Search

Abstract As a form of dementia, Alzheimer's disease (AD) suffers from no efficacious cure, yet AD treatment is still imperative, as it ameliorates the symptoms or prevents it from deteriorating or maintains the current status to the longest extent. The human brain is the most sensitive and complex organ in the body, which is protected by the blood–brain barrier (BBB). This yet induces the difficulty in curing AD as the drugs or nanomaterials that are much inhibited from reaching the lesion site. Thus, BBB crossing capability of drug delivery system remains a significant challenge in the development of neurological therapeutics. Fortunately, nano‐enabled delivery systems possess promising potential to achieve multifunctional diagnostics/therapeutics against various targets of AD owing to their intriguing advantages of nanocarriers, including easy multifunctionalization on surfaces, high surface‐to‐volume ratio with large payloads, and potential ability to cross the BBB, making them capable of conquering the limitations of conventional drug candidates. This review, which focuses on the BBB crossing ability of the multifunctional nanomaterials in AD diagnosis and treatment, will provide an insightful vision that is conducive to the development of AD‐related nanomaterials.

Abstract The mechanisms of anxiety disorders, the most common mental illness, remain incompletely characterized. The ventral hippocampus (vHPC) is critical for the expression of anxiety. However, current studies primarily focus on vHPC neurons, leaving the role for vHPC astrocytes in anxiety largely unexplored. Here, genetically encoded Ca2+ indicator GCaMP6m and in vivo fiber photometry calcium imaging are used to label vHPC astrocytes and monitor their activity, respectively, genetic and chemogenetic approaches to inhibit and activate vHPC astrocytes, respectively, patch‐clamp recordings to measure glutamate currents, and behavioral assays to assess anxiety‐like behaviors. It is found that vHPC astrocytic activity is increased in anxiogenic environments and by 3‐d subacute restraint stress (SRS), a well‐validated mouse model of anxiety disorders. Genetic inhibition of vHPC astrocytes exerts anxiolytic effects on both innate and SRS‐induced anxiety‐related behaviors, whereas hM3Dq‐mediated chemogenetic or SRS‐induced activation of vHPC astrocytes enhances anxiety‐like behaviors, which are reversed by intra‐vHPC application of the ionotropic glutamate N‐methyl‐d‐aspartate receptor antagonists. Furthermore, intra‐vHPC or systemic application of the N‐methyl‐d‐aspartate receptor antagonist memantine, a U.S. FDA‐approved drug for Alzheimer's disease, fully rescues SRS‐induced anxiety‐like behaviors. The findings highlight vHPC astrocytes as critical regulators of stress and anxiety and as potential therapeutic targets for anxiety and anxiety‐related disorders.

Abstract Conductive gel interface materials are widely employed as reliable agents for electroencephalogram (EEG) recording. However, prolonged EEG recording poses challenges in maintaining stable and efficient capture due to inevitable evaporation in hydrogels, which restricts sustained high conductivity. This study introduces a novel ion‐electron dual‐mode conductive hydrogel synthesized through a cost‐effective and streamlined process. By embedding graphite nanoparticles into ionic hyaluronic acid (HAGN), the hydrogel maintains higher conductivity for over 72 h, outperforming commercial gels. Additionally, it exhibits superior low skin contact impedance, considerable electrochemical capability, and excellent tensile and adhesion performance in both dry and wet conditions. The biocompatibility of the HAGN hydrogel, verified through in vitro cell viability assays and in vivo skin irritation tests, underscores its suitability for prolonged skin contact without eliciting adverse reactions. Furthermore, in vivo EEG tests confirm the HAGN hydrogel's capability to provide high‐fidelity signal acquisition across multiple EEG protocols. The HAGN hydrogel proves to be an effective interface for prolonged high‐quality EEG recording, facilitating high‐performance capture and classification of evoked potentials, thereby providing a reliable conductive medium for EEG‐based systems.

IntroductionMacranthoidin B (MB) is a primary active component of Flos Lonicerae. In Chinese veterinary clinics, Flos Lonicerae is frequently used in combination with florfenicol to prevent and treat infections in livestock and poultry. However, potential interactions between Flos Lonicerae and florfenicol remain unclear. To systematically study these interactions, it is crucial to investigate the individual phytochemicals within Flos Lonicerae. Therefore, MB was selected for this study to assess its effect on the pharmacokinetics of florfenicol in vivo and to explore the underlying mechanisms involved.MethodsMale Sprague-Dawley rats were administered MB (60 mg/kg BW) or sterile water orally for 7 consecutive days. On the 8th day, a single oral dose of florfenicol (25 mg/kg BW) was given. Florfenicol pharmacokinetics were analyzed using ultra-high performance liquid chromatography. The hepatic expression levels of cytochrome P450 (CYP1A2, CYP2C11, CYP3A1), UDP-glucuronosyltransferase (UGT1A1), P-glycoprotein (P-gp), and nuclear receptors, including constitutive androstane receptor (CAR), pregnane X receptor (PXR), and retinoid X receptor alpha (RXRα), were quantified via reverse transcription-quantitative polymerase chain reaction and Western blotting (WB). Hepatic CYP1A2 and CYP2C11 activities were measured using a cocktail method. Additionally, the subcellular expression and localization of CAR, PXR, and RXRαin hepatocytes was assessed using WB and immunofluorescence staining.ResultsMB significantly reduces the AUC(0-∞) and MRT(0-∞) of florfenicol. MB also markedly upregulates the mRNA and protein expression of hepatic CYP1A2 and CYP2C11, along with their catalytic activities. Substantial upregulation of CAR and PXR proteins occurs in the hepatocyte nucleus, along with significant nuclear colocalization of the transcriptionally active CAR/RXRα and PXR/RXRαheterodimers, indicating MB-induced nuclear translocation of both CAR and PXR.DiscussionThese findings suggest that MB-induced alterations in florfenicol pharmacokinetics, particularly its accelerated elimination, may be due to increased expression and activities of CYP1A2 and CYP2C11, with CAR and PXR potentially involved in these regulatory effects. Further investigation is yet needed to fully elucidate the clinical implications of these interactions concerning the efficacy of florfenicol in veterinary medicine.

Escalated aggression represents a frequent and severe form of violence, sometimes manifesting as antisocial behavior. Driven by the pressures of modern life, escalated aggression is of particular concern due to its rising prevalence and its destructive impact on both individual well-being and socioeconomic stability. However, a consistent neural circuitry underpinning it remains to be definitively identified. Here, we addressed this issue by comparing brain alterations between individuals with escalated aggression and those without such behavioral manifestations. We first conducted a meta-analysis to synthesize previous neuroimaging studies on functional and structural alterations of escalated aggression (325 experiments, 2997 foci, 16,529 subjects). Following-up network and functional decoding analyses were conducted to provide quantitative characterizations of the identified brain regions. Our results revealed that brain regions constantly involved in escalated aggression were localized in the subcortical network (amygdala and lateral orbitofrontal cortex) associated with emotion processing, the default mode network (dorsal medial prefrontal cortex and middle temporal gyrus) associated with mentalizing, and the salience network (anterior cingulate cortex and anterior insula) associated with cognitive control. These findings were further supported by additional meta-analyses on emotion processing, mentalizing, and cognitive control, all of which showed conjunction with the brain regions identified in the escalated aggression. Together, these findings advance the understanding of the risk biomarkers of escalated aggressive populations and refine theoretical models of human aggression.

The large yellow croaker (Larimichthys crocea) displays pronounced behavioral changes in response to low oxygen environments, including restlessness, constant floating, and increases in respiratory rate and tail beat frequency. However, the underlying molecular mechanisms governing these behavioral and physiological alterations remain unclear. To address this knowledge gap, the present study employed transcriptome analysis to investigate the molecular responses in the large yellow croaker muscle tissue after the fish were exposed to hypoxic treatment. A total of 4553, 1797, 3222, 3148, and 4815 differentially expressed genes (DEGs) were identified at 1 h, 6 h, 9 h, 24 h, and 72 h after hypoxia treatment, respectively. Subsequent analysis utilizing Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichments unveiled a notable up-regulation of genes related to muscular movement-related pathways, specifically the calcium pathway. This up-regulation coincided with an observed increase in the intracellular Ca2+ concentration and Ca2+ transport enzyme activity, suggesting that hypoxia-induced muscle contraction and relaxation occurred by elevating the intracellular Ca2+ concentration within the muscle tissue. Key DEGs associated with the glycolysis and the TCA cycle pathways were also found to be significantly increased in expression, indicating an activation of energy generation pathways in the muscle of hypoxic large yellow croakers. Conversely, genes related to protein synthesis and cell growth were significantly down-regulated, suggesting an inhibition of energy-consuming processes. Additionally, hypoxia was observed to impact various physiological processes such as oxygen transport, vascular control, and apoptosis. These processes may have been mediated by the up-regulation of HIF-1α and its target genes. Consequently, these results offer novel insights into comprehending the molecular basis of the changes in behavior and physiology of large yellow croaker in response to the stress induced by low oxygen levels.

The commitment of substantial resources to overseas oil and gas assets signifies a strategic endeavor of considerable scale, implicating consequential impacts on the asset valuation of comprehensive petroleum corporations. Consequently, the adept management of these assets, specifically in terms of profitability, has surfaced as a paramount area of scholarly inquiry within the domain of production and operations management for overseas oil and gas assets. In this context, the formulation of a holistic profit management decision-making framework emerges as a critical fulcrum, pivotal for harnessing and optimizing the overarching benefits of such projects. This study focuses on the formulation of an advanced optimization technique rooted in a “two-step decision-making” paradigm, predicated on a comprehensive set of globally satisfactory solutions. This technique is not merely a methodological innovation but also a strategic tool designed to achieve dual-objective optimization—it is both encompassing and focused. Such a methodological proposition enables a nuanced and refined decision-making process, enhancing the efficacy and strategic alignment of decisions within the ambit of overseas oil and gas asset management. The essence of the proposed technique lies in its capability to provide a robust and versatile decision-making framework, facilitating a balanced and informed decision-making process for stakeholders. By leveraging this approach, decision-makers are endowed with a methodological tool that aids in navigating the complexities inherent in managing overseas oil and gas assets, thereby ensuring that strategic decisions are both informed and aligned with broader organizational objectives. The practical utility of the proposed “two-step decision-making” technique has been substantiated through its application in overseas oil and gas asset management over the recent triennium. Its application has yielded noteworthy outcomes, enhancing the efficiency and production optimization of overseas oil fields and contributing to the high-quality development of these assets. The pronounced effectiveness of this technique in practical scenarios underscores its potential as a strategic tool, offering significant insights and operational advantages that extend beyond the immediate context of its application. Moreover, the implications of this technique are not only confined to the overseas context but also resonate with the operational dynamics of domestic oil companies. By providing a nuanced framework for decision-making and optimization, this technique offers valuable lessons and strategic insights that can be adapted and applied within the domestic oil sector, potentially catalyzing efficiency enhancements and operational optimization. In conclusion, the proposed technique represents a significant methodological advancement in the strategic management of overseas oil and gas assets. Its dual focus on comprehensiveness and specificity, coupled with its proven practical applicability, positions it as a valuable strategic resource, meriting consideration for broader adoption and integration within the strategic frameworks of oil and gas companies operating globally.

Four new fungi from Xizang in southwest China, Calocera ramaria, Ceraceomyces rhizomorphus, Leptosporomyces linzhiensis, and Ramaria xizangensis are described and illustrated based on the morphological and molecular evidence. Calocera ramaria is characterized by the ramal and bright orange basidiomata, a monomitic hyphal system with simple septa generative hyphae, usually 4-septate basidiospores; Ceraceomyces rhizomorphus is characterized by the cream to yellowish basidiomata with rhizomorphs, cylindrical basidiospores; Leptosporomyces linzhiensis is characterized by white with pink basidiomata, cylindrical to oblong ellipsoid basidiospores; Ramaria xizangensis is characterized by flesh pink basidiomata, branched dichotomously in 4–5 ranks, a monomitic hyphal system with clamped generative hyphae, ellipsoid to cylindrical and densely warted basidiospores.

The studies on the batch experiments and transport of 90Sr and 241Am were respectively conducted under unsaturated flow conditions in silty clay column. The results show that the linear correlation coefficient r2 of adsorption and desorption isotherms for 90Sr and 241Am in silty clay medium is greater than 0.9, which indicates that the Freundlich isotherm adsorption model can better describe the adsorption and desorption process of different nuclides in silty clay. The adsorption capacity of strongly adsorbed nuclides 241Am is much greater than that of 90Sr. As for 90Sr, the first-order rate coefficient(named as β) between the dissolved phase and the adsorbed phase was considered in the non-equilibrium adsorption model by transport column. The calculated concentration distribution curve is good agreement with the measured values. The fitting results show that the distribution coefficient(named as Kd) and β of 90Sr in the fine sand aquifer are 3.6 mL/g and 0.55/h. Respectively, in terms of 241Am, the radionuclides concentration distribution curves in equilibrium adsorption model and non-equilibrium adsorption model are in good agreement with the measured values. It shows that the stronger adsorption capacity of the nuclides have the faster rate of the adsorption-desorption in the soil, meanwhile the shorter time for the system reaction equilibrium. At this time, the fitting results of the equilibrium adsorption mode and the non-equilibrium adsorption model are closer to each other. Meanwhile the calculated Kd value by equilibrium adsorption model is 3×103 mL/g.

Abstract An increasing number of Chinese tourists exhibit reluctance in trusting and using Official Tourism Destination Websites (OTDWs). To address this hesitancy, our study developed an integrated framework and structural model based on Hofstede’s cultural values (CV) and perceived administration service power (PASP) to explore methods for enhancing tourists’ trust in OTDWs. This research investigated the impacts of collectivism, low power distance, high context, local distinctiveness, perceived economic management power, perceived tourism management power, perceived benevolence, and perceived integrity on CV and PASP. Structural Equation Modeling (SEM) was employed to analyze questionnaires completed by 324 Chinese tourists with experience in traveling and using OTDWs. The overall fit of our structural model was acceptable, and the Cronbach’s Alpha values indicated adequate reliability. Findings revealed that tourists’ trust in OTDWs is positively and significantly influenced by collectivism, low power distance, high context, and perceived benevolence. Furthermore, CV positively impacts PASP. Consequently, OTDW management departments should give special attention to collectivism, low power distance, high context, and perceived benevolence to enhance tourists’ trust in OTDWs. The study’s results offer valuable insights for tourism destination managers to understand tourists’ preferences and optimize OTDWs.

Abstract In a dynamic financial ecosystem, digitalisation is supporting banks in revamping their business processes to be more efficient, reducing costs, coping with customers’ evolving demands, and keeping them abreast of market competition. This two-stage research aims to investigate three issues in Pakistan’s banking industry from 2006 to 2020: (i) banking efficiency; (ii) the impact of digitalisation on banking efficiency; and (iii) banking efficiency’s absolute and conditional convergence. In our first-stage analysis, bootstrap data envelopment analysis has been applied, which exhibits bias-corrected overall, pure, and scale efficiencies of 74, 77, and 96%, respectively. In the second-stage analysis, we executed Tobit and two-step dynamic panel data system generalised method of moments (DPDSYS-GMM) models, and the results uncover that digitalisation has a positive influence on banking efficiency. Findings confirm that return on assets, bank size, interest rate, and gross domestic product growth rate have a positive association with banking efficiency. Our research reveals that state-controlled banks outperform their private sector and special-purpose counterparts. Our DPDSYS-GMM findings validate β and σ-convergence, implying that initially, low-efficient banks caught up (converged) to the more efficient opponents, reducing cross-sectional efficiency dispersion and attaining common equilibrium. The findings of banking efficiency conditional β-convergence assert that the adoption of digital technology has played a critical role in the convergence process and that digitalisation has acted as a catalyst for less efficient banks to catch up significantly faster to their more efficient rivals. This study displays digitalisation’s disruptive influence on the overall transformation of Pakistan’s banking system in the modern era, resulting in significant efficiency gains.

Abstract Purpose To investigate the effectiveness of problem-based learning (PBL) and case-based learning (CBL) teaching methods in clinical practical teaching in transarterial chemoembolization (TACE) treatment in China. Materials and methods A comprehensive search of PubMed, the Chinese National Knowledge Infrastructure (CNKI) database, the Weipu database and the Wanfang database up to June 2023 was performed to collect studies that evaluate the effectiveness of problem-based learning and case-based learning teaching methods in clinical practical teaching in TACE treatment in China. Statistical analysis was performed by R software (4.2.1) calling JAGS software (4.3.1) in a Bayesian framework using the Markov chain-Monte Carlo method for direct and indirect comparisons. The R packages “gemtc”, “rjags”, “openxlsx”, and “ggplot2” were used for statistical analysis and data output. Results Finally, 7 studies (five RCTs and two observational studies) were included in the meta-analysis. The combination of PBL and CBL showed more effectiveness in clinical thinking capacity, clinical practice capacity, knowledge understanding degree, literature reading ability, method satisfaction degree, learning efficiency, learning interest, practical skills examination scores and theoretical knowledge examination scores. Conclusions Network meta-analysis revealed that the application of PBL combined with the CBL teaching mode in the teaching of liver cancer intervention therapy significantly improves the teaching effect and significantly improves the theoretical and surgical operations, meeting the requirements of clinical education.

Abstract Natural polymer-based hydrogels have demonstrated great potential as wound-healing dressings. They help to maintain a moist wound environment as well as promote faster healing. In this work, a multifunctional hydrogel was prepared using keratin, sodium alginate, and carboxymethyl chitosan with tannic acid modification. Micro-morphology of hydrogels has been performed by scanning electron microscopy. Fourier Transform Infrared Spectroscopy reveals the presence of hydrogen bonding. The mechanical properties of the hydrogels were examined using a universal testing machine. Furthermore, we investigated several properties of the modified hydrogel. These properties include swelling rate, water retention, anti-freezing properties, antimicrobial and antioxidant properties, hemocompatibility evaluation and cell viability test in vitro. The modified hydrogel has a three-dimensional microporous structure, the swelling rate was 1541.7%, the elastic modulus was 589.74 kPa, the toughness was 211.74 kJ/m3, and the elongation at break was 75.39%, which was similar to the human skin modulus. The modified hydrogel also showed inhibition of S. aureus and E. coli, as well as a DPPH scavenging rate of 95%. In addition, the modified hydrogels have good biological characteristics. Based on these findings, the K/SA/CCS hydrogel holds promise for applications in biomedical engineering.

Abstract Biochar can potentially reduce heavy metals (HMs) mobility and bioavailability during composting. However, siderophores secreted by functional microbes might lead to the re-mobilization of metals like Cu and Zn. Therefore, this study intended to explore the impacts of Mikania micrantha Kunth (MM) and MM-derived biochar (MMB) in the reduction of Cu and Zn bioavailability, and siderophore-related gene abundances during composting. Compared with MM and corn straw (CS) composts, a significant decline was noticed in the extractable and reducible Cu [(2.3 mg kg−1 + 12.1 mg kg−1), and (3.3 mg kg−1 + 14.6 mg kg−1)], and Zn [(103.1 mg kg−1 + 110.1 mg kg−1), and (109.6 mg kg−1 + 117.2 mg kg−1)] in MMB and corn straw biochar (CSB) composts, respectively. Besides, the lowest relative abundance of HMs-resistant bacteria particularly Corynebacterium (0.40%), Pseudomonas (0.46%), and Enterobacter (0.47%), was noted in MMB compost. Also, a significant increase in sesquiterpenoid and triterpenoid biosynthesis abundance (5.77%) accompanied by a reduction in the abundance of clusters related to siderophore transport, and siderophore transmembrane transporter activity was detected in MMB compost. Multivariate analysis labeled temperature, moisture content, total organic carbon, Corynebacterium, and Bacillus as the primary factors significantly correlated with the Cu and Zn bioavailability (− 0.90 ≤ r ≤ 0.90, P

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) protect against diabetic cardiovascular diseases and nephropathy. However, their activity in diabetic retinopathy (DR) remains unclear. Our retrospective cohort study involving 1626 T2DM patients revealed superior efficacy of GLP-1 RAs in controlling DR compared to other glucose-lowering medications, suggesting their advantage in DR treatment. By single-cell RNA-sequencing analysis and immunostaining, we observed a high expression of GLP-1R in retinal endothelial cells, which was down-regulated under diabetic conditions. Treatment of GLP-1 RAs significantly restored the receptor expression, resulting in an improvement in retinal degeneration, vascular tortuosity, avascular vessels, and vascular integrity in diabetic mice. GO and GSEA analyses further implicated enhanced mitochondrial gene translation and mitochondrial functions by GLP-1 RAs. Additionally, the treatment attenuated STING signaling activation in retinal endothelial cells, which is typically activated by leaked mitochondrial DNA. Expression of STING mRNA was positively correlated to the levels of angiogenic and inflammatory factors in the endothelial cells of human fibrovascular membranes. Further investigation revealed that the cAMP-responsive element binding protein played a role in the GLP-1R signaling pathway on suppression of STING signaling. This study demonstrates a novel role of GLP-1 RAs in the protection of diabetic retinal vasculature by inhibiting STING-elicited inflammatory signals.

One-third of patients with autoimmune hepatitis (AIH) have cirrhosis at the time of diagnosis. The relevance of these variables, although unknown, is believed to be critical in AIH because of suspected interactions between the gut microbiome and genetic factors. Dysbiosis of the gut flora and elevated polymeric immunoglobulin receptor (pIgR) levels have been observed in both patients and mouse models. Moreover, there is a direct relationship between pIgR expression and transaminase levels in patients with AIH. In this study, we aimed to explore how pIgR influences the secretion of regenerating islet-derived 3 beta (Reg3b) and the flora composition in AIH using in vivo experiments involving patients with AIH and a concanavalin A-induced mouse model of AIH. Reg3b expression was reduced in pIgR gene (Pigr)-knockout mice compared to that in wild-type mice, leading to increased microbiota disruption. Conversely, exogenous pIgR supplementation increased Reg3b expression and maintained microbiota homeostasis. RNA sequencing revealed the participation of the interleukin (IL)-17 signaling pathway in the regulation of Reg3b through pIgR. Furthermore, the introduction of external pIgR could not restore the imbalance in gut microbiota in AIH, and the decrease in Reg3b expression was not apparent following the inhibition of signal transducer and activator of transcription 3 (STAT3). In this study, pIgR facilitated the upregulation of Reg3b via the STAT3 pathway, which plays a crucial role in preserving the balance of the intestinal microbiota in AIH. Through this research, we discovered new molecular targets that can be used for the diagnosis and treatment of AIH.

Abstract Background Early identification of patients at risk of osteopenia is an essential step in reducing the population at risk for fractures. We aimed to develop and validate a prediction model for osteopenia in Chinese middle-aged and elderly men that provides individualized risk estimates. Methods In this prospective cohort study, 1109 patients who attend regular physical examinations in the Second Medical Centre of Chinese PLA General Hospital were enrolled from 2015.03 to 2015.09. The baseline risk factors included dietary habits, exercise habits, medical histories and medication records. Osteopenia during follow-up were collected from Electronic Health Records (EHRs) and telephone interviews. Internal validation was conducted using bootstrapping to correct the optimism. The independent sample T-test analysis, Mann_Whitney U test, Chi-Square Test and multivariable Cox regression analysis were utilized to identify predictive factors for osteopenia in Chinese middle-aged and elderly men. A nomogram based on the seven variables was built for clinical use. Concordance index (C-index), receiver operating characteristic curve (ROC), decision curve analysis (DCA) and calibration curve were used to evaluate the efficiency of the nomogram. Results The risk factors included in the prediction model were bone mineral density at left femoral neck (LNBMD), hemoglobin (Hb), serum albumin (ALB), postprandial blood glucose (PBG), fatty liver disease (FLD), smoking and tea consumption. The C-index for the risk nomogram was 0.773 in the prediction model, which presented good refinement. The AUC of the risk nomogram at different time points ranged from 0.785 to 0.817, exhibiting good predictive ability and performance. In addition, the DCA showed that the nomogram had a good clinical application value. The nomogram calibration curve indicated that the prediction model was consistent. Conclusions Our study provides a novel nomogram and a web calculator that can effectively predict the 7-year incidence risk of osteopenia in Chinese middle-aged and elderly men. It is convenient for clinicians to prevent fragility fractures in the male population.

Abstract Background Diabetic retinopathy (DR) is a major cause of blindness and is characterized by dysfunction of the retinal microvasculature. Neutrophil stasis, resulting in retinal inflammation and the occlusion of retinal microvessels, is a key mechanism driving DR. These plugging neutrophils subsequently release neutrophil extracellular traps (NETs), which further disrupts the retinal vasculature. Nevertheless, the primary catalyst for NETs extrusion in the retinal microenvironment under diabetic conditions remains unidentified. In recent studies, cellular communication network factor 1 (CCN1) has emerged as a central molecule modulating inflammation in pathological settings. Additionally, our previous research has shed light on the pathogenic role of CCN1 in maintaining endothelial integrity. However, the precise role of CCN1 in microvascular occlusion and its potential interaction with neutrophils in diabetic retinopathy have not yet been investigated. Methods We first examined the circulating level of CCN1 and NETs in our study cohort and analyzed related clinical parameters. To further evaluate the effects of CCN1 in vivo, we used recombinant CCN1 protein and CCN1 overexpression for gain-of-function, and CCN1 knockdown for loss-of-function by intravitreal injection in diabetic mice. The underlying mechanisms were further validated on human and mouse primary neutrophils and dHL60 cells. Results We detected increases in CCN1 and neutrophil elastase in the plasma of DR patients and the retinas of diabetic mice. CCN1 gain-of-function in the retina resulted in neutrophil stasis, NETs extrusion, capillary degeneration, and retinal leakage. Pre-treatment with DNase I to reduce NETs effectively eliminated CCN1-induced retinal leakage. Notably, both CCN1 knockdown and DNase I treatment rescued the retinal leakage in the context of diabetes. In vitro, CCN1 promoted adherence, migration, and NETs extrusion of neutrophils. Conclusion In this study, we uncover that CCN1 contributed to retinal inflammation, vessel occlusion and leakage by recruiting neutrophils and triggering NETs extrusion under diabetic conditions. Notably, manipulating CCN1 was able to hold therapeutic promise for the treatment of diabetic retinopathy.

Abstract Background Retinal ischemia/reperfusion (RIR) is implicated in various forms of optic neuropathies, yet effective treatments are lacking. RIR leads to the death of retinal ganglion cells (RGCs) and subsequent vision loss, posing detrimental effects on both physical and mental health. Apigenin (API), derived from a wide range of sources, has been reported to exert protective effects against ischemia/reperfusion injuries in various organs, such as the brain, kidney, myocardium, and liver. In this study, we investigated the protective effect of API and its underlying mechanisms on RGC degeneration induced by retinal ischemia/reperfusion (RIR). Methods An in vivo model was induced by anterior chamber perfusion following intravitreal injection of API one day prior to the procedure. Meanwhile, an in vitro model was established through 1% oxygen and glucose deprivation. The neuroprotective effects of API were evaluated using H&E staining, spectral-domain optical coherence tomography (SD-OCT), Fluoro-Gold retrograde labeling, and Photopic negative response (PhNR). Furthermore, transmission electron microscopy (TEM) was employed to observe mitochondrial crista morphology and integrity. To elucidate the underlying mechanisms of API, the terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay, flow cytometry assay, western blot, cell counting kit-8 (CCK-8) assay, lactate dehydrogenase (LDH) assay, JC-1 kit assay, dichlorofluorescein-diacetate (DCFH-DA) assay, as well as TMRE and Mito-tracker staining were conducted. Results API treatment protected retinal inner plexiform layer (IPL) and ganglion cell complex (GCC), and improved the function of retinal ganglion cells (RGCs). Additionally, API reduced RGC apoptosis and decreased lactate dehydrogenase (LDH) release by upregulating Bcl-2 and Bcl-xL expression, while downregulating Bax and cleaved caspase-3 expression. Furthermore, API increased mitochondrial membrane potential (MMP) and decreased extracellular reactive oxygen species (ROS) production. These effects were achieved by enhancing mitochondrial function, restoring mitochondrial cristae morphology and integrity, and regulating the expression of OPA1, MFN2, and DRP1, thereby regulating mitochondrial dynamics involving fusion and fission. Conclusion API protects RGCs against RIR injury by modulating mitochondrial dynamics, promoting mitochondrial fusion and fission.

Abstract Background There is growing evidence linking the age-adjusted Charlson comorbidity index (aCCI), an assessment tool for multimorbidity, to fragility fracture and fracture-related postoperative complications. However, the role of multimorbidity in osteoporosis has not yet been thoroughly evaluated. We aimed to investigate the association between aCCI and the risk of osteoporosis in older adults at moderate to high risk of falling. Methods A total of 947 men were included from January 2015 to August 2022 in a hospital in Beijing, China. The aCCI was calculated by counting age and each comorbidity according to their weighted scores, and the participants were stratified into two groups by aCCI: low (aCCI