Paired Electrolysis-Enabled Arylation of Quinoxalin-2(1H)-ones.

The first paired electrolysis-enabled arylation of quinoxalin-2(1H)-ones was achieved using cyanoarenes as the arylation reagents. A variety of 3-arylquinoxalin-2(1H)-ones with various important functional groups were obtained in moderate to good yields under metal- and chemical oxidant-free conditions. With a pair of reductive and oxidative processes occurring among the substrates and reaction intermediates, the power consumption can be dramatically reduced.

A COX2-targeting cancer-specific fluorescent probe for hydrogen sulfide detection in living cells, Caenorhabditis elegans, and zebrafish.

A novel cyclooxygenase-2 (COX-2) targeted H2S-activated cancer-specific fluorescent probe, namely, COX2-H2S, was designed and synthesized, with naphthalimide as the fluorophore and indomethacin as the targeting group. This H2S-sensing probe was developed to differentiate tumor cells from normal cells and was tested in living cells, Caenorhabditis elegans (C. elegans), and zebrafish. The probe could successfully be used for imaging endogenous and exogenous H2S in living cells, demonstrating high sensitivity and specificity and strong anti-interference. COX2-H2S had the ability to not only discern cancer cells from normal cells but also specifically recognize 9L/lacZ cells from other glioblastoma cells (U87-MG and LN229). It could also be successfully applied for the fluorescent live imaging of H2S in both C. elegans and zebrafish.

Survival analysis of patients with extrahepatic cholangiocarcinoma: a nomogram for clinical and MRI features.

BACKGROUND: This study aimed to establish a predictive model to estimate the postoperative prognosis of patients with extrahepatic cholangiocarcinoma (ECC) based on preoperative clinical and MRI features. METHODS: A total of 104 patients with ECC confirmed by surgery and pathology were enrolled from January 2013 to July 2021, whose preoperative clinical, laboratory, and MRI data were retrospectively collected and examined, and the effects of clinical and imaging characteristics on overall survival (OS) were analyzed by constructing Cox proportional hazard regression models. A nomogram was constructed to predict OS, and calibration curves and time-dependent receiver operating characteristic (ROC) curves were employed to assess OS accuracy. RESULTS: Multivariate regression analyses revealed that gender, DBIL, ALT, GGT, tumor size, lesion's position, the signal intensity ratio of liver to paraspinal muscle (SIRLiver/Muscle), and the signal intensity ratio of spleen to paraspinal muscle (SIRSpleen/Muscle) on T2WI sequences were significantly associated with OS, and these variables were included in a nomogram. The concordance index of nomogram for predicting OS was 0.766, and the AUC values of the nomogram predicting 1-year and 2-year OS rates were 0.838 and 0.863, respectively. The calibration curve demonstrated good agreement between predicted and observed OS. 5-fold and 10-fold cross-validation show good stability of nomogram predictions. CONCLUSIONS: Our nomogram based on clinical, laboratory, and MRI features well predicted OS of ECC patients, and could be considered as a convenient and personalized prediction tool for clinicians to make decisions.

MRI-based automatic identification and segmentation of extrahepatic cholangiocarcinoma using deep learning network.

BACKGROUND: Accurate identification of extrahepatic cholangiocarcinoma (ECC) from an image is challenging because of the small size and complex background structure. Therefore, considering the limitation of manual delineation, it's necessary to develop automated identification and segmentation methods for ECC. The aim of this study was to develop a deep learning approach for automatic identification and segmentation of ECC using MRI. METHODS: We recruited 137 ECC patients from our hospital as the main dataset (C1) and an additional 40 patients from other hospitals as the external validation set (C2). All patients underwent axial T1-weighted imaging (T1WI), T2-weighted imaging (T2WI), and diffusion-weighted imaging (DWI). Manual delineations were performed and served as the ground truth. Next, we used 3D VB-Net to establish single-mode automatic identification and segmentation models based on T1WI (model 1), T2WI (model 2), and DWI (model 3) in the training cohort (80% of C1), and compared them with the combined model (model 4). Subsequently, the generalization capability of the best models was evaluated using the testing set (20% of C1) and the external validation set (C2). Finally, the performance of the developed models was further evaluated. RESULTS: Model 3 showed the best identification performance in the training, testing, and external validation cohorts with success rates of 0.980, 0.786, and 0.725, respectively. Furthermore, model 3 yielded an average Dice similarity coefficient (DSC) of 0.922, 0.495, and 0.466 to segment ECC automatically in the training, testing, and external validation cohorts, respectively. CONCLUSION: The DWI-based model performed better in automatically identifying and segmenting ECC compared to T1WI and T2WI, which may guide clinical decisions and help determine prognosis.

Identifying the factors controlling surface water and groundwater chemical characteristics and irrigation suitability in the Yarkant River Basin, northwest China.

This study investigated the geochemical processes and the suitability for irrigation purposes of surface water and groundwater in the Yarkant River Basin, northwest China. The results showed that the surface water was moderately alkaline and neutral to slightly alkaline in the groundwater. The mean values for most ions in the groundwater were higher than those in the surface water. Geochemical method and hydrogen and oxygen isotope revealed that hydrochemical were mainly affected by dissolved evaporite minerals, ion exchange processes, and anthropogenic activities. Still, the geochemical processes of in surface water and groundwater were different. Additionally, three and four factors were extracted by factor analyses of surface water and groundwater, respectively, which distinguished the hydrochemical from natural origins and anthropogenic activities in more detail. The surface water and some groundwater in the south of the study area were suitable for irrigation processes. However, many groundwaters in the north were unsuitable for irrigation, because of their high sodium levels and salinity. The study results provide a theoretical basis for the sustainable utilization of regional water resources.

AdipoRon Engages Microglia to Antinociception through the AdipoR1/AMPK Pathway in SNI Mice.

Background: Microglia-associated neuroinflammation plays a crucial role in the initiation and development of neuropathic pain (NeuP). AdipoRon is an analog of adiponectin that exerts an anti-inflammatory effect in various diseases through the adiponectin receptor 1 (AdipoR1) signaling mechanism. Adenosine monophosphate-activated protein kinase (AMPK) is a downstream target of AdipoR1, and the AdipoR1/AMPK pathway is involved in the regulation of inflammation. This study is aimed at investigating whether AdipoRon could alleviate NeuP by inhibiting the expression of microglia-derived tumor necrosis factor-alpha (TNF-α) through the AdipoR1/AMPK pathway. Methods: In vivo, the NeuP model was established in mice through the spared nerve injury. The von Frey test was used to detect the effect of AdipoRon on the mechanical paw withdrawal threshold. Western Blot was performed to detect the effects of AdipoRon on the expression of TNF-α, AdipoR1, AMPK, and p-AMPK. Immunofluorescence was performed to observe the effects of AdipoRon on spinal microglia. In vitro, lipopolysaccharide (LPS) was used to induce inflammatory responses in BV2 cells. The effect of AdipoRon on cell proliferation was detected by CCK-8. qPCR was used to examine the effects of AdipoRon on the expression of TNF-α and polarization markers. And the effect of AdipoRon on the AdipoR1/AMPK pathway was confirmed by Western Blot. Results: Intraperitoneal injection of AdipoRon alleviated mechanical nociception in SNI mice, and the application of AdipoRon reduced the expression of TNF-α and the number of microglia in the ipsilateral spinal cord. Additionally, AdipoRon decreased the protein level of AdipoR1 and increased the protein level of p-AMPK in the ipsilateral spinal cord. In vitro, AdipoRon inhibited BV2 cell proliferation and reversed LPS-induced TNF-α expression and polarization imbalance. Furthermore, AdipoRon reversed the LPS-induced increase in AdipoR1 expression and decrease in p-AMPK expression in BV2 cells. Conclusions: AdipoRon may alleviate NeuP by reducing microglia-derived TNF-α through the AdipoR1/AMPK pathway.

SNHG5/miR-299-5p/ATF2 Axis as a Biomarker in Immune Microenvironment of Intervertebral Disc Degeneration.

Methods: The data sets of GSE56081 and GSE63492 in the Gene Expression Omnibus (GEO) database were used for screening and analysis, and the key gene markers were verified by GSE34095 and GSE126883. Finally, the infiltration of immune cells in the data were analyzed by MCPcounter analysis package. Results: In this study, a ceRNA containing 15 lncRNAs, 9 miRNAs, and 103 mRNAs was constructed. After multimodel screening and verification, key gene marker was found, namely, ATF2. The lncRNA/miRNA/mRNA axis closely related to ATF2 have also been found, namely, SNHG5/miR-299-5p/ATF2. In the analysis of immune infiltration, ATF2 was negatively correlated with T cells but positively correlated with neutrophils and endothelial cells. Conclusion: The SNHG5/miR-299-5p/ATF2 can be used as biomarker of IDD, and infiltration of immune cells plays an important role in the pathological development of IDD. In addition, as a marker of IDD, the involvement of the above-mentioned axis in the pathological development of IDD remains to be further explored.

Spatial distribution, source apportionment and health risk assessment of inorganic pollutants of surface water and groundwater in the southern margin of Junggar Basin, Xinjiang, China.

Surface water (SW) and groundwater (GW) are crucial water supply sources in the southern margin of Junggar Basin in Xinjiang. The sources of toxic components in SW and GW and their negative effects on human health are of great concern. A total of 40 SW and 596 GW samples were collected at the oasis belt to analyze distribution, sources and potential health risks of inorganic pollutants in SW and GW. Results revealed that SW quality was severely affected by Hg, 30.0% of which had Hg concentration greater than the national drinking water standard. High Hg SW was mainly distributed near Manas County and Urumqi City. GW quality was mostly affected by SO42-, 24.7% of which had SO42- concentration greater than the national drinking water standard. High SO42- GW primarily occurred in the northwest and middle of the study area. Source apportionment of inorganic pollutants identified geological background, municipal wastewater disposal, water-rock interaction, geological environment, geological structure and industrial emission were the prominent potential sources of inorganic pollution in SW, with contribution rates of 1.2%, 10.0%, 43.6%, 35.1%, 6.3% and 3.8%, respectively. Five potential pollution sources in GW (including geological background, municipal wastewater disposal, water-rock interaction, geological environment and aquifer burial depth) were identified, with contribution rates of 0.7%, 9.6%, 77.6%, 11.1% and 1.0%, respectively. Probabilistic health risk assessment showed that Cl- and As in SW and GW were the main inorganic pollutants threatening human health. Non-carcinogenic risks for adults and children were negligible, while carcinogenic risks cannot be negligible. Furthermore, the contribution of potential pollution sources to health risks was quantified using positive matrix factorization coupling with health risk assessment model. Based on which, we offered the suggestion that water quality improvement in contaminated areas should be implemented in combination with pollution monitoring systems.

Heavy metal pollution and health risk assessment of agricultural land in the Southern Margin of Tarim Basin in Xinjiang, China.

The study aimed to analyze the level of heavy metal pollution in the agricultural lands in the southern margin of Tarim Basin, Xinjiang, and its risks to human health. A total of 1765 soil samples were collected from the Cele-Ruoqiang area. The contents of soil As, Cd, Cr, Cu, Hg, Ni, Pb and Zn were analyzed using the pollution load index method. The results showed that soil was slightly contaminated with Hg and Cd; the multivariate statistical analysis indicated that Cr, Ni, As, Cu, Zn, and Cd were formed mostly by geochemical genesis, whereas Hg and Pb contents by the geological origin and human activities. The health risk assessment showed that there is no unacceptable non-carcinogenic health risk. As levels posed carcinogenic risk, however, they were within human tolerance. Thus, this study provides a scientific basis for local agricultural production safety and prevention and control of soil heavy metal pollution.

Source analysis and health risk assessment of groundwater pollution based on multivariate statistical techniques in Kashgar Delta Area, Xinjiang, China.

In this study, 63 groundwater samples were collected in the Kashgar Delta Area in Xinjiang in 2016, and then, the samples were tested and the test results were analyzed. Multivariate statistical techniques were used to determine the sources of pollution, and the USEPA (United States Environmental Protection Agency) model was used to assess the long-term health risk of groundwater to adults and children in the study area. The concentrations of groundwater chemical Na+, Cl-, SO42-, NH4+-N, TDS, F-, I-, As, Fe, Mn, Pb, Hg, pH, TH, and CODMn, which exceed the permissible level in the study based on groundwater quality index and possibly pose a potential threat to the health of the residents in the area, which are mainly influenced by geological conditions. The source of the pollutants is the dissolution of minerals in the aquifer medium, which is greatly affected by the high-salinity groundwater environment, pH conditions, redox conditions, and evaporation and concentration effect. The values of the noncarcinogenic health risk index HQn follow the descending order of Cl- > F- > As > Fe > Mn > Pb > Hg > NH4+-N; There are eight nonarcinogens and one carcinogen in groundwater of which Cl- is the dominant noncarcinogenic factor, while As is the main carcinogenic pollutant in the study area. The health risk ratio results show that Cl- and As are the main pollutants that pose the greatest threat to both adults' and children's health, and they should be considered as the primary indicators for health risk management and control.

Resveratrol mediates mechanical allodynia through modulating inflammatory response via the TREM2-autophagy axis in SNI rat model.

BACKGROUND: Neuropathic pain (NeuP) is a chronic and challenging clinical problem, with little effective treatment. Resveratrol has shown neuroprotection by inhibiting inflammatory response in NeuP. Recently, the triggering receptor expressed on myeloid cells 2 (TREM2) expressed by microglia was identified as a critical factor of inflammation in nervous system diseases. In this study, we explored whether resveratrol could ameliorate neuroinflammation and produce anti-mechanical allodynia effects via regulating TREM2 in spared nerve injury rats, as well as investigated the underlying mechanisms. METHODS: A spared nerve injury (SNI) rat model was performed to investigate whether resveratrol could exert anti-mechanical allodynia effects via inhibiting neuroinflammation. To evaluate the role of TREM2 in anti-neuroinflammatory function of resveratrol, lentivirus coding TREM2 was intrathecally injected into SNI rats to activate TREM2, and the pain behavior was detected by the von Frey test. Furthermore, 3-methyladenine (3-MA, an autophagy inhibitor) was applied to study the molecular mechanisms of resveratrol-mediated anti-neuroinflammation using Western blot, qPCR, and immunofluorescence. RESULTS: The TREM2 expression and number of the microglial cells were significantly increased in the ipsilateral spinal dorsal horn after SNI. We found that intrathecal administration of resveratrol (300ug/day) alleviated mechanical allodynia; obviously enhanced autophagy; and markedly reduced the levels of interleukin-1ß, interleukin-6, and tumor necrosis factor-α in the ipsilateral spinal dorsal horn after SNI. Moreover, the number of Iba-1+ microglial cells and TREM2 expression were downregulated after resveratrol treatment. Intrathecal administration of lentivirus coding TREM2 and/or 3-MA in those rats induced deficiencies in resveratrol-mediated anti-inflammation, leading to mechanical allodynia that could be rescued via administration of Res. Furthermore, 3-MA treatment contributed to TREM2-mediated mechanical allodynia. CONCLUSIONS: Taken together, these data reveal that resveratrol relieves neuropathic pain through suppressing microglia-mediated neuroinflammation via regulating the TREM2-autophagy axis in SNI rats.

Personality Differences of Brain Networks in Placebo Analgesia and Nocebo Hyperalgesia: A Psychophysiological Interaction (PPI) Approach in fMRI.

It is generally believed that the placebo response can elicit an analgesic effect, whilst the nocebo response can elicit a hyperalgesia effect in pain. Placebo analgesia and nocebo hyperalgesia effects are increasing concerns for researchers. Growing evidence suggests personality differences have an impact on both placebo and nocebo effects. However, previous studies have not reached a unified conclusion. We designed this study to explore the personality differences of functional magnetic resonance imaging (fMRI) signals in placebo response and nocebo response by using psychophysiological interaction (PPI) analysis. 30 healthy subjects underwent conditioning induction training to establish expectations of placebo effect and nocebo effect, and then, all subjects completed the following experimental procedures: (1) baseline scanning, (2) acute pain model establishment, (3) pain status scanning, and (4) pseudorandom scanning of block design of placebo response or nocebo response. Behavioral data were collected after each scan. The results of this study showed that (1) there were significant differences of VAS placebo intervention between the extrovert group and the introvert group (p = 0.004); (2) there were significant differences of VAS nocebo intervention between the extrovert group and the introvert group (p = 0.011); (3) there were significant differences between the VAS placebo intervention and VAS pain status (baseline) in both the extrovert group (p < 0.001) and the introvert group (p = 0.001); (4) there were significant differences between the VAS nocebo intervention and VAS pain status (baseline) in both the extrovert group (p = 0.008) and the introvert group (p < 0.001). Moreover, there were significant differences in the brain network for placebo and nocebo responses between different personalities. We found that (1) deactivation differences of the pain-related network and limbic system play an important role in personality differences associated with placebo analgesia and (2) differences of control of anxiety and activation of dorsolateral prefrontal cortex may cause the personality differences observed in nocebo hyperalgesia.

Trace metal pollution and ecological risk assessment in agricultural soil in Dexing Pb/Zn mining area, China.

Surface agricultural soil samples obtained from Dexing Pb/Zn mining area in Jiangxi province were analyzed for trace metals to assess their pollution status and potential ecological risk. The spatial distributions and the major trace metals pollution sources were described and identified with the combination of chemical measures and geographic information systems technology. The level of pollution in seven metals is decreasing in the following order: zinc (Zn 128.9 mg/kg) > chromium (Cr 64.1 mg/kg) > lead (Pb 58.4 mg/kg) > arsenic (As 45.3 mg/kg) > copper (Cu 41.9 mg/kg) > nickel (Ni 31.3 mg/kg) > cadmium (Cd 1.5 mg/kg). Trace metal spatial distribution maps established by geographic information system techniques displayed two high-pollution zones around mining sites in the study area. Multivariate statistical analyses were also applied, and the results demonstrated that Cd, As, Pb, Cu and Zn in the soils originated from mining activities, whereas Cr and Ni primarily originated from natural sources. The values of pollution index ranged from 4.79 to 71.59, and the values of modified pollution index ranged from 1.98 to 24.69. Moreover, the potential ecological risk values ranged from 264.0 to 3263.5, which indicated considerable ecological risk to very high ecological risk. The potential ecological risk values and other soil contamination indices showed similar patterns that the high-risk areas were around Dexing Pb/Zn mining site. The surface agricultural soil in study area is heavily to extremely polluted , with Cd that made the most dominant contribution.

The value of an MRI-based radiomics model in predicting the survival and prognosis of patients with extrahepatic cholangiocarcinoma.

OBJECTIVES: The study aimed to establish radiomics models based on magnetic resonance imaging (MRI) multiparameter images to predict the survival and prognosis of patients with extrahepatic cholangiocarcinoma (ECC). METHODS: Seventy-eight patients with ECC confirmed by pathology were collected retrospectively. The radiomics model_a/b/c were constructed based on the 1/2/3-year survival of patients with ECC. The best texture features were selected according to postoperative survival time and ECC patient status to calculate the radiomics score (Rad-score). A cutoff value was selected, and patients were divided into high-risk and low-risk groups. RESULTS: Model_a, model_b, and model_c were used to predict 1-, 2-, and 3-year postoperative survival rates, respectively. The area under the curve values in the training and test groups were 1.000 and 0.933 for model_a, 0.909 and 0.907 for model_b, 1.000 and 0.975 for model_c, respectively. The survival prediction model based on the Rad-score showed that the postoperative mortality risk differed significantly between risk groups (p < 0.0001). CONCLUSIONS: The MRI radiomics model could be used to predict the survival and prognosis of patients with ECC.

Heatstroke Comorbid with SARS-CoV-2 Infection: A Case Report and Literature Review.

Background: Hyperthermia and multiple organ dysfunction syndrome (MODS) are the main characteristics of heatstroke and COVID-19. Differentiating between these illnesses is crucial during a summer COVID-19 pandemic, but cases of heatstroke comorbid with COVID-19 are rarely reported. Case description: We report the first case of heatstroke comorbid with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection in a 52-year-old male. After receiving intravenous antibiotics, organ protection measures, and treatment for coagulation disorders, his fever and coma resolved. However, he developed dyspnea and cerebral hemorrhage after several days. This patient experienced a multi-pathogen pulmonary infection and an intractable coagulopathy that ultimately resulted in MODS and death. Conclusion: The combination of heatstroke and SARS-CoV-2 infection exacerbated inflammation, immune abnormalities, and coagulation disorders. The interaction between inflammation and coagulation disturbances contributed to the underlying mechanism in this case, highlighting the importance of early anti-infection, treatment for coagulopathy, immune regulation, and organ protection as crucial interventions.

[Prediction Model of Groundwater Sulphate Based on Combined Multi-source Spatio-temporal Data].

The accurate prediction of spatial variation trends in groundwater SO42- is of great significance for improving groundwater quality and regional groundwater management level. The multi-source spatio-temporal data such as land cover data, soil parameter data, digital elevation data, and groundwater pH value in the plain area of the Yarkant River Basin in 2011, 2014, 2017, and 2020 were used as characteristic variables to analyze their correlation with groundwater SO42- concentration. To enhance the prediction accuracy, the Bayesian optimization algorithm (BOA) was used to optimize the random forest regression (RFR). Based on the BOA-RFR model, the importance of the characteristic variables was analyzed, the prediction accuracy of the model was evaluated, and the groundwater SO42- prediction map was generated. The results showed that pH value, ground elevation (GE), and percentage of bare land (BAR) in the contribution area were important parameters influencing groundwater hydrochemical composition, which were significantly negatively correlated with groundwater SO42- concentration, and the importance of impact factors for predicting groundwater SO42- concentration exceeded 25 %. The geostatistical interpolation method was used as an auxiliary tool for the predictive modeling of spatial distribution. After adding auxiliary samples, the R2 of groundwater SO42- concentration prediction of the BOA-RFR model was greater than 0.96, and the maximum values of RMSE and MAE were reduced by 4.7 % and 23.8 %, respectively, compared with the minimum values of the model with fewer samples. The SO42- concentration prediction map showed that high SO42- groundwater was enriched in the northeast of the plain area of the Yarkand River Basin, an area that was expanding.

Dual Factor-Loaded Artificial Periosteum Accelerates Bone Regeneration.

In the clinic, inactivation of osteosarcoma using microwave ablation would damage the periosteum, resulting in frequent postoperative complications. Therefore, the development of an artificial periosteum is crucial for postoperative healing. In this study, we prepared an artificial periosteum using silk fibroin (SF) loaded with stromal cell-derived factor-1α (SDF-1α) and calcitonin gene-related peptide (CGRP) to accelerate bone remodeling after the microwave ablation of osteosarcoma. The prepared artificial periosteum showed a sustained release of SDF-1α and CGRP after 14 days of immersion. In vitro culture of rat periosteal stem cells (rPDSCs) demonstrated that the artificial periosteum is favorable for cell recruitment, the activity of alkaline phosphatase, and bone-related gene expression. Furthermore, the artificial periosteum improved the tube formation and angiogenesis-related gene expression of human umbilical vein endothelial cells (HUVECs). In an animal study, the periosteum in the femur of a rabbit was inactivated through microwave ablation and then removed. The damaged periosteum was replaced with the as-prepared artificial periosteum and favored bone regeneration. In all, the designed dual-factor-loaded artificial periosteum is a promising strategy to replace the damaged periosteum in the therapy of osteosarcoma for a better bone-rebuilding process.

Global crotonylome identifies EP300-regulated ANXA2 crotonylation in cumulus cells as a regulator of oocyte maturation.

Lysine crotonylation (Kcr), a newly discovered post-translational modification, played a crucial role in physiology and disease progression. However, the roles of crotonylation in oocyte meiotic resumption remain elusive. As abnormal cumulus cell development will cause oocyte maturation arrest and female infertility, we report that cumulus cells surrounding human meiotic arrested oocytes showed significantly lower crotonylation, which was associated with decreased EP300 expression and blocked cumulus cell expansion. In cultured human cumulus cells, exogenous crotonylation or EP300 activator promoted cell proliferation and reduced cell apoptosis, whereas EP300 knockdown induced the opposite effect. Transcriptome profiling analysis in human cumulus cells indicated that functions of crotonylation were associated with activation of epidermal growth factor receptor (EGFR) pathway. Importantly, we characterized the Kcr proteomics landscape in cumulus cells by LC-MS/MS analysis, and identified that annexin A2 (ANXA2) was crotonylated in cumulus cells in an EP300-dependent manner. Crotonylation of ANXA2 enhanced the ANXA2-EGFR binding, and then activated the EGFR pathway to affect cumulus cell proliferation and apoptosis. Using mouse oocytes IVM model and EP300 knockout mice, we further confirmed that crotonylation alteration in cumulus cells affected the oocyte maturation. Together, our results indicated that EP300-mediated crotonylation is important for cumulus cells functions and oocyte maturation.

Single-Cell Atlas of Human Ovaries Reveals The Role Of The Pyroptotic Macrophage in Ovarian Aging.

Female fecundity declines in a nonlinear manner with age during the reproductive years, even as ovulatory cycles continue, which reduces female fertility, disrupts metabolic homeostasis, and eventually induces various chronic diseases. Despite this, the aging-related cellular and molecular changes in human ovaries that occur during these reproductive years have not been elucidated. Here, single-cell RNA sequencing (scRNA-seq) of human ovaries is performed from different childbearing ages and reveals that the activation of the pyroptosis pathway increased with age, mainly in macrophages. The enrichment of pyroptotic macrophages leads to a switch from a tissue-resident macrophage (TRM)-involve immunoregulatory microenvironment in young ovaries to a pyroptotic monocyte-derived macrophage (MDM)-involved proinflammatory microenvironment in middle-aged ovaries. This remolded ovarian immuno-microenvironment further promotes stromal cell senescence and accelerated reproductive decline. This hypothesis is validated in a series of cell and animal experiments using GSDMD-KO mice. In conclusion, the work expands the current understanding of the ovarian aging process by illustrating a pyroptotic macrophage-involved immune mechanism, which has important implications for the development of novel strategies to delay senescence and promote reproductive health.