Advances in research on autophagy mechanisms in resistance to endometrial cancer treatment.

Administering medication is a crucial strategy in improving the prognosis for advanced endometrial cancer. However, the rise of drug resistance often leads to the resurgence of cancer or less-than-ideal treatment outcomes. Prior studies have shown that autophagy plays a dual role in the development and progression of endometrial cancer, closely associated with drug resistance. As a result, concentrating on autophagy and its combination with medical treatments might be a novel approach to improve the prognosis for endometrial cancer. This study explores the impact of autophagy on drug resistance in endometrial cancer, investigates its core mechanisms, and scrutinizes relevant treatments aimed at autophagy, aiming to illuminate the issue of treatment resistance in advanced endometrial cancer.

Cathepsin B-Responsive Programmed Brain Targeted Delivery System for Chemo-Immunotherapy Combination Therapy of Glioblastoma.

Tumor-associated macrophages (TAMs) are closely related to the progression of glioblastoma multiform (GBM) and its development of therapeutic resistance to conventional chemotherapy. TAM-targeted therapy combined with conventional chemotherapy has emerged as a promising strategy to combat GBM. However, the presence of the blood-brain barrier (BBB) severely limits the therapeutic efficacy. Meanwhile, the lack of ability to distinguish different targeted cells also poses a challenge for precise therapy. Herein, we propose a cathepsin B (CTSB)-responsive programmed brain-targeted delivery system (D&R-HM-MCA) for simultaneous TAM-targeted and GBM-targeted delivery. D&R-HM-MCA could cross the BBB via low density lipoprotein receptor-associated protein 1 (LRP1)-mediated transcytosis. Upon reaching the GBM site, the outer angiopep-2 modification could be detached from D&R-HM-MCA via cleavage of the CTSB-responsive peptide, which could circumvent abluminal LRP1-mediated efflux. The exposed p-aminophenyl-α-d-mannopyranoside (MAN) modification could further recognize glucose transporter-1 (GLUT1) on GBM and macrophage mannose receptor (MMR) on TAMs. D&R-HM-MCA could achieve chemotherapeutic killing of GBM and simultaneously induce TAM polarization from anti-inflammatory M2 phenotype to pro-inflammatory M1 phenotype, thus resensitizing the chemotherapeutic response and improving anti-GBM immune response. This CTSB-responsive brain-targeted delivery system not only can improve brain delivery efficiency, but also can enable the combination of chemo-immunotherapy against GBM. The effectiveness of this strategy may provide thinking for designing more functional brain-targeted delivery systems and more effective therapeutic regimens.

What Do Higher Alanine Aminotransferase Levels Mean in Premature Ovarian Insufficiency?

The objective of this study was to investigate the relationship between alanine aminotransferase and related biochemical parameters and potential risk factors in women with premature ovarian insufficiency (POI). This is a retrospective cohort study with 126 POI patients (including subclinical POI, n= 27) and 130 healthy controls who visited our clinic between April 2021 to November 2022. Associations were investigated by multiple linear regression, Person correlation analysis, the Kruskal-Wallis test, Mann-Whitney U test, and the independent t-test. When compared to controls, analysis of POI patients showed that body mass index (BMI), uric acid (UA) and urea, alanine aminotransferase (ALT), aspartate aminotransferase (AST), monocyte/lymphocyte ratio, monocyte count (MONO), neutrophil count (NEUT), follicle-stimulating hormone (FSH), luteinizing hormone, and neutrophil/lymphocyte ratio (NLR) were significantly higher, while estradiol (E2), the lymphocyte count and the AST/ALT ratio were lower (P < 0.05). According to linear correlation, it was clear that BMI, FSH, white blood cell count (WBC), NEUT, MONO, UA, AST, and NLR were positively associated with ALT (r = 0.215, 0.388, 0.195, 0.187, 0.184, 0.605, 0.819, and 0.189, respectively, all P < 0.05) while E2 was negatively associated with ALT (r = -0.278, P < 0.05). In addition, multiple linear regression revealed a significant, independent, and positive correlation between AST, FSH, and ALT (B =1.403 and 0.069, respectively, P < 0.05). Analysis revealed that the levels of ALT were significantly higher in POI patients. In addition, BMI, FSH, UA, AST, MONO, NLR, NEUT, and WBC were positively associated with ALT in POI patients. E2 was negatively associated with ALT. Multiple linear regression revealed an independent and positive correlation between AST, FSH, and ALT. In addition, there was also a risk of liver function damage in women with POI and subclinical POI. If patients were diagnosed with POI, early examination and corresponding intervention will be required to effectively prevent the further development of liver disease.

Switchable rotation of metal nanostructures in an intensity chirality-invariant focus field.

Light-induced rotation is a fundamental motion form that is of great significance for flexible and multifunctional manipulation modes. However, current optical rotation by a single optical field is mostly unidirectional, where switchable rotation manipulation is still challenging. To address this issue, we demonstrate a switchable rotation of non-spherical nanostructures within a single optical focus field. Interestingly, the intensity of the focus field is chiral invariant. The rotation switch is a result of the energy flux reversal in front and behind the focal plane. We quantitatively analyze the optical force exerted on a metal nanorod at different planes, as well as the surrounding energy flux. Our experimental results indicate that the direct switchover of rotational motion is achievable by adjusting the relative position of the nanostructure to the focal plane. This result enriches the basic motion mode of micro-manipulation and is expected to create potential opportunities in many application fields, such as biological cytology and optical micromachining.

All-optically controlled holographic plasmonic vortex array for multiple metallic particles manipulation.

Due to the sub-diffraction-limited size and giant field enhancement, plasmonic tweezers have a natural advantage in trapping metallic particles. However, the strict excitation condition makes it difficult to generate an arbitrary plasmonic field in a controllable manner, thus narrowing its practical applications. Here, we propose an all-optical plasmonic field shaping method based on a digital holographic algorithm and generate plasmonic vortex arrays with controllable spot numbers, spatial location, and topological charge. Our experimental results demonstrate that multiple gold particles can be stably trapped and synchronously rotated in the vortex arrays, and the particles' kinestate can be dynamically switched. The proposed holographic plasmonic vortex tweezers are suitable for a broadband particle trapping, and this method can be generalized to other surface electromagnetic waves like Bloch surface wave.

Development and Validation of a Stable Isotope Dilution Headspace-SPME-GC/MS Method for the Determination of Vanillin in Fragrant Vegetable Oils.

It has been reported that vanillin has been intentionally added to enhance the taste and flavor of low-quality vegetable oils. Therefore, it is crucial to investigate the accurate concentrations of vanillin in three types of fragrant vegetable oils commonly consumed in China. In this study, a method has been developed for the quantification of vanillin in commercial fragrant vegetable oils using the stable isotope dilution assay (SIDA) and headspace-solid-phase microextraction (HS-SPME) coupled with gas chromatography/mass spectrometry (GC/MS). The limit of detection (LOD) and limit of quantification (LOQ) of the analyte were determined to be 20 µg kg-1 and 50 µg kg-1, respectively. The validation study demonstrated that the recoveries ranged from 89% to 101%, with intra-day and inter-day precision being less than 7.46%. A survey of 80 commercially available fragrant vegetable oils was performed using the present method. Vanillin was found to be widely present in fragrant vegetable oils, with sesame oils showing the highest average content (842.6 µg kg-1), followed by rapeseed oils (262.1 µg kg-1) and peanut oils (115.0 µg kg-1). The results indicate that the proposed method is a simple, accurate, and eco-friendly approach for determining the presences of vanillin in fragrant vegetable oils.

A selective CB2R agonist (JWH133) protects against pulmonary fibrosis through inhibiting FAK/ERK/S100A4 signaling pathways.

BACKGROUND: The combination of the endocannabinoid system (ECS) and the type 2 cannabinoid receptor (CB2R) can activate various signal pathways, leading to distinct pathophysiological roles. This interaction has gained significant attention in recent research on fibrosis diseases. Focal adhesion kinase (FAK) plays a crucial role in regulating signals from growth factor receptors and Integrins. It is also involved in the transformation of fibroblasts into myofibroblasts. This study aims to investigate the impact of the CB2R agonist JWH133 on lung fibrosis and its potential to alleviate pulmonary fibrosis in mice through the FAK pathway. METHODS: The C57 mice were categorized into five groups: control, BLM, BLM + JWH133, BLM + JWH133 + NC, and BLM + JWH133 + FAK groups.JWH133 was administered to mice individually or in conjunction with the FAK vector. After 21 days, pathological changes in mouse lung tissues, inflammatory factor levels, hydroxyproline levels, and collagen contents were evaluated. Moreover, the levels of the FAK/ERK/S100A4 pathway-related proteins were measured. RESULTS: JWH133 treatment decreased inflammatory factor levels, attenuated pathological changes, and reduced extracellular matrix accumulation in the mouse model of bleomycin-induced pulmonary fibrosis; however, these effects were reversed by FAK. JWH133 attenuated fibrosis by regulating the FAK/ERK/S100A4 pathway. CONCLUSIONS: The results presented in this study show that JWH133 exerts a protective effect against pulmonary fibrosis by inhibiting the FAK/ERK/S100A4 pathway.Therefore, JWH133 holds promise as a potential therapeutic target for pulmonary fibrosis.

Transversal optical singularity induced precision measurement of step-nanostructures.

Optical singularities indicate zero-intensity points in space where parameters, such as phase, polarization, are undetermined. Vortex beams such as the Laguerre-Gaussian modes are characterized by a phase factor eilθ, and contain a phase singularity in the middle of its beam. In the case of a transversal optical singularity (TOS), it occurs perpendicular to the propagation, and its phase integral is 2π in nature. Since it emerges within a nano-size range, one expects that TOSs could be sensitive in the light-matter interaction process and could provide a great possibility for accurate determination of certain parameters of nanostructure. Here, we propose to use TOSs generated by a three-wave interference to illuminate a step nanostructure. After interaction with the nanostructure, the TOS is scattered into the far field. The scattering direction can have a relation with the physical parameters of the nanostructure. We show that by monitoring the spatial coordinates of the scattered TOS, its propagation direction can be determined, and as consequence, certain physical parameters of the step nanostructure can be retrieved with high precision.

Selective plasmonic trapping of nano-particles by Archimedes metalens.

Optical tweezer is a non-invasive method for optical force tool applied in various fields like biology, physics, and lab on chip manipulation. The Archimedean helix shape is ideal for creating chiral nanostructures, and being able to generate plasmonic focused hotspot field for optical trapping. Here we design a metal disk with the Archimedean shape to own the ability of selective trapping nanoparticles based on the spin-orbit interactions with circularly polarized light. The plasmonic near field on the metalens can be designed by adjusting the geometric parameter flexibly. We numerically analyze the optimal size and screw pitch of the metal disk to realize the switch modulation of hotspot generation, and then demonstrate the novel switchable optical trapping ability in the view of optical force and potential well analysis under the circularly polarized light excitation by a 532 nm laser. The work shows significant potential for on-chip optical trapping in various fields.

Dynamic observation of circRNA and mRNA profiles in a rat model of deep vein thrombosis.

The goal of the present study was to identify different transcriptome expression profiles involved in the pathogenesis of deep vein thrombosis (DVT), and to illustrate the diagnostic and therapeutic potential of circular RNAs (circRNAs) and mRNAs in DVT progression. A Sprague-Dawley rat model of DVT was successfully established through the stenosis method and samples were sequenced at four time points (1, 6 and 12 h, and 3 days after ligation) to observe the dynamic changes in circRNAs and mRNAs during DVT progression. RNA sequencing was used to analyze the circRNA and mRNA expression profiles, and associated functions and pathways, in the blood of DVT rats at the four time points. In addition, Short Time Series Expression Miner (STEM) analysis was performed to explore temporal gene expression. Differential expression of 1,680, 4,018, 3,724, and 3,036 circRNAs, and 400, 1,176, 373, and 573 mRNAs was observed in the 1, 6 and 12 h, and 3-day groups, respectively, compared with the sham group (fold change >2.0 or <-2.0, P<0.05). Functional enrichment analysis indicated that differentially expressed mRNAs were associated with the following terms: Immune response, cell activation, blood stasis facilitated organelle, extracellular membrane-bounded organelle, and blood microparticle, oxygen transporter activity. STEM analysis indicated that the expression of 366 circRNAs in circRNA profile 45 and 270 mRNAs in mRNA profile 45 was consistent with thrombus progression. Enrichment analysis was performed on mRNA profile 45. The main Gene Ontology annotations were chromosome segregation, mitotic sister chromatid segregation, cell cycle process, and ligand-dependent nuclear receptor transcription coactivator activity. Pathway enrichment analysis identified the platelet-associated pathway, immune-associated pathway, and inflammation-relation pathway. According to the enriched platelet-associated pathways, four mRNAs and ten candidate circRNAs were selected for reverse transcription-quantitative PCR verification. The expression of nine of the ten circRNAs and all four mRNAs was consistent with the sequencing results. In summary, differentially expressed circRNAs and mRNAs are dynamically involved in DVT development. Dysregulated transcriptome profiles and the corresponding functions and pathways may provide mechanistic insights into DVT diagnosis and treatment.

Variable-Structure Proportional-Integral-Derivative Laser Solder Joint Temperature Intelligent Control Method with Adjustable Power Upper Limit.

Laser soldering is a crucial soldering technique in the realm of electronic assembly. The temperature of the solder joint is intimately connected with the quality of the solder. This paper introduces an adjustable power upper limit variable-structure Proportional-Integral-Derivative (PID) intelligent control method for regulating the temperature of the solder joint during laser soldering. Distinct laser power limits are employed for workpieces with varying heat capacities. The solder joint temperature is monitored through an infrared thermometer, which enables closed-loop temperature control via a variable-structure PID algorithm. Residual neural network (ResNet) models are utilized to predict key soldering process parameters. This method has been executed and validated on a practical testing platform. Compared to other laser soldering control techniques, the proposed method demonstrates a low overshoot, rapid dynamic response, and swift adjustment capabilities, effectively enhancing the soldering quality and production efficiency.

Effect evaluation and influencing factor analysis of vaginal carbon dioxide laser in the treatment of stress urinary incontinence.

To evaluate the clinical efficacy of carbon dioxide laser in the treatment of female stress urinary incontinence and analyze the influencing factors. A total of 46 patients with stress urinary incontinence treated in the Affiliated Hospital of Nantong University from March 2021 to August 2022 were included through strict inclusion criteria and exclusion criteria. All patients were treated with transvaginal carbon dioxide laser therapy, and Patient Global Impression of Change (PGI-C) was used to evaluate patients' subjective satisfaction after treatment. The efficacy was evaluated by patient's subjective assessment of leakage, IngelmanSundberg scale, 1-h urine pad test, and international consultation on incontinence questionnaire short form (ICI-Q-SF) before and after treatment, and the adverse reactions after treatment were recorded. The treatment effect was divided into "significant effect group" and "no significant effect group" by subjective satisfaction and post-treatment-related scale evaluation. After laser treatment, patients' subjective symptom improved, the volume of 1-h urine pad test was reduced, and the ICI-Q-SF score was decreased, and the differences were statistically significant (P < 0.05). There was no significant difference in IngelmanSundberg scale before and after treatment (P = 1.00). Multivariate logistic regression analysis showed that pad test volume was significantly correlated with treatment effect (P = 0.007). Transvaginal carbon dioxide laser is a safe and effective method for the treatment of mild to moderate stress urinary incontinence in females. The less severe the urinary leakage, the better the treatment effect.

Human Wharton's jelly-derived mesenchymal stem cells prevent pregnancy loss in a rat by JAK/STAT-mediated immunomodulation.

AIM: Spontaneous abortion (SA) is a multiple-original syndrome with immune imbalance as one of its major risk factors. As Wharton's jelly-mesenchymal stem cells (WJ-MSCs) are considered to be able to prevent abortion, this study aims to explore the currently poorly understood underlining molecular signaling pathways and regulatory mechanisms of WJ-MSCs in pregnancy maintenance. METHODS: Abortion mode is established by subcutaneous injection of bromocriptine in rat on day 9 and abortion prevention is achieved by WJ-MSCs injection via tail vein. WJ-MSCs were cultured with/without the inhibitors of JAK/STAT or NF-κB. The uterus was collected on the 14th day of gestation and the rate of embryo absorption was calculated. The expression of Th1/Th2/Th3 cytokines in decidual, placental tissue, and peripheral blood was analyzed. RESULTS: WJ-MSCs treatment significantly reduced the abortion rate in bromocriptine-treated pregnancy such that it was not significantly different from a normal pregnancy. JAK/STAT inhibition abolished pregnancy preserving effects of WJ-MSCs but NF-κB inhibition did not. The levels of Th1-related cytokines and mRNA levels in the bromocriptine abortion model were significantly higher than the normal pregnancy group and ethanol control group, while levels of the Th2-related cytokines and mRNA levels significantly decreased. WJ-MSCs transfusion into the abortion model restored cytokine profiles such that they were not significantly different from the normal pregnancy group and ethanol control group. JAK/STAT inhibition of WJ-MSCs prevented their effect on cytokine and mRNA levels, but NF-κB inhibition did not. CONCLUSIONS: WJ-MSCs significantly lower the rate of embryo resorption of spontaneous abortion by reducing Th1-related cytokines while increasing Th2 and Th3-related cytokines in JAK/STAT-dependent manner.

Amifostine attenuates bleomycin-induced pulmonary fibrosis in mice through inhibition of the PI3K/Akt/mTOR signaling pathway.

Amifostine is a normal cell protection agent, not only used in the adjuvant therapy of lung cancer, ovarian cancer, breast cancer, nasopharyngeal cancer, bone tumor, digestive tract tumor, blood system tumor and other cancers in order to reduce the toxicity of chemotherapy drugs, and recent studies have reported that the drug can also reduce lung tissue damage in patients with pulmonary fibrosis, but its mechanism of action is not yet fully understood. In this study, we explored the potential therapeutic effects and molecular mechanisms of AMI on bleomycin (BLM)-induced pulmonary fibrosis in mice. A mouse model of pulmonary fibrosis was established using BLM. We then assessed histopathological changes, inflammatory factors, oxidative indicators, apoptosis, epithelial-mesenchymal transition, extracellular matrix changes, and levels of phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling pathway-related proteins in the BLM-treated mice to determine the effect of AMI treatment on these factors. BLM-treated mice had substantial lung inflammation and abnormal extracellular matrix deposition. Overall, treatment with AMI significantly improved BLM-induced lung injury and pulmonary fibrosis. More specifically, AMI alleviated BLM-induced oxidative stress, inflammation, alveolar cell apoptosis, epithelial-mesenchymal transition, and extracellular matrix deposition by regulating the PI3K/Akt/mTOR signaling pathway. This finding that AMI can alleviate pulmonary fibrosis in a mouse model by inhibiting activation of the PI3K/Akt/mTOR signaling pathway lays a foundation for potential future clinical application of this agent in patients with pulmonary fibrosis.

Ultraviolet metalens for photoacoustic microscopy with an elongated depth of focus.

Ultraviolet photoacoustic microscopy (UV-PAM) can achieve in vivo imaging without exogenous markers and play an important role in pathological diagnosis. However, traditional UV-PAM is unable to detect enough photoacoustic signals due to the very limited depth of focus (DOF) of excited light and the sharp decrease in energy with increasing sample depth. Here, we design a millimeter-scale UV metalens based on the extended Nijboer-Zernike wavefront-shaping theory which can effectively extend the DOF of a UV-PAM system to about 220 µm while maintaining a good lateral resolution of 1.063 µm. To experimentally verify the performance of the UV metalens, a UV-PAM system is built to achieve the volume imaging of a series of tungsten filaments at different depths. This work demonstrates the great potential of the proposed metalens-based UV-PAM in the detection of accurate diagnostic information for clinicopathologic imaging.

Nintedanib Ameliorates Bleomycin-Induced Pulmonary Fibrosis, Inflammation, Apoptosis, and Oxidative Stress by Modulating PI3K/Akt/mTOR Pathway in Mice.

Idiopathic pulmonary fibrosis (IPF) seriously threatens human life and health, and no curative therapy is available at present. Nintedanib is the first agent approved by the US Food and Drug Administration (FDA) in order to treat IPF; however, its mechanism of inhibition of IPF is still elusive. According to recent studies, nintedanib is a potent inhibitor. It can antagonize platelet-derived growth factor (PDGF), basic fibroblast growth factor (b-FGF), vascular endothelial growth factor (VEGF), etc., to inhibit pulmonary fibrosis. Whether there are other signaling pathways involved in IPF remains unknown. This study focused on investigating the therapeutic efficacy of nintedanib in bleomycin-mediated pulmonary fibrosis (PF) mice through PI3K/Akt/mTOR pathway. Following the induction of pulmonary fibrosis in C57 mice through bleomycin (BLM) administration, the mice were randomized into five groups: (1) the normal control group, (2) the BLM model control group, (3) the low-dose Nintedanib administration model group, (4) the medium-dose nintedanib administration model group, and (5) the high-dose nintedanib administration model group. For lung tissues, morphological changes were found by HE staining and Masson staining, ELISA method was used to detect inflammatory factors, alkaline water method to estimate collagen content, and western blotting for protein levels. TUNEL staining and immunofluorescence methods were used to analyze the effect of nintedanib on lung tissue and the impacts and underlying mechanisms of bleomycin-induced pulmonary fibrosis. After 28 days, bleomycin-treated mice developed significant pulmonary fibrosis. Relative to bleomycin-treated mice, nintedanib-treated mice had markedly reduced degrees of PF. In addition, nintedanib showed lung-protective effects by up-regulating antioxidant levels, down-regulating inflammatory protein expression, and reducing collagen accumulation. We demonstrated that nintedanib ameliorated bleomycin-induced lung injury by inhibiting the P13K/Akt/mTOR pathway as well as apoptosis. In addition, significant improvement in pulmonary fibrosis was seen after nintedanib (30/60/120 mg/kg body weight/day) treatment through a dose-dependent way. Histopathological results further corroborated the effect of nintedanib treatment on remarkably attenuating bleomycin-mediated mouse lung injury. According to our findings, nintedanib restores the antioxidant system, suppresses pro-inflammatory factors, and inhibits apoptosis. Nintedanib can reduce bleomycin-induced inflammation by downregulating PI3K/Akt/mTOR pathway, PF, and oxidative stress (OS).

Measuring the anthropogenic cycles of light rare earths in China: Implications for the imbalance problem.

Light rare earth elements (LREEs) are of strategic importance for low carbon transition and decarbonization. However, the imbalance between LREEs exists and a systematic understanding of their flows and stocks is lacking, which impedes the attainment of resources efficiency and exacerbates the environmental burdens. This study examines the anthropogenic cycles and the imbalance problem of three representative LREEs in China, the largest LREEs producer in the world, including cerium (the most abundant), neodymium and praseodymium (the fastest demand-growing). We find that 1) from 2011 to 2020, the total consumption of Nd and Pr increased by 228 % and 223 %, respectively, mainly attributed to the increasing demand of NdFeB, whereas that of Ce increased by 157 %; 2) the supply insufficiency of Nd and Pr under the current quota system accumulated to 138,086 tons and 35,549 tons, respectively, while the oversupply of Ce reached 63,523 tons; and 3) China has become a net importer of LREEs concentrates, and a net exporter of LREEs in the form of intermediate and final products, imposing further burdens to the domestic environment. It is clear that the imbalance of LREEs occurred during the study period, raising urgent needs to adjust the LREEs production quotas, seek other Ce applications, and eliminate illegal mining.

Pillar[5]arene-based supramolecular pseudorotaxane polymer material for ultra-sensitive detection of Fe3+ and F.

Recent advancements in ultra-sensitive detection, particularly the Aggregation Induced Emission (AIE) materials, have demonstrated a promising detection method due to their low cost, real-time detection, and simplicity of operation. Here, coumarin functionalized pillar[5]arene (P5C) and bis-bromohexyl pillar[5]arene (DP5) were successfully combined to create a linear AIE supramolecular pseudorotaxane polymer (PCDP-G). The use of PCDP-G as a supramolecular AIE polymer material for recyclable ultra-sensitive Fe3+ and F- detection is an interesting application of the materials. According to measurements, the low detection limits of PCDP-G for Fe3+ and F- are 4.16 × 10-10 M and 6.8 × 10-10 M, respectively. The PCDP-G is also a very effective logic gate and a material for luminous displays.

Mechanism of ferroptosis in a rat model of premature ovarian insufficiency induced by cisplatin.

Ferroptosis is widely present in fibrosis-related diseases. The basic pathology of premature ovarian insufficiency (POI) involves ovarian tissue fibrosis, and there are currently fewer relevant studies addressing the association between ferroptosis and POI. This study aimed to demonstrate that ferroptosis induced by cisplatin (CDDP) caused ovarian tissue fibrosis, leading to POI. Vitamin E (VE), a ferroptosis inhibitor, could repair damaged ovarian function. CDDP was used to establish a rat model of POI, and VE was administered to reverse the reproductive toxicity of CDDP. Ovarian function was assessed by histological section staining, follicle counts, sex hormone levels, as well as fertility assays. The extent of ferroptosis was assessed by transmission electron microscopy (TEM), malondialdehyde (MDA), Perls staining. CCK-8, Ethynyl-2-Deoxyuridine (EdU), and scratch assays were used to determine the effect of CDDP and VE on ovarian granulosa cell (GC) viability. Western blot, quantitative reverse-transcription polymerase chain reaction (qRT-PCR) and immunohistochemistry were performed to evaluate ferroptosis-related molecular changes. Our results showed that CDDP caused follicle development disorders and ovarian tissue fibrosis, the levels of sex hormones suggested impaired ovarian function, and VE could reverse the reproductive toxicity of CDDP. The results of TEM, MDA and Perls staining suggested that the typical mitochondrial signature of ferroptosis was altered in ovarian GCs from the CDDP group, with significantly higher levels of lipid peroxidation and significant iron deposition in ovarian tissue, whereas VE mitigated the extent of ferroptosis. Molecular experiments then confirmed that the ferroptosis-related molecules acetyl CoA synthetase long chain family member 4 (ACSl4), 15-lipoxygenase-1 (ALOX15), solute carrier family 7 member 11 (SLC7A11), and glutathione peroxidase 4 (GPX4) were differentially expressed in each group. In summary, our study preliminarily demonstrated that CDDP may promote GCs to undergo ferroptosis, cause follicle development disorders, ovarian tissue fibrosis, and induce POI by regulating the expression of ACSl4, ALOX15, SLC7A11, and GPX4, while VE improved impaired ovarian function.

Bone marrow-derived mesenchymal stem cells accelerate angiogenesis in pregnant experimentally induced deep venous thrombosis rat model via up-regulation of pro-angiogenic secretogranin II.

The present study investigated whether bone marrow-derived mesenchymal stem cells (BMMSCs) facilitate angiogenesis and improve outcomes of pregnancy with obstetric deep venous thrombosis (DVT) and explored the underlying mechanism. A pregnant DVT rat model was established using a "stenosis" method on the lower segment of the inferior vena cava (IVC). The extent of vascularization in thrombosed IVC was examined by immunohistochemistry. In addition, the effect of BMMSCs on DVT pregnancy outcomes was evaluated. We also characterized the effect of BMMSC-derived conditioned medium (BM-CM) on the impaired human umbilical vein endothelial cells (HUVECs). Thereafter, transcriptome sequencing was employed to identify the differentially expressed genes in thrombosed IVC tissues of DVT and DVT plus BMMSCs (thrice) groups. Lastly, the candidate gene's role in the promotion of angiogenesis was demonstrated in vitro and in vivo. The DVT model was successfully established using IVC stenosis. The injection of three consecutive BMMSC doses into pregnant SD rats with DVT was demonstrated to be the most effective treatment, which significantly reduced the length and weight of the thrombus, induced the highest level of angiogenesis, and ameliorated the embryo absorption rate. In vitro, BM-CM efficiently increased the abilities of impaired endothelial cells to proliferate, migrate, invade, and form vessel-like tubes, while inhibiting their apoptosis. Transcriptome sequencing revealed that BMMSCs induced a prominent upregulation of a variety of pro-angiogenic genes, including secretogranin II (SCG2). When SCG2 expression was knocked down by lentivirus, the BMMSCs' and BM-CM-induced pro-angiogenic effects on pregnant DVT rats and HUVECs were markedly attenuated. In conclusion, the study results suggest that BMMSCs enhance angiogenesis via up-regulation of SCG2, providing an effective alternative regenerative agent and novel target for the therapy of obstetric DVT.