Function of proprotein convertase subtilisin/kexin type 9 and its role in central nervous system diseases: An update on clinical evidence.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) has attracted lots of attention in preventing the clearance of plasma low-density lipoprotein cholesterol (LDL-C). PCSK9 inhibitors are developed to primarily reduce the cardiovascular risk by lowering LDL-C level. Recently, a number of pleiotropic extrahepatic functions of PCSK9 beyond the regulation of cholesterol metabolism, particularly its effects on central nervous system (CNS) diseases have been increasingly identified. Emerging clinical evidence have revealed that PCSK9 may play a significant role in neurocognition, depression, Alzheimer's disease, and stroke. The focus of this review is to elucidate the functions of PCSK9 and highlight the effects of PCSK9 in CNS diseases, with the aim of identifying the potential risks that may arise from low PCSK9 level (variant or inhibitor) in the clinical practice.

Real-World Prescribing Patterns for Hypertensive Children in China from 2018 to 2021: A Cross-Sectional Multicenter Study.

Background: Pediatric hypertension become an early marker of cardiovascular diseases, but their antihypertensive drug use patterns are rarely known. Purpose: To investigate the epidemiological characteristics of pediatric hypertension and the use of antihypertensive drugs in the real world in China. Methods: In this study, the demographic, diagnosis, and medication prescription data including the antihypertensive drug types and comorbidities, were analyzed. The antihypertensive drugs use were evaluated according to the Chinese guidelines for hypertension. Results: 1301 prescriptions (number of visits) containing 1880 antihypertensive medical orders were collected. The average number of antihypertensive drugs per prescription was 1.45 (±0.75). The patients aged 16 to 18 (70.18%) accounted for the highest proportion. Kidney diseases (33.28%) were the most common comorbidities. Calcium channel blocker (CCB), angiotensin II receptor blocker (ARB), and ß receptor blocker (BB) were the most used antihypertensive drugs. The most frequent monotherapy was CCB, while that of two and three drugs combination were ARB+CCB and ARB+BB+CCB, respectively. Metoprolol (11.44%), nifedipine (10.64%), amlodipine (10.59%), valsartan (6.12%) were the most commonly used antihypertensive drugs. The utilization rate of fixed compound preparations was 7.34%. However, the percentage of recommended antihypertensive drugs was just 14.20%, while the recommended drug combination was 84.93% according to the guidelines. Conclusion: For the first time ever we reported the antihypertensive prescription analysis in children in a large area of China. Our data provided new insights into the epidemiological characteristics and drug use in hypertensive children. We found that the guidelines for medication management in hypertensive children were not routinely followed. The wide use of antihypertensive drugs in children and those with weak clinical evidence raised concerns regarding its rational use. The findings could lead to more effective management of hypertension in children.

Treatment strategies and pharmacist-led medication management for Helicobacter pylori infection.

Half of the world's population is Helicobacter pylori carrier. Updated guidelines and consensus have been issued across regions with the main aim of reducing social transmission and increasing H. pylori eradication rate. Although alternative therapies including traditional Chinese medicine and probiotics have also been used to improve H. pylori eradication rate in clinical practice, current mainstream treatment is still dependent on triple and quadruple therapies that includes antibacterial agents (e.g., amoxicillin and furazolidone) and proton pump inhibitor. Researches also assessed the eradication rate of optimized high-dose dual therapy in treating H. pylori infection. With the increase of antibiotic resistance rate, the treatment strategies for H. pylori infection are constantly adjusted and improved. Besides, low medication compliance is another key influencing factor for H. pylori treatment failure. Emerging studies indicate that pharmacists' intervention and new pharmaceutical care methods can enhance patient medication compliance, reduce adverse drug reactions, and improve H. pylori eradication rate. The purpose of this review is to summarize the advances in treating H. pylori infection and highlight the necessity of developing novel strategies to cope with the increasing challenges and to achieve personalized medication. Also, this review attaches great importance to pharmacists in optimizing H. pylori treatment outcomes as a routine part of therapy.

Escitalopram-induced sinus bradycardia in coronary heart disease combined with depression: a case report and review of literature.

For patients with cardiovascular disease, using the antidepressant escitalopram may lead to unexpected adverse events. Here, a rare repeated sinus bradycardia event due to escitalopram is first reported. In an 82-year-old female patient with cardiac dysfunction using digoxin, tachycardia (average heart rate of 93 beats/min) was demonstrated by electrocardiogram (ECG). She began to take escitalopram and lorazepam due to depression, but sinus bradycardia (93.7% heart rate was <60 beats/min) and sinus arrest were first detected after 3 months. Its proportion decreased to 0.1% after discontinuation of digoxin and escitalopram for 1 day, and the rhythm returned to normal 2 weeks later. After 2 months, escitalopram was prescribed again in combination with quetiapine; then, 17.1% heart rate was <60 beats/min. After escitalopram and quetiapine withdrawal, the ECG showed the heart rhythm had normalized again. No other drug changes were made during these periods. Escitalopram was deemed to be a highly possible cause of sinus bradycardia according to its Naranjo's Algorithm score. Furthermore, literature on escitalopram-mediated cardiovascular adverse events was reviewed and analyzed. Empirically, escitalopram should be discontinued immediately if iatrogenic causes cannot be ruled out. Furthermore, ECG monitoring in escitalopram-related cardiovascular adverse events is highlighted, especially in patients receiving certain drug classes simultaneously (i.e., sinoatrial node inhibitors, antipsychotics).

Nano-enabled delivery of EGCG ameliorates silica-induced pulmonary fibrosis in rats.

Silicosis is the most serious occupational pulmonary fibrosis caused by excessive inhalation of silica particles, whereas viable therapeutic choices are constrained. Epigallocatechin gallate (EGCG) presents massive health benefits, but unfortunately with stability absence. Here, encapsulation of EGCG in poly(n-butylcyanoacrylate) nanoparticles (EGCG/PBCA-NPs) were fabricated by self-polymerization for gastrointestinal delivery in silicosis fibrosis treatment. The obtained nano-enabled delivery of EGCG was produced using a medical adhesive approved by FDA as carrier, and presented spherical particles with approximate diameter of 160 nm, a narrow PDI value of 0.2, Zeta potential value of 30 mV as well as a high EGCG incorporation (90 %) and loading efficiency (20 %). In evaluating the protect effects of nano-formulations, EGCG/PBCA-NPs shown excellent stability in gastric fluid with pH-triggered release in intestine and strong EGCG gastrointestinal retention against degradation. After daily gastrointestinal administration, EGCG/PBCA-NPs exhibited the superior anti-fibrosis efficacy in silicosis model rats induced by silica, involving lung index decline, hydroxyproline content decrease, histological improvement, collagen accumulation reduction and α-SMA down-regulation in comparison with naked EGCG. These results strongly demonstrated that PBCA-based NPs may be a promising nano-enabled delivery carrier for enhancing the gastrointestinal stability and anti-fibrotic effects of EGCG.

Efficacy and potential mechanisms of Chinese herbal compounds in coronavirus disease 2019: advances of laboratory and clinical studies.

The Coronavirus disease 2019 (COVID-19) pandemic is still spread and has made a severe public health threat around the world. To improve disease progression, emerging Chinese herbal compounds were used in clinical practice and some agents have proven beneficial in treating COVID-19. Here, the relevant literature from basic researches to clinical application were identified and comprehensively assessed. A variety of Chinese herbal compounds have been reported to be effective in improving symptoms and outcomes in patients with COVID-19, particularly together with routine treatment strategy. The pharmacological activities were mainly attributed to the relief of clinical symptoms, inhibition of cytokine storm, and improvement of organ function. Besides, the development of novel antiviral drugs from medicinal herbs were further discussed. The updated laboratory and clinical studies provided the evidence of Chinese herbal compounds such as Lianhua Qingwen prescription, Shufeng Jiedu prescription, and Qingfei Paidu Tang for the relief of COVID-19. However, both of the randomized controlled trials and real world researches need to be done for supporting the evidence including the efficacy and safety in fighting COVID-19.

Chinese herbal injections for coronavirus disease 2019 (COVID-19): A narrative review.

BACKGROUND: The outbreak of Coronavirus disease 2019 (COVID-19) has caused more than 180 million infections and 3.9 million deaths. To date, emerging clinical evidence has shown the synergetic benefits of Chinese herbal injections in treating this contagious respiratory disease. This review aims to summarize and analyze the efficacy and safety of Chinese herbal injections in the therapy of COVID-19. METHODS: The literature from 3 electronic databases, PubMed, CNKI, and Web of Science, were searched using the search terms "COVID-19", "SARS-CoV-2", "traditional Chinese medicine", "herb", "herbal", and "injection". Then the identified articles were comprehensively evaluated. RESULTS: Limited data demonstrated that Chinese herbal injections could significantly improve the clinical outcomes of COVID-19 patients, especially in combination with conventional treatment strategies. The benefits of which were mainly associated with the relief of symptoms, prevention of secondary infection, regulation of inflammation and immune function. There was also evidence showing the inhibitory effects on SARS-CoV-2 replication in vitro. Nevertheless, available real-world data suggested the increased risk of adverse event. Furthermore, the defects of existing researches and the insights for discovering novel antiviral drugs were prospectively discussed. CONCLUSION: Evidence-based advances revealed that Chinese herbal injections such as XueBiJing injection and ShenMai injection, exerted potent effects against COVID-19. Further laboratory researches and clinical evaluation are needed to gather scientific evidence on the efficacy and safety.

Trends of complications in patients with Parkinson's disease in seven major cities of China from 2016 to 2019.

Parkinson's disease (PD) is a neurological disorder involving both motor and nonmotor symptoms. Multimorbidity acts synergistically to heighten the risk of adverse outcomes for patients with PD. Its complications have a major impact on the clinical management of PD. The present retrospective and multicenter study was first performed to describe the epidemiological characteristics of PD patients and assess the incidence of complications. The outpatient prescriptions for PD therapy were collected from hospitals in Beijing, Chengdu, Guangzhou, Hangzhou, Shanghai, Tianjin and Zhengzhou of China over a 40-day period per year, from the first half of 2016 to that of 2019. The survey covered the characteristics and representative complications of the study population. A total of 103 674 outpatient prescriptions for PD treatment from different graded hospitals of China were collected for final data analysis. It showed that 78.15% of PD patients were prescribed in the neurology department. 95.05% of the outpatient prescriptions were from general hospitals. We found that the overall PD prevalence was 0.47%, among which 52.96% of them were men. In addition, 82.10% of PD suffers were older than 60 years and 83.70% of them had complications. The top five highest frequencies of nonmotor complications in PD patients were sleep disorders, Alzheimer's disease, depression, lower urinary tract symptoms and constipation, with the proportions of 6.79, 3.87, 3.72, 3.32 and 2.40%, respectively. Meanwhile, the proportions of sleep disorders, Alzheimer's disease, and constipation were gradually increasing from 2016 to 2019. The characteristics of PD patients and the incidence of its complications were evaluated in the present prescription survey. These updated data provide evidence for further implementation of PD management.

Chronic Obstructive Pulmonary Disease Treatment and Pharmacist-Led Medication Management.

Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of death across the globe. Its repeated exacerbation will seriously worsen the quality of life, aggravate the patients' symptoms, and bring a heavy burden on the patients and the society. Understanding the current status of drug therapy and the role of pharmaceutical care is essential for the management of COPD. In addition to the drugs already on the market, recent clinical trials also show that emerging novel drugs for treating COPD are being developed to prevent the symptoms, reduce the frequency of acute exacerbation, and improve the quality of life. Recent progress in new drug research should lead to novel treatment options for COPD patients in future clinical practice. The pharmaceutical care has shown significantly favourable impacts on addressing drug-related problems, supporting its vital role in the management of COPD, especially when there are a wide range of therapeutic agents. This review not only provides an overview of current treatment strategies but also further underlines the importance of new drug development and pharmaceutical care for patients with COPD.

Evaluation of different proton pump inhibitors combined with bismuth quadruple regimens in Helicobacter pylori eradication.

To evaluate the efficacy and economics of different proton pump inhibitors (PPIs) combined with bismuth quadruple regimens for Helicobacter pylori (Hp) eradication, a retrospective analysis method was used to collect Hp-positive patients who were treated with a bismuth-containing quadruple regimen (PPIs + amoxicillin + furazolidone + colloid pectin bismuth) from the outpatient department of gastroenterology in our hospital from January to June 2017. A total of 1410 patients were included in the study and divided into four groups according to different PPIs: group A (pantoprazole sodium enteric-coated capsules, 352 cases), group B (esomeprazole magnesium enteric-coated tablets, 462 cases), group C (pantoprazole sodium enteric-coated tablets, 392 cases) and group D (rabeprazole sodium enteric-coated tablets, 204 cases). The eradication rate of Hp and cost-saving in each group were then compared. There were no significant differences of gender (P = 0.526) and age (P = 0.366) between each Hp treatment regimen. The eradication rates of groups A, B, C and D were 91.48%, 89.83%, 86.73% and 90.69%, respectively. No statistical differences of Hp eradication rates were observed between each group yet (P > 0.05). However, the cost of group A was the lowest. In the present study, the Hp eradication rates between different PPIs regimens were similar in treating Hp infection. Nevertheless, the point in favor of pantoprazole capsules is the slightly higher Hp eradication rate and lower drug cost than other PPIs, which provides a significant evidence for the clinical medication decision in treating Hp infection.

Lianhua Qingwen prescription for Coronavirus disease 2019 (COVID-19) treatment: Advances and prospects.

BACKGROUND: An outbreak of Coronavirus Disease 2019 (COVID-19) which was infected by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), is still spreading and has led to unprecedented health emergency over the world. Though no specific drug has been developed so far, emerging agents have been confirmed effective or potentially beneficial to restrain it. Lianhua Qingwen (LHQW) is a commonly used Chinese medical preparation to treat viral influenza, including in the fight against SARS in 2002-2003 in China. Recent data also showed that LHQW played a vigorous role in COVID-19 treatment. PURPOSE: This review will elucidate the pre-clinical and clinical evidence of LHQW in lung protection and antiviral activities, and provide timely data delivery for the exploration of effective treatment strategies in the therapy of COVID-19. STUDY DESIGN AND METHOD: The research data were obtained from the academic databases (up to August 8, 2020) including Pubmed, CNKI and Web of Science, on ethnobotany and ethno medicines. The search keywords for screening the literature information were "virus", "COVID-19", or "SARS-CoV-2", and "Lianhua Qingwen". The documents were filtered and summarized for final evaluation. RESULTS: The collected evidence demonstrated that LHQW exhibited benefits against COVID-19. Impressively, LHQW in conjunction with conventional treatment could significantly improve COVID-19 patients as a synergetic strategy. The mechanisms were mainly involved the antiviral activity, and regulation of inflammation response as well as immune function. CONCLUSION: Although the data were far from adequate, the latest advances had shown the benefits of LHQW in COVID-19, especially in combination with other antiviral drugs. This review provides comprehensive evidence of LHQW as a complementary strategy for treating COVID-19. Nevertheless, imperious researches should be conducted to clarify the unconfirmed effects, regulatory mechanisms and adverse reactions of LHQW in treating COVID-19 by means of well designed randomized controlled trials.

The status of proton pump inhibitor use: a prescription survey of 45 hospitals in China

Background: proton pump inhibitors (PPI) have been widely used in the clinic but inappropriate prescribing has also increased dramatically. Objective: to describe the prescribing patterns and assess the appropriateness of the prescribed PPI use in 45 hospitals in China. Materials and methods: PPI prescriptions for non-hospitalized patients were collected from hospitals in Beijing, Chengdu, Guangzhou and Hangzhou of China over a 40-day period in 2016. These data were analyzed using the prescription number, proportion and economic indicators (defined daily dose system [DDD], defined daily cost [DDC] and drug utilization index [DUI]). The evaluation criteria of PPI use was based on Martindale: The Complete Drug Reference, New Materia Medica and drug instructions. Results: in total, 357,687 prescriptions using oral PPI and 38,216 prescriptions using injectable PPI were assessed. The average age of PPI users was 53 years. The most commonly used oral PPI was rabeprazole, while the most common injectable PPI was pantoprazole. The DDD of oral rabeprazole and DDC of injectable rabeprazole were the highest. Meanwhile, only the DUI values of oral rabeprazole, lansoprazole and ilaprazole were less than 1.0. The clinical diagnosis of some users included well identified risky comorbidities such as kidney disease (2.9%). Furthermore, between 32.6% and 56.8% of the PPI prescriptions were used for inappropriate indications. Conclusion: this survey demonstrated that PPI use was accompanied by unapproved indications and excessive dosages. Comprehensive measures are urgently needed to improve PPI use and reduce unnecessary drug costs

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The status of proton pump inhibitor use: a prescription survey of 45 hospitals in China.

BACKGROUND: proton pump inhibitors (PPI) have been widely used in the clinic but inappropriate prescribing has also increased dramatically. OBJECTIVE: to describe the prescribing patterns and assess the appropriateness of the prescribed PPI use in 45 hospitals in China. MATERIALS AND METHODS: PPI prescriptions for non-hospitalized patients were collected from hospitals in Beijing, Chengdu, Guangzhou and Hangzhou of China over a 40-day period in 2016. These data were analyzed using the prescription number, proportion and economic indicators (defined daily dose system [DDD], defined daily cost [DDC] and drug utilization index [DUI]). The evaluation criteria of PPI use was based on Martindale: The Complete Drug Reference, New Materia Medica and drug instructions. RESULTS: in total, 357,687 prescriptions using oral PPI and 38,216 prescriptions using injectable PPI were assessed. The average age of PPI users was 53 years. The most commonly used oral PPI was rabeprazole, while the most common injectable PPI was pantoprazole. The DDD of oral rabeprazole and DDC of injectable rabeprazole were the highest. Meanwhile, only the DUI values of oral rabeprazole, lansoprazole and ilaprazole were less than 1.0. The clinical diagnosis of some users included well identified risky comorbidities such as kidney disease (2.9%). Furthermore, between 32.6% and 56.8% of the PPI prescriptions were used for inappropriate indications. CONCLUSION: this survey demonstrated that PPI use was accompanied by unapproved indications and excessive dosages. Comprehensive measures are urgently needed to improve PPI use and reduce unnecessary drug costs.

Astragaloside IV Improves Bleomycin-Induced Pulmonary Fibrosis in Rats by Attenuating Extracellular Matrix Deposition.

Pulmonary fibrosis is a devastating lung disorder with mysterious pathogenesis and limited treatment options. It is well-recognized that the uncontrolled proliferation of lung fibroblasts and differentiation of fibroblasts into myofibroblasts excessively produce extracellular matrix (ECM) proteins which contribute to the fibrosis change of the lungs. Thus, blocking ECM accumulation would delay fibrosis progression. In this study, we observed the effects of astragaloside IV (ASV) (10 mg/kg/d) on ECM proteins in bleomycin (BLM, 5 mg/kg)-treated rats. Our results showed that ASV not only ameliorated BLM-induced body weight loss, lung coefficient increase, histological changes and collagen secretion, but also reduced the levels of type III collagen (Col-III) in lung homogenate, laminin (LN) and hyaluronic acid (HA) in serum, as well as hydroxyproline (HYP) in lung tissue. Besides, ASV significantly down-regulated the levels of high-mobility group box1 (HMGB1) in serum and lung tissue, and inhibited the up-regulated expression of α-SMA (marker of myofibroblasts) in the lungs. Taken together, these findings indicate that ASV attenuates BLM-induced ECM deposition, supporting its use as a promising candidate to treat lung fibrosis.

Activation of Wnt/ß-catenin signalling is required for TGF-ß/Smad2/3 signalling during myofibroblast proliferation.

Fibrosis in animal models and human diseases is associated with aberrant activation of the Wnt/ß-catenin pathway. Despite extensive research efforts, effective therapies are still not available. Myofibroblasts are major effectors, responsible for extracellular matrix deposition. Inhibiting the proliferation of the myofibroblast is crucial for treatment of fibrosis. Proliferation of myofibroblasts can have many triggering effects that result in fibrosis. In recent years, the Wnt pathway has been studied as an underlying factor as a primary contributor to fibrotic diseases. These efforts notwithstanding, the specific mechanisms by which Wnt-mediated promotes fibrosis reaction remain obscure. The central role of the transforming growth factor-ß (TGF-ß) and myofibroblast activity in the pathogenesis of fibrosis has become generally accepted. The details of interaction between these two processes are not obvious. The present investigation was conducted to evaluate the level of sustained expression of fibrosis iconic proteins (vimentin, α-SMA and collagen I) and the TGF-ß signalling pathway that include smad2/3 and its phosphorylated form p-smad2/3. Detailed analysis of the possible molecular mechanisms mediated by ß-catenin revealed epithelial-mesenchymal transition and additionally demonstrated transitions of fibroblasts to myofibroblast cell forms, along with increased activity of ß-catenin in regulation of the signalling network, which acts to counteract autocrine TGF-ß/smad2/3 signalling. A major outcome of this study is improved insight into the mechanisms by which epithelial and mesenchymal cells activated by TGFß1-smad2/3 signalling through Wnt/ß-catenin contribute to lung fibrosis.

Traditional Chinese medicine for pulmonary fibrosis therapy: Progress and future prospects.

ETHNOPHARMACOLOGICAL RELEVANCE: Pulmonary fibrosis (PF) is a chronic, debilitating and often lethal lung disorder. Despite the molecular mechanisms of PF are gradually clear with numerous researchers' efforts, few effective drugs have been developed to reverse human PF or even halt the chronic progression to respiratory failure. Traditional Chinese medicine (TCM), the main component of the medical practice used for more than 5000 years especially in China, often exerts wider action spectrum than previously attempted options in treating human diseases. Recent data have shown the anti-fibrotic benefits of the active ingredients from TCM in this field, which may represent an attractive source of the drug discovery against PF. AIM OF THE REVIEW: This review summarizes the pre-clinical and clinical evidence on the benefits of TCM and their active ingredients, and provides a comprehensive information and reliable basis for the exploration of new treatment strategies of botanical drugs in the therapy of PF. METHODS: The literature information was obtained from the scientific databases on ethnobotany and ethno medicines (up to Aug 2016), mainly from the Pubmed, Web of Science and CNKI databases, and was to identify the experimental studies on the anti-fibrotic role of the active agents from TCM and the involved mechanisms. The search keywords for such work included: "lung fibrosis" or "pulmonary fibrosis", and "traditional Chinese medicine", "extract" or "herb". RESULTS: A number of studies have shown that the active agents of single herbs and TCM formulas, particularly the flavonoids, glycosides and alkaloids, exhibit potential benefits against PF, the mechanisms of which appear to involve the regulation of inflammation, oxidant stress, and pro-fibrotic signaling pathways, etc. Besides, the processing methods for discovering TCM in treating PF were prospectively discussed. CONCLUSION: These research work have shown the therapeutic benefits of TCM in the treatment of PF. However, more continued researches should be undertaken to clarify the unconfirmed chemical composition and regulatory mechanisms, conduct standard clinical trials, and evaluate the possible side effects. The insights provided in present review will be needed for further exploration of botanical drugs in the development of PF therapy.

Total Glucosides of Danggui Buxue Tang Attenuate BLM-Induced Pulmonary Fibrosis via Regulating Oxidative Stress by Inhibiting NOX4.

Pulmonary fibrosis (PF) is a serious chronic lung disease with unknown pathogenesis. Researches have confirmed that oxidative stress which is regulated by NADPH oxidase-4 (NOX4), a main source of reactive oxygen species (ROS), is an important molecular mechanism underlying PF. Previous studies showed that total glucosides of Danggui Buxue Tang (DBTG), an extract from a classical traditional Chinese herbal formula, Danggui Buxue Tang (DBT), attenuated bleomycin-induced PF in rats. However, the mechanisms of DBTG are still not clear. We hypothesize that DBTG attenuates PF through regulating the level of oxidative stress by inhibiting NOX4. And we found that fibrosis indexes hydroxyproline (HYP) and type I collagen (Col-I) were lower in DBTG groups compared with the model group. In addition, the expression of transforming growth factor-ß1 (TGF-ß1) and expression of alpha smooth muscle actin (α-SMA) were also much more decreased than the model group. For oxidative stress indicators, DBTG blunted the decrease of superoxide dismutase (SOD) activity, total antioxidant capacity (T-AOC), and the increase in malondialdehyde (MDA), 8-iso-prostaglandin in lung homogenates. Treatment with DBTG restrained the expression of NOX4 compared to the model group. Present study confirms that DBTG inhibits BLM-induced PF by modulating the level of oxidative stress via suppressing NOX4.

High-Mobility Group Box 1 Mediates Epithelial-to-Mesenchymal Transition in Pulmonary Fibrosis Involving Transforming Growth Factor-ß1/Smad2/3 Signaling.

Epithelial-to-mesenchymal transition (EMT) is a crucial event in the cellular origin of myofibroblasts that secrete extracellular matrix in the progression of pulmonary fibrosis (PF). High-mobility group box 1 (HMGB1) is a novel mediator of EMT. However, whether this process involves the recognized transforming growth factor-ß1 (TGF-ß1)/Smad signaling that also contributes to EMT in PF has not yet been elucidated. Here, we developed a model of PF induced by bleomycin (BLM) in rats and conducted several simulation experiments in A549 (human) and RLE-6TN (rat) alveolar epithelial cell (AEC) lines to unravel the role of TGF-ß1/Smad2/3 signaling in HMGB1-mediated EMT. We found that the levels of serum HMGB1 and lung hydroxyproline were severely elevated after BLM administration. Moreover, the protein expression of HMGB1, TGF-ß1, phosphorylated Smad2/3 (p-Smad2/3), and mesenchymal markers including α-smooth muscle actin, vimentin, and type I collagen were significantly increased with the reduced protein expression of an epithelial marker (E-cadherin) in the rat model by Western blot or immunohistochemical analysis. In addition, the uptake of both exogenous TGF-ß1 and HMGB1 by AECs could induce EMT; meanwhile, HMGB1 dramatically enhanced TGF-ß1 expression and triggered Smad2/3 phosphorylation. In contrast, TGF-ß1 deficiency evidently ameliorated HMGB1-mediated EMT with reduced p-Smad2/3 in A549 cells. It provides new insights that HMGB1 release from injured lungs promotes AEC damage through induction of the EMT process, in which TGF-ß1/Smad2/3 signaling is activated and contributes to PF. These results suggest that HMGB1 may constitute a therapeutic target for developing antifibrotic agents for abnormal lung remodeling.

Inositol-requiring protein 1 - X-box-binding protein 1 pathway promotes epithelial-mesenchymal transition via mediating snail expression in pulmonary fibrosis.

Epithelial-mesenchymal transition (EMT) is a complex biological program during which cells loss epithelial phenotype and acquire mesenchymal features. EMT is thought to be involved in the pathogenesis of various fibrotic diseases including pulmonary fibrosis (PF). Recent studies suggest that endoplasmic reticulum (ER) stress is associated with EMT in the progression of PF. However, the exact mechanism is unclear. Here, we developed a PF model with bleomycin (BLM) administration in rats and conducted several simulation experiments in alveolar epithelial cell (AECs) RLE-6TN to unravel the role of inositol-requiring protein 1 (IRE1) - X-box-binding protein 1 (XBP1) signal pathway in ER stress-induced EMT in PF. First, we observed that ER stress was occurred in type II AECs accompanied by EMT in BLM-induced PF. Then we explored the role of IRE1-XBP1-snail pathway in transforming growth factor (TGF)-ß1/tunicamycin (TM)-induced EMT. When TGF-ß1/TM was treated on AECs, IRE1 and XBP1 were overexpressed, meanwhile, snail expression was upregulated accompanied with EMT. However, when IRE1 or XBP1 was knockdown, TGF-ß1/TM-induced EMT were blocked while the expression of snail was inhibited. Then we silenced snail and found that TGF-ß1/TM-induced EMT were also suppressed, but it had no effect on the up-regulated expression of IRE1 and XBP1. Thus, we concluded that IRE1-XBP1 pathway promotes EMT via mediating snail expression in PF.

Emerging role of HMGB1 in fibrotic diseases.

High-mobility group box 1 (HMGB1) is originally identified as a DNA-binding protein that functions as a structural co-factor critical for proper transcriptional regulation in somatic cells. Recent studies indicate that HMGB1 can be passively released from necrotic cells or actively secreted into the extracellular milieu under appropriate signal stimulation. Extracellular HMGB1 is a multifunctional cytokine that contributes to the process of infection, injury, inflammation, apoptosis, and immune responses by binding to specific cell-surface receptors. Recently, emerging studies indicate that HMGB1 is closely involved in fibrotic disorders including cystic fibrosis, liver fibrosis and pulmonary fibrosis, while HMGB1 signal inhibitions protect against the experimental models of fibrotic diseases. From a clinical perspective, HMGB1 represents a current challenge that can be exploited orchestrate reparative responses. This review focuses on the crucial role of HMGB1 in the pathogenesis of fibrotic diseases and inhibition of which may represent a promising clinical approach for treating tissue fibrosis.