Locus coeruleus microstructural integrity is associated with vigilance vulnerability to sleep deprivation.

Insufficient sleep compromises cognitive performance, diminishes vigilance, and disrupts daily functioning in hundreds of millions of people worldwide. Despite extensive research revealing significant variability in vigilance vulnerability to sleep deprivation, the underlying mechanisms of these individual differences remain elusive. Locus coeruleus (LC) plays a crucial role in the regulation of sleep-wake cycles and has emerged as a potential marker for vigilance vulnerability to sleep deprivation. In this study, we investigate whether LC microstructural integrity, assessed by fractional anisotropy (FA) through diffusion tensor imaging (DTI) at baseline before sleep deprivation, can predict impaired psychomotor vigilance test (PVT) performance during sleep deprivation in a cohort of 60 healthy individuals subjected to a rigorously controlled in-laboratory sleep study. The findings indicate that individuals with high LC FA experience less vigilance impairment from sleep deprivation compared with those with low LC FA. LC FA accounts for 10.8% of the variance in sleep-deprived PVT lapses. Importantly, the relationship between LC FA and impaired PVT performance during sleep deprivation is anatomically specific, suggesting that LC microstructural integrity may serve as a biomarker for vigilance vulnerability to sleep loss.

A new tau dephosphorylation-targeting chimera for the treatment of tauopathies.

Abnormal accumulation of hyperphosphorylated tau protein plays a pivotal role in a collection of neurodegenerative diseases named tauopathies, including Alzheimer's disease (AD). We have recently conceptualized the design of hetero-bifunctional chimeras for selectively promoting the proximity between tau and phosphatase, thus specifically facilitating tau dephosphorylation and removal. Here, we sought to optimize the construction of tau dephosphorylating-targeting chimera (DEPTAC) and obtained a new chimera D14, which had high efficiency in reducing tau phosphorylation both in cell and tauopathy mouse models, while showing limited cytotoxicity. Moreover, D14 ameliorated neurodegeneration in primary cultured hippocampal neurons treated with toxic tau-K18 fragments, and improved cognitive functions of tauopathy mice. These results suggested D14 as a cost-effective drug candidate for the treatment of tauopathies.

GSTO1 aggravates EGFR-TKIs resistance and tumor metastasis via deglutathionylation of NPM1 in lung adenocarcinoma.

Despite significantly improved clinical outcomes in EGFR-mutant lung adenocarcinoma, all patients develop acquired resistance and malignancy on the treatment of EGFR tyrosine kinase inhibitors (EGFR-TKIs). Understanding the resistance mechanisms is crucial to uncover novel therapeutic targets to improve the efficacy of EGFR-TKI treatment. Here, integrated analysis using RNA-Seq and shRNAs metabolic screening reveals glutathione S-transferase omega 1 (GSTO1) as one of the key metabolic enzymes that is required for EGFR-TKIs resistance in lung adenocarcinoma cells. Aberrant upregulation of GSTO1 confers EGFR-TKIs resistance and tumor metastasis in vitro and in vivo dependent on its active-site cysteine 32 (C32). Pharmacological inhibition or knockdown of GSTO1 restores sensitivity to EGFR-TKIs and synergistically enhances tumoricidal effects. Importantly, nucleophosmin 1 (NPM1) cysteine 104 is deglutathionylated by GSTO1 through its active C32 site, which leads to activation of the AKT/NF-κB signaling pathway. In addition, clinical data illustrates that GSTO1 level is positively correlated with NPM1 level, NF-κB-mediated transcriptions and progression of human lung adenocarcinoma. Overall, our study highlights a novel mechanism of GSTO1 mediating EGFR-TKIs resistance and malignant progression via protein deglutathionylation, and GSTO1/NPM1/AKT/NF-κB axis as a potential therapeutic vulnerability in lung adenocarcinoma.

Advances in cell membrane-based biomimetic nanodelivery systems for natural products.

Active components of natural products, which include paclitaxel, curcumin, gambogic acid, resveratrol, triptolide and celastrol, have promising anti-inflammatory, antitumor, anti-oxidant, and other pharmacological activities. However, their clinical application is limited due to low solubility, instability, low bioavailability, rapid metabolism, short half-life, and strong off-target toxicity. To overcome these drawbacks, cell membrane-based biomimetic nanosystems have emerged that avoid clearance by the immune system, enhance targeting, and prolong drug circulation, while also improving drug solubility and bioavailability, enhancing drug efficacy, and reducing side effects. This review summarizes recent advances in the preparation and coating of cell membrane-coated biomimetic nanosystems and in their applications to disease for targeted natural products delivery. Current challenges, limitations, and prospects in this field are also discussed, providing a research basis for the development of multifunctional biomimetic nanosystems for natural products.

Relationships among self-esteem, depression and self-injury in adolescents: a longitudinal study.

Objective: Non-suicidal self-injury is a widespread mental health concern among adolescents. This study aimed to examine the relationship between self-esteem, depression, and self-injury among adolescents using a longitudinal research design. Methods: The Self-Esteem Scale (SES), Child Depression Inventory (CDI), and Adolescent Self-Injury Scale (ASIS) were used to follow up 1,265 junior middle school students on three occasions with six-month intervals. Results: At all three time points, there were significant gender differences in self-esteem, depression, and self-injury. Self-esteem was negatively correlated with depression and self-injury at all three time points, while depression and self-injury were significantly positively correlated. Cross-lagged analysis revealed that self-esteem at Time 1 (T1) did not significantly predict self-injury at Time 2 (T2), but self-esteem (T2) significantly predicted self-injury at Time 3 (T3; ß = -0.079, p < 0.05). Similarly, self-injury (T1) significantly predicted self-esteem (T2; ß = -0.140, p < 0.001), and self-injury (T2) significantly predicted self-esteem (T3; ß = -0.071, p < 0.01). Horizontal and longitudinal mediating analysis showed that depression served as a complete mediator in both the pathway from self-esteem to self-injury and from self-injury to self-esteem. Cross-lagged analysis showed that self-esteem (T1) significantly predicts depression (T2; ß = -0.070, p < 0.05), which in turn predict self-injury (T3; ß = 0.126, p < 0.001). Similarly, self-injury (T1) predicted depression (T2; ß = 0.055, p < 0.05), which further predicted self-esteem (T3; ß = -0.218, p < 0.001). Conclusion: The self-esteem, depression, and self-injury of adolescents are closely related; self-esteem and self-injury predict each other; self-esteem indirectly affects self-injury through depression; and self-injury indirectly affects self-esteem through depression. Based on the relationship of bi-directional prediction of self-esteem and self-injury mediated by depression, this study proposes a theoretical model of depression-mediated self-esteem and self-injury cycle.

TSG6-Exo@CS/GP Attenuates Endometrium Fibrosis by Inhibiting Macrophage Activation in a Murine IUA Model.

Intrauterine adhesion (IUA) is characterized by the formation of fibrous scar tissue within the uterine cavity, which significantly impacts female reproductive health and even leads to infertility. Unfortunately, severe cases of IUA currently lack effective treatments. This study presents a novel approach that utilizes tumor necrosis factor-(TNF) stimulated gene 6 (TSG6)-modified exosomes (Exos) in conjunction with an injectable thermosensitive hydrogel (CS/GP) to mitigate the occurrence of IUA by reducing endometrium fibrosis in a mouse IUA model. This study demonstrate that TSG6-modified Exos effectively inhibits the activation of inflammatory M1-like macrophages during the initial stages of inflammation and maintains the balance of macrophage phenotypes (M1/M2) during the repair phase. Moreover, TSG6 inhibits the interaction between macrophages and endometrial stromal fibroblasts, thereby preventing the activation of stromal fibroblasts into myofibroblasts. Furthermore, this research indicates that CS/GP facilitates the sustained release of TSG6-modified Exos, leading to a significant reduction in both the manifestations of IUA and the extent of endometrium fibrosis. Collectively, through the successful construction of CS/GP loaded with TSG6-modified Exos, a reduction in the occurrence and progression of IUA is achieved by mitigating endometrium fibrosis. Consequently, this approach holds promise for the treatment of IUA.

Increased levels of villus-derived exosomal miR-29a-3p in normal pregnancy than uRPL patients suppresses decidual NK cell production of interferon-γ and exerts a therapeutic effect in abortion-prone mice.

OBJECTIVE: Recurrent pregnancy loss (RPL) patients have higher absolute numbers of decidual natural killer (dNK) cells with elevated intracellular IFN-γ levels leading to a pro-inflammatory cytokine milieu, which contributes to RPL pathogenesis. The main objective of this study was twofold: first to explore the regulatory effects and mechanisms of villus-derived exosomes (vEXOs) from induced abortion patients or RPL patients at the level of intracellular IFN-γ in dNK cells; second to determine the validity of application of vEXOs in the treatment of unexplained RPL (uRPL) through in vitro experiments and mouse models. METHODS: Exosomes were isolated from villus explants by ultracentrifugation, co-cultured with dNK cells, and purified by enzymatic digestion and magnetically activated cell sorting. Flow cytometry, enzyme-linked immunosorbent assays, and RT-qPCR were used to determine IFN-γ levels. Comparative miRNA analysis of vEXOs from induced abortion (IA) and uRPL patients was used to screen potential candidates involved in dNK regulation, which was further confirmed by luciferase reporter assays. IA-vEXOs were electroporated with therapeutic miRNAs and encapsulated in a China Food and Drug Administration (CFDA)-approved hyaluronate gel (HA-Gel), which has been used as a clinical biomaterial in cell therapy for > 30 years. In vivo tracking was performed using 1,1-dioctadecyl-3,3,3,3-tetramethylindotricarbocyaine iodide (DiR) labelling. Tail-vein and uterine horn injections were used to evaluate therapeutic effects of the engineered exosomes in an abortion-prone mouse model (CBA/J × DBA/2 J). Placental growth was evaluated based on placental weight. IFN-γ mRNA levels in mouse placentas were measured by RT-qPCR. RESULTS: IFN-γ levels were significantly higher in dNK cells of uRPL patients than in IA patients. Both uRPL-vEXOs and IA-vEXOs could be efficiently internalized by dNK cells, whereas uRPL-vEXOs could not reduce the expression of IFN-γ by dNK cells as much as IA-vEXOs. Mechanistically, miR-29a-3p was delivered by vEXOs to inhibit IFN-γ production by binding to the 3' UTR of IFN-γ mRNA in dNK cells. For in vivo treatment, application of the HA-Gel effectively prolonged the residence time of vEXOs in the uterine cavity via sustained release. Engineered vEXOs loaded with miR-29a-3p reduced the embryo resorption rate in RPL mice with no signs of systemic toxicity. CONCLUSION: Our study provides the first evidence that villi can regulate dNK cell production of IFN-γ via exosome-mediated transfer of miR-29a-3p, which deepens our understanding of maternal-fetal immune tolerance for pregnancy maintenance. Based on this, we developed a new strategy to mix engineered vEXOs with HA-Gel, which exhibited good therapeutic effects in mice with uRPL and could be used for potential clinical applications in uRPL treatment.

Network analysis of the relationship between non-suicidal self-injury, depression, and childhood trauma in adolescents.

BACKGROUND: Non-suicidal self-injury seriously harm the physical and mental health of adolescents. The aim of the current study was to explore the relationship between non-suicide self-injury, depression, and childhood trauma from the perspective of symptoms in adolescents. METHODS: A cross-sectional survey was conducted in four junior high middle schools and collected 2640 valid questionnaires. There were 1329 male students and 1311 female students. The age of the participants ranged from 11 to 17 years old, with a mean age of 13.3 (± 0.94) years. Non-suicidal self-injury (NSSI), depressive symptoms, and childhood trauma were assessed using the Adolescent Self-Harm Scale, the Childhood Depression Scale, and the Childhood Trauma Questionnaire, respectively. A network analysis was performed. RESULTS: In the network, NSSI, depressive symptoms, and childhood trauma were closely related. Negative self-esteem in the depressive symptoms and emotional abuse in childhood were the most central nodes. Negative self-esteem and negative mood were directly connected to NSSI, other nodes of depressive symptoms appeared to be indirectly connected to NSSI through these two nodes. Emotional abuse was the only node in childhood trauma categories directly connected to NSSI. Nodes of other categories of childhood trauma (physical neglect, physical abuse, emotional neglect, and sexual abuse) were indirectly connected to NSSI through emotional abuse. CONCLUSIONS: NSSI, depression, and childhood trauma of teenagers were closely related. Individuals who have suffered emotional abuse in childhood were more likely to have depressive symptoms and NSSI. Improving negative self-esteem and negative emotions and reducing emotional abuse may be beneficial in alleviating depression and reducing NSSI in adolescents.

Self-assembly of differentiated dental pulp stem cells facilitates spheroid human dental organoid formation and prevascularization.

BACKGROUND: The self-assembly of solid organs from stem cells has the potential to greatly expand the applicability of regenerative medicine. Stem cells can self-organise into microsized organ units, partially modelling tissue function and regeneration. Dental pulp organoids have been used to recapitulate the processes of tooth development and related diseases. However, the lack of vasculature limits the utility of dental pulp organoids. AIM: To improve survival and aid in recovery after stem cell transplantation, we demonstrated the three-dimensional (3D) self-assembly of adult stem cell-human dental pulp stem cells (hDPSCs) and endothelial cells (ECs) into a novel type of spheroid-shaped dental pulp organoid in vitro under hypoxia and conditioned medium (CM). METHODS: During culture, primary hDPSCs were induced to differentiate into ECs by exposing them to a hypoxic environment and CM. The hypoxic pretreated hDPSCs were then mixed with ECs at specific ratios and conditioned in a 3D environment to produce prevascularized dental pulp organoids. The biological characteristics of the organoids were analysed, and the regulatory pathways associated with angiogenesis were studied. RESULTS: The combination of these two agents resulted in prevascularized human dental pulp organoids (Vorganoids) that more closely resembled dental pulp tissue in terms of morphology and function. Single-cell RNA sequencing of dental pulp tissue and RNA sequencing of Vorganoids were integrated to analyse key regulatory pathways associated with angiogenesis. The biomarkers forkhead box protein O1 and fibroblast growth factor 2 were identified to be involved in the regulation of Vorganoids. CONCLUSION: In this innovative study, we effectively established an in vitro model of Vorganoids and used it to elucidate new mechanisms of angiogenesis during regeneration, facilitating the development of clinical treatment strategies.

MiR-135a-5p regulates window of implantation by suppressing pinopodes development and decidualization of endometrial stromal cells.

PURPOSE: The window of implantation (WOI) is a brief period during which the endometrium is receptive to embryo implantation. This study investigated the relationship between miR-135a-5p and endometrial receptivity. METHODS: Peripheral blood was collected on the day of ovulation and the 5th day after ovulation for high-throughput sequencing from women who achieved clinical pregnancy through natural cycle frozen embryo transfer. RT-qPCR assessed miR-135a-5p expression in the endometrium tissue or cells during the mouse implantation window or decidualization. Scanning electron microscopy was utilized to observe pinopode morphology and quantity in mice overexpressing miR-135a-5p during the WOI. Human endometrial stromal cells (HESC) and artificial induction of mouse uterine decidualization were used to explore whether miR-135a-5p overexpression inhibits decidualization by regulating HOXA10 and BMPR2. Furthermore, the impact of miR-135a-5p on HESC proliferation and HTR8/SVneo invasion was explored. RESULTS: A total of 54 women were enrolled in the study. bioinformatics analysis and animal models demonstrated that miR-135a-5p was significantly downregulated during the WOI, and its high expression can lead to abnormal pregnancy outcomes. Overexpression of miR-135a-5p resulted in the absence of pinopode in mouse endometrial tissue during the WOI. High miR-135a-5p levels were found to potentially inhibit endometrial tissue decidualization by downregulating HOXA10 and BMPR2 expression. Finally, CEBPD was identified as a potential regulator of miR-135a-5p, which would explain the decreased miR-135a-5p expression during the WOI. CONCLUSION: MiR-135a-5p expression is significantly downregulated during the WOI. High miR-135a-5p levels suppress pinopode development and endometrial tissue decidualization through HOXA10 and BMPR2, contributing to inadequate endometrial receptivity.

Amino acids in the polymerase complex of shorebird-isolated H1N1 influenza virus impact replication and host-virus interactions in mammalian models.

A diverse population of avian influenza A viruses (AIVs) are maintained in wild birds and ducks yet the zoonotic potential of AIVs in these environmental reservoirs and the host-virus interactions involved in mammalian infection are not well understood. In studies of a group of subtype H1N1 AIVs isolated from migratory wild birds during surveillance in North America, we previously identified eight amino acids in the polymerase genes PB2 and PB1 that were important for the transmissibility of these AIVs in a ferret model of human influenza virus transmission. In this current study we found that PB2 containing amino acids associated with transmissibility at 67, 152, 199, 508, and 649 and PB1 at 298, 642, and 667 were associated with more rapid viral replication kinetics, greater infectivity, more active polymerase complexes and greater kinetics of viral genome replication and transcription. Pathogenicity in the mouse model was also impacted, evident as greater weight loss and lung pathology associated with greater inflammatory lung cytokine expression. Further, these AIVs all contained the avian-type amino acids of PB2-E627, D701, G590, Q591 and T271. Therefore, our study provides novel insights into the role of the AIV polymerase complex in the zoonotic transmission of AIVs in mammals.

Fetal growth restriction exhibits various mTOR signaling in different regions of mouse placentas with altered lipid metabolism.

Fetal growth restriction (FGR) is a common complication of pregnancy and can have significant impact on obstetric and neonatal outcomes. Increasing evidence has shown that the inhibited mechanistic target of rapamycin (mTOR) signaling in placenta is associated with FGR. However, interpretation of existing research is limited due to inconsistent methodologies and varying understanding of the mechanism by which mTOR activity contributes to FGR. Hereby, we have demonstrated that different anatomic regions of human and mouse placentas exhibited different levels of mTOR activity in normal compared to FGR pregnancies. When using the rapamycin-induced FGR mouse model, we found that placentas of FGR pregnancies exhibited abnormal morphological changes and reduced mTOR activity in the decidual-junctional layer. Using transcriptomics and lipidomics, we revealed that lipid and energy metabolism was significantly disrupted in the placentas of FGR mice. Finally, we demonstrated that maternal physical exercise during gestation in our FGR mouse model was associated with increased fetal and placental weight as well as increased placental mTOR activity and lipid metabolism. Collectively, our data indicate that the inhibited placental mTOR signaling contributes to FGR with altered lipid metabolism in mouse placentas, and maternal exercise could be an effective method to reduce the occurrence of FGR or alleviate the adverse outcomes associated with FGR.

Targeting vulnerable microcircuits in the ventral hippocampus of male transgenic mice to rescue Alzheimer-like social memory loss.

BACKGROUND: Episodic memory loss is a prominent clinical manifestation of Alzheimer's disease (AD), which is closely related to tau pathology and hippocampal impairment. Due to the heterogeneity of brain neurons, the specific roles of different brain neurons in terms of their sensitivity to tau accumulation and their contribution to AD-like social memory loss remain unclear. Therefore, further investigation is necessary. METHODS: We investigated the effects of AD-like tau pathology by Tandem mass tag proteomic and phosphoproteomic analysis, social behavioural tests, hippocampal electrophysiology, immunofluorescence staining and in vivo optical fibre recording of GCaMP6f and iGABASnFR. Additionally, we utilized optogenetics and administered ursolic acid (UA) via oral gavage to examine the effects of these agents on social memory in mice. RESULTS: The results of proteomic and phosphoproteomic analyses revealed the characteristics of ventral hippocampal CA1 (vCA1) under both physiological conditions and AD-like tau pathology. As tau progressively accumulated, vCA1, especially its excitatory and parvalbumin (PV) neurons, were fully filled with mislocated and phosphorylated tau (p-Tau). This finding was not observed for dorsal hippocampal CA1 (dCA1). The overexpression of human tau (hTau) in excitatory and PV neurons mimicked AD-like tau accumulation, significantly inhibited neuronal excitability and suppressed distinct discrimination-associated firings of these neurons within vCA1. Photoactivating excitatory and PV neurons in vCA1 at specific rhythms and time windows efficiently ameliorated tau-impaired social memory. Notably, 1 month of UA administration efficiently decreased tau accumulation via autophagy in a transcription factor EB (TFEB)-dependent manner and restored the vCA1 microcircuit to ameliorate tau-impaired social memory. CONCLUSION: This study elucidated distinct protein and phosphoprotein networks between dCA1 and vCA1 and highlighted the susceptibility of the vCA1 microcircuit to AD-like tau accumulation. Notably, our novel findings regarding the efficacy of UA in reducing tau load and targeting the vCA1 microcircuit may provide a promising strategy for treating AD in the future.

A Novel Cholesterol Metabolism-Related lncRNA Signature Predicts the Prognosis of Patients with Hepatocellular Carcinoma and Their Response to Immunotherapy.

BACKGROUND: The survival rate of hepatocellular carcinoma (HCC) is low and the prognosis is poor. Metabolic reprogramming is still an emerging hallmark of cancer, and reprogramming of cholesterol metabolism plays a crucial action in tumor pathogenesis. Increasing evidence suggests that cholesterol metabolism affects the cell proliferation, invasion, migration, and resistance to chemotherapy of HCC. To date, no long noncoding RNA (lncRNA) signature associated with cholesterol metabolism has been developed to predict the outcome of patients with HCC. METHODS: The RNA-seq data as well as the prognostic and clinical data were obtained from The Cancer Genome Atlas (TCGA) database. We conducted univariate and multivariate analyses to assess cholesterol metabolism-related lncRNAs correlated with the prognosis of patients with HCC in order to construct a prognostic signature. Functional differences between low- and high-risk groups were investigated using genomic enrichment analysis (GSEA). Kaplan-Meier (KM) curves were applied to explore the overall survival (OS) of the low- and high-risk groups. Single-sample genomic enrichment analysis (ssGSEA) was applied to investigate the association between this predictive signature and immune function. We subsequently examined how this signature relates to treatment response in HCC patients. RESULTS: A prognostic signature comprising six lncRNAs related to cholesterol metabolism was constructed (AC124798.1, AL031985.3, AC103760.1, NRAV, WAC-AS1 and AC022613.1). We found that low-risk groups showed a better prognosis than high-risk groups. In HCC patients, the cholesterol metabolism-related lncRNA signature may be served as an independent prognostic factor. Cholesterol metabolism-related lncRNA signature had higher diagnostic efficiency compared to clinicopathologic variables. After stratifying patients according to different clinicopathological variables, patients with low-risk had a longer OS compared with high-risk patients. The ssGSEA demonstrated that this signature was closely related to the immune status of HCC patients. GSEA analysis demonstrated that immune- and tumor-related pathways were predominantly enriched in the high-risk group. High-risk patients were more responsive to immune checkpoint inhibitors (ICIs) and conventional chemotherapeutic agents. CONCLUSIONS: This cholesterol metabolism-related lncRNA signature can predict the prognosis of HCC patients and guide the clinical management of HCC patients, including immunotherapy.

High estrogen during ovarian stimulation induced loss of maternal imprinted methylation that is essential for placental development via overexpression of TET2 in mouse oocytes.

BACKGROUND: Ovarian stimulation (OS) during assisted reproductive technology (ART) appears to be an independent factor influencing the risk of low birth weight (LBW). Previous studies identified the association between LBW and placenta deterioration, potentially resulting from disturbed genomic DNA methylation in oocytes caused by OS. However, the mechanisms by which OS leads to aberrant DNA methylation patterns in oocytes remains unclear. METHODS: Mouse oocytes and mouse parthenogenetic embryonic stem cells (pESCs) were used to investigate the roles of OS in oocyte DNA methylation. Global 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) levels were evaluated using immunofluorescence or colorimetry. Genome-wide DNA methylation was quantified using an Agilent SureSelectXT mouse Methyl-Seq. The DNA methylation status of mesoderm-specific transcript homologue (Mest) promoter region was analyzed using bisulfite sequencing polymerase chain reaction (BSP). The regulatory network between estrogen receptor alpha (ERα, ESR1) and DNA methylation status of Mest promoter region was further detected following the knockdown of ERα or ten-eleven translocation 2 (Tet2). RESULTS: OS resulted in a significant decrease in global 5mC levels and an increase in global 5hmC levels in oocytes. Further investigation revealed that supraphysiological ß-estradiol (E2) during OS induced a notable decrease in DNA 5mC and an increase in 5hmC in both oocytes and pESCs of mice, whereas inhibition of estrogen signaling abolished such induction. Moreover, Tet2 may be a direct transcriptional target gene of ERα, and through the ERα-TET2 axis, supraphysiological E2 resulted in the reduced global levels of DNA 5mC. Furthermore, we identified that MEST, a maternal imprinted gene essential for placental development, lost its imprinted methylation in parthenogenetic placentas originating from OS, and ERα and TET2 combined together to form a protein complex that may promote Mest demethylation. CONCLUSIONS: In this study, a possible mechanism of loss of DNA methylation in oocyte caused by OS was revealed, which may help increase safety and reduce epigenetic abnormalities in ART procedures.

Aberrant NK cell profile in gestational diabetes mellitus with fetal growth restriction.

Gestational diabetes mellitus (GDM) is a gestational disorder characterized by hyperglycemia, that can lead to dysfunction of diverse cells in the body, especially the immune cells. It has been reported that immune cells, specifically natural killer (NK) cells, play a crucial role in normal pregnancy. However, it remains unknown how hyperglycemia affects NK cell dysfunction thus participates in the development of GDM. In this experiment, GDM mice were induced by an intraperitoneal injection of streptozotocin (STZ) after pregnancy and it has been found that the intrauterine growth restriction occurred in mice with STZ-induced GDM, accompanied by the changed proportion and function of NK cells. The percentage of cytotoxic CD27-CD11b+ NK cells was significantly increased, while the proportion of nourished CD27-CD11b- NK cells was significantly reduced in the decidua of GDM mice. Likewise, the same trend appeared in the peripheral blood NK cell subsets of GDM patients. What's more, after intrauterine reinfusion of NK cells to GDM mice, the fetal growth restriction was alleviated and the proportion of NK cells was restored. Our findings provide a theoretical and experimental basis for further exploring the pathogenesis of GDM.

Efficient Sequential Co-Delivery Nanosystem for Inhibition of Tumor and Tumor-Associated Fibroblast-Induced Resistance and Metastasis.

Purpose: Triple-negative breast cancer (TNBC) is the most lethal subtype of breast cancer. However, the effect of current treatment strategies by inducing tumor cell apoptosis alone is not satisfactory. The growth, metastasis and treatment sensitivity of tumors can be strongly influenced by cancer-associated fibroblasts (CAFs) in the microenvironment. Effective cancer therapies may need to target not only the tumor cells directly but also the CAFs that protect them. Methods: Celastrol and small-sized micelles containing betulinic acid were co-encapsulated into liposomes using the thin-film hydration method (CL@BM). Folic acid was further introduced to modify liposomes as the targeting moiety (F/CL@BM). We established a novel NIH3T3+4T1 co-culture model to mimic the tumor microenvironment and assessed the nanocarrier's inhibitory effects on CAFs-induced drug resistance and migration in the co-culture model. The in vivo biological distribution, fluorescence imaging, biological safety evaluation, and combined therapeutic effect evaluation of the nanocarrier were carried out based on a triple-negative breast cancer model. Results: In the present study, a novel multifunctional nano-formulation was designed by combining the advantages of sequential release, co-loading of tretinoin and betulinic acid, and folic acid-mediated active targeting. As expected, the nano-formulation exhibited enhanced cytotoxicity in different cellular models and effectively increased drug accumulation at the tumor site by disrupting the cellular barrier composed of CAFs by tretinoin. Notably, the co-loaded nano-formulations proved to be more potent in inhibiting tumor growth in mice and also showed better anti-metastatic effects in lung metastasis models compared to the formulations with either drug alone. This novel drug delivery system has the potential to be used to develop more effective cancer therapies. Conclusion: Targeting CAFs with celastrol sensitizes tumor cells to chemotherapy, increasing the efficacy of betulinic acid. The combination of drugs targeting tumor cells and CAFs may lead to more effective therapies against various cancers.

Deep eutectic solvent (DES)-assisted extraction of pectin from Ficus carica Linn. peel: optimization, partial structure characterization, functional and antioxidant activities.

BACKGROUND: The pectin from Ficus carica Linn. (fig) peels is a valuable and recyclable constituent that may bring huge economic benefits. To maximize the utilization of this resource, deep eutectic solvent (DES)-assisted extraction was applied to extract pectin from fig peels, and the extraction process was optimized with response surface methodology. RESULTS: When DES (choline chloride/oxalic acid = 1:1) content was 168.1 g kg-1, extraction temperature was 79.8 °C, liquid-solid ratio was 23.3 mL g-1, and extraction time was 120 min, the maximum yield of 239.6 g kg-1 was obtained, which was almost twice the extraction of hot water. DES-extracted fig peel pectin (D-FP) exhibited better nature than hot water-extracted fig peel pectin (W-FP) in terms of uronic acid content, particle size distribution, and solubility, but lower molecular weight and esterification degree. D-FP and W-FP had similar infrared spectra and thermodynamic peaks but differed in monosaccharide compositions. D-FP also showed good antioxidant capacities and exhibited better functional activities than W-FP. CONCLUSION: These results indicated that D-FP was of promising quality being utilized in food or medical industries and the optimal DES-assisted extraction method might be applied as a sustainable process for the effective extraction of bioactive pectin from fig peels with the excellence of low equipment requirements and simple operation. © 2024 Society of Chemical Industry.

Identification of Novel -Glucosidase Inhibitors from Syzygium jambos (L.) Using Spectroscopy and Molecular Docking.

Fruits of Syzygium jambos (L.) are recognized as a "food", exhibiting significant antidiabetic activities. However, the α-glucosidase inhibition of the components from Syzygium jambos (L.) have not yet been investigated. In this study, a total of 14 compounds were isolated from Syzygium jambos (L.) Alston, eight of which showed significant inhibitory effects on α-glucosidase, with IC50 values in the range of 0.011-0.665 mM. Notably, compounds 1-3 (IC50: 0.013, 0.011 and 0.030 mM, respectively) exhibited much stronger activity than acarbose (IC50: 2.329 ± 0.109 mM). The enzyme kinetics study indicated that compound 1 was an uncompetitive inhibitor, and compounds 2-8 were mixed-type inhibitors. Moreover, the interactions between compounds and α-glucosidase were investigated by molecular docking, which further revealed that the number of olefin double bonds and 2-COOH of heptadeca-phenols had a notable effect on the α-glucosidase inhibitory activity. This study demonstrated that Syzygium jambos (L.) fruit might serve as a functional food for the prevention of diabetes mellitus.