B(a)P induces ovarian granulosa cell apoptosis via TRAF2-NFκB-Caspase1 axis during early pregnancy.

Benzo(a)pyrene [B(a)P] is an environmental endocrine disruptor with reproductive toxicity. The corpus luteum (CL) of the ovary plays an important role in embryo implantation and pregnancy maintenance. Our previous studies have shown that B(a)P exposure affects embryo implantation and endometrial decidualization in mouse, but its effects and mechanisms on CL function remain unclear. In this study, we explore the mechanism of ovarian toxicity of B(a)P using a pregnant mouse model and an in vitro model of human ovarian granulosa cells (GCs) KGN. Pregnant mice were gavaged with corn oil or 0.2 mg/kg.bw B(a)P from pregnant day 1 (D1) to D7, while KGN cells were treated with DMSO, 1.0IU/mL hCG, or 1.0IU/mL hCG plus benzo(a)pyrene-7,8-dihydrodiol-9,10-epoxide (BPDE), a B(a)P metabolite. Our findings revealed that B(a)P exposure damaged embryo implantation and reduced estrogen and progesterone levels in early pregnant mice. Additionally, in vitro, BPDE impaired luteinization in KGN cells. We observed that B(a)P/BPDE promoted oxidative stress (OS) and inflammation, leading to apoptosis rather than pyroptosis in ovaries and luteinized KGN cells. This apoptotic response was mediated by the activation of inflammatory Caspase1 through the cleavage of BID. Furthermore, B(a)P/BPDE inhibited TRAF2 expression and suppressed NFκB signaling pathway activation. The administration of VX-765 to inhibit the Caspase1 activation, over-expression of TRAF2 using TRAF2-pcDNA3.1 (+) plasmid, and BetA-induced activation of NFκB signaling pathway successfully alleviated BPDE-induced apoptosis and cellular dysfunction in luteinized KGN cells. These findings were further confirmed in the KGN cell treated with H2O2 and NAC. In conclusion, this study elucidated that B(a)P/BPDE induces apoptosis rather than pyroptosis in GCs via TRAF2-NFκB-Caspase1 during early pregnancy, and highlighting OS as the primary contributor to B(a)P/BPDE-induced ovarian toxicity. Our results unveil a novel role of TRAF2-NFκB-Caspase1 in B(a)P-induced apoptosis and broaden the understanding of mechanisms underlying unexplained luteal phase deficiency.

CD36-mediated podocyte lipotoxicity promotes foot process effacement.

Background: Lipid metabolism disorders lead to lipotoxicity. The hyperlipidemia-induced early stage of renal injury mainly manifests as podocyte damage. CD36 mediates fatty acid uptake and the subsequent accumulation of toxic lipid metabolites, resulting in podocyte lipotoxicity. Methods: Male Sprague-Dawley rats were divided into two groups: the normal control group and the high-fat diet group (HFD). Podocytes were cultured and treated with palmitic acid (PA) and sulfo-N-succinimidyl oleate (SSO). Protein expression was measured by immunofluorescence and western blot analysis. Boron-dipyrromethene staining and Oil Red O staining was used to analyze fatty acid accumulation. Results: Podocyte foot process (FP) effacement and marked proteinuria occurred in the HFD group. CD36 protein expression was upregulated in the HFD group and in PA-treated podocytes. PA-treated podocytes showed increased fatty acid accumulation, reactive oxygen species (ROS) production, and actin cytoskeleton rearrangement. However, pretreatment with the CD36 inhibitor SSO decreased lipid accumulation and ROS production and alleviated actin cytoskeleton rearrangement in podocytes. The antioxidant N-acetylcysteine suppressed PA-induced podocyte FP effacement and ROS generation. Conclusions: CD36 participated in fatty acid-induced FP effacement in podocytes via oxidative stress, and CD36 inhibitors may be helpful for early treatment of kidney injury.

Comprehensive quality evaluation of fermented-steaming Fructus Aurantii based on chemical composition, flavor characteristics, and intestinal microbial community.

Fructus Aurantii (FA) is an edible and medicinal functional food used worldwide that enhances digestion. Since raw FA (RFA) possesses certain side effects for some patients, processed FA (PFA) is commonly used in clinical practice. This study aimed to establish an objective and comprehensive quality evaluation of the PFA that employed the technique of steaming and fermentation. Combined with the volatile and non-volatile components, as well as the regulation of gut microbiota, the differentiation between RFA and PFA was analyzed. The results showed that the PFA considerably reduced the contents of flavonoid glycosides while increasing hesperidin-7-O-glucoside and flavonoid aglycones. The electronic nose and GC-MS (Gas chromatography/mass spectrometry) effectively detected the variation in flavor between RFA and PFA. Correlation analysis revealed that eight volatile components (relative odor activity value [ROAV] ≥ 0.1) played a key role in inducing odor modifications. The original floral and woody notes were subdued due to decreased levels of linalool, sabinene, α-terpineol, and terpinen-4-ol. After processing, more delightful flavors such as lemon and fruity aromas were acquired. Furthermore, gut microbiota analysis indicated a significant increase in beneficial microbial taxa. Particularly, Lactobacillus, Akkermansia, and Blautia exhibited higher abundance following PFA treatment. Conversely, a lower presence of pathogenic bacteria, including Proteobacteria, Flexispira, and Clostridium. This strategy contributes to a comprehensive analysis technique for the quality assessment of FA, providing scientific justifications for processing FA into high-value products with enhanced health benefits. PRACTICAL APPLICATION: This study provided an efficient approach to Fructus Aurantii quality evaluation. The methods of fermentation and steaming showed improved quality and safety.

Arabidopsis transcription factor TCP4 controls the identity of the apical gynoecium.

The style and stigma at the apical gynoecium are crucial for flowering plant reproduction. However, the mechanisms underlying specification of the apical gynoecium remain unclear. Here, we demonstrate that Class II TEOSINTE BRANCHED 1/CYCLOIDEA/PCF (TCP) transcription factors are critical for apical gynoecium specification in Arabidopsis (Arabidopsis thaliana). The septuple tcp2 tcp3 tcp4 tcp5 tcp10 tcp13 tcp17 (tcpSEP) and duodecuple tcp2 tcp3 tcp4 tcp5 tcp10 tcp13 tcp17 tcp24 tcp1 tcp12 tcp18 tcp16 (tcpDUO) mutants produce narrower and longer styles, while disruption of TCPs and CRABS CLAW (CRC) or NGATHAs (NGAs) in tcpDUO crc or tcpDUO nga1 nga2 nga4 causes the apical gynoecium to be replaced by lamellar structures with indeterminate growth. TCPs are predominantly expressed in the apex of the gynoecium. TCP4 interacts with CRC to synergistically up-regulate the expression level of NGAs, and NGAs further form high-order complexes to control the expression of auxin-related genes in the apical gynoecium by directly interacting with TCP4. Our findings demonstrate that TCP4 physically associates with CRC and NGAs to control auxin biosynthesis in forming fine structures of the apical gynoecium.

Progress of lymphocyte activation gene 3 and programmed cell death protein 1 antibodies for cancer treatment: A review.

The application of immune checkpoint inhibitors has proven to be an effective treatment for cancer. Immune checkpoints such as programmed cell death protein 1/programmed cell death protein 1 ligand 1 (PD-1/PD-L1), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), T-cell immunoglobulin-3 (TIM-3), T-cell immunoglobulin and ITIM domain (TIGIT), and lymphocyte activation gene-3 (LAG-3) have received extensive attention, and the efficacy of antibodies or inhibitors against these checkpoints (either alone or in combination) has been evaluated in many tumors. This paper provides a brief overview of the PD-1 and LAG-3 checkpoints, and then shifts focus to the combined use of PD-1 and LAG-3 antibodies in both in vivo and in vitro experiments. In the in vitro experiments, we examined the correlation between the expression and activation of these inhibitors on T cells, and also assessed toxicity in animals in preparation for in vivo experiments. The effects of the combined use of PD-1 and LAG-3 antibodies were then summarized in animal models of melanoma, MC38 carcinoma, and other tumors. In clinical studies, the combined application of these antibodies was assessed in patients with melanoma, colorectal, breast, and renal cell cancers, as well as other solid tumors. In general, the combination of PD-1 and LAG-3 antibodies has shown promising results in both in vivo and in vitro studies.

Maternal exposure to beta-Cypermethrin disrupts placental development by dysfunction of trophoblast cells from oxidative stress.

As a broad-spectrum and efficient insecticide, beta-Cypermethrin (ß-CYP) poses a health risk to pregnancy. It matters the mechanisms of maternal exposure to ß-CYP for impacting reproductive health. The placenta, a transient organ pivotal for maternal-fetal communication during pregnancy, plays a crucial role in embryonic development. The effect of ß-CYP exposure on the placenta and its underlying molecular mechanisms remain obscure. The objective of this study was to investigate the effect of ß-CYP exposure on placental development and the function of trophoblast, as well as the underlying mechanisms through CD-1 mouse model (1, 10, 20 mg/kg.bw) and in vitro HTR-8/SVneo cell model (12.5, 25, 50, 100 µM). We found slower weight gain and reduced uterine wet weight in pregnant mice with maternal exposure to ß-CYP during pregnancy, as well as adverse pregnancy outcomes such as uterine bleeding and embryo resorption. The abnormal placental development in response to ß-CYP was noticed, including imbalanced placental structure and disrupted labyrinthine vascular development. Trophoblasts, pivotal in placental development and vascular remodeling, displayed abnormal differentiation under ß-CYP exposure. This aberration was characterized by thickened trophoblast layers in the labyrinthine zone, accompanied by mitochondrial and endoplasmic reticulum swelling within trophoblasts. Further researches on human chorionic trophoblast cell lines revealed that ß-CYP exposure induced apoptosis in HTR-8/SVneo cells. This induction resulted in a notable decrease in migration and invasion abilities, coupled with oxidative stress and the inhibition of the Notch signaling pathway. N-acetylcysteine (an antioxidant) partially restored the impaired Notch signaling pathway in HTR-8/SVneo cells, and mitigated cellular functional damage attributed to ß-CYP exposure. Collectively, exposure to ß-CYP induced oxidative stress and then led to inhibition of the Notch signaling pathway and dysfunction of trophoblast cells, ultimately resulted in abnormal placenta and pregnancy. These findings indicate Reactive Oxygen Species as potential intervention targets to mitigate ß-CYP toxicity. The comprehensive elucidation contributes to our understanding of ß-CYP biosafety and offers an experimental basis for preventing and managing its reproductive toxicity.

The diversity of inhibitory receptor co-expression patterns of exhausted CD8+ T cells in oropharyngeal carcinoma.

Exhausted CD8+ T cells (Texs) are characterized by the expression of various inhibitory receptors (IRs), whereas the functional attributes of these co-expressed IRs remain limited. Here, we systematically characterized the diversity of IR co-expression patterns in Texs from both human oropharyngeal squamous cell carcinoma (OPSCC) tissues and syngeneic OPSCC model. Nearly 60% of the Texs population co-expressed two or more IRs, and the number of co-expressed IRs was positively associated with superior exhaustion and cytotoxicity phenotypes. In OPSCC patients, programmed cell death-1 (PD-1) blockade significantly enhanced PDCD1-based co-expression with other IR genes, whereas dual blockades of PD-1 and cytotoxic T lymphocyte-associated protein 4 (CTLA-4) significantly upregulated CTLA4-based co-expression with other IR genes. Collectively, our findings demonstrate that highly diverse IR co-expression is a leading feature of Texs and represents their functional states, which might provide essential clues for the rational selection of immune checkpoint inhibitors in treating OPSCC.

The relationship between thiamin, folic acid and cognitive function in a rat model of uremia.

End-stage renal disease is a worldwide health burden, but the pathogenesis of uremia-associated cognitive impairment (CI) is poorly recognized. We hypothesized that uremia brings about deficiency of thiamin and folic acid and causes CI by inducing oxidative stress. Therefore, 24 Sprague-Dawley rats were randomly divided into two groups: a 5/6 nephrectomy group (n = 12) and a sham-operated group (n = 12). The Morris water maze was used to assess the cognitive function eight weeks post-surgery, and serum levels of thiamin, folic acid and homocysteine were detected subsequently. Brain and kidney tissues were collected for pathological examination and 8-Hydroxy-2'-deoxyguanosine (8-OHdG) immunochemistry staining. Results showed that the escape latency on training days 1-2 was longer, and the time in quadrant IV on experimental day 6 was significantly shorter in 5/6 nephrectomy group. Meanwhile, the uremic rats showed decreased thiamin, folic acid and increased homocysteine. We also found the time in quadrant IV was positively correlated with thiamin and folic acid level, while negatively correlated with the blood urea nitrogen and 8-OHdG positive cell proportion. Furthermore, in 5/6 nephrectomy group, the hippocampal neuron count was significantly reduced, and a greater proportion of 8-OHdG positive cells were detected. Pretreating LPS-stimulated rat microglial cells with thiamin or folic acid in vitro alleviated the inflammatory impairment in terms of cell viability and oxidative stress. In summary, we applied a uremic rat model and proved that uremia causes serum thiamin and folic acid deficiency, homocysteine elevation, along with neuron reduction and severe oxidative stress in hippocampus, finally leading to CI.

Toll/interleukin-1 receptor (TIR) domain-containing proteins have NAD-RNA decapping activity.

The occurrence of NAD+ as a non-canonical RNA cap has been demonstrated in diverse organisms. TIR domain-containing proteins present in all kingdoms of life act in defense responses and can have NADase activity that hydrolyzes NAD+. Here, we show that TIR domain-containing proteins from several bacterial and one archaeal species can remove the NAM moiety from NAD-capped RNAs (NAD-RNAs). We demonstrate that the deNAMing activity of AbTir (from Acinetobacter baumannii) on NAD-RNA specifically produces a cyclic ADPR-RNA, which can be further decapped in vitro by known decapping enzymes. Heterologous expression of the wild-type but not a catalytic mutant AbTir in E. coli suppressed cell propagation and reduced the levels of NAD-RNAs from a subset of genes before cellular NAD+ levels are impacted. Collectively, the in vitro and in vivo analyses demonstrate that TIR domain-containing proteins can function as a deNAMing enzyme of NAD-RNAs, raising the possibility of TIR domain proteins acting in gene expression regulation.

Late gestational exposure to fenvalerate impacts ovarian reserve in neonatal mice via YTHDF2-mediated P-body assembly.

Fenvalerate (FEN), a type II pyrethroid pesticide, finds extensive application in agriculture, graziery and public spaces for pest control, resulting in severe environmental pollution. As an environmental endocrine disruptor with estrogen-like activity, exposure to FEN exhibited adverse effects on ovarian functions. Additionally, the presence of the metabolite of FEN in women's urine shows a positive association with the risk of primary ovarian insufficiency (POI). In mammals, the primordial follicle pool established during the early life serves as a reservoir for storing all available oocytes throughout the female reproductive life. The initial size of the primordial follicle pool and the rate of its depletion affect the occurrence of POI. Nevertheless, there is very limited research about the impact of FEN exposure on primordial folliculogenesis. In this study, pregnant mice were orally administrated with 0.2, 2.0 and 20.0 mg/kg FEN from 16.5 to 18.5 days post-coitus (dpc). Ovaries exposed to FEN exhibited the presence of large germ-cell cysts that persist on 1 days post-parturition (1 dpp), followed by a significant reduction in the total number of oocytes in pups on 5 dpp. Moreover, the levels of m6A-RNA and its associated proteins METTL3 and YTHDF2 were significantly increased in the ovaries exposed to FEN. The increased YTHDF2 promoted the assembly of the cytoplasmic processing bodies (P-body) in the oocytes, accompanied with altered expression of transcripts. Additionally, when YTHDF2 was knocked-down in fetal ovary cultures, the primordial folliculogenesis disrupted by FEN exposure was effectively restored. Further, the female offspring exposed to FEN displayed ovarian dysfunctions reminiscent of POI in early adulthood, characterized by decreases in ovarian coefficient and female hormone levels. Therefore, the present study revealed that exposure to FEN during late pregnancy disrupted primordial folliculogenesis by YTHDF2-mediated P-body assembly, causing enduring adverse effects on female fertility.

A gender recognition method based on EEG microstates.

BACKGROUND: Gender carries important information related to male and female characteristics, and a large number of studies have attempted to use physiological measurement methods for gender classification. Although previous studies have shown that there exist statistical differences in some Electroencephalographic (EEG) microstate parameters between males and females, it is still unknown that whether these microstate parameters can be used as potential biomarkers for gender classification based on machine learning. METHODS: We used two independent resting-state EEG datasets: the first dataset included 74 females and matched 74 males, and the second one included 42 males and matched 42 females. EEG microstate analysis based on modified k-means clustering method was applied, and temporal parameter and nonlinear characteristics (sample entropy and Lempel-Ziv complexity) of EEG microstate sequences were extracted to compare between males and females. More importantly, these microstate temporal parameters and complexity were tried to train six machine learning methods for gender classification. RESULTS: We obtained five common microstates for each dataset and each group. Compared with the male group, the female group has significantly higher temporal parameters of microstate B, C, E and lower temporal parameters of microstate A and D, and higher complexity of microstate sequence. When using combination of microstate temporal parameters and complexity or only microstate temporal parameters as classification features in an independent test set (the second dataset), we achieved 95.2% classification accuracy. CONCLUSION: Our research findings indicate that the dynamics of microstate have considerable Gender-specific alteration. EEG microstates can be used as neurophysiological biomarkers for gender classification.

Corrigendum: Ultrastructural characteristics of neuronal death and white matter injury in mouse brain tissues after intracerebral hemorrhage: coexistence of ferroptosis, autophagy, and necrosis.

[This corrects the article DOI: 10.3389/fneur.2018.00581.].

Role of mRNA-binding proteins in retinal neovascularization.

Retinal neovascularization (RNV) is a pathological process that primarily occurs in diabetic retinopathy, retinopathy of prematurity, and retinal vein occlusion. It is a common yet debilitating clinical condition that culminates in blindness. Urgent efforts are required to explore more efficient and less limiting therapeutic strategies. Key RNA-binding proteins (RBPs), crucial for post-transcriptional regulation of gene expression by binding to RNAs, are closely correlated with RNV development. RBP-RNA interactions are altered during RNV. Here, we briefly review the characteristics and functions of RBPs, and the mechanism of RNV. Then, we present insights into the role of the regulatory network of RBPs in RNV. HuR, eIF4E, LIN28B, SRSF1, METTL3, YTHDF1, Gal-1, HIWI1, and ZFR accelerate RNV progression, whereas YTHDF2 and hnRNPA2B1 hinder it. The mechanisms elucidated in this review provide a reference to guide the design of therapeutic strategies to reverse abnormal processes.

Exosomes promote pre-metastatic niche formation in colorectal cancer.

It is well known that colorectal cancer (CRC) has a high morbidity rate, a poor prognosis when metastasized, and a greatly shortened 5-year survival rate. Therefore, understanding the mechanism of tumor metastasis is still important. Based on the "seed and soil" theory, the concept of " premetastatic niche (PMN)" was introduced by Kaplan et al. The complex interaction between primary tumors and the metastatic organ provides a beneficial microenvironment for tumor cells to colonize at a distance. With further exploration of the PMN, exosomes have gradually attracted interest from researchers. Exosomes are extracellular vesicles secreted from cells that include various biological information and are involved in communication between cells. As a key molecule in the PMN, exosomes are closely related to tumor metastasis. In this article, we obtained information by conducting a comprehensive search across academic databases including PubMed and Web of Science using relevant keywords. Only recent, peer-reviewed articles published in the English language were considered for inclusion. This study aims to explore in depth how exosomes promote the formation of pre-metastatic microenvironment (PMN) in colorectal cancer and its related mechanisms.

Maternal exposure to ZIF-8 derails placental function by inducing trophoblast pyroptosis through neutrophils activation in mice.

Adverse environmental factors during maternal gestation pose a threat to pregnancy. Environmental factors, particularly nanoparticles, can impact pregnancy by causing damage to the placenta. Compared to early gestation, foetuses in late gestation are more robustly developed and at lower risk of adverse effects from environmental factors. Delivery systems for targeted therapy during pregnancy is predominantly focused on their application in late gestation. Zeolitic imidazolate framework-8 (ZIF-8) holds great potential for targeted drug therapy. To evaluate the value of ZIF-8 in targeted treatment of disorders associated with late gestation, it is crucial to investigate the biological effects of ZIF-8 exposure during late gestation. Here, a mouse model exposed to ZIF-8 particles at different doses (5, 10, and 15 mg/kg) during late gestation was constructed. We found that ZIF-8 particles were deposited in the uterus of pregnant mice. ZIF-8 could trigger placental neutrophil aggregation and induce inflammation, which led to trophoblast pyroptosis and impair placental function, adversely affecting the foetus. Neutrophil depletion alleviated placental and foetal damage induced by ZIF-8. This study provides a novel mechanistic view of the reproductive toxicity induced by ZIF-8 and may offer clues to reduce the latent harm of adverse environmental factors to pregnancy.

Anatomical changes and dosimetric analysis of the neck region based on FBCT for nasopharyngeal carcinoma patients during radiotherapy.

BACKGROUND: The study aimed to investigate anatomical changes in the neck region and their impact on dose distribution in patients with nasopharyngeal carcinoma (NPC) undergoing intensity modulated radiation therapy (IMRT), as well as to determine the optimal time for replanning during treatment. METHODS: Twenty NPC patients received IMRT with weekly pretreatment in-room kV fan beam computed tomography (FBCT) scans. Metastasized lymph nodes in the neck region and organs at risk (OARs) were recontoured based on the FBCT scans. The original treatment plan (PLAN0) was copied to each FBCT scan to create new plans of PLAN 1-6, correspondingly. The dose-volume histograms (DVH) of the new plans and the original plan were compared. One-way repeated measure ANOVA was employed to define threshold(s) at any timepoint. The presence of a threshold(s) would indicate significant anatomical change(s) such that replanning should be suggested. RESULTS: Progressive volume reductions in the neck region, gross target volume for metastatic lymph nodes (GTVnd), submandibular glands, and parotids were observed over time. Compared to PLAN0, Dmean of GTVnd-L significantly increased in PLAN5, while the D95% of PGTVnd-L showed a significant decrease from PLAN3 to PLAN6. Similarly, the Dmean of GTVnd-R significantly increased from PLAN4 to PLAN6, whereas the D95% of PGTVnd-R exhibited a significant decrease from PLAN3 to PLAN6. Furthermore, a gradual increase in the dose delivered to the bilateral parotid glands, bilateral submandibular glands, brainstem, and spinal cord from PLAN0 to PLAN6. CONCLUSION: Significant anatomic and dosimetric changes were observed in the target volumes and OARs. Based on the identified thresholds, replanning at approximately 20 fractions is crucial to ensure adequate target volumes dose and avoid overdosing to the OARs. This approach is clinically feasible and strongly recommended, particularly for centers without access to an adaptive planning system.

Pancancer analysis of the prognostic and immunological role of FANCD2: a potential target for carcinogenesis and survival.

Recent evidence has shed light on the significant role of FANCD2 in cancer initiation, development, and progression. However, a comprehensive pan-cancer analysis of FANCD2 has been lacking. In this study, we have conducted a thorough investigation into the expression profiles and prognostic significance of FANCD2, as well as its correlation with clinicopathological parameters and immune cell infiltration, using advanced bioinformatic techniques. The results demonstrate that FANCD2 is significantly upregulated in various common cancers and is associated with prognosis. Notably, higher expression levels of FANCD2 are linked to poor overall survival, as indicated by Cox regression and Kaplan-Meier analyses. Additionally, we have observed a decrease in the methylation of FANCD2 DNA in some cancers, and this decrease is inversely correlated with FANCD2 expression. Genetic alterations in FANCD2 predominantly manifest as mutations, which are associated with overall survival, disease-specific survival, disease-free survival, and progression-free survival in certain tumor types. Moreover, FANCD2 exhibits a strong correlation with infiltrating cell levels, immune checkpoint genes, tumor mutation burden (TMB), and microsatellite instability (MSI). Enrichment analysis further highlights the potential impact of FANCD2 on Fanconi anemia (FA) pathway and cell cycle regulation. Through this comprehensive pan-cancer analysis, we have gained a deeper understanding of the functions of FANCD2 in oncogenesis and metastasis across different types of cancer.

MicroRNA1432 regulates rice drought stress tolerance by targeting the CALMODULIN-LIKE2 gene.

Due to climate change, drought has become a major threat to rice (Oryza sativa L.) growth and yield worldwide. Understanding the genetic basis of drought tolerance in rice is therefore of great importance. Here, we identified a microRNA, miR1432, which regulates rice drought tolerance by targeting the CALMODULIN-LIKE2 (OsCaML2) gene. Mutation of MIR1432 (Bhardwaj et al., 2014). Moreover, recent studies have demonstrated that some miRNAs, such as miR164 (Fang et al., 2014), miR166 (Zhang et al., 2018), miR319 (Zhou et al., 2013) and miR408 (Hang et al., 2021), play important roles in regulating plant drought resistance. An improved understanding of the miRNA-mediated regulatory mechanisms involved in drought resistance would help to elucidate the regulatory networks that control drought stress responses and adaptation to water deficiency and may facilitate the genetic engineering of drought-tolerant crop varieties.

Dectin-1 aggravates neutrophil inflammation through caspase-11/4-mediated macrophage pyroptosis in asthma.

BACKGROUND: The pattern recognition receptor Dectin-1 was initially discovered to play a pivotal role in mediating pulmonary antifungal immunity and promoting neutrophil-driven inflammation. Recent studies have revealed that Dectin-1 is overexpressed in asthma, but the specific mechanism remains elusive. Additionally, Dectin-1 has been implicated in promoting pyroptosis, a hallmark of severe asthma airway inflammation. Nevertheless, the involvement of the non-classical pyroptosis signal caspase-11/4 and its upstream regulatory mechanisms in asthma has not been completely explored. METHODS: House dust mite (HDM)-induced mice was treated with Dectin-1 agonist Curdlan, Dectin-1 inhibitor Laminarin, and caspase-11 inhibitor wedelolactone separately. Subsequently, inflammatory cells in bronchoalveolar lavage fluid (BALF) were analyzed. Western blotting was performed to measure the protein expression of caspase-11 and gasdermin D (GSDMD). Cell pyroptosis and the expression of chemokine were detected in vitro. The correlation between Dectin-1 expression, pyroptosis factors and neutrophils in the induced sputum of asthma patients was analyzed. RESULTS: Curdlan appeared to exacerbate neutrophil airway inflammation in asthmatic mice, whereas wedelolactone effectively alleviated airway inflammation aggravated by Curdlan. Moreover, Curdlan enhanced the release of caspase-11 activation fragments and N-terminal fragments of gasdermin D (GSDMD-N) stimulated by HDM both in vivo or in vitro. In mouse alveolar macrophages (MH-S cells), Curdlan/HDM stimulation resulted in vacuolar degeneration and elevated lactate dehydrogenase (LDH) release. In addition, there was an upregulation of neutrophil chemokines CXCL1, CXCL3, CXCL5 and their receptor CXCR2, which was suppressed by wedelolactone. In asthma patients, a positive correlation was observed between the expression of Dectin-1 on macrophages and caspase-4 (the human homology of caspase-11), and the proportion of neutrophils in induced sputum. CONCLUSION: Dectin-1 activation in asthma induced caspase-11/4 mediated macrophage pyroptosis, which subsequently stimulated the secretion of chemokines, leading to the exacerbation of airway neutrophil inflammation.