PMID: 

Artif Cells Nanomed Biotechnol. 2019 Dec ;47(1):3465-3477. PMID: 31432702

Abstract Title: 

Inhibiting tumour metastasis by DQA modified paclitaxel plus ligustrazine micelles in treatment of non-small-cell lung cancer.

Abstract: 

Lung cancer is a kind of malignant tumour characterized as uncontrolled cell growth in lung. These malignant cell growth can spread beyond the lung by process of metastasis into other tissues or parts of the body. In this study, we developed dequalinium (DQA) modified paclitaxel plus ligustrazine micelles to destroy vasculogenic mimicry (VM) channels and inhibit tumour metastasis.assays showed that the targeting micelles with centralized particle size distribution showed not only vigoroso cytotoxicity on A549 cells but also strong inhibition on VM channels and tumour metastasis. Mechanism studies indicated that the DQA modified paclitaxel plus ligustrazine micelles could down-regulate the expressions of VEGF, MMP2, TGF-β1 and E-cadherin in A549 cells.assays indicated that the targeting drug-loaded micelles could enhance the accumulation of chemotherapeutic drugs at tumour sites and exhibit strong tumour inhibitory activity with negligible toxicity. Hence, the DQA modified paclitaxel plus ligustrazine micelles developed in this study may provide a potential strategy for treatment of NSCLC.

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PMID: 

Life Sci. 2019 Nov 1 ;236:116836. Epub 2019 Sep 4. PMID: 31493479

Abstract Title: 

Tetramethylpyrazine prevents diabetes by activating PI3K/Akt/GLUT-4 signalling in animal model of type-2 diabetes.

Abstract: 

AIMS: The present experiment was conceptualised to explore the therapeutic response of tetramethylpyrazine (TMP), a major active constituent of Ligusticum chuanxiong, a Chinese traditional medicinal plant, in high-fat diet (HFD)-streptozotocin (STZ)-induced diabetes in rats and to identify the possible mechanism of action.MAIN METHODS: Dose-reliant effect of oral treatment of TMP (100, 150 and 200 mg/kg/day) for 28 days was evaluated by calculating the alteration in body weight, level of fasting blood glucose (FBG), plasma insulin, homeostasis model assessment (HOMA), serum lipids, oral glucose&intraperitoneal insulin tolerance and glycosylated haemoglobin in HFD-STZ-induced type-2 diabetic (T2D) rats and underlying molecular mechanisms of TMP was also studied.KEY FINDINGS: TMP treatment prominently reduced the level of FBG, glycosylated haemoglobin and revived body weight gain and level of serum insulin dose-dependently in diabetic rats. TMP treatment considerably improved insulin resistance, as observed in oral glucose tolerance and insulin tolerance tests. Moreover, dose-dependent reduction in the level of pro-inflammatory cytokines, C-reactive protein (CRP) and interleukin-6 (IL-6) was observed and their level was found to be significantly reduced in highest dose TMP (200 mg/kg) treated diabetic rats, pointing towards TMP mediated recovery of insulin signalling and a decrease in insulin resistance. The expressions of p-PI3K-p85/p-Akt/GLUT-4 were also significantly up-regulated by TMP (200 mg/kg), suggesting the connection of the PI3K/Akt signal pathway in the anti-hyperglycemic action of TMP.SIGNIFICANCE: These findings suggest that TMP may be used as a potential agent for type-2 diabetes treatment.

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PMID: 

Exp Mol Pathol. 2019 Dec ;111:104317. Epub 2019 Oct 23. PMID: 31655387

Abstract Title: 

Tetramethylpyrazine alleviates lipopolysaccharide-induced damage in ATDC5 cells via down-regulating MyD88.

Abstract: 

BACKGROUND: Tetramethylpyrazine (TMP) has been reported to play a significant role in the cardiovascular and neuronal diseases. But, the functions of TMP in osteoarthritis (OA) remain unclear. In this investigation, we intended to probe the protective effectiveness of TMP in lipopolysaccharide (LPS)-caused damage in ATDC5 cells.METHODS: ATDC5 cells were managed with LPS (5 μg/mL) for 12 h, and then the effects of TMP on these cells were evaluated. Cell viability and apoptosis of these treated cells were detected by CCK-8 and flow cytometry methods. The secretions of IL-1β, IL-6 and TNF-α were examined via applying ELISA kits. qRT-PCR was utilized to measure cell inflammatory factors and MyD88 expression. After transfection with pc-MyD88, the above-involved cell processes were reassessed, and NF-κB and p38MAPK pathways were examined by western blot assay.RESULTS: LPS treatment induced a series of inflammatory destructions, which reduced viability, accelerated apoptosis and cell inflammatory factors release in ATDC5 cells. However, TMP precondition clearly mitigated LPS-triggered ATDC5 cell injury. Additionally, TMP down-regulated MyD88 expression in LPS-treated ATDC5 cells, as well as overexpression of MyD88 overturned the impacts of TMP on LPS-induced cell injury in ATDC5 cells. Beyond that, TMP restrained LPS-triggered the activations of NF-κB and p38MAPK via repression of MyD88.CONCLUSION: The above consequences exhibited that TMP exhibited a protective effect to lighten LPS-caused cell damage via mediating MyD88/NF-κB/p38MAPK pathways. These findings suggested that TMP perhaps an effective agent for the clinical treatment of OA.

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PMID: 

Eur J Pharmacol. 2019 Dec 15 ;865:172763. Epub 2019 Nov 1. PMID: 31682792

Abstract Title: 

Tetramethylpyrazine alleviates diabetic nephropathy through the activation of Akt signalling pathway in rats.

Abstract: 

In the whole world, the principal cause of end-stage renal disease is diabetic nephropathy (DN), which is one of the most relentless complications of diabetes. However, there is a shortfall of compelling DN treatments and the mechanism potentially able to alleviate renal injury remains ambiguous. In this experiment, we estimated the preventive actions of tetramethylpyrazine (TMP) on DN in rats and further investigated the underlying mechanism. The different doses of TMP (100 mg/kg, 150 mg/kg and 200 mg/kg) were orally given each day for 8 weeks in streptozotocin (STZ) – nicotinamide (NCT) – induced type-2 diabetic (T2D) rats. The metabolic parameters of diabetes, blood urea nitrogen (BUN), serum creatinine (SCR), urinary protein and oxidative stress parameters were assessed. Microstructural changes in kidney were observed, and the expression of Akt signalling pathway proteins was measured by western blotting. TMP administration in T2D rats improved diabetic condition, as demonstrated by significant (P 

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PMID: 

Microvasc Res. 2019 Nov 1 ;128:103938. Epub 2019 Nov 1. PMID: 31682800

Abstract Title: 

Ligustrazine prevents basilar artery remodeling in two-kidney-two-clip renovascular hypertension rats via suppressing PI3K/Akt signaling.

Abstract: 

OBJECTIVE: In the present study, we used a two-kidney-two-clip (2k2c) stroke-prone renovascular hypertension rat model (RHRSP) to investigate the protective effects of ligustrazine (TMP) on cerebral arteries and to examine PI3K/Akt pathway behavior under this protection.METHODS: The cerebral artery remodeling was induced by 2k2c-induced renovascular hypertension. Brain basilar artery tissues were isolated and their histological changes were detected through H&E and EVG staining,α-SMA IHC staining, and transmission electron microscopy at four, eight, and twelve weeks after 2k2c surgery, both with and without TMP treatment. Meanwhile, the ET-1, Ang II, and NO levels in basilar arteries and plasma were determined. Furthermore, the PTEN expression and the activation of PI3K/Akt in basilar artery tissues were detected through IHC and Western Blot. In addition, the primary basilar artery smooth muscle cells (BASMCs) were cultured and TMP protection of BASMCs stimulated with ET-1/Ang II in the presence or absence of insulin-like growth factor 1 (IGF-1) was determined.RESULTS: TMP attenuated basilar artery remodeling, decreased ET-1 and Ang II levels and increased NO level in basilar arteries and plasma of RHRSP rats. Moreover, TMP reduced BASMCs proliferation upon ET-1/Ang II stimulation. We also found that TMP could effectively suppress the activation of PI3K/Akt in 2k2c-RHRSP rat basilar artery and ET-1/Ang II stimulated BASMCs. Most importantly, IGF-1, as an activator of PI3K/Akt, could damage the protective effect of TMP.CONCLUSIONS: TMP exerts its protective effects and prevents basilar artery remodeling in RHRSP rats at least partly through the inhibition of PI3K/Akt pathway.

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PMID: 

Inflammation. 2019 Nov 13. Epub 2019 Nov 13. PMID: 31720990

Abstract Title: 

Tetramethylpyrazine Inhibits Platelet Adhesion and Inflammatory Response in Vascular Endothelial Cells by Inhibiting P38 MAPK and NF-κB Signaling Pathways.

Abstract: 

Damaged vascular endothelial cells after ischemic stroke release inflammatory cytokines and adhesion molecules, which could trigger platelet adhesion to vascular endothelial cells and platelet activation, and accelerate thrombus formation. Tetramethylpyrazine is the main bioactive component of Chuanxiong, which has demonstrated considerable protective effects in cerebrovascular diseases. However, the effect and mechanisms of tetramethylpyrazine on platelet adhesion to ischemia/reperfusion-injured endothelial cells have not been elucidated. In this study, we established an oxygen-glucose deprivation/reoxygenation (OGD/R)-induced brain microvascular endothelial cells (BMECs) injury model to investigate the protective effects of tetramethylpyrazine on platelet adhesion to endothelial cells and potential mechanisms. Experimental results showed that tetramethylpyrazine inhibited platelets adhesion to BMECs, alleviated expression of inflammatory cytokines and adhesion molecules on BMECs, and protected BMECs injured by OGD/R. Furthermore, tetramethylpyrazine could inhibit P38 MAPK and NF-κB activation in injured BMECs by OGD/R and inhibition of P38 MAPK with SB303580 and NF-κB with Bay-11-7082 attenuated the reduction of platelets adhesion to BMECs by tetramethylpyrazine. In conclusion, tetramethylpyrazine protected BMECs and inhibited platelets adhesion to BMECs after OGD/R injury, which was partially mediated by inhibiting P38 MAPK and NF-κB signaling pathways.

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PMID: 

Mol Cell Biochem. 2019 Nov 16. Epub 2019 Nov 16. PMID: 31732832

Abstract Title: 

Ligustrazine suppresses renal NMDAR1 and caspase-3 expressions in a mouse model of sepsis-associated acute kidney injury.

Abstract: 

Sepsis-associated acute kidney injury (AKI) is a life threatening condition with high morbidity and mortality. The pathogenesis of AKI is associated with apoptosis. In this study, we investigated the effects of ligustrazine (LGZ) on experimental sepsis-associated AKI in mice. Sepsis-associated AKI was induced in a mice model using cecal ligation and puncture (CLP) method. Mice were administered LGZ (10, 30, and 60 mg/kg) via tail vein injection 0.5 h before CLP surgery. Mice survival was evaluated. Renal water content was detected. Urine samples were collected for ELISA of Kim1. Kidneys were collected for nucleic acid analysis and histological examination. Pathological assessment was used to determine theeffect of LGZ on sepsis-associated AKI. Caspase-3 expression in kidney was assessed by immunohistochemistry. Renal NMDAR1 level was also determined. Treatment of LGZ improved mice survival rate; the effect was significant when administered at a high LGZ dose (60 mg/kg). Renal water content of miceundergoing CLP was significantly reduced by LGZ treatment. Both middle-dose and high-dose LGZ treatments reduced urine Kim1 level in sepsis-associated AKI mice. The severity of AKI in septic mice was reduced by middle-dose and high-dose LGZ administration. Immunohistochemical analysis revealed decreased caspase-3 and NMDAR1 levels in the kidney following middle-dose and high-dose LGZ treatments. RT-PCR assay showed a significant reduction in NMDAR1 mRNA expression in the kidney of middle-dose and high-dose LGZ-treated mice. LGZ exhibited protective effects against sepsis-associated AKI in mice, possibly via downregulation of renal NMDAR1 expression and its anti-apoptotic action by inhibiting caspase-3.

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PMID: 

ACS Chem Neurosci. 2019 Dec 18 ;10(12):4854-4863. Epub 2019 Dec 6. PMID: 31756074

Abstract Title: 

Tetramethylpyrazine Reduces Epileptogenesis Progression in Electrical Kindling Models by Modulating Hippocampal Excitatory Neurotransmission.

Abstract: 

Antiepileptic drugs (AEDs) are the primary agents prescribed for clinical management of limbic epilepsy. However, high incidence of pharmacoresistance and a limited armory of drugs for inhibiting the pathological progression of epilepsy pose major obstacles to managing epilepsy. Here, we investigated the effect of tetramethylpyrazine (TMP), the main bioactive alkaloid isolated from the oriental medicine, against the epileptogenesis progression of acute hippocampal and corneal (6 Hz) electrical kindling models of TLE. TMP dose-dependently limited the progression of seizures and reduced the after-discharge duration (ADDs) in a hippocampal mouse kindling model. Mice treated with TMP (20, 50 mg/kg, i.p.) remained in stage 1 of epileptic progression for a protracted period, requiring additional stimulation to induce stages 2-5 epileptic phenotypes. TMP (50 mg/kg) also inhibited 6 Hz corneal kindling progression. In contrast, TMP did not reverse the phenotypes induced in a generalized seizures (GS) model, or the maximal electroshock (MES) or pentylenetetrazole (PTZ)-induced models of epilepsy. Furthermore, patch clamp recordings revealed no effect of TMP (10μM) on CA1 hippocampal neurons' intrinsic properties but suppressed the (i) frequency of spontaneous excitatory post synaptic currents (sEPSCs), (ii) paired pulse ratio (PPR), and (iii) long-term potentiation (LTP) induction in the Schaffer collateral-CA1 pathway. TMP suppressed the activity of calcium, but not sodium, channels. Taken together, these results suggest that TMP has an antiepileptogenic effect, likely through suppression of excitatory synaptic transmission by its effects on inhibition of calcium channels; these traits distinguish TMP from currently available AEDs. As mice administered TMP did not show any neurologic impairment in the object recognition and open field tests, the data support further development of TMP as a promising treatment for epilepsy.

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PMID: 

Oxid Med Cell Longev. 2019 ;2019:1243215. Epub 2019 Dec 4. PMID: 31871537

Abstract Title: 

Pterostilbene Attenuates Fructose-Induced Myocardial Fibrosis by Inhibiting ROS-Driven Pitx2c/miR-15b Pathway.

Abstract: 

Excessive fructose consumption induces oxidative stress and myocardial fibrosis. Antioxidant compound pterostilbene has cardioprotective effect in experimental animals. This study is aimed at investigating how fructose drove fibrotic responses via oxidative stress in cardiomyocytes and explored the attenuation mechanisms of pterostilbene. We observed fructose-induced myocardial hypertrophy and fibrosis with ROS overproduction in rats. Paired-like homeodomain 2 (Pitx2c) increase, microRNA-15b (miR-15b) low expression, and p53 phosphorylation (p-p53) upregulation, as well as activation of transforming growth factor-1 (TGF-1)/drosophila mothers against DPP homolog (Smads) signaling and connective tissue growth factor (CTGF) induction, were also detected in fructose-fed rat hearts and fructose-exposed rat myocardial cell line H9c2 cells. The results fromsiRNA orsiRNA transfection showed that TGF-1-induced upregulation of CTGF expression and p-p53 activated TGF-1/Smads signaling in fructose-exposed H9c2 cells. Of note, Pitx2c negatively modulated miR-15b expressionbinding to the upstream of the miR-15b genetic loci by chromatin immunoprecipitation and transfection analysis with pEX1-Pitx2c plasmid andsiRNA, respectively. In H9c2 cells pretreated with ROS scavenger N-acetylcysteine, or transfected with miR-15b mimic and inhibitor, fructose-induced cardiac ROS overload could drive Pitx2c-mediated miR-15b low expression, then cause p-p53-activated TGF-1/Smads signaling and CTGF induction in myocardial fibrosis. We also found that pterostilbene significantly improved myocardial hypertrophy and fibrosis in fructose-fed rats and fructose-exposed H9c2 cells. Pterostilbene reduced cardiac ROS to block Pitx2c-mediated miR-15b low expression and p-p53-dependent TGF-1/Smads signaling activation and CTGF induction in high fructose-induced myocardial fibrosis. These results firstly demonstrated that the ROS-driven Pitx2c/miR-15b pathway was required for p-p53-dependent TGF-1/Smads signaling activation in fructose-induced myocardial fibrosis. Pterostilbene protected against high fructose-induced myocardial fibrosis through the inhibition of Pitx2c/miR-15b pathway to suppress p-p53-activated TGF-1/Smads signaling, warranting the consideration of Pitx2c/miR-15b pathway as a therapeutic target in myocardial fibrosis.

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PMID: 

IBRO Rep. 2019 Dec ;7:90-96. Epub 2019 Oct 22. PMID: 31720488

Abstract Title: 

Effect of Crataegus extract supplementation on diabetes induced memory deficits and serum biochemical parameters in male rats.

Abstract: 

This study was undertaken to investigate the Crataegus extract (CE) eff ;ects on diabetes-induced memory deficit in passive avoidance learning (PAL), blood glucose, and lipid profile panel. Male Wistar rats were divided into five groups:(CTRL);(DM); andwith three doses of CE (100, 300 and 1000 mg/kg) (DM + CE). Streptozotocin (STZ)-induced diabetic rats (50 mg/kg, ip) were orally administrated with CE once a day for 2 weeks. After 2 weeks, PAL task was used to evaluate the passive avoidance learning and memory. At the end of experiment, the level of plasma glucose, triglycerides(TG), cholesterol, low-density lipoprotein (LDL), and high-density lipoprotein (HDL) were determined. Our results showed that the step-through latency (STLr) in diabetic animals was less than the control group (P = 0.0009). Crataegus (300 mg) increased STLr in diabetic animals (P = 0.0418). Diabetic animals spent more time in the dark compartment (TDC) (P = 0.0009). Crataegus (300 and 1000 mg) decreased TDC in diabetic animals (P = 0.0175). Crataegus (100 and 300 mg) decreased blood glucose in diabetic animals (P 

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