Qingda Granule Attenuates Hypertension-Induced Cardiac Damage via Regulating Renin-Angiotensin System Pathway.

OBJECTIVE: To assess the efficacy of Qingda Granule (QDG) in ameliorating hypertension-induced cardiac damage and investigate the underlying mechanisms involved. METHODS: Twenty spontaneously hypertensive rats (SHRs) were used to develope a hypertension-induced cardiac damage model. Another 10 Wistar Kyoto (WKY) rats were used as normotension group. Rats were administrated intragastrically QDG [0.9 g/(kg•d)] or an equivalent volume of pure water for 8 weeks. Blood pressure, histopathological changes, cardiac function, levels of oxidative stress and inflammatory response markers were measured. Furthermore, to gain insights into the potential mechanisms underlying the protective effects of QDG against hypertension-induced cardiac injury, a network pharmacology study was conducted. Predicted results were validated by Western blot, radioimmunoassay immunohistochemistry and quantitative polymerase chain reaction, respectively. RESULTS: The administration of QDG resulted in a significant decrease in blood pressure levels in SHRs (P<0.01). Histological examinations, including hematoxylin-eosin staining and Masson trichrome staining revealed that QDG effectively attenuated hypertension-induced cardiac damage. Furthermore, echocardiography demonstrated that QDG improved hypertension-associated cardiac dysfunction. Enzyme-linked immunosorbent assay and colorimetric method indicated that QDG significantly reduced oxidative stress and inflammatory response levels in both myocardial tissue and serum (P<0.01). CONCLUSIONS: Both network pharmacology and experimental investigations confirmed that QDG exerted its beneficial effects in decreasing hypertension-induced cardiac damage by regulating the angiotensin converting enzyme (ACE)/angiotensin II (Ang II)/Ang II receptor type 1 axis and ACE/Ang II/Ang II receptor type 2 axis.

Endothelial cell-derived RSPO3 activates Gαi1/3-Erk signaling and protects neurons from ischemia/reperfusion injury.

The current study explores the potential function and the underlying mechanisms of endothelial cell-derived R-spondin 3 (RSPO3) neuroprotection against ischemia/reperfusion-induced neuronal cell injury. In both neuronal cells (Neuro-2a) and primary murine cortical neurons, pretreatment with RSPO3 ameliorated oxygen and glucose deprivation (OGD)/re-oxygenation (OGD/R)-induced neuronal cell death and oxidative injury. In neurons RSPO3 activated the Akt, Erk and ß-Catenin signaling cascade, but only Erk inhibitors reversed RSPO3-induced neuroprotection against OGD/R. In mouse embryonic fibroblasts (MEFs) and neuronal cells, RSPO3-induced LGR4-Gab1-Gαi1/3 association was required for Erk activation, and either silencing or knockout of Gαi1 and Gαi3 abolished RSPO3-induced neuroprotection. In mice, middle cerebral artery occlusion (MCAO) increased RSPO3 expression and Erk activation in ischemic penumbra brain tissues. Endothelial knockdown or knockout of RSPO3 inhibited Erk activation in the ischemic penumbra brain tissues and increased MCAO-induced cerebral ischemic injury in mice. Conversely, endothelial overexpression of RSPO3 ameliorated MCAO-induced cerebral ischemic injury. We conclude that RSPO3 activates Gαi1/3-Erk signaling to protect neuronal cells from ischemia/reperfusion injury.

What benefit can be obtained from magnetic resonance imaging diagnosis with artificial intelligence in prostate cancer compared with clinical assessments?

The present study aimed to explore the potential of artificial intelligence (AI) methodology based on magnetic resonance (MR) images to aid in the management of prostate cancer (PCa). To this end, we reviewed and summarized the studies comparing the diagnostic and predictive performance for PCa between AI and common clinical assessment methods based on MR images and/or clinical characteristics, thereby investigating whether AI methods are generally superior to common clinical assessment methods for the diagnosis and prediction fields of PCa. First, we found that, in the included studies of the present study, AI methods were generally equal to or better than the clinical assessment methods for the risk assessment of PCa, such as risk stratification of prostate lesions and the prediction of therapeutic outcomes or PCa progression. In particular, for the diagnosis of clinically significant PCa, the AI methods achieved a higher summary receiver operator characteristic curve (SROC-AUC) than that of the clinical assessment methods (0.87 vs. 0.82). For the prediction of adverse pathology, the AI methods also achieved a higher SROC-AUC than that of the clinical assessment methods (0.86 vs. 0.75). Second, as revealed by the radiomics quality score (RQS), the studies included in the present study presented a relatively high total average RQS of 15.2 (11.0-20.0). Further, the scores of the individual RQS elements implied that the AI models in these studies were constructed with relatively perfect and standard radiomics processes, but the exact generalizability and clinical practicality of the AI models should be further validated using higher levels of evidence, such as prospective studies and open-testing datasets.

Pharmaceutical and pharmacological studies of Shen Ma Yi Zhi granule for prevention of vascular dementia: A review.

Background: With dementia significantly increasing hospitalization and disability rates, worldwide aging of the population presents major challenges to public health. The majority of cases of cognitive dysfunction among the elderly, however, are characterized by an identifiable, preventable and treatable vascular component. As such, increased study of preventative methods in the context of dementia is warranted. Traditional Chinese medicine compounds have been reported to be neuroprotective and improve cognitive function via a variety of mechanisms. Shen Ma Yi Zhi granule (SMYZG) is one such collection of compounds that has been proven clinically effective. Pharmacological mechanisms of action, pharmacokinetics and clinical applications of SMYZG have been previously studied using a variety of vascular dementia animal models. SMYZG activates and regulates four main signaling pathways relevant to vascular dementia including the AMPK/PPARα/PGC-1α/UCP2, Nrf2/HO-1, HIF-1/VEGF/Notch, and VEGF/Flk-1/p8 MAPK pathways. Furthermore, SMYZG influences anti-inflammatory and anti-oxidant stress responses, reverses demyelination of brain white matter and vascular endothelium, regulates pericyte function and normalizes mitochondrial metabolism. Neuroprotective effects of SMYZG, as well as those promoting regeneration of vascular endothelium, have also been reported in studies of rat models of vascular dementia. Future research concerning SMYG is warranted for development of vascular dementia preventative management strategies.

Role of hydrogen in traumatic brain injury: a narrative review.

Traumatic brain injury (TBI) is a serious global public health problem. Survivors of TBI often suffer from long-term disability, which puts a heavy burden on society and families. Unfortunately, up to now, there is no efficacious treatment for TBI patients in clinical practice. As a reducing gas, hydrogen has been shown to be neuroprotective in multiple cerebral disease models; however, its efficacy in TBI remains controversial. In this review, we will focus on the results of hydrogen in experimental TBI, elaborate the potential mechanisms, and put forward for future researches based on our current understanding and views.

Panax quinquefolium saponin Optimizes Energy Homeostasis by Modulating AMPK-Activated Metabolic Pathways in Hypoxia-Reperfusion Induced Cardiomyocytes.

OBJECTIVE: To investigate the effects and underlying mechanisms of Panax quinquefolium saponin (PQS) on energy deficiency in hypoxia-reperfusion (H/R) induced cardiomyocytes. METHODS: The H/R injury involved hypoxia for 3 h and then reperfusion for 2 h. Cardiomyocytes recruited from neonatal rat ventricular myocytes (NRVMs) were randomly divided into control, H/R, H/R+compound C (C.C), H/R+PQS, and H/R+C. C+PQS groups. BrdU assay, lactase dehydrogenase (LDH) leakage and early apoptosis rate were evaluated to assess cell damages. Contents of high energy phosphate compounds were conducted to detect the energy production. Protein expression levels of adenosine monophosphate-activated protein kinase a (AMPKα), glucose transporter 4 (GLUT4), phosphate fructose kinase 2 (PFK2), fatty acid translocase/cluster of differentiation 36 (FAT/CD36), and acetyl CoA carboxylase 2 (ACC2) in the regulatory pathways were measured by Western blotting. Immunofluorescence staining of GLUT4 and FAT/CD36 was used to observe the mobilization of metabolic transporters. RESULTS: PQS (50 mg/L) pretreatment significantly alleviated H/R-induced inhibition of NRVMs viability, up-regulation of LDH leakage, acceleration of early apoptosis, and reduction of energy production (P<0.05). Compared with the H/R group, up-regulated expression of AMPKα, GLUT4, PFK2, FAT/CD36 and ACC2 were observed, and more GLUT4 and FAT/CD36 expressions were detected on the membrane in the H/R+PQS group (P<0.05). These effects of PQS on H/R-induced NRVMs were eliminated in the H/R+C.C+PQS group (P<0.05). CONCLUSION: PQS has prominent advantages in protecting NRVMs from H/R-induced cell damages and energy metabolic disorders, by activation of AMPKα-mediated GLUT4-PFK2 and FAT/CD36-ACC2 pathways.

Clinical Experience in Treatment of Alzheimer's Disease with Jiannao Yizhi Formula () and Routine Western Medicine.

OBJECTIVE: To investigate the long-term therapeutic effects of the Chinese medicine Jiannao Yizhi Formula (, JYF) in the treatment of Alzheimer's disease (AD). METHODS: Sixty mild-to-moderate AD participants were recruited and randomly allocated to the treatment (30 with JYF) and the control groups (30 with donepezil) for 6 months with the random numbers. The primary outcomes were scores of Alzheimer's Disease Rating Scale-Cognitive (ADAS-Cog) and Chinese Medicine Symptom Scale (CM-SS). The secondary outcomes were scores of Mini Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), and Activities of Daily Living (ADL). Safety assessments were conducted at baseline and the 6th month of treatment. Serum levels of acetylcholine (Ach), amyloid-ß protein 42 (Aß42), and the microtubule-associated protein tau (Tau) were also determined by enzyme-liked immunosorbent assay. RESULTS: Fifty-one participants were included in the final analyses (JYF n=27; donepezil n=24). Compared with baseline, both JYF and donepezil increased the MoCA and MMSE scores and decreased the ADAS-Cog and CM-SS scores (P<0.05 or P<0.01). Both drugs increased the serum levels of Ach and decreased the serum levels of Aß42 and Tau (all P<0.05). There was no significant difference in these variables between the two groups, which showed that JYF was not inferior to donepezil. No obviously significant changes were observed in the ADL. No severe adverse events were observed in both groups. CONCLUSION: The effect and safety of JYF for the treatment of AD were not inferior to those of donepezil.

Effect and Safety of Huannao Yicong Formula () in Patients with Mild-to-Moderate Alzheimer's Disease: A Randomized, Double-Blinded, Donepezil-Controlled Trial.

OBJECTIVE: To assess the effect and safety of Huannao Yicong Formula (, HYF) in the treatment of patients with mild-to-moderate Alzheimer's disease (AD). METHODS: Sixty patients with mild-tomoderate AD were evenly randomized into HYF group and donepezil group with the random number method. Patients in the HYF group took 5 g of HYF granules twice daily and 5 mg placebo of donepezil once daily. Patients in the donepezil group took 5 mg donepezil once daily and 5 g placebo of HYF granules twice daily. The intervention lasted for 6 months. Clinical researchers, participants and statisticians were blinded to the treatment assignment throughout the study. The primary outcomes were scores of Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) and Chinese Medicine Symptom Scale (CM-SS). The secondary outcomes were scores of Montreal Cognitive Assessment (MoCA) test and Mini-Mental State Exam (MMSE). The serum levels of acetylcholinesterase (AchE) and amyloid-ß protein 42 (Aß42) were detected with enzymelinked immunosorbent assay kits. The scale assessments were conducted at baseline, the 3rd and 6th months of treatment, respectively. Biochemistry tests were conducted at baseline and the 6th month of treatment. RESULTS: A total of 52 patients completed the trial, 28 in HYF group and 24 in donepezil group. Compared with the baseline, HYF and donepezil signifificantly decreased the total scores of ADAS-Cog and CM-SS, and signifificantly increased the scores of MoCA and MMSE after 6-month treatment (all P<0.01). Both treatments remarkably reduced the serum levels of AchE and Aß42 (both P<0.05). The CM-SS total effective rate of HYF was signifificantly higher than donepezil [75.00% (21/28) vs. 54.17% (13/24), P<0.05]. No severe adverse events were observed in both groups. CONCLUSION: HYF is effective and safe for improving the cognitive function in mildto-moderate AD patients. [Trial registration: Chinese Clinical Trial Registry (Reg No. ChiCTR-IOR-17011746)].

Huannao Yicong Formula () regulates γ-secretase activity through APH-1 and PEN-2 gene ragulation pathways in hippocampus of APP/PS1 double transgenic mice.

OBJECTIVE: To observe the effects of Huannao Yicong Formula (, HYF) on learning and memory and it's regulating effect on γ-secretase related anterior pharynx defective 1 (APH-1), presenilin enhancer-2 (PEN-2) signaling pathway, so as to discuss and further clarify the mechanism of HYF on Alzheimer's disease. METHODS: Sixty APP/PS1 transgenic mice, randomly allocated into 4 groups, the model group, the donepezil group (0.65 mg/kg), HYF low-dose group (HYF-L, 5.46 g/kg) and HYF high-dose group (HYF-H, 10.92 g/kg), 15 for each group. Another 15 C57BL/6J mice with the same age and same genetic background were allocated into the control group, proper dosage of drugs or distilled water were given by intragastric administration once daily for 12 weeks. After 12 weeks of administration, the learning and memory abilities of mice in each group was evaluated by the morris water maze test, amyloid precursor protein (APP), Aß1-40 and Aß1-42 levels in hippocampus were detected by enzyme-linked immunosorbent assay, γ-secretase was detected by dual luciferase assaying, the levels of APH-1a, hypoxia-inducible factor 1α (HIF-1α), cAMP response element-binding protein (CREB) and PEN-2 and their mRNA expression was measured by Western blot and real-time polymerase chain reaction. RESULTS: HYF can ameliorate learning and memory deficits in APP/PS1 transgenic mice by decreasing the escape latency, improving the number of platform crossing and swimming speed (P<0.01, P<0.05). HYF can decrease the levels of APP, Aß1-40, Aß1-42 and the activity of γ-secretase in hippocampus of Alzheimer's disease model mice. HYF can down-regulate the levels of CREB and PEN-2 and the expression of their mRNA. CONCLUSION: HYF can improve the learning and memory ability by inhibiting the activity of γ-secretase through the CREB/PEN-2 signaling pathway, and this may be one of the therapeutic mechanisms of HYF in Alzheimer's disease.

Huannao Yicong Decoction () extract reduces inflammation and cell apoptosis in Aß1-42-induced Alzheimer's disease model of rats.

OBJECTIVE: Huannao Yicong Decoction (, HYD), an effective herbal formula against Alzheimer's disease (AD), has been proven to have neuroprotective action in amyloid ß-protein1-42 (Aß1-42)-induced rat model. This study was designed to characterize mechanisms by which HYD leads to suppression of inflflammation and apoptosis in the brains of Aß1-42-induced rat. METHODS: A total of 72 rats were divided into 6 groups, which were referred to as: sham operation group, model group, donepezil-treated group, HYD low-dose group (HYDL), HYD middle-dose group (HYDM) and HYD high-dose group (HYDH). Rats in HYDL, HYDM and HYDH were injected with Aß1-42 at the CA1 region of hippocampus to form AD model and were fed the HYD extract at different dose of 3.78, 7.56 and 18.90 g crude drug/kg. The behavioral changes of rats were evaluated by Morris water maze (MWM) before sacrififice. Pathological changes of the brain tissue were evaluated using hematoxylin eosin (HE) staining. The levels of interleukin-1 (IL-1) and tumor necrosis factor-α (TNF-α) were measured by radioimmunoassay. The levels of Aß and proteins that are associated with apoptosis such as B-cell lymphoma-2 protein (Bcl-2), Bcl-2-associated X protein (Bax), cysteine-aspartic protease (caspase)-3, -8, -9 and -12 in serum were measured by immunohistochemistry. RESULTS: Compared with the sham operation group, the spatial learning and memory abilities of AD rats were signifificantly decreased (P<0.05 or P<0.01; Expressions of IL-1, TNF-α, Aß and apoptosis-signaling proteins caspase-3, -8, -9, -12 were signifificantly up-regulated (P<0.05 or P<0.01). The ratio of Bcl-2 to Bax were signifificantly decreased in the model group (P<0.01). When treated with HYD extract, the spatial learning and memory abilities of AD-model rats were significantly increased (P<0.05 or P<0.01), IL-1, TNF-α, Aß, caspase-3, -8, -9 and -12 were down-regulated (P<0.05 or P<0.01), and the ratio of Bcl-2 to Bax were reduced (P<0.05 or P<0.01). CONCLUSIONS: HYD extract can improve the learning and memory ability defificits, alleviate the inflflammatory response and pathological manifestations induced by Aß1-42 injection in the rat model of AD. HYD down-regulates the levels of IL-1, TNF-α and Aß, and decreases the rate of apoptosis by modulating apoptosis-signaling-related proteins such as caspase-3, -8, -9, and -12.