Taohong Siwu decoction alleviates cognitive impairment by suppressing endoplasmic reticulum stress and apoptosis signaling pathway in vascular dementia rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Taohong Siwu Decoction (TSD), a classic traditional Chinese medicine formula, is used for the treatment of vascular diseases, including vascular dementia (VD). However, the mechanisms remain unclear. AIM OF STUDY: This study aimed to investigate whether TSD has a positive effect on cognitive impairment in VD rats and to confirm that the mechanism of action is related to the Endoplasmic Reticulum stress (ERs) and cell apoptosis signaling pathway. MATERIALS AND METHODS: A total of 40 male adult Sprague-Dawley rats were divided into four groups: sham-operated group (Sham), the two-vessel occlusion group (2VO), the 2VO treated with 4.5 g/kg/d TSD group (2VO + TSD-L), the 2VO treated with 13.5 g/kg/d TSD group (2VO + TSD-H). The rats underwent either 2VO surgery or sham surgery. Postoperative TSD treatment was given for 4 consecutive weeks. Behavioral tests were initiated at the end of gastrulation. Open-field test (OFT) was used to detect the activity level. The New Object Recognition test (NOR) was used to test long-term memory. The Morris water maze (MWM) test was used to examine the foundation of spatial learning and memory. As a final step, the hippocampus was taken for molecular testing. The protein levels of GRP78 (Bip), p-PERK, PERK, IRE1α, p-IRE1α, ATF6, eIF2α, p-eIF2α, ATF4, XBP1, Bcl-2 and Bax were determined by Western blot. Immunofluorescence visualizes molecular expression. RESULTS: In the OFT, residence time in the central area was significantly longer in both TSD treatment groups compared to the 2VO group. In the NOR, the recognition index was obviously elevated in both TSD treatment groups. The 2VO group had a significantly longer escape latency and fewer times in crossing the location of the platform compared with the Sham group in MWM. TSD treatment reversed this notion. Pathologically, staining observations confirmed that TSD inhibited hippocampal neuronal loss and alleviated the abnormal reduction of the Nissl body. In parallel, TUNEL staining illustrated that TSD decelerated neuronal apoptosis. Western Blot demonstrated that TSD reduces the expression of ERs and apoptotic proteins. CONCLUSION: In this study, the significant ameliorative effect on cognitive impairment of TSD has been determined by comparing the behavioral data of the 4 groups of rats. Furthermore, it was confirmed that this effect of TSD was achieved by suppressing the ERs-mediated apoptosis signaling pathway.

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.

The safety and efficacy of melatonin in the treatment of COVID-19: A systematic review and meta-analysis.

BACKGROUND: As an infectious disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the common signs of coronavirus disease 2019 (COVID-19) are respiratory symptoms, fever, cough, shortness of breath, and dyspnea, with multiple organ injuries in severe cases. Therefore, finding drugs to prevent and treat COVID-19 is urgently needed and expected by the public. Several studies suggested beneficial effects of melatonin for the relevant prevention and treatment. To explore the effect and safety of melatonin in the treatment and provide theoretical support and reference for seeking the most suitable drug for COVID-19, the meta-analysis was carried out accordingly. METHODS: It included randomized clinical trials of patients with COVID-19 treated with melatonin. Total effective rate was the primary outcome, while C-reactive protein (CRP), arterial oxygen saturation (SaO2), white blood cell count (WBC) were the secondary measures. Random-effect and fixed-effect models were used to evaluate the effect size of some indicators in this meta-analysis. RESULTS: Six eligible studies with 338 participants were included. One hundred seventy subjects were treated with melatonin adjuvant therapy and 168 subjects were assigned to the control group, with total excellent effective rate in subjects treated with melatonin [odds ratio = 3.05, 95 % confidence interval (CI) = 1.47, 6.31, P = .003]. Homogeneity was analyzed by fixed effect model (I2 = 0%). There was no significant difference in CRP between the melatonin group and the control group (weighted mean difference [WMD] = -0.36, 95% CI = -3.65, 2.92, P = .83). Significant difference was not existed in SaO2 between the melatonin treatment group and the control group (WMD = 1, 95% CI = -1.21, 3.22, P = .37). In terms of WBC, there was no significant difference between the 2 groups (WMD = -1.07, 95% CI = -2.44, 0.30, P = .13). CONCLUSIONS: The meta-analysis showed that melatonin had the beneficial effects for COVID-19 prevention and treatment as an adjunctive agent in combination with basic treatment for the treatment.

Effect of Zhuang Jing Decoction on Learning and Memory Ability in Aging Rats.

With the average life span of humans on the rise, aging in the world has drawn considerable attentions. The monoamine neurotransmitters and neurotrophic factors in brain areas are involved in learning and memory processes and are an essential part of normal synaptic neurotransmission and plasticity. In the present study, the effect of Zhuang Jing Decoction (ZJD) on the learning and memory ability in aging rats was examined in vivo using Morris water maze. Furthermore, the levels of monoamine neurotransmitters and neurotrophic factors in brain were detected by high-performance liquid chromatography with a fluorescence detector and enzyme-linked immunosorbent assay, respectively. These data showed that oral administration with ZJD at the dose of 30 g·kg(-1) exerted an improved effect on learning and memory ability in aging rats. The results revealed that ZJD could effectively adjust the monoamine neurotransmitters and neurotrophic factors, restore the balance of the level of monoamine neurotransmitters and neurotrophic factors in brain, and finally attenuate the degeneration of learning and memory ability. These findings suggested that ZJD might be a potential agent as cognitive-enhancing drug in improving learning and memory ability. It may exert through regulating the levels of monoamine neurotransmitters and neurotrophic factors in brain, which demonstrated that ZJD had certain antiaging effects.

Trends in prevalence, awareness, treatment, and control of diabetes mellitus in mainland china from 1979 to 2012.

Diabetes mellitus (DM) is one of the primary causes of premature death and disability worldwide. We performed a systematic review and meta-analysis of the published literature regarding the trends in prevalence, awareness, treatment, and control of diabetes mellitus in mainland China. PUBMED, EMBASE, Chinese Biomedical Database, China National Infrastructure database, Chinese Wan Fang database, and Chongqing VIP database were searched. Fifty-six eligible studies were included. Increasing trends in the prevalence, treatment, and control of diabetes in mainland China from 1979 to 2012 were observed. The pooled prevalence, awareness, treatment, and control of diabetes mellitus were 6.41%, 45.81%, 42.54%, and 20.87%, respectively. A higher prevalence of diabetes mellitus was found in urban (7.48%, 95%CI = 5.45~9.50) than rural (6.53%, 95%CI = 4.30~8.76) areas. Furthermore, an increasing chronological tendency was shown in different subgroups of age with regard to the prevalence of diabetes. A higher awareness of DM was found in urban (44.25%, 95%CI = 32.60~55.90) than rural (34.27%, 95%CI = 21.00~47.54) populations, and no significant differences were found in the treatment, and control of diabetes among the subgroups stratified by gender and location. From 1979 to 2012, the prevalence, treatment, and control of diabetes mellitus increased; nevertheless, there was no obvious improvement in the awareness of diabetes.

[Correlation study on 12p13 single nucleotide polymorphism rs12425791 and Chinese medical syndrome types in ischemic stroke patients of the Han nationality].

OBJECTIVE: To explore the correlation between 12p13 single nucleotide polymorphism (SNP) rs12425791 and Chinese medical syndrome types of ischemic stroke patients of the Han nationality. METHODS: A case-control study was used. Recruited were 148 ischemic stroke patients of the Han nationality (67 patients of phlegm syndrome and 81 patients of blood stasis syndrome). Another 192 healthy subjects were recruited as the control group. The genotypes of rs12425791 were performed by TaqMan SNP genotyping assays to analyze the distribution of genes and the distribution frequency of alleles. RESULTS: There was no statistical difference in the genotype and alleles of rs12425791 between the ischemic stroke patients of phlegm syndrome and the control group, or between the ischemic stroke patients of blood stasis syndrome and the control group (P > 0.05). CONCLUSION: Our results did not support that 12p13 common variant rs12425791 was correlated with the pathogeneses of ischemic stroke patients of phlegm syndrome and ischemic stroke patients of blood stasis syndrome.

Induction of thoracic aortic remodeling by endothelial-specific deletion of microRNA-21 in mice.

MicroRNAs (miRs) are known to have an important role in modulating vascular biology. MiR21 was found to be involved in the pathogenesis of proliferative vascular disease. The role of miR21 in endothelial cells (ECs) has well studied in vitro, but the study in vivo remains to be elucidated. In this study, miR21 endothelial-specific knockout mice were generated by Cre/LoxP system. Compared with wild-type mice, the miR21 deletion in ECs resulted in structural and functional remodeling of aorta significantly, such as diastolic pressure dropping, maximal tension depression, endothelium-dependent relaxation impairment, an increase of opening angles and wall-thickness/inner diameter ratio, and compliance decrease, in the miR21 endothelial-specific knockout mice. Furthermore, the miR21 deletion in ECs induced down-regulation of collagen I, collagen III and elastin mRNA and proteins, as well as up-regulation of Smad7 and down-regulation of Smad2/5 in the aorta of miR21 endothelial-specific knockout mice. CTGF and downstream MMP/TIMP changes were also identified to mediate vascular remodeling. The results showed that miR21 is identified as a critical molecule to modulate vascular remodeling, which will help to understand the role of miR21 in vascular biology and the pathogenesis of vascular diseases.