Shengmaisan combined with Liuwei Dihuang Decoction alleviates chronic intermittent hypoxia-induced cognitive impairment by activating the EPO/EPOR/JAK2 signaling pathway.

Chronic intermittent hypoxia (CIH), a principal pathophysiological aspect of obstructive sleep apnea (OSA), is associated with cognitive deficits. Clinical evidence suggests that a combination of Shengmaisan and Liuwei Dihuang Decoctions (SMS-LD) can enhance cognitive function by nourishing yin and strengthening the kidneys. This study aimed to assess the efficacy and underlying mechanisms of SMS-LD in addressing cognitive impairments induced by CIH. We exposed C57BL/6N mice to CIH for five weeks (20%-5% O2, 5 min/cycle, 8 h/day) and administered SMS-LD intragastrically (15.0 or 30 g·kg-1·day) 30 min before each CIH session. Additionally, AG490, a JJanus kinase 2 (JAK2) inhibitor, was administered via intracerebroventricular injection. Cognitive function was evaluated using the Morris water maze, while synaptic and mitochondrial structures were examined by transmission electron microscopy. Oxidative stress levels were determined using DHE staining, and the activation of the erythropoietin (ER)/ER receptor (EPOR)/JAK2 signaling pathway was analyzed through immunohistochemistry and Western blotting. To further investigate molecular mechanisms, HT22 cells were treated in vitro with either SMS-LD medicated serum alone or in combination with AG490 and then exposed to CIH for 48 h. Our results indicate that SMS-LD significantly mitigated CIH-induced cognitive impairments in mice. Specifically, SMS-LD treatment enhanced dendritic spine density, ameliorated mitochondrial dysfunction, reduced oxidative stress, and activated the EPO/EPOR/JAK2 signaling pathway. Conversely, AG490 negated SMS-LD's neuroprotective and cognitive improvement effects under CIH conditions. These findings suggest that SMS-LD's beneficial impact on cognitive impairment and synaptic and mitochondrial integrity under CIH conditions may predominantly be attributed to the activation of the EPO/EPOR/JAK2 signaling pathway.

Chronic intermittent hypoxia aggravated diabetic cardiomyopathy through LKB1/AMPK/Nrf2 signaling pathway.

Chronic intermittent hypoxia (CIH) may play an important role in the development of diabetic cardiomyopathy (DCM). However, the exact mechanism of CIH-induced myocardial injury in DCM remains unclear. In vivo, the db/db mice exposed to CIH were established, and in vitro, the H9C2 cells were exposed to high glucose (HG) combined with intermittent hypoxia (IH). The body weight (BW), fasting blood glucose (FBG) and food intake were measured every two weeks. The glycolipid metabolism was assessed with the oral glucose tolerance test (OGTT) and insulin resistance (IR). Cardiac function was detected by echocardiography. Cardiac pathology was detected by HE staining, Masson staining, and transmission electron microscopy. The level of reactive oxygen species (ROS) in myocardial tissue was detected by dihydroethidium (DHE). The apoptosis was detected by TUNEL staining. The cell viability, ROS, and the mitochondrial membrane potential were detected by the cell counting kit-8 (CCK-8) assay and related kits. Western blotting was used to analyze the liver kinase B1/AMP-activated protein kinase/ nuclear factor-erythroid 2-related factor 2 (LKB1/AMPK/Nrf2) signaling pathway. CIH exposure accelerated glycolipid metabolism disorders and cardiac injury, and increased the level of cardiac oxidative stress and the number of positive apoptotic cells in db/db mice. IH and HG decreased the cell viability and the level of mitochondrial membrane potential, and increased ROS expression in H9C2 cells. These findings indicate that CIH exposure promotes glycolipid metabolism disorders and myocardial apoptosis, aggravating myocardial injury via the LKB1/AMPK/Nrf2 pathway in vitro and in vivo.

Danggui-Buxue decoction alleviated vascular senescence in mice exposed to chronic intermittent hypoxia through activating the Nrf2/HO-1 pathway.

CONTEXT: As a major risk factor for cardiovascular diseases (CVD), Obstructive sleep apnea (OSA) is characterized by chronic intermittent hypoxia (CIH). Recent studies indicated that the increased cardiovascular risk in patients with OSA may be mediated by accelerated vascular senescence. Danggui-Buxue decoction (DBD) has been used for treating cardiovascular diseases, but its mechanism of vascular senescence regulation is still unclear. OBJECTIVE: To investigate the effect of DBD on vascular senescence in mice exposed to CIH and to explore the role of the Nrf2/HO-1 pathway. MATERIALS AND METHODS: C57BL/6N mice were randomly divided into Normoxia control group (CON), CIH (21%-5% O2, 20 times/h, 8 h/d) exposed group (CIH), and DBD treatment group (intragastrically treated with 2.34, 4.68, or 9.36 g/kg/day of DBD separately for 12 weeks as DBL, DBM, or DBH). Blood pressure, cardiac and vascular function, vascular senescence, inflammation response, oxidative stress, and Nrf2/HO-1 expression were determined. RESULTS: DBD (4.68 and 9.36 g/kg) significantly decreased Tail-cuff blood pressure, increased left ventricular systolic function, and alleviated arterial stiffness and vasorelaxation dysfunction in mice exposed to CIH. DBD treatment reduced SA-ß-gal activity, decreased p16 (0.68-fold, 0.62-fold), P21 (0.58-fold, 0.52-fold), and p53 expressions (0.67-fold, 0.65-fold), and increased SIRT1 expression (2.22-fold, 2.98-fold) in the aortic. DBD treatment decreased IL-6, NF-κB, and TNF-α expressions, decreased MDA but increased SOD levels, and increased Nrf2 (1.8-fold, 1.89-fold) and HO-1 (2.25-fold, 2.43-fold) expression. DISCUSSION AND CONCLUSIONS: DBD could attenuate vascular senescence accelerated by CIH exposure through inhibiting inflammatory response and oxidative stress by activating the Nrf2/HO-1 pathway.

Tanshinone IIA inhibited intermittent hypoxia induced neuronal injury through promoting autophagy via AMPK-mTOR signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Chronic intermittent hypoxia (CIH) is the primary pathophysiological process of obstructive sleep apnea (OSA) and is closely linked to neurocognitive dysfunction. Tanshinone IIA (Tan IIA) is extracted from Salvia miltiorrhiza Bunge and used in Traditional Chinese Medicine (TCM) to improve cognitive impairment. Studies have shown that Tan IIA has anti-inflammatory, anti-oxidant, and anti-apoptotic properties and provides protection in intermittent hypoxia (IH) conditions. However, the specific mechanism is still unclear. AIM OF THE STUDY: To assess the protective effect and mechanism of Tan IIA treatment on neuronal injury in HT22 cells exposed to IH. MATERIALS AND METHODS: The study established an HT22 cell model exposed to IH (0.1% O2 3 min/21% O2 7 min for six cycles/h). Cell viability was determined using the Cell Counting Kit-8, and cell injury was determined using the LDH release assay. Mitochondrial damage and cell apoptosis were observed using the Mitochondrial Membrane Potential and Apoptosis Detection Kit. Oxidative stress was assessed using DCFH-DA staining and flow cytometry. The level of autophagy was assessed using the Cell Autophagy Staining Test Kit and transmission electron microscopy (TEM). Western blot was used to detect the expressions of the AMPK-mTOR pathway, LC3, P62, Beclin-1, Nrf2, HO-1, SOD2, NOX2, Bcl-2/Bax, and caspase-3. RESULTS: The study showed that Tan IIA significantly improved HT22 cell viability under IH conditions. Tan IIA treatment improved mitochondrial membrane potential, decreased cell apoptosis, inhibited oxidative stress, and increased autophagy levels in HT22 cells under IH conditions. Furthermore, Tan IIA increased AMPK phosphorylation and LC3II/I, Beclin-1, Nrf2, HO-1, SOD2, and Bcl-2/Bax expressions, while decreasing mTOR phosphorylation and NOX2 and cleaved caspase-3/caspase-3 expressions. CONCLUSION: The study suggested that Tan IIA significantly ameliorated neuronal injury in HT22 cells exposed to IH. The neuroprotective mechanism of Tan IIA may mainly be related to inhibiting oxidative stress and neuronal apoptosis by activating the AMPK/mTOR autophagy pathway under IH conditions.