Spatiotemporal transcriptomic changes of human ovarian aging and the regulatory role of FOXP1.

Limited understanding exists regarding how aging impacts the cellular and molecular aspects of the human ovary. This study combines single-cell RNA sequencing and spatial transcriptomics to systematically characterize human ovarian aging. Spatiotemporal molecular signatures of the eight types of ovarian cells during aging are observed. An analysis of age-associated changes in gene expression reveals that DNA damage response may be a key biological pathway in oocyte aging. Three granulosa cells subtypes and five theca and stromal cells subtypes, as well as their spatiotemporal transcriptomics changes during aging, are identified. FOXP1 emerges as a regulator of ovarian aging, declining with age and inhibiting CDKN1A transcription. Silencing FOXP1 results in premature ovarian insufficiency in mice. These findings offer a comprehensive understanding of spatiotemporal variability in human ovarian aging, aiding the prioritization of potential diagnostic biomarkers and therapeutic strategies.

Aggresome formation promotes ASK1/JNK signaling activation and stemness maintenance in ovarian cancer.

Aggresomes are the product of misfolded protein aggregation, and the presence of aggresomes has been correlated with poor prognosis in cancer patients. However, the exact role of aggresomes in tumorigenesis and cancer progression remains largely unknown. Herein, the multiomics screening reveal that OTUD1 protein plays an important role in retaining ovarian cancer stem cell (OCSC) properties. Mechanistically, the elevated OTUD1 protein levels lead to the formation of OTUD1-based cytoplasmic aggresomes, which is mediated by a short peptide located in the intrinsically disordered OTUD1 N-terminal region. Furthermore, OTUD1-based aggresomes recruit ASK1 via protein-protein interactions, which in turn stabilize ASK1 in a deubiquitinase-independent manner and activate the downstream JNK signaling pathway for OCSC maintenance. Notably, the disruption of OTUD1-based aggresomes or treatment with ASK1/JNK inhibitors, including ibrutinib, an FDA-approved drug that was recently identified as an MKK7 inhibitor, effectively reduced OCSC stemness (OSCS) of OTUD1high ovarian cancer cells. In summary, our work suggests that aggresome formation in tumor cells could function as a signaling hub and that aggresome-based therapy has translational potential for patients with OTUD1high ovarian cancer.

Multiomics insights into the female reproductive aging.

The human female reproductive lifespan significantly diminishes with age, leading to decreased fertility, reduced fertility quality and endocrine function disorders. While many aspects of aging in general have been extensively documented, the precise mechanisms governing programmed aging in the female reproductive system remain elusive. Recent advancements in omics technologies and computational capabilities have facilitated the emergence of multiomics deep phenotyping. Through the application and refinement of various high-throughput omics methods, a substantial volume of omics data has been generated, deepening our comprehension of the pathogenesis and molecular underpinnings of reproductive aging. This review highlights current and emerging multiomics approaches for investigating female reproductive aging, encompassing genomics, epigenomics, transcriptomics, proteomics, metabolomics, and microbiomics. We elucidate their influence on fundamental cell biology and translational research in the context of reproductive aging, address the limitations and current challenges associated with multiomics studies, and offer a glimpse into future prospects.

Matrix stiffness affects tumor-associated macrophage functional polarization and its potential in tumor therapy.

The extracellular matrix (ECM) plays critical roles in cytoskeletal support, biomechanical transduction and biochemical signal transformation. Tumor-associated macrophage (TAM) function is regulated by matrix stiffness in solid tumors and is often associated with poor prognosis. ECM stiffness-induced mechanical cues can activate cell membrane mechanoreceptors and corresponding mechanotransducers in the cytoplasm, modulating the phenotype of TAMs. Currently, tuning TAM polarization through matrix stiffness-induced mechanical stimulation has received increasing attention, whereas its effect on TAM fate has rarely been summarized. A better understanding of the relationship between matrix stiffness and macrophage function will contribute to the development of new strategies for cancer therapy. In this review, we first introduced the overall relationship between macrophage polarization and matrix stiffness, analyzed the changes in mechanoreceptors and mechanotransducers mediated by matrix stiffness on macrophage function and tumor progression, and finally summarized the effects of targeting ECM stiffness on tumor prognosis to provide insight into this new field.

Cancer-Erythrocyte Membrane-Mimicking Fe3O4 Nanoparticles and DHJS for Ferroptosis/Immunotherapy Synergism in Tumors.

Ferroptosis is characterized by iron accumulation and lipid peroxidation. However, a clinical dose of Fe3O4 nanoparticles could not cause effective ferroptosis in tumors, and the mechanism is yet to be completely understood. In this study, using RNA-seq data, we found that tumor cells could feedback-activate the antioxidant system by upregulating Nrf-2 expression, thus avoiding ferroptosis caused by Fe3O4 nanoparticles. We also found that DHJS (a probe for ROS generation) can antagonize Nrf-2 expression when it synergizes with Fe3O4 nanoparticles, thus inducing ferroptosis in tumor cells. Considering these findings, we created a biomimetic hybrid cell membrane camouflaged by PLGA-loaded Fe3O4 and DHJS to treat osteosarcoma. The hybrid cell membrane endowed the core nanoparticle with the extension of blood circulation life and enhanced homologous targeting ability. In addition, DHJS and Fe3O4 in nanoparticles prompted synergistically lethal ferroptosis in cancer cells and induced macrophage M1 polarization as well as the infiltration of CD8(+) T cells and dendritic cells in tumors. In summary, this study provides novel mechanistic insights and practical strategies for ferroptosis induction of Fe3O4 nanoparticles. Meanwhile, the synthesized biomimetic nanoparticles exhibited synergistic ferroptosis/immunotherapy against osteosarcoma.

Inhibition of checkpoint kinase prevents human oocyte apoptosis induced by chemotherapy and allows enhanced tumour chemotherapeutic efficacy.

STUDY QUESTION: Could inhibition of the checkpoint kinase (CHEK) pathway protect human oocytes and even enhance the anti-tumour effects, during chemotherapy? SUMMARY ANSWER: CHEK inhibitors prevented apoptosis of human oocytes induced by chemotherapy and even enhanced the anti-tumour effects. WHAT IS KNOWN ALREADY: CHEK inhibitors showed ovarian protective effects in mice during chemotherapy, while their role in human oocytes is unclear. STUDY DESIGN, SIZE, DURATION: This experimental study evaluated the ovarian reserve of young patients (120 patients) with cancer, exposed or not exposed to taxane and platinum (TP)-combined chemotherapy. Single RNA-sequencing analysis of human primordial oocytes from 10 patients was performed to explore the mechanism of oocyte apoptosis induced by TP chemotherapy. The damaging effects of paclitaxel (PTX) and cisplatin on human oocytes were also evaluated by culturing human ovaries in vitro. A new mouse model that combines human ovarian xenotransplantation and patient-derived tumour xenografts was developed to explore adjuvant therapies for ovarian protection. The mice were randomly allocated to four groups (10 mice for each group): control, cisplatin, cisplatin + CK1 (CHEK1 inhibitor, SCH 900776), and cisplatin + CK2 (CHEK2 inhibitor, BML277). PARTICIPANTS/MATERIALS, SETTING, METHODS: In the prospective cohort study, human ovarian follicles were counted and serum AMH levels were evaluated. RNA-sequencing analysis was conducted, and staining for follicular damage (phosphorylated H2AX histone; γH2AX), terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labelling (TUNEL) assays and assessments of apoptotic biomarkers (western blot and immunofluorescence) were conducted in human ovaries. After the treatments, histological analysis was performed on human ovarian samples to investigate follicular populations, and oocyte damage was measured by γH2AX staining, BAX staining, and TUNEL assays. At the same time, the tumours were evaluated for volume, weight, and apoptosis levels. MAIN RESULTS AND THE ROLE OF CHANCE: Patients who received TP chemotherapy showed decreased ovarian reserves. Single RNA-sequencing analysis of human primordial oocytes indicated that TP chemotherapy induced apoptosis of human primordial oocytes by causing CHEK-mediated TAp63α phosphorylation. In vitro culture of human ovaries showed greater damaging effects on oocytes after cisplatin treatment compared with that after PTX treatment. Using the new animal model, CHEK1/2 inhibitors prevented the apoptosis of human oocytes induced by cisplatin and even enhanced its anti-tumour effects. This protective effect appeared to be mediated by inhibiting DNA damage via the CHEK-TAp63α pathway and by generation of anti-apoptotic signals in the oocytes. LARGE SCALE DATA: N/A. LIMITATIONS, REASONS FOR CAUTION: This was a preclinical study performed with human ovarian samples, and clinical research is required for validation. WIDER IMPLICATIONS OF THE FINDINGS: These findings highlight the therapeutic potential of CHEK1/2 inhibitors as a complementary strategy for preserving fertility in female cancer patients. STUDY FUNDING/COMPETING INTEREST(S): This work was financially supported by the National Natural Science Foundation of China (nos. 82001514 and 81902669) and the Fundamental Research Funds for the Central Universities (2021yjsCXCY087). The authors declare no conflict of interest.

Ovarian reserve in reproductive-aged patients with cancer before gonadotoxic treatment: a systematic review and meta-analysis.

STUDY QUESTION: Does cancer itself, before any gonadotoxic treatment, affect ovarian function in reproductive-aged patients? SUMMARY ANSWER: Our study revealed that women with cancer may have decreased ovarian reserve markers even before cancer therapy. WHAT IS KNOWN ALREADY: With the field 'oncofertility' improving rapidly, cancer therapy-mediated ovarian damage is well characterized. However, there is a controversy about whether cancer itself affects ovarian function before gonadotoxic treatment. STUDY DESIGN SIZE DURATION: We conducted a systematic meta-analysis investigating the association between cancer and ovarian function prior to gonadotoxic treatment. Titles or abstracts related to ovarian reserve (e.g. anti-Müllerian hormone (AMH), antral follicle count (AFC), or basal follicle-stimulating hormone (FSH)) combined with titles or abstracts related to the exposure (e.g. cancer*, oncolog*, or malignan*) were searched in PubMed, Embase, and Web of Science databases from inception to 1 February 2022. PARTICIPANTS/MATERIALS SETTING METHODS: We included cohort, case-control, and cross-sectional studies in English that examined ovarian reserve in reproductive-aged patients (18-45 years) with cancer compared to age-matched controls before cancer treatment. The quality of the included studies was assessed by ROBINS-I. Fixed or random effects were conducted to estimate standard or weighted mean difference (SMD or WMD, respectively) and CI. Heterogeneity was assessed by the Q test and I2 statistics, and publication bias was evaluated by Egger's and Begg's tests. MAIN RESULTS AND THE ROLE OF CHANCE: The review identified 17 eligible studies for inclusion. The results showed that cancer patients had lower serum AMH levels compared to healthy controls (SMD = -0.19, 95% CI = -0.34 to -0.03, P = 0.001), especially women with hematological malignancies (SMD = -0.62, 95% CI = -0.99 to -0.24, P = 0.001). The AFC was also decreased in patients with cancer (WMD = -0.93, 95% CI = -1.79 to -0.07, P = 0.033) compared to controls, while inhibin B and basal FSH levels showed no statistically significant differences. LIMITATIONS REASONS FOR CAUTION: Serum AMH and basal FSH levels in this meta-analysis showed high heterogeneity, and the small number of studies contributing to most subgroup analyses limited the heterogeneity analysis. Moreover, the studies for specific cancer subtypes may be too small to draw conclusions; more studies are needed to investigate the possible impact of cancer type and stage on ovarian function. WIDER IMPLICATIONS OF THE FINDINGS: Our study confirmed the findings that cancer per se, especially hematological malignancies, negatively affects serum AMH level, and AFC values of reproductive-aged women. However, the lower AMH levels and AFC values may also be due to the changes in ovarian physiology under oncological conditions, rather than actual lower ovarian reserves. Based on the meta-analysis, clinicians should raise awareness about the possible need for personalized approaches for young women with cancer who are interested in pursuing fertility preservation strategies before anticancer treatments. STUDY FUNDING/COMPETING INTERESTS: This work was financially supported by the National Natural Science Foundation of China (nos 81873824, 82001514, and 81902669) and the Applied Basic Research Program of Wuhan Municipal Bureau of Science and Technology (2019020701011436). The authors declare that they have no conflicts of interest. REGISTRATION NUMBER: PROSPERO (CRD42021235954).

Designing Multistimuli-Responsive Anisotropic Bilayer Hydrogel Actuators by Integrating LCST Phase Transition and Photochromic Isomerization.

Stimuli-responsive hydrogel actuators have attracted tremendous interest in switches and microrobots. Based on N-isopropylacrylamide (NIPAM) monomers with LCST phase separation and photochromic molecule spiropyran which can respond to ultraviolet light and H+, we develop a novel multistimuli-responsive co-polymer anisotropic bilayer hydrogel, which can undergo complex deformation behavior under environmental stimuli. Diverse bending angles were achieved based on inhomogeneous swelling. By controlling the environmental temperature, the bilayer hydrogels achieved bending angles of 83.4° and -162.4° below and above the critical temperature of PNIPAM. Stimulated by ultraviolet light and H+, the bilayer hydrogels showed bending angles of -19.4° and -17.3°, respectively. In addition, we designed a strategy to enhance the mechanical properties of the hydrogel via double network (DN). The mechanical properties and microscopic Fourier transform infrared (micro-FTIR) spectrum showed that the bilayer hydrogel can be well bonded at the interfaces of such bilayers. This work will inspire the design and fabrication of novel soft actuators with synergistic functions.

The deubiquitinase OTUD1 noncanonically suppresses Akt activation through its N-terminal intrinsically disordered region.

Akt is commonly activated and serves as a valuable target in human cancer. In this study, OTUD1 is identified as an Akt-associated protein and is downregulated upon Akt activation. Ectopic OTUD1 inhibits Akt phosphorylation; however, its deubiquitinase activity contributes only slightly to this effect. A short peptide (OUN-36) located in the OTUD1 N-terminal intrinsically disordered region strongly binds to the Akt PH domain. The residues in the PH domain, which are required for PtdIns(3,4,5)P3 recognition, are also essential for OUN-36 binding. OUN-36 preferentially inhibits Akt-hyperactive tumor cells' proliferation and interferes with Akt cell membrane localization, presumably by disrupting PH domain-PIP3 interaction. Importantly, OUN-36-based therapy efficiently abrogates Akt feedback reactivation in response to MK-2206 treatment and sensitizes cancer cells to chemotherapy and immunotherapy. We therefore show a mechanism by which OTUD1 modulates Akt activity and suggest a potential peptide-based cancer therapeutic strategy implemented by targeting the Akt PH domain.

The effects and mechanism of taxanes on chemotherapy-associated ovarian damage: A review of current evidence.

Chemotherapy is often a cause of premature ovarian insufficiency and infertility since the ovarian follicles are extremely sensitive to the effects of chemotherapeutic agents. Different chemotherapeutic agents with varying mechanisms of action may damage ovarian function differently. Taxanes are widely used in clinical cancer treatment, but the specific reproductive toxicological information is still controversial. This review described the impact and duration of taxanes on ovarian function in women and analyzed the possible reasons for different conclusions. Furthermore, the toxicity of taxanes on ovarian function and its possible mechanisms were discussed. The potential protective strategies and agents against ovarian damage induced by taxanes are also reviewed.

Biomaterials and advanced technologies for the evaluation and treatment of ovarian aging.

Ovarian aging is characterized by a progressive decline in ovarian function. With the increase in life expectancy worldwide, ovarian aging has gradually become a key health problem among women. Over the years, various strategies have been developed to preserve fertility in women, while there are currently no clinical treatments to delay ovarian aging. Recently, advances in biomaterials and technologies, such as three-dimensional (3D) printing and microfluidics for the encapsulation of follicles and nanoparticles as delivery systems for drugs, have shown potential to be translational strategies for ovarian aging. This review introduces the research progress on the mechanisms underlying ovarian aging, and summarizes the current state of biomaterials in the evaluation and treatment of ovarian aging, including safety, potential applications, future directions and difficulties in translation.

Prevalence and Outcomes of Unilateral Versus Bilateral Oophorectomy in Women With Ovarian Cancer: A Population-Based Study.

Background: Unilateral oophorectomy has the benefits of preserving the ovarian function of fertility and hormone secretion, but the precise inclusion criteria for candidates for this procedure remain controversial. This study aimed to compare the prevalence and therapeutic efficiency of unilateral oophorectomy in women with ovarian cancer who underwent bilateral oophorectomy; moreover, it aimed to identify the appropriate candidates for unilateral oophorectomy. Methods: Female patients diagnosed with stage I-III ovarian cancer between 2000 and 2017 were retrospectively identified from the Surveillance, Epidemiology, and End Results program database. Overall survival (OS) and disease-specific survival (DSS) after unilateral or bilateral (salpingo-) oophorectomy were estimated. Cumulative mortality rates (CMRs) for non-cancer comorbidities were also estimated. Results: A total of 28,480 women with ovarian cancer were included in this study, of whom 11,517 died during the study period. Of the patients, 7.5% and 48.0% underwent unilateral and bilateral oophorectomy, respectively. Overall, for stage-Ia tumors, unilateral oophorectomy was associated with remarkably better OS and DSS than bilateral oophorectomy (OS: p < 0.001; DSS: p = 0.01). For stage-Ib and stage-Ic ovarian tumor, there was no significant difference between the OS and DSS of patients treated by unilateral oophorectomy and those treated by bilateral oophorectomy. For stage-II and stage-III ovarian cancer, unilateral oophorectomy was associated with remarkably worse OS and DSS than bilateral oophorectomy. Among the reproductive-age women younger than 50 years, the OS and DSS of patients with stage-I tumors receiving unilateral oophorectomy were comparable to those receiving bilateral oophorectomy, even for high-grade stage-Ic tumors (all p > 0.05). For those aged 50 years and older, OS and DSS of patients with stage-I tumor receiving unilateral oophorectomy were significantly worse than those receiving bilateral oophorectomy, even for low-grade stage-Ia ovarian tumor (OS: p < 0.001; DSS: p = 0.02). Conclusion: Unilateral oophorectomy exhibited excellent oncological superiority and was equivalent to bilateral oophorectomy for stage-I ovarian tumors among women of reproductive age. For women of reproductive age, the criteria of unilateral oophorectomy can be appropriately broadened to high-grade stage-Ic diseases because of the better performance of unilateral oophorectomy in this population.

Adipose tissue and ovarian aging: Potential mechanism and protective strategies.

Ovarian aging occurs approximately 10 years prior to the natural age-associated functional decline of other organ systems. With the increase of life expectancy worldwide, ovarian aging has gradually become a key health problem among women. Therefore, understanding the causes and molecular mechanisms of ovarian aging is very essential for the inhibition of age-related diseases and the promotion of health and longevity in women. Recently, studies have revealed an association between adipose tissue (AT) and ovarian aging. Alterations in the function and quantity of AT have profound consequences on ovarian function because AT is central for follicular development, lipid metabolism, and hormonal regulation. Moreover, the interplay between AT and the ovary is bidirectional, with ovary-derived signals directly affecting AT biology. In this review, we summarize the current knowledge of the complex molecular mechanisms controlling the crosstalk between the AT and ovarian aging, and further discuss how therapeutic targeting of the AT can delay ovarian aging.

Reversible Zn2+-induced 3D self-assembled aerogel of carboxyl modified copper indium diselenide quantum dots: mechanism and application for inkjet printing anti-counterfeiting.

Three-dimensional (3D) self-assembled quantum dot (QD) aerogels have attracted attention due to the combined properties of both QDs and porous materials. However, the difficulty and complexity of structural composition control limit the practical application of 3D self-assembled QDs. Hence, convenient, available and multifunction QD aerogels need to be explored to promote broader practical applications. Herein, we propose a universal and facile self-assembly method of copper indium selenium (CISe) QD aerogels based on coordination interaction between Zn2+ and carboxyl. Both experiments and Monte Carlo simulations indicate that QDs are aggregated into oligomers by Zn2+, and then the oligomers are gradually interconnected to each other to form a 3D network as the concentration of Zn2+ increases. Moreover, Zn2+-induced 3D self-assembled aerogel could be depolymerized by EDTA reversibly. In combination with CISe QDs, Zn-CISe aerogel has been successfully applied in green pollution-free environment-friendly anti-counterfeiting and encryption systems.

Suicide and Accidental Death Among Women With Primary Ovarian Cancer: A Population-Based Study.

Background: Women with ovarian cancer had the highest suicidal rate among all patients with gynecological malignancies, but no large studies about suicide and accidental death for women with ovarian cancers in detail were conducted. We aimed to determine the relative risk of suicide and accidental death among patients with ovarian cancer to that of the general population, and to identify risk factors associated with suicide and accidental death. Methods: Data are from the SEER (surveillance, epidemiology, and end results) cancer registry of women diagnosed with ovarian cancer data from 18 registries for the years 1973-2016. The study population comprised 149,204 patients after inclusion and exclusion criteria were applied. Standardized mortality ratios (SMRs) were calculated and Fine-Gray models were fitted to identify risk factors associated with suicidal and accidental death among cancer patients, with stratifications on demographic and tumor-related characteristics. Results: Women with ovarian cancer had a higher risk of suicide and accidental death than the cancer-free group [SMR = 1.86; 95% CI (1.54-2.25) and SMR = 1.54; 95% CI (1.39-1.71)]. Subgroup analysis indicated that only patients with type II epithelial ovarian cancer [SMR = 2.31; 95% CI (1.83-2.91)] had an increased risk of suicide, and those with type I and type II epithelial ovarian cancer [SMR = 1.65; 95% CI (1.39-1.97) and SMR = 1.49; 95% CI (1.30-1.70)] were at a higher risk of accidental death. Patients with ovarian cancer who were younger, white, diagnosed with high-grade, non-metastatic cancer and pelvic exenteration were at a higher risk of suicide. The advanced age, earlier year of diagnosis, and non-metastatic cancer were associated with a higher risk of accidental death. Additionally, pelvic exenteration increased the risk of suicide but not the risk of accidental death among women with primary ovarian cancer. Conclusions: Women with ovarian cancer had a higher risk of suicide and accidental death compared with the general population. The findings suggested that clinicians should identify high-risk subgroups of ovarian cancer patients for suicide and accidental death as early as possible, with appropriate prevention strategies.

Chiral Cu2-xSe Nanoparticles for Enhanced Synergistic Cancer Chemodynamic/Photothermal Therapy in the Second Near-Infrared Biowindow.

Chiral nanomaterials have great potential in improving the clinical therapeutic effect due to the unique chiral selectivity of biosystems. However, such a promising therapeutic strategy has so far received little attention in cancer treatment. Here, we report a first chiral Fenton catalyst, d-/l-penicillamine-modified Cu2-xSe nanoparticles (d-/l-NPs), for enhanced synergistic cancer chemodynamic therapy (CDT) and photothermal therapy (PTT) under the second near-infrared (NIR-II) light irradiation. The chiral effect study of chiral Cu2-xSe NPs on cancer cells shows that d-NPs exhibit stronger CDT-induced cytotoxicity than l -NPs due to the stronger internalization ability. Moreover, the hydroxyl radicals (•OH) produced in d-NP-treated cancer cells via the CDT effect can be further improved by NIR-II light irradiation, thereby increasing the apoptosis of cancer cells. In vivo experiments show that, compared with l-NPs, d-NPs exhibit a stronger photothermal effect on the tumor site under NIR-II light irradiation and could completely eliminate the tumor under the synergistic effect of CDT and PTT. This work shows that the chirality of the surface ligand of the nanomaterials could significantly affect their cancer curative effect, which opens up a new way for the development of anticancer nanomedicine.

Cancer-Erythrocyte Hybrid Membrane-Camouflaged Magnetic Nanoparticles with Enhanced Photothermal-Immunotherapy for Ovarian Cancer.

Cell-membrane-coated nanoparticles are widely studied due to their inherent cellular properties, such as immune escape and homologous homing. A cell membrane coating can also maintain the relative stability of nanoparticles during circulation in a complex blood environment through cell membrane encapsulation technology. In this study, we fused a murine-derived ID8 ovarian cancer cell membrane with a red blood cell (RBC) membrane to create a hybrid biomimetic coating (IRM), and hybrid IRM camouflaged indocyanine green (ICG)-loaded magnetic nanoparticles (Fe3O4-ICG@IRM) were fabricated for combination therapy of ovarian cancer. Fe3O4-ICG@IRM retained both ID8 and RBC cell membrane proteins and exhibited highly specific self-recognition of ID8 cells in vitro and in vivo as well as a prolonged circulation lifetime in blood. Interestingly, in the bilateral flank tumor model, the IRM-coated nanoparticles also activated specific immunity, which killed homologous ID8 tumor cells but had no effect on B16-F10 tumor cells. Furthermore, Fe3O4-ICG@IRM showed synergistic photothermal therapy, resulting in the release of whole-cell tumor antigens by photothermal-induced tumor necrosis, which further enhanced antitumor immunotherapy for primary tumor and metastatic tumor by activating CD8+ cytotoxic T cells and reducing regulatory Foxp3+ T cells. Together, the biomimetic Fe3O4-ICG@IRM nanoparticles showed synergistic photothermal-immunotherapy for ovarian cancer.

Zn-doped Cu2S quantum dots as new high-efficiency inhibitors against human insulin fibrillation based on specific electrostatic interaction with oligomers.

Inhibition of protein fibrillation process with nanomaterials is a promising strategy to combat neurodegenerative diseases. Copper-based nanomaterials have been seldom utilized in fibrillation inhibiting research due to Copper ions are generally considered as accelerators of fibrosis. Here, we proposed ultra-small Zn doped Cu2S (Zn:Cu2S) QDs as inhibitors of human insulin (HI) fibrosis. ThT, DLS, CD and TEM confirm that Zn:Cu2S QDs effectively inhibited insulin fibrosis in a dose-dependent manner with lag phase time extended (beyond 13-time by Zn:Cu2S QDs of 1 mg·mL-1), final fibril formation and the conversion from α-helix to ß-sheet reduced. Additionally, thermodynamics analyzed results reveal that the HI fluorescence quenching process is static quenching dominated, and the Zn:Cu2S QDs inhibit HI fibrosis mainly through specific electrostatic interaction with oligomers. The positively charged amino acid residues of oligomers bind to the negatively charged Zn:Cu2S QDs, which prevents the self-assembly of the oligomers from growing into mature fibers to enhance the stability of the protein. Unlike free Copper ions, the as-prepared QDs show an excellent inhibition in HI fibrillation, breaking through the bottleneck of copper-based materials in inhibiting protein fibrosis and providing a potential strategy to inhibit protein fibrosis in-situ by biosynthesizing copper-based fibrosis inhibitors.

THERAPY OF ENDOCRINE DISEASE: Novel protection and treatment strategies for chemotherapy-associated ovarian damage.

Fertility and ovarian protection against chemotherapy-associated ovarian damage has formed a new field called oncofertility, which is driven by the pursuit of fertility protection as well as good life quality for numerous female cancer survivors. However, the choice of fertility and ovarian protection method is a difficult problem during chemotherapy and there is no uniform guideline at present. To alleviate ovarian toxicity caused by anticancer drugs, effective methods combined with an individualized treatment plan that integrates an optimal strategy for preserving and restoring reproductive function should be offered from well-established to experimental stages before, during, and after chemotherapy. Although embryo, oocyte, and ovarian tissue cryopreservation are the major methods that have been proven effective and feasible for fertility protection, they are also subject to many limitations. Therefore, this paper mainly discusses the future potential methods and corresponding mechanisms for fertility protection in chemotherapy-associated ovarian damage.

Proteomic analysis of mouse ovaries during the prepubertal stages.

Postnatal folliculogenesis, primordial follicle activation and follicular development at early stage are important for normal ovarian function and fertility, and a comprehensive understanding of this process under physiological condition is necessary. To observe the regulation and mechanism of ovarian follicle development during the prepubertal stages, we collected the mouse ovaries from three time points, including 1 day, 7 days, and 4 weeks after birth. We then performed a proteomic analysis using tandem mass tags (TMT) labeling combined with a two-dimensional liquid chromatography-tandem mass spectrometry (2D LC-MS/MS) technique. A total of 706 proteins were determined to be significant differential abundance (P-SDA). Sixty upregulated proteins and 12 downregulated proteins that were P-SDA and 3 significant KEGG pathways (P < 0.05) were found at 7 days vs. 1 day after birth, while 237 upregulated proteins, 271 downregulated proteins and 42 significant KEGG pathways were found for 4 weeks vs. 7 days after birth. Some vital genes (Figla, Ooep, Padi6, Zp3, Hsd3b1, cyp11a1), key pathways (ECM-receptor interaction, focal adhesion, ovarian steroidogenesis, complement and coagulation cascades, PI3K/Akt/mTOR), and metabolic regulation (energy metabolism, lipid metabolism, metal ion metabolism) were found to be related to the postnatal folliculogenesis, primordial follicle activation and follicular development. Finally, qRT-PCR and western blotting verified some vital genes and further elucidated the developmental process of follicles, and the results may contribute to the understanding of the formation and activation of primordial follicle and follicular development. Significance: This study offers the first proteomic insights into mechanisms of follicle development under physiological condition during the prepubertal stages. By comparing P-SDA of mouse ovaries during various period of age, our data reveals that the regulation of primordial follicle formation and activation is significantly different from that of follicular development. These findings demonstrate that many unique molecular mechanisms underlie ovarian development could be used for ovarian disease research.