Gastrodin alleviates cisplatin nephrotoxicity by inhibiting ferroptosis via the SIRT1/FOXO3A/GPX4 signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Cisplatin (CP) results in acute kidney injury (AKI) and negatively affects patients' therapy and survival. The dried rhizome of Gastrodia elata Blume has been used to treat clinical kidney diseases. Gastrodin (GAS) is an active ingredient of the G. elata tuber. It is unknown whether GAS can alleviate CP-induced AKI. AIM OF THE STUDY: This study aimed to investigate whether GAS, an active ingredient of G. elata Blume, can alleviate CP-induced AKI and to explore its underlying mechanisms. MATERIALS AND METHODS: Experiments were conducted with a CP-induced AKI mouse model and an immortalized human renal tubular epithelial cell line (HK-2). Serum creatinine, Periodic acid-Schiff staining, tissue iron, glutathione, malondialdehyde, and 4-Hydroxynonenal were detected in serum and kidney samples to observe whether GAS inhibits CP-induced tubule ferroptosis. The drug target was verified by detecting the effects of GAS on sirtuin-1 (SIRT1) activity in vitro. Transcriptional regulation of glutathione peroxidase 4 (GPX4) by forkhead box O3A (FOXO3A) was verified by siRNA knockdown, overexpression, and chromatin immunoprecipitation. The effects of FOXO3A, SIRT1, and GAS on CP-induced ferroptosis were measured with propidium iodide, dihydroethidium, monobromobimane, and dipyrromethene boron difluoride staining in HK-2 cells. The relationship between GAS and the SIRT1/FOXO3A/GPX4 pathway was studied using Western blotting. RESULTS: GAS treatment inhibited CP-induced reactive oxygen species, lipid peroxidation, and tubule death in the cell and animal models. GAS activated SIRT1 in vitro. The SIRT1 inhibitor blocked the protective role of GAS in reducing lipid peroxidation in HK-2 cells. FOXO3A transcriptionally regulated GPX4 expression and inhibited CP-induced cell ferroptosis. Compared to CP-damaged mouse kidneys, GAS-treated mice demonstrated significantly increased SIRT1 and GPX4 expression levels, decreased CP-induced acetylation of FOXO3A, and inhibited lipid peroxidation and cell death. CONCLUSIONS: GAS alleviated CP-induced AKI by inhibiting ferroptosis via the SIRT1/FOXO3A/GPX4 signaling pathway. The results offer new insights into the development of new anti-AKI drugs from traditional Chinese medicine.

Post-stroke gastrodin treatment ameliorates ischemic injury and increases neurogenesis and restores the Wnt/ß-Catenin signaling in focal cerebral ischemia in mice.

Cerebral ischemic stroke is one of the leading causes of death and disability worldwide, and the only available drug treatment is limited to a short window following the ischemic event. Gastrodin is the major bioactive constituent extracted from thetuberGastrodia elata, and is currently used to treat dizziness in the clinic. "Early" application of gastrodin (before modeling or immediately after ischemic injury) has shown antioxidative and neuroprotective effects in a transient focal brain ischemia model in rodents; however, it is not known whether the delayed administration of gastrodin after permanent focal cerebral ischemia ameliorates neural injury and increases neurogenesis. In this study, we performed a permanent middle cerebral artery occlusion (MCAO) model for the study of cerebral ischemic stroke in adult male mice to examine the effects of gastrodin. Gastrodin treatment that was started "late" (one day after the ischemic injury) significantly improved neural function, reduced infarct volume and apoptosis, and increased the number of DCX/BrdU double-positive cells in permanent MCAO mice. Moreover, gastrodin treatment markedly preserved the Wnt/ß-Catenin signaling pathway, which could promote neurogenesis and provide neuroprotection brain injury. Our findings suggest that gastrodin treatment following ischemic injury can induce neuroprotection, promote neurogenesis and restored the Wnt /ß-Catenin signaling pathway.

Wip1 knockout inhibits neurogenesis by affecting the Wnt/ß-catenin signaling pathway in focal cerebral ischemia in mice.

Neurogenesis correlates closely with the recovery of neural function after brain ischemia but the critical proteins and signaling pathways involved remain unclear. The phosphatase WIP1 has been shown to regulate neurogenesis in models of aging. However, it is not known if WIP1 affects neurogenesis and functional recovery after brain ischemia. To explore these questions, we performed permanent middle cerebral artery occlusion (MCAO) in mice and performed BrdU labeling, neurobehavioral testing, western blotting, and immunofluorescence staining. We found that ischemia induced WIP1 expression in the area bordering the injury. Compared to wild-type mice, the knockout of the Wip1 gene inhibited neurological functional recovery, reduced the expression of doublecortin, and inactivated the Wnt/ß-Catenin signaling pathway in cerebral ischemia in mice. Pharmacological activation of the Wnt/ß-Catenin signaling pathway compensated for the Wip1 knockout-induced deficit in neuroblast formation in animals with MCAO. These findings indicate that WIP1 is essential for neurogenesis after brain injury by activating the Wnt/ß-Catenin signaling pathway.

A new therapy for the reduction of axon and neuron loss and promotion of axon and oligodendrocyte regeneration through inhibition of death receptor 6 pathway after ischemic cerebral stroke.

Ischemic cerebral stroke may cause disability and rehabilitation is mainly dependent on long-term exercise. However, this needs many years of consistent application. Even then, it is not certain that patients will see satisfactory recovery of function. In the ischemic stroke, disability is attributed to neuron and axon loss resulting in injury to the nervous tract. In the nerve injury model, recovery of function is dependent on axon regeneration and rewiring of the nervous tract, which may be promoted and improved through appropriate drug intervention. Death receptor 6 (DR6), a member of the tumor necrosis factor (TNF) receptor superfamily, negatively regulates neuron, axon and oligodendrocyte survival and hinders axon and oligodendrocyte regeneration. Inhibition of DR6 has shown neuroprotection in nerve injury models. We hypothesized, therefore, that pharmacological inhibition of DR6 could be beneficial to the survival of axons and neurons, the regeneration of axons and oligodendrocytes, and the improvement of neurological function after ischemic cerebral stroke.

Comparison of corneal curvature, anterior chamber depth and axial length measured by IOLMaster, Orbscan Ⅱ and ultrasound before and after LASIK / 中华实验眼科杂志

BackgroundIt is important to measure the corneal curvature, anterior chamber depth (ACD) and axial length accurately for calculating IOL power. The interchange outcomes from different measuring methods and apparatus will cause unreliable IOL power. ObjectiveThe present study was to compare the differences of corneal curvature, anterior chamber depth (ACD) measured by IOLMaster and Orbscan Ⅱbefore and after laser in situ keratomileusis(LASIK) and further compare the axial length measured by IOLMaster and A-ultrasound. Methods One hundred and thirty eyes from 65 consecutive myopic patients before LASIK and 56 eyes of 28 cases with 1-month follow-up duration after LASIK in Henan Eye Institute were enrolled in this study. The K value, ACD between IOLMaster and Orbscan Ⅱ as well as results of axial length between IOLMaster and A-ultrasound were compared by using paired t test. The agreements of the measured values among IOLMaster, Orbscan Ⅱ and A-ultrasound were evaluated using Bland-Altman plot. ResultsBefore LASIK,the K value measured by IOLMaster,Orbscan Ⅱ were ( 43.32 ± 1.52 ) D and ( 42.99 ± 1.45 ) D respectively with the difference value of( 0. 33 ±0. 03 ) D, showing a significant difference(t=10. 380,P=0.000) and a positive relation between them(r=0.971,P=0.000). After LASIK,the K value measured by IOLMaster, Orbscan Ⅱwere(39. 02±2. 14) D and ( 38.91 ±2. 04) D with the difference value (0. 12±0. 33 ) D, presenting a significant differences between them (t =2.715, P =0.009). Bland-Altman plots indicated the disagreement in K value and uninterchangeable. Before LASIK, the ACD measured by IOLMaster,Orbscan Ⅱ and A-ultrasound were ( 3.72 ± 0. 22 ) mm, ( 3.69 ±0. 22 ) mm and ( 3.75± 0.27 )mm respectively and no significant differences were found between them (P ＞ 0. 05 ). Axial length measured by IOLMaster significantly prolonged in comparison with A-ultrasound(25.59± 1. 01 mm vs 25.22±0.99 mm ) , and the difference was( -0. 37 ±0. 30 ) mm, showing significant difference ( t =- 14. 098, P =0. 000 ) and positive correlation ( r =0. 954, P =0. 000 ). Axial length values measured by IOLMaster were ( 25.54 ± 1.05 ) mm in preoperation and ( 25.48 ± 1.01 ) mm in postoperation with the difference (0.052±0. 412)mm, showing statistically insignificant difference between them (t=0. 946,P=0. 348). ConclusionsKeratometries measured by IOLMaster,Orbscan Ⅱ are much more different. Therefore,these two methods are not recommended to use interchangely. ACD measured by IOLMaster,Orbscan Ⅱ and A ultrasound are proved to obtain the similar results and is clinically interchange. Axial length measured by IOLMaster is longer than that measured by A-ultrasound.