Tannic acid alleviates 3-nitropropionic acid-induced ovarian damage in Brandt's vole (Lasiopodomys brandtii).

Tannic acid (TA) is a polyphenol with antioxidant properties present in various plants. In this study, we explored the protective effect of TA against ovarian oxidative stress in Brandt's voles and its underlying mechanism. At various doses, 3-nitropropionic acid (3-NPA) was intraperitoneally injected into Brandt's voles to simulate ovarian oxidative stress. Thereafter, various doses of TA were intragastrically administered to examine the protective effect of TA against 3-NPA-induced ovarian damage. Changes in inflammation, autophagy, apoptosis, and oxidative stress-related factors were investigated through various biochemical and histological techniques. Ovarian oxidative stress was successfully induced by the intraperitoneal administration of 12.5 mg/kg 3-NPA for 18 days. As a result, the ovarian coefficient decreased and ovarian tissue fibrosis was induced. TA treatment effectively alleviated the increase in luteinizing hormone and follicle-stimulating hormone levels; the decrease in estradiol, progesterone, and anti-Müllerian hormone levels; and the decline in fertility induced by 3-NPA. Compared to that in the 3-NPA group, TA decreased the expression of autophagy-related proteins beclin-1 and LC3, as well as the level of apoptosis. It also activated the AKT/mTOR signaling pathway, downregulated PTEN and p-NF-κB expression, and upregulated Nrf2 expression. In conclusion, our findings indicate that TA could inhibit autophagy via the regulation of AKT/mTOR signaling, suppressing oxidative damage and inflammatory responses through Nrf2 to alleviate 3-NPA-induced ovarian damage. Collectively, the current findings highlight the protective effects of TA in Brandt's vole, where it promotes the maintenance of normal ovarian function.

Efficacy and safety of novel immune checkpoint inhibitor-based combinations versus chemotherapy as first-line treatment for patients with extensive-stage small cell lung cancer: A network meta-analysis.

BACKGROUND: Patients with extensive-stage small cell lung cancer (ES-SCLC) have an exceptionally poor prognosis and immune checkpoint inhibitors (ICIs) combined with etoposide-platinum is recommended as standard first-line therapy. However, which combination pattern is the best still remains unknown. This network meta-analysis was performed to compare the efficacy and safety of currently available patterns including an antiangiogenic agent containing regimen and probed into the most appropriate therapy for patients. METHODS: Hazard ratios (HRs) and odds ratios (ORs) were generated using R software. The outcomes of overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and adverse events of grade 3 or higher (grade ≥ 3 adverse events [AEs]) were analyzed. RESULTS: A total of 10 randomized controlled trials (RCTs) involving 5544 patients were included for analysis. Drug combination patterns included adebrelimab, atezolizumab, durvalumab, durvalumab plus tremelimumab, ipilimumab, pembrolizumab, serplulimab, benmelstobart plus anlotinib, tislelizumab, tiragolumab plus atezolizumab and toripalimab in combination with chemotherapy. The novel antiangiogenic agent containing regimen benmelstobart + anlotinib + chemotherapy showed the highest possibility to present the best PFS and OS versus chemotherapy. Compared with ICI plus chemotherapy, it also achieved significantly better PFS and presented a tendency of OS benefit. As for safety and toxicity, patients treated with benmelstobart + anlotinib + chemotherapy and durvalumab + tremelimumab + chemotherapy suffered a higher likelihood of more grade ≥ 3 AEs without unexpected AEs. CONCLUSION: PD-1/PD-L1 inhibitors-based combinations are associated with significant improvement in both PFS and OS for treatment-naïve ES-SCLC patients. Benmelstobart plus anlotinib with chemotherapy (CT) yielded better survival benefit versus CT alone or other ICIs + CT with caution for more adverse effects along with the addition of an antiangiogenic agent.

Irisin alters D-galactose-induced apoptosis by increasing caveolin-1 expression in C2C12 myoblasts and skeletal muscle fibroblasts.

Muscle atrophy and skeletal muscle fibrosis are significant pathological manifestations of primary sarcopenia. The regulation of C2C12 myoblast and skeletal muscle fibroblast apoptosis is associated with these pathological changes. Previous studies have indicated that irisin, the cleaved form of fibronectin type III domain-containing protein 5 (FNDC5), can alleviate primary sarcopenia. However, the mechanisms of the effect of irisin in age-related apoptosis remain unknown. Our present research aimed to explore the effect of irisin and the underlying mechanism of D-galactose (D-gal)-induced apoptosis in skeletal muscle fibroblasts and C2C12 myoblasts. We found the opposite effects of D-gal on C2C12 myoblasts and fibroblasts. We also found that irisin suppressed C2C12 cell apoptosis and promoted fibroblast apoptosis. Mechanistically, irisin altered D-gal-induced apoptosis by increasing caveolin-1 expression. Taken together, these findings further demonstrated that irisin is a potential agent that can treat aged-relative muscle atrophy and fibrosis.

Stress reduction through cortical bone thickening improves bone mechanical behavior in adult female Beclin-1+/- mice.

Fragility fractures, which are more prevalent in women, may be significantly influenced by autophagy due to altered bone turnover. As an essential mediator of autophagy, Beclin-1 modulates bone homeostasis by regulating osteoclast and chondrocyte differentiation, however, the alteration in the local bone mechanical environment in female Beclin-1+/- mice remains unclear. In this study, our aim is to investigate the biomechanical behavior of femurs from seven-month-old female wild-type (WT) and Beclin-1+/- mice under peak physiological load, using finite element analysis on micro-CT images. Micro-CT imaging analyses revealed femoral cortical thickening in Beclin-1+/- female mice compared to WT. Three-point bending test demonstrated a 63.94% increase in whole-bone strength and a 61.18% increase in stiffness for female Beclin-1+/- murine femurs, indicating improved biomechanical integrity. After conducting finite element analysis, Beclin-1+/- mice exhibited a 26.99% reduction in von Mises stress and a 31.62% reduction in maximum principal strain in the femoral midshaft, as well as a 36.64% decrease of von Mises stress in the distal femurs, compared to WT mice. Subsequently, the strength-safety factor was determined using an empirical formula, revealing that Beclin-1+/- mice exhibited significantly higher minimum safety factors in both the midshaft and distal regions compared to WT mice. In summary, considering the increased response of bone adaptation to mechanical loading in female Beclin-1+/- mice, our findings indicate that increasing cortical bone thickness significantly improves bone biomechanical behavior by effectively reducing stress and strain within the femoral shaft.

Microbial metabolite deoxycholic acid-mediated ferroptosis exacerbates high-fat diet-induced colonic inflammation.

High-fat diet (HFD) has long been recognized as risk factors for the development and progression of ulcerative colitis (UC), but the exact mechanism remained elusive. Here, HFD increased intestinal deoxycholic acid (DCA) levels, and DCA further exacerbated colonic inflammation. Transcriptome analysis revealed that DCA triggered ferroptosis pathway in colitis mice. Mechanistically, DCA upregulated hypoxia-inducible factor-2α (HIF-2α) and divalent metal transporter-1 (DMT1) expression, causing the ferrous iron ions accumulation and ferroptosis in intestinal epithelial cells, which was reversed by ferroptosis inhibitor ferrostatin-1. DCA failed to promote colitis and ferroptosis in intestine-specific HIF-2α-null mice. Notably, byak-angelicin inhibited DCA-induced pro-inflammatory and pro-ferroptotic effects through blocking the up-regulation of HIF-2α by DCA. Moreover, fat intake was positively correlated with disease activity in UC patients consuming HFD, with ferroptosis being more pronounced. Collectively, our findings demonstrated that HFD exacerbated colonic inflammation by promoting DCA-mediated ferroptosis, providing new insights into diet-related bile acid dysregulation in UC.

Decoupling and Parameter Extraction Methods for Conical Micro-Motion Object Based on FMCW Lidar.

Micro-Doppler time-frequency analysis has been regarded as an important parameter extraction method for conical micro-motion objects. However, the micro-Doppler effect caused by micro-motion can modulate the frequency of lidar echo, leading to coupling between structure and micro-motion parameters. Therefore, it is difficult to extract parameters for micro-motion cones. We propose a new method for parameter extraction by combining the range profile of a micro-motion cone and the micro-Doppler time-frequency spectrum. This method can effectively decouple and accurately extract the structure and the micro-motion parameters of cones. Compared with traditional time-frequency analysis methods, the accuracy of parameter extraction is higher, and the information is richer. Firstly, the range profile of the micro-motion cone was obtained by using an FMCW (Frequency Modulated Continuous Wave) lidar based on simulation. Secondly, quantitative analysis was conducted on the edge features of the range profile and the micro-Doppler time-frequency spectrum. Finally, the parameters of the micro-motion cone were extracted based on the proposed decoupling parameter extraction method. The results show that our method can effectively extract the cone height, the base radius, the precession angle, the spin frequency, and the gravity center height within the range of a lidar LOS (line of sight) angle from 20° to 65°. The average absolute percentage error can reach below 10%. The method proposed in this paper not only enriches the detection information regarding micro-motion cones, but also improves the accuracy of parameter extraction and establishes a foundation for classification and recognition. It provides a new technical approach for laser micro-Doppler detection in accurate recognition.

Long-term variations in surface ozone at the Longfengshan Regional Atmosphere Background Station in Northeast China and related influencing factors.

Surface ozone (O3) is a crucial air pollutant that affects air quality, human health, agricultural production, and climate change. Studies on long-term O3 variations and their influencing factors are essential for understanding O3 pollution and its impact. Here, we conducted an analysis of long-term variations in O3 during 2006-2022 at the Longfengshan Regional Atmosphere Background Station (LFS; 44.44°N, 127.36°E, 330.5 m a.s.l.) situated on the northeastern edge of the Northeast China Plains. The maximum daily 8-h average (MDA8) O3 fluctuated substantially, with the annual MDA8 decreasing significantly during 2006-2015 (-0.62 ppb yr-1, p < 0.05), jumping during 2015-2016 and increasing clearly during 2020-2022. Step multiple linear regression models for MDA8 were obtained using meteorological variables, to decompose anthropogenic and meteorological contributions to O3 variations. Anthropogenic activities acted as the primary drivers of the long-term trends of MDA8 O3, contributing 73% of annual MDA8 O3 variability, whereas meteorology played less important roles (27%). Elevated O3 at LFS were primarily associated with airflows originating from the North China Plain, Northeast China Plain, and coastal areas of North China, primarily occurring during the warm months (May-October). Based on satellite products of NO2 and HCHO columns, the O3 photochemical regimes over LFS revealed NOx-limited throughout the period. NO2 increased first, reaching peak in 2011, followed by substantial decrease; while HCHO exhibited significant increase, contributing to decreasing trend in MDA8 O3 during 2006-2015. The plateauing NO2 and decreasing HCHO may contribute to the increase in MDA8 O3 in 2016. Subsequently, both NO2 and HCHO exhibited notable fluctuations, leading to significant changes in O3. The study results fill the gap in the understanding of long-term O3 trends in high-latitude areas in the Northeast China Plain and offer valuable insights for assessing the impact of O3 on crop yields, forest productivity, and climate change.

Ferrate(VI)/percarbonate for the oxidation of micropollutants: Interactive activation and release of low-concentration hydrogen peroxide for efficient electron utilization.

A novel "ferrate/percarbonate (Fe(VI)/SPC) co-oxidation process" was used to treat ciprofloxacin (CIP) and various micropollutants (MPs), which owned better performance than mixture of Fe(VI), Na2CO3 and H2O2. The mechanism investigation found that the low-concentration H2O2 (1-2 µM) released by SPC can promote the high-valent iron intermediates (Fe(IV)/Fe(V)) of Fe(VI) to the MP oxidation, and Fe(VI) products can also activate SPC to produce hydroxyl radical (·OH). The interactive activation of Fe(VI) and SPC was realized, which retained the high selectivity of Fe(VI) to electron-rich pollutants, and also made up the oxidation of electron-deficient pollutants through •OH, improving the degradation effect of various MPs by 20-30%, and the rate constant was increased by 1 to 3 times. Moreover, non-purgeable organic carbon (NPOC) determination confirmed that â€¢OH participation reduced the NPOC value of CIP from 5.43 mg/L to 4.37 mg/L. The transformation pathway of CIP showed that Fe(VI)/SPC resulted in more hydroxylation intermediates of CIP than Fe(VI) alone. Acute toxicity assays found that the photoinhibition rate of CIP treated with Fe(VI) alone was 14.5%, while the sample treated with Fe(VI)/SPC showed no significant photoinhibition effect, which proved that the new process had good detoxification properties for CIP.

Expression of USP25 associates with fibrosis, inflammation and metabolism changes in IgG4-related disease.

IgG4-related disease (IgG4-RD) has complex clinical manifestations ranging from fibrosis and inflammation to deregulated metabolism. The molecular mechanisms underpinning these phenotypes are unclear. In this study, by using IgG4-RD patient peripheral blood mononuclear cells (PBMCs), IgG4-RD cell lines and Usp25 knockout mice, we show that ubiquitin-specific protease 25 (USP25) engages in multiple pathways to regulate fibrotic and inflammatory pathways that are characteristic to IgG4-RD. Reduced USP25 expression in IgG4-RD leads to increased SMAD3 activation, which contributes to fibrosis and induces inflammation through the IL-1ß inflammatory axis. Mechanistically, USP25 prevents ubiquitination of RAC1, thus, downregulation of USP25 leads to ubiquitination and degradation of RAC1. Decreased RAC1 levels result in reduced aldolase A release from the actin cytoskeleton, which then lowers glycolysis. The expression of LYN, a component of the B cell receptor signalosome is also reduced in USP25-deficient B cells, which might result in B cell activation deficiency. Altogether, our results indicate a potential anti-inflammatory and anti-fibrotic role for USP25 and make USP25 a promising diagnostic marker and potential therapeutic target in IgG4-RD.

CircFOXO3 mediates hypoxia-induced autophagy of endometrial stromal cells in endometriosis.

Endometriosis is a benign gynecological disease that shares some common features of malignancy. Autophagy plays vital roles in endometriosis and influences endometrial cell metastasis, and hypoxia was identified as the initiator of this pathological process through hypoxia inducible factor 1 alpha (HIF-1α). A newly discovered circular RNA FOXO3 (circFOXO3) is critical in cell autophagy, migration, and invasion of various diseases and is reported to be related to hypoxia, although its role in endometriosis remains to be elucidated up to now. In this study, a lower circFOXO3 expression in ectopic endometrium was investigated. Furthermore, we verified that circFOXO3 could regulate autophagy by downregulating the level of p53 protein to mediate the migration and invasion of human endometrial stromal cells (T HESCs). Additionally, the effects of HIF-1α on circFOXO3 and autophagy were examined in T HESCs. Notably, overexpression of HIF-1α could induce autophagy and inhibit circFOXO3 expression, whereas overexpressing of circFOXO3 under hypoxia significantly inhibited hypoxia-induced autophagy. Mechanistically, the direct combination between HIF-1α and HIF-1α-binding site on adenosine deaminase 1 acting on RNA (ADAR1) promoter increased the level of ADAR1 protein, which bind directly with circFOXO3 pre-mRNA to block the cyclization of circFOXO3. All these results support that hypoxia-mediated ADAR1 elevation inhibited the expression of circFOXO3, and then autophagy was induced upon loss of circFOXO3 via inhibition of p53 degradation, participating in the development of endometriosis.

Ferrate(VI) assists in reducing cytotoxicity and genotoxicity to mammalian cells and organic bromine formation in ozonated wastewater.

Ozonation of wastewater containing bromide (Br-) forms highly toxic organic bromine. The effectiveness of ozonation in mitigating wastewater toxicity is minimal. Simultaneous application of ozone (O3) (5 mg/L) and ferrate(VI) (Fe(VI)) (10 mg-Fe/L) reduced cytotoxicity and genotoxicity towards mammalian cells by 39.8% and 71.1% (pH 7.0), respectively, when the wastewater has low levels of Br-. This enhanced reduction in toxicity can be attributed to increased production of reactive iron species Fe(IV)/Fe(V) and reactive oxygen species (•OH) that possess higher oxidizing ability. When wastewater contains 2 mg/L Br-, ozonation increased cytotoxicity and genotoxicity by 168%-180% and 150%-155%, respectively, primarily due to the formation of organic bromine. However, O3/Fe(VI) significantly (p < 0.05) suppressed both total organic bromine (TOBr), BrO3-, as well as their associated toxicity. Electron donating capacity (EDC) measurement and precursor inference using Orbitrap ultra-high resolution mass spectrometry found that Fe(IV)/Fe(V) and •OH enhanced EDC removal from precursors present in wastewater, inhibiting electrophilic substitution and electrophilic addition reactions that lead to organic bromine formation. Additionally, HOBr quenched by self-decomposition-produced H2O2 from Fe(VI) also inhibits TOBr formation along with its associated toxicity. The adsorption of Fe(III) flocs resulting from Fe(VI) decomposition contributes only minimally to reducing toxicity. Compared to ozonation alone, integration of Fe(VI) with O3 offers improved safety for treating wastewater with varying concentrations of Br-.

Bone age assessment based on different MRI modalities of the proximal humerus epiphysis: the comparisons of T1WI, T2WI, and PDWI.

Bone age assessment (BAA) is crucial in various fields, including legal proceedings, athletic competitions, and clinical medicine. However, the use of X-ray methods for age estimation without medical indication is subject to ethical debate, especially in forensic and athletic fields. The application of magnetic resonance imaging (MRI) with non-ionizing radiation can overcome this limitation in BAA. This study aimed to compare the application value of several MRI modalities of proximal humeral in BAA. A total of 468 patients with shoulder MRIs were retrospectively collected from a Chinese Han population aged 12-30 years (259 males and 209 females) for training and testing, including T1 weighted MRI (T1WI), T2 weighted MRI (T2WI), and Proton density weighted MRI (PDWI). Optimal regression models were established for age estimation, yielding mean absolute error (MAE) values below 2.0 years. The MAE values of T1WI were the lowest, with 1.700 years in males and 1.798 years in females. The area under the curve (AUC) and accuracy values of different MRI modalities of 16-year and 18-year thresholds were all around 0.9. For the 18-year threshold, T1WI outperformed T2WI and PDWI. In conclusion, the three MRI modalities of the proximal humerus can serve as reliable indicators for age assessment, while the T1WI performed better in age assessment and classification.

Discovery of a nitroaromatic nannocystin with potent in vivo anticancer activity against colorectal cancer by targeting AKT1.

The development of targeted chemotherapeutic agents against colorectal cancer (CRC), one of the most common cancers with a high mortality rate, is in a constant need. Nannocystins are a family of myxobacterial secondary metabolites featuring a 21-membered depsipeptide ring. The in vitro anti-CRC activity of natural and synthetic nannocystins was well documented, but little is known about their in vivo efficacy and if positive, the underlying mechanism of action. In this study we synthesized a nitroaromatic nannocystin through improved preparation of a key fragment, and characterized its in vitro activity and in vivo efficacy against CRC. We first described the total synthesis of compounds 2-4 featuring Heck macrocyclization to forge their 21-membered macrocycle. In a panel of 7 cancer cell lines from different tissues, compound 4 inhibited the cell viability with IC values of 1-6 nM. In particular, compound 4 (1, 2, 4 nM) inhibited the proliferation of CRC cell lines (HCT8, HCT116 and LoVo) in both concentration and time dependent manners. Furthermore, compound 4 concentration-dependently inhibited the colony formation and migration of CRC cell lines. Moreover, compound 4 induced cell cycle arrest at sub-G1 phase, apoptosis and cellular senescence in CRC cell lines. In three patient-derived CRC organoids, compound 4 inhibited the PDO with IC values of 3.68, 28.93 and 11.81 nM, respectively. In a patient-derived xenograft mouse model, injection of compound 4 (4, 8 mg/kg, i.p.) every other day for 12 times dose-dependently inhibited the tumor growth without significant change in body weight. We conducted RNA-sequencing, molecular docking and cellular thermal shift assay to elucidate the anti-CRC mechanisms of compound 4, and revealed that it exerted its anti-CRC effect at least in part by targeting AKT1.

Bubble Unidirectional Transportation on Multipath Aerophilic Surfaces by Adjusting the Surface Microstructure.

Comprehending and controlling the behavior of bubbles on solid surfaces is of significant importance in various fields including catalysis and drag reduction, both industrially and scientifically. Herein, Inspired by the superaerophilic properties of the lotus leaf surface, a series of asymmetrically patterned aerophilic surfaces were prepared by utilizing a facile mask-spraying method for directional transport of underwater bubbles. The ability of bubbles to undergo self-driven transportation in an asymmetric pattern is attributed to the natural tendency of bubbles to move toward regions with lower surface energy. In this work, the microstructure of the aerophilic surface is demonstrated as a critical element that influences the self-driven transport of bubbles toward regions of lower surface energy. The microstructure characteristic affects the energy barrier of forming a continuous gas film on the final regions. We classify three distinct bubble behaviors on the aerophilic surface, which align with three different underwater gas film evolution states: Model I, Model II, and Model III. Furthermore, utilizing the energy difference between the energy barrier that forms a continuous gas film and the gas-gas merging, gas-liquid microreaction in a specific destination on the multiple paths can be easily realized by preinjecting a bubble in the final region. This work provides a new view of the microevolutionary process for the diffusion, transport, and merging behavior of bubbles upon contact with an aerophilic pattern surface.

RNA-seq transcriptome analysis provides new insights into the negative effects of tannic acid on the intestinal function of Brandt's voles (Lasiopodomys brandtii).

Tannic acid (TA), a significant plant secondary metabolite, is contained in the daily food of Brandt's voles. Its adverse effect on gut function has been shown in earlier research, but the underlying molecular mechanisms remain uncertain. In this study, male Brandt's vole (13 weeks old) were divided into two groups and given 0 (control) or 1,200 (TA-treated) mg•kg-1 TA for 18 days. Then RNA sequencing was used to conduct a thorough transcriptome analysis on the duodenum, jejunum, and ileum of Brandt's voles. Results showed that TA significantly increased serum total cholesterol concentration (P < 0.05) and decreased the nutrient digestibility (P < 0.05) of Brandt's voles. Furthermore, there were 174 differentially expressed genes (DEGs) in the duodenum, 96 DEGs in the jejunum, and 88 DEGs in the ileum between the control and TA-treated groups. Enrichment analysis revealed that many genes associated with bile secretion, fat digestion and absorption, innate immune response, and tight junction such as ABCG2, ABCG8, PEAK1, and IFR2, etc. were altered after TA treatment, which were verified by quantitative real-time PCR. These findings suggested that TA can change the expression of intestinal genes, thereby, altering nutrition metabolism and immunological function, eventually hindering the growth of Brandt's voles. The results of this study provide a theoretical basis for explaining how TA affects the gut function of Brandt's voles at the molecular level.

Construction of a layer-by-layer self-assembled rosemarinic acid delivery system on the surface of CFRPEEK implants for enhanced anti-inflammatory and osseointegration activities.

Carbon fiber-reinforced polyether ether ketone (CFRPEEK) implants have attracted widespread attention in the field of clinical bone defect repair. However, the surface bioinertness confines the application of CFRPEEK implants. Inspired by the study of rosmarinic acid (RA)-promoted osteogenic differentiation, a self-assembly surface modification method based on electrostatic interactions, involving deposition of sodium carboxymethyl cellulose/chitosan and rosmarinic acid layer by layer on the surface of poly-L-lysine modified hydroxy CFRPEEK (SCPP/CC5@RA), is proposed to introduce RA on the surface of CFRPEEK for bioactivation. After layer-by-layer self-assembly (LBL), the surface of SCPP/CC5@RA exhibits weak electrophoresis (11.43 eV), suitable hydrophilicity, and bioactivity. The results of in vitro studies indicate that the RA release behavior of SCPP/CC5@RA effectively regulates the immune-inflammatory response and promotes the differentiation of osteoblasts. The rapid release of RA (0.17 µg mL-1) in the initial stage can downregulate the secretion of inflammation-related cytokines and significantly reduce oxidative stress levels; the sustained release of RA (0.06 µg mL-1) in the late stage can upregulate the expression of osteogenesis-related genes and induce mineralization of osteoblasts. Moreover, the rabbit tibia defect model demonstrates that the LBL technique can enhance the osseointegration of CFRPEEK implants. Compared with the control group, the bone trabecular thickness of the SCPP/CC5@RA group increases by 1.36 times, and the maximum pushing force increases by 2.67 times. In summary, this study provides a promising LBL based RA delivery system for the development of a dual-functional CFRPEEK implant in the field of bone implant biomaterials.

Transcriptome-wide N6-methyladenosine (m6A) methylation profiling of long non-coding RNAs in ovarian endometriosis.

N6-methyladenosine (m6A) methylation is the most prevalent internal epigenetic posttranscriptional mechanism for regulating mammalian RNA. Despite recent advances in determining the biological functions of m6A methylation, its association with the pathology of ovarian endometriosis remains uncertain. Herein, we performed m6A transcriptome-wide profiling to identify key lncRNAs with m6A modification involved in ovarian endometriosis development by bioinformatics analysis. We found the total m6A level was lower in ovarian endometriosis than in normal endometrium samples, with 9663 m6A peaks associated with 8989 lncRNAs detected in ovarian endometriosis and 9902 m6A peaks associated with 9210 lncRNAs detected in normal endometrium samples. These m6A peaks were primarily enriched within AAACU motifs. Functional enrichment analysis indicated that pathways involving the regulation of adhesion and development were significantly enriched in these differentially methylated lncRNAs. The regulatory relationships among lncRNAs, microRNAs (miRNAs), and mRNAs were identified by competing endogenous RNA (ceRNA) analysis and determination of the network regulating lncRNA-mRNA expression. Several specific lncRNA, including LINC00665, LINC00937, FZD10-AS1, DIO3OS and GATA2-AS1 which were differently expressed and modified by m6A, were validated using qRT-PCR and its interaction with infiltrating immune cells was explored. Furthermore, we found LncRNA DIO3OS promotes the invasion and migration of Human endometrial stromal cells (THESCs) and ALKBH5 regulates the expression of the lncRNA DIO3OS through m6A modification in vitro. Our study firstly revealed the transcriptome-wide map of m6A modification in lncRNAs of ovarian endometriosis. These findings may enable the determination of the underlying mechanism governing the pathogenesis of ovarian endometriosis and provide theoretical basis for further deeper research on the role of m6A in the development of ovarian endometriosis.

Delivery of SIRT1 by cancer-associated adipocyte-derived extracellular vesicles regulates immune response and tumorigenesis of ovarian cancer cells

Purpose This study intends to investigate the possible molecular mechanism of immune response and tumorigenesis in ovarian cancer cells, mediated by sirtuin 1 (SIRT1)-containing extracellular vesicles (EVs) derived from cancer-associated adipocytes (CAAs) (CAA-EVs). Methods Differentially expressed genes in EVs from CAAs were screened by RNA transcriptome sequencing, and the downstream pathway was predicted in silico. The binding between SIRT1 and CD24 was investigated by luciferase activity and ChIP-PCR assays. EVs were extracted from human ovarian cancer tissue-isolated CAAs, and the internalization of CCA-EVs by ovarian cancer cells was characterized. The ovarian cancer cell line was injected into mice to establish an animal model. Flow cytometry was performed to analyze the proportions of M1 and M2 macrophages, CD8+ T, T-reg, and CD4+ T cells. TUNEL staining was used to detect cell apoptosis in the mouse tumor tissues. ELISA detection was performed on immune-related factors in the serum of mice. Results CAA-EVs could deliver SIRT1 to ovarian cancer cells, thereby affecting the immune response of ovarian cancer cells in vitro and promoting tumorigenesis in vivo. SIRT1 could transcriptionally activate the expression of CD24, and CD24 could up-regulate Siglec-10 expression. CAA-EVs-SIRT1 activated the CD24/Siglec-10 axis and promoted CD8+ T cell apoptosis, thereby promoting tumorigenesis in mice. Conclusion CAA-EVs-mediated transfer of SIRT1 regulates the CD24/Siglec-10 axis to curb immune response and promote tumorigenesis of ovarian cancer cells (AU)

FOXP3+ regulatory T cell perturbation mediated by the IFNγ-STAT1-IFITM3 feedback loop is essential for anti-tumor immunity.

Targeting tumor-infiltrating regulatory T cells (Tregs) is an efficient way to evoke an anti-tumor immune response. However, how Tregs maintain their fragility and stability remains largely unknown. IFITM3 and STAT1 are interferon-induced genes that play a positive role in the progression of tumors. Here, we showed that IFITM3-deficient Tregs blunted tumor growth by strengthening the tumor-killing response and displayed the Th1-like Treg phenotype with higher secretion of IFNγ. Mechanistically, depletion of IFITM3 enhances the translation and phosphorylation of STAT1. On the contrary, the decreased IFITM3 expression in STAT1-deficient Tregs indicates that STAT1 conversely regulates the expression of IFITM3 to form a feedback loop. Blocking the inflammatory cytokine IFNγ or directly depleting STAT1-IFITM3 axis phenocopies the restored suppressive function of tumor-infiltrating Tregs in the tumor model. Overall, our study demonstrates that the perturbation of tumor-infiltrating Tregs through the IFNγ-IFITM3-STAT1 feedback loop is essential for anti-tumor immunity and constitutes a targetable vulnerability of cancer immunotherapy.