Toward Practical Single-Molecule/Atom Switches.

Electronic switches have been considered to be one of the most important components of contemporary electronic circuits for processing and storing digital information. Fabricating functional devices with building blocks of atomic/molecular switches can greatly promote the minimization of the devices and meet the requirement of high integration. This review highlights key developments in the fabrication and application of molecular switching devices. This overview offers valuable insights into the switching mechanisms under various stimuli, emphasizing structural and energy state changes in the core molecules. Beyond the molecular switches, typical individual metal atomic switches are further introduced. A critical discussion of the main challenges for realizing and developing practical molecular/atomic switches is provided. These analyses and summaries will contribute to a comprehensive understanding of the switch mechanisms, providing guidance for the rational design of functional nanoswitch devices toward practical applications.

OxLDL enhances procoagulant activity of endothelial cells by TMEM16F-mediated phosphatidylserine exposure.

Oxidized low-density lipoprotein (oxLDL), a key component in atherosclerosis and hyperlipidemia, is a risk factor for atherothrombosis in dyslipidemia, yet its mechanism is poorly understood. In this study, we used oxLDL-induced human aortic endothelial cells (HAECs) and high-fat diet (HFD)-fed mice as a hyperlipidemia model. Phosphatidylserine (PS) exposure, cytosolic Ca2+, reactive oxygen species (ROS), and lipid peroxidation were measured by flow cytometer. TMEM16F expression was detected by immunofluorescence, western blot, and reverse transcription polymerase chain reaction. Procoagulant activity (PCA) was measured by coagulation time, intrinsic/extrinsic factor Xase, and thrombin generation. We found that oxLDL-induced PS exposure and the corresponding PCA of HAECs were increased significantly compared with control, which could be inhibited over 90% by lactadherin. Importantly, TMEM16F expression in oxLDL-induced HAECs was upregulated by enhanced intracellular Ca2+ concentration, ROS, and lipid peroxidation, which led to PS exposure. Meanwhile, the knockdown of TMEM16F by short hairpin RNA significantly inhibited PS exposure in oxLDL-induced HAECs. Moreover, we observed that HFD-fed mice dramatically increased the progress of thrombus formation and accompanied upregulated TMEM16F expression by thromboelastography analysis, FeCl3-induced carotid artery thrombosis model, and western blot. Collectively, these results demonstrate that TMEM16F-mediated PS exposure may contribute to prothrombotic status under hyperlipidemic conditions, which may serve as a novel therapeutic target for the prevention of thrombosis in hyperlipidemia.

Melittin alleviates sepsis-induced acute kidney injury by promoting GPX4 expression to inhibit ferroptosis.

OBJECTIVES: Melittin, the main component of bee venom, is a natural anti-inflammatory substance, in addition to its ability to fight cancer, antiviral, and useful in diabetes treatment. This study seeks to determine whether melittin can protect renal tissue from sepsis-induced damage by preventing ferroptosis and explore the protective mechanism. METHODS: In this study, we investigated the specific protective mechanism of melittin against sepsis-induced renal injury by screening renal injury indicators and ferroptosis -related molecules and markers in animal and cellular models of sepsis. RESULTS: Our results showed that treatment with melittin attenuated the pathological changes in mice with lipopolysaccharide-induced acute kidney injury. Additionally, we found that melittin attenuated ferroptosis in kidney tissue by enhancing GPX4 expression, which ultimately led to the reduction of kidney tissue injury. Furthermore, we observed that melittin enhanced NRF2 nuclear translocation, which consequently upregulated GPX4 expression. our findings suggest that melittin may be a potential therapeutic agent for the treatment of sepsis-associated acute kidney injury by inhibiting ferroptosis through the GPX4/NRF2 pathway. CONCLUSIONS: Our study reveals the protective mechanism of melittin in septic kidney injury and provides a new therapeutic direction for Sepsis-AKI.

Synthesis of Dual p-n Heterojunction of Ni/Mn-MOF-74/CdS@Co3O4 Photocatalyst as a Photoassisted Fenton-like Catalyst for Removal of Tetracycline Hydrochloride.

In this study, a novel composite material, Ni/Mn-MOF-74/CdS@Co3O4 was synthesized. This material consisted of a dual p-n heterojunction, which enabled efficient separation and transfer of charge carriers. Compared to a single p-n heterojunction, the presence of this dual heterojunction significantly enhanced the overall efficiency. The improved efficiency could be attributed to the unique properties of the constituent semiconductors. Co3O4 exhibited p-type semiconductor properties, while Ni/Mn-MOF-74 and CdS exhibited n-type semiconductor properties. By a combination of these materials to form a composite photocatalyst, a Z-type heterojunction was created at the interface of the p-n junction. This design established an internal electric field at both ends, effectively separating the photogenerated electrons and holes in each individual photocatalyst. As a result, the respective photocatalytic activities of the materials were maximized. To demonstrate the practical application of this composite material, it was utilized for the activation of peroxymonosulfate under visible light irradiation, with the aim of enhancing the photocatalytic degradation efficiency of tetracycline hydrochloride. The photocatalytic mechanism of Ni/Mn-MOF-74/CdS@Co3O4 in activating peroxymonosulfate and degrading tetracycline hydrochloride was investigated in detail. Furthermore, the toxicity of tetracycline hydrochloride and its intermediates was evaluated by using toxicity evaluation software.

Synthesis of a Co/Ni-MOF-74@PDI Z-scheme photocatalyst as a highly efficient photo-assisted Fenton-like catalyst for the removal of chlortetracycline hydrochloride.

In this paper, ultra-thin nanofiber PDI was obtained by self-assembly dispersion of commercial PDINH. A novel Co/Ni-MOF-74@PDI Z-scheme heterojunction photocatalyst material was constructed by a simple solvothermal method. XRD, SEM, TEM, FT-IR and other characterization techniques proved the successful preparation of the Co/Ni-MOF-74@PDI Z-scheme heterojunction photocatalyst material. By degrading chlortetracycline hydrochloride, it was found that the photocatalytic activity of Co/Ni-MOF-74@PDI was much higher than that of pure Co/Ni-MOF-74 and PDI. Subsequently, Co/Ni-MOF-74@PDI was used to activate H2O2 to further improve the degradation efficiency of chlortetracycline hydrochloride. It was found that the photocatalytic performance was greatly improved after the addition of 19.6 mM H2O2 to the system, and the degradation rate of chlortetracycline hydrochloride was 87% within 90 min. The electron transfer pathway and H2O2 activation mechanism of the Co/Ni-MOF-74@PDI composite photocatalyst were proved by free radical quenching experiments, electron paramagnetic resonance analysis and X-ray electron spectroscopy. Finally, the easy exfoliation point and degradation pathway of chlortetracycline hydrochloride were studied using density functional theory, UPLC-MS and toxicity evaluation software. It was found that the main active substances were h+, ˙O2, 1O2 and ˙OH, and the toxicity of chlortetracycline hydrochloride and its intermediates was evaluated.

Effect of Fibroblast Growth Factor 10 and an Interacting Non-Coding RNA on Secondary Hair Follicle Dermal Papilla Cells in Cashmere Goats' Follicle Development Assessed by Whole-Transcriptome Sequencing Technology.

Cashmere, a keratinised product of secondary hair follicles (SHFs) in cashmere goats, holds an important place in international high-end textiles. However, research on the complex molecular and signal regulation during the development and growth of hair follicles (HFs), which is essential for the development of the cashmere industry, is limited. Moreover, increasing evidence indicates that non-coding RNAs (ncRNAs) participate in HF development. Herein, we systematically investigated a competing endogenous RNA (ceRNA) regulatory network mediated by circular RNAs (circRNAs), microRNAs (miRNAs), and messenger RNAs (mRNAs) in skin samples of cashmere goat embryos, using whole-transcriptome sequencing technology. We obtained 6468, 394, and 239 significantly differentially expressed mRNAs, circRNAs, and miRNAs, respectively. These identified RNAs were further used to construct a ceRNA regulatory network, mediated by circRNAs, for cashmere goats at a late stage of HF development. Among the molecular species identified, miR-184 and fibroblast growth factor (FGF) 10 exhibited competitive targeted interactions. In secondary HF dermal papilla cells (SHF-DPCs), miR-184 promotes proliferation, inhibits apoptosis, and alters the cell cycle via the competitive release of FGF10. This study reports that FGF10 and its interaction with ncRNAs significantly affect SHF-DPCs, providing a reference for research on the biology of HFs in cashmere goats and other mammals.

Deciphering genetic basis of developmental and agronomic traits by integrating high-throughput optical phenotyping and genome-wide association studies in wheat.

Dissecting the genetic basis of complex traits such as dynamic growth and yield potential is a major challenge in crops. Monitoring the growth throughout growing season in a large wheat population to uncover the temporal genetic controls for plant growth and yield-related traits has so far not been explored. In this study, a diverse wheat panel composed of 288 lines was monitored by a non-invasive and high-throughput phenotyping platform to collect growth traits from seedling to grain filling stage and their relationship with yield-related traits was further explored. Whole genome re-sequencing of the panel provided 12.64 million markers for a high-resolution genome-wide association analysis using 190 image-based traits and 17 agronomic traits. A total of 8327 marker-trait associations were detected and clustered into 1605 quantitative trait loci (QTLs) including a number of known genes or QTLs. We identified 277 pleiotropic QTLs controlling multiple traits at different growth stages which revealed temporal dynamics of QTLs action on plant development and yield production in wheat. A candidate gene related to plant growth that was detected by image traits was further validated. Particularly, our study demonstrated that the yield-related traits are largely predictable using models developed based on i-traits and provide possibility for high-throughput early selection, thus to accelerate breeding process. Our study explored the genetic architecture of growth and yield-related traits by combining high-throughput phenotyping and genotyping, which further unravelled the complex and stage-specific contributions of genetic loci to optimize growth and yield in wheat.

Graphene: Preparation, tailoring, and modification.

Graphene is a 2D material with fruitful electrical properties, which can be efficiently prepared, tailored, and modified for a variety of applications, particularly in the field of optoelectronic devices thanks to its planar hexagonal lattice structure. To date, graphene has been prepared using a variety of bottom-up growth and top-down exfoliation techniques. To prepare high-quality graphene with high yield, a variety of physical exfoliation methods, such as mechanical exfoliation, anode bonding exfoliation, and metal-assisted exfoliation, have been developed. To adjust the properties of graphene, different tailoring processes have been emerged to precisely pattern graphene, such as gas etching and electron beam lithography. Due to the differences in reactivity and thermal stability of different regions, anisotropic tailoring of graphene can be achieved by using gases as the etchant. To meet practical requirements, further chemical functionalization at the edge and basal plane of graphene has been extensively utilized to modify its properties. The integration and application of graphene devices is facilitated by the combination of graphene preparation, tailoring, and modification. This review focuses on several important strategies for graphene preparation, tailoring, and modification that have recently been developed, providing a foundation for its potential applications.

Phylogenetic analyses of antimicrobial resistant Corynebacterium striatum strains isolated from a nosocomial outbreak in a tertiary hospital in China.

Corynebacterium striatum is an emerging, multidrug-resistant pathogen that frequently causes nosocomial infections worldwide. This study aimed to investigate phylogenetic relationship and presence of genes responsible for antimicrobial resistance among C. striatum strains associated with an outbreak at the Shanxi Bethune Hospital, China, in 2021. Fecal samples were collected from 65 patients with C. striatum infection at Shanxi Bethune Hospital between February 12, 2021 and April 12, 2021. C. striatum isolates were identified by 16S rRNA and rpoB gene sequencing. E-test strips were used to examine the antimicrobial susceptibility of the isolates. Whole-genome sequencing and bioinformatics analysis were employed to assess the genomic features and identify antimicrobial resistance genes of the isolates. Crystal violet staining was conducted to determine the ability of biofilm formation of each isolate. A total of 64 C. striatum isolates were identified and categorized into 4 clades based on single nucleotide polymorphisms. All isolates were resistant to penicillin, meropenem, ceftriaxone, and ciprofloxacin but susceptible to vancomycin and linezolid. Most isolates were also resistant to tetracycline, clindamycin, and erythromycin, with susceptibility rates of 10.77, 4.62, and 7.69%, respectively. Genomic analysis revealed 14 antimicrobial resistance genes in the isolates, including tetW, ermX, and sul1. Crystal violet staining showed that all isolates formed biofilms on the abiotic surface. Four clades of multidrug-resistant C. striatum spread in our hospitals possibly due to the acquisition of antimicrobial resistance genes.

Ferroptosis of Endothelial Cells Triggered by Erythrophagocytosis Contributes to Thrombogenesis in Uremia.

BACKGROUND: Although thrombosis events are the leading complication of uremia, their mechanism is largely unknown. The interaction between endothelial cells (ECs) and red blood cells (RBCs) in uremic solutes and its prothrombotic role need to be investigated. METHODS AND RESULTS: Here, we established an in vitro co-incubation model of uremic RBC and EC as well as a uremic rat model induced by adenine. Using flow cytometry, confocal microscopy, and electron microscopy, we found increased erythrophagocytosis by EC accompanied by increased reactive oxygen species, lipid peroxidation, and impairment of mitochondria, indicating that ECs undergo ferroptosis. Further investigations showed increased proteins' expression of heme oxygenase-1 and ferritin and labile iron pool accumulation in EC, which could be suppressed by deferoxamine (DFO). The ferroptosis-negative regulators glutathione peroxidase 4 and SLC7A11 were decreased in our erythrophagocytosis model and could be enhanced by ferrostatin-1 or DFO. In vivo, we observed that vascular EC phagocytosed RBC and underwent ferroptosis in the kidney of the uremic rat, which could be inhibited by blocking the phagocytic pathway or inhibiting ferroptosis. Next, we found that the high tendency of thrombus formation was accompanied by erythrophagocytosis-induced ferroptosis in vitro and in vivo. Importantly, we further revealed that upregulated TMEM16F expression mediated phosphatidylserine externalization on ferroptotic EC, which contributed to a uremia-associated hypercoagulable state. CONCLUSION: Our results indicate that erythrophagocytosis-triggered ferroptosis followed by phosphatidylserine exposure of EC may play a key role in uremic thrombotic complications, which may be a promising target to prevent thrombogenesis of uremia.

Magnetic Resonance Imaging-CCCFLS Scoring System: Toward Predicting Clinical Symptoms and C5 Paralysis.

STUDY DESIGN: A retrospective study. OBJECTIVE: To develop a new MRI scoring system to assess patients' clinical characteristics, outcomes and complications. METHODS: A retrospective 1-year follow-up study of 366 patients with cervical spondylosis from 2017 to 2021. The CCCFLS scores (cervical curvature and balance (CC), spinal cord curvature (SC), spinal cord compression ratio (CR), cerebrospinal fluid space (CFS). Spinal cord and lesion location (SL). Increased Signal Intensity (ISI) were divided into Mild group (0-6), Moderate group (6-12), and Severe group (12-18) for comparison, and the Japanese Orthopaedic Association (JOA) scores, visual analog scale (VAS), numerical rating scale (NRS), Neck Disability Index (NDI) and Nurick scores were evaluated. Correlation and regression analyses were performed between each variable and the total model in relation to clinical symptoms and C5 palsy. RESULTS: The CCCFLS scoring system was linearly correlated with JOA, NRS, Nurick and NDI scores, with significant differences in JOA scores among patients with different CC, CR, CFS, ISI scores, with a predictive model (R2 = 69.3%), and significant differences in preoperative and final follow-up clinical scores among the 3 groups, with a higher rate of improvement in JOA in the severe group (P < .05), while patients with and without C5 paralysis had significant differences in preoperative SC and SL (P < .05). CONCLUSIONS: CCCFLS scoring system can be divided into mild (0-6). moderate (6-12), severe (12-18) groups. It can effectively reflect the severity of clinical symptoms, and the improvement rate of JOA is better in the severe group, while the preoperative SC and SL scores are closely related to C5 palsy. LEVEL OF EVIDENCE: III.

Proteome and Ubiquitylome Analyses of Maize Endoplasmic Reticulum under Heat Stress.

High temperatures severely affect plant growth and pose a threat to global crop production. Heat causes the accumulation of misfolded proteins in the endoplasmic reticulum(ER), as well as triggering the heat-shock response (HSR) in the cytosol and the unfolded protein response (UPR) in the ER. Excessive misfolded proteins undergo further degradation through ER-associated degradation (ERAD). Although much research on the plant heat stress response has been conducted, the regulation of ER-localized proteins has not been well-studied thus far. We isolated the microsome fraction from heat-treated and untreated maize seedlings and performed proteome and ubiquitylome analyses. Of the 8306 total proteins detected in the proteomics analysis, 1675 proteins were significantly up-regulated and 708 proteins were significantly down-regulated. Global ubiquitination analysis revealed 1780 proteins with at least one ubiquitination site. Motif analysis revealed that alanine and glycine are the preferred amino acids upstream and downstream of ubiquitinated lysine sites. ERAD components were found to be hyper-ubiquitinated after heat treatment, implying the feedback regulation of ERAD activity through protein degradation.

A Natural Glucan from Black Bean Inhibits Cancer Cell Proliferation via PI3K-Akt and MAPK Pathway.

A natural α-1,6-glucan named BBWPW was identified from black beans. Cell viability assay showed that BBWPW inhibited the proliferation of different cancer cells, especially HeLa cells. Flow cytometry analysis indicated that BBWPW suppressed the HeLa cell cycle in the G2/M phase. Consistently, RT-PCR experiments displayed that BBWPW significantly impacts the expression of four marker genes related to the G2/M phase, including p21, CDK1, Cyclin B1, and Survivin. To explore the molecular mechanism of BBWPW to induce cell cycle arrest, a transcriptome-based target inference approach was utilized to predict the potential upstream pathways of BBWPW and it was found that the PI3K-Akt and MAPK signal pathways had the potential to mediate the effects of BBWPW on the cell cycle. Further experimental tests confirmed that BBWPW increased the expression of BAD and AKT and decreased the expression of mTOR and MKK3. These results suggested that BBWPW could regulate the PI3K-Akt and MAPK pathways to induce cell cycle arrest and ultimately inhibit the proliferation of HeLa cells, providing the potential of the black bean glucan to be a natural anticancer drug.

Pyrotinib combining with radiotherapy on breast cancer with brain metastasis.

With the extensive application of anti-human epidermal growth factor receptor-2 (HER2) targeted therapy, the prognosis of HER2-positive breast cancer brain metastasis (BCBM) has been improved greatly. Due to the lack of prospective randomized controlled studies; however, the treatment of active brain metastasis (BM) remains a difficulty in clinic. Based upon the retrospective studies, an effective approach of radiotherapy combined with pyrotinib in HER2-positive BCBM treatment was investigated in present research. In all, 29 patients who had active BM in HER2-positive breast cancer (BC) and underwent whole-brain radiotherapy (WBRT) combined with pyrotinib from January 2019 to May 2021 were enrolled. The progression-free survival (PFS), overall survival (OS), clinical benefit rate (CBR), objective response rate (ORR), and drug-related adverse events (AEs) were analyzed among patients undergoing WBRT combined with concurrent or sequence pyrotinib + capecitabine. After the systematic treatments using WBRT combined with pyrotinib + capecitabine, the mPFS and mOS of BM patients were 6.5 months and 15.5 months, respectively. PFS (7.2 vs 6.2 months, p = 0.038) and OS (19.0 vs 14.0 months, p = 0.014) were longer after sequence treatments than those after concurrent treatment. The central nervous system (CNS) ORR of sequence treatment was superior to that of concurrent treatment (80.4% vs 58.6%, p < 0.05). Vomiting (17.2%) and diarrhea (10.3%) were the most common adverse reactions ⩾ grade 3. WBRT combined with pyrotinib is safe and effective for the treatments of active BM in HER2-positive BC. WBRT combined with sequence pyrotinib + capecitabine is more effective and less toxic than concurrent treatment. Therefore, sequence treatment is potentially a preferred regimen for patients with active BM in HER2-positive BC. The size and number of BM lesions, presence or absence of hepatic metastasis, and combination mode of radiotherapy and targeted therapy are independent risk factors for active BM prognosis.

Pyrotinib for Elderly Patients with Advanced HER2-Positive Breast Cancer.

Introduction: According to the latest global cancer data released by WHO in 2020, the incidence of breast cancer (BC) has been the most prevalent, and the mortality rate of female malignant tumor ranks the first. Methods: To evaluate toxicity and efficacy regarding oral Pyrotinib for elderly patients with advanced HER2-positive breast cancer (BC) in Xinjiang, 45 elderly patients having advanced HER2-positive BC with age ≥65 years and receiving Pyrotinib-based combined therapy from January 2019 to May 2021 in Xinjiang were enrolled in this study. PFS, CBR, ORR and drug-related adverse events (AE) of oral Pyrotinib in the patients were retrospectively analyzed. All 45 patients completed the efficacy evaluation. Results: Total ORR and CBR of the whole group was 37.8% and 77.8%, respectively. There were 14 patients with brain metastases (31.1%), with a median PFS of 6.8 months (95% CI: 5.4~9.8). In terms of the number of treatment lines, mPFS for line 1-2 was 8.3 months (95% CI: 6.3~11.4), and mPFS for line ≥3 was 3.3 months (95% CI: 2.7~5.1). At the final maintenance dose, mPFS at standard doses of 400mg, 320mg and 240mg were 9.1 months (95% CI: 4.1~9.5), 8.3 months (95% CI: 4.3~12.2) and 4.8 months (95% CI: 2.1~7.5), respectively. Discussion: Applying Pyrotinib in elderly patients, the main adverse reaction was diarrhea, accounting for 88.9% (40/45). Pyrotinib is safe and effective for elderly patients with advanced HER2 positive BC.

Pyrotinib-based treatments in HER2-positive breast cancer patients with brain metastases.

OBJECTIVES: Extensive application of anti-HER2 targeted therapy improves significantly the HER2-positive advanced breast cancer (BC) prognosis, however, it is still difficult to treat brain metastasis. In current study, we explored effective approaches via combining pyrotinib to treat brain metastasis in patients with HER2-positive advanced BC based upon clinical data. MATERIALS AND METHODS: Current study included 61 HER2-positive BC patients with brain metastases (BM) who were treated by pyrotinib-based regimens. The systemic regimens included pyrotinib combined with capecitabine, pyrotinib combined with nab-paclitaxel, and pyrotinib combined with vinorelbine. Patients' progression-free survival (PFS), overall survival (OS), clinical benefit rate (CBR) and objective response rate (ORR), as well as drug-related adverse events (AEs) in regard of each combination regimen were analyzed. RESULTS: Pyrotinib-based systemic therapy resulted in 8.6 months median PFS (mPFS) and 18.0 months median OS (mOS) among the BM patients. Regarding different regimens, the combination of pyrotinib with nab-paclitaxel was superior to the combination with capecitabine and vinorelbine with respect to PFS and OS. The central nervous system (CNS) ORR did not showcase significant difference among 3 regimens, however, nab-paclitaxel combined regimen obtained the best peripheral ORR (84.6%) (p ≤ .05). CONCLUSIONS: Pyrotinib-based combination therapy is safe for HER2-positive brain metastasis treatment. Compared with vinorelbine or capecitabine, pyrotinib combined with nab-paclitaxel is more effective with less toxicity, which is the preferable regimen for HER2-positive brain metastasis.KEY MESSAGESPresent investigation investigated effective methods through combining pyrotinib to treat brain metastasis with HER2-positive advanced brain cancer. The outcomes verified that pyrotinib-based combination therapy was safe and efficient to treat HER2-positive brain metastasis. Therefore, it is effective to treat brain metastasis applying anti-HER2 targeted therapies although pyrotinib showcases efficiency regarding its treatments for the metastasis.

Evaluation of Serum MiR-184 and MiR-326 Expression in PCOS Subjects: Correlation with PCOS Related Parameters.

BACKGROUND: MicroRNA (miRNA) is an endogenous non-coding single-stranded RNA with highly conserved characteristics, which has been proven to regulate gene expression and biological functions of organisms after transcription. Therefore, exploring the differentially expressed miRNAs during the disease process is of great significance for the diagnosis of the disease. METHODS: The focus of this study is to explore the differences in serum expression of miR-184 and miR-326 in polycystic ovary syndrome (PCOS) subjects, and analyze the Pearson's correlation with PCOS disease characterization parameters. The basic physical characteristics and related biochemical indicators and hormone levels of 60 PCOS subjects and 60 healthy subjects of the same period were tested. RESULTS: MiR-184 and miR-326 in serum were detected, and it was found that miR-184 and miR-326 in PCOS subjects were significantly increased. Correlation analysis found that miR-184 and miR-326 are positively correlated with body mass index, follicle number, ovarian volume, luteinizing hormone, prolactin, estradiol, progesterone, testosterone, fasting blood glucose, fasting serum insulin, homeostasis of insulin resistance model evaluation, and triglycerides and negatively correlated with high-density lipoprotein. CONCLUSIONS: The study showed that serum miR-184 and miR-326 are highly expressed in PCOS patients and can be used as molecular biomarkers for PCOS diagnosis. They may be involved in the metabolism and reproductive function of PCOS patients.

TAT&RGD Peptide-Modified Naringin-Loaded Lipid Nanoparticles Promote the Osteogenic Differentiation of Human Dental Pulp Stem Cells.

Background: Naringin is a naturally occurring flavanone that promotes osteogenesis. Owing to the high lipophilicity, poor in vivo bioavailability, and extensive metabolic alteration upon administration, the clinical efficacy of naringin is understudied. Additionally, information on the molecular mechanism by which it promotes osteogenesis is limited. Methods: In this study, we prepared TAT & RGD peptide-modified naringin-loaded nanoparticles (TAT-RGD-NAR-NPs), evaluated their potency on the osteogenic differentiation of human dental pulp stem cells (hDPSCs), and studied its mechanism of action through metabolomic analysis. Results: The particle size and zeta potential of TAT-RGD-NAR-NPs were 160.70±2.05 mm and -20.77±0.47mV, respectively. The result of cell uptake assay showed that TAT-RGD-NAR-NPs could effectively enter hDPSCs. TAT-RGD-NAR-NPs had a more significant effect on cell proliferation and osteogenic differentiation promotion. Furthermore, in metabolomic analysis, naringin particles showed a strong influence on the glycerophospholipid metabolism pathway of hDPSCs. Specifically, it upregulated the expression of PLA2G3 and PLA2G1B (two isozymes of phospholipase A2, PLA2), increased the biosynthesis of lysophosphatidic acid (LPA). Conclusion: These results suggested that TAT-RGD-NPs might be used for transporting naringin to hDPSCs for modulating stem cell osteogenic differentiation. The metabolomic analysis was used for the first time to elucidate the mechanism by which naringin promotes hDPSCs osteogenesis by upregulating PLA2G3 and PLA2G1B.

VEGF-Loaded Heparinised Gelatine-Hydroxyapatite-Tricalcium Phosphate Scaffold Accelerates Bone Regeneration via Enhancing Osteogenesis-Angiogenesis Coupling.

Background: Bone tissue defect, one of the common orthopaedicdiseases, is traumatizing and affects patient's lifestyle. Although autologous and xenograft bone transplantations are performed in bone tissue engineering, clinical development of bone transplantation is limited because ofvarious factors, such as varying degrees of immune rejection, lack of bone sources, and secondary damage to bone harvesting. Methods: We synthesised a heparinised gelatine-hydroxyapatite-tricalcium phosphate (HG-HA-TCP) scaffold loaded with sustained-release vascular endothelial growth factor (VEGF) analysed their structure, mechanical properties, and biocompatibility. Additionally, the effects of HG-HA-TCP (VEGF) scaffolds on osteogenic differentiation and vascularisation of stem cells from human exfoliated deciduous teeth (SHED) in vitro and bone regeneration in vivo were investigated. Results: HG-HA-TCP scaffold possessed good pore structure, mechanical properties, and biocompatibility. HG-HA-TCP scaffold loaded with VEGF could effectively promote SHED proliferation, migration, and adhesion. Moreover, HG-HA-TCP (VEGF) scaffold increased the expression of osteogenesis- and angiogenesis-related genes and promoted osteogenic differentiation and vascularisation in cells. In vivo results demonstrated that VEGF-loaded HG-HA-TCP scaffold improved new bone regeneration and enhanced bone mineral density, revealed byhistological, micro-CT and histochemical straining analyses. Osteogenic and angiogenic abilities of the three biological scaffolds wereranked as follows: HG-HA-TCP (VEGF) > G-HA-TCP (VEGF) > G-HA-TCP. Conclusion: HG-HA-TCP (VEGF) scaffold with good biocompatibility could create an encouraging osteogenic microenvironment that could accelerate vessel formation and osteogenesis, providing an effective scaffold for bone tissue engineering and developing new clinical treatment strategies for bone tissue defects.

TMEM16F mediated phosphatidylserine exposure and microparticle release on erythrocyte contribute to hypercoagulable state in hyperuricemia.

The link between hyperuricemia (HUA) and the risk of venous thromboembolism (VTE) has been well established. However, the mechanisms of thrombus generation and the effect of HUA on procoagulant activity (PCA) of erythrocytes remain unclear no matter in uremia or hyperuricemia. Here, phosphatidylserine (PS) exposure, microparticles (MPs) release, cytosolic Ca2+, TMEM16F expression, reactive oxygen species (ROS) and lipid peroxidation of erythrocyte were detected by flow cytometer. PCA was assessed by coagulation time, purified coagulation complex and fibrin production assays. The fibrin formation was observed by scanning electron microscopy (SEM). We found that PS exposure, MPs generation, TMEM16F expression and consequent PCA of erythrocyte in HUA patients significantly increased compared to those in healthy volunteers. Furthermore, high UA induced PS exposure, and MPs release of erythrocyte in concentration and time-dependent manners in vitro, which enhanced the PCA of erythrocyte and was inhibited by lactadherin, a PS inhibitor. Additionally, using SEM, we also observed compact fibrin clots with highly-branched networks and thin fibers supported by red blood cells (RBCs) and RBC-derived MPs (RMPs). Importantly, we demonstrated UA enhanced the production of ROS and lipid peroxidation and reduced the generation of glutathione (GSH) of erythrocyte, which enhanced TMEM16F activity and followed PS externalization and RMPs formation. Collectively, these results suggest that Ca2+-dependent TMEM16F activation may be responsible for UA-induced PS exposure and MPs release of RBC, which thereby contribute to the prothrombotic risk in HUA.