o8G Site-Specifically Modified tRF-1-AspGTC: A Novel Therapeutic Target and Biomarker for Pulmonary Hypertension.

RATIONALE: Hypoxia and oxidative stress contribute to the development of pulmonary hypertension (PH). tRNA-derived fragments play important roles in RNA interference and cell proliferation, but their epitranscriptional roles in PH development have not been investigated. OBJECTIVE: We aimed to gain insight into the mechanistic contribution of oxidative stress-induced 8-oxoguanine in pulmonary vascular remodeling. METHODS AND RESULTS: Through small RNA modification array analysis and quantitative polymerase chain reaction, a significant upregulation of the 8-oxoguanine-modified tRF-1-AspGTC was found in the lung tissues and the serum of patients with PH. This modification occurs at the fifth 8-oxoguanine (5o8G) tRF in the seed region of the tRNA-derived fragments. Inhibition of the 5o8G tRF reversed hypoxia-induced proliferation and apoptosis resistance in pulmonary artery smooth muscle cells. Further investigation unveiled that the 5o8G tRF retargeted mRNA of WNT5A and CASP3 and inhibited their expression. Ultimately, BMPR2 (bone morphogenetic protein receptor 2)-reactive oxygen species/5o8G tRF/WNT5A signaling pathway exacerbated the progression of PH. CONCLUSIONS: Our study highlights the role of site-specific 8-oxoguanine-modified tRF in promoting the development of PH. Our findings present a promising therapeutic avenue for managing PH and propose 5o8G tRF as a potential innovative marker for diagnosing this disease.

Integrated lipid metabolomics and proteomics analysis reveal the pathogenesis of polycystic ovary syndrome.

BACKGROUND: Polycystic ovary syndrome (PCOS) is an endocrinological and metabolic disorder that can lead to female infertility. Lipid metabolomics and proteomics are the new disciplines in systems biology aimed to discover metabolic pathway changes in diseases and diagnosis of biomarkers. This study aims to reveal the features of PCOS to explore its pathogenesis at the protein and metabolic level. METHODS: We collected follicular fluid samples and granulosa cells of women with PCOS and normal women who underwent in vitro fertilization(IVF) and embryo transfer were recruited. The samples were for the lipidomic study and the proteomic study based on the latest metabolomics and proteomics research platform. RESULTS: Lipid metabolomic analysis revealed abnormal metabolism of glycerides, glycerophospholipids, and sphingomyelin in the FF of PCOS. Differential lipids were strongly linked with the rate of high-quality embryos. In total, 144 differentially expressed proteins were screened in ovarian granulosa cells in women with PCOS compared to controls. Go functional enrichment analysis showed that differential proteins were associated with blood coagulation and lead to follicular development disorders. CONCLUSION: The results showed that the differential lipid metabolites and proteins in PCOS were closely related to follicle quality,which can be potential biomarkers for oocyte maturation and ART outcomes.

Gene associations of lipid traits, lipid-lowering drug-target genes and endometriosis.

RESEARCH QUESTION: Does the observed correlation between dyslipidaemia and endometriosis indicate a bidirectional causal association? DESIGN: Bidirectional Mendelian randomization was used to investigate the causal association between lipid traits and endometriosis. Drug-target Mendelian randomization was used to explore potential drug-target genes for managing endometriosis. In cases where lipid-mediated effects via specific drug targets were significant, aggregate analyses, such as summary-data-based Mendelian randomization and colocalization methods, were introduced to validate the outcomes. Mediation analyses supplemented these evaluations. RESULTS: The bidirectional Mendelian randomization results suggested that genetically predicted triglyceride (OR 1.15, 95% CI 1.08-1.23), high-density lipoprotein cholesterol (OR 0.87, 95% CI 0.81-0.94), low-density lipoprotein cholesterol (OR 1.20, 95% CI 1.06-1.34) and apolipoprotein A (OR 0.90, 95% CI 0.83-0.96) concentrations were causally associated with endometriosis. Reverse Mendelian randomization results revealed that genetically proxied endometriosis was causally associated with triglyceride concentration (OR 1.02, 95% CI 1.01-1.02). In drug-target Mendelian randomization, genetic mimicry in proprotein convertase subtilisin/kexin type 9 (PCSK9) (OR 1.40, 95% CI 1.13-1.72), apolipoprotein B (APOB) (OR 1.49, 95% CI 1.21-1.86) and angiopoietin-related protein 3 (ANGPTL3) (OR 1.57, 95% CI 1.14-2.16) was significantly associated with the risk of endometriosis stages 1-2. CONCLUSION: There is a potential bidirectional causal association between endometriosis and dyslipidaemia. Genetic mimicry of PCSK9, APOB and ANGPTL3 is associated with the risk of early-stage endometriosis. The development of lipid-lowering drugs to treat endometriosis is of potential clinical interest.

Targeting NKAα1 to treat Parkinson's disease through inhibition of mitophagy-dependent ferroptosis.

Dysfunction of the Na+/K+-ATPase (NKA) has been documented in various neurodegenerative diseases, yet the specific role of NKAα1 in Parkinson's disease (PD) remains incompletely understood. In this investigation, we utilized NKAα1 haploinsufficiency (NKAα1+/-) mice to probe the influence of NKAα1 on dopaminergic (DA) neurodegeneration induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Our findings reveal that NKAα1+/- mice displayed a heightened loss of DA neurons and more pronounced motor dysfunction compared to the control group when exposed to MPTP. Intriguingly, this phenomenon coincided with the activation of ferroptosis and impaired mitophagy both in vivo and in vitro. To scrutinize the role and underlying mechanism of NKAα1 in PD, we employed DR-Ab, an antibody targeting the DR-region of the NKA α subunit. Our study demonstrates that the administration of DR-Ab effectively reinstated the membrane abundance of NKAα1, thereby mitigating MPTP-induced DA neuron loss and subsequent improvement in behavioral deficit. Mechanistically, DR-Ab heightened the formation of the surface NKAα1/SLC7A11 complex, inhibiting SLC7A11-dependent ferroptosis. Moreover, DR-Ab disrupted the cytosolic interaction between NKAα1 and Parkin, facilitating the translocation of Parkin to mitochondria and enhancing the process of mitophagy. In conclusion, this study establishes NKAα1 as a key regulator of ferroptosis and mitophagy, identifying its DR-region as a promising therapeutic target for PD.

Differential expression of follicular fluid exosomal microRNA in women with diminished ovarian reserve.

PURPOSE: Decreased ovarian reserve function is mainly characterized by female endocrine disorders and fertility decline. Follicular fluid (FF) exosomal microRNAs (miRNAs) have been shown to regulate the function of granulosa cells (GCs). The present study explored differentially expressed miRNAs (DEmiRNAs) in patients with diminished ovarian reserve (DOR). METHODS: FF was collected from 12 DOR patients and 12 healthy controls. DEmiRNAs between the two groups were identified and analyzed using high-throughput sequencing technology and validated by real-time quantitative PCR (RT-qPCR). RESULTS: A total of 592 DEmiRNAs were identified using high-throughput miRNA sequencing, of which 213 were significantly upregulated and 379 were significantly downregulated. The sequencing results were further validated by RT-qPCR. These DEmiRNA target genes were mainly involved in the cancer pathway, phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway, regulation of actin cytoskeleton signaling pathway, and biological processes related to protein binding, nucleoplasm, cytoplasm, and cell membrane. CONCLUSION: FF exosomal miRNAs are significantly differentially expressed in DOR patients versus non-DOR patients, underscoring their crucial role in regulating the pathogenesis of DOR.

Disruption of the Na+/K+-ATPase-purinergic P2X7 receptor complex in microglia promotes stress-induced anxiety.

Na+/K+-ATPase (NKA) plays an important role in the central nervous system. However, little is known about its function in the microglia. Here, we found that NKAα1 forms a complex with the purinergic P2X7 receptor (P2X7R), an adenosine 5'-triphosphate (ATP)-gated ion channel, under physiological conditions. Chronic stress or treatment with lipopolysaccharide plus ATP decreased the membrane expression of NKAα1 in microglia, facilitated P2X7R function, and promoted microglia inflammatory activation via activation of the NLRP3 inflammasome. Accordingly, global deletion or conditional deletion of NKAα1 in microglia under chronic stress-induced aggravated anxiety-like behavior and neuronal hyperexcitability. DR5-12D, a monoclonal antibody that stabilizes membrane NKAα1, improved stress-induced anxiety-like behavior and ameliorated neuronal hyperexcitability and neurogenesis deficits in the ventral hippocampus of mice. Our results reveal that NKAα1 limits microglia inflammation and may provide a target for the treatment of stress-related neuroinflammation and diseases.

Assessing spatiotemporal characteristics of atmospheric water cycle processes over the Tibetan Plateau using the WRF model and finer box model.

The Tibetan Plateau (TP) is the highest and one of the most extensive plateaus in the world and serves as a hotspot of climate change. In the context of climate warming, changes in evapotranspiration (ET) and external water vapor transport have a significant impact on assessing atmospheric water cycle processes over the TP. By using the Weather Research and Forecasting (WRF) model for long-term simulations and the finer box model for the calculation of water vapor along the boundary of the TP, the external atmospheric water vapor transport and its spatiotemporal characteristics over the TP are finely described. The simulated precipitation and ET are well-simulated compared with observation. Research results show that: (1) The total water path on the TP decreases from southeast to northwest. Water vapor is mainly transported into the TP from the western and southern boundaries. The net water vapor flux transported from the western boundary to the TP by westerly wind is negative, while the net water vapor flux transported from the southern boundary to the TP by southerly wind is positive. (2) In spring and winter, water vapor is mainly transported into the TP by mid-latitude westerlies from the western boundary. In summer, water vapor transport controlled by mid-latitude westerlies weakens, and water vapor is mainly transported into the TP from the southern boundary. In autumn, water vapor controlled by mid-latitude westerlies gradually strengthens, and water vapor is mainly transported into the TP from the western boundary. In addition, the ratio of ET to precipitation on the TP is about 0.48, and the moisture recycling is about 0.37. Water vapor mainly comes from external water vapor transport.

ErbB3 Governs Endothelial Dysfunction in Hypoxia-Induced Pulmonary Hypertension.

BACKGROUND: Pulmonary hypertension, characterized by vascular remodeling, currently lacks curative therapeutic options. The dysfunction of pulmonary artery endothelial cells plays a pivotal role in the initiation and progression of pulmonary hypertension (PH). ErbB3 (human epidermal growth factor receptor 3), also recognized as HER3, is a member of the ErbB family of receptor tyrosine kinases. METHODS: Microarray, immunofluorescence, and Western blotting analyses were conducted to investigate the pathological role of ErbB3. Blood samples were collected for biomarker examination from healthy donors or patients with hypoxic PH. The pathological functions of ErbB3 were further validated in rodents subjected to chronic hypoxia- and Sugen-induced PH, with or without adeno-associated virus-mediated ErbB3 overexpression, systemic deletion, or endothelial cell-specific ErbB3 knockdown. Primary human pulmonary artery endothelial cells and pulmonary artery smooth muscle cells were used to elucidate the underlying mechanisms. RESULTS: ErbB3 exhibited significant upregulation in the serum, lungs, distal pulmonary arteries, and pulmonary artery endothelial cells isolated from patients with PH compared with those from healthy donors. ErbB3 overexpression stimulated hypoxia-induced endothelial cell proliferation, exacerbated pulmonary artery remodeling, elevated systolic pressure in the right ventricle, and promoted right ventricular hypertrophy in murine models of PH. Conversely, systemic deletion or endothelial cell-specific knockout of ErbB3 yielded opposite effects. Coimmunoprecipitation and proteomic analysis identified YB-1 (Y-box binding protein 1) as a downstream target of ErbB3. ErbB3 induced nuclear translocation of YB-1 and subsequently promoted hypoxia-inducible factor 1/2α transcription. A positive loop involving ErbB3-periostin-hypoxia-inducible factor 1/2α was identified to mediate the progressive development of this disease. MM-121, a human anti-ErbB3 monoclonal antibody, exhibited both preventive and therapeutic effects against hypoxia-induced PH. CONCLUSIONS: Our study reveals, for the first time, that ErbB3 serves as a novel biomarker and a promising target for the treatment of PH.

ADAR1 regulates vascular remodeling in hypoxic pulmonary hypertension through N1-methyladenosine modification of circCDK17.

Pulmonary hypertension (PH) is an extremely malignant pulmonary vascular disease of unknown etiology. ADAR1 is an RNA editing enzyme that converts adenosine in RNA to inosine, thereby affecting RNA expression. However, the role of ADAR1 in PH development remains unclear. In the present study, we investigated the biological role and molecular mechanism of ADAR1 in PH pulmonary vascular remodeling. Overexpression of ADAR1 aggravated PH progression and promoted the proliferation of pulmonary artery smooth muscle cells (PASMCs). Conversely, inhibition of ADAR1 produced opposite effects. High-throughput whole transcriptome sequencing showed that ADAR1 was an important regulator of circRNAs in PH. CircCDK17 level was significantly lowered in the serum of PH patients. The effects of ADAR1 on cell cycle progression and proliferation were mediated by circCDK17. ADAR1 affects the stability of circCDK17 by mediating A-to-I modification at the A5 and A293 sites of circCDK17 to prevent it from m1A modification. We demonstrate for the first time that ADAR1 contributes to the PH development, at least partially, through m1A modification of circCDK17 and the subsequent PASMCs proliferation. Our study provides a novel therapeutic strategy for treatment of PH and the evidence for circCDK17 as a potential novel marker for the diagnosis of this disease.

Projected changes in soil freeze depth and their eco-hydrological impacts over the Tibetan Plateau during the 21st century.

In the context of global warming, the soil freeze depth (SFD) over the Tibetan Plateau (TP) has undergone significant changes, with a series of profound impacts on the hydrological cycle and ecosystem. The complex terrains and high elevations of the TP pose great challenges in data acquisition, presenting difficulties for studying SFD in this region. This study employs Stefan's solution and downscaled datasets from the Coupled Model Intercomparison Project Phase 6 (CMIP6) to simulate the future SFDs over the TP. The changing trends of the projected SFDs under different Shared Socio-economic Pathways (SSP) scenarios are investigated, and; the responses of SFDs to potential climatic factors, such as temperature and precipitation, are analyzed. The potential impacts of SFD changes on eco-hydrological processes are analyzed based on the relationships between SFDs, the distribution of frozen ground, soil moisture, and the Normalized Difference Vegetation Index (NDVI). Results show that the projected SFDs of the TP are estimated to decrease at rates of 0.100 cm/yr under the SSP126, 0.330 cm/yr under the SSP245, 0.565 cm/yr under the SSP370, and 0.750 cm/yr under the SSP585. Additionally, the SFD decreased at a rate of 0.160 cm/yr during the historical period from 1950 to 2014, which was between the decreasing rates of the SSP126 and SSP245 scenarios. The projected SFDs are negatively correlated with air temperature and precipitation, more significant under the higher emissions scenario. The projected decrease in SFDs will significantly impact eco-hydrological processes. A rapid decrease in SFD may lead to a decline in soil moisture content and have adverse impacts on vegetation growth. This research provides valuable insights into the future changes in SFD on the TP and their impacts on eco-hydrological processes.

Single-cell sequencing provides insights into the landscape of ovary in PCOS and alterations induced by CUMS.

Polycystic ovary syndrome (PCOS) is a common endocrine disorder related to psychological distress. However, the mechanism underlying increased prevalence of depression in PCOS remained unclear. This study aimed to explore the unique transcriptional landscape of ovary and offered a platform to explore the mechanism of PCOS, as well as the influences caused by depression. The PCOS rat model was established by letrozole whereas PCOS rat model with depression was established by letrozole combined with chronic unpredicted mild stress (CUMS). Then single-cell RNA sequencing (scRNA-Seq) was applied to analyze the transcriptional features of rat ovaries. Granulosa cells (GCs) and fibroblasts (Fibros) accounted for the top two clusters of total 12 cell types. There were nine clusters in GCs, related to inflammatory response, endoplasmic reticulum (ER) stress, and steroidogenesis. The expression of differentially expressed genes (DEG) Hes1 was higher in PCOS and PCOS + CUMS groups, exhibiting enhanced expression by pseudotime and positively related to inflammation. Pseudotemporal analysis revealed that inflammation contributed to the different GCs distributions. Moreover, analysis of DEGs and gene ontology (GO) function enrichment revealed CUMS aggravated inflammation in PCOS GCs possibly via interferon signaling pathway. In theca cells (TCs), nine clusters were observed and some of them were relevant to inflammation, ER stress, and lipid metabolism. DEGs Ass1, Insl3, and Ifi27 were positively related to Cyp17a1, and Ces1d might contribute to the different trajectory of TCs. Subsequent scRNA-seq revealed a signature profile of endothelial cells (ECs) and Fibros, which suggest that inflammation-induced damage of ECs and Fibro, further exacerbated by CUMS. Finally, analysis of T cells and mononuclear phagocytes (MPs) revealed the existence of immune dysfunction, among which interferon signaling played a critical role. These findings provided more knowledge for a better understanding PCOS from the view of inflammation and identified new biomarkers and targets for the treatment of PCOS with psychological diseases.NEW & NOTEWORTHY In this study, we mapped the landscape of polycystic ovary syndrome (PCOS) ovary with rat model induced by letrozole and provided a novel insight into the molecular mechanism of PCOS accompanied by chronic unpredicted mild stress (CUMS) at single-cell transcriptomic level. These observations highlight the importance of inflammation in the pathogenesis of PCOS, which might also be the bridge between PCOS and psychological diseases.

Protocatechuic acid alleviates polycystic ovary syndrome symptoms in mice by PI3K signaling in granulosa cells to relieve ROS pressure and apoptosis.

BACKGROUND: Polycystic ovary syndrome (PCOS) is a complicated gynecological endocrine disease that occurs in women of childbearing age. Protocatechuic acid is a phenol-rich compound derived from herbs and owns vital functions in numerous diseases. Howbeit, protocatechuic acid's impact on PCOS is unknown. METHODS: A combination of in vivo and in vitro models was examined in this study. C57BL/6 mice were injected subcutaneously daily with dehydroepiandrosterone to establish a PCOS mouse model, and protocatechuic acid was intraperitoneally injected into PCOS mice. Granulosa cells of PCOS ovaries were also isolated. The function of protocatechuic acid was appraised using enzyme-linked immunosorbent assay, hematoxylin-eosin staining, reactive oxygen species (ROS) and LC3 levels analysis, flow cytometry, quantitative real-time PCR, and western blot. Meanwhile, the mechanism of protocatechuic acid was assessed with a series of molecular experiments. RESULTS: Protocatechuic acid owned no apparent toxic effect on mice. Functionally, protocatechuic acid owned a function of mitigating PCOS in vivo. Meanwhile, protocatechuic acid repressed ROS, autophagy, and apoptosis of PCOS ovarian granulosa cells in vitro. Mechanistically, rescue assays elucidated that the protective function of protocatechuic acid against PCOS was interrelated to the activation of the PI3K/AKT/mTOR axis. CONCLUSION: Protocatechuic acid alleviated PCOS symptoms in mice through PI3K signaling in granulosa cells to reduce ROS levels and apoptosis.

Efficiency of Chinese medicine Bushen Huatan formula for treatment of polycystic ovary syndrome in mice via regulating gut microbiota and PPARγ pathway. / è¡¥è‚¾åŒ–ç—°æ–¹é€šè¿‡è°ƒæŽ§è‚ é“èŒåŠPPARγ通路治疗多囊卵巢综合征的机制.

OBJECTIVES: To explore the effect and mechanism of Chinese medicine Bushen Huatan formula in treatment of polycystic ovary syndrome (PCOS). METHODS: Twenty-four SPF female C57BL/6J mice were randomly divided into 3 groups with 8 animals in each group. Control group was given drinking water ad libitum; PCOS was induced by giving letrozole gavage and high-fat diet in model group and treatment group; treatment group received Bushen Huatan formula suspension for 35 d. The sex hormone levels of mice were detected by enzyme-linked immunosorbent assay. Ovary morphology was observed under light microscope after hematoxylin and eosin staining. The feces in the colon of mice were collected, and the gut microbiota was detected by 16S rRNA sequencing. The short chain fatty acids were detected by gas chromatography-mas spectrometry. The expression of peroxisome proliferator activated receptor (PPARγ) was detected by immunohistochemistry. The mRNA expression of mucin-2, occludin-1, tight junction protein zonula occludens 1 (ZO-1) and PPARγ in intestinal epithelium were detected by realtime RT-PCR. The expression of inducible nitric oxide synthase (iNOS) and PPARγ was detected by Western blotting. RESULTS: Compared with the control group, the body weight, serum levels of follicle stimulating hormone, luteinizing hormone and testosterone in the model group were increased, and serum levels of estradiol were decreased (all P<0.01); the ovarian structure under light microscope was consistent with the characteristics of PCOS. Compared with the model group, the serum levels of sex hormone and ovarian structure in treatment group were improved. The overall structure of gut microbiota in PCOS model mice changed. Compared with control group, there were significantly reduced abundance of Firmicutes, and increased abundance of Verrucomicrobia, Proteobacteria and Actinobacteria inthe model group at phylum level (all P<0.05); there were significantly reduced abundance of Lactobacillus, and increased abundance of Akkermansia, Lachnoclostridium, Lactococcus and Eubacterium_coprostanoligenes at genus level (all P<0.05). The disordered condition of gut microbiota was significantly improved in treatment group. Compared with control group, the contents of acetic acid, propionic acid and butyric acid in feces of model group were significantly decreased (all P<0.05); while the contents of propionic acid and butyric acid in treatment group were significantly increased compared with model control group (both P<0.05). Compared with control group, the mRNA expression of ZO-1 and protein expression of iNOS in model group were significantly increased, and the protein expression of PPARγ and the mRNA expressions of mucin-2 and occludin-1 were significantly decreased (all P<0.05). Compared with model group, the mRNA expression of ZO-1 and protein expression of iNOS in treatment group were decreased, and the protein expression of PPARγ and the mRNA expressions of mucin-2 and occludin-1 were increased. CONCLUSIONS: PCOS induced by letrozole high-fat diet induces microflora imbalance in mice. Chinese medicine Bushen Huatan formula may increase the level of short chain fatty acid by regulating gut microbiota, thereby activating the intestinal PPARγ pathway and improving intestinal barrier function to act as a cure for PCOS.

Challenges of hesitancy in human papillomavirus vaccination: Bibliometric and visual analysis.

BACKGROUND: Human papillomavirus (HPV) vaccine has immense research value in the prevention of related tumours. A huge body of work has been published in this field, which may pose difficulties for researchers aiming to investigate all the available information. However, bibliometrics can provide deep insights into this research field. OBJECTIVE: We aimed to study HPV vaccine development, visually analyse the development status, trends, research hotspots, and frontiers of this field, and provide a reference for research on it. METHODS: Articles were acquired from the Web of Science Core Collection. VOS viewer and CiteSpace software were used to analyse publication growth, country/region, institution, journal distribution, author, reference, and keywords, and collected burst keyword words to display research hotspots. RESULTS: A total of 4831 references were obtained, and the annual number of publications increased fluctuating over the past decade. The United States of America ranked at the top in terms of percentage of articles. The institution with the highest number of research publications in this field was the Centers for Disease Control and Prevention. The most productive and frequently cited authors was Lauri E Markowitz. The journal with the most publications in this field was Vaccine, and the most influential journal was Paediatrics. The most frequently cited reference was 'A 9-Valent HPV Vaccine against Infection and Intraepithelial Neoplasia in Women'. Burst detection analysis of top keywords showed that 'national immunisation survey', 'social media', and 'hesitancy' are the current research frontiers in this field. CONCLUSION: This study provides useful information for acquiring knowledge on HPV vaccine. Research on solving the hesitation of HPV vaccination will become an academic trend in this field, which can offer guidance for more extensive and in-depth studies in the future.

DR region of NKAα1 is a target to ameliorate hepatic lipid metabolism disturbance in obese mice.

BACKGROUND: Na+/K+-ATPase (NKA), an ion pumping enzyme ubiquitously expressed in various cells, is critically involved in cellular ion homeostasis and signal transduction. However, the role of NKA in hepatic lipid homeostasis has yet to be fully characterized. METHODS: The activity of NKA and NKAα1 expression were determined in steatotic cells, mice and patients. The roles of NKAα1 in hepatosteatosis were detected using hepatocyte knockout or specific overexpression of NKAα1 in mice. RESULTS: Herein, we demonstrated that the expression and activity of α1 subunit of NKA (NKAα1) were lowered in the livers of nonalcoholic fatty liver disease (NAFLD) patients, high-fat diet (HFD)-induced obese mice, and genetically obese (ob/ob, db/db) mice, as well as oleic acid-induced hepatocytes. Hepatic deficiency of NKAα1 exacerbated, while adeno-associated virus-mediated liver specific overexpression of NKAα1 alleviated hepatic steatosis through regulation of fatty acid oxidation (FAO) and lipogenesis. Mechanistically, we revealed that NKAα1 upregulated sirtuin 1 (SIRT1) via interacting with ubiquitin specific peptidase 22 (USP22), a deubiquitinating enzyme for the stabilization and deubiquitination of SIRT1, thus activating the downstream autophagy signaling. Blockade of the SIRT1/autophagy signaling pathway eliminated the protective effects of NKAα1 against lipid deposition in hepatocytes. Importantly, we found that an antibody against the DR region (897DVEDSYGQQWTYEQR911) of NKAα1 subunit (DR-Ab) ameliorated hepatic steatosis through maintaining the membrane density of NKAα1 and inducing its activation. CONCLUSIONS: Collectively, this study renews the functions of NKAα1 in liver lipid metabolism and provides a new clue for gene therapy or antibody treatment of hepatic lipid metabolism disturbance by targeting NKAα1.

Short-chain fatty acid-butyric acid ameliorates granulosa cells inflammation through regulating METTL3-mediated N6-methyladenosine modification of FOSL2 in polycystic ovarian syndrome.

Polycystic ovary syndrome (PCOS) is an endocrine and metabolic disorder characterized by chronic low-grade inflammation. Previous studies have demonstrated that the gut microbiome can affect the host tissue cells' mRNA N6-methyladenosine (m6A) modifications. This study aimed to understand the role of intestinal flora in ovarian cells inflammation by regulating mRNA m6A modification particularly the inflammatory state in PCOS. The gut microbiome composition of PCOS and Control groups was analyzed by 16S rRNA sequencing, and the short chain fatty acids were detected in patients' serum by mass spectrometry methods. The level of butyric acid was found to be decreased in the serum of the obese PCOS group (FAT) compared to other groups, and this was correlated with increased Streptococcaceae and decreased Rikenellaceae based on the Spearman's rank test. Additionally, we identified FOSL2 as a potential METTL3 target using RNA-seq and MeRIP-seq methodologies. Cellular experiments demonstrated that the addition of butyric acid led to a decrease in FOSL2 m6A methylation levels and mRNA expression by suppressing the expression of METTL3, an m6A methyltransferase. Additionally, NLRP3 protein expression and the expression of inflammatory cytokines (IL-6 and TNF-α) were downregulated in KGN cells. Butyric acid supplementation in obese PCOS mice improved ovarian function and decreased the expression of local inflammatory factors in the ovary. Taken together, the correlation between the gut microbiome and PCOS may unveil crucial mechanisms for the role of specific gut microbiota in the pathogenesis of PCOS. Furthermore, butyric acid may present new prospects for future PCOS treatments.

Targeting the Na+/K+ ATPase DR-region with DR-Ab improves doxorubicin-induced cardiotoxicity.

Doxorubicin (DOX) is a potent chemotherapeutic drug for various cancers. Yet, the cardiotoxic side effects limit its application in clinical uses, in which ferroptosis serves as a crucial pathological mechanism in DOX-induced cardiotoxicity (DIC). A reduction of Na+/K + ATPase (NKA) activity is closely associated with DIC progression. However, whether abnormal NKA function was involved in DOX-induced cardiotoxicity and ferroptosis remains unknown. Here, we aim to decipher the cellular and molecular mechanisms of dysfunctional NKA in DOX-induced ferroptosis and investigate NKA as a potential therapeutic target for DIC. A decrease activity of NKA further aggravated DOX-triggered cardiac dysfunction and ferroptosis in NKAα1 haploinsufficiency mice. In contrast, antibodies against the DR-region of NKAα-subunit (DR-Ab) attenuated the cardiac dysfunction and ferroptosis induced by DOX. Mechanistically, NKAα1 interacted with SLC7A11 to form a novel protein complex, which was directly implicated in the disease progression of DIC. Furthermore, the therapeutic effect of DR-Ab on DIC was mediated by reducing ferroptosis by promoting the association of NKAα1/SLC7A11 complex and maintaining the stability of SLC7A11 on the cell surface. These results indicate that antibodies targeting the DR-region of NKA may serve as a novel therapeutic strategy to alleviate DOX-induced cardiotoxicity.