The functional subclasses of AT1 receptor autoantibody in patients with coronary heart disease.

Recently, the identification of autoantibodies (AT1-AA) targeting the second extracellular loop of angiotensin II type 1 receptor (AT1R-ECII) in patients with coronary heart disease (CHD) offers a novel perspective on the interplay between immunity and cardiovascular disease. However, much remains unknown regarding the functional diversity of AT1-AA. In this study, we measured the levels of AT1-AA in the sera of 306 CHD patients and purified AT1-AA from patient's sera (n = 127). The subclasses of AT1-AA were categorized based on their impact on intracellular calcium ([Ca2+]i) levels in mouse arterial smooth muscle cells (MASMCs). Our findings revealed 4 distinct [Ca2+]i response patterns indicating the existence of 4 functional subclasses named H1-, H2-, H3-, and H4-AT1-AA. The correlation analysis demonstrated a positive association between H1-AT1-AA and endogenous coagulation, as well as between H2-AT1-AA and exogenous coagulation; no significant correlation was observed between H3-AT1-AA and the indicators we analyzed. Conversely, H4-AT1-AA exhibited a negative correlation with both leukocyte number and bile acid levels. Logistic regression analysis showed that H2-AT1-AA possessed predictive value for severe CHD. Furthermore, in vitro experiments indicated that both H1- and H2-AT1-AA exerted cytotoxic effects on MASMCs, while H4-AT1-AA increased cell viability. Additionally, an AT1-AA-positive rat model was established by subcutaneously injecting with AT1R-ECII peptide, which produced four similar functional subclasses of rat AT1-AA upon active immunization. This study suggested that classifying different functional subclasses of AT1-AAs can facilitate more accurate evaluation of the condition and prognosis in patients with CHD, thereby providing a novel basis for clinical diagnosis and treatment.

Exploring the effects of short-course antibiotics on children's gut microbiota by using 16S rRNA gene sequencing: a case-control study.

BACKGROUND: With the widespread use of antibiotics, more attention has been paid to their side effects. We paid extra attention to the impact of antibiotics on children's bodies. Therefore, we analyzed the characteristic changes in the gut microbiota of children after antibiotic treatment to explore the pathogenesis of antibiotic-associated diseases in more depth and to provide a basis for diagnosis and treatment. METHODS: We recruited 28 children with bronchopneumonia in the western district of Zhuhai, China, and divided them into three treatment groups based on antibiotic type. We took stool samples from children before and 3-5 days after antibiotic treatment. 16S rRNA gene sequencing was used to analyze the effects of antibiotic therapy on the gut microbiota of children. Continuous nonparametric data are represented as median values and analyzed using the Wilcoxon rank-sum test. RESULTS: While alpha diversity analysis found no significant changes in the mean abundance of the gut microbiota of children after a short course of antibiotic treatment, beta diversity analysis demonstrated significant changes in the composition and diversity of the gut microbiota of children even after a short course of antibiotic therapy. We also found that meloxicillin sulbactam can inhibit the growth of Proteobacteria, Bacteroidetes, and Verrucomicrobia, ceftriaxone inhibits Verrucomicrobia and Bacteroides, and azithromycin inhibits Fusobacteria, Actinobacteria, Proteobacteria, and Verrucomicrobia. We further performed a comparative analysis at the genus level and found significantly different clusters in each group. Finally, we found that azithromycin had the greatest effect on the metabolic function of intestinal microbiota, followed by ceftriaxone, and no significant change in the metabolic process of intestinal microbiota after meloxicillin sulbactam treatment. CONCLUSIONS: Antibiotic treatment significantly affects the diversity of intestinal microbiota in children, even after a short course of antibiotic treatment. Different classes of antibiotics affect diverse microbiota primarily, leading to varying alterations in metabolic function. Meanwhile, we identified a series of intestinal microbiota that differed significantly after antibiotic treatment. These groups of microbiota could be used as biomarkers to provide an additional basis for diagnosing and treating antibiotic-associated diseases.

Recent progress and new insights on semiconductor heterojunctions powered photocatalytic desulphurization: A review.

Desulphurization of fossil fuels is a critical process in reducing the sulphur content from environment, which is a major contributor to atmospheric pollution. Traditional desulphurization techniques, while effective, often involve high energy consumption and the use of harsh chemicals. Recently, photocatalytic desulphurization has emerged as a promising, eco-friendly alternative, leveraging the potential of photocatalysts especially semiconductor heterojunctions to enhance photocatalytic efficiency. This review comprehensively discusses the significance and mechanism of photocatalytic desulphurization reactions, designing of various heterojunctions such as conventional, p-n, Z-scheme and S-scheme, their charge transfer mechanism and properties and their contribution to the photocatalytic desulphurization activity. Heterojunctions, formed by combining different semiconductor materials, facilitate efficient charge separation and broaden the light absorption range, thereby improving the photocatalytic performance under visible light. Furthermore, the recent advancements in the heterojunction systems in the field of photocatalytic desulphurization activity have been discussed in detail and summarized. The current limitations and challenges in this particular field are also explored. The paper concludes with an outlook on future research directions and the potential industrial applications of heterojunction-powered photocatalytic desulphurization, emphasizing its role in achieving cleaner energy production and environmental sustainability.

Endothelial metabolic control of insulin sensitivity through resident macrophages.

Endothelial cells (ECs) not only form passive blood conduits but actively contribute to nutrient transport and organ homeostasis. The role of ECs in glucose homeostasis is, however, poorly understood. Here, we show that, in skeletal muscle, endothelial glucose transporter 1 (Glut1/Slc2a1) controls glucose uptake via vascular metabolic control of muscle-resident macrophages without affecting transendothelial glucose transport. Lowering endothelial Glut1 via genetic depletion (Glut1ΔEC) or upon a short-term high-fat diet increased angiocrine osteopontin (OPN/Spp1) secretion. This promoted resident muscle macrophage activation and proliferation, which impaired muscle insulin sensitivity. Consequently, co-deleting Spp1 from ECs prevented macrophage accumulation and improved insulin sensitivity in Glut1ΔEC mice. Mechanistically, Glut1-dependent endothelial glucose metabolic rewiring increased OPN in a serine metabolism-dependent fashion. Our data illustrate how the glycolytic endothelium creates a microenvironment that controls resident muscle macrophage phenotype and function and directly links resident muscle macrophages to the maintenance of muscle glucose homeostasis.

Chromosome 1q21 Aberrations Are Poor Prognostic Factors for Newly Diagnosed Multiple Myeloma Patients.

BACKGROUND: Chromosome 1q21 aberrations are one of the most common cytogenetic abnormalities in patients with multiple myeloma (MM). However, the prognostic value remains controversial. This study aimed to determine the prognostic value of numerical abnormalities of chromosome 1q21 for newly diagnosed patients with MM patients in Chinese population. METHODS: We retrospectively analyzed 629 patients with newly diagnosed MM who received the detection of chromosome 1q21 by fluorescence in situ hybridization in China. RESULTS: Among 629 patients, 309 (49.1%) had 1q21 abnormalities, of which 187 (29.7%) had three copies and 122 (19.4%) had four or more copies. Patients with two copies of 1q21 had a significantly longer median overall survival (OS) than those with three copies or ≥4 copies and also had longer progression-free survival (PFS). However, patients with three or ≥4 copies had similar OS and PFS. Univariate Cox proportional hazards regression analyses determined that 1q21 aberrations are associated with shorter OS and PFS. 1q21 aberrations are also independent poor prognostic factors for OS and PFS in multivariable analyses. Del(17p), t(4;14), and t(14;16) are common high-risk cytogenetic abnormalities (HRCAs) in patients with MM. Patients with 1q21+ alone or 1q21+ combined with HRCAs had shorter OS and PFS than patients without cytogenetic abnormalities. Patients with 1q21+ and t(11;14) also had shorter PFS but had similar OS than patients without cytogenetic abnormalities. CONCLUSION: Our study showed that chromosome 1q21 aberrations are poor prognostic factors for newly diagnosed patients with MM.

Adsorption characteristics and mechanisms of bisphenol A on novel nitrogen-modified biochar derived from waste masks and biomass.

Resource utilization of waste masks has become an urgent scientific issue. In this work, with sustainably, waste masks and biomass were co-pyrolysis with oxygen limitation to prepare mask-based biochar (MB). Then, urea was introduced to prepare novel nitrogen modified mask-based biochar (NMB) via a one-step hydrothermal synthesis method. The adsorption characteristics of NMB on the emerging environmental pollutant, bisphenol A (BPA), were evaluated via batch adsorption tests. Moreover, the physicochemical properties of the materials were characterized with various advanced techniques. Also, the roles of waste masks and nitrogen modification were explored. The adsorption mechanisms of NMB on BPA were revealed as well as the performance differences between different adsorbents. The results showed that waste masks participated in thermochemical reactions, shaped the microsphere structure of biochar, and increased the types of surface functional groups. The nitrogen modification enriched the surface elemental composition and activated the specific surface area via the mesopore. These would enhance the adsorption performance. The maximum adsorption of BPA by NMB was 62.63 mg·g-1, which was approximately 2.35-5.58 times higher than that of the control materials. Temkin model and pseudo-second-order model optimally simulate the isothermal and kinetic adsorption, respectively. The adsorption mechanisms are jointly by physical and chemical adsorption, which mainly includes π-π interaction, hydrogen bonding, intraparticle diffusion, surface adsorption, and ion exchange. After discussion and evaluation, NMB has lower preparation process cost (7.21 USD·kg-1) and safety, with potential for environmental applications. This study aims to expand new ideas for the comprehensive utilization of waste masks and the preparation of eco-friendly materials. Moreover, it provides a theoretical basis for the removal of BPA.

The Synthesis and Properties of Spirophenanthrene.

Motivated by the success of 9,9'-spirobifluorene (SBF) in optoelectronic materials, we synthesized a novel spiro compound, spirophenanthrene (SP). Incorporating a phenanthrene unit as the core, we aimed to leverage the π-conjugation of SPs to surpass the limitations of SBF. Experimental and theoretical studies revealed significant advantages over SBF, including red-shifted wavelengths, tunable LUMO energy levels, and enhanced thermal stability. These advantages suggest the potential of SPs as versatile building blocks for diverse optoelectronic devices.

A novel sustainable photo/chemical magnetic nanomaterial effectively mitigates the allergenicity of phospholipase A2.

Reducing the allergenicity of edible insects is crucial for the comprehensive utilization of insect resources. Phospholipase A2 (PLA2) exists in various edible insects and mammalian tissues, which can cause serious allergic reactions. Herein, we constructed a magnetic nanocomposite with photo/chemical synergistic capability to mitigate the allergenicity of PLA2. The formation of prepared nanocomposite was systematically confirmed using various techniques. The nanocomposite exhibited uniform diameters, abundant functional groups, excellent magnetic capabilities. An effective photo/chemical method was established to reduce the allergenicity of PLA2 in vitro. The feasibility of the method was demonstrated through circular dichroism, fluorescence spectrum and IgE-binding analysis. The allergenicity and IgE-binding effect of PLA2 were significantly reduced due to conformational changes after nanomaterial treatment. These results demonstrate the sensitivity and effectiveness a strategy for reducing PLA2 allergenicity, providing a basis for development of nanomaterials to reduce the risk of novel food allergies in response to edible insect products.

Bioactive Compounds and Probiotics Mitigate Mastitis by Targeting NF-κB Signaling Pathway.

Mastitis is a significant inflammatory condition of the mammary gland in dairy cows. It is caused by bacterial infections and leads to substantial economic losses worldwide. The disease can be either clinical or sub-clinical and presents challenges such as reduced milk yield, increased treatment costs, and the need to cull affected cows. The pathogenic mechanisms of mastitis involve the activation of Toll-like receptors (TLRs), specifically TLR2 and TLR4. These receptors play crucial roles in recognizing pathogen-associated molecular patterns (PAMPs) and initiating immune responses through the NF-κB signaling pathway. Recent in vitro studies have emphasized the importance of the TLR2/TLR4/NF-κB signaling pathway in the development of mastitis, suggesting its potential as a therapeutic target. This review summarizes recent research on the role of the TLR2/TLR4/NF-κB signaling pathway in mastitis. It focuses on how the activation of TLRs leads to the production of proinflammatory cytokines, which, in turn, exacerbate the inflammatory response by activating the NF-κB signaling pathway in mammary gland tissues. Additionally, the review discusses various bioactive compounds and probiotics that have been identified as potential therapeutic agents for preventing and treating mastitis by targeting TLR2/TLR4/NF-κB signaling pathway. Overall, this review highlights the significance of targeting the TLR2/TLR4/NF-κB signaling pathway to develop effective therapeutic strategies against mastitis, which can enhance dairy cow health and reduce economic losses in the dairy industry.

Association between longitudinal biomarkers and major adverse liver outcomes in patients with non-cirrhotic metabolic dysfunction-associated steatotic liver disease.

BACKGROUND AND AIMS: Noninvasive biomarkers provide prognostic information for the development of major adverse liver outcomes (MALOs) in patients with metabolic dysfunction-associated steatotic liver disease (MASLD), but the predictive value of longitudinal biomarker measurements has not been evaluated. We assessed whether changes in biomarkers could predict incident MALO in MASLD. APPROACH AND RESULTS: We analyzed a cohort of 1260 patients (71.7% on biopsy) with non-cirrhotic MASLD between 1974 and 2019. Data at baseline and follow-up visits were obtained from medical charts. MALO was determined through medical charts and linkage to national registers until the end of 2020. A joint modeling approach was used to quantify the associations between the trajectory of biomarkers and the risk of MALO. MASLD was diagnosed at a median age of 52 years (IQR: 39-60), and 59% were male. During a median follow-up of 12.2 years, 111 (8.8%) patients developed MALO. The joint modeling showed that an elevated fibrosis-4 score (HR: 2.60, 95% CI: 1.89-3.50), aspartate aminotransferase (HR: 2.69, 95% CI: 2.57-3.05), and lower platelet count (HR: 0.93, 95% CI: 0.90-0.97) at any time point were associated with an increased risk of MALO, whereas the rate of change in these biomarkers had no association with this risk. CONCLUSIONS: In addition to baseline measurements of noninvasive biomarkers such as fibrosis-4 score, aspartate aminotransferase, and platelets taken at MASLD diagnosis, monitoring their values over time is important, as the latest value of these biomarkers is closely associated with the risk of future MALO. The rate of change may not be as important.

Synthesis of N-N Axially Chiral Pyrrolyl-oxoisoindolin via Isothiourea-Catalyzed Acylative Dynamic Kinetic Resolution.

The development of methods for the asymmetric synthesis of N-N axial chirality remains elusive and challenging. Here, we disclose a method for the construction of N-N axially chiral pyrrolyl-oxoisoindolins along with central chirality via the isothiourea (ITU)-catalyzed acylative dynamic kinetic resolution (DKR). Axial chirality was introduced into the acylative DKR of hemiaminals for the first time. This protocol features mild conditions with excellent yields and enantioselectivities.

An Overview of Infectious and Non-Infectious Causes of Pregnancy Losses in Equine.

Equine breeding plays an essential role in the local economic development of many countries, and it has experienced rapid growth in China in recent years. However, the equine industry, particularly large-scale donkey farms, faces a significant challenge with pregnancy losses. Unfortunately, there is a lack of systematic research on abortion during equine breeding. Several causes, both infectious and non-infectious, of pregnancy losses have been documented in equines. The infectious causes are viruses, bacteria, parasites, and fungi. Non-infectious causes may include long transportation, ingestion of mycotoxins, hormonal disturbances, twinning, placentitis, umbilical length and torsion, etc. In current review, we discuss the transmission routes, diagnostic methods, and control measures for these infectious agents. Early detection of the cause and appropriate management are crucial in preventing pregnancy loss in equine practice. This review aims to provide a comprehensive understanding of the potential causes of abortion in equines, including infectious agents and non-infectious factors. It emphasizes the importance of continued research and effective control measures to address this significant challenge in the equine industry.

Single-nucleus transcriptomics identifies separate classes of UCP1 and futile cycle adipocytes.

Adipose tissue can recruit catabolic adipocytes that utilize chemical energy to dissipate heat. This process occurs either by uncoupled respiration through uncoupling protein 1 (UCP1) or by utilizing ATP-dependent futile cycles (FCs). However, it remains unclear how these pathways coexist since both processes rely on the mitochondrial membrane potential. Utilizing single-nucleus RNA sequencing to deconvolute the heterogeneity of subcutaneous adipose tissue in mice and humans, we identify at least 2 distinct subpopulations of beige adipocytes: FC-adipocytes and UCP1-beige adipocytes. Importantly, we demonstrate that the FC-adipocyte subpopulation is highly metabolically active and utilizes FCs to dissipate energy, thus contributing to thermogenesis independent of Ucp1. Furthermore, FC-adipocytes are important drivers of systemic energy homeostasis and linked to glucose metabolism and obesity resistance in humans. Taken together, our findings identify a noncanonical thermogenic adipocyte subpopulation, which could be an important regulator of energy homeostasis in mammals.

Development of a functional beige fat cell line uncovers independent subclasses of cells expressing UCP1 and the futile creatine cycle.

Although uncoupling protein 1 (UCP1) is established as a major contributor to adipose thermogenesis, recent data have illustrated an important role for alternative pathways, particularly the futile creatine cycle (FCC). How these pathways co-exist in cells and tissues has not been explored. Beige cell adipogenesis occurs in vivo but has been difficult to model in vitro; here, we describe the development of a murine beige cell line that executes a robust respiratory response, including uncoupled respiration and the FCC. The key FCC enzyme, tissue-nonspecific alkaline phosphatase (TNAP), is localized almost exclusively to mitochondria in these cells. Surprisingly, single-cell cloning from this cell line shows that cells with the highest levels of UCP1 express little TNAP, and cells with the highest expression of TNAP express little UCP1. Immunofluorescence analysis of subcutaneous fat from cold-exposed mice confirms that the highest levels of these critical thermogenic components are expressed in distinct fat cell populations.

Blebbistatin as a novel antiviral agent targeting equid herpesvirus type 8.

Introduction: Equid herpesvirus type 8 (EqHV-8) poses a significant threat to equine health, leading to miscarriages and respiratory diseases in horses and donkeys, and results in substantial economic losses in the donkey industry. Currently, there are no effective drugs or vaccines available for EqHV-8 infection control. Methods: In this study, we investigated the in vitro and in vivo antiviral efficacy of Blebbistatin, a myosin II ATPase inhibitor, against EqHV-8. Results: Our results demonstrated that Blebbistatin significantly inhibited EqHV-8 infection in Rabbit kidney (RK-13) and Madin-Darby Bovine Kidney (MDBK) cells in a concentration-dependent manner. Notably, Blebbistatin was found to disrupt EqHV-8 infection at the entry stage by modulating myosin II ATPase activity. Moreover, in vivo experiments revealed that Blebbistatin effectively reduced EqHV-8 replication and mitigated lung pathology in a mouse model. Conclusion: Collectively, these findings suggest that Blebbistatin holds considerable potential as an antiviral agent for the control of EqHV-8 infection, presenting a novel approach to addressing this veterinary challenge.

Amplifying colorectal cancer progression: impact of a PDIA4/SP1 positive feedback loop by circPDIA4 sponging miR-9-5p.

OBJECTIVE: Colorectal cancer (CRC) is a prevalent malignant tumor with a high fatality rate. CircPDIA4 has been shown to have a vital role in cancer development by acting as a facilitator. Nevertheless, the impact of the circPDIA4/miR-9-5p/SP1 axis on development of CRC has not been studied. METHODS: Western blot, immunohistochemistry, and reverse transcription-quantitative polymerase chain reaction assays were used to analyze gene expression. The CCK-8 assay was used to assess cell growth. The Transwell assay was used to detect invasion and migration of cells. The luciferase reporter and RNA immunoprecipitation tests were used to determine if miR-9-5p and circPDIA4 (or SP1) bind to one another. An in vivo assay was used to measure tumor growth. RESULTS: It was shown that circPDIA4 expression was greater in CRC cell lines and tissues than healthy cell lines and tissues. CircPDIA4 knockdown prevented the invasion, migration, and proliferation of cells in CRC. Additionally, the combination of circPDIA4 and miR-9-5p was confirmed, as well as miR-9-5p binding to SP1. Rescue experiments also showed that the circPDIA4/miR-9-5p/SP1 axis accelerated the development of CRC. In addition, SP1 combined with the promoter region of circPDIA4 and induced circPDIA4 transcription. CircPDIA4 was shown to facilitate tumor growth in an in vivo assay. CONCLUSIONS: The circPDIA4/miR-9-5p/SP1 feedback loop was shown to aggravate CRC progression. This finding suggests that the ceRNA axis may be a promising biomarker for CRC patient treatment.

Astrocyte-derived CHI3L1 signaling impairs neurogenesis and cognition in the demyelinated hippocampus.

Cognitive dysfunction is a feature in multiple sclerosis (MS), a chronic inflammatory demyelinating disorder. A notable aspect of MS brains is hippocampal demyelination, which is closely associated with cognitive decline. However, the mechanisms underlying this phenomenon remain unclear. Chitinase-3-like (CHI3L1), secreted by activated astrocytes, has been identified as a biomarker for MS progression. Our study investigates CHI3L1's function within the demyelinating hippocampus and demonstrates a correlation between CHI3L1 expression and cognitive impairment in patients with MS. Activated astrocytes release CHI3L1 in reaction to induced demyelination, which adversely affects the proliferation and differentiation of neural stem cells and impairs dendritic growth, complexity, and spine formation in neurons. Our findings indicate that the astrocytic deletion of CHI3L1 can mitigate neurogenic deficits and cognitive dysfunction. We showed that CHI3L1 interacts with CRTH2/receptor for advanced glycation end (RAGE) by attenuating ß-catenin signaling. The reactivation of ß-catenin signaling can revitalize neurogenesis, which holds promise for therapy of inflammatory demyelination.

Rutin prevents EqHV-8 induced infection and oxidative stress via Nrf2/HO-1 signaling pathway.

Introduction: The Nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) signaling pathway has been extensively studied for its role in regulating antioxidant and antiviral responses. The Equid herpesvirus type 8 (EqHV-8) poses a significant threat to the equine industry, primarily manifesting as respiratory disease, abortions, and neurological disorders in horses and donkeys. Oxidative stress is considered a key factor associated with pathogenesis of EqHV-8 infection. Unfortunately, there is currently a dearth of therapeutic interventions available for the effective control of EqHV-8. Rutin has been well documented for its antioxidant and antiviral potential. In current study we focused on the evaluation of Rutin as a potential therapeutic agent against EqHV-8 infection. Methods: For this purpose, we encompassed both in-vitro and in-vivo investigations to assess the effectiveness of Rutin in combatting EqHV-8 infection. Results and Discussion: The results obtained from in vitro experiments demonstrated that Rutin exerted a pronounced inhibitory effect on EqHV-8 at multiple stages of the viral life cycle. Through meticulous experimentation, we elucidated that Rutin's antiviral action against EqHV-8 is intricately linked to the Nrf2/HO-1 signaling pathway-mediated antioxidant response. Activation of this pathway by Rutin was found to significantly impede EqHV-8 replication, thereby diminishing the viral load. This mechanistic insight not only enhances our understanding of the antiviral potential of Rutin but also highlights the significance of antioxidant stress responses in combating EqHV-8 infection. To complement our in vitro findings, we conducted in vivo studies employing a mouse model. These experiments revealed that Rutin administration resulted in a substantial reduction in EqHV-8 infection within the lungs of the mice, underscoring the compound's therapeutic promise in vivo. Conclusion: In summation, our finding showed that Rutin holds promise as a novel and effective therapeutic agent for the prevention and control of EqHV-8 infections.

Immunoglobulin Superfamily Containing Leucine-Rich Repeat (ISLR) Serves as a Redox Sensor That Modulates Antioxidant Capacity by Suppressing Pyruvate Kinase Isozyme M2 Activity.

Cells defend against oxidative stress by enhancing antioxidant capacity, including stress-activated metabolic alterations, but the underlying intracellular signaling mechanisms remain unclear. This paper reports that immunoglobulin superfamily containing leucine-rich repeat (ISLR) functions as a redox sensor that responds to reactive oxygen species (ROS) stimulation and modulates the antioxidant capacity by suppressing pyruvate kinase isozyme M2 (PKM2) activity. Following oxidative stress, ISLR perceives ROS stimulation through its cysteine residue 19, and rapidly degrades in the autophagy-lysosome pathway. The downregulated ISLR enhances the antioxidant capacity by promoting the tetramerization of PKM2, and then enhancing the pyruvate kinase activity, PKM2-mediated glycolysis is crucial to the ISLR-mediated antioxidant capacity. In addition, our results demonstrated that, in triple-negative breast cancer, cisplatin treatment reduced the level of ISLR, and PKM2 inhibition sensitizes tumors to cisplatin by enhancing ROS production; and argued that PKM2 inhibition can synergize with cisplatin to limit tumor growth. Our results demonstrate a molecular mechanism by which cells respond to oxidative stress and modulate the redox balance.

Cellular communication network factor 1 promotes retinal leakage in diabetic retinopathy via inducing neutrophil stasis and neutrophil extracellular traps extrusion.

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.