HAF prevents hepatocyte apoptosis and progression to MASH and hepatocellular carcinoma through transcriptional regulation of the NF-κB pathway.

BACKGROUND: HCC incidence is increasing worldwide due to the obesity epidemic, which drives metabolic dysfunction-associated steatohepatitis (MASH) that can lead to HCC. However, the molecular pathways driving MASH-HCC are poorly understood. We have previously reported that male mice with haploinsufficiency of hypoxia-associated factor, HAF (SART1+/-) spontaneously develop MASH-HCC. However, the cell type(s) responsible for HCC associated with HAF loss are unclear. RESULTS: We generated SART1-floxed mice, which were crossed with mice expressing Cre-recombinase within hepatocytes (Alb-Cre; hepS-/-) or myeloid cells (LysM-Cre, macS-/-). HepS-/- mice (both male and female) developed HCC associated with profound inflammatory and lipid dysregulation suggesting that HAF protects against HCC primarily within hepatocytes. HAF-deficient hepatocytes showed decreased P-p65 and P-p50 and in many components of the NF-κB pathway, which was recapitulated using HAF siRNA in vitro. HAF depletion also triggered apoptosis, suggesting that HAF protects against HCC by suppressing hepatocyte apoptosis. We show that HAF regulates NF-κB activity by regulating transcription of TRADD and RIPK1. Mice fed a high-fat diet (HFD) showed marked suppression of HAF, P-p65 and TRADD within their livers after 26 weeks, but showed profound upregulation of these proteins after 40 weeks, implicating deregulation of the HAF-NF-κB axis in the progression to MASH. In humans, HAF was significantly decreased in livers with simple steatosis but significantly increased in HCC compared with normal liver. CONCLUSIONS: HAF is novel transcriptional regulator of the NF-κB pathway and is a key determinant of cell fate during progression to MASH and MASH-HCC.

Strategy for Simple Control of High Performance PQ/PMMA Holographic Media.

Holographic data storage technology is a cost-effective solution for long-term archival data storage. However, the development of suitable holographic recording materials remains a challenge. Among these materials, phenanthraquinone-doped poly(methyl methacrylate) (PQ/PMMA) stands out due to its low cost and controllable thickness. Nevertheless, its limited photosensitivity and diffraction efficiency hinder its widespread application. In order to solve these problems, we put forward a kind of convenient and simple, low cost strategy, by adding plasticizer N,N-dimethylformamide (DMF) for preparation of DMF-PQ/PMMA photopolymer, avoid the use of complex compounds. The addition of DMF not only influences the thermal polymerization stage but also forms weak interactions with PQ during the photoreaction process, thereby enhancing the holographic performance of DMF-PQ/PMMA. Consequently, we achieved a remarkable 9.1-fold increase in photosensitivity (from ∼0.35 to 3.18 cm J-1), improved diffraction efficiency by 20% (from 65% to 80%), and reduced volume shrinkage by a factor of 8 (from 0.4% to 0.05%). Furthermore, utilizing a collinear holographic storage system with multiplexing shift at a scale of 5 µm resulted in an impressively low minimum bit error rate (BER) of only 0.36% (with an average BER of 1.4%), highlighting the fast processing capability and potential for low BER applications in holographic information storage using DMF-PQ/PMMA.

Correlations between blood vessel distribution, lung function and structural change in idiopathic pulmonary fibrosis.

BACKGROUND AND OBJECTIVE: Correlations between the image analysis of CT scan, lung function and quality of life in patients with idiopathic pulmonary fibrosis (IPF) remain unclear. This study aimed to investigate the impacts of pulmonary blood-vessel distribution and the extent of fibrosis on the lung function and quality of life of patients with IPF. METHODS: Patients were enrolled in an IPF registry and had completed pulmonary function tests, chest HRCT, St. George Respiratory Questionnaire (SGRQ) and echocardiography. Pulmonary blood-vessel distribution, specific image-derived airway volume (siVaw) and fibrosis extent (siVfib) were quantitatively calculated by functional respiratory imaging on HRCT. RESULTS: The study subjects were categorized into DLco <40% pred. (n = 40) and DLco ≥40% pred. (n = 19) groups. Patients with DLco <40% pred. had significantly higher scores of SGRQ, composite physiologic index (CPI), exercise oxygen desaturation (∆SpO2), siVaw, lower FVC% pred. and 6-minute walking distance% pred. The proportion of small blood vessels in the upper lobes (BV5PR-UL) was significantly correlated with CPI, DLco % Pred., FVC% pred., SGRQ and ∆SpO2. Only BV5PR-UL had a significant impact on all indices but not BV5PR in the lower lobes (BV5PR-LL). siVfib was significantly negatively correlated with BV5PR-UL, DLco% pred. and FVC% pred., as well as positively correlated with CPI, ∆SpO2 and siVaw. CONCLUSION: BV5PR-UL and siVfib had significant correlations with lung function and may become important indicators to assess the severity of IPF and the impact on quality of life.

Profiling Cell-Free DNA from Malignant Pleural Effusion for Oncogenic Driver Mutations in Patients with Treatment-Naive Stage IV Adenocarcinoma: A Multicenter Prospective Study.

INTRODUCTION: Comprehensive next-generation sequencing (NGS) of non-small-cell lung cancer specimens can identify oncogenic driver mutations and their corresponding targeted therapies. Plasma cell-free DNA (cfDNA) genotyping is easy to perform; however, false negatives cannot be overlooked. We explored malignant pleural effusion (MPE), a rich source of cfDNA, as a non-inferior alternative to tumor tissues for genotyping. METHODS: We conducted a prospective trial including 39 patients with newly diagnosed stage IV lung adenocarcinoma who presented with MPE. Tissue tests matching hotspot variants, including EGFR, ALK, and ROS1, were compared with the AlphaLiquid100 of PE-cfDNA. RESULTS: Among the 39 PE-cfDNA samples successfully sequenced, 32 (82.1%) had a PE cell-block tumor content of < 10%. Standard tissue or cell-block testing for EGFR, ALK, and ROS1 identified 20 mutations (51.3%), whereas PE cfDNA identified 25 mutations (64.1%). Five EGFR mutations were observed in PE cfDNA but not in Cobas EGFR owing to coverage or insufficient tumor content issues. The overall rate of oncogenic mutations identified in the PE cfDNA was 92.3%, and the mutation distribution was as follows: even with a very low cfDNA input, high detection rates could be achieved. Otherwise, most patients harbored co-mutations. Comparison of pleural fluid NGS with traditional testing revealed differences in accuracy. We also followed up with patients with EGFR-sensitizing mutations who had a treatment response rate of 97.2% after 3 months. CONCLUSIONS: Genotyping of MPE supernatant cfDNA is feasible in clinical practice, in addition to plasma and tumor testing, to improve diagnostic yield and extend patients' benefit from targeted therapies.

[Synergistic effect and compatibility structure of active anti-inflammatory ingredients from Lamiophlomis rotata based on network pharmacology and component structure theory].

The synergistic effect and compatibility structure of active anti-inflammatory ingredients(iridoid glycosides: shanzhiside methylester and 8-O-acetylshanzhiside methyl ester, flavonoid glycoside: luteoloside, and phenylethanoid glycoside: forsythoside B) from Lamiophlomis rotata were explored based on network pharmacology and component structure theory. In network pharmacology, CTD, SwisseTargetPrediction, and PharmMapper databases were used to collect and screen the targets of all active ingredients. The inflammation-related targets were obtained from CTD and GeneCards databases. The core targets were obtained by Venny 2.1.0, STRING, and Cytoscape 3.9.1. Core targets were annotated by the GO function and enriched by the KEGG pathway based on the DAVID database. In terms of component structure, based on a uniform design method and xylene-induced ear swelling model in mice, tumor necrosis factor-α and interleukin-6 were taken as the dependent variables, and the compatibility relationship among anti-inflammatory ingredients from L. rotata was explored through the quadratic polynomial stepwise regression. In addition, in vivo pharmacological experiments were conducted to verify the results. A network pharmacology study showed that compared with a single ingredient, the combined action of the three ingredients can synergistically exert anti-inflammatory effects through more biological processes, pathways, and targets. Component structure study showed that the optimal structural ratio of shanzhiside methylester and 8-O-acetylshanzhiside methyl ester in the iridoid glycoside ingredient was 1.21∶1. The optimal structural ratio among the three types of ingredients(iridoid glycosides∶phenylethanol glycoside∶flavonoid glycoside) was 4.8∶1.6∶1. In conclusion, each anti-inflammatory ingredient from L. rotata can work synergistically, and there is an optimal compatibility ratio relationship among these ingredients. This work provides a new experimental basis for the intrinsic quality control of L. rotata.

Nanoparticles of Cs0.33WO3 as Antibiofilm Agents and Photothermal Treatment to Inhibit Biofilm Formation.

Metal oxide nanoparticles with photothermal properties have attracted considerable research attention for their use in biomedical applications. Cesium tungsten oxide (Cs0.33WO3) nanoparticles (NPs) exhibit strong absorption in the NIR region due to localized surface plasmon resonance, through which they convert light to heat; hence, they can be applied to photothermal treatment for bacteria and biofilm ablation. Herein, Cs0.33WO3 NPs were synthesized through solid-phase synthesis, and their physical properties were characterized through Zetasizer, energy dispersive X-ray spectroscopy, Fourier transform infrared spectrometer, and scanning and transmission electron microscopy (SEM and TEM, respectively). Burkholderia cenocepacia isolates were cultured in tryptic soy broth supplemented with glucose, and the biofilm inhibition and antibiofilm effects of the NPs were determined using a crystal violet assay and the Cell Counting Kit-8 (CCK-8) assay. The biofilm morphology and viability of NP-treated cultures after NIR irradiation were evaluated through SEM and confocal microscopy, respectively. The cytotoxicity of NPs to human macrophages was also assessed using the CCK-8 assay. The NPs effectively inhibited biofilm formation, with a formation rate of <10% and a viability rate of <50% at the concentration of ≥200 µg/mL. The confocal analysis revealed that NIR irradiation markedly enhanced biofilm cytotoxicity after treatment with the NPs. The assay of cytotoxicity to human macrophages demonstrated the biocompatibility of the NPs and NIR irradiation. In sum, the Cs0.33WO3 NPs displayed effective biofilm inhibition and antibiofilm activity at 200 µg/mL treatment concentration; they exhibited an enhancement effect under the NIR irradiation, suggesting Cs0.33WO3 NPs are a potential candidate agent for NIR-irradiated photothermal treatment in bacterial biofilm inhibition and antibiofilm.

Correction: Chen et al. Bromelain Ameliorates Atherosclerosis by Activating the TFEB-Mediated Autophagy and Antioxidant Pathways. Antioxidants 2023, 12, 72.

In the original publication [...].

Sensitivity-Enhancing Modified Holographic Photopolymer of PQ/PMMA.

Phenanthrenequinone-doped poly(methyl methacrylate) (PQ/PMMA) photopolymers are potential holographic storage media owing to their high-density storage capacities, low costs, high stability, and negligible shrinkage in volume holographic permanent memory. However, because of the limitations of the substrate, conventional Plexiglas materials do not exhibit a good performance in terms of photosensitivity and molding. In this study, the crosslinked structure of PMMA was modified by introducing a dendrimer monomer, pentaerythritol tetraacrylate (PETA), which increases the photosensitivity of the material 2 times (from ~0.58 cm/J to ~1.18 cm/J), and the diffraction efficiency is increased 1.6 times (from ~50% to ~80%). In addition, the modified material has a superior ability to mold compared to conventional materials. Moreover, the holographic performance enhancement was evaluated in conjunction with a quantum chemical analysis. The doping of PETA resulted in an overall decrease in the energy required for the reaction system of the material, and the activation energy decreased by ~0.5 KJ/mol in the photoreaction stage.

Comparison of downsizing strategy (HANGZHOU Solution) and standard annulus sizing strategy in type 0 bicuspid aortic stenosis patients undergoing transcatheter aortic valve replacement: Rationale and design of a randomized clinical trial.

BACKGROUND: There has not been a consensus on the prothesis sizing strategy in type 0 bicuspid aortic stenosis (AS) patients undergoing transcatheter aortic valve replacement (TAVR). Modifications to standard annular sizing strategies might be required due to the distinct anatomical characteristics. We have devised a downsizing strategy for TAVR using a self-expanding valve specifically for patients with type 0 bicuspid AS. The primary aim of this study is to compare the safety and efficacy of downsizing strategy with the Standard Annulus Sizing Strategy in TAVR for patients with type 0 bicuspid AS. TRIAL DESIGN: It is a prospective, multi-center, superiority, single-blinded, randomized controlled trial comparing the Down Sizing and Standard Annulus Sizing Strategy in patients with type 0 bicuspid aortic stenosis undergoing transcatheter aortic valve replacement. Eligible participants will include patients with severe type 0 bicuspid AS, as defined by criteria such as mean gradient across aortic valve ≥40 mmHg, peak aortic jet velocity ≥4.0 m/s, aortic valve area (AVA) ≤1.0 cm², or AVA index ≤0.6 cm2/m2. These patients will be randomly assigned, in a 1:1 ratio, to either the Down Sizing Strategy group or the Standard Sizing Strategy group. In the Down Sizing Strategy group, a valve one size smaller will be implanted if the "waist sign" manifests along with less than mild regurgitation during balloon pre-dilatation. The primary end point of the study is a composite of VARC-3 defined device success, absence of both permanent pacemaker implantation due to high-degree atrioventricular block and new-onset complete left bundle branch block. CONCLUSION: This study will compare the safety and efficacy of Down Sizing Strategy with the Standard Annulus Sizing Strategy and provide valuable insights into the optimal approach for sizing in TAVR patients with type 0 bicuspid AS. We hypothesize that the Down Sizing Strategy will demonstrate superiority when compared to the Standard Annulus Sizing Strategy. (Down Sizing Strategy (HANGZHOU Solution) vs Standard Sizing Strategy TAVR in Bicuspid Aortic Stenosis (Type 0) (TAILOR-TAVR), NCT05511792).

Single-cell multiomics guided mechanistic understanding of Fontan-associated liver disease.

The Fontan operation is the current standard of care for single-ventricle congenital heart disease. Individuals with a Fontan circulation (FC) exhibit central venous hypertension and face life-threatening complications of hepatic fibrosis, known as Fontan-associated liver disease (FALD). The fundamental biology and mechanisms of FALD are little understood. Here, we generated a transcriptomic and epigenomic atlas of human FALD at single-cell resolution using multiomic snRNA-ATAC-seq. We found profound cell type-specific transcriptomic and epigenomic changes in FC livers. Central hepatocytes (cHep) exhibited the most substantial changes, featuring profound metabolic reprogramming. These cHep changes preceded substantial activation of hepatic stellate cells and liver fibrosis, suggesting cHep as a potential first "responder" in the pathogenesis of FALD. We also identified a network of ligand-receptor pairs that transmit signals from cHep to hepatic stellate cells, which may promote their activation and liver fibrosis. We further experimentally demonstrated that activins A and B promote fibrotic activation in vitro and identified mechanisms of activin A's transcriptional activation in FALD. Together, our single-cell transcriptomic and epigenomic atlas revealed mechanistic insights into the pathogenesis of FALD and may aid identification of potential therapeutic targets.

Huang Qin decoction increases SLC6A4 expression and blocks the NFκB-mediated NLRP3/Caspase1/GSDMD pathway to disrupt colitis-associated carcinogenesis.

Huang Qin decoction (HQD) is a traditional Chinese medicine formula for treating colitis, but the effects and molecular mechanism of action of HQD in colitis-associated carcinogenesis (CAC) are still unclear. Therefore, we aimed to determine the beneficial effects of HQD on CAC in mice and to reveal the underlying mechanism involved. AOM/DSS was used to induce CAC in mice, and the effects of HQD on tumorigenesis in mice were examined (with mesalazine serving as a positive control). Mesalazine or HQD treatment alleviated body weight loss and decreased the disease activity index in mice induced by AOM/DSS. Mesalazine or HQD treatment also suppressed the shortening of colon tissue length, the number of tumors, and the infiltration of inflammatory cells. The genes targeted by HQD were predicted and verified, followed by knockout experiments. Elevated SLC6A4 and inhibited serotonin production and inflammation were observed in HQD-treated mice. HQD inhibited the NFκB and NLRP3/caspase1/GSDMD pathways. The therapeutic effect of HQD was diminished in SLC6A4-deficient AOM/DSS mice. Additionally, the downregulation of SLC6A4 mitigated the inhibitory effect of HQD-containing serum on MODE-K cell pyroptosis. Our findings suggest that SLC6A4 is a pivotal regulator of HQD-alleviated CAC via its modulation of the NLRP3/caspase1/GSDMD pathway.

Apigenin targets fetuin-A to ameliorate obesity-induced insulin resistance.

Fetuin-A, a hepatokine secreted by hepatocytes, binds to insulin receptors and consequently impairs the activation of the insulin signaling pathway, leading to insulin resistance. Apigenin, a flavonoid isolated from plants, has beneficial effects on insulin resistance; however, its regulatory mechanisms are not fully understood. In the present study, we investigated the molecular mechanisms underlying the protective effects of apigenin on insulin resistance. In Huh7 cells, treatment with apigenin decreased the mRNA expression of fetuin-A by decreasing reactive oxygen species-mediated casein kinase 2α (CK2α)-nuclear factor kappa-light-chain-enhancer of activated B activation; besides, apigenin decreased the levels of CK2α-dependent fetuin-A phosphorylation and thus promoted fetuin-A degradation through the autophagic pathway, resulting in a decrease in the protein levels of fetuin-A. Moreover, apigenin prevented the formation of the fetuin-A-insulin receptor (IR) complex and thereby rescued the PA-induced impairment of the insulin signaling pathway, as evidenced by increased phosphorylation of IR substrate-1 and Akt, and translocation of glucose transporter 2 from the cytosol to the plasma membrane. Similar results were observed in the liver of HFD-fed mice treated with apigenin. Collectively, our findings revealed that apigenin ameliorates obesity-induced insulin resistance in the liver by targeting fetuin-A.

An investigation into the HIF-dependent intestinal barrier protective mechanism of Qingchang Wenzhong decoction in ulcerative colitis management.

ETHNOPHARMACOLOGICAL RELEVANCE: Ulcerative colitis (UC) is a chronic, non-specific inflammatory disease affecting the colon and rectum with an etiology that remains elusive. Traditional Chinese medicine (TCM) has been widely used on long-term UC treatment to better maintain the efficacy than traditional aminosalicylic acid or glucocorticosteroids and to ease financial burden of patients. Qingchang Wenzhong Decoction (QCWZD) is a modern TCM decoction with established clinical efficacy but the mechanism of its protection on intestinal barrier function remains unclear. AIM OF THE STUDY: Current findings highlight that the activation of the hypoxia inducible factor (HIF) pathway can facilitate the repair of intestinal epithelium barrier. This study is to investigate the protective effects of QCWZD and its HIF-targeted ingredients on hypoxia-dependent intestinal barrier. METHODS: The mice model of UC was induced by dextran sulfate sodium (DSS). Disease activity index (DAI) and histopathology scores and colon length were used to measure the severity of colitis. The DAO activity in serum and protein expression of tight junction (TJ) proteins were detected to explore the function of intestinal barrier. The protein levels of HIF-1α and its downstream gene heme oxygenase-1 (HO-1) were measured as well. HIF-targeted active ingredients in QCWZD were selected by network pharmacology and molecular docking. Protective effects of six constituents on HIF-related anti-oxidative and barrier protective pathway were evaluated by lipopolysaccharide (LPS)-induced HT29 and RAW264.7 cells, through the measurement of the production of ROS and mRNA level of pro-inflammatory cytokines. HIF-1α knockdown was carried out to explore the correlation of protection effects with HIF-related pathway of the active ingredients. RESULTS: QCWZD effectively alleviated colitis induced by DSS and demonstrated a protective effect on intestinal barrier function by upregulating HIF-related pathways. Six specific ingredients in QCWZD, targeting HIF, successfully reduced the production of cellular ROS and proinflammatory cytokines in LPS-induced cells. It is noteworthy that the barrier protection provided by these molecules is intricately linked with the HIF-related pathway. CONCLUSIONS: This study elucidates the HIF-related molecular mechanism of QCWZD in protecting the function of the epithelial barrier. Six compounds targeting the activation of the HIF-dependent pathway were demonstrated to unveil a novel therapeutic approach for managing UC.

Study on CO source identification and spontaneous combustion warning concentration in the return corner of working face in shallow buried coal seam.

Coal spontaneous combustion is a common problem faced by many coal mines. Spontaneous combustion in goaf releases a large amount of harmful gases, polluting the environment while causing a large amount of wasted resources, and even endangering the lives of workers. Due to the collapse of the interior of the mining area, it is impossible to measure the internal gas composition directly. In order to more accurately predict the spontaneous combustion state inside the mining airspace, this paper obtains the CO generation law and the main source of the working face through the combination of laboratory experiments and on-site monitoring. The CO concentration prediction model of the return corner is established with CO as the index gas. Finally, the safe concentration and warning concentration of the working face are calculated according to the example, which provides theoretical basis for the prediction of spontaneous combustion of coal.

Highly sensitive and repeatable recording photopolymer for holographic data storage containing N-methylpyrrolidone.

The low photosensitivity of phenanthraquinone-doped poly(methyl methacrylate) (PQ/PMMA) severely limits its recording speed for holographic data storage. A high-performance holographic recording medium based on a unique combination of N-methylpyrrolidone (NMP) regulated PQ/PMMA has been developed. A NMP-PQ/PMMA photopolymer with high sensitivity, high diffraction efficiency and negligible volume shrinkage was successfully fabricated by tuning the composition of the PMMA matrix by varying the ratio of NMP to monomers. The photosensitivity is increased by 6.9 times (from 0.27 cm J-1 to 1.86 cm J-1), the diffraction efficiency is increased from 60% to > 80%, and volume shrinkage is decreased by a factor of 2 (from 0.4% to 0.2%). Further investigation revealed that the addition of NMP significantly reduced the molecular weight of PMMA and increased the amount of MMA residuals, while also improving the solubility of PQ molecules. More interestingly, for the first time, the NMP-PQ/PMMA material could record data information repeatedly at least 6 times. The present study elucidates that the introduction of NMP not only modulates the molecular weight of PMMA but also enables the residual monomer MMA to more easily combine with PQ to form a photoproduct for improved holographic performance.

Daily Physical Activity Measured by Wearable Smartwatch for Patients Undergoing Transcatheter Aortic Valve Replacement: Insights From the SMART TAVR Study.

BACKGROUND: This study aims to evaluate limited data about daily physical activity patterns, influential factors, and their association with 1-year mortality or rehospitalization after transcatheter aortic valve replacement (TAVR) through smartwatches. METHODS: Consecutive severe aortic stenosis patients undergoing elective transfemoral TAVR in a Chinese tertiary hospital were enrolled from July 2021 to May 2022 and received a Huawei smartwatch at least 1 day before TAVR. The primary outcome was a composite of all-cause mortality or hospital readmission within 1 year. Linear mixed-effects models were applied to determine influential factors of daily step counts, and Cox proportional hazard regression models were to estimate the association between baseline step counts within 1 month since discharge and composite outcome from months 2 to 12. The dose-response association was assessed using restricted cubic spline curves. RESULTS: A total of 222 participants and 59 469 valid monitoring person-day records were included (mean age, 72.7 years; 61% women). Step counts increased rapidly within the first 2 months (P<0.001), followed by a slower increase for those without composite outcomes (P=0.029) and a gradual decrease for those who developed composite outcomes (P<0.001). In multivariate linear mixed models, a 1-m increase in baseline 6-minute walk test and a 1-month delay after discharge were associated with 4 (95% CI, 1-7) and 170 (95% CI, 145-194) additional step counts, respectively. In restricted cubic spline analysis, the hazard ratio declined progressively until ≈5000 steps per day, after which they leveled. Below 5000 steps, the adjusted hazard ratio of composite outcome associated with each 1000-step count increase was 0.67 (0.50-0.89; P=0.007). However, above 5000 steps, step counts were not significantly associated with the composite outcome (P=0.645), with a hazard ratio of 1.12 (0.70-1.79). CONCLUSIONS: Daily step counts rapidly increased within the first 2 months post-TAVR. Increased physical activity was associated with a lower risk of 1-year mortality or rehospitalization after TAVR for patients with daily step counts below 5000. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04454177.

Molecular mechanisms of Chengshi Beixie Fenqing Decoction based on network pharmacology: pivotal roles of relaxin signaling pathway and its associated target proteins against Benign prostatic hyperplasia.

Benign prostatic hyperplasia (BPH) is a common disease that affects the quality of life of middle-aged and older men. We investigated the therapeutical effects of Chengshi Beixie Fenqing Decoction (CBFD), a classic traditional Chinese medicine prescription, on BPH through in vivo model and network pharmacology. Bioactives in CBFD were detected through UPLC-Q-Tof-MS/MS and GC-MS, and filtered by the modified Lipinski's rule. Target proteins associated with the filtered compounds and BPH are selected from public databases. Venn diagram identified the overlapping target proteins between the bioactives-interacted target proteins and the BPH-targeted proteins. The bioactive-protein interactive networking of BPH was analyzed through the KEGG pathway on STRING to identify potential ligand-target and visualized the rich factors on the R packet. After that, the molecular docking test (MDT) was performed between bioactives and target proteins. It showed that the mechanism of CBFD against BPH was related to 104 signaling pathways of 42 compounds. AKT1, 6-demethyl-4'-methyl-N-methylcoclaurine and relaxin signaling pathways were selected as a hub target, key bioactivitie and hub signaling pathway, respectively. In addition, three major compounds, 6-demethyl-4'-methyl-N-methylcoclaurine, isoliensinine and liensinine, had the highest affinity on MDT for the three crucial target proteins, AKT1, JUN and MAPK1. These proteins were associated with the relaxin signaling pathway, which regulated the level of nitric oxide and is implicated in both BPH development and CBFD. We concluded that the three key bioactivities found in Plumula nelumbinis of CBFD may contribute to improving BPH condition by activating the relaxin signaling pathways.Communicated by Ramaswamy H. Sarma.

Real world experience on the effectiveness and safety of pirfenidone in patients with idiopathic pulmonary fibrosis in Taiwan.

Introduction: Randomized controlled trials have demonstrated a reduction in the decline of lung function and a reduced risk of acute exacerbation in patients with idiopathic pulmonary fibrosis treated with the antifibrotic prifenidone. The present study aimed to investigate the real-world effectiveness and safety profile of pirfenidone treatment for patients with IPF in Taiwan. Methods: Between January 1, 2019 and December 31, 2020, we enrolled 50 patients who were newly diagnosed with IPF and had at least 12 months follow-up period after pirfenidone administration. Result: The primary outcome of pharmacologic effect showed that the mean differences in the absolute values of forced vital capacity from baseline were 0.2 liter (n = 36), 0.13 liter (n = 32), 0.04 liter (n = 26), and - 0.004 liter (n = 26) after 3, 6, 9, and 12 months of administration, respectively. A slight improvement in quality of life, including scores of chronic obstructive pulmonary disease assessment test and St. George's respiratory questionnaire scores. The most common adverse effects were gastrointestinal upset and dermatological problems. No new safety concerns were observed in the present study. Conclusion: Our real-world study describe for the first time in Taiwan, the use of pirfenidone over a 12 months period. This drug preserves the lung function and improves quality of life with tolerable side effects.

Angiotensin-(1-7) attenuates SARS-CoV2 spike protein-induced interleukin-6 and interleukin-8 production in alveolar epithelial cells through activation of Mas receptor.

BACKGROUND: SARS-CoV-2 spike proteins (SP) can bind to the human angiotensin-converting enzyme 2 (ACE2) in human pulmonary alveolar epithelial cells (HPAEpiC) and trigger an inflammatory process. Angiotensin-(1-7) may have an anti-inflammatory effect through activation of Mas receptor. This study aims to investigate whether SARS-CoV-2 SP can induce inflammation through ACE2 in the alveolar epithelial cells which can be modulated through angiotensin-(1-7)/Mas receptor axis. METHODS: HPAEpiC were treated with SARS-CoV-2 SP in the presence or absence of ACE2 antagonist-dalbavancin and Mas receptor agonist-angiotensin-(1-7). Proinflammatory cytokine production (IL-6 and IL-8) were measured at mRNA and protein levels. MAP kinase phosphorylation and transcription factor activation was determined by Western Blot. Mas receptor was blocked by either antagonist (A779) or knockdown (specific SiRNA). Experiments were replicated using A549 cells. FINDINGS: SARS-CoV-2 SP (5 µg/mL) significantly induced MAP kinase (ERK1/2) phosphorylation, downstream transcription factor (activator protein-1, AP-1) activation and cytokine production (IL-6 and IL-8) at both mRNA and protein levels. Pretreatment with dalbavancin (10 µg/mL), or angiotensin-(1-7) (10 µM) significantly reduced ERK1/2 phosphorylation, AP-1 activation, and cytokine production. However, these angiotensin-(1-7)-related protective effects were significantly abolished by blocking Mas receptor with either antagonist (A799,10 µM) or SiRNA knockdown. INTERPRETATION: SARS-CoV-2 SP can induce proinflammatory cytokine production, which can be inhibited by either ACE2 antagonist or Mas receptor agonist-angiotensin-(1-7). Angiotensin-(1-7)-related protective effect on cytokine reduction can be abolished by blocking Mas receptor. Our findings suggest that ACE2/angiotensin-(1-7)/Mas axis may serve as a therapeutic target to control inflammatory response triggered by SARS-CoV-2 SP.