High-Throughput Acoustic Ejection Mass Spectrometry with Adjustable Signal Durations.

High-throughput mass spectrometry (MS) has witnessed rapid advancements and has found extensive applications across various disciplines. It enables the fast and accurate analysis of large sample sets, delivering a 10-fold or greater enhancement in analytical throughput when compared to conventional LC-MS methods. However, the signal duration in these high-throughput MS technologies is typically confined to a narrow range, presenting challenges for workflows demanding prolonged signal durations. In this study, we introduce a method that enables precise modulation of the signal duration on an acoustic ejection mass spectrometry (AEMS) system while ensuring high signal reproducibility. This flexibility allows for simultaneous and precise analysis of a significantly greater number of MS/MS transitions in high-throughput MS environments. Additionally, it offers a unique approach for parameter optimization and method development with minimal sample volume requirements. This advancement enhances the efficiency of MS-based analyses across diverse applications and facilitates broader utilization of MS technologies in high-throughput settings, including data-dependent acquisition (DDA) and data-independent acquisition (DIA).

Preparation of Indolin-3-one-Containing 1,4-Naphthoquinone Derivatives via Organocatalytic Asymmetric Michael Addition Reaction.

This article explores the asymmetric Michael addition reaction of 2-hydroxy-1,4-naphthoquinone and indole-3-ones catalyzed by cinchona alkaloids. This strategy utilizes 2-hydroxy-1,4-naphthoquinone and easily prepared indole-3-one as substrates, resulting in the synthesis of 23 unprecedented indolin-3-ones bearing a 1,4-naphthoquinone unit at the C2 position of indole under simple and mild reaction conditions, with up to 88% yield, 98% ee, and >20:1 dr.

Design, synthesis and biological evaluation of prostate-specific membrane antigen (PSMA)-targeted SIRT2 inhibitors.

Sirtuins belong to a specific class of enzymes called NAD+-dependent protein deacetylases. Among them, SIRT2 is predominantly localized in the cytoplasm and plays a vital role in tumor development and progression. As a result, it becomes an important target for the development of anticancer drugs. While SIRT2 inhibitors have shown broad-spectrum cytotoxicity against various cancer cells, their ability to inhibit the growth of certain cancers like prostate cancer has been limited, possibly due to insufficient targeting properties. To overcome this limitation, our goal was to target prostate-specific membrane antigen (PSMA), a valuable biomarker for prostate cancer, using lysine-urea-glutamic acid (KUE) as a PSMA ligand. This approach allowed us to systematically design new SIRT2 inhibitors. Evaluation showed that compound 17 exhibited superior inhibitory activity, improved targeting properties, and enhanced antiproliferative efficacy specifically in prostate cancer cells. These findings suggest a promising strategy for utilizing SIRT2 inhibitors in prostate cancer therapy.

Psychological stress: neuroimmune roles in periodontal disease.

Periodontitis is a chronic inflammatory disease that starts with pathogenic bacteria and is mediated by a combination of multiple factors. Psychosomatic factors are considered to be one of the most critical risk factors for periodontal disease. Psychological stress may threaten periodontal immune homeostasis in multiple ways by affecting the hypothalamic-pituitary-adrenal cortex system, the locus ceruleus-sympathetic-adrenal medulla system, and the peptidergic nervous system. In this review, we outline the complex role of psychological stress in promoting the development of periodontal disease, focusing on the effects of stress on flora metabolism, tissue inflammation, and alveolar bone homeostasis. At the same time, we broadly and deeply summarize the potential mechanisms of psychological stress-induced periodontal disease, emphasize the importance of neuroimmune modulation for periodontal health, and expect to provide a new perspective for periodontal science based on psychoneuroimmunology.

Zinc-dependent deacetylases (HDACs) as potential targets for treating Alzheimer's disease.

Alzheimer's disease (AD) as the most prevalent dementia type has become one of the greatest threats to the health and life of the elder people worldwide. Although there has been a great effort in the discovery of anti-AD drugs, those approval drugs only demonstrated the temporarily relieving the symptoms without completely stopping the progression of the neuropathology. It is very urgent and reasonable to develop more effective agents against other therapeutic targets. In the last two decades, zinc-dependent deacetylases (HDACs) have attracted much attention as an important group of epigenetic targets in drug discovery, because five HDAC inhibitors have been approved for clinically treating cancers. This review is to summarize the possible roles of HDACs in AD pathophysiology and their inhibitors used in AD studies. And the future perspectives related to HDACs as epigenetic targets for treating AD by their selective inhibitors, multi-target inhibitors or PROTACs are also discussed.

Development of a single-step fluorogenic sirtuin assay and its applications for high-throughput screening.

Sirtuins (SIRTs) are a class of nicotinamide adenine dinucleotide (NAD+)-dependent histone deacetylases. Since SIRTs have different subcellular locations and different preferences for deacylation activity, SIRTs are not only highly gaining significance in biological functions but also implications in human diseases. Therefore, it is valuable to establish a high-throughput screening method for the rapid and accurate discovery of SIRT modulators. In this study, we designed and synthesized small molecules 4a-d as fluorogenic probes based on the different lysine substrates of SIRTs, which can be recognized and catalyzed by SIRTs and then spontaneous intramolecular transesterification can give the fluorescence. We have undertaken a comprehensive study of these fluorogenic probes with different SIRTs for assay optimization, validation, kinetics, parameters, and applications of high-throughput screening formats. We envision that these probes will provide useful and powerful tools for the highly efficient discovery of more SIRT inhibitors.

Knowledge, perception of HIV symptom severity and cervical cancer screening behaviour among women living with HIV in China.

OBJECTIVE: This study aimed to examine the previous uptake of cervical cancer screening and intention to be screened and its associated factors among women living with HIV in China. METHODS: We conducted a cross-sectional survey of 213 women living with HIV to collect information about cervical cancer screening behaviour, demographics, knowledge about cervical cancer and screening, and perception of HIV symptom severity. RESULTS: Seventy-eight women living with HIV (36.6%) had undergone cervical cancer screening, and 83 (61.5%) of the nonscreened women had the intention to be screened in the future. Using multivariate analysis, women who had more knowledge about cervical cancer screening (OR = 2.373, 95% CI = 1.593-3.534, p = 0.000) and had at least one nongynecological symptom (OR = 0.446, 95% CI = 0.204-0.978, p = 0.044) were more likely to have received screening previously. CONCLUSION: This study emphasised that knowledge, as a salient factor, was crucial to promoting cervical cancer screening behaviour among women living with HIV. Effective measures should be taken to promote the knowledge about cervical cancer prevention. A new healthcare model, including preventive healthcare in addition to HIV/AIDS care, may be needed to address the complex needs of women living with HIV in China.

Enhanced Water Solubility and Anti-Tumor Activity of Oleanolic Acid through Chemical Structure Modification.

Cancer has been a major health problem in the world in the past decades. It is urgent to develop new, effective and safe drugs for the treatment of cancer. There are many pentacyclic triterpenoids with positive anti-tumor activity and safety in nature. Oleanolic acid (OA), as one of the pentacyclic triterpenoids, also has broad biological activities including liver protection, anti-inflammatory, hypoglycemic, antiviral and anti-tumor. Therefore, to investigate its anti-tumor activity and mechanism, many OA derivatives have been developed. Some derivatives are less toxic to normal hepatocytes, which may be due to the strong liver protection ability of OA. However, the poor water solubility of OA is one of the main reasons for the weak anti-tumor activity. It is reported that some OA derivatives could enhance solubility by chemically linking some hydrophilic groups to improve anti-tumor activity. This review not only summarizes the highly water-soluble OA derivatives that can improve anti-tumor activity reported in recent years, but also introduces their possible anti-tumor mechanisms.

Constitutive nuclear expression of dentin matrix protein 1 fails to rescue the Dmp1-null phenotype.

Dentin matrix protein 1 (DMP1) plays multiple roles in bone, tooth, phosphate homeostasis, kidney, salivary gland, reproductive cycles, and the development of cancer. In vitro studies have indicated two different biological mechanisms: 1) as a matrix protein, DMP1 interacts with αvß3 integrin and activates MAP kinase signaling; and 2) DMP1 serves as a transcription co-factor. In vivo studies have demonstrated its key role in osteocytes. This study attempted to determine whether DMP1 functions as a transcription co-factor and regulates osteoblast functions. For gene expression comparisons using adenovirus constructs, we targeted the expression of DMP1 either to the nucleus only by replacing the endogenous signal peptide with a nuclear localization signal (NLS) sequence (referred to as (NLS)DMP1) or to the extracellular matrix as the WT type (referred to as (SP)DMP1) in MC3T3 osteoblasts. High levels of DMP1 in either form greatly increased osteogenic gene expression in an identical manner. However, the targeted (NLS)DMP1 transgene driven by a 3.6-kb rat Col 1α1 promoter in the nucleus of osteoblasts and osteocytes failed to rescue the phenotyope of Dmp1-null mice, whereas the (SP)DMP1 transgene rescued the rickets defect. These studies support the notion that DMP1 functions as an extracellular matrix protein, rather than as a transcription co-factor in vivo. We also show that DMP1 continues its expression in osteoblasts during postnatal development and that the deletion of Dmp1 leads to an increase in osteoblast proliferation. However, poor mineralization in the metaphysis indicates a critical role for DMP1 in both osteoblasts and osteocytes.

Relatively low level of antigen-specific monocytes detected in blood from untreated tuberculosis patients using CD4+ T-cell receptor tetramers.

The in vivo kinetics of antigen-presenting cells (APCs) in patients with advanced and convalescent tuberculosis (TB) is not well characterized. In order to target Mycobacterium tuberculosis (MTB) peptides- and HLA-DR-holding monocytes and macrophages, 2 MTB peptide-specific CD4(+) T-cell receptor (TCR) tetramers eu and hu were successfully constructed. Peripheral blood (PBL) samples from inpatients with advanced pulmonary TB (PTB) were analyzed using flow cytometry, and the percentages of tetramer-bound CD14(+) monocytes ranged from 0.26-1.44% and 0.21-0.95%, respectively; significantly higher than those measured in PBL samples obtained from non-TB patients, healthy donors, and umbilical cords. These tetramers were also able to specifically detect macrophages in situ via immunofluorescent staining. The results of the continuous time-point tracking of the tetramer-positive rates in PBL samples from active PTB outpatients undergoing treatment show that the median percentages were at first low before treatment, increased to their highest levels during the first month, and then began to decrease during the second month until finally reaching and maintaining a relatively low level after 3-6 months. These results suggest that there is a relatively low level of MTB-specific monocytes in advanced and untreated patients. Further experiments show that MTB induces apoptosis in CD14(+) cells, and the percentage of apoptotic monocytes dramatically decreases after treatment. Therefore, the relatively low level of MTB-specific monocytes is probably related to the apoptosis or necrosis of APCs due to live bacteria and their growth. The bactericidal effects of anti-TB drugs, as well as other unknown factors, would induce a peak value during the first month of treatment, and a relatively low level would be subsequently reached and maintained until all of the involved factors reached equilibrium. These tetramers have diagnostic potential and can provide valuable insights into the mechanisms of antigen presentation and its relationship with TB infection and latent TB infection.

Advances in dual-targeting inhibitors of HDAC6 for cancer treatment.

Histone Deacetylase 6 (HDAC6) is an essential regulator of histone acetylation processes, exerting influence on a multitude of cellular functions such as cell motility, endocytosis, autophagy, apoptosis, and protein trafficking through its deacetylation activity. The significant implications of HDAC6 in diseases such as cancer, neurodegenerative disorders, and immune disorders have motivated extensive investigation into the development of specific inhibitors targeting this enzyme for therapeutic purposes. Single targeting drugs carry the risk of inducing drug resistance, thus prompting exploration of dual targeting therapy which offers the potential to impact multiple signaling pathways simultaneously, thereby lowering the likelihood of resistance development. While pharmacological studies have exhibited promise in combined therapy involving HDAC6, challenges related to potential drug interactions exist. In response to these challenges, researchers are investigating HDAC6 hybrid molecules which enable the concomitant targeting of HDAC6 and other key proteins, thus enhancing treatment efficacy while mitigating side effects and reducing the risk of resistance compared to traditional combination therapies. The published design strategies for dual targeting inhibitors of HDAC6 are summarized and discussed in this review. This will provide some valuable insights into more novel HDAC6 dual targeting inhibitors to meet the urgent need for innovative therapies in oncology and other related fields.

Efficacy of Poria cocos and Alismatis rhizoma against diet-induced hyperlipidemia in rats based on transcriptome sequencing analysis.

Hyperlipidemia, a common metabolic disease, is a risk factor for cardiovascular diseases, Poria cocos (PC) and Alismatis rhizoma (AR) serve as a potential treatment. A systematic approach based on transcriptome sequencing analysis and bioinformatics methods was developed to explore the synergistic effects of PC-AR and identify major compounds and potential targets. The phenotypic characteristics results indicated that the high dose (4.54 g/kg) of PC-AR reduced total cholesterol (TC), elevated high-density lipoprotein cholesterol (HDL-C) levels, and improved hepatocyte morphology, as assessed via hematoxylin and eosin (H&E) staining. Transcriptomic profiling processing results combined with GO enrichment analysis to identify the overlapping genes were associated with inflammatory responses. The cytokine-cytokine receptor interaction pathway was found as a potential key pathway using geneset enrichment analysis. Core enrichment targets were selected according to the PC-AR's fold change versus the model. Real-time quantitative PCR analysis validated that PC-AR significantly downregulated the expression of Cxcl10, Ccl2, Ccl4, Cd40 and Il-1ß mRNA (P < 0.05). Molecular docking analysis revealed the significant compounds of PC-AR and the potential binding patterns of the critical compounds and targets. This study provides further evidence that the therapeutic effects of PC-AR on hyperlipidemia in rats through the regulation of inflammation-related targets.

Histone Deacetylases as Epigenetic Targets for Treating Parkinson's Disease.

Parkinson's disease (PD) is a chronic progressive neurodegenerative disease that is increasingly becoming a global threat to the health and life of the elderly worldwide. Although there are some drugs clinically available for treating PD, these treatments can only alleviate the symptoms of PD patients but cannot completely cure the disease. Therefore, exploring other potential mechanisms to develop more effective treatments that can modify the course of PD is still highly desirable. Over the last two decades, histone deacetylases, as an important group of epigenetic targets, have attracted much attention in drug discovery. This review focused on the current knowledge about histone deacetylases involved in PD pathophysiology and their inhibitors used in PD studies. Further perspectives related to small molecules that can inhibit or degrade histone deacetylases to treat PD were also discussed.

Indirubin Derivatives as Dual Inhibitors Targeting Cyclin-Dependent Kinase and Histone Deacetylase for Treating Cancer.

To utilize the unique scaffold of a natural product indirubin, we herein adopted the strategy of combined pharmacophores to design and synthesize a series of novel indirubin derivatives as dual inhibitors against cyclin-dependent kinase (CDK) and histone deacetylase (HDAC). Among them, the lead compound 8b with remarkable CDK2/4/6 and HDAC6 inhibitory activity of IC50 = 60.9 ± 2.9, 276 ± 22.3, 27.2 ± 4.2, and 128.6 ± 0.4 nM, respectively, can efficiently induce apoptosis and S-phase arrest in several cancer cell lines. In particular, compound 8b can prevent the proliferation of a non-small-cell lung cancer cell line (A549) through the Mcl-1/XIAP/PARP axis, in agreement with the unique modes of action of the combined agents of HDAC inhibitors and CDK inhibitors. In an A549 xerograph model, compound 8b showed significant antitumor efficacy correlated with its dual inhibition. Our data demonstrated that compound 8b as a single agent could be a promising drug candidate for cancer therapy in combination with CDK and HDAC inhibitors.

Osteocytes but not osteoblasts directly build mineralized bone structures.

Bone-forming osteoblasts have been a cornerstone of bone biology for more than a century. Most research toward bone biology and bone diseases center on osteoblasts. Overlooked are the 90% of bone cells, called osteocytes. This study aims to test the hypothesis that osteocytes but not osteoblasts directly build mineralized bone structures, and that defects in osteocytes lead to the onset of hypophosphatemia rickets. The hypothesis was tested by developing and modifying multiple imaging techniques, including both in vivo and in vitro models plus two types of hypophosphatemia rickets models (Dmp1-null and Hyp, Phex mutation mice), and Dmp1-Cre induced high level of ß-catenin models. Our key findings were that osteocytes (not osteoblasts) build bone similar to the construction of a high-rise building, with a wire mesh frame (i.e., osteocyte dendrites) and cement (mineral matrices secreted from osteocytes), which is a lengthy and slow process whose mineralization direction is from the inside toward the outside. When osteoblasts fail to differentiate into osteocytes but remain highly active in Dmp-1-null or Hyp mice, aberrant and poor bone mineralization occurs, caused by a sharp increase in Wnt-ß-catenin signaling. Further, the constitutive expression of ß-catenin in osteocytes recaptures a similar osteomalacia phenotype as shown in Dmp1 null or Hyp mice. Thus, we conclude that osteocytes directly build bone, and osteoblasts with a short life span serve as a precursor to osteocytes, which challenges the existing dogma.

Attenuation of NLRP3 Inflammasome Activation by Indirubin-Derived PROTAC Targeting HDAC6.

Histone deacetylase 6 (HDAC6) is a potential therapeutic target for treating several diseases. A recent study revealed that HDAC6 is important for NLRP3 inflammasome activation, suggesting that targeting HDAC6 could be useful for treating many inflammatory disorders. Using the proteolysis targeting chimera (PROTAC) strategy, we herein report an HDAC6 degrader with low cytotoxicity by tethering a selective HDAC6 inhibitor derived from a natural product, indirubin, with pomalidomide, a CRBN E3 ligand. Our HDAC6 degrader efficiently and selectively decreased HDAC6 levels in several cell lines, including activated THP-1 cells. Application of this HDAC6 degrader attenuated NLRP3 inflammasome activation in LPS-induced mice, which for the first time demonstrates that HDAC6 PROTAC could be a novel strategy to treat NLRP3 inflammasome-associated diseases.

Rutaecarpine Inhibits Intimal Hyperplasia in A Balloon-Injured Rat Artery Model.

OBJECTIVE: To investigate the effect and potential mechanisms of rutaecarpine (Rut) in a rat artery balloon-injury model. METHODS: The intimal hyperplasia model was established by rubbing the endothelia with a balloon catheter in the common carotid artery (CCA) of rats. Fifty rats were randomly divided into five groups, ie. sham, model, Rut (25, 50 and 75 mg/kg) with 10 rats of each group. The rats were treated with or without Rut (25, 50, 75 mg/kg) by intragastric administration for 14 consecutive days following injury. The morphological changes of the intima were evaluated by hematoxylin-eosin staining. The expressions of proliferating cell nuclear antigen (PCNA) and smooth muscle (SM) α-actin in the ateries were assayed by immunohistochemical staining. The mRNA expressions of c-myc, extracellular signal-regulated kinase 2 (ERK2), MAPK phosphatase-1 (MKP-1) and endothelial nitric oxide synthase (eNOS) were determined by real-time reverse transcription-polymerase chain reaction. The protein expressions of MKP-1 and phosphorylated ERK2 (p-ERK2) were examined by Western blotting. The plasma contents of nitric oxide (NO) and cyclic guanosine 3',5'-monophosphate (cGMP) were also determined. RESULTS: Compared with the model group, Rut treatment significantly decreased intimal thickening and ameliorated endothelial injury (P<0.05 or P<0.01). The positive expression rate of PCNA was decreased, while the expression rate of SM α-actin obviously increased in the vascular wall after Rut (50 and 75 mg/kg) administration (P<0.05 or P<0.01). Furthermore, the mRNA expressions of c-myc, ERK2 and PCNA were downregulated while the expressions of eNOS and MKP-1 were upregulated (P<0.05 or P<0.01). The protein expressions of MKP-1 and the phosphorylation of ERK2 were upregulated and downregulated after Rut (50 and 75 mg/kg) administration (P<0.05 or P<0.01), respectively. In addition, Rut dramatically reversed balloon injury-induced decrease of NO and cGMP in the plasma (P<0.05 or P<0.01). CONCLUSION: Rut could inhibit the balloon injury-induced carotid intimal hyperplasia in rats, possibly mediated by promotion of NO production and inhibiting ERK2 signal transduction pathways.

Time-Phase Sequential Utilization of Adipose-Derived Mesenchymal Stem Cells on Mesoporous Bioactive Glass for Restoration of Critical Size Bone Defects.

The effective transportation of oxygen, nutrients, and metabolic wastes through new blood vessel networks is key to the survival of engineered constructs in large bone defects. Adipose-derived mesenchymal stem cells (ADSCs), which are regarded as excellent candidates for both bone and blood vessel engineering, are the preferred option for the restoration of massive bone defects. Therefore, we propose to induce ADSCs into osteogenic and endothelial cells differently. A modified hierarchical mesoporous bioactive glass (MBG) scaffold with an enhanced compressive strength was constructed and prevascularized by seeding with endothelial-induced ADSCs (EI-ADSCs). The prevascularized scaffolds were combined with osteogenically induced ADSCs (OI-ADSCs) to repair critical-size bone defects. To validate the angiogenesis of the prevascularized MBG scaffolds in vivo, green fluorescent protein (GFP) was used to label EI-ADSCs. The labeled EI-ADSCs were demonstrated to survive and participate in vascularization at day 7 after subcutaneous implantation in nude mice by double immunofluorescence staining of CD31 and GFP. Regarding the restoration of critical size bone defects, early angiogenesis of rat femur plug defects was evaluated by perfusion of Microfil after 3 weeks. Compared to nonvascularized MBG carrying OI-ADSCs (MBG/OI-ADSCs) and non-cell-seeded MBG scaffolds, the prevascularized MBG carrying OI-ADSCs (Pv-MBG/OI-ADSCs) showed enhanced angiogenesis on the surface and interior. Through dynamic bone formation analysis with sequential fluorescent labeling and Van Gieson's picro-fuchsin staining, we found that the Pv-MBG/OI-ADSCs exhibited the highest mineral deposition rate after surgery, which may be contributed by rapid vascular anastomosis facilitating increased survival of the seeded OI-ADSCs and by the recruitment function for bone mesenchymal stem cells. Therefore, the strategy of time-phase sequential utilization of ADSCs on MBG scaffolds is a practical design for the repair of massive bone defects.

Synergistic effects of dual growth factor delivery from composite hydrogels incorporating 2-N,6-O-sulphated chitosan on bone regeneration.

A promising strategy to accelerate bone generation is to deliver a combination of certain growth factors to the integration site via a controlled spatial and temporal delivery mode. Here, a composite hydrogel incorporating poly(lactide-co-glycolide) (PLGA) microspheres was accordingly prepared to load and deliver the osteogenic rhBMP-2 and angiogenic rhVEGF165 in the required manner. In addition, 2-N,6-O-sulphated chitosan (26SCS), which is a synergetic factor of growth factors, was incorporated in the composite hydrogel as well. The system showed a similar release behaviour of the two growth factors regardless of 26SCS inclusion. RhBMP-2 loaded in PLGA microspheres showed a sustained release over a period of 2 weeks, whereas rhVEGF165 loaded in hydrogel eluted almost completely from the hydrogel over the first 16 days. Both growth factors retained their efficacy, as quantified with relevant in vitro assays. Moreover, an enhanced cell response was achieved upon the delivery of dual growth factors, compared to that obtained with a single factor. Furthermore, in the presence of 26SCS, the system revealed significantly upregulated alkaline phosphatase activity, human umbilical vein endothelial cell proliferation, sprouting, nitric oxide secretion, and angiogenic gene expression. This study highlighted that the composite hydrogel incorporated with 26SCS appears to constitute a promising approach to deliver multiple growth factors. From our findings, we could also conclude that rhBMP-2 can promote angiogenesis and that the mechanism is worthy of further study in subsequent research.

Tailored biomimetic hydrogel based on a photopolymerised DMP1/MCF/gelatin hybrid system for calvarial bone regeneration.

Searching for effective osteoinduction factors with higher specificity and biosafety for the preparation of biomimetic materials, which mimic the natural bone extracellular matrix (ECM), seems to be an optimum strategy for achieving ideal bone regeneration. Dentin matrix protein 1 (DMP1) seems to be a highly promising candidate due to its pleiotropic bio-regulation roles in several bone formation processes including osteoinduction, osteogenesis and biomineralization. In this study, we first generated a novel meso/macro-structured photopolymerised hybrid hydrogel system, in which DMP1 was loaded in mesocellular silica foam (MCF) and then evenly embedded in the photopolymerised gelatin hydrogel. This DMP1-loaded hybrid system (DMP1/MCF/gel) exhibited a hierarchical porous structure according to the surface area and pore size distribution analysis, TEM and SEM. Protein loading quantification and release kinetics experiments demonstrated that DMP1 is well protected and stably released for a longer duration in the DMP1/MCF/gel system. The expression levels of bone markers in the BMSCs under the co-treatment of both Si ion and DMP1 suggested there was a synergistic effect between Si ion and DMP1, both of which could be released from DMP1/MCF/gel system. Further in vitro osteoinductive experiments of bone marrow stem cells (BMSCs) showed that the DMP1/MCF/gel system enhanced the activity of alkaline phosphatase (ALP), promoted the formation of mineralized bone nodules, and up-regulated the expression levels of several osteogenic markers (including Runx2, Osx, Bsp, Ocn, Opn, and Dmp1). In addition, both µ-CT and histological studies suggested that the in vivo repair of rat calvarial defects using the DMP1/MCF/gel system led to accelerated bone regeneration with better mineralization and higher quality. In summary, this work generated a tailored biomimetic hydrogel based on a photopolymerised DMP1/MCF/gel hybrid system, which mimicked the non-mineralized bone ECM and resulted in improved bone regeneration.