Effects of sodium ferulate for injection on anticoagulation of warfarin in rats in vivo.

BACKGROUND: Herb-drug interactions may result in increased adverse drug reactions or diminished drug efficacy, especially for drugs with a narrow therapeutic index such as warfarin. The current study investigates the effects of sodium ferulate for injection (SFI) on anticoagulation of warfarin from aspects of pharmacodynamics and pharmacokinetics in rats and predicts the risk of the combination use. METHODS: Rats were randomly divided into different groups and administered single- or multiple-dose of warfarin (0.2 mg/kg) with or without SFI of low dose (8.93 mg/kg) or high dose (26.79 mg/kg). Prothrombin time (PT) and activated partial thromboplastin time (APTT) were detected by a blood coagulation analyzer, and international normalized ratio (INR) values were calculated. UPLC-MS/MS was conducted to measure concentrations of warfarin enantiomers and pharmacokinetic parameters were calculated by DAS2.0 software. RESULTS: The single-dose study demonstrated that SFI alone had no effect on coagulation indices, but significantly decreased PT and INR values of warfarin when the two drugs were co-administered (P < 0.05 or P < 0.01), while APTT values unaffected (P > 0.05). Cmax and AUC of R/S-warfarin decreased but CL increased significantly in presence of SFI (P < 0.01). The multiple-dose study showed that PT, APTT, INR, and concentrations of R/S-warfarin decreased significantly when SFI was co-administered with warfarin (P < 0.01). Warfarin plasma protein binding rate was not significantly changed by SFI (P > 0.05). CONCLUSIONS: The present study implied that SFI could accelerate warfarin metabolism and weaken its anticoagulation intensity in rats.

The efficacy of sodium ferulate combination therapy in coronary heart disease: A systematic review and meta-analysis.

BACKGROUND: Sodium ferulate (SF), a derivative of ferulic acid, is one of the active constituents in medicinal plants thought to be useful in fighting cardiovascular diseases. However, there still lacks a systematic review of the efficacy and safety of SF in treating coronary heart disease (CHD). It is therefore the purpose of this study to comprehensively review all clinical randomized controlled trials (RCTs) of SF in CHD to assess its efficacy and safety. METHODS: All analysis is based on 8 databases as of February 2023, which includes 35 outcomes of RCTs that investigate the effect of SF combination therapy in CHD. The present study evaluates the quality and bias of selected literature by the Jadad scale and Cochrane Collaboration's tools, and also the quality of evidence by GRADE Profiler. Furthermore, it applies sensitivity analysis to assess the high heterogeneity impact of outcomes and conducted subgroup analysis to estimate the influence factors in these studies. The study protocol was set documented, and published beforehand in PROSPERO (Registration No.CRD42022348841). RESULTS: The meta-analysis of 36 studies (with 3207 patients) shows that SF combined with conventional drugs has improved clinical effectiveness for patients with CHD [RR: 1.21 (95% CI 1.17,1.26); p < 0.00001]. Statistically significant results of meta-analyses are also seen in electrocardiography (ECG) efficacy, frequency of angina attacks, endothelium-dependent flow-mediated vasodilation (FMD), nitric oxide (NO), endothelin (ET), whole Blood low shear rate (LS), platelet aggregation test (PAgT), C-reactive protein (CRP), tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL6), triglyceride (TG). Adverse events are reported in 6 RCTs. By GRADE approaches, 2 outcomes (clinical efficacy, CRP) indicate a moderate quality of evidence, 17 outcomes indicate low quality of evidence, with the other 16 very low-quality. CONCLUSION: SF combination therapy has a better curative effect than conventional therapy. However, due to items with low-quality evidence demonstrated in the study, the presence of clinical heterogeneity, and imprecision in partial outcome measures, all these led to limitations in the evidence of this study. Thus, the conclusion needs to be further verified by more in-depth research.

Inhibitory effect of sodium ferulate on inflammatory response in migraine rats based on c-Jun N-terminal kinase / p38 mitogen-activated protein kinase signaling pathway / 解剖学报

[Abstract] Objective To explore the inhibitory effect of sodium ferulate (SF) on the inflammatory response in migraine rats by regulating the c-Jun N-terminal kinase (JNK) / p38 mitogen-activated protein kinase (p38 MAPK) signaling pathway. Methods The migraine rat model was prepared by intraperitoneal injection of nitroglycerin. After successful modeling, the rats were randomly grouped into model group, SF low dose (SF-L) group (50 mg/ kg), SF high dose (SF-H) group (100 mg/ kg), SF+JNK inhibitor (SF + SP600125) group (SF 100 mg/ kg +SP600125 10 mg/ kg), and SF+JNK activator [SF + anisomycin(AN)] group (SF 100 mg/ kg +AN 5 mg/ kg), 12 in each group, another 12 SD rats without treatment were taken as blank group. The behavioral changes of the rats in each group were observed 24 hours after the administration, the levels of 5-hydroxytryptamine (5-HT), nitric oxide (NO), tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in serum were detected by ELISA, the neuronal apoptosis in brain tissue was observed by TUNEL staining, immunohistochemistry was used to evaluate the expressions of TNF-α, IL-6 and calcitonin gene-related peptide (CGRP) in brain tissue, Western blotting was used to detect the expressions of JNK/ p38 MAPK pathway-related proteins in brain tissue. Results Compared with the blank group, the number of times of scratching the head and climbing the cage of the rats in the model group increased significantly, and the apoptosis rate of neurons increased significantly; the content of 5-HT in serum decreased significantly, and the levels of NO, TNF-α and IL-6 increased significantly; the expressions of TNF-α, IL-6 and CGRP, and the ratios of phosphorylated JNK (p-JNK) / JNK and phosphorylated p38 MAPK(p-p38 MAPK) / p38 MAPK in brain tissue obviously increased (all P<0. 05). Compared with the model group, the number of times of scratching the head and the times of climbing the cage of the rats in the SF-L group and the SF-H group reduced significantly, and the neuron apoptosis rate reduced significantly; the content of 5-HT in serum increased significantly, and the levels of NO, TNF-α and IL-6 decreased significantly; the expressions of TNF-α, IL-6 and CGRP, and the ratios of p-JNK/ JNK and p-p38 MAPK/ p38 MAPK in brain tissue obviously decreased (all P<0. 05). Compared with SF-H group, the protective effect of SF on migraine rats in SF+SP600125 group enhanced significantly; the protective effect of SF on migraine rats in the SF+AN group reversed significantly. Conclusion SF may inhibit the expression of JNK/ p38 MAPK signaling pathway, effectively inhibit neurogenic inflammatory response in migraine rats, reduce neuronal apoptosis, and achieve a protective effect on migraine rats.

Effect and potential mechanism of sodium ferulate on corneal endothelial dysfunction and CEC injury / 中国药房

OBJECTIVE To investigate the effect and potential mechanism of sodium ferulate （SF） on corneal endothelial dysfunction and corneal endothelial cell （CEC） injury. METHODS The male New Zealand rabbits were divided into control group， benzalkonium chloride （BAK） group and BAK+SF group， with 6 rabbits in each group. Except for control group， the other groups were given BAK into the anterior chamber to induce bullous keratopathy model， and BAK+SF group then given SF solution 200 mg/kg intraperitoneally the next day after surgery， twice a day， for consecutive 14 d. The transparency of corneal and edema of corneal stroma in each group of rabbits （before and on the 1st， 7th， and 14th day after surgery） were observed， and the corneal thickness （14th day after surgery） and intraocular pressure （1st to 14th day after surgery） were measured. On the 14th day after operation， the corneal endothelial structure was evaluated and the expressions of functionally related proteins [phalloidin， zonula occludens-1 （ZO-1）， Na+/K+-ATPase， Ki67] were detected. On the 14th day after surgery， the corneal tissue was collected in BAK group， the primary rabbit CECs were isolated and cultured， and they were divided into blank group and SF groups with different mass concentrations. The cell viabilities after being cultured for different time， and the protein expressions of Ras homologous gene family A （RhoA）， bone morphogenetic protein receptor 1A （BMPR1A） and BMRP2 were determined in each group. RESULTS Compared with BAK group， the transparency of corneal and edema of corneal stroma were gradually improved， and the corneal thickness was significantly decreased in BAK+SF group （P＜0.05）. The rabbit CECs in BAK+SF group were only damaged to zone B and showed a normal hexagonal endothelial cells structure. The protein expressions of phalloidin， ZO-1， Na+/K+-ATPase and Ki67 in BAK+SF group were significantly increased （P＜0.05）. When SF concentration was lower than and equal to 200 mg/L， it could promote the proliferation of rabbit CEC， in concentration manner （P＜0.05） and time-dependent trend. SF at concentrations of 50， 100， and 200 mg/L could up-regulate the protein expressions of RhoA， BMPR1A and BMPR2 in concentration-dependent manner （P＜0.05）. CONCLUSIONS SF can improve the transparency of corneal and edema of corneal stroma in bullous keratopathy model rabbits， reduce corneal thickness， maintain the integrity of corneal endothelium structure， and promote the recovery of corneal endothelial function； this compound can promote the proliferation of CEC， the mechanism of which may be related to the activation of RhoA-ROCK-BMP pathway.

Sodium ferulate-functionalized silver nanopyramides with synergistic antithrombotic activity for thromboprophylaxis.

Thrombosis is one of the feared complications contributing to death in patients with cardiovascular diseases. Ferulic acid (FA), a bioactive compound extracted from traditional Chinese medicines, has drawn tremendous attention in prevention and treatment of thrombosis because of its notable antithrombotic potency. However, the poor aqueous solubility and pharmacokinetic profile of FA limit its clinical use. In this study, sodium ferulate-functionalized silver nanopyramides (SF-pAgNPs) with narrow size distribution were synthesized to overcome these obstacles and enhance the suppression effect of platelet activation and thrombosis formation. The cytotoxicity and hemolysis assays demonstrated that the prepared nanopyramides have a favorable biocompatibility pattern. In vitro studies revealed that SF-pAgNPs could effectively suppress platelet activation, aggregation and adhesion through the synergetic antithrombotic potential of SF and nano silver. Furthermore, SF-pAgNPs exhibited potent antithrombotic activity and prolonged inhibitory effect, much better than PEG-Ag and free SF in mouse model. With enhanced antithrombotic effect and acceptable biocompatibility, we believe the sodium ferulate-functionalized silver nanopyramides might hold the potential to be a promising strategy for the prevention and treatment of thrombosis.

Effects of Sodium Ferulate on Cardiac Hypertrophy Are via the CaSR-Mediated Signaling Pathway.

As a common complication of many cardiovascular diseases, cardiac hypertrophy is characterized by increased cardiac cell volume, reorganization of the cytoskeleton, and the reactivation of fetal genes such as cardiac natriuretic peptide and ß-myosin heavy chain. Cardiac hypertrophy is a distinguishing feature of some cardiovascular diseases. Our previous study showed that sodium ferulate (SF) alleviates myocardial hypertrophy induced by coarctation of the abdominal aorta, and these protective effects may be related to the inhibition of protein kinase C (PKC) and mitogen-activated protein kinase (MAPK) signaling pathways. This study investigated the inhibitory effect and mechanism of SF on myocardial hypertrophy in spontaneously hypertensive rats (SHRs). The effects of SF on cardiac hypertrophy were evaluated using echocardiographic measurement, pathological analysis, and detection of atrial natriuretic peptide (ANP) and ß-myosin heavy chain (ß-MHC) expression. To investigate the mechanisms underlying the anti-hypertrophic effects of SF, the calcium-sensing receptor (CaSR), calcineurin (CaN), nuclear factor of activated T cells 3 (NFAT3), zinc finger transcription factor 4 (GATA4), protein kinase C beta (PKC-ß), Raf-1, extracellular signal-regulated kinase 1/2 (ERK 1/2), and mitogen-activated protein kinase phosphatase-1 (MKP-1) were detected by molecular biology techniques. Treatment with SF ameliorated myocardial hypertrophy in 26-week-old SHRs. In addition, it downregulated the levels of ANP, ß-MHC, CaSR, CaN, NFAT3, phosphorylated GATA4 (p-GATA4), PKC-ß, Raf-1, and p-ERK 1/2; and upregulated the levels of p-NFAT3 and MKP-1. These results suggest that the effects of SF on cardiac hypertrophy are related to regulation of the CaSR-mediated signaling pathway.

Influence of sodium ferulate on miR-133a and left ventricle remodeling in rats with myocardial infarction.

To explore the influence of sodium ferulate (SF) on miR-133a and left ventricle remodeling (LVR) in rats with myocardial infarction (MI). The left coronary artery was ligated to create 36 ischemia-reperfusion (IR) rat models that were randomly divided into mock surgical group (MSG) (not ligated), model group (MG), and sodium ferulate group (SFG). After the successful modeling, SFG was intravenously injected with SF at the dose of 10 mg/kg, and the other two groups were injected with the same volume of normal saline. After 28 days, cardiac hemodynamic indices of all groups were measured; the myocardial infarction size (MIS), left ventricular mass index (LVMI), and collagen volume fraction (CVF) were calculated, the content of serum malondialdehyde (MDA) and activities of catalase (CAT), superoxide dismutase (SOD) and glutathione catalase (GSH-px) were detected by ELISA, and miR-133a expression in myocardial tissues of the left ventricle (LV) was detected by RT-qPCR. SF improved the cardiac hemodynamic indices of rat model and reduced the MIS, LVMI and CVF. SF decreased the serum MDA level and increased the serum CAT, SOD and GSH-px levels in rat model. SF increased the expression of miR-133a in myocardial tissue of rat model. Therefore, SF could effectively reduce the myocardial injury of IR rats and improve the LVR. Its mechanism may be related to the antioxygenation and upregulation of miR-133a.

Protective effects of sodium ferulate on flap transplantation via anti-inflammatory modulation and oxidative stress inhibition

Ischemia-reperfusion injury (IRI) has brought attention to flap failure in reconstructive surgery. To improve the prognosis of skin transplantation, we performed experimental IRI by surgical obstruction of blood flow and used sodium ferulate (SF) to prevent IRI in rats. After SF treatment, the morphological and histological changes of the skin flaps were observed by H&E and Masson's trichrome staining. We also detected the expression levels of COX-1, HO-1, and Ki67 by immunohistochemical and western blot analysis. Moreover, enzyme-linked immunosorbent assay was used to identify the content of tumor necrosis factor (TNF)-α, myeloperoxidase (MPO), malondialdehyde (MDA), and nitric oxide (NO) in peripheral blood and skin tissue. Compared with the model group, SF treatment significantly improved the recovered flap area (%) and promoted collagen synthesis. Cyclooxygenase-2 (COX-2) expression was significantly inhibited by heme oxygenase-1 (HO-1) induction after SF treatment. Furthermore, SF significantly inhibited the levels of TNF-α in peripheral blood, MPO and MDA in the skin tissue, and the increased synthesis of NO. Our results showed the protective effects of SF on IRI after flap transplantation and we believe that the protective effects of SF was closely related to the alleviation of the inflammatory response and the inhibition of the oxidative stress injury.

Renal protective effect of sodium ferulate on pulmonary hypertension patients undergoing computed tomography pulmonary angiography.

This study aimed to explore the correlation of sodium ferulate and the renal protective effect on computed tomography pulmonary angiography in patients suffering from pulmonary hypertension. This prospective study enrolled 92 consecutive patients with pulmonary hypertension diagnosed by echocardiography, and all included patients underwent computed tomography pulmonary angiography after admission. The participants were randomized, divided into sodium ferulate group (n = 49) and control group (n = 43), of which patients in the sodium ferulate group received intravenous sodium ferulate 3.0 g per day from 12 h before computed tomography pulmonary angiography examination to 72 h after that, and patients in the control group were provided with routine treatment. Renal function was assessed by measuring serum creatinine, estimated glomerular filtration rate, Cystatin-C as well as 24 h, 48 h, and 72 h after computed tomography pulmonary angiography, followed by the calculation of the incidence of contrast-induced nephropathy for contrast-induced nephropathy and non-contrast-induced nephropathy grouping. Besides, renal resistive index was determined via Doppler ultrasound examination before, after 1 h and 24 h after computed tomography pulmonary angiography. There were no significant differences between the two groups in serum creatinine at baseline and 24 h after computed tomography pulmonary angiography (P > 0.05, respectively), but at 48 h and 72 h, it was lower in the sodium ferulate group (P < 0.05). There were no significant differences of estimated glomerular filtration rate between the two groups (P > 0.05). The level of Cystatin-C at 48 h and 72 h after computed tomography pulmonary angiography was lower than in the sodium ferulate group (P < 0.05). Contrast-induced nephropathy was identified in nine patients (9.78%). Sodium ferulate was associated with a decline in the incidence of contrast-induced nephropathy (4.08 vs. 16.28 %, P < 0.05). Compared to patients with contrast-induced nephropathy, lower renal resistive index were observed at 1 h and 24 h after computed tomography pulmonary angiography in patients without contrast-induced nephropathy (P < 0.05). Infusion of sodium ferulate before and after computed tomography pulmonary angiography was associated with a decline in incidence of contrast-induced nephropathy.

Sodium ferulate attenuates high-glucose-induced oxidative injury in HT22 hippocampal cells.

The aim of the present study was to investigate the protective effects of sodium ferulate (SF) on HT22 hippocampal cells under a high glucose concentration. Cells were cultured in normal glucose (25 mM D-glucose) or high glucose (50 mM D-glucose) with various concentrations of SF (50, 100, 250 or 500 µM) for 0, 48 and 72 h. Cell viability was tested using a Cell Counting Kit-8 assay. Reactive oxygen species (ROS) production was detected using flow cytometry. The expression of nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1) and nuclear factor-κB (NF-κB) at the mRNA and protein levels were detected using a reverse transcription-quantitative polymerase chain reaction analysis and western blotting. HT22 hippocampal cell viability was revealed to be substantially decreased following culturing in high glucose medium (50 mM) for 48 and 72 h. The addition of 100 µM SF abrogated this high-glucose-induced toxicity, but higher concentrations of SF (250 and 500 µM) were harmful to the cells. Furthermore, a high glucose concentration increased the generation of ROS, downregulated the expression of Nrf2/HO-1 and upregulated the expression of NF-κB subsequent to culturing for 72 h, whereas the addition of the appropriate concentration of SF attenuated these effects. To the best of our knowledge, the present study is the first to report such results and provide evidence that SF protects HT22 cells from high glucose-induced toxicity by activating the Nrf2/HO-1 pathway and inhibiting the expression of NF-κB, which may be of therapeutic value in diabetic encephalopathy.

Sodium ferulate inhibits myocardial hypertrophy induced by abdominal coarctation in rats: Involvement of cardiac PKC and MAPK signaling pathways.

Sodium ferulate (SF) is the sodium salt of ferulic acid which is an active ingredient of Radix Angelica Sinensis and Ligusticum chuanxiong hort. Here, we investigated SF inhibition in a rat model of myocardial hypertrophy induced by coarctation of the abdominal aorta. Following coarctation, rats were given SF (20, 40, and 80 mg/kg/day) for 25 consecutive days. We characterized myocardial hypertrophy using myocardial hypertrophic parameters, histopathology, and gene expression of atrial natriuretic factor (ANF) -a gene related to myocardial hypertrophy. We detected the levels of angiotensin II (Ang II) and endothelin-1 (ET-1), protein kinase C beta (PKC-ß), Raf-1, extracellular regulated protein kinase 1/2 (ERK1/2), and mitogen-activated protein kinase phosphatase-1 (MKP-1) in myocardium. Notably, coarctation of the abdominal aorta increases myocardial hypertrophic parameters, cardiac myocyte diameter, the concentration of Ang II and ET-1 in myocardium, and gene expression of ANF. SF significantly ameliorates myocardial hypertrophy caused by coarctation of the abdominal aorta; reduces concentrations of Ang II and ET-1; suppresses the overexpression of ANF, PKC-ß, Raf-1, and ERK1/2; and increases the expression of MKP-1. These results indicate that SF alleviates myocardial hypertrophy induced by coarctation of the abdominal aorta, and these protective effects could be related to the inhibition of PKC and mitogen-activated protein kinase (MAPK) signaling pathways.

Sodium ferulate protects against influenza virus infection by activation of the TLR7/9-MyD88-IRF7 signaling pathway and inhibition of the NF-κB signaling pathway.

Influenza A virus (IAV) is highly contagious and causes considerable mortality worldwide. TLR3, 7, 8 and 9 recognize viral nucleic acids and rapidly trigger different signaling cascades that contribute to the production of interferons (IFNs) to antiviral defense. Therefore, a host immune response induced by the activation of these receptors can be used as a new antiviral strategy. In this study, the protective effect of sodium ferulate (SF) is investigated on mice infected with influenza virus A/FM/1/47(H1N1). SF improved survival and mitigated weight loss in infected mice. SF inhibited influenza virus replication by activating TLR7 and TLR9, which resulted in the promotion of IRF7 translocation into the nucleus and the production of typeⅠIFNs. Moreover, SF inhibited the NF-κB pathway by preventing p65 translocation from the cytoplasm to the nucleus. These findings demonstrate that SF plays a critical role in protection against IAV infection by activation of the TLR7/9-MyD88-IRF7 signaling pathway and inhibition of the NF-κB signaling pathway.

Tetramethylpyrazine­2'O­sodium ferulate provides neuroprotection against neuroinflammation and brain injury in MCAO/R rats by suppressing TLR-4/NF-κB signaling pathway.

BACKGROUND: Neuroinflammation following cerebral ischemia is a serious risk factor in stroke patients. The purpose of this study was to investigate the neuroprotective effects of tetramethylpyrazine­2'O­sodium ferulate (TSF), a structurally modified compound from tetramethylpyrazine and ferulate, on cerebral ischemic injury and the underlying mechanisms. METHODS: Focal transient cerebral ischemia was induced in rat for 2 h by middle cerebral artery occlusion (MCAO) and the protective effect of TSF was studied using different doses of the drug (10.8, 18, 30 mg/kg, intravenously); Ozagrel (18 mg/kg) was used as the positive control. The drugs were given immediately after MCAO and the efficacy and mechanisms were evaluated at 72 h of reperfusion. The level of pro-inflammatory cytokines such as TNF-α, IL-1ß and anti-inflammatory molecules such as IL-10 was measured; other factors such as neurological deficit, brain water content and infarct size and the level of MCP-1, ICAM-1, iNOS, CD11b, TLR-4/NF-κBp65 were also measured. RESULTS: TSF at the doses of 18, 30 mg/kg significantly improved neurological deficit, reduced brain water content and infarct size, accompanied by a decrease in the concentration of TNF-α, IL-1ß, MCP-1, ICAM-1, iNOS and an increase in the concentration of IL-10. The amount of CD11b and ICAM-1 was found largely decreased and the expression of TLR-4 and the nuclear NF-κBp65 was weakened in TSF-treatment group. CONCLUSIONS: Our study suggests that TSF possesses a neuroprotective effect against ischemic stroke which might be mediated through suppression of the inflammatory pathways in the brain following ischemic stroke.

Combined treatment of sodium ferulate, n-butylidenephthalide, and ADSCs rehabilitates neurovascular unit in rats after photothrombotic stroke.

The remodelling of structural and functional neurovascular unit (NVU) becomes a central therapeutic strategy after cerebral ischaemic stroke. In the present study, we investigated the effect of combined therapy of sodium ferulate (SF), n-butylidenephthalide (BP) and adipose-derived stromal cells (ADSCs) to ameliorate the injured NVU in the photochemically induced thrombotic stroke in rats. After solely or combined treatment, the neovascularization, activation of astrocytes, neurogenesis, expressions of vascular endothelial growth factor (VEGF) and claudin-5 were assessed by immunohistochemical or immunofluorescence staining. In order to uncover the underlying mechanism of therapeutic effect, signalling of protein kinase B/mammalian target of rapamycin (AKT/mTOR), extracellular signal-regulated kinase 1/2 (ERK1/2), and Notch1 in infarct zone were analysed by western blot. 18 F-2-deoxy-glucose/positron emission tomography, magnetic resonance imaging, Evans blue staining were employed to evaluate the glucose metabolism, cerebral blood flow (CBF), and brain-blood barrier (BBB) permeability, respectively. The results showed that combined treatment increased the neovascularization, neurogenesis, and VEGF secretion, modulated the astrocyte activation, enhanced the regional CBF, and glucose metabolism, as well as reduced BBB permeability and promoted claudin-5 expression, indicating the restoration of structure and function of NVU. The activation of ERK1/2 and Notch1 pathways and inhibition of AKT/mTOR pathway might be involved in the therapeutic mechanism. In summary, we have demonstrated that combined ADSCs with SF and BP, targeting the NVU remodelling, is a potential treatment for ischaemic stroke. These results may provide valuable information for developing future combined cellular and pharmacological therapeutic strategy for ischaemic stroke.

Pharmacological research progress of sodium ferulate in cardio-cerebral vascular disease / 中草药

Sodium ferulate is the sodium salt of ferulic acid, an extract of traditional Chinese herbal medicines for promoting blood circulation and detoxification, and it is rich in sources, with few side effects and high safety. Sodium ferulate has many pharmacological effects, which is a cardiovascular drug researched and developed independently in China. It was first approved in 1990 for the clinical treatment of cardiovascular diseases. In recent years, the clinical application of sodium ferulate has become increasingly widespread, and the research field is continuously expanding. Sodium ferulate is effective in treating respiratory diseases, diabetes and complications, and protecting the liver and kidney from damage. Meanwhile it has been widely used in cardiovascular diseases. Here we reviewed the research status of the prominent pharmacological effects of sodium ferulate on cardiovascular diseases in the past 30 years, mainly focusing on the antithrombotic effects, the protection of blood vessels, and the anti-oxidative effect of sodium ferulate. It is expected to provide guidance for clinical applications of sodium ferulate.

Effect of ferulate-heparin-poloxamer thermosensitive hydrogels on nerve regeneration in rats with spinal cord injury / 中国药理学通报

Aim To investigate the effect of ferulate-heparin-poloxamer (SF-HP) thermosensitive hydrogels on nerve regeneration in ratswith spinal cord injury, and provide experimental basis for clinical application. Methods SD rats were randomly divided into five groups: sham group, SCI group, SCI + HP group, SCI + SF group and SCI + SF-HP group. Rats were performed moderate contusion injuries using a vascular clip for 2 min to establish SCI animal model, then rats were given BBB score and inclined plate scoring function test after SCI. BDA tracing was employed to observe the recovery of nerve conduction function. Moreover, immunohistochemical staining and Western blot-were used to measure GAP43, Nestin and GFAP levels. Results BBB score and inclined plane test score significantly increased in SF-HP treated group as compared with the model group (P < 0. 01). Staining data showed that the structure of spinal cord was void, and this phenomenon was reversed after SF-HP administration. Data showed that the level of GAP43 and Nestin increased after SF treatment (P < 0. 05), the expression of GFAP decreased (P <0. 05), and the treatment effect of SF-HP hydrogels were better than those of SF alone (P < 0. 0 5) . BDA tracing data showed that the number of positive neurons markedly increased and the repair of nerve conduction function was significantly improved in SF-HP hydrogel group compared with SF group. Conclusion HP hydrogels enhance the effect of SF on the nerve regeneration in damaged spinal cord in rats.

Protective Effect and Mechanism of Sodium Ferulate on Cerebral Ischemia-reperfusion Inflammatory Injury in Rats / 中国实验方剂学杂志

Objective: To investigate the protective effect of sodium ferulate on cerebral ischemia-reperfusion injury in rats and to explore its possible mechanism.Method: The cerebral ischemia reperfusion injury model was established by middle cerebral artery occlusion (MCAO) in SD male rats. 36 modeled rats with neurologic damage were randomly divided into 4 groups:model group, low,medium,high-dose sodium ferulate groups (25,50,100 mg·kg-1).Another nine rats were selected as a sham operation group.Neurological function was assessed by neurological scoring system in rats.Hematoxylin-eosin (HE) staining was performed to observe the pathological changes of the rats' brain. The levels of tumor necrosis factor α (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6) in serum and brain tissues were detected by enzyme-linked immunosorbent assay (ELISA). Western blot was used to detect the protein expression of nucleus and cytoplasm nuclear factor-kappa B p65 (NF-κB p65) in brain tissues.Result: As compared with normal group, neurological deficit score was increased; the neuronal necrosis and inflammatory cell number were present;the serum and brain tissue levels of TNF-α, IL-1β and IL-6 were increased; nucleus/cytoplasm NF-κB p65 protein expression ratio was increased significantly in model group (PPPα, IL-1β and IL-6(PPκB p65 protein(PPConclusion: Sodium ferulate protects the brain against focal cerebral ischemia reperfusion injury, and the mechanism may be related to inhibiting nuclear translocation of NF-κB p65 protein to alleviate inflammatory response.

[Sodium Ferulate Attenuates Oxidative Stress Induced Inflammation via Suppressing NALP3 Inflammasome and p38 MAPK Signal Pathway].

OBJECTIVE: To investigate the changes of NACHT-PYD-containing protein 3(NALP3) inflammasome and p38 mitogen-activated protein kinase (MARK),and the interventional mechanism of sodium ferulate (SF) in mouse embryonic fibroblasts (NIH-3T3 cells) under oxidative stress. METHODS: NIH-3T3 cells cultured in vitro were divided into 6 groups,including control group,H2O2 stress group (H2O2 200 µmol/L),SF group (SF 400 µg/mL),antioxidant group (H2O2 200 µmol/L+NAC 5 mmol/L),p38 MAPK blockers group (H2O2 200 µmol/L+SB203580 5 µmol/L),H2O2+SF group (H2O2 200 µmol/L+SF 400 µg/mL). The mRNA expression levels of NALP3, Caspase-1 and p38α were evaluated by fluorescent quantitative real-time PCR (qRT-PCR) at 24 h after cell culture; Western blot was performed to detect the expressions of NALP3,p-p38 to p38 protein (the activation of p38 MAPK signaling pathway expressed by the ratio of p-p38 to p38) at 48 h after cell culture; The levels of interleukin-1beta (IL-1ß) in different groups were detected by ELISA at 2 h after cell culture. RESULTS: Compared with control group,H2O2 could not only increase the expression levels of NALP3, Caspase-1,p38α mRNAs and NALP3,p-p38/p38 proteins but also the secretion of IL-1ß in NIH-3T3 cells when compared with the control group (P<0.05); Antioxidant NAC,p38 MAPK blockers and H2O2+SF group could partly resisted the effects of H2O2 on NIH-3T3 cells,that decreased the level of mRNA expressions of NALP3, Caspase-1,p38α and protein expressions of NALP3 and p-p38/p38,and reduced the secretion of IL-1ß when compared to the H2O2 stress group (P<0.05); However,H2O2+NAC group,SB203580 group and H2O2+SF group showed no statistical difference of those indicators (P>0.05). CONCLUSION: The mechanism of sodium ferulate attenuated oxidative stress induced inflammation may be through blunting p38 MAPK signal pathway,the expression of NALP3 inflammasome,Caspase-1 and the secretion of IL-1ß are reduced.

Anti-exudation effects of sodium ferulate and oxymatrine combination via modulation of aquaporin 1.

The present study aimed to investigate the anti-exudative effects of sodium ferulate combined with oxymatrine in a mouse model of acetic acid-induced peritonitis. Furthermore, the underlying mechanisms were explored by determining the effects of these drugs on the volume and aquaporin 1 (AQP1) expression in vascular endothelial cells on omentum majus and human umbilical vein endothelial cells (HUVEC). Treatment with sodium ferulate combined with oxymatrine was shown to significantly inhibit acetic acid-induced vascular permeability in the peritonitis model mice and furthermore to significantly decrease the optical density of Evans blue, the leukocyte number and the levels of interleukin-6, C-reactive protein and interferon-γ in peritoneal lavage fluid. Pathological analysis of the omentum majus revealed that sodium ferulate and oxymatrine combination treatment significantly alleviated vascular endothelial cell edema and capillary loss. In vitro, flow cytometry revealed that the volume of HUVECs was significantly reduced in the drug treatment groups, as reflected in the forward scatter value. The optical density of AQP1 on the membrane of the vascular endothelial cells on omentum majus and HUVECs were significantly increased in the drug treatment groups compared with the model group. These results indicated that sodium ferulate and oxymatrine combination treatment possessed prominent anti-exudative effects and that the underlying mechanisms are likely to include the improvement of vascular endothelial cellular edema, possibly by upregulation of AQP1 expression on their membrane, which requires further exploration.

[The Effect of Sodium Ferulate in Experimental Pulmonary Fibrosis via NALP3 Inflammasome].

OBJECTIVE: To investigate the activation of NALP3 inflammasome in the process of experimental pulmonary fibrosis (PF), and evaluate the effect of sodium ferulate (SF) in the relationship of NALP3 and PF. METHODS: Establishing PF experimental model via bleomycin (BLM) intratracheal injection (BLM group, SF group), treated with SF daily (SF group) or PBS [BLM group, control (CON) group] and mice were executed on day 21. Ashcroft score was used to assess lung fibrosis in mice PF model. The content of hydroxyproline (HYP) in lung tissue was determined by alkaline hydrolysis. Fibroblast NIH-3T3 was treated with H2O2 to trigger cell oxidative stress in vitroexperiments (H2O2group). Cell was pre-administrated with SF 2 h before H2O2 stimulation in H2O2+SF group. Blank group without any treatments, was set as control. Real time-PCR was used to investigate the expressions of three elements of inflammasome[NALP3, caspase-1, apoptosis-associated speck-like protein (ASC)], collagen-1 and α smooth muscle actin (α-SMA) mRNA in both lung tissue and fibroblast. Western blot was used to detect protein level of NALP3 in mice lung tissue and collagen-1, α-SMA in fibroblast as well. Meanwhile, IL-1ß content in lung tissue and cell supernatant was measured by ELISA. RESULTS: in vitro experiment, SF treated mice showed lower Ashcroft score and HYP content and decreased NALP3, ASC, caspase-1 mRNA expressions and IL-1ß production, NALP3 protein level compared with BLM group (P<0.05). in vitroexperiment, H2O2 increased NALP3 (P<0.05), ASC (P<0.01), caspase-1 (P<0.05) expressions and IL-1ß releasing (P<0.05)and promoted the expressions of collagen-1 and α-SMA in both gene and protein levels (P<0.05) in NIH-3T3. NALP3 activation was partly inhibited in H2O2+SF group (P<0.05). The mRNA expression levels of collagen-1 and α-SMA were reduced in H2O2+SF group (P<0.05) and the protein expressions of α-SMA and collagen-1 were decreased (P<0.05) compared with those of H2O2 group. CONCLUSION: Sodium ferulate may suppress oxidative stress mediated NALP3 activation to inhibit fibroblast activation in the anti-fibrosis effect.