The mechanism of Shenlong Jianji treatment of idiopathic pulmonary fibrosis inhibits fibroblast-to-myofibroblast transformation via the TGF-ß1/smads signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Shenlong Jianji (SLJJ) is a Chinese herbal compound composed of traditional medicines for supplementing Qi, nourishing Yin, promoting blood circulation, and removing obstruction in channels. It is widely used to treat idiopathic pulmonary fibrosis (IPF) in China. However, the underlying mechanism of SLJJ remains unclear. AIM OF THIS STUDY: To elucidate the efficacy and mechanisms of SLJJ in the treatment of IPF through in vivo and in vitro experiments. MATERIAL AND METHODS: 84 Wistar rats were randomly and equally divided into 7 groups: the control group (CTRL), the sham operation group (SHAM), the model group (IPF), the low dose of SLJJ group (L-SLJJ), the middle dose of SLJJ group (M-SLJJ), the high dose of SLJJ group (H-SLJJ), and the pirfenidone group (PFD). The rats in the CTRL, SHAM, and IPF groups were given normal saline each time for 28 days; the SLJJ groups were given Shenlong Jianji (9 g kg-1·d-1, 18 g kg-1·d-1, 36 g kg-1·d-1), and pirfenidone was administered as a sequential dose. After 28 days, the general condition of the rats was evaluated, and samples were collected. The lung coefficient was measured. The pathological changes of lung in each group were observed by H&E staining and Masson staining. α-SMA, collagen 1, and E-cadherin proteins were detected by immunohistochemistry. α-SMA, collagen 1, vimentin, E-cadherin, N-cadherin, TGF-ß1, smad2, and smad3 proteins were detected by WB in vivo.In vitro, A scratch test was used to assess the ratio of cell migration. α-SMA, vimentin, E-cadherin, and N-cadherin protein levels were evaluated by a cellular immunofluorescence assay. TGF-ß1/smads signaling pathway was detected by WB. HPLC-Q-TOF/MS analysis was used to identify the active compounds in the SLJJ. Molecular docking determined the free binding energy of the compound with the TGF-ß1 protein. RESULTS: SLJJ significantly improved the respiratory symptoms, heart rate, mental state, and food intake of IPF group rats and decreased the lung coefficient. In the IPF group, inflammatory cells were infiltrated, and the thickened alveoli wall and alveoli collapse were shown, while significantly alleviating pathological changes in the SLJJ and PFD groups. Masson staining showed that SLJJ and PFD decreased the collagen expression. Immunohistochemical results showed that the expressions of α-SMA, collagen 1, and N-cadherin decreased in the SLJJ and PFD groups, while E-cadherin increased significantly compared with the IPF group. SLJJ regulates TGF-ß1/smads signaling pathway proteins in vivo. SLJJ decreased the ratio of migration in HFL-1 cells; SLJJ reduced the fluorescence intensity of α-SMA, vimentin, and N-cadherin and increased the fluorescence intensity of E-cadherin in primary rat lung (PRL) fibroblast cells and HFL-1 cells. WB results showed that SLJJ significantly down-regulated α-SMA, Vimentin, N-cadherin, TGF-ß1, smad2, and p-smad2/3 proteins expression and up-regulated E-cadherin protein expression in vitro, whereas SRI-011381 (a TGF-ß1 agonist) antagonized the effects of SLJJ. CONCLUSION: SLJJ inhibits idiopathic pulmonary fibrosis. The TGF- ß1/Smads signaling pathway can be the target of SLJJ, which inhibits fibroblast-to-myofibroblast transformation and is expected to be a new drug for the treatment of IPF.

Transcriptome Sequencing of lncRNAs, circRNAs, miRNAs, mRNAs, and Interaction Network Constructing in Acute Exacerbation of Idiopathic Pulmonary Fibrosis.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) patients who suffer from acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) are at increased risk of respiratory deterioration and death. Non-coding RNAs (ncRNAs) play a vital role in AE-IPF, but studies of crosstalk between transcripts of IPF based on Traditional Chinese Medicine (TCM) syndrome type are relatively few. The construction of long non-coding RNAs (lncRNA)/circular RNAs (circRNA)-microRNAs (miRNA)-mRNA interaction networks can promote understanding RNA interaction in different syndrome types of AE-IPF. The study aimed to identify the difference in RNA transcription expression between IPF patients with "lung heat and collateral stasis (LHCS)" and "lung deficiency with collateral stasis (LDCS)" syndromes, further to construct the potential RNA networks. METHODS: Five IPF patients with LHCS and five IPF patients with LDCS were recruited in this study to perform RNA sequencing and miRNA sequencing. Further analysis was carried out on the differential expression profiles of lncRNAs, circRNAs, miRNAs, and mRNAs among patients with LHCS and LDCS. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed. The lncRNA/circRNA-miRNA-mRNA competing endogenous RNAs (ceRNAs) network was constructed, and the key regulatory molecules were analyzed. RESULTS: For LHCS and LDCS, we identified 69 lncRNAs, 150 circRNAs, 27 miRNAs, and 56 mRNAs. Differential expression analysis through GO and KEGG highlights that differentially expressed mRNAs have significant associations with pathways such as tight junction and Hepatitis C. Within the ceRNA network, all nodes have a direct or indirect association with LHCS progression. The hsa-miR-150-5p core sub-network is composed of 1 lncRNA, 6 circRNAs, 1 miRNA, and 5 mRNAs. From the ceRNA sub-network analysis, NR_120628/hsa-miR-150-5p/E2F3 and hsa-circ-0053515/hsa-miR-150-5p/E2F3 emerged as the pivotal ceRNA pairs. CONCLUSIONS: This study highlights that the NR_120628/hsa-miR-150-5p/E2F3 and hsa-circ-0053515/hsa-miR-150-5p/E2F3 axes could be central in the regulation of LHCS, providing valuable insights into potential directions for subsequent research on LHCS. TRIAL REGISTRATION: Chinese clinical trial registry (CHiCTR23007405). Registered on July 27, 2023. https://www.chictr.org.cn/.

DNA damage resulting from human endocrine disrupting chemical exposure: Genotoxicity, detection and dietary phytochemical intervention.

In recent years, exposure to endocrine disrupting chemicals (EDCs) has posed an increasing threat to human health. EDCs are major risk factors in the occurrence and development of many diseases. Continuous DNA damage triggers severe pathogenic consequences, such as cancer. Beyond their effects on the endocrine system, EDCs genotoxicity is also worthy of attention, owing to the high accessibility and bioavailability of EDCs. This review investigates and summarizes nearly a decade of DNA damage studies on EDC exposure, including DNA damage mechanisms, detection methods, population marker analysis, and the application of dietary phytochemicals. The aims of this review are (1) to systematically summarize the genotoxic effects of environmental EDCs (2) to comprehensively summarize cutting-edge measurement methods, thus providing analytical solutions for studies on EDC exposure; and (3) to highlight critical data on the detoxification and repair effects of dietary phytochemicals. Dietary phytochemicals decrease genotoxicity by playing a major role in the detoxification system, and show potential therapeutic effects on human diseases caused by EDC exposure. This review may support research on environmental toxicology and alternative chemo-prevention for human EDC exposure.

Effectiveness and safety of acupoint application for chronic obstructive pulmonary disease: A protocol for updated systematic review and meta-analysis.

BACKGROUND: Acute exacerbation is a primary cause of repeated hospitalization and death in chronic obstructive pulmonary disease (COPD) patients. Therefore, how to control the symptoms of COPD at stable stage and reduce the number of acute exacerbation is a hot spot of medical research. Acupoint application (AA) is a significant part of external treatment of traditional Chinese medicine (TCM), Previous researches have reported that AA can be applied to the treatment of COPD. Nevertheless, its effectiveness is still inconclusive. This systematic review (SR) and meta-analysis is designed to appraise its effectiveness and safety for the treatment of patients with COPD. METHODS: Eight databases will be systematically retrieved from their inceptions to February 2021. Inclusion criteria are randomized control trials of AA combined with routine western medicine interventions in the treatment of COPD at stable stage. The primary outcomes we focus on comprise clinical effective rate, TCM symptom score, quality of life, dyspnea, exercise capacity, lung function, frequency of acute exacerbation, adverse events. The research screening, data extraction, and risk of bias assessment will be conducted by 2 individuals independently, and divergence will be adjudicated by a third senior investigator. The Stata 13.1 software will be used for meta-analysis. The confidence of evidence will be classified adopting grading of recommendations assessment, development and evaluation (GRADE) algorithm and methodological quality of this SR will be assessed using assessment of multiple systematic reviews-2 (AMSTAR-2) tool. RESULTS: This SR will provide evidence-based medical proof for the treatment of COPD at stable stage by AA combined with conventional western medicine interventions. The findings of this SR will be presented at relevant conferences and submitted for peer-review publication. CONCLUSIONS: The findings of this SR will provide up-todated summary proof for evaluating the effectiveness and safety of AA for COPD. REGISTRATION NUMBER: INPLASY 202140080.

Risk factors for bronchiectasis in patients with chronic obstructive pulmonary disease: a systematic review and meta-analysis.

The risk factors of bronchiectasis in patients with chronic obstructive pulmonary disease have not yet been established. This systematic review and meta-analysis aimed to investigate and identify potential risk factors for patients with chronic obstructive pulmonary disease accompanied by bronchiectasis. We reviewed eight electronic journal databases from their inception to November 2019 for observational studies with no language restrictions. The Newcastle-Ottawa Scale was applied to evaluate the quality of the literature. Binary variables were pooled using odds ratios and continuous variables using the standardized mean difference with 95% confidence intervals. The confidence of evidence was assessed according to the grading of the recommendations assessment, development, and evaluation method. Eight case-control studies met the inclusion criteria. Tuberculosis history, smoking history, hospitalization stays, admissions in the past year, and duration of symptoms were considered risk factors. In addition, the ratio between the forced expiratory volume in 1s and forced vital capacity, the percentage of forced expiratory volume in 1s, the forced expiratory volume in 1s as a percentage of the predicted value, purulent sputum, purulent mucus sputum, positive sputum culture, Pseudomonas aeruginosa infection, arterial oxygen pressure, daily dyspnea, C-reactive protein, leukocytes, and the percentage of neutrophils were found to be closely related to bronchiectasis. However, these were not considered risk factors. The evidence of all outcomes was judged as "low" or "very low." Additional prospective studies are required to elucidate the underlying risk factors and identify effective preventive interventions.

Risk factors for bronchiectasis in patients with chronic obstructive pulmonary disease: a systematic review and meta-analysis

The risk factors of bronchiectasis in patients with chronic obstructive pulmonary disease have not yet been established. This systematic review and meta-analysis aimed to investigate and identify potential risk factors for patients with chronic obstructive pulmonary disease accompanied by bronchiectasis. We reviewed eight electronic journal databases from their inception to November 2019 for observational studies with no language restrictions. The Newcastle-Ottawa Scale was applied to evaluate the quality of the literature. Binary variables were pooled using odds ratios and continuous variables using the standardized mean difference with 95% confidence intervals. The confidence of evidence was assessed according to the grading of the recommendations assessment, development, and evaluation method. Eight case-control studies met the inclusion criteria. Tuberculosis history, smoking history, hospitalization stays, admissions in the past year, and duration of symptoms were considered risk factors. In addition, the ratio between the forced expiratory volume in 1s and forced vital capacity, the percentage of forced expiratory volume in 1s, the forced expiratory volume in 1s as a percentage of the predicted value, purulent sputum, purulent mucus sputum, positive sputum culture, Pseudomonas aeruginosa infection, arterial oxygen pressure, daily dyspnea, C-reactive protein, leukocytes, and the percentage of neutrophils were found to be closely related to bronchiectasis. However, these were not considered risk factors. The evidence of all outcomes was judged as "low" or "very low." Additional prospective studies are required to elucidate the underlying risk factors and identify effective preventive interventions.

Multiple Traditional Chinese Medicine interventions for idiopathic pulmonary fibrosis: A protocol for systematic review and meta-analysis of overview.

BACKGROUND: The therapeutic strategies of idiopathic pulmonary fibrosis (IPF) tend to be comprehensive. Improving the major symptoms and quality of life (QoL) is as important as postponing the process of fibrosis. However, only pirfenidone and nintedanib conditionally recommended by guidelines and no definite proof indicate that they can significantly ameliorate the main symptoms and QoL of IPF sufferers. At present, multiple types of Traditional Chinese Medicine (TCM) interventions alone or in combination with conventional western medicine managements are widespreadly applied in IPF treatment, which seemingly have a promising clinical effect, especially in ameliorating the main symptoms and improving QoL. Subsequently, the number of relevant studies in systematic reviews(SRs) and meta-analyses of randomized controlled trials(RCTs) increased significantly. Hence, we plan to implement an overview to collect, evaluate, and summarize the results of these SRs. METHODS: An all-round literature retrieval will be conducted in 9 electronic databases, including PubMed, EMBASE, CINAHL, Cochrane Library, Epistemonikos, CNKI, CBM, Wanfang, and VIP. We will focus on the systematic review and meta-analysis of RCTs for multiple TCM interventions alone or in combination with routine western medicine measures in IPF treatment. The main outcomes we follow with interest include the improvement of major symptoms (cough, dyspnea) and QoL. Secondary outcomes will consist of minor symptoms improvement, clinical total effective rate, lung function, blood gas analysis, 6-minute walk text, adverse events, acute exacerbation, all-cause mortality, and IPF-related mortality. Two reviewers will independently select the SRs satisfactory with the enrolling criteria, extract key characteristics, and datas on predefined form, evaluate methodological quality by AMSTAR-2, ROBIS and PRISMA tools, and the quality of evidences adopting GRADE method. In case of any divergence will be reached an agreement by discussion or adjudicated by a third senior reviewer. We will perform a narrative synthesis of the proofs from SRs included. RESULTS: The findings of this overvew will be presented at relevant conferences and submitted for peer-review publication. CONCLUSIONS: We expect to obtain comprehensive and reliable evidence of IPF treated by diversified TCM interventions from the potential standard SRs, which may provide suggestions for future RCTs and SRs. REGISTRATION NUMBER: INPLASY 202080110.

Preventive and therapeutic effectiveness of Sanfu acupoint herbal patching for chronic obstructive pulmonary disease at stable stages: a systematic review and Meta-analysis.

OBJECTIVE: To evaluate the preventive and therapeutic effects of Sanfu acupoint herbal patching (SAHP) in adjuvant treatment in patients with stable chronic obstructive pulmonary disease (COPD). METHODS: We had searched eight electronic databases and six major trial registries from their inception to July 2017 for randomized controlled trials (RCTs). We utilized RevMan 5.3 to evaluate the methodological quality and to perform data analyses. RESULTS: A total of 28 RCTs involving 1615 records were included in the descriptive analysis, and 25 RCTs were performed for Meta-analysis. Lung function such as forced vital capacity rate of one second FEV1/predicted%, forced vital capacity (FVC) % found no significant difference. The results of Meta-analysis showed that SAHP plus conventional therapy (CT) in the treatment of stable COPD were better than CT, in second sessions' data of FEV1, in third sessions' data of FEV1/FVC, in three sessions' data of SGRQ, in third session's data of Modified Medical Research Council and 6MWT. The symptoms of SAHP's adverse reactions seem to be mild and the incidence of that seems to be low. Descriptive analysis shows that SAHP with CT seems to improve clinical effective rate and had a certain preventive effect on acute exacerbation of COPD, which the curative effect may be better with the increase of treatment course. CONCLUSION: SAHP with CT appears to be more effective than CT or CT plus placebo only on improving the quality of life, but the effect on lung function is not obvious. Improve clinical effective rate and preventive effect is uncertainty. SAHP with CT may be used in any Grade to safely treat patients with stable COPD. The more exactly clinical effect still needs to be proved by more high-quality, large sampling, multilingual RCTs.

Comparative effectiveness of 3 Traditional Chinese Medicine treatment methods for idiopathic pulmonary fibrosis: A systematic review and network meta-analysis protocol.

INTRODUCTION: The morbidity of idiopathic pulmonary fibrosis (IPF) was found in an increasing trend, progressive worsening of symptoms and deterioration in lung function tend to trigger off a lower quality of life (QoL). Only pirfenidone and nintedanib have been recommended in the guidelines, which can modify the disease process. However, no evidence was verified to significantly alleviate the main clinical manifestations of IPF. At present, Chinese herbal formula (CHF) is widely prescribed as an adjunct to western medicine to treat the disease, and have shown promising benefits on clinical symptoms and QoL. There are mainly 3 Traditional Chinese Medicine (TCM) treatment methods guiding the composition of CHFs, which are devoting to comfort the common symptoms of IPF. Nevertheless, the paucity of direct comparative evidence of them posed a challenge for clinicians to determine the relative merits options. Therefore, we formulate this protocol, which is described for a systematic review to investigate relative advantages among different TCM treatment method and provide more reliable evidence for clinical decision-making. METHODS AND ANALYSIS: A systematic literature search will be employed in 10 electronic databases. Inclusion criteria are randomized control trials of CHFs composed based on the 3 TCM treatment methods, which act as an adjuvant treatment with routine drugs, compared with routine drugs alone. The primary outcomes we focus on include St George's Hospital Respiratory Questionnaire (SGRQ) scores, TCM symptom (dyspnea, cough) scores. The research screening, data extraction, and methodological quality assessment will be conducted by 2 individuals separately, and dispute will be adjudicated by a third senior reviewer. We will employ network meta-analysis (NMA) in a Bayesian framework with vague priors and the surface under the cumulative ranking curve (SUCRA) to obtain the comprehensive rank for the 3 TCM treatment methods. RESULTS: This systematic review will provide an evidence of CHFs composed under the guidance by 3 TCM treatment methods with routine drugs, compared with routine drugs alone for IPF, and will submit to a peer-reviewed journal for publication. CONCLUSION: The conclusion of this systematic review will provide evidence for relative advantages among the 3 TCM treatment methods.

[Clinical efficacy on pediatric recurrent pneumonia treated with point application in summer for the prevention in winter].

OBJECTIVE: To study retrospectively the clinical efficacy on pediatric recurrent pneumonia treated with point application in summer for the prevention in winter, as well as the relationship of age, sick duration, attack frequency and skin reaction with the clinical efficacy. METHODS: One hundred and thirty-five cases of pediatric recurrent pneumonia were divided into a one-year group, a two-year group and a three-year group, 45 cases in each one according to the duration of treatment. The acupoints for the application were Dingchuan (EX-B1), Feishu (BL 13), Gaohuang (BL 43) and Danzhong (CV 17) with the same herbal plaster (prepared with rhizome corydalis, semen brassicae, euphorbia kansui and asarum sieboldii at the ratio of 2:2:1:1) on the first day of each of the three periods of the hot season, 2 to 4 h in each treatment. The attack frequency and change rate were observed before and after treatment in the three groups. The clinical efficacy was assessed in the three groups. RESULTS: (1) After treatment, the attack frequency of pediatric pneumonia was reduced apparently in the three groups (all P < 0.01). The result in the three-year group was less than that in the one-year group and the two-year group and the change rate was the highest (all P < 0.01). (2) After treatment, the sick duration was shortened apparently in the three groups (P < 0.05, P < 0.01). The result in the three-year group was the most remarkable, statistically and significantly different as compared with the other two groups (both P < 0.01). (3) The total effective rate in the three-year group was better than that in either of the other two groups [84.4% (35/45) vs 51.1% (23/45, P < 0.01), 84.4% (35/45) vs 71.1% (32/45, P < 0.05)]. (4) The total effective rate in the children aged from 4 to 7 years was better than that in the group aged from 8 to 10 years and the group aged from 11 to 14 years [79. 7% (47/59) vs 71.7% (33/46, P < 0.05); 79.7% (47/59) vs 43.3% (13/30, P < 0.01)]. (5) The total effective rate in the children with the sick duration ≥ 4 year was lower than that in the group with the sick duration <2 years and that 2 to 4 years (both P < 0. 01). (6) The total effective rate in the children with the annual attack frequency of 2 to 4 times was better than that with the frequency ≥ 4 times (P < 0.01). (7) For the cases with skin reaction after treatment, the total effective rate was better than that in the cases without reaction (P < 0.05). CONCLUSION: The point application in summer for the prevention in winter reduces the attack frequency of pediatric pneumonia, shortens the sick duration and has achieved the better significant efficacy in the cases of lower age, shorter sick duration, less attack frequency and moderate skin reaction.

Effects of Chinese herbal medicine Shenlong Decoction on mRNA expressions of matrix metalloproteinase-2 and tissue inhibitor of metalloproteinase-1 in lung tissue of rats with pulmonary fibrosis induced by bleomycin.

OBJECTIVE: To observe the expressions of matrix metalloproteinase-2 (MMP-2) and tissue inhibitor of metalloproteinase-1 (TIMP-1) in rats with pulmonary fibrosis (PF) induced by bleomycin, and to explore the mechanisms of Shenlong Decoction in preventing and treating PF. METHODS: A total of 230 Wistar rats were divided into normal control group, untreated group, prednisone group, and low-, medium- and high-dose Shenlong Decoction groups. Wistar rats were intratracheally injected with bleomycin to induce PF. From the 2nd day, rats in the normal control and untreated groups were lavaged with normal saline (NS), and rats in the other groups were lavaged with prepared Shenlong Decoction by the same amount. Hematoxylin-eosin (HE) staining and Masson staining were used to observe pathological changes in lung tissue at different time points, and to evaluate whether the model was successfully induced. Expressions of MMP-2 and TIMP-1 mRNAs in rats' lung tissue were measured by reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: Expressions of MMP-2 and TIMP-1 mRNAs in lung tissue of rats were observed from all groups at each time point. In comparison with the normal control group, on the 7th day, the transcription levels of MMP-2 and TIMP-1 mRNAs, especially the former, of the untreated group increased significantly (P<0.05 or P<0.01). On the 14th day, the transcription levels of MMP-2 and TIMP-1 mRNAs kept rising, especially the latter (P<0.05 or P<0.01). On the 28th day, the transcription level of MMP-2 decreased a little, while the transcription level of TIMP-1 mRNA did not stop increasing (P<0.05 or P<0.01). Compared with the untreated group, decrease of the transcription levels of MMP-2 and TIMP-1 mRNAs were observed in the treatment groups, especially the former, and this effect continued to the 28th day with the medium-dose Shenlong Decoction group decreasing most obviously (P<0.05 or P<0.01). CONCLUSION: Shenlong Decoction may inhibit the expression of MMP-2 mRNA by up-regulating the expression of TIMP-1 mRNA so as to slow the progression of PF.