Ethanol extract of Evodia lepta Merr. ameliorates cognitive impairment through inhibiting NLRP3 inflammasome in scopolamine-treated mice.

Evodia lepta Merr. (Evodia lepta) is a well-known traditional Chinese medicine, which has been widely used in herbal tea. We previously reported that the coumarin compounds from the root of Evodia lepta exhibited neuroprotective effects. However, whether Evodia lepta could inhibit NLRP3 inflammasome in dementia was still unknown. In this study, the components of the Evodia lepta extract were identified by HPLC-Q-TOF HRMS. We employed a scopolamine-treated mouse model. Evodia lepta extract (10 or 20 mg/kg) and donepezil were treated by gavage once a day for 14 consecutive days. Following the behavioral tests, oxidative stress levels were measured. Then, Western blot and immunofluorescence analysis were used to evaluate the expressions of NLRP3 inflammasome. 14 major components of the Evodia lepta extract were identified by HPLC-Q-TOF HRMS. The results of Morris water maze, object recognition task and open field test indicated that Evodia lepta extract could ameliorate cognitive impairment in scopolamine-treated mice. Evodia lepta extract improved cholinergic system. Moreover, Evodia lepta extract improved the expressions of PSD95 and BDNF. Evodia lepta extract suppressed neuronal oxidative stress and apoptosis. In addition, Evodia lepta extract inhibited NLRP3 inflammasome in the hippocampus of scopolamine-treated mice. Evodia lepta extract could protect against cognitive impairment by inhibiting NLRP3 inflammasome in scopolamine-treated mice.

Tanshinone IIA, the key compound in Salvia miltiorrhiza, improves cognitive impairment by upregulating Aß-degrading enzymes in APP/PS1 mice.

In Alzheimer's disease (AD), amyloid-beta (Aß) plays a crucial role in pathogenesis. Clearing Aß from the brain is considered as a key therapeutic strategy. Previous studies indicated that Salvia miltiorrhiza (Danshen) could protect against AD. However, the main anti-AD components in Danshen and their specific mechanisms are not clear. In this study, pharmacological network analysis indicated that Tanshinone IIA (Tan IIA) was identified as the key active compound in Danshen contributing to protect against AD. Then, APP/PS1 double transgenic mice were employed to examine the neuroprotective effect of Tan IIA. APP/PS1 mice (age, 6 months) were administered (10 and 20 mg/kg) for 8 weeks. Tan IIA improved learning and anxiety behaviors in APP/PS1 mice. Furthermore, Tan IIA reduced oxidative stress, inhibited neuronal apoptosis, improved cholinergic nervous system and decreased endoplasmic reticulum stress in the brain of APP/PS1 mice. Moreover, Tan IIA treatment reduced the level of Aß. Molecular docking result showed that Tan IIA might block AD by upregulating Aß-degrading enzymes. Western blot results confirmed that the expressions of insulin degrading enzymes (IDE) and neprilysin (NEP) were significantly increased after Tan IIA treatment, which demonstrated that Tan IIA improved AD by increasing Aß-degrading enzymes.

Taohong siwu decoction ameliorates cognitive dysfunction through SIRT6/ER stress pathway in Alzheimer's disease.

ETHNOPHARMACOLOGICAL RELEVANCE: A growing number of people suffer from Alzheimer's disease (AD), but there is currently no effective treatment yet. Taohong Siwu Decoction (TSD) has been proved to take strong neuropharmacological activity on dementia, but the effect and mechanism of TSD against AD are still elusive. AIM OF STUDY: To investigate whether TSD could be effective in ameliorating cognitive deficits through SIRT6/ER stress pathway. MATERIALS AND METHODS: Herein, the APP/PS1 mice, an AD model, and HT-22 cell lines were utilized. Different dosages of TSD (4.25, 8.50 and 17.00 g/kg/d) were administered to the mice for 10 weeks by gavage. Following the behavioral tests, oxidative stress levels were measured using malondialdehyde (MDA) and superoxide dismutase (SOD) kits. Nissl staining and Western blot analyses were used to detect the neuronal function. Then, immunofluorescence and Western blot analysis were applied to evaluate silent information regulator 6 (SIRT6) and ER Stress related protein levels in APP/PS1 mice and HT-22 cells. RESULTS: Behavioral tests revealed that APP/PS1 mice administered with TSD orally took more time in the target quadrant, crossed more times in the target quadrant, had a higher recognition coefficient, and spent more time in the central region. In addition, TSD could ameliorate oxidative stress and inhibit neuronal apoptosis in APP/PS1 mice. Furthermore, TSD could up-regulate the SIRT6 protein expression and inhibit ER sensing proteins expressions, such as p-PERK and ATF6, in APP/PS1 mice and Aß1-42-treated HT22 cells. CONCLUSION: According to the abovementioned findings, TSD could alleviate cognitive dysfunction in AD by modulating the SIRT6/ER stress pathway.

Hydroxysafflor Yellow A Exerts Neuroprotective Effect by Reducing Aß Toxicity Through Inhibiting Endoplasmic Reticulum Stress in Oxygen-Glucose Deprivation/Reperfusion Cell Model.

Ischemia stroke is thought to be one of the vascular risks associated with neurodegenerative diseases, such as Alzheimer's disease (AD). Hydroxysafflor yellow A (HSYA) has been reported to protect against stroke and AD, while the underlying mechanism remains unclear. In this study, SH-SY5Y cell model treated with oxygen-glucose deprivation/reperfusion (OGD/R) was used to explore the potential mechanism of HSYA. Results from cell counting kit-8 (CCK-8) showed that 10 µM HSYA restored the cell viability after OGD 2 hours/R 24 hours. HSYA reduced the levels of malondialdehyde and reactive oxygen species, while improved the levels of superoxide dismutase and glutathione peroxidase. Furthermore, apoptosis was inhibited, and the expression of brain-derived neurotrophic factor was improved after HSYA treatment. In addition, the expression levels of amyloid-ß peptides (Aß) and BACE1 were decreased by HSYA, as well as the expression levels of binding immunoglobulin heavy chain protein, PKR-like endoplasmic reticulum (ER) kinase pathway, and activating transcription factor 6 pathway, whereas the expression level of protein disulfide isomerase was increased. Based on these results, HSYA might reduce Aß toxicity after OGD/R by interfering with apoptosis, oxidation, and neurotrophic factors, as well as relieving ER stress.

Tanshinone IIA ameliorates Aß transendothelial transportation through SIRT1-mediated endoplasmic reticulum stress.

BACKGROUND: The disruption of blood-brain barrier (BBB), predominantly made up by brain microvascular endothelial cells (BMECs), is one of the characteristics of Alzheimer's disease (AD). Thus, improving BMEC function may be beneficial for AD treatment. Tanshinone IIA (Tan IIA) has been proved to ameliorate the cognitive dysfunction of AD. Herein, we explored how Tan IIA affected the function of BMECs in AD. METHODS: Aß1-42-treated brain-derived endothelium cells.3 (bEnd.3 cells) was employed for in vitro experiments. And we performed molecular docking and qPCR to determine the targeting molecule of Tan IIA on Sirtuins family. The APPswe/PSdE9 (APP/PS1) mice were applied to perform the in vivo experiments. Following the behavioral tests, protein expression was determined through western blot and immunofluorescence. The activities of oxidative stress-related enzymes were analyzed by biochemically kits. Nissl staining and thioflavin T staining were conducted to reflect the neurodegeneration and Aß deposition respectively. RESULTS: Molecular docking and qPCR results showed that Tan IIA mainly acted on Sirtuin1 (SIRT1) in Sirtuins family. The inhibitor of SIRT1 (EX527) was employed to further substantiate that Tan IIA could attenuate SIRT1-mediated endoplasmic reticulum stress (ER stress) in BMECs. Behavioral tests suggested that Tan IIA could improve the cognitive deficits in APP/PS1 mice. Tan IIA administration increased SIRT1 expression and alleviated ER stress in APP/PS1 mice. In addition, LRP1 expression was increased and RAGE expression was decreased after Tan IIA administration in both animals and cells. CONCLUSION: Tan IIA could promote Aß transportation by alleviating SIRT1-mediated ER stress in BMECs, which ameliorated cognitive deficits in APP/PS1 mice.

Ligustilide Improves Cognitive Impairment via Regulating the SIRT1/IRE1α/XBP1s/CHOP Pathway in Vascular Dementia Rats.

Vascular dementia (VaD), the second cause of dementia, is caused by chronic cerebral hypoperfusion, producing progressive damage to cerebral cortex, hippocampus, and white matter. Ligustilide (LIG), one of the main active ingredients of Angelica sinensis, exerts the neuroprotective effect on neurodegenerative diseases. However, the mechanism remains unclear. An in vivo model of bilateral common carotid artery occlusion and in vitro model of oxygen glucose deprivation (OGD) were employed in this study. LIG (20 or 40 mg/kg/day) was intragastrically administered to the VaD rats for four weeks. The results of the Morris water maze test demonstrated that LIG effectively ameliorated learning and memory deficiency in VaD rats. LIG obviously relieved neuronal oxidative stress damage by increasing the activities of catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GSH-PX) and decreasing the level of malondialdehyde (MDA) in VaD rats. Nissl staining showed that LIG increased the number of the Nissl body in VaD rats. After LIG administration, the apoptotic-related protein, Bax, was decreased and Bcl-2 was increased in the hippocampus of VaD rats. Moreover, the expressions of sirtuin 1 (SIRT1) and protein disulfide isomerase (PDI) were decreased, binding immunoglobulin protein (BIP) and phospho-inositol-requiring enzyme-1α (P-IRE1α), X-box binding protein 1 (XBP1s), and C/EBP-homologous protein (CHOP) were increased in VaD rats. After LIG treatment, these changes were reversed. The immunofluorescence results further showed that LIG upregulated the expression of SIRT1 and downregulated the expression of P-IRE1α in VaD rats. In addition, in vitro experiment showed that EX-527 (SIRT1 inhibitor) partly abolished the inhibitory effect of LIG on the IRE1α/XBP1s/CHOP pathway. In conclusion, these studies indicated that LIG could improve cognitive impairment by regulating the SIRT1/IRE1α/XBP1s/CHOP pathway in VaD rats.

Ligustilide ameliorates cognitive impairment via AMPK/SIRT1 pathway in vascular dementia rat.

Vascular dementia (VaD) is the second cause of dementia after Alzheimer's disease. Ligustilide (LIG) is one of the main active ingredients of traditional Chinese medicines, such as Angelica. Studies have reported that LIG could protect against VaD. However, the mechanism is still confused. In this study, we employed a bilateral common carotid artery occlusion rat model to study. LIG (20 or 40 mg/kg/day) and Nimodipine (20 mg/kg) were orally administered to the VaD rats for four weeks. Morris water maze test showed that LIG effectively ameliorated learning and memory impairment in VaD rats. LIG obviously reduced neuronal oxidative stress damage and the level of homocysteine in the brain of VaD rats. Western blot results showed that pro-apoptotic protein Bax and cleaved caspase 3 increased and anti-apoptotic protein Bcl-2 decreased in the hippocampi of VaD rats. But after LIG treatment, these changes were reversed. Moreover, Nissl staining result showed that LIG could reduce neuronal degeneration in VaD rats. Furthermore, LIG enhanced the expressions of P-AMPK and Sirtuin1(SIRT1) in VaD rats. In conclusion, these studies indicated that LIG could ameliorate cognitive impairment in VaD rats, which might be related to AMPK/SIRT1 pathway activation.

Carnosine Improves Cognitive Impairment Through Promoting SIRT6 Expression and Inhibiting Endoplasmic Reticulum Stress in a Diabetic Encephalopathy Model.

Diabetic encephalopathy (DE) is one of complications of diabetes mellitus. Carnosine is a dipeptide composed of ß-alanine and l-histidine. Study has shown that carnosine could ameliorate cognitive impairment in animal model with diabetes mellitus. However, the mechanism remains unclear. An animal model of type 2 diabetes (db/db mice) was used in this study. The animals were treated with 0.9% saline or carnosine (100 mg/kg) for 8 weeks. Morris water maze was tested after drug administration. Oxidative stress-related factors malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-PX), and pro-inflammatory factors inducible nitric oxide synthase (iNOS) were measured. Synapse-related protein postsynaptic density 95 (PSD95) and brain-derived neurotrophic factor (BDNF) were detected by western blot. Besides, the expressions of sirtuin 6 (SIRT6), binding immunoglobulin protein (BIP), protein kinase R-like endoplasmic reticulum kinase (PERK), phospho-protein kinase R-like endoplasmic reticulum kinase (P-PERK), inositol-requiring enzyme-1α (IRE1α), phospho-inositol-requiring enzyme-1α (P-IRE1α), activating transcription factor 6 (ATF6), and C/EBP-homologous protein (CHOP) in the hippocampus of the brain were detected. The results showed that treatment with carnosine ameliorated cognitive impairment in db/db mice. Carnosine reduced neuronal oxidative stress damage and iNOS expression in db/db mice. Meanwhile, carnosine relieved neurodegeneration in the hippocampus of db/db mice. Furthermore, carnosine promoted the expression of SIRT6 and reduced the expressions of endoplasmic reticulum (ER)-related factors (BIP, P-PERK, P-IRE1α, ATF6, and CHOP). In conclusion, these data suggested that the protective effect of carnosine against DE might be related to SIRT6/ER stress pathway.

Sodium tanshinone IIA sulfonate improves cognitive impairment via regulating Aß transportation in AD transgenic mouse model.

Alzheimer's disease (AD) is a most common neurodegenerative disease. Sodium Tanshinone IIA Sulfonate (STS) has been reported to ameliorate AD pathology. However, the underlying mechanism is still unclear. In this study, AD transgenic mouse model (APP/PS1) was used to explore the potential mechanism of STS against AD. Morris water maze and Y-maze tests showed that administration of STS improved learning and memory abilities of APP/PS1 mice. STS reduced the levels of reactive oxygen species and malondialdehyde, while improved the activity of superoxide dismutase in both hippocampus and cortex in APP/PS1 mice. STS inhibited the activity of acetylcholinesterase, while improved the activity of choline acetyltransferase in APP/PS1 mice. In addition, STS elevated the protein expressions of neurotrophic factors and synapse-related proteins in both the hippocampus and cortex in APP/PS1 mice. At last, STS improved the protein expressions of glucose transporter 1 (GLUT1) and low-density lipoprotein receptor-related protein 1 (LRP1). These results indicated that the potential mechanism of STS on AD might be related to Aß transportation function via GLUT1/LRP1 pathway. HIGHLIGHTS: STS improves cognitive impairment of APP/PS1 mice. STS ameliorates the oxidative stress damage and improves the cholinergic system. STS protects against neuronal dysfunction and enhances the synaptic plasticity. STS mediates the Aß transportation of BMECs.

Different training durations and styles of tai chi for glucose control in patients with type 2 diabetes: a systematic review and meta-analysis of controlled trials.

BACKGROUND: Physical activity is an important part of the diabetes management plan. However, the effects caused by different training durations and styles of Tai Chi have not been evaluated. We conducted an updated systematic review of the effects of Tai Chi on patients with type 2 diabetes based on different training durations and styles. METHODS: We performed a search for Chinese and English studies in 8 databases. Two reviewers independently selected the eligible trials and conducted a critical appraisal of the methodological quality. RESULTS: Seventeen trials were included. Tai Chi was found to have reduced fasting blood glucose (FBG) [SMD = - 0.54, 95% CI (- 0.91, - 0.16), P = 0.005] and HbA1c [SMD = - 0.68, 95% CI (- 1.17, - 0.19), P = 0.006] overall, compared with a control group. Considering the subgroup analysis, the pooled results showed that 24 movements or Yang-style Tai Chi did not significantly reduce FBG after a duration of ≤3 months [SMD = - 0.46, 95% CI (- 1.42, 0.50), P = 0.35] or > 3 months [SMD = - 0.50, 95% CI (- 1.49, 0.49), P = 0.32], nor did it reduce HbA1c [SMD = - 1.22, 95% CI (- 2.90, 0.47), P = 0.16] after a duration > 3 months in all studies. However, other styles of Tai Chi significantly reduced FBG [SMD = - 0.90, 95% CI (- 1.28, - 0.52), P < 0.00001] and HbA1c [SMD = - 0.90, 95% CI (- 1.28, - 0.52), P < 0.00001] after a duration > 3 months, while no significant reduction in FBG [SMD = - 0.34, 95% CI (- 0.76, 0.08), P = 0.12] or HbA1c [SMD = - 0.34, 95% CI (- 0.76, 0.08), P = 0.12] was found after a duration ≤3 months. CONCLUSIONS: Tai Chi seems to be effective in treating type 2 diabetes. Different training durations and styles result in variable effectiveness. The evidence was insufficient to support whether long-term Tai Chi training was more effective.