Inhalable Textile Microplastic Fibers Impair Airway Epithelial Differentiation.

Rationale: Microplastics are a pressing global concern, and inhalation of microplastic fibers has been associated with interstitial and bronchial inflammation in flock workers. However, how microplastic fibers affect the lungs is unknown. Objectives: Our aim was to assess the effects of 12 × 31 µm nylon 6,6 (nylon) and 15 × 52 µm polyethylene terephthalate (polyester) textile microplastic fibers on lung epithelial growth and differentiation. Methods: We used human and murine alveolar and airway-type organoids as well as air-liquid interface cultures derived from primary lung epithelial progenitor cells and incubated these with either nylon or polyester fibers or nylon leachate. In addition, mice received one dose of nylon fibers or nylon leachate, and, 7 days later, organoid-forming capacity of isolated epithelial cells was investigated. Measurements and Main Results: We observed that nylon microfibers, more than polyester, inhibited developing airway organoids and not established ones. This effect was mediated by components leaching from nylon. Epithelial cells isolated from mice exposed to nylon fibers or leachate also formed fewer airway organoids, suggesting long-lasting effects of nylon components on epithelial cells. Part of these effects was recapitulated in human air-liquid interface cultures. Transcriptomic analysis revealed upregulation of Hoxa5 after exposure to nylon fibers. Inhibiting Hoxa5 during nylon exposure restored airway organoid formation, confirming Hoxa5's pivotal role in the effects of nylon. Conclusions: These results suggest that components leaching from nylon 6,6 may especially harm developing airways and/or airways undergoing repair, and we strongly encourage characterization in more detail of both the hazard of and the exposure to microplastic fibers.

Inhibition of OGG1 ameliorates pulmonary fibrosis via preventing M2 macrophage polarization and activating PINK1-mediated mitophagy.

BACKGROUND: 8-Oxoguanine DNA glycosylase (OGG1), a well-known DNA repair enzyme, has been demonstrated to promote lung fibrosis, while the specific regulatory mechanism of OGG1 during pulmonary fibrosis remains unclarified. METHODS: A bleomycin (BLM)-induced mouse pulmonary fibrosis model was established, and TH5487 (the small molecule OGG1 inhibitor) and Mitochondrial division inhibitor 1 (Mdivi-1) were used for administration. Histopathological injury of the lung tissues was assessed. The profibrotic factors and oxidative stress-related factors were examined using the commercial kits. Western blot was used to examine protein expression and immunofluorescence analysis was conducted to assess macrophages polarization and autophagy. The conditional medium from M2 macrophages was harvested and added to HFL-1 cells for culture to simulate the immune microenvironment around fibroblasts during pulmonary fibrosis. Subsequently, the loss- and gain-of function experiments were conducted to further confirm the molecular mechanism of OGG1/PINK1. RESULTS: In BLM-induced pulmonary fibrosis, OGG1 was upregulated while PINK1/Parkin was downregulated. Macrophages were activated and polarized to M2 phenotype. TH5487 administration effectively mitigated pulmonary fibrosis, M2 macrophage polarization, oxidative stress and mitochondrial dysfunction while promoted PINK1/Parkin-mediated mitophagy in lung tissues of BLM-induced mice, which was partly hindered by Mdivi-1. PINK1 overexpression restricted M2 macrophages-induced oxidative stress, mitochondrial dysfunction and mitophagy inactivation in lung fibroblast cells, and OGG1 knockdown could promote PINK1/Parkin expression and alleviate M2 macrophages-induced mitochondrial dysfunction in HFL-1 cells. CONCLUSION: OGG1 inhibition protects against pulmonary fibrosis, which is partly via activating PINK1/Parkin-mediated mitophagy and retarding M2 macrophage polarization, providing a therapeutic target for pulmonary fibrosis.

Distinct latitudinal patterns and drivers of topsoil nitrogen and phosphorus across urban forests in eastern China.

Nitrogen (N) and phosphorus (P) are the two most important macronutrients supporting forest growth. Unprecedented urbanization has created growing areas of urban forests that provide key ecosystem services for city dwellers. However, the large-scale patterns of soil N and P content remain poorly understood in urban forests. Based on a systematic soil survey in urban forests from nine large cities across eastern China, we examined the spatial patterns and key drivers of topsoil (0-20 cm) total N content, total P content, and N:P ratio. Topsoil total N content was found to change significantly with latitude in the form of an inverted parabolic curve, while total P content showed an opposite latitudinal pattern. Variance partition analysis indicated that regional-scale patterns of topsoil total N and P contents were dominated by climatic drivers and partially regulated by time and pedogenic drivers. Conditional regression analyses showed a significant increase in topsoil total N content with lower mean annual temperature (MAT) and higher mean annual precipitation (MAP), while topsoil total P content decreased significantly with higher MAP. Topsoil total N content also increased significantly with the age of urban park and varied with pre-urban soil type, while no such effects were found for topsoil total P content. Moreover, topsoil N:P ratio showed a latitudinal pattern similar to that of topsoil total N content and also increased significantly with lower MAT and higher MAP. Our findings demonstrate distinct latitudinal trends of topsoil N and P contents and highlight a dominant role of climatic drivers in shaping the large-scale patterns of topsoil nutrients in urban forests.

Metabolomic insights into pulmonary fibrosis: a mendelian randomization study.

BACKGROUND: This study leverages a two-sample Mendelian Randomization (MR) approach to explore the causal relationships between 1,400 metabolites and pulmonary fibrosis, using genetic variation as instrumental variables. By adhering to stringent criteria for instrumental variable selection, the research aims to uncover metabolic pathways that may influence the risk and progression of pulmonary fibrosis, providing insights into potential therapeutic targets. METHODS: Utilizing data from the OpenGWAS project, which includes a significant European cohort, and metabolite GWAS data from the Canadian Longitudinal Aging Study (CLSA), the study employs advanced statistical methods. These include inverse variance weighting (IVW), weighted median estimations, and comprehensive sensitivity analyses conducted using the R software environment to ensure the robustness of the causal inferences. RESULTS: The study identified 62 metabolites with significant causal relationships with pulmonary fibrosis, highlighting both risk-enhancing and protective metabolic factors. This extensive list of metabolites presents a broad spectrum of potential therapeutic targets and biomarkers for early detection, underscoring the metabolic complexity underlying pulmonary fibrosis. CONCLUSIONS: The findings from this MR study significantly advance our understanding of the metabolic underpinnings of pulmonary fibrosis, suggesting that alterations in specific metabolites could influence the risk and progression of the disease. These insights pave the way for the development of novel diagnostic and therapeutic strategies, emphasizing the potential of metabolic modulation in managing pulmonary fibrosis.

Genetic association of telomere length, obesity and tobacoo smoking with idiopathic pulmonary fibrosis risk.

BACKGROUND: Due to the inadequacy of published evidence, association of telomere length (TL), obesity and tobacco smoking with idiopathic pulmonary fibrosis (IPF) remains unclear. The aim of the study was to explore whether these exposures genetically affected the risk of the disease. METHODS: Genetic variants from genome-wide association studies for TL, body mass index (BMI), body fat percentage (BFP) and tobacco smoking (including maternal smoking) were used as instrumental variables. Inverse-variance weighted were mainly adopted to determine the genetic association of these exposures with IPF. All analyses were conducted by R-software (version 3.6.1). RESULTS: Firstly, longer TL was associated with the decreased risk of IPF (OR = 0.475 per SD increase in TL, 95%CI = 0.336 ~ 0.670, P<0.001). Secondly, higher levels of BMI and BFP were related to the increased risk of the disease (OR = 1.425 per SD increase in BMI level, 95%CI = 1.114 ~ 1.823, P = 0.005; OR = 1.702 per SD increase in BFP level, 95%CI = 1.202 ~ 2.409, P = 0.003). Thirdly, maternal smoking was implicated in the increased risk of the disease (OR = 13.183 per SD increase in the prevalence of maternal smoking, 95%CI = 1.820 ~ 95.484, P = 0.011). CONCLUSION: TL should be a genetic risk factor for IPF. Obesity and exposure to tobacco smoking as a fetus might also contribute to the development of this fibrotic diseases. These findings should be verified by future studies.

VX-11e protects articular cartilage and subchondral bone in osteoarthritis by inhibiting the RIP1/RIP3/MLKL and MAPK signaling pathways.

Necroptosis of chondrocytes contributes to the progression of osteoarthritis (OA). Recent studies have shown that VX-11e, an ERK inhibitor, exhibited a contrasting expression pattern to RIP3, the key protein of necroptosis. However, its effect on OA remains to be determined. Therefore, we investigated whether VX-11e affected the loss of articular cartilage and subchondral bone during OA. In in vivo experiments, a mouse OA model induced by medial meniscus instability (destabilization of the medial meniscus [DMM]) was used. In in vitro experiments, interleukin-1ß (IL-1ß) was used to simulate the inflammatory microenvironment of chondrocytes, and RANKL was used to induce osteoclast differentiation. Histological analysis, cell viability experiments, high-density cell culture experiments, immunofluorescence assay, western blot assay, quantitative PCR, and molecular docking experiments were conducted to determine the protective effect of VX-11e on articular cartilage during OA. We also performed histological analysis, tartrate-resistant acid phosphatase (TRAP) staining, F-actin ring formation test, quantitative PCR, and western blot assay to study the effect of VX-11e on subchondral bone during OA progression. We found that after the medial meniscus was severed, the articular cartilage of the mice showed pathological changes, accompanied with the loss of subchondral bone. However, an intraperitoneal injection of VX-11e protected the cartilage and subchondral bone of the mouse knee joint. The results of in vitro experiments showed that VX-11e promoted the anabolism of the extracellular matrix of chondrocytes by inhibiting the expression and phosphorylation of RIP3 and MLKL. VX-11e also inhibited RANKL-induced osteoclast differentiation by inhibiting the ERK/RSK signaling pathway, but not the NF-κB pathway. Overall, VX-11e inhibited the loss of articular cartilage and subchondral bone during OA by regulating the RIP1/RIP3/MLKL and MAPK signaling pathways.

Effect of goal-directed fluid therapy on renal function in critically ill patients: a systematic review and meta-analysis.

OBJECTIVE: To evaluate whether goal-directed fluid therapy (GDFT) reduces the risk of renal injury in critical illness. METHODS: MEDLINE via PubMed, EMBASE, CENTRAL and CBM was searched from inception to 13 March 2022, for studies comparing the effect of GDFT with usual care on renal function in critically ill patients. GDFT was defined as a protocolized intervention based on hemodynamic and/or oxygen delivery parameters. A fixed or random effects model was applied to calculate the pooled odds ratio (OR) based on heterogeneity through the included studies. RESULTS: A total of 28 studies with 9,019 patients were included. The pooled data showed that compared with usual care, GDFT reduced the incidence of acute kidney injury (AKI) in critical illness (OR 0.62, 95% confidence interval (CI) 0.47 to 0.80, p< 0.001). Sensitivity analysis with only low risk of bias studies showed the same result. Subgroup analyses found that GDFT was associated with a lower AKI incidence in both postoperative and medical patients. The reduction was significant in GDFT aimed at dynamic indicators. However, no significant difference was found between groups in RRT support (OR 0.88, 95% CI 0.74 to 1.05, p= 0.17). GDFT tended to increase fluid administration within the first 6 h, decrease fluid administration after 24 h, and was associated with more vasopressor requirements. CONCLUSIONS: This meta-analysis suggests that GDFT aimed at dynamic indicators may be an effective way to prevent AKI in critical illness. This may indicate a benefit from early adequate fluid resuscitation and the combined effect of vasopressors.

Yangonin treats inflammatory osteoporosis by inhibiting the secretion of inflammatory factors and RANKL expression.

OBJECTIVES: As the main cause of osteoporosis, abnormal activity of osteoclasts could disrupt the balance between bone resorption and formation. Moreover, up-regulation of nuclear factor-kappa ligand (RANKL) expression by chronic inflammation-mediated inflammatory factors might contribute to the differentiation of osteoclast precursor cells. Therefore, an anti-inflammatory agent named yangonin was presented for inhibiting osteoclast and relieving inflammatory osteoporosis through down-regulating inflammatory factors. METHODS: We established a model of macrophage inflammation and then verified the anti-inflammatory effect of yangonin. The inhibitory effect of yangonin on osteoclasts was detected by tartrate-resistant acid phosphatase (TRAP) staining, Western blotting and quantitative real-time PCR (qRT-PCR). Finally, micro-CT, TRAP and hematoxylin-eosin (HE) staining were used to show the effect of yangonin on inflammatory osteoporosis in vivo. RESULTS: Our results suggested that yangonin was able to reduce the secretion of inflammatory factors, down-regulate osteoclast-related genes such as TRAP, RANKL, cathepsin K (CTSK) and nuclear factor-activated T-cell 1 (NFATc1). Furthermore, it was demonstrated that yangonin could suppress the function of inflammatory cytokines in osteoclast differentiation and reporting, wherein NF-κB, AKT and downstream c-Fos/NFATc1 signaling pathways were involved. In an in vivo study, we implied that yangonin has a relieving effect on inflammatory osteoporosis. CONCLUSION: Our research shows that yangonin down-regulates inflammatory factors and inhibits the bone-breaking effect of inflammation through NF-κB, AKT and downstream c-Fos/NFATc1 signaling pathways to achieve the purpose of treating inflammatory osteoporosis.

LL-37 and HMGB1 induce alveolar damage and reduce lung tissue regeneration via RAGE.

The receptor for advanced glycation end-products (RAGE) has been implicated in the pathophysiology of chronic obstructive pulmonary disease (COPD). However, it is still unknown whether RAGE directly contributes to alveolar epithelial damage and abnormal repair responses. We hypothesize that RAGE activation not only induces lung tissue damage but also hampers alveolar epithelial repair responses. The effects of the RAGE ligands LL-37 and HMGB1 were examined on airway inflammation and alveolar tissue damage in wild-type and RAGE-deficient mice and on lung damage and repair responses using murine precision cut lung slices (PCLS) and organoids. In addition, their effects were studied on the repair response of human alveolar epithelial A549 cells, using siRNA knockdown of RAGE and treatment with the RAGE inhibitor FPS-ZM1. We observed that intranasal installation of LL-37 and HMGB1 induces RAGE-dependent inflammation and severe alveolar tissue damage in mice within 6 h, with stronger effects in a mouse strain susceptible for emphysema compared with a nonsusceptible strain. In PCLS, RAGE inhibition reduced the recovery from elastase-induced alveolar tissue damage. In organoids, RAGE ligands reduced the organoid-forming efficiency and epithelial differentiation into pneumocyte-organoids. Finally, in A549 cells, we confirmed the role of RAGE in impaired repair responses upon exposure to LL-37. Together, our data indicate that activation of RAGE by its ligands LL-37 and HMGB1 induces acute lung tissue damage and that this impedes alveolar epithelial repair, illustrating the therapeutic potential of RAGE inhibitors for lung tissue repair in emphysema.

TGF-ß activation impairs fibroblast ability to support adult lung epithelial progenitor cell organoid formation.

Transforming growth factor-ß (TGF-ß)-induced fibroblast-to-myofibroblast differentiation contributes to remodeling in chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis, but whether this impacts the ability of fibroblasts to support lung epithelial repair remains little explored. We pretreated human lung fibroblasts [primary (phFB) or MRC5 cells] with recombinant human TGF-ß to induce myofibroblast differentiation, then cocultured them with adult mouse lung epithelial cell adhesion molecule-positive cells (EpCAM+) to investigate their capacity to support epithelial organoid formation in vitro. While control phFB and MRC5 lung fibroblasts supported organoid formation of mouse EpCAM+ cells, TGF-ß pretreatment of both phFB and MRC5 impaired organoid-supporting ability. We performed RNA sequencing of TGF-ß-treated phFB, which revealed altered expression of key Wnt signaling pathway components and Wnt/ß-catenin target genes, and modulated expression of secreted factors involved in mesenchymal-epithelial signaling. TGF-ß profoundly skewed the transcriptional program induced by the Wnt/ß-catenin activator CHIR99021. Supplementing organoid culture media recombinant hepatocyte growth factor or fibroblast growth factor 7 promoted organoid formation when using TGF-ß pretreated fibroblasts. In conclusion, TGF-ß-induced myofibroblast differentiation results in Wnt/ß-catenin pathway skewing and impairs fibroblast ability to support epithelial repair likely through multiple mechanisms, including modulation of secreted growth factors.

The possible FAT1-mediated apoptotic pathways in porcine cumulus cells.

Porcine cumulus cells are localized around oocytes and act as a specific type of granulosa that plays essential roles in the development and maturation of oocytes, the development and atresia of follicles, and the development of embryos. Studies of FAT1 have demonstrated its functions in cell-cell contact, actin dynamics, and cell growth suppression. To understand whether the FAT1 gene affects the apoptosis of porcine cumulus cells and to elucidate the mechanism of this potential action, FAT1 was knocked down using RNA interference. The lack of FAT1 resulted in stable expression of CTNNB, enhanced expression of cleaved CASP3, but decreased the BCL2/BAX ratios at both the mRNA and protein levels. These results indicated that FAT1 inhibited porcine cumulus cell apoptosis via different pathways. Taken together, these data provide new insights into the mechanisms of the association between FAT1 and porcine cumulus cell apoptosis.

The effects of demecolcine, alone or in combination with sucrose on bovine oocyte protrusion rate, MAPK1 protein level and c-mos gene expression level.

AIMS: Our study aims to clarify the effects of demecolcine, alone or in combination with sucrose on bovine oocyte protrusion rate, MAPK1 protein level and c-mos gene expression level. METHODS: The effects of the demecolcine concentration, treatment duration, and synergistic effects with sucrose solution on the rate of membrane protrusions of bovine oocytes were investigated. Using real-time fluorescent quantitative PCR, western blot analysis, and immunofluorescence assays, the expression of the maternal c-mos gene, the protein level of mitogen-activated protein kinase 1 (MAPK1), and the change in the localization of spindles and nuclei during the demecolcine treatment were analyzed in bovine oocytes. RESULTS: Treatment of bovine oocytes with both demecolcine (0.6 µg/mL) and sucrose (0.05 M) for 1 h led to the highest rate of membrane protrusions, and synergistic effects were also observed. Real-time fluorescent quantitative PCR analysis revealed that the demecolcine treatment up-regulated the expression of the maternal c-mos gene. Western blot analysis indicated that the demecolcine treatment enhanced the protein level of MAPK1 in bovine oocytes. Immunofluorescence analysis indicated that the spindles and nuclei were localized at the place of the membrane protrusions. CONCLUSIONS: The present results suggest that demecolcine might contribute to the activation of the Mos/MAPK pathway and affect spindle structure. These results provide a reference for more efficient generation of enucleated bovine oocytes.

Buyang Huanwu decoction ameliorates bleomycin-induced pulmonary fibrosis in rats by attenuating the apoptosis of alveolar type II epithelial cells mediated by endoplasmic reticulum stress.

ETHNOPHARMACOLOGICAL RELEVANCE: According to the theory of traditional Chinese medicine, the pathogenesis of idiopathic pulmonary fibrosis (IPF) can be attributed to qi deficiency and blood stasis. Buyang Huanwu decoction (BHD), a representative Chinese herbal prescription for qi deficiency and blood stasis syndrome, is widely used to treat IPF in clinical practice. However, its potential mechanisms against IPF remain unclear. AIMS OF THE STUDY: This study was carried out to explore the therapeutic effects and underlying mechanisms of BHD on bleomycin (BLM)-induced pulmonary fibrosis in rats. MATERIALS AND METHODS: UPLC-MS/MS method was performed to identify the quality of BHD used in this study. Concurrently, a IPF rat model was established by single intratracheal injection of BLM. Pulmonary function test, H&E staining, Masson staining, hydroxyproline assay were conducted to evaluate the therapeutic effects of BHD on BLM-induced pulmonary fibrosis in rats, and the regulatory effect of BHD on endoplasmic reticulum stress (ERS)-mediated alveolar type II epithelial cells (AEC2s) apoptosis in rats was further investigated by TUNEL staining, Western blot, real-time fluorescence quantitative PCR and immunofluorescence co-staining to reveal the potential mechanisms of BHD against IPF. RESULTS: The UPLC-MS/MS analysis showed that the BHD we used complied with the relevant quality control standards. The data from animal experiments confirmed that BHD administration ameliorated BLM-induced pulmonary function decline, lung fibrotic pathological changes and collagen deposition in rats. Further mechanism study revealed that BHD increased the Bcl-2 protein expression, decreased the Bax protein expression and inhibited the cleavage of CASP3 via suppressing the activation of PERK-ATF4-CHOP pathway under continuous ERS, thereby alleviating BLM-induced AEC2s apoptosis of rats. CONCLUSION: This study demonstrated that BHD ameliorated BLM-induced pulmonary fibrosis in rats by suppressing ERS-mediated AEC2s apoptosis. Our findings can provide some fundamental research basis for the clinical application of BHD in the treatment of IPF.

Research progress of protein complex systems and their application in food: A review.

Among the common natural biomolecules, the excellent properties of proteins have attracted extensive attention from researchers for functional applications, however, in native form proteins have many limitations in the performance of their functional attribute. However, with the deepening of research, it has been found that the combination of natural active substances such as polyphenols, polysaccharides, etc. with protein molecules will make the composite system have stronger functional properties, while the utilization of pH-driven method, ultrasonic treatment, heat treatment, etc. not only provides a guarantee for the overall protein-based composite system, but also gives more possibilities to the protein-composite system. Protein composite systems are emerging in the fields of novel active packaging, functional factor delivery systems and gel systems with high medical value. The products of these protein composite systems usually have high functional properties, mainly due to the interaction of the remaining natural active substances with protein molecules, which can be broadly categorized into covalent interactions and non-covalent interactions, and which, despite the differences in these interactions, together constitute the cornerstone for the stability of protein composite systems and for in-depth research.

Quercetin influences intestinal dysbacteriosis and delays alveolar epithelial cell senescence by regulating PTEN/PI3K/AKT signaling in pulmonary fibrosis.

Pulmonary fibrosis is a chronic and progressive lung disease with high mortality. This study aims to explore the protective mechanism of quercetin against pulmonary fibrosis regarding cell senescence and gut microbiota. Rats were intratracheally injected with bleomycin (BLM) to establish a pulmonary fibrosis rat model. RLE-6TN cells were stimulated with BLM to build the model of alveolar epithelial cell senescence, and RLE-6TN-derived conditional medium (CM) was harvested to further culture fibroblasts. Histopathological changes were assessed by H&E and Masson staining. α-SMA expression was assessed by immunofluorescence assay. Senescence-associated ß-galactosidase (SA-ß-gal) staining and senescence-associated secretory phenotype (SASP) cytokine assay were conducted to assess cellular senescence. Gut microbiota was analyzed by 16S rRNA gene sequencing. The fibrosis-, senescence-, and PTEN/PI3K/AKT signaling-related proteins were examined by western blot. In BLM-induced pulmonary fibrosis rats, quercetin exerted its protective effects by reducing histological injury and collagen deposition, lessening cellular senescence, and regulating gut microbiota. In BLM-induced alveolar epithelial cell senescence, quercetin inhibited senescence, lessened SASP cytokine secretion of alveolar epithelial cells, and further ameliorated collagen deposition in fibroblasts. In addition, quercetin might exert its functional effects by regulating the PTEN/PI3K/AKT signaling pathway. Moreover, quercetin regulated intestinal dysbacteriosis in BLM-induced pulmonary fibrosis rats, especially boosting the abundance of Akkermansia. To conclude, our findings provide an in-depth understanding of the potential mechanism behind the protective role of quercetin against pulmonary fibrosis.

Does the Digital Economy Promote the Reduction of Urban Carbon Emission Intensity?

The impact of the digital economy is increasing, and its environmental effect has attracted more and more attention. The digital economy promotes the improvement of production efficiency and the government's environmental governance capacity, and contributes to the reduction of urban carbon emission intensity. In order to study the impact of digital economy development on urban carbon emission intensity, this paper analyzes the theoretical basis of the digital economy on the reduction of carbon emission intensity, and then, based on the panel data of cities from 2011 to 2019, uses the two-way fixed effect model for empirical testing. The regression results show that the development of the digital economy has promoted the reduction of carbon emission intensity of cities, promoted the green transformation and upgrading of cities, and lays a foundation for China to achieve carbon peaking and carbon neutralization through the improvement of human capital investment and green innovation level. The basic conclusion is robust by changing core explanatory variables, changing samples, replacing regression methods, and shrinking and truncating tests. The impact of the digital economy on urban carbon emission intensity varies with the location, grade and size of the city. Specifically, the development of the digital economy in cities in the eastern and central regions, cities at or above the sub provincial level, large cities and non-resource-based cities has promoted the reduction of urban carbon emission intensity. In terms of resource-based cities, the development of the digital economy in renewable resource-based cities and resource-based cities dominated by iron ore and oil mining has promoted the decline in urban carbon emission reduction intensity.

The m6A-regulation and single cell effect pattern in sunitinib resistance on clear cell renal cell carcinoma: Identification and validation of targets.

Background: Sunitinib is the main target drug for clear cell renal cell carcinoma. However, the effect of sunitinib is often limited by acquired drug resistance. Methods: The open-accessed data used in this study were obtained from different online public databases, which were analyzed using the R software. The RNA level of specific genes was detected using quantitative Real-Time PCR. Sunitinib-resistant cell lines were constructed based on protocol get from the previous study. Colony formation and Cell Counting Kit-8 assays were applied to detect cell proliferation ability. Results: In this study, through publicly available data and high-quality analysis, we deeply explored the potential biological mechanisms that affect the resistance of sunitinib. Detailed, data from GSE64052, GSE76068 and The Cancer Genome Atlas were extracted. We identified the IFITM1, IL6, MX2, PCOLCE2, RSAD2 and SLC2A3 were associated with sunitinib resistance. Single-cell analysis, prognosis analysis and m6A regulatory network were conducted to investigate their role. Moreover, the MX2 was selected for further analysis, including its biological role and effect on the ccRCC microenvironment. Interestingly, we noticed that MX2 might be an immune-related gene that could affect the response rate of immunotherapy. Then, in vitro experiments validated the overexpression of MX2 in sunitinib-resistance cells. Colony formation assay indicated that the knockdown of MX2 could remarkably inhibit the proliferation ability of 786-O-Res and Caki-1-Res when exposed to sunitinib. Conclusion: In summary, through publicly available data and high-quality analysis, we deeply explored the potential biological mechanisms that affect the resistance of sunitinib. MX2 was selected for further analysis, including its biological role and effect on the ccRCC microenvironment. Finally, in vitro experiments were used to validate its role in ccRCC.

Pericytes: The lung-forgotten cell type.

Pericytes are a heterogeneous population of mesenchymal cells located on the abluminal surface of microvessels, where they provide structural and biochemical support. Pericytes have been implicated in numerous lung diseases including pulmonary arterial hypertension (PAH) and allergic asthma due to their ability to differentiate into scar-forming myofibroblasts, leading to collagen deposition and matrix remodelling and thus driving tissue fibrosis. Pericyte-extracellular matrix interactions as well as other biochemical cues play crucial roles in these processes. In this review, we give an overview of lung pericytes, the key pro-fibrotic mediators they interact with, and detail recent advances in preclinical studies on how pericytes are disrupted and contribute to lung diseases including PAH, allergic asthma, and chronic obstructive pulmonary disease (COPD). Several recent studies using mouse models of PAH have demonstrated that pericytes contribute to these pathological events; efforts are currently underway to mitigate pericyte dysfunction in PAH by targeting the TGF-ß, CXCR7, and CXCR4 signalling pathways. In allergic asthma, the dissociation of pericytes from the endothelium of blood vessels and their migration towards inflamed areas of the airway contribute to the characteristic airway remodelling observed in allergic asthma. Although several factors have been suggested to influence this migration such as TGF-ß, IL-4, IL-13, and periostin, recent evidence points to the CXCL12/CXCR4 pathway as a potential therapeutic target. Pericytes might also play an essential role in lung dysfunction in response to ageing, as they are responsive to environmental risk factors such as cigarette smoke and air pollutants, which are the main drivers of COPD. However, there is currently no direct evidence delineating the contribution of pericytes to COPD pathology. Although there is a lack of human clinical data, the recent available evidence derived from in vitro and animal-based models shows that pericytes play important roles in the initiation and maintenance of chronic lung diseases and are amenable to pharmacological interventions. Therefore, further studies in this field are required to elucidate if targeting pericytes can treat lung diseases.