Efficiently directing differentiation and homing of mesenchymal stem cells to boost cartilage repair in osteoarthritis via a nanoparticle and peptide dual-engineering strategy.

Mesenchymal stem cells (MSCs) are expected to be useful therapeutics in osteoarthritis (OA), the most common joint disorder characterized by cartilage degradation. However, evidence is limited with regard to cartilage repair in clinical trials because of the uncontrolled differentiation and weak cartilage-targeting ability of MSCs after injection. To overcome these drawbacks, here we synthesized CuO@MSN nanoparticles (NPs) to deliver Sox9 plasmid DNA (favoring chondrogenesis) and recombinant protein Bmp7 (inhibiting hypertrophy). After taking up CuO@MSN/Sox9/Bmp7 (CSB NPs), the expressions of chondrogenic markers were enhanced while hypertrophic markers were decreased in response to these CSB-engineered MSCs. Moreover, a cartilage-targeted peptide (designated as peptide W) was conjugated onto the surface of MSCs via a click chemistry reaction, thereby prolonging the residence time of MSCs in both the knee joint cavity of mice and human-derived cartilage. In a surgery-induced OA mouse model, the NP and peptide dual-modified W-CSB-MSCs showed an enhancing therapeutic effect on cartilage repair in knee joints compared with other engineered MSCs after intra-articular injection. Most importantly, W-CSB-MSCs accelerated cartilage regeneration in damaged cartilage explants derived from OA patients. Thus, this new peptide and NPs dual engineering strategy shows potential for clinical applications to boost cartilage repair in OA using MSC therapy.

Red light-induced localized release of carbon monoxide for alleviating postoperative cognitive dysfunction.

Inflammation within the central nervous system (CNS), which may be triggered by surgical trauma, has been implicated as a significant factor contributing to postoperative cognitive dysfunction (POCD). The relationship between mitigating inflammation at peripheral surgical sites and its potential to attenuate the CNS inflammatory response, thereby easing POCD symptoms, remains uncertain. Notably, carbon monoxide (CO), a gasotransmitter, exhibits pronounced anti-inflammatory effects. Herein, we have developed carbon monoxide-releasing micelles (CORMs), a nanoparticle that safely and locally liberates CO upon exposure to 650 nm light irradiation. In a POCD mouse model, treatment with CORMs activated by light (CORMs + hv) markedly reduced the concentrations of interleukin (IL)-6, IL-1ß, and tumor necrosis factor-alpha (TNF-α) in both the peripheral blood and the hippocampus, alongside a decrease in ionized calcium-binding adapter molecule 1 in the hippocampal CA1 region. Furthermore, CORMs + hv treatment diminished Evans blue extravasation, augmented the expression of tight junction proteins zonula occludens-1 and occludin, enhanced neurocognitive functions, and fostered fracture healing. Bioinformatics analysis and experimental validation has identified Htr1b and Trhr as potential key regulators in the neuroactive ligand-receptor interaction signaling pathway implicated in POCD. This work offers new perspectives on the mechanisms driving POCD and avenues for therapeutic intervention.

HumanIslets.com: Improving accessibility, integration, and usability of human research islet data.

HumanIslets.com supports diabetes research by offering easy access to islet phenotyping data, analysis tools, and data download. It includes molecular omics, islet and cellular function assays, tissue processing metadata, and phenotypes from 547 donors. As it expands, the resource aims to improve human islet data quality, usability, and accessibility.

The first in-human study to evaluate the antiplatelet properties of the clopidogrel conjugate DT-678 in acute coronary syndrome patients and healthy volunteers.

BACKGROUND AND PURPOSE: DT-678 is a novel antiplatelet prodrug, capable of releasing the antiplatelet active metabolite of clopidogrel (AM) upon exposure to glutathione. In this study, we investigated factors responsible for clopidogrel high on-treatment platelet reactivity (HTPR) in acute coronary syndrome (ACS) patients and evaluated the capacity of DT-678 to overcome HTPR. EXPERIMENTAL APPROACH: A total of 300 consecutive ACS patients naive to P2Y12 receptor inhibitors were recruited and genotyped for CYP2C19 alleles. Blood samples were drawn before and after administration of 600-mg clopidogrel. Platelet reactivity index (PRI) and plasma AM concentrations were determined and grouped according to their CYP2C19 genotypes. DT-678 was applied ex vivo to whole blood samples to examine its inhibitory effects. To further examine the antiplatelet effectiveness of DT-678 in vivo, 20 healthy human subjects were recruited in a Phase I clinical trial, and each received a single dose of either 3-mg DT-678 or 75-mg clopidogrel. The pharmacokinetics and pharmacodynamics in different CYP2C19 genotype groups were compared. KEY RESULTS: Statistical analyses revealed that CYP2C19 genotype, body mass index, hyperuricaemia, and baseline PRI were significantly associated with a higher risk of clopidogrel HTPR in ACS patients. The addition of DT-678 ex vivo decreased baseline PRI regardless of CYP2C19 genotypes, overcoming clopidogrel HTPR. This observation was further confirmed in healthy volunteers receiving 3 mg of DT-678. CONCLUSION AND IMPLICATIONS: These results suggest that DT-678 effectively overcomes clopidogrel HTPR resulting from genetic and/or clinical factors in Chinese ACS patients, demonstrating its potential to improve antiplatelet therapy.

Reinforced Nacre-Like MXene/Sodium Alginate Composite Films for Bioinspired Actuators Driven by Moisture and Sunlight.

MXene-based soft actuators have attracted increasing attention and shown competitive performance in various intelligent devices such as supercapacitors, bionic robots and artificial muscles. However, the development of robust MXene-based actuators with multi-stimuli responsiveness remains challenging. In this study, a nacre-like structure soft actuator based on MXene and sodium alginate (SA) composite films is prepared using a straightforward solvent casting self-assembly method, which not only enhances the mechanical performance (tensile strength of 72 MPa) but also diversifies the stimuli responsiveness of the material. The composite actuators can be powered by external stimuli from renewable energy sources, from moisture inducing a maximum bending angle of 190 degrees at a relative humidity (RH) of 91%, and sunlight irradiation generating a maximum curvature of 1.45 cm-1 under 100 mW cm-2. The feasibility of practical applications, including moisture-responsive flowers and walkers, sunlight-responsive oscillators, and smart switches, is demonstrated through comprehensive experimental characterization and performance evaluation. The work presented here provides insight into the design of robust actuators via the utilization and conversion of environmentally renewable energy sources.

In-vitro fertilization experience with follitropin-delta in poor responders identified by POSEIDON Classification.

BACKGROUND: Controlled ovarian stimulation during in-vitro fertilization (IVF) is personalized based on anticipated hyper, normal, poor response. With respect to poor responders, who are often treated using higher gonadotropin dosing and combination of urinary and recombinant gonadotropins (rFSH) with marginal benefit, we report our experience with a newer, more potent rFSH (Follitropin-δ) undergoing IVF. METHODS: Retrospective analysis of all IVF cycles in which follitropin-δ was used alone or combined with urinary gonadotropins over a 3-year period. Patients were grouped according to the POSEIDON Classification as expected low responders (POSEIDON 3-4; AMH<1.2; N.=45), unexpected low responders (POSEIDON 1-2; retrieval of ≤9 oocytes; N.=67) and those with a normal response (N.=93). Demographic, stimulation (including target number of retrieved oocytes [8 to14]), embryology and clinical outcome parameters (clinical pregnancy rate [CPR], live birth rate [LBR], cumulative live birth rate [cLBR]) were compared. RESULTS: Those categorized as POSEIDON patients were older, had lower ovarian reserve, were more likely to use a mixed protocol, less likely to reach the target oocytes retrieved (35.7% vs. 51.6%, P<0.001), and had a lower cLBR per patient (29.5% vs. 38.7%, P=0.006) when compared to non-POSEIDON patients. Expected low responders (POSEIDON 3-4) were older and had lower AMH when compared to unexpected low responders (POSEIDON 1-2), but no differences in the target of oocytes retrieved (33.3% vs. 37.3%, P=0.66) and cLBR (28.9% vs. 37.3%, P=0.06) were noted. CONCLUSIONS: In expected low responders, follitropin-δ can be used to optimize oocyte collection and clinical outcome though one may need to deviate from the algorithm-suggested dose. Future studies should explore stimulation modifications in unexpected low responders.

Fetal hypoxia exposure induced Hif1a activation and autophagy in adult ovary granulosa cells.

Environmental hypoxia adversely impacts the reproduction of humans and animals. Previously, we showed that fetal hypoxia exposure led to granulosa cell (GC) autophagic cell death via the Foxo1/Pi3k/Akt pathway. However, the upstream regulatory mechanisms underlying GC dysfunction remain largely unexplored. Here, we tested the hypothesis that fetal hypoxia exposure altered gene expression programs in adult GCs and impaired ovarian function. We established a fetal hypoxia model in which pregnant mice were maintained in a high-plateau hypoxic environment from gestation day (E) 0--16.5 to study the impact of hypoxia exposure on the ovarian development and subsequent fertility of offspring. Compared with the unexposed control, fetal hypoxia impaired fertility by disordering ovarian function. Specifically, fetal hypoxia caused mitochondrial dysfunction, oxidant stress and autophagy in GCs in the adult ovary. RNA-seq analysis revealed that 437 genes were differentially expressed in the adult GCs of exposed animals. Western blotting results also revealed that fetal exposure induced high levels of hypoxia-inducible factor 1-alpha (Hif1a) expression in adult GCs. We then treated GCs isolated from exposed mice with PX-478, a specific pharmacological inhibitor of Hif-1a, and found that autophagy and apoptosis were effectively alleviated. Finally, by using a human ovarian granulosa-like tumor cell line (KGN) to simulate hypoxia in vitro, we showed that Hif1a regulated autophagic cell death in GCs through the Pi3k/Akt pathway. Together, these findings suggest that fetal hypoxia exposure induced persistent Hif1a expression, which impaired mitochondrial function and led to autophagic cell death in the GCs of the adult ovary.

NAD+-boosting agent nicotinamide mononucleotide potently improves mitochondria stress response in Alzheimer's disease via ATF4-dependent mitochondrial UPR.

Extensive studies indicate that mitochondria dysfunction is pivotal for Alzheimer's disease (AD) pathogenesis; while cumulative evidence suggests that increased mitochondrial stress response (MSR) may mitigate neurodegeneration in AD, explorations to develop a MSR-targeted therapeutic strategy against AD are scarce. We combined cell biology, molecular biology, and pharmacological approaches to unravel a novel molecular pathway by which NAD+-boosting agent nicotinamide mononucleotide (NMN) regulates MSR in AD models. Here, we report dyshomeostasis plasma UPRmt-mitophagy-mediated MSR profiles in AD patient samples. NMN restores NAD+ metabolic profiles and improves MSR through the ATF4-dependent UPRmt pathway in AD-related cross-species models. At the organismal level, NAD+ repletion with NMN supplementation ameliorates mitochondrial proteotoxicity, decreases hippocampal synaptic disruption, decreases neuronal loss, and brain atrophy in mice model of AD. Remarkably, omics features of the hippocampus with NMN show that NMN leads to transcriptional changes of genes and proteins involved in MSR characteristics, principally within the astrocyte unit rather than microglia and oligodendrocytes. In brief, our work provides evidence that MSR has an active role in the pathogenesis of AD, as reducing mitochondrial homeostasis via atf4 depletion in AD mice aggravates the hallmarks of the disease; conversely, bolstering mitochondrial proteostasis by NMN decreases protein aggregation, restores memory performance, and delays disease progression, ultimately translating to increased healthspan.

Long noncoding RNA AK144717 exacerbates pathological cardiac hypertrophy through modulating the cellular distribution of HMGB1 and subsequent DNA damage response.

DNA damage induced by oxidative stress during cardiac hypertrophy activates the ataxia telangiectasia mutated (ATM)-mediated DNA damage response (DDR) signaling, in turn aggravating the pathological cardiomyocyte growth. This study aims to identify the functional associations of long noncoding RNA (lncRNAs) with cardiac hypertrophy and DDR. The altered ventricular lncRNAs in the mice between sham and transverse aortic constriction (TAC) group were identified by microarray analysis, and a novel lncRNA AK144717 was found to gradually upregulate during the development of pathological cardiac hypertrophy induced by TAC surgery or angiotensin II (Ang II) stimulation. Silencing AK144717 had a similar anti-hypertrophic effect to that of ATM inhibitor KU55933 and also suppressed the activated ATM-DDR signaling induced by hypertrophic stimuli. The involvement of AK144717 in DDR and cardiac hypertrophy was closely related to its interaction with HMGB1, as silencing HMGB1 abolished the effects of AK144717 knockdown. The binding of AK144717 to HMGB1 prevented the interaction between HMGB1 and SIRT1, contributing to the increased acetylation and then cytosolic translocation of HMGB1. Overall, our study highlights the role of AK144717 in the hypertrophic response by interacting with HMGB1 and regulating DDR, hinting that AK144717 is a promising therapeutic target for pathological cardiac growth.

[Research progress on the role of pyroptosis in sepsis-related coagulation disorder].

Sepsis is a common and severe infectious disease, and its associated coagulation dysfunction can cause disseminated intravascular coagulation (DIC) and organ failure, leading to a significant increase in mortality. Pyroptosis is a form of programmed cell death mediated by caspase-1 in the classical pathway and caspase-4/caspase-5/caspase-11 in the non-classical pathway, along with the effector molecule gasdermin (GSDM) family. Recent studies have shown that pyroptosis plays an important role in the development of coagulation disorders in sepsis. Pyroptosis leads to the formation of cytoplasmic membrane pores, cell swelling and membrane rupture, as well as the release and enhanced activity of procoagulant contents, strongly promoting the development of systemic coagulation activation and DIC in sepsis. Therefore, exploring the role and molecular mechanisms of pyroptosis in sepsis-related coagulation disorders is of great significance for the prevention and treatment of sepsis. This article provides a review of the mechanisms involved in pyroptosis and coagulation disorders in sepsis, as well as the role and mechanisms of pyroptosis in sepsis-associated coagulation disorders to provide new ideas for sepsis related research.

Insight into the growth and metabolic characteristics of indigenous commercial S. cerevisiae NX11424 at high and low levels of yeast assimilable nitrogen based on metabolomic approach.

Yeast assimilable nitrogen (YAN) is one of the important factors affecting yeast growth and metabolism. However, the nitrogen requirement of indigenous commercial S. cerevisiae NX11424 is unclear. In this study, metabolomics was used to analyze the metabolite profiles of the yeast strain NX11424 under high (433 mg/L) and low (55 mg/L) YAN concentrations. It was found that yeast biomass exhibited different trends under different YAN conditions and was generally positively correlated with the initial YAN concentration, while changes of key biomarkers of yeast strain NX11424 at different stages of fermentation showed a similar trend under high and low YAN concentrations. The YAN concentration affected the metabolite levels of the yeast strain NX11424, which resulted in the significant difference in the levels of pyruvic acid, α-oxoglutarate, palmitoleic acid, proline, butane-2,3-diol, citrulline, ornithine, galactinol, citramalic acid, tryptophan, alanine, phosphate and phenylethanol, mainly involving pathways such as central carbon metabolism, amino acid metabolism, fatty acid metabolism, purine metabolism, and energy metabolism. Yeast strain NX11424 could utilize proline to produce protein under a low YAN level. The intracellular level of citrulline and ornithine under high YAN concentration was higher than that under low YAN level. Yeast strain NX11424 is more suitable for fermentation at lower YAN level. The results obtained here will help to rational utilize of YAN by S. cerevisiae NX11424, and is conducive to precise control of the alcohol fermentation and improve wine quality.

Bibliometrics analysis on the research status and trends of small bowel adenocarcinoma: 1923-2023.

Objectives: The aim of this research is to discuss the research status, hotspots, frontiers, and development trends in the field of small bowel adenocarcinoma based on bibliometrics and visual analysis by CiteSpace software. Methods: The relevant research articles on SBA from 1923 to 2023 were retrieved from the Web of Science Core Collection database. CiteSpace software was used to form a visual knowledge map and conduct analysis for the countries/regions, journals, authors, keywords, clusters, research hotspots and frontiers of the included articles. Results: There were 921 articles included, and the number of articles published during 1923-2023 is increasing. The country with the highest number of articles published was the United States (443, 38.76%), followed by Japan (84, 9.12%) and France (72, 7.82%). The author with the highest number of publications is Ansell, Overman MJ (33, 3.58%), and the author with the highest co-citation frequency is Overman MJ (218). Journal of Clinical Oncology is the journal with the highest publication frequency. The top five cluster groups were "chemotherapy", "inflammatory bowel disease", "celiac disease", "tumor" and "small intestine". The related disease, chemotherapy drugs, and treatment regimens of SBA form the main research fields, and prognosis and diagnosis are the research hotspots and trends. Conclusion: The global research field in SBA has expanded in the past 100 years. The prognosis and new diagnosis of SBA are hotspots in this field and require further study in the future.

USSC-YOLO: Enhanced Multi-Scale Road Crack Object Detection Algorithm for UAV Image.

Road crack detection is of paramount importance for ensuring vehicular traffic safety, and implementing traditional detection methods for cracks inevitably impedes the optimal functioning of traffic. In light of the above, we propose a USSC-YOLO-based target detection algorithm for unmanned aerial vehicle (UAV) road cracks based on machine vision. The algorithm aims to achieve the high-precision detection of road cracks at all scale levels. Compared with the original YOLOv5s, the main improvements to USSC-YOLO are the ShuffleNet V2 block, the coordinate attention (CA) mechanism, and the Swin Transformer. First, to address the problem of large network computational spending, we replace the backbone network of YOLOv5s with ShuffleNet V2 blocks, reducing computational overhead significantly. Next, to reduce the problems caused by the complex background interference, we introduce the CA attention mechanism into the backbone network, which reduces the missed and false detection rate. Finally, we integrate the Swin Transformer block at the end of the neck to enhance the detection accuracy for small target cracks. Experimental results on our self-constructed UAV near-far scene road crack i(UNFSRCI) dataset demonstrate that our model reduces the giga floating-point operations per second (GFLOPs) compared to YOLOv5s while achieving a 6.3% increase in mAP@50 and a 12% improvement in mAP@ [50:95]. This indicates that the model remains lightweight meanwhile providing excellent detection performance. In future work, we will assess road safety conditions based on these detection results to prioritize maintenance sequences for crack targets and facilitate further intelligent management.

Intracellular Generation of Alkyl Radicals Enabled by a Self-Catalytic ATRP Nanoinitiator.

Oxygen-independent alkyl radicals (R•) have demonstrated great promise in combating tumor hypoxia. Currently, Azo compounds have been the primary source of R•, suffering from external stimuli and decomposition during circulation. Herein, we developed a self-catalytic ATRP nanoinitiator that could generate R• via glutathione (GSH) reduction and thus selectively induce apoptosis of tumor cells. Specifically, a conjugation of laccase (possessing a copper(II) complex) and polymeric alkyl bromide, poly(iBBr), was fabricated to yield an ATRP nanoinitiator (Lac-P(iBBr)). After internalization by cells featured with overexpressed GSH, copper(II) in Lac-P(iBBr) was reduced to copper(I) by GSH, which abstracted the Br atom in poly(iBBr) to yield toxic R•. Moreover, GSH-depletion intensified the oxidative damage caused by R•. Efficient generation of R• by Lac-P(iBBr) could happen in lab flasks, living cells, and tumor-bearing mice without any external stimuli, as demonstrated by the radical product, as well as the consumption of GSH. Moreover, the self-catalytic ATRP nanoinitiator significantly induced cell apoptosis and suppressed tumor growth. Our study expands the chemical toolbox to manipulate cell fates.

Potential drug targets for osteoporosis identified: A Mendelian randomization study.

Background: Osteoporosis is a prevalent global health condition, primarily affecting the aging population, and several therapies for osteoporosis have been widely used. However, available drugs for osteoporosis are far from satisfactory because they cannot alleviate disease progression. This study aimed to explore potential drug targets for osteoporosis through Mendelian randomization analysis. Methods: Using cis-expression quantitative trait loci (cis-eQTL) data of druggable genes and two genome-wide association studies (GWAS) datasets related to osteoporosis (UK Biobank and FinnGen cohorts), we employed mendelian randomization (MR) analysis to identify the druggable genes with causal relationships with osteoporosis. Subsequently, a series of follow-up analyses were conducted, such as colocalization analysis, cell-type specificity analysis, and correlation analysis with risk factors. The association between potential drug targets and osteoporosis was validated by qRT-PCR. Results: Six druggable genes with causal relationships with osteoporosis were identified and successfully replicated, including ACPP, DNASE1L3, IL32, PPOX, ST6GAL1, and TGM3. Cell-type specificity analysis revealed that PPOX and ST6GAL1 were expressed in all cell types in the bone samples, while IL32, ACPP, DNASE1L3, and TGM3 were expressed in specific cell types. The GWAS data showed there were seven risk factors for osteoporosis, including vitamin D deficiency, COPD, physical activity, BMI, MMP-9, ALP and PTH. Furthermore, ACPP was associated with vitamin D deficiency and COPD; DNASE1L3 was linked to physical activity; IL32 correlated with BMI and MMP-9; and ST6GAL1 was related to ALP, physical activity, and MMP-9. Among these risk factors, only MMP-9 had a high genetic correlation with osteoporosis. The results of qRT-PCR demonstrated that IL32 was upregulated while ST6GAL1 was downregulated in peripheral blood of osteoporosis patients. Conclusion: Our findings suggested that those six druggable genes offer potential drug targets for osteoporosis and require further clinical investigation, especially IL32 and ST6GAL1.

Multi-modality MRI radiomics phenotypes in intermediate-high risk endometrial cancer: correlations with histopathology and prognosis.

OBJECTIVES: This study aimed to identify the magnetic resonance imaging (MRI)-based radiomics phenotypes of intermediate-to-high-risk endometrial cancers (ECs), explore their association with histopathologic features, and compare their prognostic ability with the International Federation of Gynecology and Obstetrics (FIGO) stage. METHODS: This study retrospectively recruited 355 patients with pathologically confirmed EC from 01/2016 to 06/2023. 166(46.8%) were classified as intermediate-to-high-risk ECs according to the European Society for Medical Oncology guidelines. Radiomics clustering analysis was performed on preoperative MRI to identify the radiomics phenotype of intermediate-to-high-risk ECs. The association between the radiomics phenotypes and the clinicopathologic information was explored, and the added value in predicting the recurrence was also evaluated using concordance index (C-index). RESULTS: Of the included 166 patients (average age 56.83 ± 9.25 years), 23 were recurrent patients. The corresponding tumors in various clusters were assigned to phenotypes 1 and 2. Larger tumor diameter (P < .01), cervical mucosa invasion [30(36.15%) vs 15(18.07%), P = .01], deep myometrial infiltration [51(61.45%) vs 31(37.35%), P = .00], and histologic subtype [17(20.48%) vs 5(6.02%), P = .01] were associated with subtype 1. The risk of recurrence (P = .01) was higher in phenotype 1, and the FIGO stage could further differentiate higher recurrence risk in phenotype 1 (P < .01). The C-index was 0.66 for the radiomics phenotype model, 0.69 for the FIGO stage model, and 0.72 for the combined model. CONCLUSIONS: MRI-based radiomics consensus clustering enabled the identification of associations between radiomics features and histopathologic features in intermediate-to-high-risk EC. The FIGO stage could further elevate the prediction ability of recurrence risk.

Management strategies and outcomes in pregnancy-related acute aortic dissection: a multicentre cohort study in China.

BACKGROUND: Acute aortic dissection (AD) in pregnancy poses a lethal risk to both mother and fetus. However, well-established therapeutic guidelines are lacking. This study aimed to investigate clinical features, outcomes and optimal management strategies for pregnancy-related AD. METHODS: We conducted a retrospective multicentre cohort study including 67 women with acute AD during pregnancy or within 12 weeks postpartum from three major cardiovascular centres in China between 2003 and 2021. Patient characteristics, management strategies and short-term outcomes were analysed. RESULTS: Median age was 31 years, with AD onset at median 32 weeks gestation. Forty-six patients (68.7%) had type A AD, of which 41 underwent immediate surgery. Overall maternal mortality was 10.4% (7/67) and fetal mortality was 26.9% (18/67). Compared with immediate surgery, selective surgery was associated with higher risk of composite maternal and fetal death (adjusted RR: 12.47 (95% CI 3.26 to 47.73); p=0.0002) and fetal death (adjusted RR: 8.77 (95% CI 2.33 to 33.09); p=0.001). CONCLUSIONS: Immediate aortic surgery should be considered for type A AD at any stage of pregnancy or postpartum. For pregnant women with AD before fetal viability, surgical treatment with the fetus in utero should be considered. Management strategies should account for dissection type, gestational age, and fetal viability. TRIAL REGISTRATION NUMBER: NCT05501145.

Rapid Real-Time PCR Based on Core-Shell Tecto-Dendrimer-Entrapped Au Nanoparticles.

Rapid real-time PCR (generally <1 h) has broad prospects. In this study, we synthesized a new type of nanomaterial core-shell tecto-dendrimer coated with Au nanoparticles (Au CSTDs) for research in this field. The experimental results showed that Au CSTDs could significantly shorten the time of real-time PCR (from 72 to 28 min) with different templates, while the detection limit reached 10 copies and the nonspecific amplification was significantly reduced. Furthermore, experimental analyses and theoretical studies using the finite element simulation method confirmed that Au CSTDs function by synergistically enhancing electrostatic adsorption and thermal conductivity. These properties play a key role in improving real-time PCR, especially in particle-particle interactions. This study contributes an advanced method to rapid real-time PCR, which is expected to remarkably improve the efficiency, lower the detection limit, and enhance the specificity of molecular detection.

Novel perspectives on leptin in osteoarthritis: Focus on aging.

Osteoarthritis (OA) is a common chronic joint disease characterized by articular cartilage degeneration, subchondral sclerosis, synovitis, and osteophyte formation. OA is associated with disability and impaired quality of life, particularly among the elderly. Leptin, a 16-kD non-glycosylated protein encoded by the obese gene, is produced on a systemic and local basis in adipose tissue and the infrapatellar fat pad located in the knee. The metabolic mechanisms employed by leptin in OA development have been widely studied, with attention being paid to aging as a corroborative risk factor for OA. Hence, in this review, we have attempted to establish a potential link between leptin and OA, by focusing on aging-associated mechanisms and proposing leptin as a potential diagnostic and therapeutic target in aging-related mechanisms of OA that may provide fruitful guidance and emphasis for future research.

Interplay Between FoxM1 and Dab2 Promotes Endothelial Cell Responses in Diabetic Wound Healing.

Diabetes mellitus can cause impaired and delayed wound healing, leading to lower extremity amputations; however, the mechanisms underlying the regulation of vascular endothelial growth factor (VEGF)-dependent angiogenesis remain uncertain and could reveal new therapeutic targets. In our study, the molecular underpinnings of endothelial dysfunction in diabetes were investigated, focusing on the roles of Disabled-2 (Dab2) and Forkhead Box M1 (FoxM1) in VEGF receptor 2 (VEGFR2) signaling and endothelial cell (EC) function. Bulk RNA-sequencing analysis identified significant downregulation of Dab2 in high concentrations glucose treated primary mouse skin ECs, simulating hyperglycemic conditions in diabetes mellitus. In diabetic mice with a genetic EC deficiency of Dab2 angiogenesis was reduced in vivo and in vitro when compared with wild-type mice. Restoration of Dab2 expression by injected mRNA-containing lipid nanoparticles rescued impaired angiogenesis and wound healing in diabetic mice. At the same time, FoxM1 was downregulated in skin ECs subjected to high glucose conditions as determined by RNA-sequencing analysis. FoxM1 was found to bind to the Dab2 promoter, regulating its expression and influencing VEGFR2 signaling. The FoxM1 inhibitor FDI-6 reduced Dab2 expression and phosphorylation of VEGFR2. These findings indicate that restoring Dab2 expression through targeted therapies can enhance angiogenesis and wound repair in diabetes. To explore this therapeutic potential, we tested LyP-1-conjugated lipid nanoparticles (LNPs) containing Dab2 or control mRNAs to target ECs and found the former significantly improved wound healing and angiogenesis in diabetic mice. This study provides evidence of the crucial roles of Dab2 and FoxM1 in diabetic endothelial dysfunction and establishes targeted delivery as a promising treatment for diabetic vascular complications.