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This study aimed to elucidate the role of the G protein-coupled receptor 35 (GPR35)/AMP-activated protein kinase (AMPK)/mechanistic target of rapamycin (mTOR) signaling axis in mediating mitochondrial energy metabolism in radiation-induced myocardial fibrosis (RIMF) and to evaluate the interventional effect of astragaloside Ⅳ (AS-Ⅳ). Forty Wistar rats were randomly divided into four groups (n=10 per group). Except for the blank group, all rats were anesthetized and subjected to a single 40-Gy local thoracic X-ray irradiation to establish the RIMF model. After irradiation, AS-Ⅳ was administered intragastrically once daily at doses of 80 and 160 mg·kg-1 for 30 consecutive days. After 30 days of continuous administration, the serum levels of N-terminal pro-B-type natriuretic peptide (NT-proBNP), cardiac troponinI (cTnI), and creatine kinase-MB (CK-MB) were quantified by ELISA. Hematoxylin-eosin (HE) and Masson staining were used to observe myocardial histopathological changes, and TUNEL staining was performed to detect cardiomyocyte apoptosis. The levels of adenosine triphosphate (ATP), adenosine diphosphate (ADP), and adenosine monophosphate (AMP), as well as the activities of mitochondrial respiratory chain complexes Ⅰ-Ⅳ, were measured colorimetrically. The fluorescence intensity of Ca2+ in myocardial tissue was detected using a fluorescent probe, and ultrastructural changes were observed by transmission electron microscopy. The fluorescence intensity and protein expression levels of GPR35, phosphorylated AMPK (p-AMPK), phosphorylated mTOR (p-mTOR), Caspase-3, Caspase-9, B-cell lymphoma-2 (Bcl-2), Bcl-2-associated X protein (Bax), type Ⅰ collagen (COL-Ⅰ), and α-smooth muscle actin (α-SMA) in myocardial tissue were analyzed by immunofluorescence and Western blot. Results showed that compared with the blank group, serum NT-proBNP, cTnI, and CK-MB levels in the model group were significantly increased. Myocardial tissue exhibited focal myocyte necrosis and dissolution, connective tissue hyperplasia, and an increased area of collagen fiber positivity. The cardiomyocyte apoptosis rate was elevated. Myocardial ATP levels were significantly decreased, while ADP and AMP levels were significantly increased. The activities of mitochondrial respiratory chain complexes Ⅰ-Ⅳ were markedly reduced. The Ca2+ fluorescence intensity in myocardial cells was significantly enhanced. Severe mitochondrial damage was observed, showing flocculent changes, increased numbers of damaged mitochondria, swelling, rupture, disordered arrangement, disrupted cristae, and partial vacuolation. The fluorescence intensity and protein expression levels of GPR35, p-AMPK, Bax, Caspase-3, Caspase-9, COL-Ⅰ, and α-SMA in myocardial tissue were significantly increased, whereas those of p-mTOR and Bcl-2 were decreased. Compared with the model group, AS-Ⅳ significantly reduced serum NT-proBNP, cTnI, and CK-MB levels, markedly decreased the cardiomyocyte apoptosis rate, significantly increased ATP levels while reducing ADP and AMP content, enhanced the activities of mitochondrial respiratory chain complexes Ⅰ-Ⅳ, diminished Ca2+ fluorescence intensity, and alleviated mitochondrial damage, with mitochondria arranged more regularly. The fluorescence intensity and protein expression levels of GPR35, p-AMPK, Bax, Caspase-3, Caspase-9, COL-Ⅰ, and α-SMA were significantly decreased, while those of p-mTOR and Bcl-2 were increased. In conclusion, AS-Ⅳ exerts an inhibitory effect on RIMF, and its mechanism may be associated with the regulation of the GPR35/AMPK/mTOR signaling axis to improve mitochondrial energy metabolism.
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| 科 Family | 属数 Number of genus | 种数 Number of species | 占总种数比例 Percentage of total species (%) | 属 Genus | 种数 Number of species | 占总种数比例 Percentage of total species (%) |
|---|---|---|---|---|---|---|
| 鹅膏菌科Amanitaceae | 2 | 11 | 5.26 | 鹅膏菌属 Amanita | 10 | 4.78 |
| 小菇科 Mycenaceae | 2 | 12 | 5.74 | 丝盖伞属 Inocybe | 5 | 2.39 |
| 多孔菌科 Polyporaceae | 8 | 14 | 6.70 | 蜡蘑属 Laccaria | 5 | 2.39 |
| 红菇科 Russulaceae | 3 | 23 | 11.00 | 小皮伞属 Marasmius | 6 | 2.87 |
| 小菇属 Mycena | 11 | 5.26 | ||||
| 光柄菇属 Pluteus | 5 | 2.39 | ||||
| 红菇属 Russula | 17 | 8.13 | ||||
| 栓菌属 Trametes | 5 | 2.39 |
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