Extracellular vesicle-derived circCEBPZOS attenuates postmyocardial infarction remodeling by promoting angiogenesis via the miR-1178-3p/PDPK1 axis.

Emerging studies indicate that extracellular vesicles (EVs) and their inner circular RNAs (circRNAs), play key roles in the gene regulatory network and cardiovascular repair. However, our understanding of EV-derived circRNAs in cardiac remodeling after myocardial infarction (MI) remains limited. Here we show that the level of circCEBPZOS is downregulated in serum EVs of patients with the adverse cardiac remodeling compared with those without post-MI remodeling or normal subjects. Loss-of-function approaches in vitro establish that circCEBPZOS robustly promote angiogenesis. Overexpression of circCEBPZOS in mice attenuates MI-induced left ventricular dysfunction, accompanied by a larger functional capillary network at the border zone. Further exploration of the downstream target gene indicates that circCEBPZOS acts as a competing endogenous RNA by directly binding to miR-1178-3p and thereby inducing transcription of its target gene phosphoinositide-dependent kinase-1 (PDPK1). Together, our results reveal that circCEBPZOS attenuates detrimental post-MI remodeling via the miR-1178-3p/PDPK1 axis, which facilitates revascularization, ultimately improving the cardiac function.

VX-765 Alleviates ß-Amyloid Deposition and Secondary Degeneration in the Ipsilateral Hippocampus and Ameliorates Cognitive Decline after Focal Cortical Infarction in Rats.

Focal cortical infarction leads to secondary degeneration of the ipsilateral hippocampus, which is associated with poststroke cognitive impairment. VX-765 is a potent small-molecule caspase-1 inhibitor that protects against central nervous system diseases. The present study aimed to determine the protective effects of VX-765 on ß-amyloid (Aß) deposition and secondary degeneration in the hippocampus as well as cognitive decline after cortical infarction. Sprague-Dawley rats were used to establish a distal middle cerebral artery occlusion (dMCAO) model and randomly divided into the vehicle and VX-765 groups. Rats in the vehicle and VX-765 groups, respectively, were subcutaneously injected with VX-765 (50 mg/kg/d) and an isopycnic vehicle once a day for 28 days, starting 1 h after dMCAO. At the end of this 28-day period, cognitive impairment was evaluated with the Morris water maze, and secondary hippocampal damage was evaluated with Nissl staining and immunostaining methods. Neuronal damage and pyroptosis were detected by TUNEL and immunoblotting. The results revealed that VX-765 treatment ameliorated poststroke cognitive dysfunction after ischemia. VX-765 reduced Aß deposition, neuronal loss, and glial activation compared with the vehicle control. In addition, VX-765 treatment increased BDNF levels and normalized synaptophysin protein levels in the hippocampus after cortical infarction. Notably, VX-765 treatment significantly reduced the expression of the pyroptosis-related molecules caspase-1, NLRP3, apoptosis-associated speck-like protein (ASC), gasdermin D, IL-1ß, and IL-18. Additionally, VX-765 significantly decreased the numbers of TUNEL-positive cells and the levels of Bax and cleaved caspase-3 (cC3) and enhanced the levels of Bcl-2 and Bcl-xl after ischemia. Inflammatory pathways, such as the NF-κB and mitogen-activated protein kinase (MAPK) pathways, were inhibited by VX-765 treatment after ischemia. These findings revealed that VX-765 reduced Aß deposition, pyroptosis, and apoptosis in the ipsilateral hippocampus, which may be associated with reduced secondary degeneration and cognitive decline following focal cortical infarction.

Berberine Improves Cognitive Impairment by Simultaneously Impacting Cerebral Blood Flow and ß-Amyloid Accumulation in an APP/tau/PS1 Mouse Model of Alzheimer's Disease.

Alzheimer's disease (AD) is accompanied by ß-amyloid (Aß), neurofibrillary tangles, and neuron cell death, and is one of the most commonly occurring diseases among the elderly. The pathology of AD is complex, involving Aß overproduction and accumulation, tau hyperphosphorylation, and neuronal loss. In addition, chronic cerebral hypoperfusion (CCH) is ubiquitous in the AD patients and plans a pivotal role in triggering and exacerbating the pathophysiological progress of AD. The goal of this study was to investigate the neuroprotective properties of berberine (BBR) and the underlying mechanism. During the study, BBR was administrated to treat the triple-transgenic mouse model of Alzheimer's disease (3×Tg AD). To thoroughly evaluate the effects of the BBR administration, multiple manners were utilized, for instance, 3D arterial spin labeling technique, Morris water maze assay, immunofluorescence staining, TUNEL assay, laser speckle contrast imaging, western blotting, etc. The results showed that BBR ameliorated cognitive deficits in 3×Tg AD mice, reduced the Aß accumulation, inhibited the apoptosis of neurons, promoted the formation of microvessels in the mouse brain by enhancing brain CD31, VEGF, N-cadherin, Ang-1. The new vessels promoted by BBR were observed to have a complete structure and perfect function, which in turn promoted the recovery of cerebral blood flow (CBF). In general, berberine is effective to 3×Tg AD mice, has a neuroprotective effect, and is a candidate drug for the multi-target prevention and treatment of AD.

Berberine Improves Behavioral and Cognitive Deficits in a Mouse Model of Alzheimer's Disease via Regulation of ß-Amyloid Production and Endoplasmic Reticulum Stress.

Alzheimer's disease (AD) is a neurodegenerative disease characterized by ß-amyloid (Aß), neurofibrillary tangles, and neuronal cell death. Aggressive Aß accumulation accelerates senile plaque formation and perturbs endoplasmic reticulum (ER) function. Aß accumulation-induced changes stimulate the unfolded protein response (UPR), which can trigger neuronal apoptosis. Protein kinase RNA-like endoplasmic reticulum kinase (PERK), whose activation is stress-dependent, increases the phosphorylation of eukaryotic translation initiation factor-2α (eIF2α). eIF2α promotes the synthesis of ß-site APP cleavage enzyme 1 (BACE1), which in turn facilitates Aß generation and subsequent neuronal apoptosis. In this study, we investigated whether berberine could improve cognitive deficits in the triple-transgenic mouse model of Alzheimer's disease (3 × Tg AD) mice. Our results revealed that berberine treatment may inhibit PERK/eIF2α signaling-mediated BACE1 translation, thus reducing Aß production and resultant neuronal apoptosis. Further, berberine may have neuroprotective effects, via attenuation of ER stress and oxidative stress. In sum, our study demonstrates the therapeutic potential of berberine for treating AD.

Fat-1 transgenic mice rich in endogenous omega-3 fatty acids are protected from lipopolysaccharide-induced cardiac dysfunction.

AIMS: Cardiac malfunctions developing in result of sepsis are hard to treat so they eventually contribute to the increased mortality. Previous reports indicated for therapeutic potential of exogenous ω-3 polyunsaturated fatty acids (PUFA) in sepsis, but potential benefits of this compound on the malfunctional heart have not been explored yet. In the present study, we investigated whether the constantly elevated levels of endogenous ω-3 PUFA in transgenic fat-1 mice would alleviate the lipopolysaccharide (LPS)-induced cardiac failure and death. METHODS AND RESULTS: After both wild type (WT) and transgenic fat-1 mice were challenged with LPS, a Kaplan-Meier curve and echocardiography were performed to evaluate the survival rates and cardiac function. Proteomics analysis, RT-PCR, western blotting, immune-histochemistry, and transmission electron microscopy were further performed to investigate the underlying mechanisms. Results showed that transgenic fat-1 mice exhibited the significantly lower mortality after LPS challenge as compared with their WT counterparts (30% vs. 42.5%, P < 0.05). LPS injection consistently impaired the left ventricular contractile function and caused the cardiac injury in the wild type mice, but not significantly affected the fat-1 mice (P < 0.05). Proteomic analyses, ELISA, and immunohistochemistry further revealed that myocardium of the LPS-challenged fat-1 mice demonstrated the significantly lower levels of pro-inflammatory markers and ROS than WT mice. Meaningfully, the LPS-treated fat-1 mice also demonstrated a significantly higher levels of LC3 II/I and Atg7 expressions than the LPS-treated WT mice (P < 0.05), as well as displayed a selectively increased levels of peroxisome proliferator-activated receptor (PPAR) γ and sirtuin (Sirt)-1 expression, associated with a parallel decrease in NFκB activation. CONCLUSIONS: The fat-1 mice were protected from the detrimental LPS-induced inflammation and oxidative stress, and exhibited enhancement of the autophagic flux activities, associating with the increased Sirt-1 and PPARγ signals.

TREM-1-targeting LP17 attenuates cerebral ischemia-induced neuronal injury by inhibiting oxidative stress and pyroptosis.

Stroke ranks as the second leading cause of disability and death globally. Trigger receptors expressed on myeloid cells (TREM) -1 are responsible for the activation of the innate immune response and also play a critical role in inflammation. In this study, we reported the contribution of TREM-1 after ischemic damage in a rat middle cerebral artery occlusion (MCAO) model. This study also demonstrated that TREM-1 expression was upregulated following cerebral infarction in rats. TREM-1 inhibition was determined using its selective inhibitor, LP17, which indicated a neuroprotective effect on cerebral infarction damage. The findings revealed that inhibition of TREM-1 by administering LP17 improved cerebral damage and decreased ischemic areas and brain water contents. Moreover, LP17 decreased MCAO-induced microglial activation and neurodegeneration, evidenced by a reduction in the expression of microglial Iba-1 and FJ-B positive cells, and reversed neuronal loss. Besides, the contribution of LP17 to ischemic neuronal damage may be associated with a decrease in the production of pro-inflammatory cytokines, and enhanced production of anti-inflammatory cytokine IL-10. Both in vivo and in vitro studies showed that inhibiting TREM-1 attenuated ROS accumulation, lipid per-oxidation (LPO) contents such as malondialdehyde (MDA) and enhanced the superoxide dismutase (SOD) activity after ischemia. Inhibiting TREM-1 alleviated inflammation and pyroptosis found in MCAO rats. This was achieved through the inhibition of the levels of NLRP3, caspase-1, ASC (an apoptosis-associated speck-like protein containing a CARD) and gasdermin D. These results confirmed that inhibiting TREM-1 protects against ischemia-induced neuronal damage and alleviates microglial mediated neuro-inflammation by reducing oxidative stress and pyroptosis. Therefore, blocking TREM-1 expression provides an effective intervention for improving ischemic stroke.

In-depth proteomics approach reveals novel biomarkers of cardiac remodelling after myocardial infarction: An exploratory analysis.

Cardiac remodelling following myocardial infarction (MI) is a maladaptive change associated with progressive heart failure and compromises long-term clinical outcome. A substantial proportion of patients afflicted by MI still develop adverse outcomes associated with cardiac remodelling. Therefore, it is crucial to identify biomarkers for the early prediction of cardiac remodelling. An in-depth proteomics approach, including both semi-quantitative and quantitative antibody arrays, was used to identify circulating biomarkers that may be associated with detrimental cardiac remodelling. Furthermore, statistical correlation analysis was performed between the candidate biomarkers and clinical cardiac remodelling data to demonstrate their clinical utility. A systematic proteomics approach revealed that sclerostin (SOST), growth differentiation factor-15 (GDF-15), urokinase-type plasminogen activator (uPA), and midkine (MK) were increased, while monocyte chemotactic protein-3 (MCP-3) was uniquely decreased in MI patients who developed cardiac remodelling, compared to MI patients who did not develop cardiac remodelling and healthy humen. Moreover, correlation analyses between serum proteomes and cardiac remodelling echocardiographic parameters demonstrated a moderate positive association between left ventricular end-diastolic volume index (LVEDVi) and the three serum proteins, uPA, MK and GDF-15 (P < .05, respectively), and a moderate negative correlation between LV ejection fraction (LVEF) and these serum proteins (P < .05, respectively). Importantly, uPA and MK were firstly identified to be associated with the development of cardiac remodelling. The present study contributes to a better understanding of the various cytokines expressed during adverse cardiac remodelling. The identified biomarkers may facilitate early identification of patients at high risk of ischaemic heart failure pending further confirmation through larger clinical trials.

Memantine ameliorates tau protein deposition and secondary damage in the ipsilateral thalamus and sensory decline following focal cortical infarction in rats.

Previous studies have reported that memantine presents evidence of therapeutic benefits in several animal models of ischemic stroke and neurodegenerative diseases. However, the effect of memantine on secondary damage in the ipsilateral thalamus after focal cortical infarction remains undefined. Present study investigated whether memantine has a protective effect on secondary damage in the ipsilateral thalamus after focal cerebral infarction in rats. At 24 h after distal middle cerebral artery occlusion (MCAO), rats in the memantine and vehicle groups were intraperitoneal injected with memantine and isopycnic vehicle, respectively, was once daily administered for consecutive 7 days. Infarct size was evaluated through Nissl staining and sensory decline determined using adhesive removal test. Secondary thalamic damage was assessed using Nissl staining and immunofluorescence 8 days after MCAO. Immunoboltting was used to identify tau and apoptosis-associated proteins in the ipsilateral thalamus after MCAO. Results revealed that memantine ameliorated sensory decline compared to the vehicle controls. Subsequently, tau phosphorylated at threonine 231 (p-tau-231), glycogen synthase kinase3ßpY216 (GSK3ßpY216) and protein phosphatase 2A (PP2ApY307) were reduced by memantine, causing greater reduction in neuronal loss and inhibition of reactive astrogliosis in the ipsilateral ventroposterior thalamic nucleus (VPN) compared with the vehicle groups. In addition, increase in secondary damage-induced TUNEL-positive cells was blunted by memantine, as demonstrated by the significant reduction in expression of apoptosis-associated proteins. Our results suggest that memantine has a neuro-protective effect on secondary damage in the ipsilateral thalamus following MCAO by inhibiting the activity of GSK3ßpY216/PP2ApY307 and down regulating the levels of p-tau-231 protein.

Inhibition of Caspase-1 Ameliorates Ischemia-Associated Blood-Brain Barrier Dysfunction and Integrity by Suppressing Pyroptosis Activation.

Ischemic cerebral infarction represents a significant cause of disability and death worldwide. Caspase-1 is activated by the NLRP3/ASC pathway and inflammasomes, thus triggering pyroptosis, a programmed cell death. In particular, this death is mediated by gasdermin D (GSDMD), which induces secretion of interleukin (IL)-1ß and IL-18. Accordingly, inhibition of caspase-1 prevents the development and worsening of multiple neurodegenerative diseases. However, it is not clear whether inhibition of caspase-1 can preserve blood-brain barrier (BBB) integrity following cerebral infarction. This study therefore aimed at understanding the effect of caspase-1 on BBB dysfunction and its underlying mechanisms in permanent middle cerebral artery occlusion (MCAO). Our findings in rat models revealed that expression of caspase-1 was upregulated following MCAO-induced injury in rats. Consequently, pharmacologic inhibition of caspase-1 using vx-765 ameliorated ischemia-induced infarction, neurological deficits, and neuronal injury. Furthermore, inhibition of caspase-1 enhanced the encapsulation rate of pericytes at the ischemic edge, decreased leakage of both Evans Blue (EB) and matrix metalloproteinase (MMP) proteins, and upregulated the levels of tight junctions (TJs) and tissue inhibitors of metalloproteinases (TIMPs) in MCAO-injured rats. This in turn improved the permeability of the BBB. Meanwhile, vx-765 blocked the activation of ischemia-induced pyroptosis and reduced the expression level of inflammatory factors such as caspase-1, NLRP3, ASC, GSDMD, IL-1ß, and IL-18. Similarly, vx-765 treatment significantly reduced the expression levels of inflammation-related receptor for advanced glycation end products (RAGE), high-mobility family box 1 (HMGB1), mitogen-activated protein kinase (MAPK), and nuclear factor-κB (NF-κB). Evidently, inhibition of caspase-1 significantly improves ischemia-associated BBB permeability and integrity by suppressing pyroptosis activation and the RAGE/MAPK pathway.

Berberine mitigates cognitive decline in an Alzheimer's Disease Mouse Model by targeting both tau hyperphosphorylation and autophagic clearance.

Berberine is a natural isoquinoline alkaloid isolated from the Rhizoma coptidis. Recent advances in research throw more lights of its beneficial role towards Alzheimer's disease (AD), including promoting ß-amyloid (Aß) clearance, as well as inhibiting Aß production in the triple-transgenic mouse model of Alzheimer's disease (3×Tg AD). However, it remains unclarified if berberine has an effect on tau pathology. According to our study, berberine did not only significantly improve 3×Tg AD mice's spatial learning capacity and memory retentions, but also attenuated the hyperphosphorylation of tau. via modulating the activity of Akt/glycogen synthase kinase-3ß and protein phosphatase 2A. Moreover, berberine reduced the level of tau through an autophagy-based route. It promoted autophagic clearance of tau by enhancing the activity of autophagy via the class III PI3K/beclin-1 pathway. Thus, our results suggest that berberine could mitigate cognitive decline by simultaneously targeting the hyperphosphorylation of tau and the autophagic clearance of tau in AD mice. These findings strongly support berberine as a potential drug candidate for AD.

The association between vascular endothelial growth factor gene polymorphisms and stroke: A PRISMA-compliant meta-analysis.

BACKGROUND: Numerous studies showed that vascular endothelial growth factor (VEGF) gene polymorphisms were linked with the regularity of stroke, but the results remained controversial. The aim of this meta-analysis was to determine the associations between VEGF gene polymorphisms and the risk of stroke. METHODS: A systematic literature search of PubMed, Embase, Wed of Science, The Cochrane Library, Elsevier, China National Knowledge Infrastructure, China Biology Medicine disc, WanFang Data, VIP Database for Chinese Technical Periodicals, and Science paper Online was conducted. Two authors independently assessed trial quality and extracted data. The pooled odds ratio (OR) with 95% confidence interval (CI) was used to assess the strength of associations. Begger funnel plot and Egger test were used to estimate the publication bias of included studies. Heterogeneity assumption was assessed by Cochran Chi-squared-based Q-statistic test and I test. RESULTS: Thirteen publications including 23 trails with a total of 3794 stroke patients and 3094 control subjects were enrolled. About 3747 cases and 2868 controls for +936C/T, 2134 cases and 1424 controls for -2578C/A, and 2187 cases and 1650 controls for -1154G/A were examined, respectively. The results indicated that VEGF +936C/T (T vs C, OR = 1.19, 95% CI = 1.01-1.40) or -2578C/A (A vs C, OR = 1.13, 95% CI = 1.02-1.27) was positively associated with the risk of stroke, whereas there was no association between -1154G/A (A vs G, OR = 0.99, 95% CI = 0.87-1.11) polymorphism and stroke risk in our study. Among the subgroup analyses on ethnicity, the results showed that VEGF +936C/T was an increased risk of stroke in Asian population (T vs C, OR = 1.21, 95% CI = 1.01-1.44), but not -1154G/A. CONCLUSION: Our findings suggest that VEGF +936C/T and -2578C/A might be related to the risk of stroke, especially in the Asian population, but not -1154G/A.

Beneficial Role of Rosuvastatin in Blood-Brain Barrier Damage Following Experimental Ischemic Stroke.

Hemorrhage transformation is the most challenging preventable complication in thrombolytic therapy and is related to recombinant tissue plasminogen activator (rt-PA)-induced blood-brain barrier (BBB) damage. Intraperitoneal injections of normal or high doses of rosuvastatin were administered to Balb/c mice 20 min prior to middle cerebral artery occlusion (MCAO) surgery for 3 h followed by reperfusion with rt-PA thrombolytic therapy and cerebral blood flow monitoring to investigate whether a high or normal dose of rosuvastatin reduces BBB damage after brain ischemia and rt-PA reperfusion. The integrity of the BBB was ameliorated by normal and high doses of rosuvastatin as determined from Evans blue staining, ultrastructure assessments and immunochemistry at 24 h after reperfusion. The levels of TJ proteins were preserved, potentially by targeting platelet-derived growth factor receptor α (PDGFR-α) and low-density lipoprotein receptor-related protein 1 (LRP1) to inhibit the expression of matrix metalloproteinase proteins (MMPs) by reducing the levels of phosphorylated c-jun-N-terminal kinase (pJNK), phosphorylated mitogen-activated protein kinase (MAPK) p38 (pP38) and increasing the levels of phosphorylated extracellular regulated protein kinases (pERK), and tissue inhibitor of metalloproteinases (TIMPs), as inferred from Western blotting and molecular docking analyses. In summary, rosuvastatin reduced rt-PA therapy-associated BBB permeability by PDGFR-α- and LRP1-associated MAPK pathways to reduce the mortality of mice, and a normal dose of rosuvastatin exerted greater preventative effects on reducing BBB damage than did a high dose in the time window of thrombolytic therapy.

The Role of Fluoxetine in Activating Wnt/ß-Catenin Signaling and Repressing ß-Amyloid Production in an Alzheimer Mouse Model.

Fluoxetine (FLX) is one of the selective serotonin reuptake inhibitors (SSRIs) antidepressants, which could be used to relieve depression and anxiety among AD patients. This study was designed to search for new mechanisms by which fluoxetine could activate Wnt/ß-catenin signaling pathway and reduce amyloidosis in AD brain. Fluoxetine was administered via intragastric injection to APP/tau/PS1 mouse model of Alzheimer's disease (3×Tg-AD) mice for 4 months. In the hippocampus of AD mouse model, there could be observed neuronal apoptosis, as well as an increase in Aß (amyloid-ß) production. Moreover, there is a strong association between down-regulation of Wnt/ß-catenin signaling and the alteration of AD pathology. The activity of protein phosphatases of type 2A (PP2A) could be significantly enhanced by the treatment of fluoxetine. The activation of PP2A, caused by fluoxetine, could then play a positive role in raising the level of active ß-catenin, and deliver a negative impact in GSK3ß activity in the hippocampal tissue. Both the changes mentioned above would lead to the activation of Wnt/ß-catenin signaling. Meanwhile, fluoxetine treatment would reduce APP cleavage and Aß generation. It could also prevent apoptosis in 3×Tg-AD primary neuronal cell, and have protective effects on neuron synapse. These findings imply that Wnt/ß-catenin signaling could be a potential target outcome for AD prevention, and fluoxetine has the potential to be a promising drug in both AD prevention and treatment.

The neuroprotective effects of Berberine against amyloid ß-protein-induced apoptosis in primary cultured hippocampal neurons via mitochondria-related caspase pathway.

BACKGROUND AND PURPOSE: Neuronal cell apoptosis is an important pathological change in Alzheimer's disease (AD). Berberine, an isoquinoline alkaloid isolated and extracted from Coptidis and rhizome and Cortex phellodendri, has a wide range of pharmacological effects. In this study, we investigated the neuroprotective effects of Berberine against neuronal insults induced by Aß25-35 in primary cultured hippocampal neurons. METHODS: Primary neuron cells have been isolated from hippocampus of C57BL/6 newborn mice. We investigated effect of Berberine against neuronal insults induced by Aß25-35 in primary cultured hippocampal neurons. TdT-mediated dUTP nick-end labeling, MTT, Propidium iodide, MMP, Caspase activity measurement, Western blot. RESULT: These neurons explosure to the ß25-35 protein resulted in a loss in cell viability and a surge in apoptosis. However, the presence of Berberine significantly reversed the effects induced by Aß25-35. Through decreasing viability and caspase activity in neurons, the pretreatment with Berberine attenuated the cytotoxic effect of the Aß25-35. Furthermore, it's found that expression of cytochrome C, as well as the restoration of Bcl-2/Bax and Bcl-xl/Bax ratio in the presence of Berberine, led to a decline in the apoptotic rate. CONCLUSION: The neuroprotective effects of Berberine against Aß25-35-induced neuronal apoptosis, suggesting that this may be a promising therapeutics against AD.

Combination of Panaxadiol and Panaxatriol Type Saponins and Ophioponins From Shenmai Formula Attenuates Lipopolysaccharide-induced Inflammatory Injury in Cardiac Microvascular Endothelial Cells by Blocking NF-kappa B Pathway.

Vascular inflammatory injury leads to vascular endothelial dysfunction, thereby resulting in a variety of cardiovascular diseases (CVDs). Thus, attenuating vascular inflammatory injury has great significance for the prevention and treatment of CVDs. In China, Shenmai formula, a well-known ancient Chinese prescription, has been widely used to treat CVDs, such as coronary atherosclerosis and viral myocarditis. In vivo study has demonstrated that the optimal combination of 3 major active components from Shenmai formula, panaxadiol and panaxatriol type saponins and ophioponins, in a ratio of 1:2:2 might exert significant cardioprotective effects and anti-inflammatory activities. The aim of this study was to investigate whether the combination may exert anti-inflammatory effects on lipopolysaccharide-induced inflammatory injury in cardiac microvascular endothelial cells by blocking nuclear factor-kappa B (NF-κB) pathway. We found that the combination could exert anti-inflammatory effects by inhibiting the mRNA and protein expression of interleukin-1, interleukin-6, tumor necrosis factor alpha, and intercellular adhesion molecule, as well as reducing the lactate dehydrogenase content in lipopolysaccharide-injured cardiac microvascular endothelial cells supernatant. Further experiments showed that the combination could suppress the NF-κB p65 expression and IκBα phosphorylation in these cells. These findings suggested that the combination inhibits vascular inflammatory injury by blocking NF-κB pathway, which proves a new molecular mechanism of the Shenmai formula to treat CVDs.

Berberine improves cognitive impairment by promoting autophagic clearance and inhibiting production of ß-amyloid in APP/tau/PS1 mouse model of Alzheimer's disease.

This study investigates the neuroprotective properties of berberine (a natural isoquinoline alkaloid isolated from the Rhizoma coptidis) and finds that berberine could promote ß-amyloid (Aß) clearance and inhibit Aß production in the triple-transgenic mouse model of Alzheimer's disease (3×Tg-AD). During the study, berberine was first administrated to treat 3×Tg-AD mice and primary neurons. Morris water maze assay, western blotting, enzyme-linked immunosorbent assay (ELISA), immunofluorescence staining and histological analysis, transmission electron microscopic analysis were then used to evaluate the effects of the berberine administration. The result showed that berberine significantly improved 3×Tg-AD mice's spatial learning capacity and memory retention, promoted autophagy activity identified by the enhancement of brain LC3-II, beclin-1, hVps34, and Cathepsin-D levels as well as the reduction of brain P62 and Bcl-2 levels in AD mice, facilitated reduction of Aß and APP levels, reduced Aß plaque deposition in the hippocampus of AD mice, and inhibited b-site APP cleavage enzyme 1 (BACE1) expression. Similar results were also found in 3×Tg-AD primary hippocampal neurons: berbernine treatment decreased the levels of extracellular and intracellular Aß1-42, increased the protein levels of LC3-II, beclin-1, hVps34, and Cathepsin-D, and decreased the levels of P62, Bcl-2, APP and BACE1 levels. In summary, berberine shows neuroprotective effects on 3×Tg-AD mice and may be a promising multitarget drug in the preventionand protection against AD.

The Role of Berberine in the Multi-Target Treatment of Senile Dementia.

Dementia is an acquired progressive cognitive dysfunction, affecting the content of consciousness rather than the level of consciousness. Most dementia is senile dementia, accounting for the majority of dementia. The most important and common form of senile dementia is refractory dementia, which includes Alzheimer's disease (AD) and vascular dementia (VD). Due to the diversity and uncertainty of the pathogenic mechanism of VD and AD, no significantly effective drug currently exists. Berberine is a natural isoquinoline alkaloid extracted from Coptis chinensis that has a wide range of pharmacological effects. studies in recent years have also found that berberine can additionally treat senile dementia by affecting neurotransmitter, anti-oxidative stress, metabolism and other multi-target pathways. Multi-target treatment of senile dementia by berberine is a potential avenue of study for senile dementia treatment.

Traditional Chinese medicine's intervention in endothelial nitric oxide synthase activation and nitric oxide synthesis in cardiovascular system.

Cardiovascular disease (CVD) is one of the most dangerous diseases which has become a major cause of human death. Many researches evidenced that nitric oxide (NO)/endothelial nitric oxide synthase (eNOS) system plays a significant role in the occurrence and development of CVD. NO, an important signaling molecule, closely associated with the regulation of vasodilatation, blood rheology, blood clotting and other physiological and pathological processes. The synthesis of NO in the endothelial cells primarily depends on the eNOS activity, thus the exploration of the mechanisms and effects of the eNOS activation on NO production is of great significance. Recently, studies on the effects of traditional Chinese medicine (TCM) and its extracts on eNOS activation and NO synthesis have gradually attracted more and more attentions. In this paper, we reviewed the mechanisms of NO synthesis and eNOS activation in the vascular endothelial cells (VECs) and intervention of TCM, so as to provide reference and train of thought to the intensive study of NO/eNOS system and the research and development of new drug for the treatment of CVD.