Antimicrobial spiroketal macrolides and dichloro-diketopiperazine from Micromonospora sp. FIMYZ51.

Four compounds (1-4) featuring with an L-rhodinose and spiroketal, possess uncommon continuous hydroxy groups in the macrolide skeleton, and a dichloro-diketopiperazine (5) were isolated from a marine derived Micromonospora sp. FIMYZ51. The determination of the relative and absolute configurations of all isolates was achieved by extensive spectroscopic analyses, single-crystal X-ray diffraction analysis, and ECD calculations. According to structural characteristic and genomic sequences, a plausible biosynthetic pathway for compound 1-4 was proposed and a spirocyclase was inferred to be responsible for the formation of the rare spirocyclic moiety. Compounds 1-4 exhibited potent antifungal activities which is equal to itraconazole against Aspergillus niger. Compounds 1-5 exhibited different degree of inhibitory activities against opportunistic pathogenic bacteria of endocarditis (Micrococcus luteus) with MIC values ranging from 0.0625 µg/mL to 32 µg/mL. Compounds 2 and 3 showed moderate cytotoxicity against drug-resistant tumor cell lines (Namalwa and U266). The result not only provides active lead-compounds, but also reveal the potential of the spirocyclase gene resources from Micromonospora sp., which highlights the promising potential of the strain for biomedical applications.

Acoustic hologram-induced virtual in vivo enhanced waveguide (AH-VIEW).

Optical imaging and phototherapy in deep tissues face notable challenges due to light scattering. We use encoded acoustic holograms to generate three-dimensional acoustic fields within the target medium, enabling instantaneous and robust modulation of the volumetric refractive index, thereby noninvasively controlling the trajectory of light. Through this approach, we achieved a remarkable 24.3% increase in tissue heating rate in vitro photothermal effect tests on porcine skin. In vivo photoacoustic imaging of mouse brain vasculature exhibits an improved signal-to-noise ratio through the intact scalp and skull. These findings demonstrate that our strategy can effectively suppress light scattering in complex biological tissues by inducing low-angle scattering, achieving an effective depth reaching the millimeter scale. The versatility of this strategy extends its potential applications to neuroscience, lithography, and additive manufacturing.

Effects of Cadmium Exposure on Oxidative Stress in Atherosclerotic Rats by Downregulating TopBP1 Expression to Induce Mitochondrial DNA Damage.

Objective: To explore the mechanism of the effect of cadmium exposure on TopBP1-induced mitochondrial DNA damage in atherosclerotic rats to affect oxidative stress. Methods: 50 rats were established atherosclerotic model, and they were divided into model control group (MC group), low-dose cadmium exposure group (LD group), medium-dose cadmium exposure group (MD group), high-dose cadmium exposure group (HD group), and positive control group, with 10 rats in each group. Rats in the LD group, MD group, and HD group were intraperitoneally injected with different doses of cadmium acetate solution for intervention, rats in the PC group were intraperitoneally injected with oxidized banking solution, and those in the MC group were injected with normal saline. 10 rats were taken as the normal control group (NC group). Human umbilical vein endothelial cells were taken for cell experiments, normal saline was added as the blank control group (group A), cadmium acetate solution was added (group B), oxidized bankning solution was added (Group C), and oxidized bankning solution and cadmium acetate solution were added (Group D). Western blot and fluorescence quantitative PCR were used to detect the protein and mRNA expressions respectively. ROS, MDA, and SOD were detected by ELISA, apoptosis of endothelial cells was detected by flow cytometry, and arterial plaque damage was observed by oil red O staining. Results: The relative expressions of TopBP, Bax, and Bcl-2 proteins in rat aortic tissues in each group were significantly different (all P < .05). The relative expressions of TopBP1 and Bcl-2 proteins in the aortic tissues of rats in NC group, MC group, LD group, MD group, HD group, and PC group decreased (all P < .05), while the relative expressions of Bax protein in those groups were increased (all P < .05). Similarly, the relative expression levels of Topbp1mRNA, BaxmRNA, and Bcl-2mRNA in the aortic tissues of rats in each group were significantly different (all P < .05). There were statistically significant differences in the expression levels of ROS, MDA, SOD, and mtDNA expression levels in the aortic tissues of rats in each group. There were statistically significant differences in TopBP1, Topbp1mRNA, and mtDNA among groups (all P < .05); while the relative expression of TopBP1 and Topbp1mRNA in groups A, B, C, and D decreased (all P < .05), the expression levels of mtDNA in those group increased (all P < .05), and the apoptosis rates of endothelial cells were also increased (all P < .05). Conclusion: Cadmium exposure can down-regulate the expression of TopBP1 in atherosclerotic rats, aggravate mitochondrial DNA damage, promote oxidative stress response, and then induce the development of atherosclerosis.

Assessing Mailuoning injection in wound healing and thrombophlebitis management: A rat model study.

Thrombophlebitis is the inflammatory condition characterized by obstruction of one or more vessels, commonly in the legs, due to the formation of blood clots. It has been reported that traditional Chinese medicine, including Mailuoning injection, is advantageous for treating inflammatory and blood disorders. This research assessed the therapeutic efficacy of Mailuoning injection in the treatment of thrombophlebitis in rodents, as well as investigated its impact on fibrinolysis, inflammation, and coagulation. An experimental setup for thrombophlebitis was established in rodents via modified ligation technique. Five groups comprised the animals: sham operation group, model group, and three Mailuoning treatment groups (low, medium, and high dosages). The pain response, edema, coagulation parameters (PT, APTT, TT, FIB), serum inflammatory markers (IL-6, TNF-α, CRP), and expression levels of endothelial markers (ICAM-1, VCAM-1, NF-κB) were evaluated. Blood flow and vascular function were further assessed by measuring hemorheological parameters and the concentrations of TXB2, ET, and 6-k-PGF1α. In contrast to the sham group, model group demonstrated statistically significant increases in endothelial expression levels, coagulation latencies, and inflammatory markers (p < 0.05). The administration of mailing, specifically at high and medium dosages, resulted in a substantial reduction in inflammatory markers, enhancement of coagulation parameters, suppression of ICAM-1 and VCAM-1 expression, and restoration of hemorheological measurements to baseline (p < 0.05). Significantly higher concentrations of 6-k-PGF1α and lower levels of TXB2 and ET were observed in high-dose group, suggesting that pro- and anti-thrombotic factors were restored to equilibrium. Utilization of Mailuoning injection in rat model of thrombophlebitis exhibited significant therapeutic impact. This effect was manifested through pain alleviation, diminished inflammation, enhanced blood viscosity and facilitation of fibrinolysis. The study indicated that Mailuoning injection may serve as a viable therapeutic option for thrombophlebitis, potentially aiding in the improvement of wound healing by virtue of its anti-inflammatory and blood flow-enhancing characteristics.

China's public health initiatives for climate change adaptation.

China's health gains over the past decades face potential reversals if climate change adaptation is not prioritized. China's temperature rise surpasses the global average due to urban heat islands and ecological changes, and demands urgent actions to safeguard public health. Effective adaptation need to consider China's urbanization trends, underlying non-communicable diseases, an aging population, and future pandemic threats. Climate change adaptation initiatives and strategies include urban green space, healthy indoor environments, spatial planning for cities, advance location-specific early warning systems for extreme weather events, and a holistic approach for linking carbon neutrality to health co-benefits. Innovation and technology uptake is a crucial opportunity. China's successful climate adaptation can foster international collaboration regionally and beyond.

Guideline on Establishing Diagnostic Criteria for Chinese Medicine Syndromes.

AIM: To formulate the guideline for the development of diagnostic criteria for Chinese medicine syndromes, which can contribute to standardization of development of Chinese medicine syndrome diagnostic standards. METHODS: We embark into account on the development of Guideline on Establishing Diagnostic Criteria for Chinese Medicine Syndromes through Delphi method with reference to the existing technical system of diagnostic criteria for Chinese medicine syndromes and relevant criteria. RESULTS: Our guideline specifies principles, methods, and procedures for the formulation of diagnostic criteria for Chinese medicine syndromes. CONCLUSIONS: It is a comprehensive and systematic evidence-based guideline, and we hope this guideline can be applied as a reference in developing diagnostic criteria for Chinese medicine syndromes in other disciplines. It is also applicable to the formulation of diagnostic criteria for relevant clinical, educational, and scientific research by hospitals, institutes, and academies.

Further Refinement is Required for Patient-Reported Outcome Scales for Respiratory Diseases Based on Traditional Chinese Medicine Theory for Applicability.

Objective: To summarize the contents and assess the methodological quality and measurement properties of the patient-reported outcome (PRO) scales featured with Traditional Chinese Medicine (TCM) for respiratory diseases based on the guideline of COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN). Methods: PubMed, Web of Science, Embase, China National Knowledge Infrastructure (CNKI), Wanfang Data, VIP, and China Biology Medicine (CBM) were searched for studies on PRO scales featured with TCM for respiratory diseases from their inception until December 2022. The characteristics of the PRO scales were qualitatively summarized. Following the COSMIN guideline, the risk of bias was assessed according to the checklist, and different measurement properties (content validity, structural validity, internal consistency, reliability, criterion validity, and responsiveness) were evaluated. Finally, the evidence's overall quality was assessed, and the recommendation was formulated using the modified GRADE approach. Results: A total of 13 scales were included, with 6 for chronic obstructive pulmonary disease (COPD), 3 for lung cancer, 2 for idiopathic pulmonary fibrosis (IPF), 1 for community-acquired pneumonia (CAP), and 1 for bronchiectasis. All 13 scales are disease-specific scales and were developed based on Chinese cultural background to measure the efficacy of TCM. The study did not provide information on measurement error, cross-cultural validity, and hypothesis testing for the construct validity of these measures. No scale was rated as sufficient in content validity and responsiveness. Two scales showed sufficient structural validity, while 11 scales exhibited sufficient internal consistency. Three scales demonstrated sufficient reliability, and 7 scales showed sufficient criterion validity. All 13 scales have a recommendation level of B. Conclusion: The 13 scales could reflect the clinical efficacy of TCM and are suitable for the Chinese population. Nevertheless, the validation of these scales was not comprehensive enough, and the methodological quality of their studies needs to be further strengthened.

Exploring the Targets and Molecular Mechanisms of Thalidomide in the Treatment of Ulcerative Colitis: Network Pharmacology and Experimental Validation.

BACKGROUND: Ulcerative colitis (UC) is a chronic, nonspecific, inflammatory disease of the intestine with an unknown cause. Thalidomide (THA) has been shown to be an effective drug for the treatment of UC. However, the molecular targets and mechanism of action of THA for the treatment of UC are not yet clear. OBJECTIVES: Combining network pharmacology with in vitro experiments, this study aimed to investigate the potential targets and molecular mechanisms of THA for the treatment of UC. METHODS: Firstly, relevant targets of THA against UC were obtained from public databases. Then, the top 10 hub targets and key molecular mechanisms of THA for UC were screened based on the network pharmacology approach and bioinformatics method. Finally, an in vitro cellular inflammation model was constructed using lipopolysaccharide (LPS) induced intestinal epithelial cells (NCM460) to validate the top 10 hub targets and key signaling pathways. RESULTS: A total of 121 relevant targets of THA against UC were obtained, of which the top 10 hub targets were SRC, LCK, MAPK1, HSP90AA1, EGFR, HRAS, JAK2, RAC1, STAT1, and MAP2K1. The PI3K-Akt pathway was significantly associated with THA treatment of UC. In vitro experiments revealed that THA treatment reversed the expression of HSP90AA1, EGFR, STAT1, and JAK2 differential genes. THA was able to up- regulate the mRNA expression of pro-inflammatory factor IL-10 and decrease the mRNA levels of anti-inflammatory factors IL-6, IL-1ß, and TNF-α. Furthermore, THA also exerted anti-inflammatory effects by inhibiting the activation of the PI3K/Akt pathway. CONCLUSION: THA may play a therapeutic role in UC by inhibiting the PI3K-Akt pathway. HSP90AA1, EGFR, STAT1, and JAK2 may be the most relevant potential therapeutic targets for THA in the treatment of UC.

A Pharmacokinetic Study of Sixteen Major Bioactive Components of Jinshui-Huanxian Granules in Pulmonary Fibrosis Model and Control Rats Using Orbitrap Fusion Mass Spectrometry.

Jinshui-Huanxian granules (JHGs), a Chinese herbal compound prescription, have shown a therapeutic effect in reducing lung tissue damage, improving the degree of pulmonary fibrosis, replenishing lungs and kidneys, relieving cough and asthma, reducing phlegm, and activating blood circulation. However, these active compounds' pharmacokinetics and metabolic processes were unclear. This study aimed to compare the pharmacokinetics, reveal the metabolic dynamic changes, and obtain the basic pharmacokinetic parameters of 16 main bioactive compounds after intragastric administration of JHGs in control and pulmonary fibrosis (PF) model rats by using Orbitrap Fusion MS. After administration of JHGs, the rat plasma was collected at different times. Pretreating the plasma sample with methanol and internal standard (IS) solution carbamazepine (CBZ), and it was then applied to a C18 column by setting gradient elution with a mobile phase consisting of methanol 0.1% formic acid aqueous solution. Detection was performed on an electrospray ionization source (ESI), and the scanning mode was SIM. Pharmacokinetic parameters were analyzed according to the different analytes' concentrations in plasma. The matrix effect was within the range of 79.01-110.90%, the extraction recovery rate was 80.37-102.72%, the intra-day and inter-day precision relative standard deviation (RSD) was less than 7.76%, and the stability was good, which met the requirements of biological sample testing. The method was validated (r ≥ 0.9955) and applied to compare the pharmacokinetic profiles of the control group and PF model group after intragastric administration of the JHGs. The 16 analytes exhibited different pharmacokinetic behaviors in vivo. In the pathological state of the PF model, most of the components were more favorable for metabolism and absorption, and it was more meaningful to study the pharmacokinetics. Above all, this study provided an essential reference for exploring the mechanism of action of JHGs and guided clinical medication as well.

Differentiation in TCM patterns of chronic obstructive pulmonary disease by comprehensive metabolomic and lipidomic characterization.

Introduction: Chronic obstructive pulmonary disease (COPD) is a complex disease involving inflammation, cell senescence, and autoimmunity. Dialectical treatment for COPD with traditional Chinese medicine (TCM) has the advantage of fewer side effects, more effective suppression of inflammation, and improved immune function. However, the biological base of TCM pattern differentiation in COPD remains unclear. Methods: Liquid Chromatography-Quadrupole-Orbitrap mass spectrometry (LC-Q-Orbitrap MS/MS) based metabolomics and lipidomics were used to analyze the serum samples from COPD patients of three TCM patterns in Lung Qi Deficiency (n=65), Lung-Kidney Qi Deficiency (n=54), Lung-Spleen Qi Deficiency (n=52), and healthy subjects (n=41). Three cross-comparisons were performed to characterize metabolic markers for different TCM patterns of COPD vs healthy subjects. Results: We identified 28, 8, and 16 metabolites with differential abundance between three TCM patterns of COPD vs healthy subjects, respectively, the metabolic markers included cortisol, hypoxanthine, fatty acids, alkyl-/alkenyl-substituted phosphatidylethanolamine, and phosphatidylcholine, etc. Three panels of metabolic biomarkers specific to the above three TCM patterns yielded areas under the receiver operating characteristic curve of 0.992, 0.881, and 0.928, respectively, with sensitivity of 97.1%, 88.6%, and 91.4%, respectively, and specificity of 96.4%, 81.8%, and 83.9%, respectively. Discussion: Combining metabolomics and lipidomics can more comprehensively and accurately trace metabolic markers. As a result, the differences in metabolism were proven to underlie different TCM patterns of COPD, which provided evidence to aid our understanding of the biological basis of dialectical treatment, and can also serve as biomarkers for more accurate diagnosis.

Magnolol alleviates pulmonary fibrosis inchronic obstructive pulmonary disease by targeting transient receptor potential vanilloid 4-ankyrin repeat domain.

Transient receptor potential vanilloid 4 (TRPV4) plays a role in regulating pulmonary fibrosis (PF). While several TRPV4 antagonists including magnolol (MAG), have been discovered, the mechanism of action is not fully understood. This study aimed to investigate the effect of MAG on alleviating fibrosis in chronic obstructive pulmonary disease (COPD) based on TRPV4, and to further analyze its mechanism of action on TRPV4. COPD was induced using cigarette smoke and LPS. The therapeutic effect of MAG on COPD-induced fibrosis was evaluated. TRPV4 was identified as the main target protein of MAG using target protein capture with MAG probe and drug affinity response target stability assay. The binding sites of MAG at TRPV4 were analyzed using molecular docking and small molecule interaction with TRPV4-ankyrin repeat domain (ARD). The effects of MAG on TRPV4 membrane distribution and channel activity were analyzed by co-immunoprecipitation, fluorescence co-localization, and living cell assay of calcium levels. By targeting TRPV4-ARD, MAG disrupted the binding between phosphatidylinositol 3 kinase γ and TRPV4, leading to hampered membrane distribution on fibroblasts. Additionally, MAG competitively impaired ATP binding to TRPV4-ARD, inhibiting TRPV4 channel opening activity. MAG effectively blocked the fibrotic process caused by mechanical or inflammatory signals, thus alleviating PF in COPD. Targeting TRPV4-ARD presents a novel treatment strategy for PF in COPD.

Astragaloside IV targets PRDX6, inhibits the activation of RAC subunit in NADPH oxidase 2 for oxidative damage.

BACKGROUND: Radix Astragali Mongolici, as a traditional Chinese medicine, is widely used in the treatment of qi deficiency, viral or bacterial infection, inflammation and cancer. Astragaloside IV (AST), a key active compound in Radix Astragali Mongolici, has been shown to reduce disease progression by inhibiting oxidative stress and inflammation. However, the specific target and mechanism of action of AST in improving oxidative stress are still unclear. PURPOSE: This study aims to explore the target and mechanism of AST to improve oxidative stress, and to explain the biological process of oxidative stress. METHODS: AST functional probes were designed to capture target proteins and combined with protein spectrum to analyze target proteins. Small molecule and protein interaction technologies were used to verify the mode of action, while computer dynamics simulation technology was used to analyze the site of interaction with the target protein. The pharmacological activity of AST in improving oxidative stress was evaluated in a mouse model of acute lung injury induced by LPS. Additionally, pharmacological and serial molecular biological approaches were used to explore the underlying mechanism of action. RESULTS: AST inhibits PLA2 activity in PRDX6 by targeting the PLA2 catalytic triad pocket. This binding alters the conformation and structural stability of PRDX6 and interferes with the interaction between PRDX6 and RAC, hindering the activation of the RAC-GDI heterodimer. Inactivation of RAC prevents NOX2 maturation, attenuates superoxide anion production, and improves oxidative stress damage. CONCLUSION: The findings of this research indicate that AST impedes PLA2 activity by acting on the catalytic triad of PRDX6. This, in turn, disrupts the interaction between PRDX6 and RAC, thereby hindering the maturation of NOX2 and diminishing the oxidative stress damage.

[Characteristics of Soil Carbon, Nitrogen, Phosphorus, and Ecological Stoichiometry in Vegetable Fields and Orchard in the Coastal Area of Fuzhou].

The soil ecological stoichiometric characteristics of different agricultural land use types have a certain indicator function for characterizing the level of soil nutrient supply and are of great significance to the management of nutrient resources in farmland ecosystems. In order to reveal the soil carbon (C), nitrogen (N), and phosphorus (P) contents and their ecological stoichiometric characteristics in different vegetable fields and orchard agricultural land use types, this study took vegetable fields (taro field and jicama field) and orchards (citrus tree orchard, watermelon field, and pear tree orchard) as the research objects in the coastal area of Fuzhou City. The contents of soil C, N, and P and their ecological stoichiometric characteristics in different vegetable fields and orchard agricultural land uses were measured and analyzed. The soil C and N contents were in the order of orchard>vegetable field (P<0.05). The C content in the citrus tree orchard was the highest (4.44 g·kg-1), and the N content in the watermelon field was the highest (1.46 g·kg-1). The soil P content was vegetable field>orchard (P<0.05), and the jicama field had the highest P content (0.19 g·kg-1). The soil carbon and nitrogen ratio (C/N), carbon and phosphorus ratio (C/P), and nitrogen and phosphorus ratio (N/P) were orchard>vegetable field (P<0.05). Among them, the citrus tree orchard had the highest C/N (7.40) and C/P (61.43), and the watermelon field had the highest N/P (10.27). Soil N content was significantly and negatively correlated with bulk density and conductivity (r=-0.49, r=-0.28, P<0.05), and there was a significant and positive correlation with soil water content (r=0.61, P<0.05). C/P and C/N were significantly and positively correlated with SOM (r=0.71, r=0.64, P<0.01). In the process of crop planting and management in the coastal area of Fuzhou City, it is necessary to reasonably add nitrogen fertilizer to compensate for the N limitation, and slow-release nitrogen fertilizer is better for promoting the sustainable supply of nitrogen nutrients in the growth and development of crops.

The efficacy of traditional Chinese medicine in the treatment of the COVID-19 pandemic in Henan Province: a retrospective study.

BACKGROUND: Since 2020, novel coronavirus disease (COVID-19) has posed serious threats to health systems and led to tremendous economic decline worldwide. Traditional Chinese medicine (TCM) is considered a promising treatment strategy for COVID-19 in China and is increasingly recognized as a key participant in the battle against COVID-19. Clinicians also need accurate evidence regarding the effectiveness of TCM treatments for COVID-19. METHODS: We retrospectively analyzed patients diagnosed with COVID-19 by collected from the electronic medical records of the hospitals in Henan Province from January 19, 2020, to March 2, 2020. Demographic characteristics, clinical data, frequency analysis of Chinese patent medicines (CPMs), Chinese medicine injections (CMIs), evaluation of baseline symptom scores, nucleic acid negative conversion, length of hospitalization, and mortality rates were studied. RESULTS: Between 15 January 2020 and 2 March 2020, 131 hospitals with 1245 patients were included. Survey response Chinese herbal decoction, CPMs, and CMIs combined with conventional Western medicine (CWM) used for the treatment of COVID-19. The top 8 CPMs were Lianhua Qingwen capsules, Shuanghuanglian oral liquid, Pudilan Xiaoyan oral liquid, Banlangen granules, Lanqin oral liquid, compound licorice tablets, Bailing capsules, montmorillonite powder. The most frequently used CMIs were Xuebijing, Tanreqing, Reduning, Xiyanping and Yanhuning. TCM combined with CWM improved the patients' symptom scores for fever, cough, chest tightness, shortness of breath, and fatigue. Nucleic acid negative conversion occurred at11.55 ± 5.91 d and the average length of hospitalization was 14.92 ± 6.15 d. The mortality rate was approximately 1.76%, which is a reduction in patient mortality. CONCLUSIONS: TCM combined with CWM improved clinical symptoms and reduced hospitalization and mortality rates.

Impacts of microplastic-petroleum pollution on nutrient uptake, growth, and antioxidative activity of Chlorella vulgaris.

As one of the emerging pollutants, microplastics (MPs; <5 mm) can interact with co-contaminants such as petroleum in marine aquatic systems, and their combined toxicity has not been fully investigated. Therefore, this study focused on pollutants such as micro-sized polyethylene (mPE) and petroleum, aiming to explore their single and combined toxicities to microalga Chlorella vulgaris in terms of the cell growth, antioxidative enzymes, and nutrients utilization. The results showed that the MPs alone (particle sizes (i.e., 13, 165, 550 µm), concentrations (i.e., 0.01, 0.1, and 1 g/L), and aging degrees (i.e., aged for 0 d and 90 d under UVA)), and petroleum alone (5% water accommodated fraction, WAF), and their combinations (i.e., 5% WAF + 165 µm-0.1 g/L-aged 0 d mPE, 5% WAF + 165 µm-0.1 g/L-aged 90 d mPE) all posed toxicities risk to C. vulgaris, following an increase in oxidative stress. The cellular utilization of elements such as Fe, Si, Ca, and Mg was inhibited, whereas the uptake of Mn, NO3--N, and PO43--P increased as compared to the control experiments. Furthermore, the relationship between nutrients and growth indicators was analyzed using a structural equation model. The results indicated that Fe and Mn directly affected the indirect NO3--N absorption by C. vulgaris, which indirectly affected the dry cell weight (DCW) of the microalgae. The path coefficient of Fe and Mn affecting nitrate was 0.399 and 0.388, respectively. The absorption of N was the key step for C. vulgaris resist stress. This study provides a novel analysis of the effects of MPs on the growth of microalgae from the perspective of nutrient elements, thereby providing a useful basis for further exploration of the associated mechanisms.

Ligustilide attenuates airway remodeling in COPD mice by covalently binding to MH2 domain of Smad3 in pulmonary epithelium, disrupting the Smad3-SARA interaction.

Airway remodeling is one of the hallmarks of chronic obstructive pulmonary disease (COPD) and is closely related to the dysregulation of epithelial-mesenchymal transition (EMT). Smad3, an important transcriptional regulator responsible for transducing TGF-ß1 signals, is a promising target for EMT modulation. We found that ligustilide (Lig), a novel Smad3 covalent inhibitor, effectively inhibited airway remodeling in cigarette smoke (CS) combined with lipopolysaccharide (LPS)-induced COPD mice. Oral administration of an alkynyl-modified Lig probe was used to capture and trace target proteins in mouse lung tissue, revealing Smad3 in airway epithelium as a key target of Lig. Protein mass spectrometry and Smad3 mutation analysis via in-gel imaging indicated that the epoxidized metabolite of Lig covalently binds to the MH2 domain of Smad3 at Cys331/337. This irreversible bonding destroys the interaction of Smad3-SARA, prevents Smad3 phosphorylation activation, and subsequently suppresses the nuclear transfer of p-Smad3, the EMT process, and collagen deposition in TGF-ß1-stimulated BEAS-2B cells and COPD mice. These findings provide experimental support that Lig attenuates COPD by repressing airway remodeling which is attributed to its suppression on the activation of EMT process in the airway epithelium via targeting Smad3 and inhibiting the recruitment of the Smad3-SARA heterodimer in the TGF-ß1/Smad3 pathway.

Breathing Exercises in the Treatment of COPD: An Overview of Systematic Reviews.

Background: The effectiveness of breathing exercises in the treatment of chronic obstructive pulmonary disease (COPD) has been demonstrated in several systematic reviews (SRs), but a comprehensive review is still lacking. The aim of this study was to synthesize evidence from SRs, to summarise the effects of breathing exercises interventions for COPD patients. Methods: We conducted an overview of the SRs of breathing exercises in the treatment of COPD. We include Systematic Reviews of randomized-controlled clinical trials. In the included COPD, control of breathing exercises alone was the only variable and no restriction was placed on relevant outcome measures. The SRs were screened by computer retrieval from the Chinese National Knowledge Infrastructure (CNKI), WanFang database, Chinese Science and Technology Journal Database (CSTJ), Chinese Biological Medicine (CBM), MEDLINE (PubMed), Embase, Cochrane library, and Web of Science. The Risk of Bias in Systematic reviews (ROBIS) tool, the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) statement, a Measure Tool to Assess Systematic Reviews (AMSTAR) 2, and the Grades of Recommendations, Assessment, Development and Evaluation (GRADE) were used to evaluate the risk of bias, reporting quality, methodology quality, and evidence quality. Results: Nine SRs met the inclusion criteria and were included in the overview, 4 SRs in Chinese, and 3 SRs in English. All the SRs were published between 2015-2021. According to the ROBIS tool, 4 SRs (57.14%) were rated as low risk of bias. The PRISMA scale showed that 5 SRs had some defects, and 2 SRs were relatively complete. Reporting deficiencies exist primarily in protocol and registration (28.6%), search (42.9%), risk of bias across studies (0%), additional analyses (42.9%), and funding (28.6%). Based on the AMSTAR-2 scale, 3 SRs were low quality, and the other 4 SRs were very low. The result of evidence quality assessment showed that among the 34 outcomes involved in the 7 studies, 19 were low-level outcomes, 15 were very low-level outcomes, and there were no moderate and high-level quality outcomes. Limitations and publication bias were two major factors that reduced the quality of evidence. Conclusion: Breathing exercises in certain can improve pulmonary function, exercise endurance, dyspnea, quality of life, and respiratory muscle strength of COPD patients. However, there is an urgent need for high-quality studies to guide clinical practice due to certain deficiencies in reporting quality and the low quality of methodology and outcomes.

Efficacy and safety of traditional Chinese medicine treatment for idiopathic pulmonary fibrosis: An exploratory, randomized, double-blinded and placebo controlled trial.

Background and objective: Idiopathic pulmonary fibrosis (IPF) is a critical disease, with limited treatments available. Clinical practices show that traditional Chinese medicine (TCM) has certain efficacy. This study was preliminarily to evaluate the efficacy and safety of TCM treatment based on syndrome differentiation in IPF. Methods: A study design of exploratory, multi-centers, randomized, double-blinded, placebo controlled trial has been adopted. A total of 80 IPF patients from four sub-centers were enrolled. All the patients were randomly assigned into TCM group (TCMG) or control group (CG) in 1:1. Patients in TCMG were given CM granules, as patients in CG given with the placebo of CM granule. All the patients received a 26-week treatment. The efficacy was assessed by acute exacerbations (AEs) of IPF, pulmonary function, clinical symptoms, dyspnea scores (mMRC), health-related quality of life (HRQoL), 6-min walk test (6MWT) and all-cause mortality. Safety has also been assessed. Results: A total of 67 patients completed the trial with 35 in TCM group and 32 in control group. Meaningful differences have been observed in mean changes in AEs (-1.56 times; 95% CI, -2.69 to -0.43, p = 0.01), DLco% (5.29; 95% CI, 0.76 to 9.81, p = 0.02), cough scores (-0.38 points; 95% CI, -0.73 to -0.04, p = 0.03), and 6MWT (30.43 m; 95% CI, 2.85 to 58.00, p = 0.03), with no statistical differences in FEV1, FVC, expectoration, chest tightness, Shortness of breath, Fatigue, Cyanosis, mMRC, CAT, SF-36, and SGRQ total scores in 26 weeks after treatment than before treatment. At of the end of follow-up, a total of 10 patients died, including three and seven in the TCM and control group respectively. And the HR (Hazard ratio) for CM granules in all-cause mortality was 0.39 (95% CI, 0.10-1.52). The drug-related adverse events were not observed. Conclusion: CM granules, as compared with placebo, could reduce frequencies of AEs, improve pulmonary function, HRQoL, exercise capacity and symptoms and signs for IPF to some extent with acceptable side-effect.

Efficacy and safety of Jin-shui Huan-xian granule for idiopathic pulmonary fibrosis: study protocol for a multicenter, randomized, double-blind, placebo-controlled trial.

BACKGROUND AND RATIONALE: Idiopathic pulmonary fibrosis is a critical disease with a poor prognosis. Although different studies have been conducted for the treatment of idiopathic pulmonary fibrosis, limited treatments are available. Jin-shui Huan-xian granule (JHG), which is a Chinese medicine herbal compound, has shown promising efficacy in reducing frequencies of acute exacerbations, improving exercise capacity the quality of life of patients with idiopathic pulmonary fibrosis. This study is to evaluate the efficacy and safety of JHG for IPF. SUBJECTS AND METHODS: This is a multicenter, randomized, double-blind, placebo-controlled clinical trial. A total of 312 idiopathic pulmonary fibrosis patients will be enrolled and randomly allocated to one of the two groups with 1:1. After a 2-week washout period, 52-week treatment will also be performed for all the patients. Patients in the experimental group and the control group will be given JHG and JHG placebo, respectively. Outcome measures including acute exacerbations, pulmonary function, dyspnea, exercise capacity, and quality of life will be evaluated in this study. DISCUSSION: Based on our previous study, it is hypothesized that JHG will reduce acute exacerbations; improve exercise capacity, pulmonary function, and quality of life; and delay the disease progression-free. High-level evidence-based support for TCM in IPF will also be obtained in this study. TRIAL REGISTRATION: ClinicalTrials.gov NCT04187690. Register on December 11, 2019.

Elucidating the negatively influential and potentially toxic mechanism of single and combined micro-sized polyethylene and petroleum to Chlorella vulgaris at the cellular and molecular levels.

Although microplastics (MPs; <5 mm) may interact with co-contaminants (e.g., petroleum) in marine aquatic systems, little is known about their combined toxicity. Therefore, this study explored the toxicities and their mechanisms of micro-sized polyethylene (mPE) and their combination with petroleum to Chlorella vulgaris. The single MPs at various particle sizes, concentrations, and aging degree, single petroleum, and their combinations, were found to pose toxicities to C. vulgaris. This study also found the microcosm's microbial diversity changed. The microbial communities in the C. vulgaris biotopes were altered under exposure to mPE and petroleum, and were disturbed by external factors such as MPs particle size, concentration, aging time, and the combination with petroleum. Furthermore, as compared with the toxicity of petroleum on microalgal transcriptional function, mPE caused less toxic to C. vulgaris, and only impact the posttranslational modification, protein turnover, and signal transduction processes. Most importantly, mPE reduced petroleum toxicity in C. vulgaris via regulating the ABC transporter, eukaryotic ribosome synthesis, and the citrate cycle metabolic pathways. Overall, our findings could fundamentally provide insights into the joint ecotoxicological effects of MPs and petroleum, and highlight the potential risks of co-exsiting pollutants.