancer is unclear. The expression level and prognostic value of ACAA2 were analyzed by databases. Gain and loss of function were carried out to explore the function of ACAA2 in ovarian cancer. RNA-seq and bioinformatics methods were applied to illustrate the regulatory mechanism of ACAA2. ACAA2 overexpression promoted the growth, proliferation, migration, and invasion of ovarian cancer, and ACAA2 knockdown inhibited the malignant progression of ovarian cancer as well as the ability of subcutaneous tumor formation in nude mice. At the same time, we found that OGT can induce glycosylation modification of ACAA2 and regulate the karyoplasmic distribution of ACAA2. OGT plays a vital role in ovarian cancer as a function of oncogenes. In addition, through RNA-seq sequencing, we found that ACAA2 regulates the expression of DIXDC1. ACAA2 regulated the malignant progression of ovarian cancer through the WNT/ß-Catenin signaling pathway probably. ACAA2 is an oncogene in ovarian cancer and has the potential to be a target for ovarian cancer therapy.

3.
Biol Direct ; 19(1): 1, 2024 01 02.
Article in English | MEDLINE | ID: mdl-38163864

ABSTRACT

BACKGROUND: Phosphoglycerate kinase 1 (PGK1) is a metabolic enzyme that participates in various biological and pathological processes. Dysregulated PGK1 has been observed in numerous malignancies. However, whether and how PGK1 affects non-small cell lung cancer (NSCLC) is not yet fully elucidated. METHODS: Herein, the non-metabolic function of PGK1 in NSCLC was explored by integrating bioinformatics analyses, cellular experiments, and nude mouse xenograft models. The upstream regulators and downstream targets of PGK1 were examined using multiple techniques such as RNA sequencing, a dual-luciferase reporter assay, Co-immunoprecipitation, and Western blotting. RESULTS: We confirmed that PGK1 was upregulated in NSCLC and this upregulation was associated with poor prognosis. Further in vitro and in vivo experiments demonstrated the promoting effects of PGK1 on NSCLC cell growth and metastasis. Additionally, we discovered that PGK1 interacted with and could be O-GlcNAcylated by OGT. The inhibition of PGK1 O-GlcNAcylation through OGT silencing or mutation at the T255 O-GlcNAcylation site could weaken PGK1-mediated NSCLC cell proliferation, colony formation, migration, and invasion. We also found that a low miR-24-3p level led to an increase in OGT expression. Additionally, PGK1 exerted its oncogenic properties by augmenting ERK phosphorylation and MCM4 expression. CONCLUSIONS: PGK1 acted as a crucial mediator in controlling NSCLC progression. The miR-24-3p/OGT axis was responsible for PGK1 O-GlcNAcylation, and ERK/MCM4 were the downstream effectors of PGK1. It appears that PGK1 might be an attractive therapeutic target for the treatment of NSCLC.


Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , MicroRNAs , Animals , Mice , Humans , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/metabolism , Carcinoma, Non-Small-Cell Lung/pathology , Lung Neoplasms/genetics , Lung Neoplasms/pathology , MicroRNAs/genetics , Cell Proliferation/genetics , Up-Regulation , Cell Line, Tumor , Cell Movement/genetics , Phosphoglycerate Kinase/genetics , Phosphoglycerate Kinase/metabolism
4.
Toxics ; 11(2)2023 Jan 24.
Article in English | MEDLINE | ID: mdl-36850989

ABSTRACT

Curcumol, a natural product isolated from the traditional Chinese medicine Rhizoma curcumae, possesses various potential therapeutic values in many diseases. However, evidence of its toxicological profile is currently lacking. In this study, a repeated toxicity study of curcumol was conducted for the first time. SD rats were exposed to doses of 250, 500, 1000 mg/kg in a selected dose formulation for 28 days through oral administration. The potential toxic effects of curcumol on the blood system were observed and further validated in vivo and in vitro. Moreover, other hematology and biochemistry parameters as well as the weight of organs were altered, but no related histopathological signs were observed, indicating these changes were not regarded as toxicologically relevant. Our current findings provide a complete understanding of the safety profile of curcumol, which may contribute to its further study of investigational new drug application.

5.
Acta Pharmacol Sin ; 44(7): 1442-1454, 2023 Jul.
Article in English | MEDLINE | ID: mdl-36658427

ABSTRACT

Acute kidney injury (AKI) caused by anti-tumor drugs, such as cisplatin, is a severe complication with no effective treatment currently, leading to the reduction or discontinuation of chemotherapy. Natural products or herbal medicines are gradually considered as promising agents against cisplatin-induced AKI with the advantages of multi-targeting, multi-effects, and less resistance. In this study, we investigated the effects of kaempferide, a natural flavonoid extracted from the rhizome of Kaempferia galanga, in experimental AKI models in vitro and in vivo. We first conducted pharmacokinetic study in mice and found a relative stable state of kaempferide with a small amount of conversion into kaempferol. We showed that both kaempferide (10 µM) and kaempferol (10 µM) significantly inhibited cisplatin-caused injuries in immortalized proximal tubule epithelial cell line HK-2. In AKI mice induced by injection of a single dose of cisplatin (15 mg/kg), oral administration of kaempferide (50 mg/kg) either before or after cisplatin injection markedly improved renal function, and ameliorated renal tissue damage. We demonstrated that kaempferide inhibited oxidative stress and induced autophagy in cisplatin-treated mice and HK-2 cells, thus increasing tubular cell viability and decreasing immune responses to attenuate the disease progression. In addition, treatment with kaempferide significantly ameliorated ischemia-reperfusion-induced renal injury in vitro and in vivo. We conclude that kaempferide is a promising natural product for treating various AKI. This study has great implications for promotion of its use in healthcare products, and help to break through the limited use of cisplatin in the clinic.


Subject(s)
Acute Kidney Injury , Cisplatin , Mice , Animals , Cisplatin/pharmacology , Kaempferols/pharmacology , Kaempferols/therapeutic use , Acute Kidney Injury/chemically induced , Acute Kidney Injury/drug therapy , Acute Kidney Injury/pathology , Oxidative Stress , Autophagy , Apoptosis , Mice, Inbred C57BL
6.
Front Pharmacol ; 13: 1036732, 2022.
Article in English | MEDLINE | ID: mdl-36532730

ABSTRACT

Objective: Curcumol is one of the major active ingredients isolated from the traditional Chinese medicine Curcumae Rhizoma and is reported to exhibit various bioactivities, such as anti-tumor and anti-liver fibrosis effects. However, studies of curcumol pharmacokinetics and tissue distribution are currently lacking. This study aims to characterize the pharmacokinetics, tissue distribution, and protein binding rate of curcumol. Methods: Pharmacokinetics properties of curcumol were investigated afte doses of 10, 40, and 80 mg/kg of curcumol for rats and a single dose of 2.0 mg/kg curcumol was given to rats via intravenous administration to investigate bioavailability. Tissue distribution was investigated after a single dose of 40 mg/kg of orally administered curcumol. Plasma protein binding of curcumol was studied in vitro via the rapid equilibrium dialysis system. Bound and unbound curcumol in rat plasma were analyzed to calculate the plasma protein binding rate. A UHPLC-MS/MS method was developed and validated to determine curcumol in rat plasma and tissues and applied to study the pharmacokinetics, tissue distribution, and plasma protein binding in rats. Results: After oral administration of 10, 40, and 80 mg/kg curcumol, results indicated a rapid absorption and quick elimination of curcumol in rats. The bioavailability ranging from 9.2% to 13.1% was calculated based on the area under the curves (AUC) of oral and intravenous administration of curcumol. During tissue distribution, most organs observed a maximum concentration of curcumol within 0.5-1.0 h. A high accumulation of curcumol was found in the small intestine, colon, liver, and kidney. Moreover, high protein binding rates ranging from 85.6% to 93.4% of curcumol were observed in rat plasma. Conclusion: This study characterized the pharmacokinetics, tissue distribution, and protein binding rates of curcumol in rats for the first time, which can provide a solid foundation for research into the mechanisms of curcumol's biological function and clinical application.

7.
Chemosphere ; 308(Pt 2): 136337, 2022 Dec.
Article in English | MEDLINE | ID: mdl-36084834

ABSTRACT

The non-point source pollution induced by phosphorus (P) leaching from fertile soils is accelerating the eutrophication phenomena in aqueous ecosystems. Herein, to alleviate and intercept the P leaching from the fertile soils, diverse P immobilization materials (PIM) which can transform labile P into stable P via a range of physicochemical and biological interactions have been adopted and received increasing research interest. However, the remediation mechanisms of different PIMs were complex and vary with soil properties and PIM application methods. In this review, the P fraction and mobility characteristics of different fertile soils were first introduced. Then, three kinds of PIM including inorganic materials (e.g., clay minerals and red mud), organic materials (e.g., polyacrylamide), and composites (e.g., modified biochar) applied in soil P leaching interception were concluded. The key factors (i.e., soil pH, soil texture, organic matter content and variable soil moisture) influencing PIM performance and potential PIMs used for reducing soil P leaching were also introduced. Current review can favor for proposing more suitable and insightful strategies to regulate the fertile soil P and achieve the dual goals of improving the crop land quality and yield, and preventing agricultural non-point source pollution.


Subject(s)
Soil Pollutants , Soil , Clay , Ecosystem , Minerals , Phosphorus/chemistry , Soil/chemistry , Soil Pollutants/analysis
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