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1.
Food Chem ; 305: 125483, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31610420

RESUMO

Kiwifruit (Actinidia deliciosa cv. Jinkui) were treated with 0.1 mmol/L methyl jasmonate (MeJA) to investigate the effects on disease resistance to soft rot caused by Botryosphaeria dothidea. The results showed that MeJA treatment significantly reduced the diameter of lesions after inoculation with B. dothidea. This treatment significantly enhanced the activities of related antioxidant protective enzymes, defence-related enzymes including catalase (CAT), peroxidase (POD), superoxide dismutase (SOD), polyphenol oxidase (PPO), chitinase (CHI), ß-1,3 glucanase (GLU) and increased the accumulation of total phenolic content, while the degree of membrane lipid peroxidation was reduced. MeJA treatment effectively enhanced gene expression of AcPOD, AcSOD, AcCHI and AcGLU. The results from this research suggest that MeJA treatment is a promising and safe strategy for controlling postharvest rot soft of kiwifruit.

2.
Mol Cell Endocrinol ; 499: 110595, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31563469

RESUMO

The pentose phosphate pathway (PPP) plays an important role in the biosynthesis of ribonucleotide precursor and NADPH. Cancer cells frequently increase the flux of glucose into the PPP to support the anabolic demands and regulate oxidative stress. Consistently, metabolomic analyses indicate an upregulation of the PPP in thyroid cancer. In the present study, we found that the combination of glucose-6-phosphate dehydrogenase (G6PD) and transketolase inhibitors (6-aminonicotinamide and oxythiamine) exerted an additive or synergistic effect on cell growth inhibition in thyroid cancer cells. Targeting PPP significantly increased cellular reactive oxygen species (ROS) and induced endoplasmic reticulum (ER) stress and apoptosis. Suppressed cell viability could be partially rescued with treatment with the ROS scavenger or apoptosis inhibitor but not ER-stress inhibitor. Taken together, dual PPP blockade leads to pharmacologic additivity or synergism and causes ROS-mediated apoptosis in thyroid cancer cells.

3.
Chem Commun (Camb) ; 2019 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-31799555

RESUMO

N-Doped amber necklace-like structured MoS2@carbon nanofibers (ANL MoS2@CNFs) were fabricated via the confined growth method, constructing a hierarchical structure with 1D nanofibers, 2D nanosheets, and 3D cross-linked networks. This special structure could effectively alleviate the volume effect and enhance the storage performance of lithium/sodium ion batteries.

4.
Front Immunol ; 10: 2599, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31787979

RESUMO

Copper has been revealed to negatively affect the hematopoietic system, which has an important function in immune pathogen defense, but little is known about the potential mechanism. In this study, copper-stressed larvae exhibited significantly increased mortality as well as reduced percentages of GFP-labeled macrophages and neutrophils after Aeromonas hydrophila (A. hydrophila) infection. However, those copper-stressed GFP-labeled macrophages and neutrophils showed more rapid responses to A. hydrophila infection. The transcriptional profiles in copper-stressed macrophages or neutrophils were unveiled by RNA-Sequencing, and KEGG pathway analysis revealed enrichment of differentially expressed genes (DEGs) in lysosome, apoptosis, oxidative phosphorylation, phagosome, etc. The copper-stressed macrophages or neutrophils were revealed to have an increase in reactive oxygen species (ROS) and mitochondria ROS (mROS)-mediated apoptosis, and a reduction in phagocytosis. Furthermore, the A. hydrophila-infected copper-stressed macrophages or neutrophils were found to be unable to maintain a consistently increased expression in immune responsive genes. This study demonstrated for the first time that copper might induce the susceptibility of fish larvae to inflammatory stimuli via triggering macrophage or neutrophil apoptosis, leading to reduced phagocytic activities and non-sustainable immune responses in immune macrophages or neutrophils.

5.
Brief Funct Genomics ; 2019 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-31788683

RESUMO

Cancer immunotherapy, consisting of antibodies, adoptive T-cell transfer, vaccines and cytokines, is a novel strategy for fighting cancer by artificially stimulating the immune system. It has developed rapidly in recent years, and its efficacy in hematological malignancies and solid tumors has been remarkable. It is regarded as one of the most promising methods for cancer therapy. The current trend in immunotherapy research seeks to improve its efficacy and to ensure the safety of cancer immunotherapy through the use of gene editing technologies. As it is an efficient and simple technology, the CRISPR-Cas9 system is highly anticipated to dramatically strengthen cancer immunotherapy. Intensive research on the CRISPR-Cas9 system has provided increasing confidence to clinicians that this system can be put into clinical use in the near future. This paper reviews the application and challenges of CRISPR-Cas9 in this field, based on various strategies including adaptive cell therapy and antibody therapy, and also highlights the function of CRISPR/Cas9 in the screening of new cancer targets.

6.
Strahlenther Onkol ; 2019 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-31784801

RESUMO

PURPOSE: The optimal radiotherapy dose/fraction for limited-stage small cell lung cancer (SCLC) is undefined. Our objectives were to compare efficacy between hyperfractionated thoracic radiotherapy (TRT; 1.5 Gy 2 times per day [bid] in 30 fractions) and hypofractionated TRT (2.5 Gy once per day [qd] in 22 fractions), and to explore prognostic factors influencing the prognosis, such as the timing of TRT. METHODS: Patients enrolled in two independent prospective studies were combined and analyzed. The primary endpoint was local/regional control (LRC). The prognosis was analyzed using the Cox proportional hazards regression model. RESULTS: Ninety-two and 96 patients were treated with hyperfractionated TRT and hypofractionated TRT, respectively. The 1­ and 2­year LRC rates of the two arms were 82.1 and 60.7%, and 84.9 and 68.8% (P = 0.27), respectively. The median overall survival (OS) times (months) were 28.3 (95% confidence interval, CI 16.4-40.1) and 22.0 (95% CI 16.4-27.5), while the 1­year, 3­year, and 5­year OS rates were 85.2, 40.8, and 27.1%, and 76.9, 34.3, and 26.8% (P = 0.37), respectively. Using a multivariate Cox regression study, time (days) from the initiation of chemotherapy to TRT (TCT) ≤43 was associated with improved LRC (hazard radio, HR 0.39, 95% CI 0.20-0.76; P = 0.005). Time (days) from the start of chemotherapy to the end of TRT (SER) ≤63 (HR 0.50, 95% CI 0.32-0.80; P = 0.003) and prophylactic cranial irradiation (HR 0.43; 95% CI 0.29-0.63; P = 0.000) were favorably related to OS. Grade 2/3 acute radiation esophagitis was observed in 37.0 and 17.7% of patients in the hyperfractionated and hypofractionated arms, respectively (P = 0.003). CONCLUSION: Both hyperfractionated and hypofractionated TRT schedules achieved good LRC and OS for patients with limited-stage SCLC in this study. Keeping TCT ≤43 and SER ≤63 resulted in a better prognosis. The incidence of acute esophagitis was significantly higher in the hyperfractionated arm.

7.
Org Lett ; 2019 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-31793302

RESUMO

Stereoselective synthesis of γ,δ-bifunctionalized homoallylic alcohols and ethers via chemoselective allylation is reported. Pd-catalyzed 1,2-diboration of allenylsilane provided a novel 1,1,2-trifunctional allylation reagent. Allylboration of aldehydes with the reagent followed by in situ protection gave TES-protected homoallylic alcohols with excellent Z-selectivities. Chemoselective allylsilation with the same reagent delivered γ,δ-bifunctionalized homoallylic ethers with high E-selectivities. The bifunctionalized alkene group in the products underwent various transformations without erosion of the olefin geometry.

8.
Eur J Pharmacol ; : 172811, 2019 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-31756335

RESUMO

Abnormal proliferation of airway smooth muscle cells (ASMCs) is a hallmark of airway remodeling. Platelet-derived growth factor (PDGF) is known to be a major stimulus inducing the proliferation of ASMCs. It has been reported that triptolide demonstrates protective effects against airway remodeling. In this study, we investigated the antiproliferative effects of triptolide on PDGF-induced ASMCs and its underlying mechanisms. Cell proliferation was determined using the Cell Counting Kit-8 (CCK-8) assay. Flow cytometry was used to study the influence of triptolide on cell cycle and apoptosis. Quantitative real-time PCR and Western blot analysis were employed to detect the expression of proliferating cell nuclear antigen (PCNA), cyclinD1 and cyclin dependent kinase 4 (CDK4). Proteins involved in the protein kinase B (AKT) and nuclear factor kappa B (NF-κB) signaling pathways were evaluated using Western blot analysis. Triptolide could significantly inhibit cell proliferation, induce cell cycle arrest in the G0/G1 phase, and reduce the expression of PCNA, cyclinD1, and CDK4 in PDGF-treated ASMCs. Levels of phosphorylated AKT, p65 and NF-κB inhibitor α (IκBα) stimulated by the presence of PDGF were markedly suppressed after triptolide treatment. Moreover, triptolide cotreatment with the phosphatidylinositol 3 kinase (PI3k) inhibitor, 2-(4-morpholinyl)-8-phenylchromone (LY294002), could further suppress the proliferation, NF-κB activation and cyclinD1 expression. Similar results were observed after triptolide cotreatment with the NF-κB inhibitor, ammonium pyrrolidinedithiocarbamate (PDTC). Our results suggest that triptolide could inhibit the PDGF-induced proliferation of ASMCs through G0/G1 cell cycle arrest and suppression of the AKT/NF-κB/cyclinD1 signaling pathway.

9.
Mol Med Rep ; 20(5): 4499-4506, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31702036

RESUMO

The aberrant expression of sialyltransferase has a role in cell differentiation, neoplastic transformation and the progression of various types of cancer. Our previous studies have shown that high expression of ß­galactoside­α2,3­sialyltransferase III (ST3Gal3) in the metastatic ovarian cancer cell line HO8910PM attenuated cisplatin­induced apoptosis. The present study demonstrated that paclitaxel­induced chemoresistance in ovarian cancer cells upregulated the expression of ST3Gal3 and reduced the activity of caspase­8/3. The results of the present study revealed that the endogenous levels of ST3Gal3 mRNA and protein were significantly higher in HO8910PM cells compared with SKOV3 cells. A higher expression of ST3Gal3 was correlated with an increased resistance to paclitaxel, while the downregulation of ST3Gal3 resulted in paclitaxel­induced apoptosis. Paclitaxel upregulated ST3Gal3 expression at the mRNA and protein levels in HO8910PM cells, but not in SKOV3 cells. Silencing of ST3Gal3 by small interfering RNA reversed these effects and increased the protein levels of caspase­8/3, which may contribute to paclitaxel­induced apoptosis. The results of the present study suggested that ST3Gal3 was a target for paclitaxel­-related resistance during ovarian cancer chemotherapy.

10.
Opt Express ; 27(21): 29817-29828, 2019 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-31684238

RESUMO

Optical discrete multi-tone (DMT) is one type of direct-detection optical orthogonal frequency-division multiplexing (DDO-OFDM), and it is more suitable for cost-sensitive access networks and optical interconnections due to its simple structure. In DMT transmitter, inverse fast Fourier transform (IFFT) is an essential function for achieving OFDM modulation, and its input data are constrained to have Hermitian symmetry (HS). To support high-speed DMT signal generation, a fully-parallel implementation of IFFT is preferable. However, the hardware implementation of the conventional complex-valued IFFT (CC-IFFT) requires large area and has high power consumption. Based on the nature of HS, we design and implement a fully-parallel pipelined 128-point radix-2 decimation-in-time Hermitian-symmetric IFFT (HS-IFFT) by using a single field programmable gate array (FPGA) chip. On-chip resource utilization is analyzed for both the proposed HS-IFFT and CC-IFFT. It exhibits that the HS-IFFT can save up to 35% multipliers, 49% registers and 43% look-up tables (LUTs) compared to the CC-IFFT. Also, by using the HS-IFFT and CC-IFFT, two FPGA-based real-time baseband DMT transmitters are implemented and power consumption is estimated. More than 32% of on-chip power is saved by using the HS-IFFT. Moreover, the two DMT transmitters are also experimentally demonstrated in a short-reach directly-modulated laser (DML)-based optical DMT system. The experimental results show that the HS-IFFT-DMT has the same bit error rate (BER) and error vector magnitude (EVM) performances as the CC-IFFT-DMT in both electrical/optical back-to-back cases (EB2B/OB2B) and post 20-km single-mode fiber (SMF) transmission.

11.
Opt Express ; 27(20): 27927-27935, 2019 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-31684553

RESUMO

Since the electromagnetic resonance that happens in dielectric nanobricks can be meticulously designed to control both amplitude and polarization of light, an ultracompact, high-resolution and continuous grayscale image display method based on resonant dielectric metasurfaces is proposed. Magnetic resonance occurs in dielectric nanobricks can yield unusual high reflectivity depending on the polarization state of incident light, which paves a new way for ultracompact image display when the resonant metasurfaces consisting of nano-polarizer arrays operate. Governed by Malus's law, nano-polarizer arrays featured with different orientations have been demonstrated to continuously manipulate the intensity of linearly polarized light cell-by-cell. Hence, it can practically enable recording a high fidelity grayscale image right at the sample surface with resolution as high as 84,667 dpi (dots per inch). This proposed resonant metasurface image (meta-image) display enjoys the advantages including continuous grayscale modulation, broadband working window, high-stability and high-density, which can easily find promising applications in ultracompact displays, high-end anti-counterfeiting, high-density optical information storage and information encryption, etc.

12.
Artigo em Inglês | MEDLINE | ID: mdl-31710581

RESUMO

A Gram-stain-positive, aerobic, coccus-shaped, non-spore-forming actinobacterium, designated strain N5BH11T, was isolated from a surface-sterilized sample of Mentha haplocalyx Briq. collected from Guizhou, PR China and tested by a polyphasic approach to determine its taxonomic position. Strain N5BH11T grew optimally at 30 °C, pH 6.0-7.0. Substrate mycelia and aerial mycelia were not formed, and no diffusible pigments were observed on the media tested. Phylogenetic analysis based on 16S rRNA gene sequence suggested that strain N5BH11T belonged to the genus Nakamurella and had the highest 16S rRNA gene sequence similarity to Nakamurella flavida DS-52T (98.1 %). The DNA G+C content of strain N5BH11T was 71.6 mol%. The average nucleotide identity values between strain N5BH11T and the type strains of Nakamurella panacisegetis, Nakamurella multipartita and Nakamurella lactea were 74.0, 76.5 and 73.6 %, respectively. The estimated DDH values between strain N5BH11T and the type strains of N. panacisegetis, N. multipartita and N. lactea were 20.3%, 21.4 and 20.2 %, respectively. The cell-wall peptidoglycan contained meso-diaminopimelic acid, and MK-8(H4) was the predominant menaquinone. The predominant polar lipids were diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylmonomethylethanolamine and unidentified phospholipids. The major fatty acids were iso-C15  :  0, anteiso-C15  :  0, C16  :  0 and C16  :  1ω7c. On the basis of the results of phylogenetic analysis and phenotypic and chemotaxonomic characteristics, strain N5BH11T represents a novel species of the genus Nakamurella, for which the name Nakamurella flava sp. nov. is proposed. The type strain is N5BH11T (=KCTC 49196T=CGMCC 4.7524T).

13.
Artigo em Inglês | MEDLINE | ID: mdl-31735338

RESUMO

Early secreted antigenic target 6-kDa protein (ESAT6) is an essential virulence factor of Mycobacterium tuberculosis (MTb). However, ESAT6 helped fighting MTb infection according to vaccine studies. It's unclear whether ESAT6 confers protection via enhancing the innate immunity of macrophages, which are the first-line defense against MTb. We profiled the global transcriptional changes and characterized the innate immunity of THP-1 macrophages treated with ESAT6. We found ESAT6 promoted the phagocytosis ability, enhanced reactive oxygen species (ROS) generation and accelerated glucose metabolism in macrophages. Meanwhile, ESAT6 induced a distinctive phenotype of macrophages with a concurrence of pro-inflammatory and anti-inflammatory cytokines and chemokines. ESAT6 increased the expression of HIF1α mRNA and protein. Interfering HIF1α with siRNA defected the capacity of phagocytosis and ROS generation as well as glucose metabolism. Thus, ESAT6 enhanced the protective innate immunity of macrophages partially via HIF1α. This study provided clues for developing therapies against tuberculosis by targeting ESAT6.

14.
J AAPOS ; 2019 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-31756436

RESUMO

Multiple cranial nerve palsies often lead to complex clinical presentations. We report 2 cases in which a combination of multiple palsies resulted in paralytic esotropia with the medial rectus being the sole functioning rectus muscle. Both cases were treated with temporal transposition of split medial rectus.

15.
Artigo em Inglês | MEDLINE | ID: mdl-31674103

RESUMO

The development of metal-N-C materials as efficient non-precious metal (NPM) catalysts for catalysing the oxygen reduction reaction (ORR) as alternatives to platinum is important for the practical use of proton exchange membrane fuel cells (PEMFCs). However, metal-N-C materials have high structural heterogeneity. As a result of their high-temperature synthesis they often consist of metal-Nx sites and graphene-encapsulated metal nanoparticles. Thus it is hard to identify the active structure of metal-N-C catalysts. Herein, we report a low-temperature NH4 Cl-treatment to etch out graphene-encapsulated nanoparticles from metal-N-C catalysts without destruction of co-existing atomically dispersed metal-Nx sites. Catalytic activity is much enhanced by this selective removal of metallic nanoparticles. Accordingly, we can confirm the spectator role of graphene-encapsulated nanoparticles and the pivotal role of metal-Nx sites in the metal-N-C materials for ORR in the acidic medium.

16.
Oncogene ; 2019 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-31754213

RESUMO

EGFR-mutant non-small-cell lung cancer (NSCLC) patients inevitably develop drug resistance when treated with EGFR tyrosine kinase inhibitors (TKIs). Systematic genetic analysis is important to understand drug-resistant mechanisms; however, the clinical significance of co-occurring genetic alterations at baseline, co-acquired mutations at progressive disease (PD), and the clonal evolution remain underinvestigated. We performed targeted sequencing of pre-treatment and PD tumor samples from 54 EGFR-mutant NSCLC patients. Ten additional patients were sequenced using whole-exome sequencing to infer the clonal evolution patterns. We observed a domain-dependent effect of PIK3CA mutation at baseline on patient progression-free survival (PFS). In addition, at baseline, 9q34.3/19p13.3 (NOTCH1/STK11/GNA11) showed a co-deletion pattern, which was associated with a significantly worse PFS (p = 0.00079). T790M-postive patients with other concurrent acquired oncogenic mutations had a significantly shorter PFS (p = 0.005). Besides acquired T790M mutation, chromosomal instability (CIN) related genes, including AURKA and TP53 alterations, were the most frequently acquired events. CIN significantly increased during TKI treatment in T790M-negative patients and is a candidate resistance mechanism to the first-generation TKIs. Clonal evolution analyses suggest that the composition and relationship among resistant subclones, particularly relationship with T790M subclone, affect patients' outcomes. Overall, our findings of novel co-occurring alterations and clonal evolution patterns can be served as predictive biomarkers to stratify patients and help to better understand the drug-resistant mechanism to TKIs.

17.
Nat Cell Biol ; 21(12): 1490-1503, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31768046

RESUMO

Tendon injuries cause prolonged disability and never recover completely. Current mechanistic understanding of tendon regeneration is limited. Here, we use single-cell transcriptomics to identify a tubulin polymerization-promoting protein family member 3-expressing (Tppp3+) cell population as potential tendon stem cells. Through inducible lineage tracing, we demonstrate that these cells can generate new tenocytes and self-renew upon injury. A fraction of Tppp3+ cells expresses platelet-derived growth factor receptor alpha (Pdfgra). Ectopic platelet-derived growth factor-AA (PDGF-AA) protein induces new tenocyte production while inactivation of Pdgfra in Tppp3+ cells blocks tendon regeneration. These results support Tppp3+Pdgfra+ cells as tendon stem cells. Unexpectedly, Tppp3-Pdgfra+ fibro-adipogenic progenitors coexist in the tendon stem cell niche and give rise to fibrotic cells, revealing a clandestine origin of fibrotic scars in healing tendons. Our results explain why fibrosis occurs in injured tendons and present clinical challenges to enhance tendon regeneration without a concurrent increase in fibrosis by PDGF application.

18.
Anal Chem ; 2019 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-31724393

RESUMO

ICP-MS is powerful in evaluating elemental species at the single-cell level, where high throughput/efficiency/precision are the keys for achieving statistically significant information based on massive data. We report an ultrahigh-throughput single-cell sampling system, consisting of a 3D spiral-helix tubing array to facilitate single-cell focusing into an orderly flow by inertial lift force and Dean drag force. The spiral-helix array ensures a superb single-cell sampling rate of 40 000 cells min-1 at a favorable temporal-spatial resolution of 41.55 ± 17.46 µm (distance between adjacent cells) or 0.97 ± 0.41 ms (time interval between adjacent cells). With a laboratory-made nebulization device, a cell measurement efficiency up to 42.1 ± 7.2% is achieved in ICP-MS assay. Analysis of Au nanoparticles (AuNPs) in living K562 cells after incubation illustrates obvious diversification of AuNPs among cells. The ultrahigh throughput and cell measurement efficiency generate massive data on single-cell assay, make statistical analysis more comprehensive, and enable interpreting extremely subtle differences among individual cells.

19.
Cancer Commun (Lond) ; 39(1): 75, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31730020

RESUMO

BACKGROUND: The National Comprehensive Cancer Network guidelines recommend intensity-modulated radiotherapy (IMRT) as the primary curative treatment for newly diagnosed nasopharyngeal carcinoma (NPC), but the radiation-related complications and relatively high medical costs remain a consequential burden for the patients. Endoscopic nasopharyngectomy (ENPG) was successfully applied in recurrent NPC with radiation free and relatively low medical costs. In this study, we examined whether ENPG could be an effective treatment for localized stage I NPC. METHODS: Ten newly diagnosed localized stage I NPC patients voluntarily received ENPG alone from June 2007 to September 2017 in Sun Yat-sen University Cancer Center. Simultaneously, the data of 329 stage I NPC patients treated with IMRT were collected and used as a reference cohort. The survival outcomes, quality of life (QOL), and medical costs between two groups were compared. RESULTS: After a median follow-up of 59.0 months (95% CI 53.4-64.6), no death, locoregional recurrence, or distant metastasis was observed in the 10 patients treated with ENPG. The 5-year overall survival, local relapse-free survival, regional relapse-free survival, and distant metastasis-free survival among the ENPG-treated patients was similar to that among the IMRT-treated patients (100% vs. 99.1%, 100% vs. 97.7%, 100% vs. 99.0%, 100% vs. 97.4%, respectively, P > 0.05). In addition, compared with IMRT, ENPG was associated with decreased total medical costs ($ 4090.42 ± 1502.65 vs. $ 12620.88 ± 4242.65, P < 0.001) and improved QOL scores including dry mouth (3.3 ± 10.5 vs. 34.4 ± 25.8, P < 0.001) and sticky saliva (3.3 ± 10.5 vs. 32.6 ± 23.3, P < 0.001). CONCLUSIONS: ENPG alone was associated with promising long-term survival outcomes, low medical costs, and satisfactory QOL and might therefore be an alternative strategy for treating newly diagnosed localized stage I NPC patients who refused radiotherapy. However, the application of ENPG should be prudent, and prospective clinical trials were needed to further verify the results.

20.
Life Sci ; 239: 116881, 2019 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-31678285

RESUMO

AIM: To investigate anti-liver fibrosis effects of Salvianolic acid B (Sal B) from Salvia miltiorrhiza Bunge involved mitogen-activated protein kinase (MAPK)-mediated transforming growth factor-beta (TGF-ß) signaling. MAIN METHODS: Diethylnitrosamine (DEN)-induced liver fibrosis in mice and TGF-ß1-activated hepatic stellate cells (HSCs) were established and treated with dosage/concentration-graded Sal B and/or MAPK activator (Vacquinol-1: MKK4-specific activator)/inhibitors (PD98059: ERK-specific inhibitor; SP600125: JNK-specific inhibitor; SB203580: p38-specific inhibitor). Histopathological characteristics and cell migration were assessed, α-SMA, Collagen I and members of TGF-ß/MAPK/Smad signal transduction pathway were measured. KEY FINDINGS: Results in vivo showed that Sal B alleviated DEN-caused liver fibrosis embodied in ameliorative histopathological characteristics and decreased protein levels of hepatic fibrosis related markers (α-SMA, Collagen I, TGF-ß1), its molecular mechanisms of action were correlative with inhibited activation of MAPK and phosphorylation of Smad2/3 at linker regions (P-Smad2/3L) and Smad2 at C-terminal (P-Smad2C) while increased phosphorylation of Smad3 at C-terminal (P-Smad3C). Results in vitro showed that Sal B restrained TGF-ß1-induced HSCs activation, Collagen I production and cell migration; Sal B inhibited activation of MAPK and markedly decreased protein levels of P-Smad2/3L and P-Smad2C while slightly increased P-Smad3C in TGF-ß1-stimulated HSCs, the expression of PAI-1 was inhibited by Sal B; activating MAPK receded inhibitory effects of Sal B on α-SMA, Collagen I, P-Smad2L and P-Smad3L expression while inhibited activation of MAPK reinforced those. SIGNIFICANCE: Sal B attenuates liver fibrosis via mediation of TGF-ß/Smad and MAPK pathways, especially inhibition of MAPK-mediated P-Smad2/3L signaling, which maybe provides theoretical foundation of Sal B for treating clinically liver fibrosis.

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