Puerarin ameliorates hyperglycemia in HFD diabetic mice by promoting β-cell neogenesis via GLP-1R signaling activation

BackgroundDiabetes is characterized by β-cell loss and dysfunction. A strategy for diabetes treatment is to promote new β-cell formation. Puerarin is an isoflavone from the root of Pueraria lobata (Willd.) Ohwi. Our previous study demonstrated puerarin could ameliorate hyperglycemia in diabetic mice. However, related mechanisms and potential roles of puerarin in β-cell neogenesis have not been elucidated.PurposeThe present study aims to investigate whether anti-diabetic effect of puerarin is dependent on promoting β-cell neogenesis via GLP-1R signaling activation.MethodsA high-fat diet (HFD) induced diabetic mouse model was applied to investigate effects of puerarin in vivo, exendin-4 (GLP-1R agonist) and metformin were used as positive controls. Moreover, related mechanisms and GLP-1R downstream signal transduction were explored in isolated cultured mouse pancreatic ductal cells.ResultsPuerarin improved glucose homeostasis in HFD diabetic mice significantly. Markers of new β-cell formation (insulin, PDX1 and Ngn3) were observed in pancreatic ducts of HFD mice treated by puerarin. Of note, efficacy of puerarin in vivo was suppressed by GLP-1R antagonist exendin9-39, but enhanced by exendin-4 respectively. In cultured mouse pancreatic ductal cells, puerarin induced expressions of insulin and PDX1, upregulated GLP-1R expression and activated β-catenin and STAT3 subsequently. Expressions of insulin and PDX1 in ductal cells could be blocked by exendin9-39, or β-catenin inhibitor ICG001, or JAK2 inhibitor AG490.ConclusionThese data clarified puerarin ameliorated hyperglycemia of HFD mice via a novel mechanism involved promoting β-cell neogenesis. Our finding highlights the potential value of puerarin developing as an anti-diabetic agent.     

TNF receptor type 1 regulates RANK ligand expression by stromal cells and modulates osteoclastogenesis

TNFalpha is a major osteoclastogenic cytokine and a primary mediator of inflammatory osteoclastogenesis. We have previously shown that this cytokine directly targets osteoclasts and their precursors and that deletion of its type-1 receptor (TNFr1) lessens osteoclastogenesis and impacts RANK signaling molecules. Osteoclastogenesis is primarily a RANK/RANKL-dependent event and occurs in an environment governed by both hematopoietic and mesenchymal compartments. Thus, we reasoned that TNF/TNFr1 may regulate RANKL and possibly RANK expression by stromal cells and osteoclast precursors (OCPs), respectively. RT-PCR experiments reveal that levels of RANKL mRNA in WT stromal cells are increased following treatment with 1,25-VD3 compared to low levels in TNFr1-null cells. Expression levels of OPG, the RANKL decoy protein, were largely unchanged, thus supporting a RANKL/OPG positive ratio favoring WT cells. RANK protein expression by OCPs was lower in TNFr1-null cells despite only subtle differences in mRNA expression in both cell types. Mix and match experiments of different cell populations from the two mice phenotypes show that WT stromal cells significantly, but not entirely, restore osteoclastogenesis by TNFr1-null OCPs. Similar results were obtained when the latter cells were cultured in the presence of exogenous RANKL. Altogether, these findings indicate that in the absence of TNFr1 both cell compartments are impaired. This was further confirmed by gain of function experiments using TNFr1- null cultures of both cell types at which exogenous TNFr1 cDNA was virally expressed. Thus, restoration of TNFr1 expression in OCPs and stromal cells was sufficient to reinstate osteoclastogenesis and provides direct evidence that TNFr1 integrity is required for optimal RANK-mediated osteoclastogenesis.     

Crosstalk between dihydroceramides produced by Porphyromonas gingivalis and host lysosomal cathepsin B in the promotion of osteoclastogenesis

Emerging studies indicate that intracellular eukaryotic ceramide species directly activate cathepsin B (CatB), a lysosomal‐cysteine‐protease, in the cytoplasm of osteoclast precursors (OCPs) leading to elevated RANKL‐mediated osteoclastogenesis and inflammatory osteolysis. However, the possible impact of CatB on osteoclastogenesis elevated by non‐eukaryotic ceramides is largely unknown. It was reported that a novel class of phosphoglycerol dihydroceramide (PGDHC), produced by the key periodontal pathogen Porphyromonas gingivalis upregulated RANKL‐mediated osteoclastogenesis in vitro and in vivo. Therefore, the aim of this study was to evaluate a crosstalk between host CatB and non‐eukaryotic PGDHC on the promotion of osteoclastogenesis. According to a pulldown assay, high affinity between PGDHC and CatB was observed in RANKL‐stimulated RAW264.7 cells in vitro. It was also demonstrated that PGDHC promotes enzymatic activity of recombinant CatB protein ex vivo and in RANKL‐stimulated osteoclast precursors in vitro. Furthermore, no or little effect of PGDHC on the RANKL‐primed osteoclastogenesis was observed in male and female CatB‐knock out mice compared with their wild type counterparts. Altogether, these findings demonstrate that bacterial dihydroceramides produced by P. gingivalis elevate RANKL‐primed osteoclastogenesis via direct activation of intracellular CatB in OCPs.     

Tiliroside is a new potential therapeutic drug for osteoporosis in mice

Osteoporosis is a class of metabolic bone disease caused by complexed ramifications. Overactivation of osteoclasts due to a sudden decreased estrogen level plays a pivotal role for postmenopausal women suffering from osteoporosis. Therefore, inhibiting osteoclast formation and function has become a major direction for the treatment of osteoporosis. Tiliroside (Tle) is a salutary dietary glycosidic flavonoid extracted from Oriental Paperbush flower, which has been reported to have an anti-inflammation effect. However, whether Tle affects the osteoclastogenesis and bone resorption remains unknown. Herein, we demonstrate that Tle prevents bone loss in ovariectomy in mice and inhibits osteoclast differentiation and bone resorption stimulated by receptor activator of nuclear factor-κB ligand (RANKL) in vitro. Molecular mechanism studies reveal that Tle reduces RANKL-induced activation of mitogen-activated protein kinase and T-cell nuclear factor 1 pathways, and osteoclastogenesis-related marker gene expression, including cathepsin K (Ctsk), matrix metalloproteinase 9, tartrate-resistant acid phosphatase (Acp5), and Atp6v0d2. Our research indicates that Tle suppresses osteoclastogenesis and bone loss by downregulating the RANKL-mediated signaling protein activation and expression. In addition, Tle inhibits intracellular reactive oxygen species generation which is related to the formation of osteoclasts. Therefore, Tle might serve as a potential drug for osteolytic disease such as osteoporosis.     

ERK5/KLF2 activation is involved in the reducing effects of puerarin on monocyte adhesion to endothelial cells and atherosclerotic lesion in apolipoprotein E-deficient mice

Puerarin has properties of anti-oxidation and anti-inflammation, which has been demonstrated protective effects in atherosclerosis and other cardiovascular diseases. However, the detail molecular mechanism still remains unclear. Here, we determined whether the atheroprotective effect of puerarin was by reducing monocyte adhesion and explored the underlying mechanism. The results showed that puerarin dose- and time-dependently reduced oxLDL-induced monocyte THP-1 adhesion to HUVECs and the expression of adhesion-related genes such as VCAM-1, ICAM-1, MCP-1 and IL-8 in HUVECs. Puerarin activated ERK5 phosphorylation and up-regulated expressions of downstream KLF2 and its targeted genes endothelial nitric oxide synthase and thrombomodulin. However, the protective effects were reversed by ERK5/KLF2 pathway inhibitor XDM8-92, BIX02189 or KLF2 siRNA suggesting the pathway involved in the function. The ex vivo assay, in which THP-1 adhesion to endothelium isolated from apoE?/? mice received various treatments further confirmed the results from HUVECs. Finally, we found that the atherosclerotic lesions in both cross sections at aortic root and whole aorta were significantly reduced in high fat-diet (HFD) mice with puerarin treatment compared with the HFD-only mice, but were increased respectively by 76% and 71% in XMD8-92 group, and 82% and 73% in BIX02189 group. Altogether, the data revealed that puerarin inhibited the monocyte adhesion in vitro and in vivo and thus reduced atherosclerotic lesions in apoE?/? mice; the protective effects were mediated by activation of ERK5/KLF2 signaling pathway. Our findings advance the understanding of puerarin function in atherosclerosis and point out a way to prevent the disease.     

Monocyte-chemoattractant-protein-1-mediated migration of human monocytes towards blasts from patients with acute myeloid leukemia

 Purpose: In the present study the possible clinical relevance of monocyte chemoattractant protein (MCP)-1 in patients with acute myeloid leukemia (AML) was established. Methods: The pattern of migration of human monocytes towards the supernatants of blasts from 15 patients with AML was studied and the role of MCP-1, produced by these blasts, was assessed. Results: In 4 patients (group 1) the amount of monocyte migration was low and not inhibited by the addition of anti-hMCP-1. In 11 patients, the amount of monocyte migration was high; after addition of anti-hMCP-1, monocyte migration was either completely (8 patients, group 2), or partly or not (3 patients, group 3) inhibited to the level of chemokinesis. In groups 1 and 2, there was a good correlation (r=0.67) between the concentration of MCP-1 in the supernatants and the amount of monocyte migration. In group 3, such a correlation was not evident, suggesting that another chemokine might be involved or MCP-1 function was impaired by an unknown substance. Finally, measurements of MCP-1 during culture of AML blasts showed that the time at which maximal amounts of MCP-1 are produced differs between the AML samples. Conclusions: AML blasts produce different amounts of MCP-1, which plays an important role in monocyte migration towards most AML blasts. Therefore, in the context of adoptive immunotherapy, MCP-1 might be involved in future tumor vaccination programmes using autologous MCP-1-transfected irradiated AML blasts. Received: 4 May 2000 / Accepted: 26 October 2000     

Puerarin Protects Against β-Amyloid-Induced Microglia Apoptosis Via a PI3K-Dependent Signaling Pathway

Puerarin extracted from Radix puerariae is well-known for its anti-oxidative and neuroprotective activities. In this study, we investigated the protective effect of puerarin on amyloid-β protein (Aβ)-induced cytotoxicity and its potential mechanisms in BV-2 and primary microglial cells. We found that pretreatment with puerarin afforded protection against Aβ-induced cytotoxicity through inhibiting apoptosis in BV-2 and primary microglial cells. This result was also confirmed by the activated caspase-3 assay. Phospho-Akt and Bcl-2 expression increased after pretreatment with puerarin in BV-2 and primary microglial cells exposed to Aβ, whereas Bax expression and cytochrome c release decreased. In addition, puerarin treatment prevented the loss of mitochondrial membrane potential and reactive oxygen species production. Interestingly, these effects of puerarin against Aβ insult were abolished by LY294002, an inhibitor of PI3K phosphorylation. Taken together, these findings suggest that puerarin prevents Aβ-induced microglial apoptosis via the activation of PI3K/Akt signaling pathway, and might be a potential preventive or therapeutic agent for Alzheimer’s disease.     

Tissue distribution of puerarin and its conjugated metabolites in rats assessed by liquid chromatography–tandem mass spectrometry

Puerarin (an isoflavone C-glucoside from kudzu root) has been the focus of several studies investigating its potential effects on health benefits. In this study, we determined single dose tissue distribution of puerarin and its metabolites in order to examine whether they undergo selective uptake by specific organs. Puerarin was administered orally (50 mg/kg) to rats and the concentration of puerarin in tissue compartments was determined using liquid chromatography–tandem mass spectrometry (LC–MS/MS). Puerarin was widely distributed in rat tissues with highest concentrations in lungs (799±411.6 ng/g wet tissues). In addition, we examined the excretion of puerarin into the bile. LC–MS/MS analysis of bile samples collected after infusing puerarin directly into the portal vein indicated that puerarin was excreted into the bile predominantly in the form of unconjugated puerarin. This report identifying puerarin in several organs including kidney and pancreas may explain its beneficial effects in diabetes.     

葛根素联合小檗碱干预非酒精性脂肪性肝炎两种动物模型的病理学研究

目的:从病理学的角度探讨葛根素及小檗碱对非酒精性脂肪性肝炎(NASH)的干预作用。方法:制备高脂饮食诱导的SD大鼠NASH模型及蛋氨酸-胆碱缺乏饮食诱导的C57BL/6小鼠NASH模型,各给药组造模并同时灌胃给药,大鼠持续8周后取材,小鼠持续2周后取材。肝组织制成石蜡切片进行HE染色,制成冰冻切片进行油红O染色,经光镜观察摄片后,采用NAFLD活动度积分对各组进行NASH评估。结果:HE及油红O检测提示葛根素联合小檗碱可减轻两种NASH动物模型肝脏的脂肪变性、抑制肝细胞空泡化的发生,减少肝小叶内炎性病灶的数量。给予葛根素联合小檗碱的SD大鼠NAS总分为2.60±0.52(3),给予葛根素联合小檗碱的C57BL/6小鼠NAS总分为2.80±0.79(3),均已排除NASH。结论:葛根素联合小檗碱可显著抑制NASH相关病理变化的发生发展,对NASH具有一定的干预作用。     

Puerarin concurrently stimulates osteoprotegerin and inhibits receptor activator of NF-κB ligand (RANKL) and interleukin-6 production in human osteoblastic MG-63 cells

Puerarin, a daidzein-8-C-glucoside, is the major isoflavone glycoside found in the Chinese herb radix of Pueraria lobata (Willd.) Ohwi, and has received increasing attention because of its possible role in the prevention of osteoporosis. In our previous studies, puerarin reduced the bone resorption of osteoclasts and promoted long bone growth in fetal mouse in vitro. Further study confirmed that puerarin stimulated proliferation and differentiation of osteoblasts in rat. However, the mechanisms underlying its actions on human bone cells have remained largely unknown. Here we show that puerarin concurrently stimulates osteoprotegerin (OPG) and inhibits receptor activator of nuclear factor-κB ligand (RANKL) and Interleukin-6 (IL-6) production by human osteoblastic MG-63 cells containing two estrogen receptor (ER) isotypes. Treatment with the ER antagonist ICI 182,780 abrogates the above actions of puerarin on osteoblast-derived cells. Using small interfering double-stranded RNAs technology, we further demonstrate that the effects of puerarin on OPG and RANKL expression are mediated by both ERα and ERβ but those on IL-6 production primarily by ERα. Moreover, we demonstrate that puerarin may promote activation of the classic estrogen response element (ERE) pathway through increasing ERα, ERβ and steroid hormone receptor coactivator (SRC)-1 expression. Therefore, puerarin will be a promising agent that prevents or retards osteoporosis.     

葛根素对U14宫颈癌小鼠血液流变学、脾淋巴细胞增殖及细胞毒性影响

摘要 目的：研究葛根素治疗对U14宫颈癌小鼠血液流变学、脾淋巴细胞增殖活性及对宫颈癌细胞毒性的影响。方法：45只雌性昆明小鼠随机分为对照组、模型组和葛根素组。模型组和葛根素组小鼠通过腋下注射U14小鼠宫颈癌细胞建立U14宫颈癌移植瘤小鼠,并且葛根素小鼠通过葛根素灌胃进行治疗,对照组和模型组小鼠给予等量生理盐水。比较各组小鼠血流变学、脾淋巴细胞增殖活性及对宫颈癌细胞毒性。结果：经葛根素治疗的葛根素组宫颈癌小鼠肿瘤重量显著低于模型组小鼠（P<0.05）,葛根素治疗宫颈癌小鼠的抑瘤率是（42.91±12.91）%。宫颈癌小鼠低切/高切全血粘度、血浆粘度值以及血细胞比容均显著升高（P<0.05）,而葛根素治疗可显著降低宫颈癌小鼠低切/高切全血粘度、血浆粘度值以及血细胞比容（P<0.05）。宫颈癌小鼠脾脏重量、脾脏指数和脾淋巴细胞体外增殖能力均显著下降（P<0.05）,而葛根素治疗可显著提高宫颈癌小鼠脾脏重量、脾脏指数和脾淋巴细胞体外增殖能力（P<0.05）。此外,经葛根素治疗的宫颈癌小鼠脾淋巴细胞对U14宫颈癌细胞细胞毒性显著高于模型组宫颈癌小鼠（P<0.05）。结论：葛根素治疗可降低U14宫颈癌小鼠血液粘度、改善血流变性质,并且可以提高脾淋巴细胞的增殖活性和对宫颈癌细胞的杀伤力。     

IL-17A modulates osteoclast precursors' apoptosis through autophagy-TRAF3 signaling during osteoclastogenesis

Osteoclasts play an important role in bone remodeling. The inflammatory cytokine IL-17A could modulate the RANKL-induced osteoclastogenesis by regulating the autophagic activity. It is well accepted that protective autophagy has an anti-apoptotic effect. It is necessary to elucidate whether IL-17A can influence the apoptosis of osteoclast precursors (OCPs) through autophagy responses during osteoclastogenesis. The results showed that apoptosis of RAW264.7-derived OCPs was promoted by high levels of IL-17A, but the opposite anti-apoptotic function was shown by low levels of IL-17A. Furthermore, the enhanced apoptosis by high levels of IL-17A was reversed by overexpression of autophagy protein Beclin1; conversely, the inhibited apoptosis by low levels of IL-17A was restored by knockdown of Beclin1. It was also found that Beclin1 suppression with Beclin1 inhibitor (spautin1) could block the reduced apoptosis by low levels of IL-17A, which was recovered by TRAF3 knockdown. Moreover, the enhanced apoptosis by high levels of IL-17A decreased following the downregulation of TRAF3. Importantly, overexpression of caspase3 further attenuated osteoclastogenesis treated by high levels of IL-17A, without significantly affecting osteoclastogenesis stimulated by low levels of IL-17A. In conclusion, IL-17A modulates apoptosis of OCPs through Beclin1-autophagy-TRAF3 signaling pathway, thereby influencing osteoclastogenesis. Therefore, our study sheds lights on the improvement of clinical strategies of dental implantation or orthodontic treatment by revealing the novel targets in the bone remodeling.     

Mutation in Osteoactivin Promotes Receptor Activator of NFκB Ligand (RANKL)-mediated Osteoclast Differentiation and Survival but Inhibits Osteoclast Function

We previously reported on the importance of osteoactivin (OA/Gpnmb) in osteogenesis. In this study, we examined the role of OA in osteoclastogenesis, using mice with a nonsense mutation in the Gpnmb gene (D2J) and wild-type controls (D2J/Gpnmb⁺). In these D2J mice, micro-computed tomography and histomorphometric analyses revealed increased cortical thickness, whereas total porosity and eroded surface were significantly reduced in D2J mice compared with wild-type controls, and these results were corroborated by lower serum levels of CTX-1. Contrary to these observations and counterintuitively, temporal gene expression analyses supported up-regulated osteoclastogenesis in D2J mice and increased osteoclast differentiation rates ex vivo, marked by increased number and size. The finding that MAPK was activated in early differentiating and mature D2J osteoclasts and that survival of D2J osteoclasts was enhanced and mediated by activation of the AKT-GSK3β pathway supports this observation. Furthermore, this was abrogated by the addition of recombinant OA to cultures, which restored osteoclastogenesis to wild-type levels. Moreover, mix and match co-cultures demonstrated an induction of osteoclastogenesis in D2J osteoblasts co-cultured with osteoclasts of D2J or wild-type. Last, in functional osteo-assays, we show that bone resorption activity of D2J osteoclasts is dramatically reduced, and these osteoclasts present an abnormal ruffled border over the bone surface. Collectively, these data support a model whereby OA/Gpnmb acts as a negative regulator of osteoclast differentiation and survival but not function by inhibiting the ERK/AKT signaling pathways.     

丁苯酞对缺血性脑卒中大鼠脂联素、MCP-1及slCAM-1的影响

目的:探讨丁苯酚对卒中大鼠脂联素、MCP-1和sl CAM-1表达的影响。方法:建立大鼠永久性大脑中动脉梗塞(Permanent middle cerebral occlusion, pMCAO)局灶性脑缺血模型,将SD大鼠分为Sham组、pMCAO模型组和NBP治疗组;甲酚紫染色法测定大鼠脑部梗塞面积;改良神经功能损害评分(Modified neurological severity score, m NSS)用于评定各组大鼠的神经功能变化情况;Elisa法检测大鼠脑部和血清中脂联素水平以及脑部MCP-1和sl CAM-1水平。结果:药物处理后pMCAO组大鼠存活率明显低于Sham组;NBP处理能够有效逆转pMCAO诱导的大鼠m NSS得分的升高;与Sham组相比,pMCAO组大鼠脑部梗塞面积显著增加,NBP处理明显减少了损伤大鼠的梗塞范围;与Sham组相比,p MCAO组大鼠脑部和血清中脂联素表达明显降低,而大脑MCP-1及sl CAM-1水平显著升高,NBP处理上调了大脑和血清脂联素的水平并抑制脑部MCP-1和sl CAM-1的表达。结论:丁苯酞通过上调脂联素表达,抑制MCP-1及sl CAM-1的水平对缺血性脑卒中大鼠起到神经保护作用。     

Puerarin induces mitochondria-dependent apoptosis in hypoxic human pulmonary arterial smooth muscle cells

Background

Pulmonary vascular medial hypertrophy in hypoxic pulmonary arterial hypertension (PAH) is caused in part by decreased apoptosis in pulmonary artery smooth muscle cells (PASMCs). Puerarin, an isoflavone purified from the Chinese medicinal herb kudzu, ameliorates chronic hypoxic PAH in animal models. Here we investigated the effects of puerarin on apoptosis of hypoxic human PASMCs (HPASMCs), and to determine the possible underlying mechanisms.

Methodology/Principal Findings

HPASMCs were cultured for 24 h in normoxia or hypoxia (5% O₂) conditions with and without puerarin. Cell number and viability were determined with a hemacytometer or a cell counting kit. Apoptosis was detected with a TUNEL test, rhodamine-123 (R-123) fluorescence, a colorimetric assay, western blots, immunohistochemical staining and RT-PCR. Hypoxia inhibited mitochondria-dependent apoptosis and promoted HPASMC growth. In contrast, after puerarin (50 µM or more) intervention, cell growth was inhibited and apoptosis was observed. Puerarin-induced apoptosis in hypoxic HPASMCs was accompanied by reduced mitochondrial membrane potential, cytochrome c release from the mitochondria, caspase-9 activation, and Bcl-2 down-regulation with concurrent Bax up-regulation.

Conclusions/Significance

Puerarin promoted apoptosis in hypoxic HPASMCs by acting on the mitochondria-dependent pathway. These results suggest a new mechanism of puerarin relevant to the management of clinical hypoxic pulmonary hypertension.     

Puerarin Suppresses Proliferation of Endometriotic Stromal Cells Partly via the MAPK Signaling Pathway Induced by 17?-estradiol-BSA

Background

Puerarin is a major isoflavonoid compound extracted from Radix puerariae. It has a weak estrogenic action by binding to estrogen receptors (ERs). In our early clinical practice to treat endometriosis, a better therapeutic effect was achieved if the formula of traditional Chinese medicine included Radix puerariae. The genomic and non-genomic effects of puerarin were studied in our Lab. This study aims to investigate the ability of puerarin to bind competitively to ERs in human endometriotic stromal cells (ESCs), determine whether and how puerarin may influence phosphorylation of the non-genomic signaling pathway induced by 17ß-estradiol conjugated to BSA (E₂-BSA).

Methodology

ESCs were successfully established. Binding of puerarin to ERs was assessed by a radioactive competitive binding assay in ESCs. Activation of the signaling pathway was screened by human phospho-kinase array, and was further confirmed by western blot. Cell proliferation was analyzed according to the protocol of CCK-8. The mRNA and protein levels of cyclin D1, Cox-2 and Cyp19 were determined by real-time PCR and western blotting. Inhibitor of MEK1/2 or ER antagonist was used to confirm the involved signal pathway.

Principal Findings

Our data demonstrated that the total binding ability of puerarin to ERs on viable cells is around 1/3 that of 17ß-estradiol (E₂). E₂-BSA was able to trigger a rapid, non-genomic, membrane-mediated activation of ERK1/2 in ESCs and this phenomenon was associated with an increased proliferation of ESCs. Treating ESCs with puerarin abrogated the phosphorylation of ERK and significantly decreased cell proliferation, as well as related gene expression levels enhanced by E₂-BSA.

Conclusions/Significance

Puerarin suppresses proliferation of ESCs induced by E₂-BSA partly via impeding a rapid, non-genomic, membrane-initiated ERK pathway, and down-regulation of Cyclin D1, Cox-2 and Cyp19 are involved in the process. Our data further show that puerarin may be a new candidate to treat endometriosis.     

Resveratrol downregulates acute pulmonary thromboembolism-induced pulmonary artery hypertension via p38 mitogen-activated protein kinase and monocyte chemoattractant protein-1 signaling in rats

AimsIn the present study, we explored the hypothesis that initiation of PH involves the upregulation of monocyte chemoattractant protein-1 (MCP-1) in acute PTE. We evaluated the effects of resveratrol and the role of p38 mitogen-activated protein kinase (MAPK) in this process.Main methodsA rat model of acute PTE was established by infusion of an autologous blood clot into the pulmonary artery through a polyethylene catheter. Rats were randomly divided into 1, 4, and 8 hour time groups. Resveratrol, C1142 (a rodent chimeric mAb that neutralizes rat MCP-1) or SB203580 (a p38MAPK specific inhibitor) was administered to the animals beginning 1 h prior to the start of the acute PTE protocol. At each time point, the mean pulmonary artery pressure (mPAP), mRNA and protein expressions of MCP-1 were measured. The phosphorylation of p38 MAPK (p-pMAPK) was also detected.Key findingsAcute PTE elicited significant increases in mean pulmonary artery pressure (mPAP), and up-regulated the expression of monocyte chemoattractant protein-1 (MCP-1) and phosphorylation of p38 mitogen-activated protein kinase (p-p38 MAPK). Administration of C1142 markedly reduced mPAP. Furthermore, pre-treatment of rats with resveratrol significantly reduced mPAP and down-regulated the expression of MCP-1, which was associated with robustly suppressed acute PTE-induced p-p38MAPK expression.SignificanceThese findings suggested that MCP-1 was involved in the formation of acute PTE-induced PH, and resveratrol down-regulated the expression of MCP-1 by inhibiting acute PTE-induced p-p38MAPK activation, which contributed to the decrease in PH.