Annexin A5 derived from matrix vesicles protects against osteoporotic bone loss via mineralization.

Matrix vesicles (MVs) have shown strong effects in diseases such as vascular ectopic calcification and pathological calcified osteoarthritis and in wound repair of the skeletal system due to their membranous vesicle characteristics and abundant calcium and phosphorus content. However, the role of MVs in the progression of osteoporosis is poorly understood. Here, we report that annexin A5, an important component of the matrix vesicle membrane, plays a vital role in bone matrix homeostasis in the deterioration of osteoporosis. We first identified annexin A5 from adherent MVs but not dissociative MVs of osteoblasts and found that it could be sharply decreased in the bone matrix during the occurrence of osteoporosis based on ovariectomized mice. We then confirmed its potential in mediating the mineralization of the precursor osteoblast lineage via its initial binding with collagen type I to achieve MV adhesion and the subsequent activation of cellular autophagy. Finally, we proved its protective role in resisting bone loss by applying it to osteoporotic mice. Taken together, these data revealed the importance of annexin A5, originating from adherent MVs of osteoblasts, in bone matrix remodeling of osteoporosis and provided a new strategy for the treatment and intervention of bone loss.

[Latest Findings on the Pathogenic Mechanisms of Thoracic Aortic Dissection].

Thoracic aortic dissection (TAD) is a cardiovascular disease entailing a high lethality between 65% and 85%. Surgery-assissed implant/interventional stenting is the prevailing treatment of TAD. However, surgical treatment can cause severe postoperative complications and patients incur a relatively higher risk of postoperative mortality. Since the pathogenic mechanism underlying TAD is not clear, effective medication therapies are still not available. In recent years, along with advances in single-cell sequencing and other molecular biological technologies, there have been prelimiary findings suggesting the special role of dysfunctional vascular smooth muscle cells (VSMCs) in the pathogenesis and development of TAD. Furthermore, the molecular mechanisms regulating the dysfunction of VSMCs have been initially explored. It is expected that these new findings will contribute to the development of new strategies to prevent TAD and lead to new ideas for the identifiction of potential drug therapeutic targets. Herein, we summarized the critical role of dysfunctional VSMCs in the pathogenesis and development of TAD and presented in detail the biological factors and the related molecular mechanisms that regulate the dysfunction of VSMCs. We hope this review will provide a reference for further investigation into the central role of dysfunctional VSMCs in the pathogenesis and development of TAD and exploration for effective molecular drug targets for TAD.

Live birth in woman with premature ovarian insufficiency and 46, XY karyotype after chemotherapy and bone marrow transplant: a case report.

BACKGROUND: Premature ovarian insufficiency (POI) is a clinical syndrome defined by loss of ovarian function before the age of 40 years, characterized by elevated serum gonadotropin levels and decreased estrogen levels with menstrual disturbance. POI can be natural or iatrogenic such as after chemotherapy, radiotherapy and surgery. CASE PRESENTATION: In this study, we describe a successful live birth in a 31-year-old woman with POI and 46, XY Karyotype after being treated with chemotherapy and bone marrow transplant (BMT) for acute non-lymphocytic leukemia when she was 17 years old. With amenorrhea or oligomenorrhea for 11 years, her serum level of FSH was up to 35.0 IU/L and 53.0 IU/L taken 4 weeks apart, which can be diagnosed as POI. After controlled ovarian stimulation treatment for three cycles with different protocols and frozen-thawed embryo transfer (FET), she finally got a successful pregnancy and had a live birth later. CONCLUSIONS: This case report serves as a reminder that karyotype of peripheral blood may mislead the diagnosis as disorders of sex development (DSD). It also demonstrates that it is possible for a woman with chemotherapy and bone marrow transplant induced POI can have successful pregnancy and live birth with appropriate therapy. Furthermore, as age may plays a predominant role in fertility rather than residual ovarian reserve, active treatment may be concerned for women with POI at younger age.

Fluid Shear Stress Regulates Osteogenic Differentiation via AnnexinA6-Mediated Autophagy in MC3T3-E1 Cells.

Fluid shear stress (FSS) facilitates bone remodeling by regulating osteogenic differentiation, and extracellular matrix maturation and mineralization. However, the underlying molecular mechanisms of how mechanical stimuli from FSS are converted into osteogenesis remain largely unexplored. Here, we exposed MC3T3-E1 cells to FSS with different intensities (1 h FSS with 0, 5, 10, and 20 dyn/cm2 intensities) and treatment durations (10 dyn/cm2 FSS with 0, 0.5, 1, 2 and 4 h treatment). The results demonstrate that the 1 h of 10 dyn/cm2 FSS treatment greatly upregulated the expression of osteogenic markers (Runx2, ALP, Col I), accompanied by AnxA6 activation. The genetic ablation of AnxA6 suppressed the autophagic process, demonstrating lowered autophagy markers (Beclin1, ATG5, ATG7, LC3) and decreased autophagosome formation, and strongly reduced osteogenic differentiation induced by FSS. Furthermore, the addition of autophagic activator rapamycin to AnxA6 knockdown cells stimulated autophagy process, and coincided with more expressions of osteogenic proteins ALP and Col I under both static and FSS conditions. In conclusion, the findings in this study reveal a hitherto unidentified relationship between FSS-induced osteogenic differentiation and autophagy, and point to AnxA6 as a key mediator of autophagy in response to FSS, which may provide a new target for the treatment of osteoporosis and other diseases.

Nanovaccines with cell-derived components for cancer immunotherapy.

Cancer nanovaccines as one of immunotherapeutic approaches are able to attack tumors by stimulating tumor-specific immunological responses. However, there still exist multiple challenges to be tackled for cancer nanovaccines to evoke potent antitumor immunity. Particularly, the administration of exogenous materials may cause the off-target immunotherapy responses. In recent years, biomimetic nanovaccines by using cell lysates, cell-derived nanovesicles, or extracted cell membranes as the functional components have received extensive attention. Such nanovaccines based on cell-derived components would show many unique advantages including inherent biocompatibility and the ability to trigger immune responses against a range of tumor-associated antigens. In this review article, we will introduce the recent research progresses of those cell-derived biomimetic nanovaccines for cancer immunotherapy, and discuss the perspectives and challenges associated with the future clinical translation of these emerging vaccine platforms.

Pregnancy outcomes of infertile women with ultrasound-diagnosed adenomyosis for in vitro fertilization and frozen-thawed embryo transfer.

OBJECTIVE: This study aimed to investigate the effect of ultrasound-diagnosed adenomyosis on assisted pregnancy outcomes, i.e., in vitro fertilization-embryo transfer (IVF-ET). METHODS: This was a retrospective cohort study of 18,568 women who had received their first frozen-thawed ET cycle in Center of Reproductive Medicine, Children's Hospital of Shanxi and Women Health Center of Shanxi and the Reproductive Medicine Center of Tianjin Central Obstetrics and Gynecology Hospital from January 2014 to May 2019. A total of 5,087 patients met the inclusion and exclusion criteria, and they were divided into two groups: adenomyosis with tubal factor infertility (study group, n = 193) and only tubal factor infertility (control group, n = 4894). After a 1:1 propensity score match (caliper value = 0.005), 360 cases were matched in the end. RESULT: There was no statistical difference in the embryo implantation rate, clinical pregnancy rate, or multiple pregnancy rate between the two groups (28.4% vs. 31.7%, 42.2% vs. 42.8%, and 11.7% vs. 12.8%, respectively; P > 0.05). However, the early miscarriage rate in the adenomyosis group was significantly higher than that in the control group (13.3% vs. 5.6%, respectively; P = 0.012). The live birth rate was 22.8% in the women with adenomyosis and was observed to be significantly lower than 33.3% in the control group (P = 0.026). The patients with adenomyosis had a higher incidence of pregnancy complications than those without (4.4% vs. 0.6%, respectively; P = 0.018), but the neonatal birth weight was not related to adenomyosis. CONCLUSION: Women with adenomyosis should be treated as being at high risk of early miscarriage. However, maternal adenomyosis has no effect on the birth weight of the newborn.

Ultrasound-Mediated Remotely Controlled Nanovaccine Delivery for Tumor Vaccination and Individualized Cancer Immunotherapy.

Vaccines are one of utmost important weapons in modern medicine to fight a wide range of diseases. To achieve optimal vaccination effects, repeated injections of vaccines are often required, which would largely decrease patient comfort. Herein, an ultrasound-responsive self-healing hydrogel system loaded with nanovaccines is designed for remotely controlled tumor vaccine release and individualized cancer immunotherapy. The gel could be transformed into sol status in response to ultrasound treatment, allowing a burst release of nanovaccines, and self-healed to gel afterward. For mice with a single subcutaneous injection of nanovaccine-loaded gel and multiple ultrasound treatments, repeatedly released nanovaccines could elicit antitumor immune responses, which in combination with immune checkpoint blockade could effectively inhibit established tumors, and prevent postoperative tumor metastases and recurrence based on our personalized nanovaccine system. This work presents an easy-to-operate strategy to realize controllable and durable delivery of vaccines against cancer and potentially other types of diseases.

Zearalenone perturbs the circadian clock and inhibits testosterone synthesis in mouse Leydig cells.

Zearalenone (ZEA), a mycotoxin, is known to impair reproductive capability by disrupting the synthesis and secretion of testosterone by Leydig cells (LCs), although the mechanism is unknown. Robust rhythmicity of circadian clock and steroidogenic genes were identified in LCs. The aim of this study was to examine whether ZEA significantly attenuated the transcription of core clock genes (Bmal1, Dbp, Per2, and Nr1d1) as well as steroidogenic genes (StAR, Hsd3b2, and Cyp11a1) in mouse testis Leydig cell line (TM3). Western blotting confirmed declines in BMAL1, NR1D1, and StAR protein levels. ZEA also suppressed secreted testosterone levels. In primary LCs, isolated from PER2::LUCIFERASE reporter gene knock in mice, ZEA diminished the amplitude of PER2::LUC expression, and induced a phase shift and period extension. In primary LCs, ZEA also suppressed the expression levels of core clock and steroidogenic genes, reduced protein levels of BMAL1, and decreased testosterone secretion. In vivo expression of core clock and steroidogenic genes were reduced in testes of mice exposed to ZEA for 1 week leading to decreased serum testosterone levels. In summary, data suggest that ZEA may impair testosterone synthesis through attenuation of the circadian clock in LCs culminating in reproductive dysfunction in male mammals .

Thermo-Triggered In Situ Chitosan-Based Gelation System for Repeated and Enhanced Sonodynamic Therapy Post a Single Injection.

Sonodynamic therapy (SDT) by utilizing ultrasonic waves triggers the generation of reactive oxygen species (ROS) with the help of sonosensitizers to destruct deep-seated tumors has attracted great attention. However, the efficacy of SDT may not be robust enough due to the insufficient oxygen supply within solid tumors. Additionally, repeated injections and treatments, which are often required to achieve the optimal therapeutic responses, may cause additional side effects and patient incompliance. Herein, a thermo-triggered in situ hydrogel system is developed in which catalase (CAT) conjugated with sonosensitizer meso-tetra (4-carboxyphenyl) porphine (TCPP) is mixed into chitosan (CS) and beta-glycerol phosphate disodium (GP) to form the precursor solution. After injection of the precursor solution into tumors, the in situ sol-gel transformation will occur as triggered by the body temperature, resulting in the localized tumor retention of TCPP-CAT. The locally restrained TCPP-CAT not only produces ROS under ultrasonic treatment, but also sustainably reverses the oxygen-deficient status in solid tumors by triggering the O2 generation from the decomposition of endogenous H2 O2 , further promoting the efficacy of SDT. As a result, the repeated SDT after a single dose injection of such a hydrogel can offer robust treatment effects to effectively eradicate tumors.

Near-Infrared Light-Responsive Nitric Oxide Delivery Platform for Enhanced Radioimmunotherapy.

Radiotherapy (RT) is a widely used way for cancer treatment. However, the efficiency of RT may come with various challenges such as low specificity, limitation by resistance, high dose and so on. Nitric oxide (NO) is known a very effective radiosensitizer of hypoxic tumor. However, NO cannot circulate in body with high concentration. Herein, an NIR light-responsive NO delivery system is developed for controlled and precisely release of NO to hypoxic tumors during radiotherapy. Tert-Butyl nitrite, which is an efficient NO source, is coupled to Ag2S quantum dots (QDs). NO could be generated and released from the Ag2S QDs effectively under the NIR irradiation due to the thermal effect. In addition, Ag is also a type of heavy metal that can benefit the RT therapy. We demonstrate that Ag2S NO delivery platforms remarkably maximize radiotherapy effects to inhibit tumor growth in CT26 tumor model. Furthermore, immunosuppressive tumor microenvironment is improved by our NO delivery system, significantly enhancing the anti-PD-L1 immune checkpoint blockade therapy. 100% survival rate is achieved by the radio-immune combined therapy strategy based on the Ag2S NO delivery platforms. Our results suggest the promise of Ag2S NO delivery platforms for multifunctional cancer radioimmunotherapy.

Ultrasound-Responsive Conversion of Microbubbles to Nanoparticles to Enable Background-Free in Vivo Photoacoustic Imaging.

Photoacoustic (PA) imaging based on the photon-to-ultrasound conversion allows the imaging of optical absorbers in deep tissues with high spatial resolution. However, the inherent optical absorbance of biomolecules (e.g., hemoglobin, melanin, etc.) would show up as tissue background signals to interfere with signals from the contrast agent during in vivo PA imaging, limiting the imaging sensitivity. Herein, an ultrasound (US)-responsive PA imaging probe based on microbubbles (MBs) containing gold nanoparticles (Au NPs) is designed for in vivo "background-free" PA imaging. The obtained Au@lip MBs with separated Au NPs decorated within the lipid shell of MBs show low PA signals under near-infrared (NIR) excitation. Interestingly, under exposure to US pulses, those Au@lip MBs would burst to form nanoscale aggregates of Au@lip NPs, which exhibit significantly enhanced NIR PA signals due to their red-shifted surface plasmon resonance. Therefore, by subtracting the PA image captured pre-US burst from that captured post-US burst, the tissue background PA signals could be deducted to enable background-free PA imaging with high sensitivities as demonstrated by multiple ex vivo and in vivo experiments. This work presents a simple yet effective strategy to deduct background signals during PA imaging, which is promising for accurate PA detection of targets in tissues with a strong background.

Light-Triggered In Situ Gelation to Enable Robust Photodynamic-Immunotherapy by Repeated Stimulations.

Photodynamic therapy (PDT) has shown the potential of triggering systemic antitumor immune responses. However, while the oxygen-deficient hypoxic tumor microenvironment is a factor that limits the PDT efficacy, the immune responses after conventional PDT usually are not strong enough to eliminate metastatic tumors. Herein, a light-triggered in situ gelation system containing photosensitizer-modified catalase together with poly(ethylene glycol) double acrylate (PEGDA) as the polymeric matrix is designed. Immune adjuvant nanoparticles are further introduced into this system to trigger robust antitumor immune responses after PDT. Following local injection of the mixed precursor solution into tumors and the subsequent light exposure, polymerization of PEGDA can be initiated to induce in situ gelation. Such hybrid hydrogel with long-term tumor retention of various agents and the ability to enable persistent tumor hypoxia relief can enable multiple rounds of PDT, which results in significantly enhanced immune responses by multiround stimulation. Further combination of such gel-based multiround PDT with anticytotoxic T-lymphocyte antigen-4 checkpoint blockade offers not only the abscopal effect to inhibit growth of distant tumors but also effective long-term immune memory protection from rechallenged tumors. Therefore, such a light-triggered in situ gelation system by a single-dose injection can enable greatly enhanced photoimmunotherapy by means of repeated stimulations.

Incorporation of Nanostructured Carbon Composite Materials into Counter Electrodes for Highly Efficient Dye-Sensitized Solar Cells.

Dye-sensitized solar cells (DSSCs) composed of nanostructured carbon composite materials-stacked counter electrodes (CEs) were fabricated in the present study. As the potential replacement of expensive platinum (Pt) thin film, various carbon composite materials, including zero-dimensional carbon nanoparticles (CNPs), one-dimensional multiwalled carbon nanotubes (MWCNTs), and two-dimensional graphene flakes (GFs) as a suitable charge transfer medium were deposited on the surface of CEs using a screen printing process. As the results, CNPs were found to result in deteriorating the charge transfer from CE to liquid electrolyte due to the formation of highly aggregated structures with very low specific surface area. However, MWCNTs and MWCNTs-added carbon composites (e.g., CNP/MWCNT, MWCNT/GF, CNP/MWCNT/GF) were found to enhance the charge transfer from CE to liquid electrolyte due to the formation of highly networked structures with high specific surface area. The resulting PCE of DSSCs composed of pure MWCNTs- and MWCNTs-added carbon composites-based CEs were very similar with that of DSSCs composed of Pt-based CEs. This suggests that the nanostructured carbon materials especially composed of MWCNTs and their composites are one of the promising candidates to replace the expensive Pt in the CEs of DSSCs.