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Dahuang Danshen Decoction Inhibits Pancreatic Fibrosis by Regulating Oxidative Stress and Endoplasmic Reticulum Stress

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Dahuang Danshen Decoction Inhibits Pancreatic Fibrosis by Regulating Oxidative Stress and Endoplasmic Reticulum Stress Hindawi Evidence-Based Complementary and Alternative Medicine Volume 2021, Article ID 6629729, 12 pages https://doi.org/10.1155/2021/6629729 Research Article Dahuang Danshen Decoction Inhibits Pancreatic Fibrosis by Regulating Oxidative Stress and Endoplasmic Reticulum Stress Xiaoqiang Liang ,1 Mian Han ,1 Xuelin Zhang ,1 Xun Sun ,1 Kui Yu ,1 Congying Liu ,2 Jiaqi Zhang ,3 Cheng Hu ,2 and Jingzhe Zhang 1 1Longhua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China 2Experiment Center for Science and Technology, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China 3Shanghai TCM-Integrated Institute of Vascular Anomalies, Shanghai TCM-Integrated Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China Correspondence should be addressed to Cheng Hu; [email protected] and Jingzhe Zhang; [email protected] Received 9 December 2020; Revised 26 July 2021; Accepted 30 July 2021; Published 10 August 2021 Academic Editor: Yanxia Jin Copyright © 2021 Xiaoqiang Liang et al. .is is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Background. In Traditional Chinese Medicine (TCM), Dahuang Danshen decoction (DD) is used to treat pancreatic fibrosis. Pancreatic fibrosis is a typical manifestation of chronic pancreatitis (CP), which affects the digestive system. .e therapeutic mechanisms of DD in pancreatic fibrosis are unclear. Aim. .is study aimed to investigate the regulatory mechanisms of DD on oxidative stress and en- doplasmic reticulum stress in CP. Materials and Methods. Experimental rats were intraperitoneally injected with 500 mg/kg BW of diethyldithiocarbamate (DDC) twice a week for six weeks to induce CP. At the same time, DD was administered orally at daily doses of 1.37 g/kg BW, 2.74 g/kg BW, and 5.48 g/kg BW to evaluate its treatment effects on CP. After all treatments, pancreatic tissues were harvested and subjected to H&E staining. Transmission electron microscopy (TEM) was also performed to show the endoplasmic reticulum structure in the pancreatic tissues. Immunohistochemistry was used to detect the α-SMA expression level in the pancreatic tissues. Metabolomics analysis of the serum and proteomics analysis of the pancreatic tissues were performed to reveal the changes of endogenous metabolites and proteins, respectively. Concentrations of GSH, MDA, SOD, ROS, col-1, and col-3 were determined using corresponding kits. .e western blotting method was used to determine the protein levels of Keap-1, HO-1, NQO1, Nrf2, GRP, JNK, and caspase 12. .e pancreatic mRNA levels of NQO1, GPX1, HO-1, GST-π, GRP, JNK, and caspase 12 were also determined by quantitative PCR. .e interactions between TCM components and Keap-1 were investigated by molecular docking modeling. Results. .e pathohistological results demonstrated that DD could ameliorate DDC-induced CP in vivo, indicated by reduction of α-SMA, col-1, col-3, TNF-α, and IL-6. DD increased serum levels of GSH and SOD but reduced pancreatic ROS. DD decreased cytoplasmic Keap-1 and increased Nrf2 nuclear localization. Correspondingly, DD increased the expression levels of Nrf2 downstream antioxidant genes NQO1, GPX1, HO-1, and GST-π. DD also decreased ERS hallmarks caspase 12 cleavage and GRP expression. Eventually, DD inhibited PSC activation by reducing JNK phosphorylation and MMK-3/p38 expression. Molecular docking analysis showed that salvianolic acid B and emodin had a good binding affinity toward Keap-1. Conclusions. .ese results demonstrated that DD could ameliorate the oxidative and endoplasmic reticulum stress through releasing Nrf2 from Keap-1 binding and inducing the downstream antioxidant enzymes. As a result, DD could thwart pancreatic fibrosis by inhibiting PSCs activation, which was induced by OS and ERS through JNK and MMK3/p38 pathways. 1. Introduction endocrine disorders [1]. Pancreatic fibrosis is also a typical feature of CP caused by various reasons [2, 3]. .e associated Chronic pancreatitis (CP) is a common digestive system pathological events comprise the recruitment of inflam- disease. Its typical clinical manifestations are steatorrhea, matory cells, parenchymal atrophy, and excessive extracel- abdominal pain, weight loss, polyuria, and other pancreatic lular matrix (ECM) deposition in the pancreas’ exocrine 2 Evidence-Based Complementary and Alternative Medicine region [4]. .e hallmark feature of pancreatic fibrosis is the water (2 L) for 30 minutes. .e mixture was concentrated to deposition of ECM caused by the activation of pancreatic yield 500 mL of decoction. .e concentration of raw herbs in stellate cells (PSCs), which increases ECM synthesis [5, 6]. the decoction was 0.548 g/mL. Inflammation plays an important role in the occurrence and development of pancreatic fibrosis. Recent studies have shown that some inflammation factors such as tumor ne- 2.3. Composition Analysis of the DD by UPLC-MS/MS. In this crosis factor-α (TNF-α) and interleukin-6 (IL-6) can induce study, 1 mL of the DD was mixed with methanol in a 10 mL OS. ERS usually happens together with or after OS, shown by brown volumetric flask and ultrasonicated completely. .e the expression of its marker gene Glucose-regulated protein supernatant was used for composition analysis after cen- 78 (GRP78). OS induces PSCs activation through JNK and trifugation at 15000 g for 10 min and filtration through a MMK3/p38 pathways, while ERS induces caspase 12 0.22 μm membrane. A C18 column (100 mm × 2.1 mm, cleavage and thus increases apoptosis, which promotes PSCs 1.8 μm) was used for chromatographic separation. .e activation [7, 8]. mobile phase consisted of a mixture of water with 0.1% Some researches have demonstrated that therapies of formic acid (A) and methanol (B). .e elution conditions preventing OS and ERS can effectively alleviate pancreatic were as follows: 0–5 min, 90% A; 5–17 min, 90%-5% A; and tissue damage and pancreatic fibrosis degree in chronic 17–20 min, 5% A. pancreatitis [9]. .erefore, antioxidants and ER stress re- duction are important targets for the treatment of pancreatic fibrosis. One such target is nuclear erythroid-related factor 2 2.4. Experimental Animals and Experimental Design. (Nrf2). When dissociating from Keap-1 and translocating According to the guidelines approved by the experimental into nucleus, it drives ROS detoxification through induction animal ethical committee, male SD rats (200 ± 20 g) were of many antioxidant enzymes, such as superoxide dismutase housed in the laboratory animal center of Shanghai Uni- (SOD), heme oxygenase (HO)-1, GST-π, and GPX1. versity of Traditional Chinese Medicine (Ethical license .e Dahuang Danshen decoction (DD) is used to treat number: PZSHUTCM190927018). Fifty rats were randomly � pancreatic fibrosis in Traditional Chinese Medicine (TCM) divided into five groups (n 10) as follows: vehicle group, with appreciable therapeutic effects [10]. It is composed of intraperitoneal injection of normal saline; DDC model, Rheum palmatum L. stem and Salvia miltiorrhiza Bge., intraperitoneal injection of 500 mg/kg BW of DDC in saline which promote blood circulation and curb blood stasis [10]. twice a week for 6 weeks; and DDC + DD groups (1.37 g/kg Our previous studies confirmed that DD could inhibit ECM BW, 2.74 g/kg BW, and 5.48 g/kg BW, respectively), DD synthesis, promote ECM degradation, and downregulate orally administered with different dosages once a day for 6 TGF-β1 expression to inhibit PSCs activation, thereby al- weeks, starting at the same time with DDC treatment. .e tering the course of pancreatic fibrosis [11]. .is study was dosage in rats was calculated from the clinical adult dose. designed to shed further light on the therapeutic effect and Animals were sacrificed 24 h after the last administration, mechanism of DD on DDC induced rat CP model based on and the plasma and pancreatic tissues were immediately proteomics and metabolomics study. collected for further analysis. 2. Materials and Methods 2.5. Histopathological Assessment. Half of the pancreatic tissues were fixed in 10% formalin, then embedded in 2.1. Reagents and Chemicals. .e Rheum palmatum L. stem paraffin, sliced, stained with hematoxylin and eosin (H&E) and Salvia miltiorrhiza Bge. were purchased from Longhua dyes, and assessed under a microscope. .e other half of the Hospital, Shanghai University of Traditional Chinese Medicine, pancreatic tissues were fixed in 2.5% glutaraldehyde sta- China. Acetonitrile and methanol were purchased from Fisher tionary solution, followed by dehydration, embedding, and Chemicals (Waltham USA). FASP Kits for col-1, col-3, ROS, solidification. .e pancreatic tissue’s ultrastructural changes MDA, SOD, and GSH were purchased from Nanjing Jiancheng were observed under a projection electron microscope (FEI Bioengineering Institute (Nanjing, China). Cytoplasmic ex- company, Tecnai G2 Spirit BioTWIN, USA). traction reagents and Pierce BCA Protein Assay Kit were purchased from .ermo Fisher Scientific (Waltham, MA). PrimeScript RT Master Mix and SYBR Premix Ex Taq were 2.6. ELISA Assay for Profibrotic and Proinflammatory from TaKaRa (Shiga, Japan). Antibodies for immunoblotting, Cytokines. Plasma was kept at room temperature and including anti-GAPDH, anti-Keap1, anti-HO-1, anti-Nrf2, centrifuged at 860 g to collect serum. .e serum concen- anti-GRP, anti-caspase 12, anti-JNK, and anti-p38, were trations of col-1, col-3, TNF-α, and IL-6 were determined by purchased from Cell Signaling Technology (Danvers, MA). the ELISA method using their specific assay kits (Nanjing Carboxymethyl cellulose sodium (CMC-Na) was obtained Jiancheng Bioengineering Institute). from Sigma Co. (St. Louis, MO). 2.7. Analysis of Serum GSH, MDA, SOD, and ROS in the 2.2. Preparation of the Dahuang Danshen Decoction Extract. Pancreas. Weighted pancreatic tissues were homogenized in .e DD decoction was prepared by soaking 137 g of Rheum normal saline (tissue: solvent � 1 : 9). .e serum GSH, MDA, palmatum L. stem and 137 g of Salvia miltiorrhiza Bge.
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