The PTM profiling of CTCF reveals the regulation of 3D chromatin structure by O-GlcNAcylation.

CCCTC-binding factor (CTCF), a ubiquitously expressed and highly conserved protein, is known to play a critical role in chromatin structure. Post-translational modifications (PTMs) diversify the functions of protein to regulate numerous cellular processes. However, the effects of PTMs on the genome-wide binding of CTCF and the organization of three-dimensional (3D) chromatin structure have not been fully understood. In this study, we uncovered the PTM profiling of CTCF and demonstrated that CTCF can be O-GlcNAcylated and arginine methylated. Functionally, we demonstrated that O-GlcNAcylation inhibits CTCF binding to chromatin. Meanwhile, deficiency of CTCF O-GlcNAcylation results in the disruption of loop domains and the alteration of chromatin loops associated with cellular development. Furthermore, the deficiency of CTCF O-GlcNAcylation increases the expression of developmental genes and negatively regulates maintenance and establishment of stem cell pluripotency. In conclusion, these results provide key insights into the role of PTMs for the 3D chromatin structure.

Nod-like receptor protein 3 inflammasome-mediated pyroptosis contributes to chronic NaAsO2 exposure-induced fibrotic changes and dysfunction in the liver of SD rats.

The metalloid arsenic, known for its toxic properties, is widespread presence in the environment. Our previous research has confirmed that prolonged exposure to arsenic can lead to liver fibrosis injury in rats, while the precise pathogenic mechanism still requires further investigation. In the past few years, the Nod-like receptor protein 3 (NLRP3) inflammasome has been found to play a pivotal role in the occurrence and development of liver injury. In this study, we administered varying doses of sodium arsenite (NaAsO2) and 10 mg/kg.bw MCC950 (a particular tiny molecular inhibitor targeting NLRP3) to Sprague-Dawley (SD) rats for 36 weeks to explore the involvement of NLRP3 inflammasome in NaAsO2-induced liver injury. The findings suggested that prolonged exposure to NaAsO2 resulted in pyroptosis in liver tissue of SD rats, accompanied by the fibrotic injury, extracellular matrix (ECM) deposition and liver dysfunction. Moreover, long-term NaAsO2 exposure activated NLRP3 inflammasome, leading to the release of pro-inflammatory cytokines in liver tissue. After treatment with MCC950, the induction of NLRP3-mediated pyroptosis and release of pro-inflammatory cytokines were significantly attenuated, leading to a decrease in the severity of liver fibrosis and an improvement in liver function. To summarize, those results clearly indicate that hepatic fibrosis and liver dysfunction induced by NaAsO2 occur through the activation of NLRP3 inflammasome-mediated pyroptosis, shedding new light on the potential mechanisms underlying arsenic-induced liver damage.

Machine Learning Exploration of the Relationship Between Drugs and the Blood-Brain Barrier: Guiding Molecular Modification.

OBJECTIVE: This study aimed to improve the efficiency of pharmacotherapy for CNS diseases by optimizing the ability of drug molecules to penetrate the Blood-Brain Barrier (BBB). METHODS: We established qualitative and quantitative databases of the ADME properties of drugs and derived characteristic features of compounds with efficient BBB penetration. Using these insights, we developed four machine learning models to predict a drug's BBB permeability by assessing ADME properties and molecular topology. We then validated the models using the B3DB database. For acyclovir and ceftriaxone, we modified the Hydrogen Bond Donors and Acceptors, and evaluated the BBB permeability using the predictive model. RESULTS: The machine learning models performed well in predicting BBB permeability on both internal and external validation sets. Reducing the number of Hydrogen Bond Donors and Acceptors generally improves BBB permeability. Modification only enhanced BBB penetration in the case of acyclovir and not ceftriaxone. CONCLUSIONS: The machine learning models developed can accurately predict BBB permeability, and many drug molecules are likely to have increased BBB penetration if the number of Hydrogen Bond Donors and Acceptors are reduced. These findings suggest that molecular modifications can enhance the efficacy of CNS drugs and provide practical strategies for drug design and development. This is particularly relevant for improving drug penetration of the BBB.

Construction of An Oral Bioavailability Prediction Model Based on Machine Learning for Evaluating Molecular Modifications.

OBJECTIVE: This study aims to explore the impact of ADME on the Oral Bioavailability (OB) of drugs and to construct a machine learning model for OB prediction. The model is then applied to predict the OB of modified berberine and atenolol molecules to obtain structures with higher OB. METHODS: Initially, a drug OB database was established, and corresponding ADME characteristics were obtained. The relationship between ADME and OB was analyzed using machine learning, with Morgan fingerprints serving as molecular descriptors. Compounds from the database were input into Random Forest, XGBoost, CatBoost, and LightGBM machine learning models to train the OB 7prediction model and evaluate its performance. Subsequently, berberine and atenolol were modified using Chemdraw software with ten different substituents for mono-substitution, and chlorine atoms for a full range of double substitutions. The modified molecular structures were converted into the same format as the training set for OB prediction. The predicted OB values of the modified structures of berberine and atenolol were compared. RESULTS: An OB database of 386 drugs was obtained. It was found that smaller molecular weight and a higher number of rotatable bonds (ten or less) could potentially lead to higher OB. The four machine learning models were evaluated using MSE, R2 score, MAE, and MFE as metrics, with Random Forest performing the best. The models' predictions for the test set were particularly accurate when OB ranged from 30% to 90%. After mono-substitution and double substitution of berberine and atenolol, the OB of both drugs was significantly improved. CONCLUSIONS: This study found that some ADME properties of molecules do not have an absolute impact on OB. The database played a decisive role in the process of the machine learning OB prediction model, and the performance of the model was evaluated based on predictions within a range of strong generalization ability. In most cases, mono-substitution and double substitution were beneficial for enhancing the OB of berberine and atenolol. In summary, this study successfully constructed a machine learning regression prediction model that can accurately predict drug OB, which can guide drug design to achieve higher OB to some extent.

The impact of Lactococcus lactis KUST48 on the transcription profile of Aeromonas hydrophila-infected zebrafish spleen.

Aeromonas hydrophila, an aquatic pathogenic bacterium, has been found to infect many fish species and cause huge aquaculture losses. Antibiotics are the most common drugs used to treat these infections. However, antibiotic abuse can lead to the development of antibiotic resistance. Probiotics have the potential to replace antibiotics for preventing infections. Zebrafish (Danio rerio) is a model organism used to study the innate immune system and host-pathogen interactions. Currently, there is little information on how the fish immune system responds to A. hydrophila and probiotic treatment. To increase the understanding of the molecular mechanisms behind the zebrafish defense against A. hydrophila and provide evidence that antibiotics can be replaced by probiotics, a transcriptome analysis of the zebrafish spleen was conducted 48 hours after infection by A. hydrophila, as well as after treatment using Lactococcus lactis KUST48 4 hours after infection. A total of 36,499 genes were obtained. There were 3,337 genes found to have significant differential expression between treatment and control groups. According to further annotation and enrichment analysis, differentially expressed genes (DEGs) were involved in signal transduction, endocrine system cancer, and the immune system. Insulin resistance disappeared in the zebrafish after treatment. Quantitative real-time PCR was performed to confirm the significant regulation of immune defense DEGs, the results of which were consistent with the RNA-sequencing data. These results could serve as a basis for future studies on the immune response to A. hydrophila and provide suggestions for probiotic alternatives to antibiotics, which will be of great significance to aquaculture and environmental protection.IMPORTANCEIn recent years, the unreasonable use of antibiotics has led to the emergence of drug-resistant pathogenic bacteria, antibiotic residues, cross infection, toxic side effects, and so on, which has caused a serious threat to human food safety and life health. In recent years, many studies have demonstrated the potential of probiotics as a substitute for antibiotics, but there is still a lack of understanding of the molecular mechanisms underlying probiotic therapy. We conduct a research on the impact of Lactococcus lactis KUST48 on the transcription profile of Aeromonas hydrophila-infected zebrafish spleen. Mortality of zebrafish infected with A. hydrophila was significantly reduced after treatment with L. lactis KUST48. Our results can help to strengthen our understanding of the pathogenic mechanisms of zebrafish and provide a valuable reference for the molecular mechanisms of probiotic therapy.

Precise prediction of phase-separation key residues by machine learning.

Understanding intracellular phase separation is crucial for deciphering transcriptional control, cell fate transitions, and disease mechanisms. However, the key residues, which impact phase separation the most for protein phase separation function have remained elusive. We develop PSPHunter, which can precisely predict these key residues based on machine learning scheme. In vivo and in vitro validations demonstrate that truncating just 6 key residues in GATA3 disrupts phase separation, enhancing tumor cell migration and inhibiting growth. Glycine and its motifs are enriched in spacer and key residues, as revealed by our comprehensive analysis. PSPHunter identifies nearly 80% of disease-associated phase-separating proteins, with frequent mutated pathological residues like glycine and proline often residing in these key residues. PSPHunter thus emerges as a crucial tool to uncover key residues, facilitating insights into phase separation mechanisms governing transcriptional control, cell fate transitions, and disease development.

A primary pulmonary artery sarcoma masquerading pulmonary embolism: a case report and literature review.

BACKGROUND: Primary pulmonary artery sarcoma (PAS) is an extremely rare malignant tumor with a poor prognosis. The clinical manifestations of PAS are diverse, including dyspnea, chest pain, cough, and hemoptysis. The poor prognosis is often due to delayed diagnosis caused by similarity in imaging findings with pulmonary thromboembolism (PTE). These cues of diagnosis include the "wall eclipsing sign", lobulated bulging margins, gadolinium enhancement during MRI imaging, and FDG uptake during PET/CT imaging. However, there are still many misdiagnoses. CASE PRESENTATION: This article reports a woman of reproductive age presenting with a pulmonary artery mass. The computed tomographic pulmonary angiography and positron emission tomography/computed tomography did not show obvious signs of pulmonary artery sarcoma, however, contrast-enhanced echocardiography showed moderate perfusion, which helped differentiate between pulmonary artery sarcoma and pulmonary artery thrombosis, leading to timely surgical treatment. CONCLUSIONS: PAS is a rare form of cancer that can occasionally be visually similar to PTE on radiographic images. Early diagnosis of PAS is of vital importance to the prognosis of the patients. There are several visual cues that can help differentiate between the two conditions. Additionally, contrast-enhanced echocardiography provides additional information on tumor perfusion, offering another effective approach for a prompt and accurate diagnosis.

Erratum: Non-canonical signaling pathway of SNAI2 induces EMT in ovarian cancer cells by suppressing miR-222-3p transcription and upregulating PDCD10: Erratum.

[This corrects the article DOI: 10.7150/thno.43198.].

Solution processing of crystalline porous material based membranes for CO2 separation.

The carbon emission problem is a significant challenge in today's society, which has led to severe global climate issues. Membrane-based separation technology has gained considerable interest in CO2 separation due to its simplicity, environmental friendliness, and energy efficiency. Crystalline porous materials (CPMs), such as zeolites, metal-organic frameworks, covalent organic frameworks, hydrogen-bonded organic frameworks, and porous organic cages, hold great promise for advanced CO2 separation membranes because of their ordered and customizable pore structures. However, the preparation of defect-free and large-area crystalline porous material (CPM)-based membranes remains challenging, limiting their practical use in CO2 separation. To address this challenge, the solution-processing method, commonly employed in commercial polymer preparation, has been adapted for CPM membranes in recent years. Nanosheets, spheres, molecular cages, and even organic monomers, depending on the CPM type, are dissolved in suitable solvents and processed into continuous membranes for CO2 separation. This feature article provides an overview of the recent advancements in the solution processing of CPM membranes. It summarizes the differences among the solution-processing methods used for forming various CPM membranes, highlighting the key factors for achieving continuous membranes. The article also summarizes and discusses the CO2 separation performance of these membranes. Furthermore, it addresses the current issues and proposes future research directions in this field. Overall, this feature article aims to shed light on the development of solution-processing techniques for CPM membranes, facilitating their practical application in CO2 separation.

Advances in the Study of the Pathology and Treatment of Alzheimer's Disease and Its Association with Periodontitis.

Alzheimer's disease (AD) has become one of the leading causes of health problems in the elderly, and studying its causes and treatments remains a serious challenge for researchers worldwide. The two main pathological features of Alzheimer's disease are the extracellular deposition of ß-amyloid (Aß) to form senile plaques and the intracellular aggregation of hyperphosphorylated Tau protein to form neurofibrillary tangles (NFTs). Researchers have proposed several hypotheses to elucidate the pathogenesis of AD, but due to the complexity of the pathophysiologic factors involved in the development of AD, no effective drugs have been found to stop the progression of the disease. Currently, the mainstay drugs used to treat AD can only alleviate the patient's symptoms and do not have a therapeutic effect. As researchers explore interactions among diseases, much evidence suggests that there is a close link between periodontitis and AD, and that periodontal pathogenic bacteria can exacerbate Aß deposition and Tau protein hyperphosphorylation through neuroinflammatory mechanisms, thereby advancing the pathogenesis of AD. This article reviews recent advances in the pathogenesis of AD, available therapeutic agents, the relevance of periodontitis to AD, and mechanisms of action.

Roles of microglia in adult hippocampal neurogenesis in depression and their therapeutics.

Adult hippocampal neurogenesis generates functional neurons from neural progenitor cells in the hippocampal dentate gyrus (DG) to complement and repair neurons and neural circuits, thus benefiting the treatment of depression. Increasing evidence has shown that aberrant microglial activity can disrupt the appropriate formation and development of functional properties of neurogenesis, which will play a crucial role in the occurrence and development of depression. However, the mechanisms of the crosstalk between microglia and adult hippocampal neurogenesis in depression are not yet fully understood. Therefore, in this review, we first introduce recent discoveries regarding the roles of microglia and adult hippocampal neurogenesis in the etiology of depression. Then, we systematically discuss the possible mechanisms of how microglia regulate adult hippocampal neurogenesis in depression according to recent studies, which involve toll-like receptors, microglial polarization, fractalkine-C-X3-C motif chemokine receptor 1, hypothalamic-pituitary-adrenal axis, cytokines, brain-derived neurotrophic factor, and the microbiota-gut-brain axis, etc. In addition, we summarize the promising drugs that could improve the adult hippocampal neurogenesis by regulating the microglia. These findings will help us understand the complicated pathological mechanisms of depression and shed light on the development of new treatment strategies for this disease.

Alterations of Bax/Bcl-2 ratio contribute to NaAsO2 induced thyrotoxicity in human thyroid follicular epithelial cells and SD rats.

The environmental toxicant arsenic causes various human diseases and threatens millions of people worldwide. Recently, a limited number of studies have revealed that exposure to arsenic is associated with thyroid dysfunction, indicating its toxicological impact on the thyroid gland, however, its precise forms of damage and underlying mechanisms remain largely unknown. Here, we sought to observe the thyrotoxicity of sodium arsenite (NaAsO2) on human thyroid follicular epithelial cells (Nthy-ori 3-1) and SD rats, and explore the role of Bax/Bcl-2 ratio in the above process. Our results displayed that NaAsO2 exerted a dose-dependent inhibitory effect on the viability of Nthy-ori 3-1 cells. Alongside the increase doses of NaAsO2 exposure, morphological changes and elevated LDH levels were observed. Furthermore, apoptosis rates increased in a dose- and time-dependent manner, accompanied by a decrease in Bcl-2 and an opposite change in Bax expression. SD rats were treated with 0, 2.5, 5, and 10 mg/kg NaAsO2 for 36 weeks. Our findings revealed that NaAsO2 exposure resulted in arsenic accumulation in thyroid tissue, elevated ratio of Bax/Bcl-2, and histopathological changes of thyroid in rats, which accompanied by the decreased serum T3 and T4 levels and the increased serum TSH level. Furthermore, T3 and T4 levels were negatively correlated with Bax expression, whereas positively correlated with Bcl-2 expression. Collectively, our results suggest that NaAsO2 exposure induces cytotoxicity in Nthy-ori 3-1 cells, causes structural damages and dysfunction of thyroid in SD rats, in which the imbalance of Bax/Bcl-2 ratio may play a significant role.

Possible Role of Mitochondrial Transfer RNA Gene 5816 A > G Genetic Polymorphism (m.5816A > G) in a 3-Year-Old Child with Dystonia: Report of a Case.

Background Mutations in the mitochondrial transfer RNA (mt-tRNA) gene are a hotspot for mitochondrial DNA (mtDNA) mutations and are most common in mitochondrial diseases. Methods We identified the mt-tRNA gene 5816 A > G (m.5816 A > G) mutation in a 3-year-old child with dystonia who died. We performed clinical evaluation, genetic analysis, and biochemical investigation with mitochondrial function testing. Results Our patient was found to have dystonia with hyperlactatemia. Electroencephalogram findings were abnormal in children with numerous multifocal spikes, multispike, spikes and slow waves, slow waves and low amplitude fast waves, more pronounced in the occipital region bilaterally, and occurring continuously during sleep. One year later, the preexisting patient had seizures lasting 1 to 2 hours and subsequently died. mtDNA sequencing revealed that the proband, her mother, and her grandmother all carried the m.5816A > G mutation. Oxygen consumption rate (OCR) assays revealed that the proband's basal resting OCR, adenosine triphosphate production, proton leak, maximal respiration, and spare capacity OCR were all significantly lower compared with healthy children of the same age. Conclusion The present case demonstrates a childhood dystonia caused by a mt-tRNA gene 5816 A > G mutation, which has never been reported before. Our findings provide valuable new insights into the pathogenic mechanism and function of the m.5816A > G mutation.

Homoplantaginin attenuates high glucose-induced vascular endothelial dysfunction via inhibiting store-operated calcium entry channel and endoplasmic reticulum stress.

OBJECTIVES: The activation of store-operated calcium entry (SOCE) channel and endoplasmic reticulum stress (ERS) induced by high glucose (HG) is recognized as a major cause of vascular endothelial dysfunction. This study aims to investigate the protective effect of homoplantaginin (Hom) on HG-induced endothelial dysfunction. METHODS: HG-induced vascular endothelial dysfunction model in human umbilical vein endothelial cells (HUVECs) and rat-isolated thoracic aortas were established to observe the protective effect of Hom, further evaluated the mechanism of SOCE channel and ERS in the pathogenesis. KEY FINDINGS: Hom increased the levels of nitric oxide (NO) and phospho-endothelial nitric oxide synthase (p-eNOS) in HUVECs and isolated rat thoracic aortas in a dose-dependent manner, restored acetylcholine-mediated endothelium-dependent vasodilation. Network pharmacology showed that the pathogenesis of diabetic vascular complications may involve calcium (Ca2+) signal pathway. Hom reduced Ca2+ concentration via blocking SOCE channel in HUVECs, and resisted ERS activation by down-regulating ERS-related proteins expression. Importantly, SKF96365 (SOCE inhibitor) intervention experiment showed that Hom inhibited ERS activation by blocking the SOCE channel, further increased the levels of NO and p-eNOS. CONCLUSION: Hom could alleviate HG-induced vascular endothelial dysfunction by inhibiting SOCE channel and ERS. This provided a potential pharmacological intervention strategy for the treatment of vascular endothelial dysfunction.

Carbapenem-resistant Klebsiella pneumoniae Osteoarthritis in Two Preterm Infants Treated With Ceftazidime-avibactam.

BACKGROUND: The emergence of carbapenem-resistant Klebsiella pneumoniae (CRKP) poses a major threat to global public health. CRKP infections are challenging to treat owing to the limited number of antibiotic species, especially in preterm infants. Ceftazidime-avibactam (CAZ-AVI) is a novel antibiotic with activity against CRKP. At present, there have been no reports of using CAZ-AVI to treat osteoarthritis in premature infants. METHODS: We describe 2 preterm infants with CRKP osteoarthritis treated with CAZ-AVI in a tertiary children's hospital in China. Clinical characteristics, laboratory and microbiologic data, treatment and follow-up information were retrospectively collected and analyzed. RESULTS: The 2 cases were both premature infants who contracted sepsis and CRKP osteoarthritis. Meropenem and polymyxin B were initially chosen for the first infant. CAZ-AVI was then used due to persistent infection. The second infant was commenced immediately on CAZ-AVI after receipt of antimicrobial susceptibility on the 4th day after admission. Both recovered with CAZ-AVI (50 mg/kg q8h) and surgical incision and drainage. Neither had a joint deformity or limb length discrepancy at 36 and 34 months, respectively. CONCLUSIONS: This is the first report on the use of CAZ-AVI to treat CRKP osteoarthritis in premature infants. Successful treatment depends on prompt recognition of the pathogen and treatment with a combination of antibiotics with or without surgery. Further study is needed to determine the pharmacokinetics and pharmacodynamics of CAZ-AVI for treating preterm infants with serious CRKP osteoarthritis.

Simultaneous profiling of chromatin architecture and transcription in single cells.

The three-dimensional structure of chromatin plays a crucial role in development and disease, both of which are associated with transcriptional changes. However, given the heterogeneity in single-cell chromatin architecture and transcription, the regulatory relationship between the three-dimensional chromatin structure and gene expression is difficult to explain based on bulk cell populations. Here we develop a single-cell, multimodal, omics method allowing the simultaneous detection of chromatin architecture and messenger RNA expression by sequencing (single-cell transcriptome sequencing (scCARE-seq)). Applying scCARE-seq to examine chromatin architecture and transcription from 2i to serum single mouse embryonic stem cells, we observe improved separation of cell clusters compared with single-cell chromatin conformation capture. In addition, after defining the cell-cycle phase of each cell through chromatin architecture extracted by scCARE-seq, we find that periodic changes in chromatin architecture occur in parallel with transcription during the cell cycle. These findings highlight the potential of scCARE-seq to facilitate comprehensive analyses that may boost our understanding of chromatin architecture and transcription in the same single cell.

An Ultrastable Bifunctional Electrocatalyst Derived from a Co2+-Anchored Covalent-Organic Framework for High-Efficiency ORR/OER and Rechargeable Zinc-Air Battery.

It remains a great challenge to develop alternative electrocatalysts with high stability for the oxygen reduction reaction (ORR) and oxygen evolution reaction (OER). Herein, a bifunctional electrocatalyst composed of hollow CoOx (Co3O4/CoO) nanoparticles embedded in lamellar carbon nanofibers is derived from a Co2+-anchored covalent-organic framework. The as-fabricated electrocatalyst (CoOx@NC-800) exhibits a half-wave potential (E1/2) of 0.89 V with ultrahigh long-term stability (100% current retention after 3000 CV cycles). Together with promising OER performance, the CoOx@NC-800 based reversible Zn-air battery displays a small potential gap (0.70 V), superior to that of the commercial 20% Pt/C + RuO2. The density functional theory (DFT) calculations reveal that the remarkable electrocatalytic performance and stability of CoOx@NC-800 are attributed to the optimized adsorption of the *OOH intermediate and reduced free energy of the potential-limiting step. This study establishes the functionalization of COF structure for fabrication of high-performance carbon-based electrocatalysts.

Laparoscopic common bile duct exploration with primary closure could be safely performed among elderly patients with choledocholithiasis.

BACKGROUND: For patients with choledocholithiasis, laparoscopic common bile duct exploration (LCBDE) is preferred over open surgery. Whether primary closure of the common bile duct (CBD) should be performed upon completion of choledochotomy remains unclear, and the corresponding indications for primary closure of the common bile duct have yet to be fully identified. This study was performed to evaluate the safety and feasibility of primary closure of CBD among elderly patients (≥ 70 years) after LCBDE. METHODS: Patients with choledocholithiasis who had undergone LCBDE with primary closure of the CBD between July 2014 and December 2020 were retrospectively reviewed. Included patients were assigned into two groups (Group A: ≥70 years and Group B: <70 years) according to age. Group A was compared with Group B in terms of preoperative characteristics, intraoperative results and postoperative outcomes. RESULTS: The mean operative time for Group A was 176.59 min (± 68.950), while the mean operative time for Group B was 167.64 min (± 69.635) (P = 0.324). The mean hospital stay after surgery for Group A was 8.43 days (± 4.440), while that for Group B was 8.30 days (± 5.203) (P = 0.849). Three patients in Group A experienced bile leakage, while bile leakage occurred in 10 patients in Group B (3.8% vs. 4.5%, P = 0.781). Group A was not significantly different from Group B in terms of postoperative complications and 30-day mortality except pneumonia (P = 0.016), acute cardiovascular event (P = 0.005) and ICU observation (P = 0.037). After a median follow-up time of 60 months, 2 patients in Group A and 2 patients in Group B experienced stone recurrence (2.5% vs. 0.9%, P = 0.612). One patient in Group A experienced stenosis of the CBD, while stenosis of the CBD occurred in 5 patients in Group B (1.3% vs. 2.2%, P = 0.937). CONCLUSIONS: Primary closure of CBD upon completion of LCBDE could be safely performed among patients ≥ 70 years.

Esaxerenone Inhibits Renal Angiogenesis and Endothelial-Mesenchymal Transition via the VEGFA and TGF-ß1 Pathways in Aldosterone-Infused Mice.

Renal fibrosis is an inevitable process in the progression of chronic kidney disease (CKD). Angiogenesis plays an important role in this process. Vascular endothelial cells are involved in renal fibrosis by phenotypic transformation and secretion of extracellular matrix. Aldosterone stimulates mineralocorticoid receptor (MR) activation and induces inflammation, which is important for angiogenesis. Clinically, MR blockers (MRBs) have a protective effect on damaged kidneys, which may be associated with inhibition of angiogenesis. In this study, we used aldosterone-infused mice and found that aldosterone induced angiogenesis and that endothelial-mesenchymal transition (EndMT) in neovascular endothelial cells was involved in renal fibrosis. Notably, aldosterone induced inflammation and stimulated macrophages to secrete vascular endothelial growth factor (VEGF) A to regulate angiogenesis by activating MR, whereas EndMT occurred in response to transforming growth factor-ß1 (TGF-ß1) induction and participated in renal fibrosis. These effects were antagonized by the MRB esaxerenone. These findings suggest that reducing angiogenesis may be an effective strategy for treating renal fibrosis.

Diagnostic accuracy of interleukin-2 receptor in sarcoidosis: a systematic review and meta-analysis.

INTRODUCTION: Soluble interleukin-2 receptor (sIL-2 R), a valuable diagnostic biomarker for sarcoidosis, has been reported with variable results. Based on the literatures currently accessible, a systematic review and meta-analysis of the diagnostic performance of serum sIL-2 R for sarcoidosis were performed. METHODS: Relevant studies investigating sIL-2 R for sarcoidosis diagnosis in several databases were searched and data on sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), and diagnostic odds ratio (DOR) were pooled by STATA 16.0 software. Overall test performance was assessed using summary receiver operating characteristic curves and the area under the curve (AUC). Potential publication bias was assessed by Deeks test. RESULTS: We included eleven studies involving 1,424 subjects, with 1,099 cases of sarcoidosis and 325 of non-sarcoidosis. The pooled parameters of sIL-2 R in diagnosing sarcoidosis were summarized as follows: sensitivity, 0.85 (95% CI: 0.72-0.93); specificity, 0.88 (95% CI: 0.72-0.96); PLR, 7.3 (95% CI: 2.7-20.1); NLR, 0.17 (95% CI:0.08-0.36); DOR, 44 (95% CI: 8-231); and the AUC, 0.93 (95% CI: 0.90-0.95). No publication bias was identified (P = 0.64). CONCLUSIONS: Evidence suggests sIL-2 R performs well in diagnosing sarcoidosis. Nevertheless, results of sIL-2 R assay should be interpreted with other diagnostic examinations.