Cellular senescence in chronic lung diseases from newborns to the elderly: An update literature review.

The role of cellular senescence in age-related diseases has been fully recognized. In various age-related-chronic lung diseases, the function of alveolar epithelial cells (AECs) is impaired and alveolar regeneration disorders, especially in bronchopulmonary dysplasia，pulmonary fibrosis (PF), chronic obstructive pulmonary disease (COPD), cancer, etc. Except for age-related-chronic lung diseases, an increasing number of studies are exploring the role of cellular senescence in developmental chronic lung diseases, which typically originate in childhood and even in the neonatal period. This review provides an overview of cellular senescence and lung diseases from newborns to the elderly, attempting to draw attention to the relationship between cellular senescence and developmental lung diseases.

Asia's Growing Contribution to Obesity Surgery Research: A 40-year Bibliometric Analysis.

Bariatric metabolic surgery's global research interest is growing, particularly in Asia due to its high obesity rates. This study focuses on Asia, especially China, analyzing 3904 publications (1221 from China) from 1980 to 2022. Research output accelerated until the COVID-19 pandemic, driven by economic growth and rising obesity rates. China led contributions from 2010, but Western Asia led when adjusted for population. An intra-regional research collaboration network emerged, driven by geographic proximity and similar economic environments. Keyword analysis highlighted emerging topics like "laparoscopic sleeve gastrectomy" and "non-alcoholic fatty liver disease," indicating a shift in focus. The study recommends disseminating research in top-tier journals to enhance visibility and impact.

Targeting ESE3/EHF With Nifurtimox Inhibits CXCR2+ Neutrophil Infiltration and Overcomes Pancreatic Cancer Resistance to Chemotherapy and Immunotherapy.

BACKGROUND & AIMS: Because pancreatic cancer responds poorly to chemotherapy and immunotherapy, it is necessary to identify novel targets and compounds to overcome resistance to treatment. METHODS: This study analyzed genomic single nucleotide polymorphism sequencing, single-cell RNA sequencing, and spatial transcriptomics. Ehf-knockout mice, KPC (LSL-KrasG12D/+, LSL-Trp53R172H/+ and Pdx1-Cre) mice, CD45.1+ BALB/C nude mice, and CD34+ humanized mice were also used as subjects. Multiplexed immunohistochemistry and flow cytometry were performed to investigate the proportion of tumor-infiltrated C-X-C motif chemokine receptor 2 (CXCR2)+ neutrophils. In addition, multiplexed cytokines assays and chromatin immunoprecipitation assays were used to examine the mechanism. RESULTS: The TP53 mutation-mediated loss of tumoral EHF increased the recruitment of CXCR2+ neutrophils, modulated their spatial distribution, and further induced chemo- and immunotherapy resistance in clinical cohorts and preclinical syngeneic mice models. Mechanistically, EHF deficiency induced C-X-C motif chemokine ligand 1 (CXCL1) transcription to enhance in vitro and in vivo CXCR2+ neutrophils migration. Moreover, CXCL1 or CXCR2 blockade completely abolished the effect, indicating that EHF regulated CXCR2+ neutrophils migration in a CXCL1-CXCR2-dependent manner. The depletion of CXCR2+ neutrophils also blocked the in vivo effects of EHF deficiency on chemotherapy and immunotherapy resistance. The single-cell RNA-sequencing results of PDAC treated with Nifurtimox highlighted the therapeutic significance of Nifurtimox by elevating the expression of tumoral EHF and decreasing the weightage of CXCL1-CXCR2 pathway within the microenvironment. Importantly, by simultaneously inhibiting the JAK1/STAT1 pathway, it could significantly suppress the recruitment and function of CXCR2+ neutrophils, further sensitizing PDAC to chemotherapy and immunotherapies. CONCLUSIONS: The study demonstrated the role of EHF in the recruitment of CXCR2+ neutrophils and the promising role of Nifurtimox in sensitizing pancreatic cancer to chemotherapy and immunotherapy.

A gold-complex initiated functionalization of biologically active polyphenols applied to a 18F-labeled chemical probe.

(-)-Epigallocatechin gallate (EGCG), a key component of green tea, exerts therapeutic anticancer and antiallergic properties through its binding to the 67 kDa laminin receptor. The functionalization of EGCG is a promising strategy for creating new drug candidates and chemical probes. In our study, we developed a method for effectively modifying the A ring of EGCG through an electrophilic aromatic substitution with amidomethyl 2-alkynylbenzoates initiated with a gold complex. The 2-alkynylbenzoates treated with (Ph3P)AuOTf under neutral conditions yielded N-acylimines. A further electrophilic aromatic substitution resulted in a mixture of EGCG substituted with acylaminomethyl groups at the 6 and 8 positions with a significant amount noted at the 6 position. We then explored the synthesis of 18F-labeled EGCG with a neopentyl labeling group, an effective labeling group for radiohalogens of not only fluorine-18 but also of astatine-211. To achieve this, we prepared precursors that possessed acid-sensitive protecting groups and base-unstable leaving groups using our established method. Substitution of EGCG with a neopentyl labeling group at either the C6 or C8 position did not affect its anticancer efficacy in U266 cells. Finally, we investigated the preparation of 18F-labeled EGCG. The 18F-fluorination of a mixture of 6- and 8-substituted precursors yielded the corresponding 18F-labeled compounds in 4.5% and 3.0% radiochemical yields (RCYs), respectively. Under acidic conditions, the 18F-labeled 8-substituted compound produced 18F-labeled EGCG in 37% RCY, which heralds the potential of our functionalization approach.

Irbesartan overcomes gemcitabine resistance in pancreatic cancer by suppressing stemness and iron metabolism via inhibition of the Hippo/YAP1/c-Jun axis.

BACKGROUND: Chemoresistance is the main reason for the poor prognosis of pancreatic ductal adenocarcinoma (PDAC). Thus, there is an urgent need to screen out new targets and compounds to reverse chemotherapeutic resistance. METHODS: We established a bio-bank of human PDAC organoid models, covering a representative range of PDAC tumor subtypes. We screened a library of 1304 FDA-approved compounds to identify candidates efficiently overcoming chemotherapy resistance. The effects of the compounds were evaluated with a CellTiter-Glo-3D assay, organoid apoptosis assay and in vivo patient-derived xenograft (PDX), patient-derived organoid (PDO) and LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx1-Cre (KPC) genetically engineered mouse models. RNA-sequencing, genome editing, sphere formation assays, iron assays and luciferase assays were conducted to elucidate the mechanism. RESULTS: High-throughput drug screening of chemotherapy-resistant PDOs identified irbesartan, an angiotensin ‖ type 1 (AT1) receptor antagonist, which could synergistically enhance the ability of chemotherapy to kill PDAC cells. In vitro and in vivo validation using PDO, PDX and KPC mouse models showed that irbesartan efficiently sensitized PDAC tumors to chemotherapy. Mechanistically, we found that irbesartan decreased c-Jun expression by inhibiting the Hippo/YAP1 pathway and further overcame chemotherapy resistance in PDAC. We also explored c-Jun, a potential target of irbesartan, which can transcriptionally upregulate the expression of key genes involved in stemness maintenance (SOX9/SOX2/OCT4) and iron metabolism (FTH1/FTL/TFRC). More importantly, we observed that PDAC patients with high levels of c-Jun expression demonstrated poor responses to the current standard chemotherapy regimen (gemcitabine plus nab-paclitaxel). Moreover, patients with PDAC had significant survival benefits from treatment with irbesartan plus a standard chemotherapy regimen in two-center retrospective clinical cohorts and patients with high c-Jun expression exhibited a better response to combination chemotherapy. CONCLUSIONS: Irbesartan could be used in combination with chemotherapy to improve the therapeutic efficacy in PDAC patients with high levels of c-Jun expression. Irbesartan effectively inhibited chemotherapy resistance by suppressing the Hippo/YAP1/c-Jun/stemness/iron metabolism axis. Based on our findings, we are designing an investigator-initiated phase II clinical trial on the efficacy and safety of irbesartan plus a standard gemcitabine/nab-paclitaxel regimen in the treatment of patients with advanced III/IV staged PDAC and are hopeful that we will observe patient benefits.

Artificial intelligence-based comprehensive analysis of immune-stemness-tumor budding profile to predict survival of patients with pancreatic adenocarcinoma.

OBJECTIVE: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy. CD8+ T cells, cancer stem cells (CSCs), and tumor budding (TB) have been significantly correlated with the outcome of patients with PDAC, but the correlations have been independently reported. In addition, no integrated immune-CSC-TB profile for predicting survival in patients with PDAC has been established. METHODS: Multiplexed immunofluorescence and artificial intelligence (AI)-based comprehensive analyses were used for quantification and spatial distribution analysis of CD8+ T cells, CD133+ CSCs, and TB. In vivo humanized patient-derived xenograft (PDX) models were established. Nomogram analysis, calibration curve, time-dependent receiver operating characteristic curve, and decision curve analyses were performed using R software. RESULTS: The established 'anti-/pro-tumor' models showed that the CD8+ T cell/TB, CD8+ T cell/CD133+ CSC, TB-adjacent CD8+ T cell, and CD133+ CSC-adjacent CD8+ T cell indices were positively associated with survival of patients with PDAC. These findings were validated using PDX-transplanted humanized mouse models. An integrated nomogram-based immune-CSC-TB profile that included the CD8+ T cell/TB and CD8+ T cell/CD133+ CSC indices was established and shown to be superior to the tumor-node-metastasis stage model in predicting survival of patients with PDAC. CONCLUSIONS: 'Anti-/pro-tumor' models and the spatial relationship among CD8+ T cells, CSCs, and TB within the tumor microenvironment were investigated. Novel strategies to predict the prognosis of patients with PDAC were established using AI-based comprehensive analysis and machine learning workflow. The nomogram-based immune-CSC-TB profile can provide accurate prognosis prediction for patients with PDAC.

SDCBP promotes pancreatic cancer progression by preventing YAP1 from ß-TrCP-mediated proteasomal degradation.

OBJECTIVE: Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal tumour with limited treatment options. Here, we identified syndecan binding protein (SDCBP), also known as syntenin1, as a novel targetable factor in promoting PDAC tumour progression. We also explored a therapeutic strategy for suppressing SDCBP expression. DESIGN: We used samples from patients with PDAC, human organoid models, LSL-KrasG12D/+mice, LSL-Trp53R172H/+ and Pdx1-Cre (KPC) mouse models, and PDX mouse models. Immunostaining, colony formation assay, ethynyl-2-deoxyuridine incorporation assay, real-time cell analysis, cell apoptosis assay, automated cell tracking, invadopodia detection and gelatin degradation assays, coimmunoprecipitation, and pull-down assays were performed in this study. RESULTS: The median overall survival and recurrence-free survival rates in the high-SDCBP group were significantly shorter than those in the low-SDCBP group. In vitro and in vivo studies have demonstrated that SDCBP promotes PDAC proliferation and metastasis. Mechanically, SDCBP inhibits CK1δ/ε-mediated YAP-S384/S387 phosphorylation, which further suppresses ß-TrCP-mediated YAP1 ubiquitination and proteasome degradation by directly interacting with YAP1. SDCBP interacts with the TAD domain of YAP1, mainly through its PDZ1 domain. Preclinical KPC mouse cohorts demonstrated that zinc pyrithione (ZnPT) suppresses PDAC tumour progression by suppressing SDCBP. CONCLUSIONS: SDCBP promotes the proliferation and metastasis of PDAC by preventing YAP1 from ß-TrCP-mediated proteasomal degradation. Therefore, ZnPT could be a promising therapeutic strategy to inhibit PDAC progression by suppressing SDCBP.

Co-expression network analysis for identification of novel biomarkers of bronchopulmonary dysplasia model.

Background: Bronchopulmonary dysplasia (BPD) is the most common neonatal chronic lung disease. However, its exact molecular pathogenesis is not understood. We aimed to identify relevant gene modules that may play crucial roles in the occurrence and development of BPD by weighted gene co-expression network analysis (WGCNA). Methods: We used RNA-Seq data of BPD and healthy control rats from our previous studies, wherein data from 30 samples was collected at days 1, 3, 7, 10, and 14. Data for preprocessing analysis included 17,613 differentially expressed genes (DEGs) with false discovery rate <0.05. Results: We grouped the highly correlated genes into 13 modules, and constructed a network of mRNA gene associations, including the 150 most associated mRNA genes in each module. Lgals8, Srpra, Prtfdc1, and Thap11 were identified as the key hub genes. Enrichment analyses revealed Golgi vesicle transport, coated vesicle, actin-dependent ATPase activity and endoplasmic reticulum pathways associated with these genes involved in the pathological process of BPD in module. Conclusions: This is a study to analyze data obtained from BPD animal model at different time-points using WGCNA, to elucidate BPD-related susceptibility modules and disease-related genes.

Up-regulated IL-17 and Tnf signaling in bone marrow cells of young male osteogenesis imperfecta mice.

Osteogenesis imperfecta (OI) is a congenital bone dysplasia mainly caused by either defective production or assembly of type I collagen. The skeletal phenotypes especially fractures are often seen in OI adolescents. Studies have found that an increased number of osteoclasts and excessive bone resorption existed in collagen-related OI, which has not been well understood. Emerging evidence has suggested that inflammation may be associated with OI. We speculated that the bone marrow (BM) niche had similar inflammatory changes and performed RNA-sequencing (RNA-seq) in BM cells derived from young male mice to analyze the related differentially expressed genes (DEGs) and pathways. Data showed that there were 117 shared DEGs (Q ≤ 0.05, |log2FC| ≥ 1) in BM cells isolated from two types of OI murine models that respectively simulate different OI types. Gene Ontology (GO) (Q ≤ 0.05) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) (Q ≤ 0.05) analysis and real-time PCR validation indicated the dysregulated biology process of cellular response to interferon (Ifn) together with upregulated IL-17 signaling, tumor necrosis factor (Tnf) signaling and osteoclast differentiation in OI BM niche. Either defective collagen production or abnormal collagen assembly shared similar alterations in gene profiles and pathways involving inflammation and osteoclast activation. Data presented here not only contributed to understanding of the mechanism of the enhanced bone absorption in the bones of OI, but also provided more evidence to develop potential anti-inflammation therapies.

Toll-like receptor 4-mediated necroptosis in the development of necrotizing enterocolitis.

BACKGROUND: Dramatic intestinal epithelial cell death leading to barrier dysfunction is one of the mechanism of neonatal necrotizing enterocolitis (NEC), in which Toll-like receptor 4 (TLR4) plays a pivotal role. This study explored the role of necroptosis, a drastic way of cell death in NEC. METHODS: The expression of necroptotic proteins was tested in NEC intestinal tissue and compared with controls. NEC was induced in neonatal wild-type mice and a necroptosis inhibitor was given to investigate whether NEC could be relieved. The general condition, macroscopic scoring, and histological evaluations were performed. The expression of tight junction proteins, inflammatory cytokines, and necroptosis-related proteins was measured, and barrier function was examined. Then, NEC was induced in TLR4-knockout pups to confirm the role of TLR4 in necroptosis. RESULTS: Necroptotic proteins were significantly upregulated in both NEC patient and animal models, together with the expression of TLR4. NEC could be relieved and inflammatory infiltration was decreased by necrostatin-1s. TLR4-knockout mice showed milder tissue degradation and less necroptosis after NEC induction. CONCLUSIONS: Necroptosis is an essential pathological process of NEC. TLR4 may be one stimulator of necroptosis in NEC. Inhibiting the intestinal cell necroptosis might be a useful strategy in the treatment of NEC. IMPACT: Necroptosis is a key pathological process in NEC, which appears to involve TLR4. Anti-necroptosis treatment is a promising strategy that could significantly relieve the symptoms of NEC.

A systematic review and meta-analysis of effect evaluation of traditional Chinese medicine in treating acute respiratory distress syndrome.

BACKGROUND: It was to systematically evaluate the effects of traditional Chinese medicine (TCM) in the treatment of acute respiratory distress syndrome (ARDS), and provide a theoretical basis for the clinical treatment of ARDS. METHODS: English databases of PubMed, Embase, Medline, Spring, Cochrane Library, and Web of Science were searched, and the randomized controlled trial literatures on the treatment of ARDS patients with TCM published from January 1, 2001 to December 31, 2020 were screened. Then, Cochrane Handbook 5.0.2 was employed to evaluate the risk of bias in the included literatures, and Review Manager 5.3 was utilized for meta-analysis. RESULTS: A total of 16 studies met the requirements and were included, with a total of 1,460 participants. The meta-analysis results showed that the mortality rate of patients in the observation group was remarkably reduced after treatment with TCM [mean deviation (MD) =0.51; 95% confidence interval (CI): 0.32-0.84; Z=2.69; P=0.007]. The effective rate of clinical treatment was improved (MD =2.64; 95% CI: 1.79-3.90; Z=4.90; P<0.00001). Arterial partial pressure of oxygen (PaO2) increased remarkably (MD =12.29; 95% CI: 8.88-15.71; Z=7.05; P<0.00001). The oxygenation index (PaO2/FiO2) increased remarkably (MD =50.70; 95% CI: 32.78-68.63; Z=5.54; P<0.00001). Interleukin-6 (IL-6) levels were remarkably reduced (MD =-8.32; 95% CI: -11.48 to -5.17; Z=5.17; P<0.00001). The level of C-reactive protein (CRP) decreased remarkably (MD =-9.23; 95% CI: -14.23 to -4.24; Z=3.62; P=0.0003). Compared with the control group, the above 8 analysis indicators showed statistically considerable differences. However, difference of partial pressure of carbon dioxide (PaCO2) level (MD =-0.16; 95% CI: -2.97-2.65; Z=0.11; P=0.91) was not obvious between groups. DISCUSSION: The treatment of ARDS with TCM can reduce the mortality rate of patients, improves the effective rate of clinical treatment, reduces the average mechanical ventilation time, increases the levels of PaO2, PaO2/FiO2, and reduces the levels of IL-6, tumor necrosis factor α (TNF-α), and CRP. The use of TCM has a significant treatment effect on ARDS.

Hydrochar and pyrochar for sorption of pollutants in wastewater and exhaust gas: A critical review.

Pollutants in wastewater and exhaust gas bring out serious concerns to public health and the environment. Biochar can be developed as a sustainable adsorbent originating from abundant bio-wastes, such as agricultural waste, forestry residue, food waste and human waste. Here we highlight the state-of-the-art research progress on pyrochar and hydrochar for the sorption of pollutants (heavy metal, organics, gas, etc) in wastewater and exhaust gases. The adsorption performance of pyrochar and hydrochar are compared and discussed in-depth, including preparation procedures (carbonization and activation), sorption possible mechanisms, and physiochemical properties. Challenges and perspective for designing efficient and environmental benign biochar-based adsorbents are finally addressed.

Hyperoxia exposure arrests alveolarization in neonatal rats via PTEN­induced putative kinase 1­Parkin and Nip3­like protein X­mediated mitophagy disorders.

Bronchopulmonary dysplasia (BPD), also known as chronic lung disease, is one of the most common respiratory diseases in premature new­born humans. Mitochondria are not only the main source of reactive oxygen species but are also critical for the maintenance of homeostasis and a wide range of biological activities, such as producing energy, buffering cytosolic calcium and regulating signal transduction. However, as a critical quality control method for mitochondria, little is known about the role of mitophagy in BPD. The present study assessed mitochondrial function in hyperoxia­exposed alveolar type II (AT­II) cells of rats during lung development. New­born Sprague­Dawley rats were divided into hyperoxia (85% oxygen) and control (21% oxygen) groups. Histopathological and morphological properties of the lung tissues were assessed at postnatal days 1, 3, 7 and 14. Ultrastructural mitochondrial alteration was observed using transmission electron microscopy and the expression of the mitophagy proteins putative kinase (PINK)1, Parkin and Nip3­like protein X (NIX) in the lung tissues was evaluated using western blotting. Immunofluorescence staining was used to determine the co­localisation of PINK1 and Parkin. Real­time analyses of extracellular acidification rate and oxygen consumption rate were performed using primary AT­II cells to evaluate metabolic changes. Mitochondria in hyperoxia­exposed rat AT­II cells began to show abnormal morphological and physiological features. These changes were accompanied by decreased mitochondrial membrane potential and increased expression levels of PINK1­Parkin and NIX. Increased binding between a mitochondria marker (cytochrome C oxidase subunit IV isoform I) and an autophagy marker (microtubule­associated protein­1 light chain­3B) was observed in primary AT­II cells and was accompanied by decreased mitochondrial metabolic capacity in model rats. Thus, mitophagy mediated by PINK1, Parkin and NIX in AT­II cells occurred in hyperoxia­exposed new­born rats. These findings suggested that the accumulation of dysfunctional mitochondria may be a key factor in the pathogenesis of BPD and result in attenuated alveolar development.

Microstructure and Mechanical Properties of 4Al Alumina-Forming Austenitic Steel after Cold-Rolling Deformation and Annealing.

Microstructural evolutions of the 4Al alumina-forming austenitic steel after cold rolling with different reductions from 5% to 30% and then annealing were investigated using electron backscattering diffraction (EBSD), X-ray diffraction (XRD) and transmission electron microscopy (TEM). Tensile properties and hardness were also measured. The results show that the average grain size gradually decreases with an increase in the cold-rolling reduction. The low angle grain boundaries (LAGBs) are dominant in the cold-rolled samples, but high angle grain boundaries (HAGBs) form in the annealed samples, indicating that the grains are refined under the action of dislocations. During cold rolling, high-density dislocations are initially introduced in the samples, which contributes to a large number of dislocations remaining after annealing. With the sustaining increase in cold-rolled deformation, the samples exhibit more excellent tensile strength and hardness due to the decrease in grain size and increase in dislocation density, especially for the samples subjected to 30% cold-rolling reduction. The contribution of dislocations on yield strength is more than 60%.

Liver function tests may be useful tools for advanced cancer patient care: a preliminary single-center result.

Accurate prognostication in advanced cancer may facilitate better palliative care. An objective marker may be more applicable and appropriate than a subjective evaluation by physicians. The aim of this study was to evaluate liver function tests as useful prognostic factors for survival in patients with advanced cancer. We recruited advanced cancer patients from January 2007 to December 2009. Data on age, sex, cancer diagnosis, site of metastases, clinical symptoms, and performance status were collected at the time of admission to the palliative care unit. Analyzed laboratory data were obtained on the Day 1 of admission to the palliative care unit. A total of 522 patients were enrolled; 322 (61.7%) of them were males. The mean age was 60.6 ± 13.2 years. Multiple logistic regression analysis adjusting for age and sex demonstrated aspartate transaminase (AST) > 80 IU/L [odds ratio (OR) = 2.01, p = 0.010] and alanine transaminase > 80 IU/L (OR = 1.89, p = 0.047) were independently significant prognostic factors of death within 14 days. AST > 80 IU/L (OR = 3.67, p = 0.017) and albumin < 3.0 g/dL (OR = 1.98, p = 0.048) were independently significant prognostic factors of death within 6 months. Liver function tests may be useful prognostic factors for patients in the palliative care unit, in addition to being useful for patients with hepatobiliary cancer or liver metastasis. These biochemical tests of liver function with cutoff values can easily be used in palliative care.