Predictive Value of Smoking Index Combined with NT-proBNP for Patients with Pulmonary Hypertension Due to Chronic Lung Disease: A Retrospective Study.

Purpose: Smoking is a major risk factor for the group 3 PH. NT-proBNP is a biomarker for risk stratification in PH. This study aims to investigate the effects of smoking status and smoking index (SI) on group 3 PH and to evaluate the value of SI and SI combined with NT-proBNP in early diagnosis and prediction of disease severity. Patients and Methods: Four hundred patients with group 3 PH at the First Hospital of Shanxi Medical University between January 2020 and December 2021 were enrolled and divided into two groups: mild (30 mmHg ≤ pulmonary artery systolic pressure (PASP)≤50 mmHg) and non-mild (PASP >50 mmHg). The effect of smoking on group 3 PH was analyzed using univariate analysis, and logistic analysis was conducted to evaluate the risk of group 3 PH according to smoking status and SI. Spearman correlation coefficient was used to test the correlation between SI and the index of group 3 PH severity. The predictive value of SI was evaluated using a receiver operating characteristic (ROC) curve. Results: Correlation and logistic analyses showed that SI was associated with PH severity. Smoking status (P=0.009) and SI (P=0.039) were independent risk factors for non-mild group 3 PH, and ROC showed that the predictive value of SI (AUC:0.596) for non-mild PH was better than that of the recognized pro-brain natriuretic peptide (NT-proBNP) (AUC:0.586). SI can be used as a single predictive marker. SI and NT-proBNP can be formulated as prediction models for screening non-mild clinical cases (AUC:0.628). Conclusion: SI is a potentially ideal non-invasive predictive marker for group 3 PH. SI and NT-proBNP could be used to develop a prediction model for screening non-mild PH cases. This can greatly improve the predictive specificity of the established PH marker, NT-proBNP.

Effective lung nodule detection using deep CNN with dual attention mechanisms.

Novel methods are required to enhance lung cancer detection, which has overtaken other cancer-related causes of death as the major cause of cancer-related mortality. Radiologists have long-standing methods for locating lung nodules in patients with lung cancer, such as computed tomography (CT) scans. Radiologists must manually review a significant amount of CT scan pictures, which makes the process time-consuming and prone to human error. Computer-aided diagnosis (CAD) systems have been created to help radiologists with their evaluations in order to overcome these difficulties. These systems make use of cutting-edge deep learning architectures. These CAD systems are designed to improve lung nodule diagnosis efficiency and accuracy. In this study, a bespoke convolutional neural network (CNN) with a dual attention mechanism was created, which was especially crafted to concentrate on the most important elements in images of lung nodules. The CNN model extracts informative features from the images, while the attention module incorporates both channel attention and spatial attention mechanisms to selectively highlight significant features. After the attention module, global average pooling is applied to summarize the spatial information. To evaluate the performance of the proposed model, extensive experiments were conducted using benchmark dataset of lung nodules. The results of these experiments demonstrated that our model surpasses recent models and achieves state-of-the-art accuracy in lung nodule detection and classification tasks.

Chinese expert consensus on cone-beam CT-guided diagnosis, localization and treatment for pulmonary nodules.

Cone-beam computed tomography (CBCT) system can provide real-time 3D images and fluoroscopy images of the region of interest during the operation. Some systems can even offer augmented fluoroscopy and puncture guidance. The use of CBCT for interventional pulmonary procedures has grown significantly in recent years, and numerous clinical studies have confirmed the technology's efficacy and safety in the diagnosis, localization, and treatment of pulmonary nodules. In order to optimize and standardize the technical specifications of CBCT and guide its application in clinical practice, the consensus statement has been organized and written in a collaborative effort by the Professional Committee on Interventional Pulmonology of China Association for Promotion of Health Science and Technology.

Genetic association analysis of dietary intake and idiopathic pulmonary fibrosis: a two-sample mendelian randomization study.

BACKGROUND: IPF is a complex lung disease whose aetiology is not fully understood, but diet may have an impact on its development and progression. Therefore, we investigated the potential causal connection between dietary intake and IPF through TSMR to offer insights for early disease prevention recommendations. METHODS: The study incorporated 29 dietary exposure factors, oily fish intake, bacon intake, processed meat intake, poultry intake, beef intake, pork intake, lamb/mutton intake, non-oily fish intake, fresh fruit intake, cooked vegetable intake, baked bean intake, fresh tomato intake, tinned tomato intake, salad/raw vegetable intake, Fresh fruit intake, coffee intake, tea intake, water intake, red wine intake, average weekly beer plus cider intake, alcoholic drinks per week, cereal intake, bread intake, whole-wheat intake, whole-wheat cereal intake, cheese intake, yogurt intake, salt added to food and whole egg intake. The study explored the causal link between diet and IPF using TSMR analysis, predominantly the IVW method, and performed sensitivity analyses to validate the results. RESULT: The study revealed that consuming oily fish, yogurt, and dried fruits had a protective effect against IPF, whereas the consumption of alcoholic beverages and beef was linked to an increased risk of IPF. CONCLUSION: In this MR study, it was discovered that the consumption of oily fish, yogurt, and dried fruits exhibited a protective effect against IPF, whereas the intake of alcoholic beverages and beef was associated with an elevated risk of IPF. These findings underscore the significance of making informed and timely dietary decisions in IPF prevention.

APOBEC3A suppresses cervical cancer via apoptosis.

Background: Family members of Apolipoprotein B mRNA-editing enzyme catalytic 3 (APOBEC3) play critical roles in cancer evolution and development. However, the role of APOBEC3A in cervical cancer remains to be clarified. Methods: We used bioinformatics to investigate APOBEC3A expression and outcomes using The Cancer Genome Atlas (TCGA)-cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC) dataset, GTEx, and GSE7803. Immunohistochemistry was then used to identify APOBEC3A's expression pattern. We performed Cell Counting Kit-8, wound-healing, Transwell, and flow cytometry assays to measure proliferation, migration, invasion, and apoptosis, respectively, using the SiHa and HeLa cell lines transfected with APOBEC3A. BALB/c nude mice were used to investigate the effects of APOBEC3A in vivo. The phosphorylated gamma-H2AX staining assay was applied to measure DNA damage. RNA sequencing (RNA-Seq) was applied to explore APOBEC3A-related signaling pathways. Results: APOBEC3A was more significantly expressed in cancer tissues than in adjacent normal tissues. Higher expression of APOBEC3A was associated with better outcomes in TCGA-CESC and GTEx. Immunohistochemistry showed that the expression of APOBEC3A was significantly higher in cancer tissues than in normal tissues. Transfection experiments showed that APOBEC3A inhibited proliferation, upregulated S-phase cells, inhibited migration and invasion, induced DNA damage, and promoted apoptosis. Overexpression of APOBEC3A inhibited tumor formation in the mouse model. RNA-seq analysis showed that ectopic expression of APOBEC3A inhibited several cancer-associated signaling pathways. Conclusions: APOBEC3A is significantly upregulated in cervical cancer, and higher expression of APOBEC3A is associated with better outcomes. APOBEC3A is a tumor suppressor whose overexpression induces apoptosis in cervical cancer.

Design of flexible hollow core fiber based photoacoustic gas sensor with high cell constant and compact size.

Here we designed, optimized, and proposed a flexible low frequency resonant photoacoustic (PA) gas sensor by using a large core leaky hollow core fiber (L-HCF). The influences from the dimensions, the transmission loss and the bending loss on the performance of the flexible PA gas sensor were systematically investigated. In this work, the optimized inner diameter and length of the L-HCF were 1.7 mm and 300 mm, respectively. The L-HCF based PA cell constant was calculated to be 12115 Pa/(W·cm-1). The minimum detectable limit (MDL) for trace C2H2 detection achieved 23.0 ppb when the lock-in integration time was 200 s by using a near-infrared distributed feedback (DFB) laser source and a low-cost electrical micro-electro-mechanical system (MEMS) microphone. Besides, the amplitude decay ratio of the of the PA signal was only 11.3% when the bending radius of the L-HCF was 100 mm. The normalized noise equivalent absorption (NNEA) coefficient is calculated to be 6.6 × 10-9 W•cm-1•Hz-1/2. The L-HCF based PA cell was proved to own merits of compact size, high cell constant, small gas volume and low cost.

Flexible Hollow Core Fiber Photoacoustic Gas Sensor Based on Embedded Acoustic Resonant Structure.

In this paper, we demonstrate a flexible leaky hollow core fiber (LHCF) photoacoustic (PA) gas sensor based on an embedded acoustic resonant structure. The sensor employs a part of a gas conduit as the buffer chamber to construct an equivalent T-type half-open PA cell. The LHCF is installed inside of the gas conduit and the LHCF is hence replaceable. Also, the flexibility of the LHCF and the gas conduit make the gas sensor flexible to reduce spatial size. The inner diameter and length of the LHCF are 1.6 mm and 70 mm, respectively. The inner diameter and length of the gas conduit are 4 mm and 210 mm, respectively. The total gas volume of the sensor is only ∼2.6 mL. Trace acetylene (C2H2) is selected as the target gas to evaluate the performance of the PA gas sensor. A near-infrared distributed feedback (DFB) laser is utilized to generate the PA signal, and an electrical micro-electro-mechanical system (MEMS) microphone is employed to extract the PA signal. The experimental results show that the minimum detection limit (MDL) can be as low as 21.1 ppb when the lock-in integration time is 200 s. And the normalized noise equivalent absorption coefficient (NNEA) is calculated to be 5.7 × 10-9·W/cm-1·Hz-1/2.

Highly sensitive photoacoustic gas sensor with micro-embedded acoustic resonator for gas leakage detection.

In this work, a photoacoustic (PA) gas sensor with a micro-embedded acoustic resonator for gas leakage detection was demonstrated. The micro-embedded acoustic resonator was fabricated by putting a leaky hollow-core fiber (L-HCF) into a cylindrical buffer chamber. The L-HCF was utilized as the PA cavity and the light transmission media simultaneously. The optimal inner diameter of the L-HCF was 1.7 mm. The embedded acoustic resonator was experimentally proven to be equivalent to a T-type half-open acoustic resonator, but the structure became much more compact. The volume of the amount of gas in the cell was only ∼0.3 mL, and the gas diffusion time to fill the sensor under room temperature (25°C) and ambient pressure (101 kPa) was ∼44 s. Trace acetylene (C2H2) in pure nitrogen (N2) was chosen as the target gas, and the minimum detectable limit (MDL) reached 29 ppb when the lock-in integration time was 1 s. The normalized noise equivalent absorption (NNEA) coefficient was calculated to be 3.0 × 10-9 W·cm-1·Hz-1/2. The micro-resonant PA gas sensor, with merits of compactness, low gas consumption, and low cost, has the potential to be a remote gas sensing scheme in fields of environmental protection, industrial process monitoring, and so on.

Low-frequency Resonant Photoacoustic Gas Sensor by Employing Hollow Core Fiber-Based O-Shaped Multipass Cells.

A low-frequency flexible resonant photoacoustic (PA) gas sensor using an O-shaped multipass cell is demonstrated. The PA sensor employed a flexible gradually tapered leaky hollow core fiber (LHCF). The LHCF was bent to be an end-to-end structure to make full use of the incident light. Additionally, the two ends of the LHCF were put inside a single buffer chamber, yielding an equivalent H-type acoustic resonator. The geometric size was reduced thanks to the bending structure. The geometric length of the LHCF was 500 mm. A micro-electro-mechanical-systems electrical microphone was installed at the center of the resonant tube to detect the PA signal. The proposed PA gas sensor exhibited a first-order longitudinal resonance frequency of 408 Hz. Trace acetylene (C2H2) was used as the target gas. The minimum detectable limit was calculated to be 25.8 parts-per-billion (ppb) with an average time of 400 s, which was 1.93 times higher than that of a single-pass PA gas sensor. The normalized noise-equivalent absorption coefficient and the PA cell constant were calculated to be 9.6 × 10-9 W·cm-1·Hz-1/2 and 8295 Pa/W·cm-1, respectively. The PA gas sensor owns a low resonance frequency and can be used for detection of most of the polar gaseous molecules, especially suitable for gas molecules with a long V-T relation time, such as carbon monoxide and carbon dioxide.

Potential Value of FAPI PET/CT in the Detection and Treatment of Fibrosing Mediastinitis: Preclinical and Pilot Clinical Investigation.

Fibrosing mediastinitis (FM) is a rare proliferative disease within the mediastinum that leads to pulmonary hypertension, which has been regarded as a major cause of death. This study aims to evaluate the potential value of fibroblast activation protein inhibitor (FAPI)-PET/CT in the integration of diagnosis and treatment of FM through targeting FAPI in fibrosis rats and provide a theoretical basis for clinical management of FM patients. By performing a 18F-FAPI PET/CT scan, the presence of FAPI-avid in the fibrotic lesion was determined. Through a fibrosis rat model, 18F-FAPI-74 was used for lesion imaging and 177Lu-FAPI-46 was utilized to investigate the potential therapeutic effect on FM in vivo. In addition, biodistribution analysis and radiation dosimetry were carried out. With the 177Lu-FAPI-46 pharmacokinetic data of rats as the input, the estimated dose for female adults was computed, which can provide some useful information for the safe application of radiolabeled FAPI in the detection and treatment of FM in patients. Then, major findings on the use of FAPI PET/CT and SPECT/CT in FM were presented. 18F-FAPI-74 showed a high-level uptake in FM lesions of patients (SUVmax 7.94 ± 0.26), which was also observed in fibrosis rats (SUVmax 2.11 ± 0.23). Consistently, SPECT/CT imaging of fibrosis rats also revealed that 177Lu-FAPI-46-avid was active for up to 60 h in fibrotic lesions. In addition to this robust diagnostic performance, a possible therapeutic impact was evaluated as well. It turned out that no spontaneous healing of lesions was observed in the control group, whereas there was complete healing on day 9, day 11, and day 14 in the 30, 100, and 300 MBq groups, respectively. With a significant difference in the free of event rate in the Kaplan-Meier curve among four groups (P < 0.001), a dose of 300 MBq displayed the best therapeutic effect, and no obvious damage was observed in the kidney. Furthermore, organ-absorbed doses and an effective dose (0.4320 mSv/MBq) of 177Lu-FAPI-46 presumed for patients were assumed to give a preliminary indication of its safe use in clinical practice. In conclusion, 18F-FAPI-46 PET/CT can be a potentially valuable tool for the diagnosis of FM. Of note, 177Lu-FAPI-46 may be a novel and safe radiolabeled reagent for the integration of diagnosis and treatment of FM.

The Application of Single-Cell RNA Sequencing in the Inflammatory Tumor Microenvironment.

The initiation and progression of tumors are complex. The cancer evolution-development hypothesis holds that the dysregulation of immune balance is caused by the synergistic effect of immune genetic factors and environmental factors that stimulate and maintain non-resolving inflammation. Throughout the cancer development process, this inflammation creates a microenvironment for the evolution and development of cancer. Research on the inflammatory tumor microenvironment (TME) explains the initiation and progression of cancer and guides anti-cancer immunotherapy. Single-cell RNA sequencing (scRNA-seq) can detect the transcription levels of cells at the single-cell resolution level, reveal the heterogeneity and evolutionary trajectory of infiltrated immune cells and cancer cells, and provide insight into the composition and function of each cell group in the inflammatory TME. This paper summarizes the application of scRNA-seq in inflammatory TME.

CH4, C2H6, and CO2 Multi-Gas Sensing Based on Portable Mid-Infrared Spectroscopy and PCA-BP Algorithm.

A multi-gas sensing system was developed based on the detection principle of the non-dispersive infrared (NDIR) method, which used a broad-spectra light source, a tunable Fabry-Pérot (FP) filter detector, and a flexible low-loss infrared waveguide as an absorption cell. CH4, C2H6, and CO2 gases were detected by the system. The concentration of CO2 could be detected directly, and the concentrations of CH4 and C2H6 were detected using a PCA-BP neural network algorithm because of the interference of CH4 and C2H6. The detection limits were achieved to be 2.59 ppm, 926 ppb, and 114 ppb for CH4, C2H6, and CO2 with an averaging time of 429 s, 462 s, and 297 s, respectively. The root mean square error of prediction (RMSEP) of CH4 and C2H6 were 10.97 ppm and 2.00 ppm, respectively. The proposed system and method take full advantage of the multi-component gas measurement capability of the mid-infrared broadband source and achieve a compromise between performance and system cost.

Diagnosis and Treatment of Water-Contaminated Severe Legionella Pneumonia with Digestive Symptoms as the First Symptom: A Case Report and Review of the Literature.

Introduction: Although Legionella is not the most common pathogen of community-acquired pneumonia, the epidemiological distribution of pneumonia pathogens has changed in recent years, with a gradual increase in some rare pathogens. For example, pneumonia that occurs after water source contamination is mostly caused by Legionella infection. This paper reports the diagnosis and treatment process of a patient after Legionella infection, who had misdiagnosis at the beginning, rapidly progressed to severe disease and combined with fungal infection. This article focuses on the timely and effective treatment of rapidly progressing Legionella pneumonia, in anticipation of a better understanding of the diagnosis and treatment of the disease. Case Presentation: Here, we report a case of legionella infection with the nausea, vomiting as the first symptoms accompanied by weakness, chills, dizziness, abdominal discomfort in a 75-year-old female. The patient had a history of type 2 diabetes for 30 years, diabetic peripheral neuropathy for more than 20 years, arterial hypertension for 10 years, bone hyperplasia for more than 5 years, resection of right-sided thyroid cystadenoma in 1990. The patient had firstly been diagnosed with cholecystitis and gallbladder neck stones, diet abstinence, metronidazole, cefoperazone sulbactam, and rehydration were given. The patient responded poorly to these empiric treatments. The patient was given moxifloxacin in combination with azithromycin after the onset of respiratory symptoms, but the condition continued to deteriorate, and tigecycline was subsequently added. After the mechanical ventilation and the treatment plan adjusting, she improved significantly. Conclusion: Immunocompromised patient combined with underlying diseases are more susceptible to infection in an environment contaminated with Legionella, and the rapid onset and atypical respiratory symptoms make it easy to misdiagnose the disease, thus delaying treatment and leading to further deterioration. Timely diagnosis, early mechanical ventilation and rational drug administration were fundamental to treat Legionella pneumonia.

Down-regulation of connexin 43 contributes to structure and function of pulmonary artery in nicotine-administered mice.

Dysregulated connexin signaling is implicated in the pathophysiology of pulmonary artery hypertension (PAH). Nicotine affects pulmonary vascular remodeling. However, the potential mechanistic link between connexin signaling and nicotine-induced pulmonary artery remodeling remains unclear. We aimed to investigate the role of connexin 43 (Cx43) in pulmonary artery remodeling in nicotine-administered C57BL/6 J wild-type (WT) and Cx43 heterozygous (Cx43+/-) mice. Hemodynamic parameters and right ventricle pathology were assessed in the mice. Serum biochemical indices of hepatic and renal function were measured. The RT-PCR, immunofluorescence, and western blotting were conducted to evaluate Cx43 mRNA and protein levels. We performed histological staining to identify pulmonary arteries. Wire myography was used to examine contraction and relaxation responses in the pulmonary arteries. Pulmonary vascular permeability was assessed through Evans blue staining. Compared with the WT group, the Cx43+/- group showed lower Cx43 mRNA and protein expression in the pulmonary arteries (P < 0.01). Nicotine treatment significantly increased Cx43 expression (P < 0.01) and induced morphological changes in the pulmonary arteries (P < 0.01). Our findings suggest that Cx43 plays a crucial role in pulmonary artery reactivity and permeability in mice. Furthermore, downregulation of Cx43 expression may contribute to alterations in pulmonary artery structure and function.

Enhancing the Antitumor Immunity of T Cells by Engineering the Lipid-Regulatory Site of the TCR/CD3 Complex.

The engagement of the T-cell receptor (TCR) by a specific peptide-MHC ligand initiates transmembrane signaling to induce T-cell activation, a key step in most adaptive immune responses. Previous studies have indicated that TCR signaling is tightly regulated by cholesterol and its sulfate metabolite, cholesterol sulfate (CS), on the membrane. Here, we report a novel mechanism by which CS modulates TCR signaling through a conformational change of CD3 subunits. We found that the negatively charged CS interacted with the positively charged cytoplasmic domain of CD3ε (CD3εCD) to enhance its binding to the cell membrane and induce a stable secondary structure. This secondary structure suppressed the release of CD3εCD from the membrane in the presence of Ca2+, which in turn inhibited TCR phosphorylation and signaling. When a point mutation (I/A) was introduced to the intracellular immunoreceptor tyrosine-based activation motifs (YxxI-x6-8-YxxL) of CD3ε subunit, it reduced the stability of the secondary structure and regained sensitivity to Ca2+, which abolished CS-mediated inhibition and enhanced the signaling of the TCR complex. Notably, the I/A mutation could be applied to both murine and human TCR-T cell therapy to improve the antitumor efficacy. Our study reveals insights into the regulatory mechanism of TCR signaling and provides a strategy to functionally engineer the TCR/CD3 complex for T cell-based cancer immunotherapy.

Construction of a novel blood brain barrier-glioma microfluidic chip model: Applications in the evaluation of permeability and anti-glioma activity of traditional Chinese medicine components.

Since most anti-glioma drug candidates hardly permeate through the blood-brain barrier (BBB), preclinical models that can integrate the complexity of the tumor microenvironment and the structure and function of the BBB is urgently needed for the treatment of glioma. Herein, we constructed an in vitro BBB-glioma microfluidic chip model lined by primary human brain microvascular endothelial cells, pericytes, astrocytes and glioma cells, which could recapitulate the high level of barrier function of the in vivo human BBB and glioma microenvironment. The BBB unit in BBB-glioma microfluidic chip (BBB-U251 chip) displayed selective permeability to fluorescein isothiocyanate isomer-dextran (FITC-dextran) with different molecular weights and three model drugs with different permeability behavior across BBB, which indicated that this glioma model included a functional barrier. Six potential anti-glioma components in traditional Chinese medicine (TCM) were delivered into the blood channel and the permeated amount was quantified by high-performance liquid chromatography combined with ultraviolet (HPLC-UV). The permeated drugs then directly acted on 3D cultured glioma cells (U251) to evaluate the drug efficacy. The results of permeability coefficients of drugs showed that the data were closer to the in vivo data of traditional Transwell model. The effect of the drugs on U251 cells in the BBB-U251 chip was significantly lower due to the existence of BBB. Drug responses on glioma demonstrated the necessity to take BBB into account during the development of anti-glioma new drugs. Therefore, this 3D glioma microfluidic models integrating the BBB functionality can be a useful platform for screening the anticancer drug for brain tumors.

Screening potential P-glycoprotein inhibitors by combination of a detergent-free membrane protein extraction with surface plasmon resonance biosensor.

P-glycoprotein (P-gp) highly expressed in cancer cells can lead to multidrug resistance (MDR) and the combination of anti-cancer drugs with P-gp inhibitor has been a promising strategy to reverse MDR in cancer treatment. In this study, we established a label-free and detergent-free system combining surface plasmon resonance (SPR) biosensor with styrene maleic acid (SMA) polymer membrane proteins (MPs) stabilization technology to screen potential P-gp inhibitors. First, P-gp was extracted from MCF-7/ADR cells using SMA polymer to form SMA liposomes (SMALPs). Following that, SMALPs were immobilized on an SPR biosensor chip to establish a P-gp inhibitor screening system, and the affinity between P-gp and small molecule ligand was determined. The methodological investigation proved that the screening system had good specificity and stability. Nine P-gp ligands were screened out from 50 natural products, and their affinity constants with P-gp were also determined. The in vitro cell verification experiments demonstrated that tetrandrine, fangchinoline, praeruptorin B, neobaicalein, and icariin could significantly increase the sensitivity of MCF-7/ADR cells to Adriamycin (Adr). Moreover, tetrandrine, praeruptorin B, and neobaicalein could reverse MDR in MCF-7/ADR cells by inhibiting the function of P-gp. This is the first time that SMALPs-based stabilization strategy was applied to SPR analysis system. SMA polymer can retain P-gp in the environment of natural lipid bilayer and thus maintain the correct conformation and physiological functions of P-gp. The developed system can quickly and accurately screen small molecule ligands of complex MPs and obtain affinity between complex MPs and small molecule ligands without protein purification.

Connexins may play a critical role in cigarette smoke-induced pulmonary hypertension.

Pulmonary hypertension (PH) is a chronic progressive disease characterized by pulmonary vasoconstriction and remodeling. It causes a gradual increase in pulmonary vascular resistance leading to right-sided heart failure, and may be fatal. Chronic exposure to cigarette smoke (CS) is an essential risk factor for PH group 3; however, smoking continues to be prevalent and smoking cessation is reported to be difficult. A majority of smokers exhibit PH, which leads to a concomitant increase in the risk of mortality. The current treatments for PH group 3 focus on vasodilation and long-term oxygen supplementation, and fail to stop or reverse PH-associated continuous vascular remodeling. Recent studies have suggested that pulmonary vascular endothelial dysfunction induced by CS exposure may be an initial event in the natural history of PH, which in turn may be associated with abnormal alterations in connexin (Cx) expression. The relationship between Cx and CS-induced PH development has not yet been directly investigated. Therefore, this review will describe the roles of CS and Cx in the development of PH and discuss the related downstream pathways. We also discuss the possible role of Cx in CS-induced PH. It is hoped that this review may provide new perspectives for early intervention.

The pharmacological properties and corresponding mechanisms of farrerol: a comprehensive review.

CONTEXT: Farrerol, a typical natural flavanone isolated from the traditional Chinese herb 'Man-shan-hong' [Rhododendron dauricum L. (Ericaceae)] with phlegm-reducing and cough-relieving properties, is widely used in China for treating bronchitis and asthma. OBJECTIVE: To present the anti-inflammatory, antioxidant, vasoactive, antitumor, and antimicrobial effects of farrerol and its underlying molecular mechanisms. METHODS: The literature was reviewed by searching PubMed, Medline, Web of Knowledge, Scopus, and Google Scholar databases between 2011 and May 2021. The following key words were used: 'farrerol,' 'flavanone,' 'anti-inflammatory,' 'antioxidant,' 'vasoactive,' 'antitumor,' 'antimicrobial,' and 'molecular mechanisms'. RESULTS: Farrerol showed anti-inflammatory effects mainly mediated via the inhibition of interleukin (IL)-6/8, IL-1ß, tumour necrosis factor(TNF)-α, NF-κB, NO, COX-2, JNK1/2, AKT, PI3K, ERK1/2, p38, Keap-1, and TGF-1ß. Farrerol exhibited antioxidant effects by decreasing JNK, MDA, ROS, NOX4, Bax/Bcl-2, caspase-3, p-p38 MAPK, and GSK-3ß levels and enhancing Nrf2, GSH, SOD, GSH-Px, HO-1, NQO1, and p-ERK levels. The vasoactive effects of farrerol were also shown by the reduced α-SMA, NAD(P)H, p-ERK, p-Akt, mTOR, Jak2, Stat3, Bcl-2, and p38 levels, but increased OPN, occludin, ZO-1, eNOS, CaM, IP3R, and PLC levels. The antitumor effects of farrerol were evident from the reduced Bcl-2, Slug, Zeb-1, and vimentin levels but increased p27, ERK1/2, p38, caspase-9, Bax, and E-cadherin levels. Farrerol reduced α-toxin levels and increased NO production and NF-κB activity to impart antibacterial activity. CONCLUSIONS: This review article provides a theoretical basis for further studies on farrerol, with a view to develop and utilise farrerol for treating of vascular-related diseases in the future.

Palbociclib Enhances Migration and Invasion of Cancer Cells via Senescence-Associated Secretory Phenotype-Related CCL5 in Non-Small-Cell Lung Cancer.

Palbociclib is the first CDK4/6 inhibitor approved by FDA and has been studied in many types of cancer. However, some studies showed that it could induce epithelial-mesenchymal transition (EMT) of cancer cells. To test the effect of palbociclib on non-small-cell lung cancer (NSCLC) cells, we treated NSCLC cells with different concentrations of palbociclib and detected its effects via MTT, migration and invasion assays, and apoptosis test. Further RNA sequencing was performed in the cells treated with 2 µM palbociclib or control. And Gene Ontology, Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Set Enrichment Analysis (GSEA), and protein-protein interaction network (PPI) were analyzed to explore the mechanism of palbociclib. The results showed that palbociclib significantly inhibited the growth of NSCLC cells and promoted apoptosis of cells, however, enhanced the migration and invasion abilities of cancer cells. RNA sequencing showed that cell cycle, inflammation-/immunity-related signaling, cytokine-cytokine receptor interaction, and cell senescence pathways were involved in the process, and CCL5 was one of the significantly differential genes affected by palbociclib. Further experiments showed that blocking CCL5-related pathways could reverse the malignant phenotype induced by palbociclib. Our results revealed that palbociclib-induced invasion and migration might be due to senescence-associated secretory phenotype (SASP) rather than EMT and suggested that SASP could act as a potential target to potentiate the antitumor effects of palbociclib in cancer treatment.