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Background: Chronic cerebral hypoperfusion (CCH) has been confirmed as one of the pathogenesis underlying vascular cognitive impairment. A series of pathological changes, including inflammation, oxidative stress, and apoptosis, are involved in this pathophysiology and contribute to cognitive impairment and neuropathological alterations. The traditional Chinese medicine (TCM) of Buqi Huoxue Tongnao (BQHXTN) prescription possesses a remarkable clinical efficacy for treating patients with CCH, but still lacks a scientific foundation for its pharmacological mechanisms., Purpose: To investigate the role and underlying mechanism of the effects of BQHXTN on CCH both in vitro and in vivo., Methods: In this study, we established a two-vessel occlusion (2-VO) induced CCH model in Sprague-Dawley rats, an oxygen-glucose deprivation model in BV2 cells, and a steatosis cell model in L02 cells to reveal the underlying mechanisms of BQHXTN by behavioral test, histopathological analysis and the detection of pro-inflammatory cytokine, apoptotic factors and reactive oxide species. Donepezil hydrochloride and Buyang Huanwu decoction were used as positive drugs., Results: Compared with the 2-VO group, BQHXTN treatment at three doses significantly enhanced the memory and learning abilities in the Y-maze and novel object recognition tests. The hematoxylin-eosin staining indicated that BQHXTN protected against hippocampal injury induced by CCH. Of note, in both in vivo and in vitro experiments, BQHXTN prominently inhibited the production of IL-1β, TNF-α, cleaved-caspase 3, and iNOS by regulating the PI3K/AKT pathway, consequently exerting anti-inflammatory, anti-apoptotic, and antioxidant effects. Moreover, it provided the first initial evidence that BQHXTN treatment mitigated dyslipidemia by increasing the LXRα/CYP7A1 expression, thereby delaying the neuropathological process., Conclusion: In summary, these findings firstly revealed the pharmacodynamics and mechanism of BQHXTN, that is, BQHXTN could alleviate cognitive impairment, neuropathological alterations and dyslipidemia in CCH rats by activating PI3K/AKT and LXRα/CYP7A1 signaling pathways, as well as providing a TCM treatment strategy for CCH., Competing Interests: Declaration of competing interest We declare no conflict of interest., (Copyright © 2024. Published by Elsevier GmbH.)

Asperulosidic acid is a bioactive iridoid isolated from Hedyotis diffusa Willd. with anti-inflammatory and renal protective effects. However, its mechanism on renal interstitial fibrosis has not been elucidated yet. The present study aims to explore whether asperulosidic acid could retard renal fibrosis by reducing the circulating indoxyl sulfate (IS), which is a uremic toxin and accelerates chronic kidney disease progression by inducing renal fibrosis. In this paper, a unilateral ureteral obstruction (UUO) model of Balb/C mice was established. After the mice were orally administered with asperulosidic acid (14 and 28 mg/kg) for two weeks, blood, liver and kidney were collected for biochemical, histological, qPCR and Western blot analyses. Asperulosidic acid administration markedly reduced the serum IS level and significantly alleviated the histological changes in glomerular sclerosis and renal interstitial fibrosis. It is noteworthy that the mRNA and protein levels of the organic anion transporter 1 (OAT1), OAT3 and hepatocyte nuclear factor 1α (HNF1α) in the kidney were significantly increased, while the mRNA expressions of cytochrome P450 2e1 (Cyp2e1) and sulfotransferase 1a1 (Sult1a1) in the liver were not altered after asperulosidic acid administration. These results reveal that asperulosidic acid could accelerate the renal excretion of IS by up-regulating OATs via HNF1α in UUO mice, thereby alleviating renal fibrosis, but did not significantly affect its production in the liver, which might provide important information for the development of asperulosidic acid.

Designing oral drug delivery systems using intestinal glucose transporters (IGTs) may be one of the strategies for improving oral bioavailability of drugs. However, little is known about the biological factors affecting the drug transport capacity of IGTs. Gastrodin is a sedative drug with a structure very similar to glucose. It is a highly water-soluble phenolic glucoside. It can hardly enter the intestine through simple diffusion but exhibits good oral bioavailability of over 80%. We confirmed that gastrodin is absorbed via the intestinal glucose transport pathway. It has the highest oral bioavailability among the reported glycosides' active ingredients through this pathway. Thus, gastrodin is the most selective drug substrate of IGTs and can be used to evaluate the drug transport capacity of IGTs. Obviously, strain is one of the main biological factors affecting drug absorption. This study firstly compared the drug transport capacity of IGTs between SD rats and Wistar rats and between C57 mice and KM mice by pharmacokinetic experiments and single-pass intestinal perfusion experiments of gastrodin. Then, the sodium-dependent glucose transporter type 1 (SGLT1) and sodium-independent glucose transporters type 2 (GLUT2) in the duodenum, jejunum, ileum and colon of these animals were quantified using RT-qPCR and Western blot. The results showed that the oral bioavailability of gastrodin in Wistar rats was significantly higher than in SD rats and significantly higher in KM mice than in C57 mice. Gastrodin absorption significantly differed among different intestinal segments in SD rats, C57 mice and KM mice, except Wistar rats. RT-qPCR and Western blot demonstrated that the intestinal expression distribution of SGLT1 and GLUT2 in SD rats and C57 mice was duodenum ≈ jejunum > ileum > colon. SGLT1 expression did not differ among different intestinal segments in KM mice, whereas the intestinal expression distribution of GLUT2 was duodenum ≈ jejunum ≈ ileum > colon. However, the expression of SGLT1 and GLUT2 did not differ among different intestinal segments in Wistar rats. It was reported that the intestinal expression distribution of SGLT1 and GLUT2 in humans is duodenum > jejunum > ileum > colon. Hence, the intestinal expression distribution of SGLT1 and GLUT2 of SD rats and C57 mice was more similar to that in humans. In conclusion, the drug transport capacity of IGTs differs in different strains of rats and mice. SD rats and C57 mice are more suitable for evaluating the pharmacokinetics of glycosides' active ingredients absorbed via the intestinal glucose transport pathway., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)