Paracrine signaling of ferroptotic airway epithelium in crystalline silica-induced pulmonary fibrosis augments local fibroblast activation through glycolysis reprogramming.

Chronic exposure to crystalline silica (CS) contributes to pulmonary fibrosis. Airway epithelium dysfunction and fibroblast activation have both been recognized as pivotal players, alongside disturbances in ferroptosis and glycolysis reprogramming. However, the mechanisms involved remain unclear. In this study, we investigated the crosstalk between airway epithelium and fibroblast in the context of CS-induced pulmonary fibrosis. CS was employed in vivo and the in vitro co-culture system of airway epithelium and fibroblast. Spatial transcriptome analysis of CS-induced fibrotic lung tissue was conducted as well. Results showed that epithelium ferroptosis caused by CS enhanced TGFß1-induced fibroblast activation through paracrine signaling. tPA was further identified to be the central mediator that bridges epithelium ferroptosis and fibroblast activation. And increased fibroblast glycolysis reprogramming was evidenced to promote fibroblast activation. By inhibition of epithelium ferroptosis or silencing tPA of airway epithelium, fibroblast AMPK phosphorylation was inhibited. Moreover, we revealed that tPA secreted by ferroptotic epithelium transmits paracrine signals to fibroblasts by governing glycolysis via p-AMPK/AMPK mediated Glut1 accumulation. Collectively, our study demonstrated the regulation of airway epithelium ferroptosis on fibroblast activation in CS-induced pulmonary fibrosis, which would shed light on the complex cellular crosstalk within pulmonary fibrosis and identify potential therapeutic targets.

Association between depressive symptoms in the postpartum period and COVID-19: A meta-analysis.

BACKGROUND: With the pandemic of COVID, the public are faced with tremendous threatens both physically and mentally. Postpartum depression (PPD) is one of the most serious complications of childbearing, bringing severe impact on a woman's mental state and mood after birth. Research has shown that maternal mental state is closely correlated with PPD, those undergo the emergency or significant life changes during the postpartum period are more likely to suffer from PPD. In this study, we conducted the meta-analysis to estimate the association between PPD and COVID-19 pandemic. METHODS: PubMed, Web of Science, PsycINFO, ScienceDirect, CNKI, China Science and Technology Journal Database, and WANFANG Database were searched for potentially relevant articles published before April 2022. Review Manager 5.2 was used to perform a meta-analysis and subgroup analysis to compute the pooled odds ratio. RESULTS: A total of 26 studies were included in this review. The overall pooled prevalence of PPD in the review was 24 % (95 % CI: 0.19-0.29), with China's at 22 % (95 % CI 0.16-0.28) and other countries at 25 % (95 % CI 0.18-0.32) during the COVID-19 pandemic. Moreover, compared to those who did not experience COVID-19, those who experienced it had an increased risk of PPD[OR:1.83(95 % CI 1.70-1.97)]. CONCLUSIONS: According to this analysis, there was a significantly higher prevalence and odds of PPD in those who suffered from the COVID-19 pandemic. Additionally, we also found that China had a lower prevalence of postpartum depression than other countries during the COVID-19 pandemic. Our study may provide the instruction for the care of new mother under the situation of COVID-19 prevalence.

Vitamin D protects silica particles induced lung injury by promoting macrophage polarization in a KLF4-STAT6 manner.

Silicosis is one of the severest occupational diseases worldwide, manifesting as infiltration of inflammatory cells, excessive secretion of pro-inflammatory mediators and pulmonary diffuse fibrosis. Macrophages polarization to M2 is one of the major strategies that attenuates inflammatory response. Our previous study found that vitamin D could protect against silica-induced lung injury by damping the secretion of pro-inflammatory cytokines. Here we further identified that vitamin D attenuated silica particles-induced lung inflammation by regulating macrophage polarization in a KLF4-STAT6 manner. Myeloid-specific Stat6 knockout (cKO) mice were generated for in vivo studies. Primary macrophages purified from bronchoalveolar lavage fluid (BALF) of wildtype or Stat6 cKO mice and differentiated THP-1 cells were used for in vitro studies. Vitamin D was found to promote alveolar macrophage polarizing to M2 phenotype through the STAT6 signaling pathway, as demonstrated by worse lung inflammation and ablated protection of vitamin D in silica particles-instilled Stat6 cKO mice. Mechanismly, vitamin D upregulated KLF4 expression in the alveolar macrophage, which synergistically activated STAT6. Additionally, KLF4 was found to upregulate macrophages autophagy, which protected them from silica particles-induced oxidative stress and cell apoptosis. The protective effects of vitamin D were dismissed by silencing KLF4. Our study demonstrates the potential mechanism of vitamin D-mediated macrophage polarization and reveals the therapeutic application of vitamin D in inflammatory disease.

STAT6 inhibits ferroptosis and alleviates acute lung injury via regulating P53/SLC7A11 pathway.

Compelling evidences have revealed the emerging role of ferroptosis in the pathophysiological process of acute lung injury (ALI), but its modulation is not clear. Here, we identified that STAT6 acted as a critical regulator of epithelium ferroptosis during ALI. Firstly, STAT6 expression and activity were increased in the ALI mice models caused by crystalline silica (CS), LPS and X-ray exposure. Followed by confirming the contribution of ferroptosis in the above ALI with ferrostatin-1 and deferoxamine intervention, bioinformatic analyses revealed that STAT6 expression was negatively correlated with ferroptosis. Consistently, lung epithelium-specific depletion of STAT6 in mice or STAT6 knockdown in cultured epithelial cells exacerbated ferroptosis in the above ALI. While overexpression of STAT6 in lung epithelial cells attenuated the ferroptosis. Mechanistically, SLC7A11 is a typical ferroptosis-related gene and negatively regulated by P53. CREB-binding protein (CBP) is a critical acetyltransferase of P53 acetylation, showing valuable regulation on targets' transcription. Herein, we found that STAT6 negatively regulates ferroptosis through competitively binding with CBP, which inhibits P53 acetylation and transcriptionally restores SLC7A11 expression. Finally, pulmonary-specific STAT6 overexpression decreased the ferroptosis and attenuated CS and LPS induced lung injury. Our findings revealed that STAT6 is a pivotal regulator of ferroptosis, which may be a potential therapeutic target for the treatment of acute lung injury.

Echem methods and electrode types of the current in vivo electrochemical sensing.

For a long time, people have been eager to realize continuous real-time online monitoring of biological compounds. Fortunately, in vivo electrochemical biosensor technology has greatly promoted the development of biological compound detection. This article summarizes the existing in vivo electrochemical detection technologies into two categories: microdialysis (MD) and microelectrode (ME). Then we summarized and discussed the electrode surface time, pollution resistance, linearity and the number of instances of simultaneous detection and analysis, the composition and characteristics of the sensor, and finally, we also predicted and prospected the development of electrochemical technology and sensors in vivo.

STAT6 contributes to renal fibrosis by modulating PPARα-mediated tubular fatty acid oxidation.

Lipid metabolism, especially fatty acid oxidation (FAO) dysfunction, is a major driver of renal fibrosis; however, the detailed regulatory mechanisms involved remain unclear. In this study, we showed that there existed an association between the signal transducer and activator of transcription 6 (STAT6) and tubular lipid metabolism in fibrotic kidneys. Specifically, STAT6 was activated along with the accumulation of lipids via the downregulation of FAO-related genes when mice were subjected to unilateral ureteral obstruction (UUO) or high-fat diet challenge. Tubular-specific depletion, or pharmacologic inhibitor of Stat6 in mice, and Stat6 knockdown in cultured tubular cells attenuated lipid accumulation and renal fibrosis by enhancing FAO. Mechanistically, STAT6 transcriptionally inhibited the expression of PPARα and its FAO-related target genes through a sis-inducible element located in the promoter region of the protein. In conclusion, our study demonstrates the mechanistic details of STAT6-mediated FAO dysregulation in the progression of renal fibrosis and provides a preclinical rationale for efforts to improve the management of renal fibrosis brought about by FAO dysregulation.

STAT6/VDR Axis Mitigates Lung Inflammatory Injury by Promoting Nrf2 Signaling Pathway.

Lung inflammatory injury is a global public health concern. It is characterized by infiltration of diverse inflammatory cells and thickening of pulmonary septum along with oxidative stress to airway epithelial cells. STAT6 is a nuclear transcription factor that plays a crucial role in orchestrating the immune response, but its function in tissue inflammatory injury has not been comprehensively studied. Here, we demonstrated that STAT6 activation can protect against particle-induced lung inflammatory injury by resisting oxidative stress. Specifically, genetic ablation of STAT6 was observed to worsen particle-induced lung injury mainly by disrupting the lungs' antioxidant capacity, as reflected by the downregulation of the Nrf2 signaling pathway, an increase in malondialdehyde levels, and a decrease in glutathione levels. Vitamin D receptor (VDR) has been previously proved to positively regulate Nrf2 signals. In this study, silencing VDR expression in human bronchial epithelial BEAS-2B cells consistently suppressed autophagy-mediated activation of the Nrf2 signaling pathway, thereby aggravating particle-induced cell damage. Mechanically, STAT6 activation promoted the nuclear translocation of VDR, which increased the transcription of autophagy-related genes and induced Nrf2 signals, and silencing VDR abolished these effects. Our research provides important insights into the role of STAT6 in oxidative damage and reveals its potential underlying mechanism. This information not only deepens the appreciation of STAT6 but also opens new avenues for the discovery of therapies for inflammatory respiratory system disorders.

m6A eraser FTO modulates autophagy by targeting SQSTM1/P62 in the prevention of canagliflozin against renal fibrosis.

The dysregulation of autophagy contributes to renal fibrosis. N6-Methyladenosine (m6A) RNA modification is a critical mediator of autophagy. Our previous studies have reported that the disorder of the PPARα/fatty acid oxidation (FAO) axis in renal tubular cells is suppressed by STAT6, which is involved in the regulation of renal fibrotic processes. Here, we found that canagliflozin significantly upregulates SQSTM1/P62, promoting PPARα-mediated FAO by inducing autophagy-dependent STAT6 degradation both in TGF-ß1-treated HK2 cells and in unilateral ureteral occlusion (UUO) and ischemia-reperfusion (I/R) renal fibrosis mouse models. Knockdown of P62/SQSTM1 led to the impairment autophagic flux and the dysregulation of the STAT6/PPARα axis, which was confirmed by SQSTM1/P62cKO mice with UUO treatment along with bioinformatics analysis. Furthermore, SQSTM1/P62 deficiency in renal tubular cells inhibited canagliflozin's effects that prevent FAO disorder in renal tubular cells and renal fibrosis. Mechanistically, the level of m6A eraser FTO, which interacted with SQSTM1 mRNA, decreased in the renal tubular cells both in vitro and in vivo after canagliflozin administration. Decrease in FTO stabilized SQSTM1 mRNA, which induced autophagosome formation. Collectively, this study uncovered a previously unrecognized function of canagliflozin in FTO in the autophagy modulation through the regulation of SQSTM1 mRNA stability in the renal tubular STAT6/PPARα/FAO axis and renal fibrosis.

Upregulation of autophagy in M2 macrophage by vitamin D alleviates crystalline silica-induced pulmonary inflammatory damage.

Crystalline silica (CS) is a universal environmental pollutant, which causes a typical inflammatory lung injury. Vitamin D shows huge potential against particles-induced lung injury, while little known about the molecular mechanism involved in macrophage autophagy. In this study, we aim to identify the protective effects of vitamin D on CS caused lung inflammatory injury and clarify the detail mechanism. After exposure to CS (3 mg/mice in 50 µl PBS), wildtype and Atg7flox/flox Lyz2-cre mice were treated with or without vitamin D3 (40,000 IU/kg). The results indicated that exposure to CS caused an obvious lung injury, manifesting as pathological structural changes, macrophage-dominated inflammatory cell infiltration and increased pro-inflammatory cytokines. Remarkably, these damages were more serious in Atg7flox/flox Lyz2-cre mice. Vitamin D was found to inverse CS-induced inflammatory cell infiltration and restored anti-inflammatory M2 macrophages by inducing autophagy, which attenuated lung injury, as determined by decreased levels of apoptosis and inflammatory response. While, this effects of vitamin D were slashed in Atg7flox/flox Lyz2-cre mice. This study reveals the adverse effect of CS on lung tissue and the protective mechanism of vitamin D involved in M2 macrophages autophagy, which attenuates CS-caused lung injury.