Novel selective agents for the degradation of AR/AR-V7 to treat advanced prostate cancer.

The androgen receptor AR antagonists, such as enzalutamide and apalutamide, are efficient therapeutics for the treatment of prostate cancer (PCa). Even though they are effective at first, resistance to both drugs occurs frequently. Resistance is mainly driven by aberrations of the AR signaling pathway including AR gene amplification and the expression of AR splice variants (e.g. AR-V7). This highlights the urgent need for alternative therapeutic strategies. Here, a total of 24 compounds were synthesized and biologically evaluated to disclose compound 20i, exhibiting potent AR antagonistic activities (IC50 = 172.85 ± 21.33 nM), promising AR/AR-V7 protein degradation potency, and dual targeting site of probably AR (ligand-binding domain, LBD and N-terminal domain, NTD). It potently inhibits cell growth with IC50 values of 4.87 ± 0.52 and 2.07 ± 0.34 µM in the LNCaP and 22RV1 cell lines, respectively, and exhibited effective tumor growth inhibition (TGI = 50.9 %) in the 22RV1 xenograft study. These data suggest that 20i has the potential for development as an AR/AR-V7 inhibitor with degradation ability to treat advanced prostate cancer.

MdPRX34L, a class III peroxidase gene, activates the immune response in apple to the fungal pathogen Botryosphaeria dothidea.

MAIN CONCLUSION: MdPRX34L enhanced resistance to Botryosphaeria dothidea by increasing salicylic acid (SA) and abscisic acid (ABA) content as well as the expression of related defense genes. The class III peroxidase (PRX) multigene family is involved in complex biological processes. However, the molecular mechanism of PRXs in the pathogen defense of plants against Botryosphaeria dothidea (B. dothidea) remains unclear. Here, we cloned the PRX gene MdPRX34L, which was identified as a positive regulator of the defense response to B. dothidea, from the apple cultivar 'Royal Gala.' Overexpression of MdPRX34L in apple calli decreased sensitivity to salicylic acid (SA) and abscisic acid（ABA). Subsequently, overexpression of MdPRX34L in apple calli increased resistance to B. dothidea infection. In addition, SA contents and the expression levels of genes related to SA synthesis and signaling in apple calli overexpressing MdPRX34L were higher than those in the control after inoculation, suggesting that MdPRX34L enhances resistance to B. dothidea via the SA pathway. Interestingly, infections in apple calli by B. dothidea caused an increase in endogenous levels of ABA followed by induction of ABA-related genes expression. These findings suggest a potential mechanism by which MdPRX34L enhances plant-pathogen defense against B. dothidea by regulating the SA and ABA pathways.

Promises and challenges of organoids: From humanized to human derived.

Kastenschmidt et al.1 present a groundbreaking organoid culture model for follicular lymphoma, which is capable of maintaining stable compositions of B and T cells. This model is utilized in testing bispecific antibodies in effective killing of tumor B cells with the activation of T cells.

Topical delivery of drugs in the treatment of high-grade cervical squamous intraepithelial lesions: A meta-analysis.

OBJECTIVE: The present study aims to evaluate the efficacy and effect of localized delivery of drugs in the treatment of high-grade squamous intraepithelial lesion (HSIL) based on a meta-analysis. STUDY DESIGN: Databases including Cochrane Library, PubMed, Embase, Scopus, CNKI, and Wanfang were searched from their inception till August 2022. Randomized controlled trials (RCTs) that compared the efficacy of drugs and surgery in the treatment of HSIL were collected. A meta-analysis was performed using the software of Review Manager (version 5.4.1). RESULTS: Eight RCTs involving 523 patients were included in the meta-analysis. For HSIL, the rate of cervical lesions histological regression was 69.85 % in the surgery group and 59.88 % in the drug group, there was no significant difference between the two groups [OR = 0.45, 95 % CI (0.07, 3.03), P = 0.41]. The histological regression rate of cervical lesions in the placebo group was 37.76 %, and the difference between the drug group and the placebo group was statistically significant [OR = 4.94, 95 % CI (2.65, 9.20), P < 0.00001]. CONCLUSION: A total of four drugs were involved in the eight RCTS included in this study, which were imiquimod, 5-fluorouracil (5-FU), cidofovir and interferon. The results showed that although drug administration was effective in the histological regression of HSIL, the efficacy was less than about 10% of surgical treatment. Considering the recurrence of the disease after surgery and the problems of abortion, premature delivery and premature rupture of membranes after cervical conization in reproductive women, drug therapy can be used as a supplement to surgery or conservative treatment to promote the histological regression of cervical lesions in patients with HSIL.

Dual-targeting tigecycline nanoparticles for treating intracranial infections caused by multidrug-resistant Acinetobacter baumannii.

Multidrug-resistant (MDR) Acinetobacter baumannii (A. baumannii) is a formidable pathogen responsible for severe intracranial infections post-craniotomy, exhibiting a mortality rate as high as 71%. Tigecycline (TGC), a broad-spectrum antibiotic, emerged as a potential therapeutic agent for MDR A. baumannii infections. Nonetheless, its clinical application was hindered by a short in vivo half-life and limited permeability through the blood-brain barrier (BBB). In this study, we prepared a novel core-shell nanoparticle encapsulating water-soluble tigecycline using a blend of mPEG-PLGA and PLGA materials. This nanoparticle, modified with a dual-targeting peptide Aß11 and Tween 80 (Aß11/T80@CSs), was specifically designed to enhance the delivery of tigecycline to the brain for treating A. baumannii-induced intracranial infections. Our findings demonstrated that Aß11/T80@CSs nanocarriers successfully traversed the BBB and effectively delivered TGC into the cerebrospinal fluid (CSF), leading to a significant therapeutic response in a model of MDR A. baumannii intracranial infection. This study offers initial evidence and a platform for the application of brain-targeted nanocarrier delivery systems, showcasing their potential in administering water-soluble anti-infection drugs for intracranial infection treatments, and suggesting promising avenues for clinical translation.

Discovery of Novel Antitumor Small-Molecule Agent with Dual Action of CDK2/p-RB and MDM2/p53.

Cell cycle-dependent kinase 2 (CDK2) is located downstream of CDK4/6 in the cell cycle and regulates cell entry into S-phase by binding to Cyclin E and hyper-phosphorylating Rb. Proto-oncogene murine double minute 2 (MDM2) is a key negative regulator of p53, which is highly expressed in tumors and plays an important role in tumorigenesis and progression. In this study, we identified a dual inhibitor of CDK2 and MDM2, III-13, which had good selectivity for inhibiting CDK2 activity and significantly reduced MDM2 expression. In vitro results showed that III-13 inhibited proliferation of a wide range of tumor cells, regardless of whether Cyclin E1 (CCNE1) was overexpressed or not. The results of in vivo experiments showed that III-13 significantly inhibited proliferation of tumor cells and did not affect body weight of mice. The results of the druggability evaluation showed that III-13 was characterized by low bioavailability and poor membrane permeability when orally administered, suggesting the necessity of further structural modifications. Therefore, this study provided a lead compound for antitumor drugs, especially those against CCNE1-amplified tumor proliferation.

Ki-67 Change in Anthracyline-containing Neoadjuvant Chemotherapy Response in Breast Cancer.

OBJECTIVE: Anthracycline-containing regimens are irreplaceable in neoadjuvant chemotherapy (NAC) for breast cancer (BC) at present. However, 30% of early breast cancer (EBC) patients are resistant to anthracycline-containing chemotherapy, leading to poor prognosis and higher mortality. Ki-67 is associated with the prognosis and response to therapy, and it changes after NAC. METHODS: A total of 105 BC patients who received anthracycline-containing NAC were enrolled. Then, the optimal model of Ki-67 was selected, and its predictive efficacy was analyzed. Immunohistochemistry (IHC) was used to determine the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER-2) status and Ki-67 level. Fluorescent in situ hybridization (FISH) was used to verify the HER-2 when the IHC score was 2+. RESULTS: The post-NAC Ki67 level after treatment with anthracycline drugs was lower than pre-NAC Ki-67 (19.6%±23.3% vs. 45.6%±23.1%, P<0.001). Furthermore, patients with the Ki-67 decrease had a border line higher pathological complete response (pCR) rate (17.2% vs. 0.0%, P=0.068), and a higher overall response rate (ORR) (73.6% vs. 27.8%, P<0.001), when compared to patients without the Ki-67 decrease. The ΔKi-67 and ΔKi-67% were valuable markers for the prediction of both the pCR rate and ORR. The area under the curve (AUC) for ΔKi-67 on pCR and ORR was 0.809 (0.698-0.921) and 0.755 (0.655-0.855), respectively, while the AUC for ΔKi-67% on pCR and ORR was 0.857 (0.742-0.972) and 0.720 (0.618-0.822), respectively. Multivariate logistic regression model 1 revealed that ΔKi-67 was an independent predictor for both pCR [odds ratio (OR)=61.030, 95% confidence interval (CI)=4.709-790.965; P=0.002] and ORR (OR=10.001, 95% CI: 3.044-32.858; P<0.001). Multivariate logistic regression model 2 revealed that ΔKi-67% was also an independent predictor for both pCR (OR=408.922, 95% CI=8.908-18771.224; P=0.002) and ORR (OR=5.419, 95% CI=1.842-15.943; P=0.002). CONCLUSIONS: The present study results suggest that ΔKi67 and ΔKi67% are candidate predictors for anthracycline-containing NAC response, and that they may provide various information for further systematic therapy after surgery in clinical practice.

Association of Oxidative Stress and Proinflammation with Insomnia in Perimenopause.

Background: The levels of oxidative stress and proinflammatory factors in perimenopausal females increased, and they were also deeply troubled by insomnia. The occurrence of insomnia is related to the changes of oxidative stress and inflammation levels in the body. Perimenopausal insomnia may be related to mild systemic inflammation, and oxidative stress can promote chronic inflammation. However, the underlying mechanism behind the phenomenon is still unclear. Objective: The aim was to investigate whether the occurrence of perimenopausal insomnia disorder is related to higher levels of oxidative stress and inflammation in the body, and to explore the role of inducible nitric oxide synthase (iNOS) in perimenopausal insomnia. Methods: A total of 127 perimenopausal participants were recruited in this study. Participants with global scores of the Pittsburgh sleep quality index (PSQI) >7 were diagnosed with insomnia (n = 54). The patient health questionnaire-9 (PHQ-9) and generalized anxiety disorder-7 (GAD-7) were evaluated, and sociodemographic data were obtained. The serum concentrations of iNOS, interleukin 6 (IL6), and tumor necrosis factor α (TNFα) were measured using commercial assays. Results: In the insomnia group, IL6 levels were positively correlated with scores of component 5 and component 7 of PSQI, respectively. PHQ-9 and GAD-7 were positively correlated with the global score of PSQI component 7 and PSQI, respectively; PHQ-9 was positively correlated with the global score of PSQI component 1. Finally, PHQ-9, iNOS, and IL6 were found to be independent predictors of perimenopausal insomnia using logistic regression. Conclusions: Moderate oxidative stress caused by a certain concentration of iNOS plays a protective role in perimenopausal insomnia, while proinflammation and depression are potential risk factors.

Population Pharmacokinetic Analysis to Support and Facilitate Switching from Risperidone Formulations to Rykindo in Patients with Schizophrenia.

INTRODUCTION: RYKINDO® (Rykindo) is a novel, long-acting injectable risperidone formulation administered biweekly (Q2W) through intramuscular gluteal injection for the treatment of schizophrenia in adult patients. This analysis was conducted to demonstrate that the clinical outcomes of Rykindo are equivalent to those of RISPERDAL CONSTA® (Consta; Q2W), and to establish a dosing methodology to switch from Consta to Rykindo, as well as to introduce Rykindo to patients who are currently on oral RISPERDAL® (Risperdal). METHODS: Population pharmacokinetic (PK) models for Rykindo and Consta were developed using a nonlinear mixed-effects model with the data from phase 1 studies. A model-based simulation was also conducted using NONMEM. RESULTS: The PK profiles of Rykindo and Consta were adequately represented by a one-compartment model with an immediate release followed by an intermediate and third main release. Drug release of Rykindo was faster than for Consta, reaching steady state approximately 2-3 weeks earlier. The exposures of the active moiety of Rykindo and Consta were comparable at steady state. Model-based simulation indicated that switching from Consta to Rykindo requires administration of the first Rykindo injection within 4-5 weeks following the last Consta injection. For patients taking Risperdal, introducing Rykindo with 1 week of Risperdal supplemental for once-daily dosing (QD) can achieve comparable or superior exposure to that of Consta with 3 weeks of oral QD supplements. A dosing window of ± 3 days for Rykindo was recommended. CONCLUSIONS: This established approach provides guidance to physicians to initiate Rykindo therapy in adult patients with schizophrenia. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT02055287, NCT02186769 and NCT02091388.

Pediatric H3K27M­mutant diffuse midline glioma with vertebral metastasis: A case report and literature review.

H3K27M-mutant diffuse midline glioma (DMG) is a type of high-grade glial tumor, which occurs in the midline structure and develops mostly in children. Extraneural metastases (ENM) are exceedingly rare in patients with H3K27M-mutant DMG. A 9-year-old male patient presented with a headache, nausea and vomiting. Following magnetic resonance imaging and immunohistochemical molecular testing examination, the patient was diagnosed with H3K27M-mutant DMG and received chemoradiotherapy plus five cycles of chemotherapy with temozolomide intermittently as an adjuvant therapy. The treatment resulted in a slight reduction of the tumor volume. However, 2 months later, the patient was admitted to hospital with complaints of drooping of the mouth, and waist and back pain. Magnetic resonance imaging and positron-emission tomography-computed tomography revealed an unusual presentation with multiple vertebral metastases and craniospinal leptomeningeal dissemination. Following discussion between the members of a multidisciplinary medical team, the patient underwent one cycle of chemotherapy with cyclophosphamide, vincristine and cisplatin. However, the condition did not improve and the patient died 4 weeks after the diagnosis of ENM. The mechanisms underlying the development of these rare metastases remain unclear. The present case report provides insights into the clinical characteristics and potential metastasis mechanisms of this aggressive disease and may help to elucidate new pathways for the management of ENM.

A novel scaffold long-acting selective estrogen receptor antagonist and degrader with superior preclinical profile against ER+ breast cancer.

Breast cancer is one of the most common malignant tumors in women worldwide, with the majority of cases showing expression of estrogen receptors (ERs). Although drugs targeting ER have significantly improved survival rates in ER-positive patients, drug resistance remains an unmet clinical need. Fulvestrant, which overcomes selective estrogen receptor modulator (SERM) and AI (aromatase inhibitor) resistance, is currently the only long-acting selective estrogen receptor degrader (SERD) approved for both first and second-line settings. However, it fails to achieve satisfactory efficacy due to its poor solubility. Therefore, we designed and synthesized a series of novel scaffold (THC) derivatives, identifying their activities as ER antagonists and degraders. G-5b, the optimal compound, exhibited binding, antagonistic, degradation or anti-proliferative activities comparable to fulvestrant in ER+ wild type and mutants breast cancer cells. Notably, G-5b showed considerably improved stability and solubility. Research into the underlying mechanism indicated that G-5b engaged the proteasome pathway to degrade ER, subsequently inhibiting the ER signaling pathway and leading to the induction of apoptosis and cell cycle arrest events. Furthermore, G-5b displayed superior in vivo pharmacokinetics and pharmacodynamics properties, coupled with a favorable safety profile in the MCF-7 tamoxifen-resistant (MCF-7/TR) tumor xenograft model. Collectively, G-5b has emerged as a highly promising lead compound, offering potent antagonistic and degradation activities, positioning it as a novel long-acting SERD worthy of further refinement and optimization.

Inflammation affects the pharmacokinetics of risperidone: Does the dose need to be adjusted during the acute-phase reaction?

BACKGROUND: Several studies have indicated that the plasma concentration of risperidone increases 3-5-fold during the acute-phase reaction (APR) of inflammation or infection. Psychiatric symptoms are present or deteriorate when the dose is lowered; thus, the complex effects of inflammation on the pharmacokinetics of risperidone need to be examined. METHODS: We established a APR model in rabbits induced by lipopolysaccharide (LPS) and studied the effect of APR on pharmacokinetics, distribution and disposition of risperidone in vivo and in vitro. RESULTS: Following intramuscular administration, the plasma exposures for risperidone and its active metabolite (9-hydroxyrisperidone) were increased approximately 6-fold on day 2 of inflammation. The exposure values did not change between day 2 and 5 of inflammation, nor did the metabolite-to-parent ratio before and during inflammation. Following oral administration, the increase of risperidone exposure was twice as high as that following intramuscular administration during APR. However, the concentration of risperidone and 9-hydroxyrisperidone in brain tissue was similar between the inflammatory and control groups. Moreover, the plasma protein binding (PPB) of risperidone and 9-hydroxyrisperidone associated with inflammation were all increased to >99 %. In addition, risperidone and 9-hydroxyrisperidone were not substrates of the key transporters, OATP1B3, OCT2, OAT3, MATE-1, or MATE-2 K. The expression of progesterone X receptor and P-glycoprotein was inhibited by LPS. CONCLUSION: During APR, reduced expression of P-glycoprotein and increased PPB were responsible for increased exposure in plasma, while maintaining stable concentrations in the brain, and risperidone does not need to be dose-adjusted so as to achieve psychopharmacological outcomes.

Determination of alectinib and its active metabolite in plasma by pipette-tip solid-phase extraction using porous polydopamine graphene oxide adsorbent coupled with high-performance liquid chromatography-ultraviolet detection.

Alectinib is known as an effective targeted drug, which has excellent therapeutic effect on non-small cell lung cancer and can significantly prolong the survival of patients. Therapeutic drug monitoring is necessary due to the photo-instability of alectinib and the individual differences in patients. In this work, a porous polydopamine graphene oxide composite (PDAG) was prepared by a simple surface modification method. A PDAG-based pipette-tip solid-phase extraction (PT-SPE) coupled with HPLC-UV detection was proposed for the separation and detection of alectinib and its active metabolite M4 in plasma. The method was methodologically validated and showed good linearity in the range of 50-5000 ng mL-1 (R2 > 0.9995). The limit of detection (LOD) was 4.8 ng mL-1 and 3.9 ng mL-1 for alectinib and M4, respectively, and the limit of quantitation (LOQ) was 16.1 ng mL-1 and 13.1 ng mL-1, respectively. The intra-day and inter-day precision expressed by coefficient of variation was less than 4.8 %. The recovery of this method ranged from 84.9 % to 103.5 % with a standard deviation of less than 4.3 %. In conclusion, the established method is accurate, stable and inexpensive, and can be used to monitor the levels of alectinib and M4 in plasma, which provide technical and data support for exploring optimal individualized remedial dosing regimens.

Roles of mechanosensitive ion channels in immune cells.

Mechanosensitive ion channels are a class of membrane-integrated proteins that convert externalmechanical forces, including stretching, pressure, gravity, and osmotic pressure changes, some of which can be caused by pathogen invasion, into electrical and chemical signals transmitted to the cytoplasm. In recent years, with the identification of many of these channels, their roles in the initiation and progression of many diseases have been gradually revealed. Multiple studies have shown that mechanosensitive ion channels regulate the proliferation, activation, and inflammatory responses of immune cells by being expressed on the surface of immune cells and further responding to mechanical forces. Nonetheless, further clarification is required regarding the signaling pathways of immune-cell pattern-recognition receptors and on the impact of microenvironmental changes and mechanical forces on immune cells. This review summarizes the roles of mechanosensitive ion channels in immune cells.

TP53TG1/STAT axis is involved in the development of colon cancer through affecting PD-L1 expression and immune escape mechanism of tumor cells.

This research is dedicated to investigating the mechanism of programmed cell death ligand 1 (PD-L1) and tumor protein 53 target gene 1 (TP53TG1) in immune regulation of colon cancer (CC). Expressions of TP53TG1, PD-L1 and signal transducers and activators of transcription (STATs) in CC and their correlation were detected through bioinformatics analysis. Effects of PD-L1 and TP53TG1 on the CC were assessed by in vivo and in vitro experiments. Herein, PD-L1 level was negatively correlated with TP53TG1 expression, but was positively correlated with the levels of STATs. Both overexpressed TP53TG1 and PD-L1 antibody reversed the effects of CT26 cells on inhibiting cell proliferation, cytokine secretion and PD-L1 level, and enhancing the cytotoxicity of NK cells and CD8+ T cells. TP53TG1 reduced PD-L1 level by inactivating STATs pathway. Downregulation of PD-L1 increased cytokine secretion and T lymphocyte killing ability, promoted tumor cell apoptosis, and inhibited the tumor growth. Altogether, TP53TG1/STAT axis regulates the immunomodulatory mechanism of CC by reducing PD-L1 expression.

Quantifying the effects of plant density on soybean lodging resistance and growth dynamics in maize-soybean strip intercropping.

Shading-induced soybean stem lodging is a prevalent concern in the maize (Zea mays L.)-soybean (Glycine max L. Merr.) strip intercropping system, leading to a substantial decline in yield. Nevertheless, the associations between soybean growth, stem lodging, and yield formation in this scenario remain unclear. To investigate this, the logistic and beta growth models were utilized to analyze the growth process of soybean organs (stems, leaves, branches, and pods) and the accumulation of carbohydrates (lignin, cellulose, and sucrose) at three planting densities (8.5, 10, and 12.5 plants m-2) in both strip intercropping and skip strip monoculture systems. The results indicate that shading stress caused by maize in the intercropping system reduced lignin and cellulose accumulation in soybean stems, thus decelerating soybean organ growth compared to monoculture. Furthermore, intercropped soybean at higher planting density (PD3) exhibited a 28% reduction in the maximum dry matter growth rate (cm) and a 11% decrease in the time taken to reach the maximum dry matter growth rate (te) compared to the lower planting density (PD1). Additionally, a 29% decrease in the maximum accumulation rate (cmax) of sucrose, lignin, and cellulose was observed, along with a 13% decrease in the continuous accumulation time (tc) of these carbohydrates in intercropped soybean at PD3. Interspecific and intraspecific shading stress led to a preferential allocation of assimilates into soybean stems, enhancing plant height during the initial stage, while at later stages, a greater proportion of sucrose was allocated to leaves. Consequently, this hindered the conversion of sucrose into lignin and cellulose within the stems, ultimately resulting in a reduction in the lodging resistance index (LRI). Overall, this study provides valuable insights into the effects of shading stress on soybean growth and yield. It also emphasizes how optimizing planting density in intercropping systems can effectively alleviate shading stress and enhance crop productivity.

A Review on Probable Causes of Cardiotoxicity Caused by Common Cancer Drugs and the Role of Traditional Chinese Medicine in Prevention and Treatment.

Cancer is a widespread disease in our nation, characterized by a high occurrence rate. The use of tumor medications has been linked to an increased chance of cardiovascular complications, including a notable occurrence of heart toxicity. This has caused significant concern among healthcare professionals. This article provides a comprehensive compilation of drugs recognized for their potential to cause heart toxicity. Furthermore, extensive research has been conducted to investigate and categorize the effects of heart toxicity, with the purpose of promoting awareness, facilitating early intervention, and ultimately reducing the occurrence of heart toxicity. At the same time, there is an anticipation that Traditional Chinese Medicine (TCM) can capitalize on its unique attributes to address such ailments. To establish its effectiveness, it is crucial to carry out extensive clinical trials or retrospective analyses. The purpose of this article is to summarize the possible mechanisms of cardiac toxicity caused by commonly used chemotherapy drugs and summarize the possible mechanisms of adverse cardiac toxicity, laying the groundwork for subsequent research.

Regulation of a vacuolar proton-pumping P-ATPase MdPH5 by MdMYB73 and its role in malate accumulation and vacuolar acidification.

As the main organic acid in fruits, malate is produced in the cytoplasm and is then transported into the vacuole. It accumulates by vacuolar proton pumps, transporters, and channels, affecting the taste and flavor of fruits. Among the three types of proton pumps (V-ATPases, V-PPases, and P-ATPases), the P-ATPases play an important role in the transport of malate into vacuoles. In this study, the transcriptome data, collected at different stages after blooming and during storage, were analyzed and the results demonstrated that the expression of MdPH5, a vacuolar proton-pumping P-ATPase, was associated with both pre- and post-harvest malate contents. Moreover, MdPH5 is localized at the tonoplast and regulates malate accumulation and vacuolar pH. In addition, MdMYB73, an upstream MYB transcription factor of MdPH5, directly binds to its promoter, thereby transcriptionally activating its expression and enhancing its activity. In this way, MdMYB73 can also affect malate accumulation and vacuolar pH. Overall, this study clarifies how MdMYB73 and MdPH5 act to regulate vacuolar malate transport systems, thereby affecting malate accumulation and vacuolar pH. Supplementary Information: The online version contains supplementary material available at 10.1007/s42994-023-00115-7.

CircFKBP3 absence alleviates oxygen glucose deprivation-induced function loss of human brain microvascular endothelial cells in vitro via governing the miR-766-3p/TRAF3 axis.

BACKGROUND: Brain microvascular endothelial cell (BMEC) functions loss is a key event in the development of ischemic stroke, which may be affected by the dysregulation of circular RNAs (circRNAs). We aimed to unveil the role of circRNA FKBP Prolyl Isomerase 3 (circFKBP3) in cell models of ischemic stroke. METHODS: Cell models of ischemic stroke were constructed in human BEMCs (HBMECs) with the treatment of oxygen glucose deprivation (OGD). Quantitative real-time PCR (qPCR) and western blotting were conducted for expression analysis of circFKBP3, miR-766-3p and TNF receptor associated factor 3 (TRAF3). CCK-8, transwell, wound healing, flow cytometry, tube formation and ELISA assays were implemented to monitor cell viability, migration, apoptosis, angiogenesis and inflammation production. The putative binding relationship between miR-766-3p and circFKBP3 or TRAF3 was validated by dual-luciferase, RIP and pull-down assays. RESULTS: CircFKBP3 expression was elevated in OGD-treated HBMECs. OGD suppressed HBMEC viability, migration, angiogenesis, and provoked cell apoptosis and inflammation production, while knockdown of circFKBP3 attenuated these effects. CircFKBP3 interacted with miR-766-3p, and circFKBP3 absence-repressed HBMEC function loss and inflammation were recovered by miR-766-3p inhibition. CircFKBP3 targeted miR-766-3p to regulate TRAF3 expression. MiR-766-3p enrichment-repressed HBMEC function loss and inflammation were recovered by TRAF3 overexpression. CONCLUSION: CircFKBP3 absence alleviated OGD-induced function loss and inflammatory responses of HBMECs via governing the miR-766-3p/TRAF3 axis.

CircFKBP3 expression is elevated in OGD-treated HBMECs.OGD-induced HBMEC function loss and inflammation are alleviated by circFKBP3 absence.CircFKBP3 directly targets miR-766-3p to regulate TRAF3 expression.

The crosstalk between ILC3s and adaptive immunity in diseases.

RORγt+ group 3 innate lymphoid cells (ILC3s), the innate counterpart of Th17 cells, are enriched in the mucosal area and lymphoid tissues. ILC3s interact with a variety of cells through their effector molecules and play an important role in the host defense against a spectrum of infections. Recent studies suggest that the extensive crosstalk between ILC3s and adaptive immune cells, especially T cells, is essential for maintaining tissue homeostasis. Here we discuss recent advances in the crosstalk between ILC3s and adaptive immune responses in multiple tissues and diseases. Understanding how ILC3s engage with adaptive immune cells will enhance our comprehension of diseases and facilitate the identification of novel therapeutic targets.