Bioinformatic analysis of the role of immune checkpoint genes and immune infiltration in the pathogenesis and development of premature ovarian insufficiency.

PURPOSE: With advances in immunology, increasing evidence suggests that immunity is involved in premature ovarian insufficiency (POI) pathogenesis. This study investigated the roles of immune checkpoint genes and immune cell infiltration in POI pathogenesis and development. METHODS: The GSE39501 dataset and immune checkpoint genes were obtained from the Gene Expression Omnibus database and related literature. The two datasets were intersected to obtain immune checkpoint-related differentially expressed genes (ICRDEGs), which were analyzed using Gene Ontology and Kyoto Encyclopedia of Gene and Genomes enrichment analysis, weighted correlation network analysis, protein-protein interaction and related microRNAs, transcription factors, and RNA binding proteins. The immune cell infiltration of ICRDEGs was explored, and receiver operating characteristic curves were used to validate the diagnostic value of ICRDEGs in POI. RESULTS: We performed ICRDEG functional enrichment analysis and found that these genes were closely related to immune processes, such as T cell activation. Specifically, they are enriched in various biological processes and pathways, such as cell adhesion molecule and T cell receptor signaling pathways. Weighted correlation network analysis identified seven hub genes: Cd200, Cd274, Cd28, neurociliary protein-1, Cd276, Cd40lg, and Cd47. Furthermore, we identified 112 microRNAs, 17 RNA-binding proteins, and 101 transcription factors. Finally, immune infiltration analysis showed a clear positive correlation between hub genes and multiple immune cell types. CONCLUSION: Bioinformatic analysis identified seven potential ICRDEGs associated with POI, among which the immune checkpoint molecules CD200 and neurociliary protein-1 may be involved in the pathogenesis of POI.

Insights from multi-omic modeling of neurodegeneration in xeroderma pigmentosum using an induced pluripotent stem cell system.

Xeroderma pigmentosum (XP) is caused by defective nucleotide excision repair of DNA damage. This results in hypersensitivity to ultraviolet light and increased skin cancer risk, as sunlight-induced photoproducts remain unrepaired. However, many XP patients also display early-onset neurodegeneration, which leads to premature death. The mechanism of neurodegeneration is unknown. Here, we investigate XP neurodegeneration using pluripotent stem cells derived from XP patients and healthy relatives, performing functional multi-omics on samples during neuronal differentiation. We show substantially increased levels of 5',8-cyclopurine and 8-oxopurine in XP neuronal DNA secondary to marked oxidative stress. Furthermore, we find that the endoplasmic reticulum stress response is upregulated and reversal of the mutant genotype is associated with phenotypic rescue. Critically, XP neurons exhibit inappropriate downregulation of the protein clearance ubiquitin-proteasome system (UPS). Chemical enhancement of UPS activity in XP neuronal models improves phenotypes, albeit inadequately. Although more work is required, this study presents insights with intervention potential.

Sepsis as a Potential Risk Factor for Upper Gastrointestinal Bleeding in Critically Ill Patients: A Systematic Review and Meta-analysis.

Purpose: Sepsis is a common and critical condition in intensive care units (ICUs) known to complicate patient outcomes. Previous studies have indicated an association between sepsis and various ICU morbidities, including upper gastrointestinal bleeding (UGIB). However, the extent of this relationship and its implications in ICU settings remain inadequately quantified. This study aims to elucidate the association between sepsis and the risk of UGIB in ICU patients. Methods: A comprehensive meta-analysis was conducted, encompassing nine studies with a total of nearly 9000 participants. These studies reported events for both sepsis and nonsepsis patients separately. Pooled odds ratios (ORs) were calculated to assess the risk of UGIB in septic versus nonseptic ICU patients. Subgroup analyses were conducted based on age and study design, and both unadjusted and adjusted ORs were examined. Results: The pooled OR indicated a significant association between sepsis and UGIB (OR = 3.276, 95% CI: 1.931 to 5.557). Moderate heterogeneity was observed (I² = 43.9%). The association was significant in adults (pooled OR = 4.083) but not in children. No difference in association was found based on the study design. Unadjusted and adjusted ORs differed slightly, indicating the influence of confounding factors. Conclusion: This meta-analysis reveals a significant association between sepsis and an increased risk of UGIB in ICU patients, particularly in adults. These findings highlight the need for vigilant monitoring and proactive management of septic ICU patients to mitigate the risk of UGIB. Future research should focus on understanding the underlying mechanisms and developing tailored preventive strategies.

Radiation-based immunogenic vaccine combined with a macrophage "checkpoint inhibitor" for boosting innate and adaptive immunity against metastatic colon cancers.

Immunogenic dying tumor cells hold promising prospects as cancer vaccines to activate systemic immunity against both primary and metastatic tumors. Especially, X-ray- induced dying tumor cells are rich in highly immunogenic tumor-associated antigens and self-generated dsDNA as potent adjuvants. However, we found that the X-ray induction process can result in the excessive exposure of phosphatidylserine in cancer vaccines, which can specifically bind with the MerTK receptor on macrophages, acting as a "checkpoint" to facilitate immune silence in the tumor microenvironment. Therefore, we developed a novel strategy combining X-ray-induced cancer vaccines with UNC2250, a macrophage MerTK "checkpoint inhibitor," for treating peritoneal carcinomatosis in colon cancer. By incorporating UNC2250 into the treatment regimen, immunosuppressive efferocytosis of macrophages, which relies on MerTK-directed recognition of phosphatidylserine on vaccines, was effectively blocked. Consequently, the immune analysis revealed that this combination strategy promoted the maturation of dendritic cells and M1-like repolarization of macrophages, thereby simultaneously eliciting robust adaptive and innate immunity. This innovative approach utilizing X-ray-induced vaccines combined with a checkpoint inhibitor may provide valuable insights for developing effective cancer vaccines and immunotherapies targeting colon cancer.

Effects of sintilimab plus chemotherapy as first-line treatment on health-related quality of life in patients with advanced esophageal squamous cell carcinoma: results from the randomized phase 3 ORIENT-15 study.

Background: In ORIENT-15 study, sintilimab plus chemotherapy demonstrated significant improvement on overall survival (OS) versus placebo plus chemotherapy in first-line treatment of advanced esophageal squamous cell carcinoma (ESCC). Here, we report effect of sintilimab plus chemotherapy on health-related quality of life (HRQoL) in patients with advanced ESCC. Methods: From December 14, 2018 to August 28, 2022, HRQoL was evaluated in all randomized patients using European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 items (QLQ-C30), EORTC Quality of Life Questionnaire Oesophageal Cancer Module 18 items (QLQ-OES18), and visual analogue scale (VAS) of the EuroQol five-dimensional five-level questionnaire (EQ-5D-5L). Mean scores of each scale were described by treatment group through week 60. Least-squares mean (LSM) score change from baseline through week 24 were analyzed using the mixed-model repeated-measures method. Time to the first onset of deterioration (TTD) and OS for each scale were estimated. Clinical Trials Registration: NCT03748134. Findings: As of August 28, 2022, 689 of 690 enrolled patients were assessed for HRQoL analysis (sintilimab group: 340, placebo group: 349). Median follow-up was 32.2 months. Differences in LSM favored sintilimab over placebo for QLQ-C30 social functioning (LSM difference: 3.06, 95% CI: 0.55 to 5.57; P = 0.0170), pain (-2.24, 95% CI: -4.30 to -0.17; P = 0.0337), fatigue (-2.24, 95% CI: -4.46 to -0.02; P = 0.0479), constipation (-3.27, 95% CI -5.49 to -1.05; P = 0.0039), QLQ-OES18 pain (-1.77, 95% CI -3.11 to -0.43; P = 0.0097), trouble swallowing saliva (-2.09, 95% CI: -3.77 to -0.42; P = 0.0146), and choked when swallowing (-3.23, 95% CI: -5.60 to -0.86; P = 0.0076). TTD favored sintilimab over placebo for QLQ-OES18 dysphagia (Hazard ratio [HR]: 0.76, 95% CI: 0.61-0.94, P = 0.0104), and trouble swallowing saliva (HR: 0.48, 95% CI: 0.35-0.67, P < 0.0001). Improved OS were observed in patients with better performance in several functioning and symptom scales of QLQ-C30 and QLQ-QES18. Interpretation: The statistically significant differences of several HRQoL scales and improvements in delayed deterioration observed in our study further support the use of sintilimab plus chemotherapy as first-line treatment for advanced ESCC. Funding: This study was funded by Innovent Biologics and was co-funded by Eli Lilly.

A glycolytic metabolite bypasses "two-hit" tumor suppression by BRCA2.

Knudson's "two-hit" paradigm posits that carcinogenesis requires inactivation of both copies of an autosomal tumor suppressor gene. Here, we report that the glycolytic metabolite methylglyoxal (MGO) transiently bypasses Knudson's paradigm by inactivating the breast cancer suppressor protein BRCA2 to elicit a cancer-associated, mutational single-base substitution (SBS) signature in nonmalignant mammary cells or patient-derived organoids. Germline monoallelic BRCA2 mutations predispose to these changes. An analogous SBS signature, again without biallelic BRCA2 inactivation, accompanies MGO accumulation and DNA damage in Kras-driven, Brca2-mutant murine pancreatic cancers and human breast cancers. MGO triggers BRCA2 proteolysis, temporarily disabling BRCA2's tumor suppressive functions in DNA repair and replication, causing functional haploinsufficiency. Intermittent MGO exposure incites episodic SBS mutations without permanent BRCA2 inactivation. Thus, a metabolic mechanism wherein MGO-induced BRCA2 haploinsufficiency transiently bypasses Knudson's two-hit requirement could link glycolysis activation by oncogenes, metabolic disorders, or dietary challenges to mutational signatures implicated in cancer evolution.

Hybrid biomineralized nanovesicles to enhance inflamed lung biodistribution and reduce side effect of glucocorticoid for ARDS therapy.

Acute respiratory distress syndrome (ARDS) is a critical illness characterized by severe lung inflammation. Improving the delivery efficiency and achieving the controlled release of anti-inflammatory drugs at the lung inflammatory site are major challenges in ARDS therapy. Taking advantage of the increased pulmonary vascular permeability and a slightly acidic-inflammatory microenvironment, pH-responsive mineralized nanoparticles based on dexamethasone sodium phosphate (DSP) and Ca2+ were constructed. By further biomimetic modification with M2 macrophage membranes, hybrid mineralized nanovesicles (MM@LCaP) were designed to possess immunomodulatory ability from the membranes and preserve the pH-sensitivity from core nanoparticles for responsive drug release under acidic inflammatory conditions. Compared with healthy mice, the lung/liver accumulation of MM@LCaP in inflammatory mice was increased by around 5.5 times at 48 h after intravenous injection. MM@LCaP promoted the polarization of anti-inflammatory macrophages, calmed inflammatory cytokines, and exhibited a comprehensive therapeutic outcome. Moreover, MM@LCaP improved the safety profile of glucocorticoids. Taken together, the hybrid mineralized nanovesicles-based drug delivery strategy may offer promising ideas for enhancing the efficacy and reducing the toxicity of clinical drugs.

In situ neutrophil apoptosis and macrophage efferocytosis mediated by Glycyrrhiza protein nanoparticles for acute inflammation therapy.

In the progression of acute inflammation, the activation and recruitment of macrophages and neutrophils are mutually reinforcing, leading to amplified inflammatory response and severe tissue damage. Therefore, to regulate the axis of neutrophils and macrophages is essential to avoid tissue damage induced from acute inflammatory. Apoptotic neutrophils can regulate the anti-inflammatory activity of macrophages through the efferocytosis. The strategy of in situ targeting and inducing neutrophil apoptosis has the potential to modulate macrophage activity and transfer anti-inflammatory drugs. Herein, a natural glycyrrhiza protein nanoparticle loaded with dexamethasone (Dex@GNPs) was constructed, which could simultaneously regulate neutrophil and macrophage function during acute inflammation treatment by combining in situ neutrophil apoptosis and macrophage efferocytosis. Dex@GNPs can be rapidly and selectively internalized by neutrophils and subsequently induce neutrophils apoptosis through a ROS-dependent mechanism. The efferocytosis of apoptotic neutrophils not only promoted the polarization of macrophages into anti-inflammatory state, but also facilitated the transfer of Dex@GNPs to macrophages. This enabled dexamethasone to further modulate macrophage function. In mouse models of acute respiratory distress syndrome and sepsis, Dex@GNPs significantly ameliorated the disordered immune microenvironment and alleviated tissue injury. This study presents a novel strategy for drug delivery and inflammation regulation to effectively treat acute inflammatory diseases.

Betulinic acid attenuates T-2 toxin-induced lung injury by activating Nrf2 signaling pathway and inhibiting MAPK/NF-κB signaling pathway.

T-2 toxin, a type-A trichothecene mycotoxin, exists ubiquitously in mildewed foods and feeds. Betulinic acid (BA), a pentacyclic triterpenoid derived from plants, has the effect of relieving inflammation and oxidative stress. The purpose of this study was to investigate whether BA mitigates lung impairment caused by T-2 toxin and elucidate the underlying mechanism. The results indicated that T-2 toxin triggered the inflammatory cell infiltration, morphological alterations and cell apoptosis in the lungs. It is gratifying that BA ameliorated T-2 toxin-caused lung injury. The protein expression of nuclear factor erythrocyte 2-related factor 2 (Nrf2) pathway and the markers of antioxidative capability were improved in T-2 toxin induced lung injury by BA mediated protection. Simultaneously, BA supplementation could suppress T-2 toxin-induced mitogen-activated protein kinase (MAPK)/nuclear factor-kappa B (NF-κB)-dependent inflammatory response and mitochondrial apoptotic pathway. Therefore, T-2 toxin gave rise to pulmonary toxicity, but these changes were moderated by BA administration through regulation of the Nrf2/MAPK/NF-κB pathway, which maybe offer a viable alternative for mitigating the lung impairments caused by the mycotoxin.

Energy transfer for Ce3+ → Tb3+ → Sm3+ induced bright white emission in single-phase CaLa4(SiO4)3O:Ce3+, Tb3+, Sm3+ phosphors and their application in white-light-emitting diodes.

The emergence of phosphor-converted white-light-emitting diodes has crucial significance in the sustainable development of energy; hence, the evolution of phosphors with eminent luminescence and high stability is imperative. In this study, a tri-doped system composed of rare earth ions Ce3+, Tb3+, and Sm3+ incorporated into a CaLa4(SiO4)3O host is reported, and the energy transfer, tunable single-phase white emission, and favorable thermostability of the Ce3+-Tb3+-Sm3+ system were explored. Rietveld refinement results coincided with the original model of the crystal structure, and a band gap energy of 4.612 eV calculated using density functional theory (DFT) demonstrated the system as an appropriate luminescent host with a wide energy gap. Furthermore, ET processes for Ce3+ → Tb3+, Tb3+ → Sm3+, and Ce3+ → Tb3+ → Sm3+ were investigated via steady-state photoluminescence and decay measurements. Besides, the activation energies of CLSO:3%Ce3+, 9%Tb3+, y%Sm3+ (y = 7, 9) were 0.205 eV and 0.223 eV, respectively, showing outstanding thermal quenching resistance. Devices made with LED beads containing CLSO:3%Ce3+, 9%Tb3+, y%Sm3+ (y = 7, 9) phosphors exhibited bright white light with CCT ≈ 3586 and 3307 K and Ra ≈ 81.0 and 78.5, respectively. This study demonstrates that energy transfer for Ce3+-Tb3+-Sm3+ in a tri-doped system offers an interesting design prospect for promoting single-phase white emission phosphors.

Practical application of the patient data-based quality control method: the potassium example.

Introduction: Internal quality control (IQC) is a core pillar of laboratory quality control strategies. Internal quality control commercial materials lack the same characteristics as patient samples and IQC contributes to the costs of laboratory testing. Patient data-based quality control (PDB-QC) may be a valuable supplement to IQC; the smaller the biological variation, the stronger the ability to detect errors. Using the potassium concentration in serum as an example study compared error detection effectiveness between PDB-QC and IQC. Materials and methods: Serum potassium concentrations were measured by using an indirect ion-selective electrode method. For the training database, 23,772 patient-generated data and 366 IQC data from April 2022 to September 2022 were used; 15,351 patient-generated data and 246 IQC data from October 2022 to January 2023 were used as the testing database. For both PDB-QC and IQC, average values and standard deviations were calculated, and z-score charts were plotted for comparison purposes. Results: Five systematic and three random errors were detected using IQC. Nine systematic errors but no random errors were detected in PDB-QC. The PDB-QC showed systematic error warnings earlier than the IQC. Conclusions: The daily average value of patient-generated data was superior to IQC in terms of the efficiency and timeliness of detecting systematic errors but inferior to IQC in detecting random errors.

Effectiveness of bevacizumab in the treatment of metastatic colorectal cancer: a systematic review and meta-analysis.

OBJECTIVE: To evaluate the benefit of bevacizumab under the comprehensive treatment strategy and its advantages over other drugs, so as to provide reference for the formulation of clinical plans. METHODS: As of October 1, 2022, the randomized controlled clinical trials of bevacizumab in combination with metastatic colorectal cancer published in PubMed, Cochrane Library and Medline databases were searched. The odds ratio (OR) and its 95% confidence interval (CI) were used to evaluate the short-term disease control effect and long-term survival of the treatment strategy. RESULTS: 21 RCTs (6665 patients; 3356 patients in the experimental group and 3309 patients in the control group; average age, 55-75 years) were treated with bevacizumab as the experimental group for metastatic colorectal cancer. BEV has stronger anti-tumor activity than the single treatment scheme (OR = 1.30, 95% CI: 1.11-1.52). And Benefits of the BEV group were 0.73 (0.55, 0.96), 1.26 (0.71, 2.24), 1.63 (0.92, 2.87) and 0.07 (0.02, 0.25) compared with CET, VAN, CED and PAN respectively. The disease control of BEV combined therapy was better (OR = 1.36, 95% CI: 1.04-1.78). The same as compared with cediranib (OR = 1.94, 95% CI: 1.06-3.55). However, the long-term prognosis of BEV, including the overall survival (HRs = 0.98, 95% CI: 0.84-1.15) and progression-free survival (HRs = 1.05,95% CI: 0.97-1.13) were not prolonged. The survival benefits of cetuximab and panitumumab were not reflected. CONCLUSION: The addition of BEV can enhance the anti-tumor ability and disease control, while cetuximab and panitumumab may have stronger ability. However, it did not effectively improve the survival of patients. A more reasonable and effective treatment plan needs more clinical experimental support.

The network characteristics in schizophrenia with prominent negative symptoms: a multimodal fusion study.

Previous studies on putative neural mechanisms of negative symptoms in schizophrenia mainly used single modal imaging data, and seldom utilized schizophrenia patients with prominent negative symptoms (PNS).This study adopted the multimodal fusion method and recruited a homogeneous sample with PNS. We aimed to identify negative symptoms-related structural and functional neural correlates of schizophrenia. Structural magnetic resonance imaging (sMRI) and resting-state functional MRI (rs-fMRI) were performed in 31 schizophrenia patients with PNS and 33 demographically matched healthy controls.Compared to healthy controls, schizophrenia patients with PNS exhibited significantly altered functional activations in the default mode network (DMN) and had structural gray matter volume (GMV) alterations in the cerebello-thalamo-cortical network. Correlational analyses showed that negative symptoms severity was significantly correlated with the cerebello-thalamo-cortical structural network, but not with the DMN network in schizophrenia patients with PNS.Our findings highlight the important role of the cerebello-thalamo-cortical structural network underpinning the neuropathology of negative symptoms in schizophrenia. Future research should recruit a large sample and schizophrenia patients without PNS, and apply adjustments for multiple comparison, to verify our preliminary findings.

Study on the preparation and enzyme inhibitory activity of polyphenols from Sargassum pallidum.

This study aimed to obtain a high yield and purity of Sargassum pallidum polyphenol extracts (SPPE) and study its enzyme activity. Fresh Sargassum pallidum seaweed was selected for optimization of ultrasound-assisted extraction (UAE) conditions and purification conditions using macroporous resin and Sephadex LH20 to obtain SPPE. The SPPE was characterized using UPLC-QTOF-MS/MS and α-amylase, α-glucosidase, tyrosinase, and AchE inhibitory activity were determined. The maximum extraction rate of SPPE was 7.56 mg GAE/g and the polyphenol purity reached 70.5% after macroporous resin and Sephadex LH-20 purification. A total of 50 compounds were identified by UPLC-QTOF-MS/MS. The IC50 values of SPPE were 334.9 µg/mL, 6.290 µg /mL, 0.834 mg /mL and 0.6538 mg /mL for α-amylase, α-glucosidase, tyrosinase and AchE, respectively. Molecular docking technology further revealed the effects of SPPE on the above enzymes. This study provided information on the potential hypoglycemic, whitening and anti-Alzheimer's disease biological activities of SPPE, which had guiding significance for the purification and development of other seaweed polyphenols.

Engineered Biomimetic Nanovesicles Based on Neutrophils for Hierarchical Targeting Therapy of Acute Respiratory Distress Syndrome.

Acute Respiratory Distress Syndrome (ARDS) is a clinically severe respiratory disease that causes severe medical and economic burden. To improve therapeutic efficacy, effectively targeting delivery to the inflamed lungs and inflamed cells remains an ongoing challenge. Herein, we designed engineered biomimetic nanovesicles (DHA@ANeu-DDAB) by fusion of lung-targeting functional lipid, neutrophil membrane containing activated ß2 integrins, and the therapeutic lipid, docosahexaenoic acid (DHA). By the advantage of lung targeting lipid and ß2 integrin targeting adhesion, DHA@ANeu-DDAB can first target lung tissue and further target inflammatory vascular endothelial cells, to achieve "tissue first, cell second" hierarchical delivery. In addition, the ß2 integrins in DHA@ANeu-DDAB could bind to the intercellular cell adhesion molecule-1/2 (ICAM-1/2) ligand on the endothelium in the inflamed blood vessels, thus inhibiting neutrophils' infiltration in the blood circulation. DHA administration to inflamed lungs could effectively regulate macrophage phenotype and promote its anti-inflammatory activity via enhanced biosynthesis of specialized pro-resolving mediators. In the lipopolysaccharide-induced ARDS mouse model, DHA@ANeu-DDAB afforded a comprehensive and efficient inhibition of lung inflammation and promoted acute lung damage repair. Through mimicking physiological processes, these engineered biomimetic vesicles as a delivery system possess good potential in targeting therapy for ARDS.

Biofunctional coacervate-based artificial protocells with membrane-like and cytoplasm-like structures for the treatment of persistent hyperuricemia.

Coacervate droplets formed by liquid-liquid phase separation have attracted considerable attention due to their ability to enrich biomacromolecules while preserving their bioactivities. However, there are challenges to develop coacervate droplets as delivery vesicles for therapeutics resulting from the lack of physiological stability and inherent lack of membranes in coacervate droplets. Herein, polylysine-polynucleotide complex coacervate droplets with favorable physiological stability are formulated to efficiently and facilely concentrate small molecules, biomacromolecules and nanoparticles without organic solvents. To improve the biocompatibility, the PEGylated phospholipid membrane is further coated on the surface of the coacervate droplets to prepare coacervate-based artificial protocells (ArtPC) with membrane-like and cytoplasm-like structures. The ArtPC can confine the cyclic catalytic system of uricase and catalase inside to degrade uric acid and deplete the toxicity of H2O2. This biofunctional ArtPC effectively reduces blood uric acid levels and prevents renal injuries in mice with persistent hyperuricemia. The ArtPC-based therapy can bridge the disciplines of synthetic biology, pharmaceutics and therapeutics.

Bone-Targeted Biomimetic Nanogels Re-Establish Osteoblast/Osteoclast Balance to Treat Postmenopausal Osteoporosis.

Insufficient bone formation and excessive bone resorption caused by estrogen deficiency are the major factors resulting in the incidence of postmenopausal osteoporosis (PMOP). The existing drugs usually fail to re-establish the osteoblast/osteoclast balance from both sides and generate side-effects owing to the lack of bone-targeting ability. Here, engineered cell-membrane-coated nanogels PNG@mR&C capable of scavenging receptor activator of nuclear factor-κB ligand (RANKL) and responsively releasing therapeutic PTH 1-34 in the bone microenvironment are prepared from RANK and CXCR4 overexpressed bone mesenchymal stem cell (BMSC) membrane-coated chitosan biopolymers. The CXCR4 on the coated-membranes confer bone-targeting ability, and abundant RANK effectively absorb RANKL to inhibit osteoclastogenesis. Meanwhile, the release of PTH 1-34 triggered by osteoclast-mediated acid microenvironment promote osteogenesis. In addition, the dose and frequency are greatly reduced due to the smart release property, prolonged circulation time, and bone-specific accumulation. Thus, PNG@mR&C exhibits satisfactory therapeutic effects in the ovariectomized (OVX) mouse model. This study provides a new paradigm re-establishing the bone metabolic homeostasis from multitargets and shows great promise for the treatment of PMOP.