A CLIC1 network coordinates matrix stiffness and the Warburg effect to promote tumor growth in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) features substantial matrix stiffening and reprogrammed glucose metabolism, particularly the Warburg effect. However, the complex interplay between these traits and their impact on tumor advancement remains inadequately explored. Here, we integrated clinical, cellular, and bioinformatics approaches to explore the connection between matrix stiffness and the Warburg effect in PDAC, identifying CLIC1 as a key mediator. Elevated CLIC1 expression, induced by matrix stiffness through Wnt/ß-catenin/TCF4 signaling, signifies poorer prognostic outcomes in PDAC. Functionally, CLIC1 serves as a catalyst for glycolytic metabolism, propelling tumor proliferation. Mechanistically, CLIC1 fortifies HIF1α stability by curbing hydroxylation via reactive oxygen species (ROS). Collectively, PDAC cells elevate CLIC1 levels in a matrix-stiffness-responsive manner, bolstering the Warburg effect to drive tumor growth via ROS/HIF1α signaling. Our insights highlight opportunities for targeted therapies that concurrently address matrix properties and metabolic rewiring, with CLIC1 emerging as a promising intervention point.

The optimal dose of metformin to control conversion to diabetes in patients with prediabetes: A meta-analysis.

AIM: This study aims to investigate the optimal dose of metformin for controlling the transition to diabetes in patients diagnosed with prediabetes. METHODS: We systematically searched randomized controlled trials (RCTs) in CNKI, Wanfang, VIP, SinoMed, Scopus, PubMed, Embase, Cochrane Library, Web of Science, and Cumulative Index to Nursing and Allied Health Literature (CINAHL) from inception to February 2024. Meta-analysis was conducted using RevMan 5.4 software. RESULTS: We included 25 randomized controlled trials comprising 2437 patients. The results of the meta-analysis revealed that compared to dose groups of 500 mg/d, 850 mg/d, 1000 mg/d, 1500 mg/d, 1700 mg/d, and 2000 mg/d, a dosage of 750 mg/d of metformin significantly reduced the incidence of diabetes in patients (risk ratio [RR] = 0.21, 95 % confidence interval [CI]: 0.11, 0.41; p < 0.00001), lowered Postprandial Blood Glucose (PBG) (mean difference[MD] = -2.60, 95 % CI: -4.34, -0.86; p = 0.003), and promoted the normalization of blood glucose levels (RR = 2.13, 95 % CI: 1.68, 2.71; p < 0.00001). Regarding safety evaluation, no significant differences were identified among the various dose groups. In contrast, the cohort receiving a daily dosage of 750 mg demonstrated the most pronounced decrease in the incidence of adverse reactions. CONCLUSION: Based on the efficacy and safety evaluation results, our findings suggest that a daily dosage of 750 mg of metformin may represent the optimal dose for controlling the progression from pre-diabetes to diabetes. REGISTRATION: PROSPERO registration ID: CRD42024538322.

The lncRNA LINC01605 promotes the progression of pancreatic ductal adenocarcinoma by activating the mTOR signaling pathway.

BACKGROUND: This study investigated the molecular mechanism of long intergenic non-protein coding RNA 1605 (LINC01605) in the process of tumor growth and liver metastasis of pancreatic ductal adenocarcinoma (PDAC). METHODS: LINC01605 was filtered out with specificity through TCGA datasets (related to DFS) and our RNA-sequencing data of PDAC tissue samples from Renji Hospital. The expression level and clinical relevance of LINC01605 were then verified in clinical cohorts and samples by immunohistochemical staining assay and survival analysis. Loss- and gain-of-function experiments were performed to estimate the regulatory effects of LINC01605 in vitro. RNA-seq of LINC01605-knockdown PDAC cells and subsequent inhibitor-based cellular function, western blotting, immunofluorescence and rescue experiments were conducted to explore the mechanisms by which LINC01605 regulates the behaviors of PDAC tumor cells. Subcutaneous xenograft models and intrasplenic liver metastasis models were employed to study its role in PDAC tumor growth and liver metastasis in vivo. RESULTS: LINC01605 expression is upregulated in both PDAC primary tumor and liver metastasis tissues and correlates with poor clinical prognosis. Loss and gain of function experiments in cells demonstrated that LINC01605 promotes the proliferation and migration of PDAC cells in vitro. In subsequent verification experiments, we found that LINC01605 contributes to PDAC progression through cholesterol metabolism regulation in a LIN28B-interacting manner by activating the mTOR signaling pathway. Furthermore, the animal models showed that LINC01605 facilitates the proliferation and metastatic invasion of PDAC cells in vivo. CONCLUSIONS: Our results indicate that the upregulated lncRNA LINC01605 promotes PDAC tumor cell proliferation and migration by regulating cholesterol metabolism via activation of the mTOR signaling pathway in a LIN28B-interacting manner. These findings provide new insight into the role of LINC01605 in PDAC tumor growth and liver metastasis as well as its value for clinical approaches as a metabolic therapeutic target in PDAC.

Liver X receptor inverse agonist SR9243 attenuates rheumatoid arthritis via modulating glycolytic metabolism of macrophages.

Liver X receptors (LXRs) which link lipid metabolism and inflammation, were overexpressed in experimental rheumatoid arthritis (RA) rats as observed in our previous studies, while suppression of LXRα by silybin ameliorates arthritis and abnormal lipid metabolism. However, the role of LXRs in RA remains undefined. In this study, we investigated the inhibition role of LXRs in the polarization and activation of M1 macrophage by using a special LXRs inverse agonist SR9243, which led to ameliorating the progression of adjuvant-induced arthritis (AIA) in rats. Mechanistically, SR9243 disrupted the LPS/IFN-γ-induced Warburg effect in M1 macrophages, while glycolysis inhibitor 2-DG attenuated the inhibition effect of SR9243 on M1 polarization and the cytokines expression of M1 macrophages including iNOS, TNF-α, and IL-6 in vitro. Furthermore, SR9243 downregulated key glycolytic enzymes, including LDH-A, HK2, G6PD, GLUT1, and HIF-1α in M1 macrophages, which is mediated by increased phosphorylation of AMPK (Thr172) and reduced downstream phosphorylation of mTOR (Ser2448). Importantly, gene silencing of LXRs compromises the inhibition effect of SR9243 on M1 macrophage polarization and activation. Collectively, for the first time, our findings suggest that the LXR inverse agonist SR9243 mitigates adjuvant-induced rheumatoid arthritis and protects against bone erosion by inhibiting M1 macrophage polarization and activation through modulation of glycolytic metabolism via the AMPK/mTOR/HIF-1α pathway.

OCIAD2 promotes pancreatic cancer progression through the AKT signaling pathway.

BACKGROUND: OCIAD2（Ovarian carcinoma immunoreactive antigen-like protein 2） is a protein reported in various cancers. However, the role of OCIAD2 has not been explored in pan-cancer datasets. The purpose of this research lies in analyzing the expression level and prognostic-related value of OCIAD2 in different human cancers, as well as revealing the underlying mechanism in specific cancer type (pancreatic adenocarcinoma, PAAD). METHODS: The correlation between OCIAD2 expression level and clinical relevance in different human cancers was investigated from bioinformatical perspective (GTEx and TCGA). The OCIAD2 expression level and clinical significance in PAAD were explored in GEO datasets and tissue microarray. Functional experiments were used to determine the OCIAD2 cell functions in vitro and in vivo. GSEA, western blot and immunohistochemistry were used to uncover the potential mechanism. RESULTS: OCIAD2 expression level was closely correlated with clinical relevance in many cancer types through pan-cancer analysis, and we found OCIAD2 was highly expressed in PAAD and associated with poorer prognosis. OCIAD2 acted as the promotor of Warburg effect and influenced PAAD cells proliferation, migration and apoptosis. Mechanistically, OCIAD2 upregulation may boost glycolysis in PAAD via activating the AKT signaling pathway in PAAD. CONCLUSIONS: In PAAD, OCIAD2 promotes Warburg effect via AKT signaling pathway and targeting cancer cells metabolic reprogramming could be a potential treatment.

[Analysis of the Current Application Status for Clinical and Home Monitoring of Obstructive Sleep Apnea-Hypopnea Syndrome].

The study provides an overview of the development status of sleep disorder monitoring devices. Currently, polysomnography (PSG) is the gold standard for diagnosing sleep disorders, necessitating multiple leads and requiring overnight monitoring in a sleep laboratory, which can be cumbersome for patients. Nevertheless, the performance of PSG has been enhanced through research on sleep disorder monitoring and sleep staging optimization. An alternative device is the home sleep apnea testing (HSAT), which enables patients to monitor their sleep at home. However, HSAT does not attain the same level of accuracy in sleep staging as PSG, rendering it inappropriate for screening individuals with asymptomatic or mild obstructive sleep apnea-hypopnea syndrome (OSAHS). The study suggests that establishing a Chinese sleep staging database and developing home sleep disorder monitoring devices that can serve as alternatives to PSG will represent a future development direction.

Construction of blackberry polysaccharide nano-selenium particles: Structure features and regulation effects of glucose/lipid metabolism in HepG2 cells.

In this study, blackberry polysaccharide-selenium nanoparticles (BBP-24-3Se) were first prepared via Na2SeO3/Vc redox reaction, followed by coating with red blood cell membrane (RBC) to form core-shell structure polysaccharide-selenium nanoparticles (RBC@BBP-24-3Se). The particle size of BBP-24-3Se (167.1 nm) was increased to 239.8 nm (RBC@BBP-24-3Se) with an obvious core-shell structure after coating with RBC. FT-IR and XPS results indicated that the interaction between BBP-24-3 and SeNPs formed a new C-O···Se bond with valence state of Se0. Bioassays indicated that RBC coating markedly enhanced both the biocompatibility and bioabsorbability of RBC@BBP-24-3Se, and the absorption rate of RBC@BBP-24-3Se in HepG2 cells was 4.99 times higher than that of BBP-24-3Se at a concentration of 10 µg/mL. Compared with BBP-24-3Se, RBC@BBP-24-3Se possessed significantly heightened protective efficacy against oxidative damage and better regulation of glucose/lipid metabolism disorder induced by palmitic acid in HepG2 cells. Mechanistic studies demonstrated that RBC@BBP-24-3Se could effectively improve PI3K/AKT signaling pathway to promote glucose metabolism, inhibit the expression of lipid synthesis genes and up-regulate the expression of lipid-decomposing genes through AMPK signaling pathway to improve lipid metabolism. These results provided a theoretical basis for developing a new type of selenium supplement for the treatment of insulin resistance.

Smoking behavior associated upregulation of SERPINB12 promotes proliferation and metastasis via activating WNT signaling in NSCLC.

BACKGROUND: Non-small cell lung cancer (NSCLC) is the leading cause of morality among all malignant tumors. Smoking is one of the most important causes of NSCLC, which contributes not only to the initiation of NSCLC but also to its progression. The identification of specific biomarkers associated with smoking will promote diagnosis and treatment. METHODS: Data mining was used to identify the smoking associated gene SERPINB12. CCK8 assays, colony formation assays, a mouse xenograft model and transwell assays were performed to measure the biological functions of SERPINB12 in NSCLC. GSEA, luciferase reporter assays and immunofluorescence were conducted to explore the potential molecular mechanisms of SERPINB12 in NSCLC. RESULTS: In this study, by data mining the TCGA database, we found that SERPINB12 was greatly upregulated in NSCLC patients with cigarette consumption behavior, while the expression level was positively correlated with disease grade and poor prognosis. SERPINB12 is a kind of serpin peptidase inhibitor, but its function in malignant tumors remains largely unknown. Functionally, knockdown of SERPINB12 observably inhibited the proliferation and metastasis of NSCLC cells in vitro and in vivo. Moreover, downregulation of SERPINB12 attenuated Wnt signaling by inhibiting the nuclear translocation of ß-catenin, which explained the molecular mechanism underlying tumor progression. CONCLUSIONS: In conclusion, SERPINB12 functions as a tumorigenesis factor, which could be a promising biomarker for NSCLC patients with smoking behavior, as well as a therapeutic target.

Novel nano-drug delivery system for natural products and their application.

The development of natural products for potential new drugs faces obstacles such as unknown mechanisms, poor solubility, and limited bioavailability, which limit the broadened applicability of natural products. Therefore, there is a need for advanced pharmaceutical formulations of active compounds or natural products. In recent years, novel nano-drug delivery systems (NDDS) for natural products, including nanosuspensions, nanoliposomes, micelle, microemulsions/self-microemulsions, nanocapsules, and solid lipid nanoparticles, have been developed to improve solubility, bioavailability, and tissue distribution as well as for prolonged retention and enhanced permeation. Here, we updated the NDDS delivery systems used for natural products with the potential enhancement in therapeutic efficiency observed with nano-delivery systems.

Knowledge, Attitudes, Willingness, and Associated Factors to Organ Donation Among Intensive Care Unit Health Care Workers: Findings of a Cross-Sectional Study.

BACKGROUND: The lack of donor organs is a major barrier to the advancement of organ transplantation. This study aimed to understand the current status of knowledge, attitudes, and willingness to donate organs among intensive care unit (ICU) health care workers and analyzed the influencing factors to provide a scientific basis for improving the situation of a serious imbalance between the ratio of organ supply and demand. METHODS: From November 2021 to March 2022, 160 ICU health care workers from 3 level 3A hospitals in Huzhou City, Zhejiang Province, China were chosen as subjects by the cluster sampling method. A cross-sectional study of the participants was carried out using a general information questionnaire, Organ Donation Knowledge Scale, Organ Donation Attitude Scale, and Organ Donation Willingness Scale. The determinants of ICU health care workers' knowledge, attitudes, and willingness toward organ donation were examined using multiple linear regression analysis. RESULTS: A total of 150 ICU health care workers completed the survey within the prescribed time, and the recovery rate of this questionnaire was 93.75%. The score on the Organ Donation Knowledge Scale was 7 (5, 7) points, and the full score was 10 points. The score on the Organ Donation Attitude Scale was (3.87 ± 0.93), and the full score was 7. The Organ Donation Willingness Scale score was 2 (2, 3) out of 5. The results of the multiple linear regression analysis revealed that several factors significantly influenced the score of organ donation knowledge. These factors were identified as the professional title and persuasive experience related to organ donation. Additionally, the score of organ donation attitude was found to be influenced primarily by the persuasive experience of organ donation. Furthermore, the score of organ donation willingness was influenced by 3 main factors: marital status, professional title, and persuasive experience in the context of organ donation. CONCLUSIONS: Although the level of ICU health care workers' knowledge and attitudes toward organ donation was above the median level, they still needed to be improved. The current status of ICU health care workers' desire to donate organs is not optimistic; thus, relevant departments should take specific actions to improve the situation.

Insights into the population pharmacokinetics and pharmacodynamics of quetiapine: a systematic review.

INTRODUCTION: Quetiapine exhibits notable pharmacokinetic and pharmacodynamic (PK/PD) variability, the origins of which are poorly understood. This systematic review summarizes published population PK/PD studies and identifies significant covariates accounting for this variability to inform precision dosing. METHODS: We systematically searched the PubMed, Web of Science, and Embase databases and compared study characteristics, model parameters, and covariate effects. Visual predictive distributions were used to compare different models. Forest plots and Monte Carlo simulations were used to assess the influence of covariates. RESULTS: Six population PK and three population PK/PD studies were included. The median apparent clearance in adults was 87.7 L/h. Strong and moderate cytochrome P450 3A4 inducers increased the apparent clearance approximately fourfold, while strong cytochrome P450 3A4 inhibitors reduced it by 93%. The half-maximum effect concentrations were 82.8 ng/mL for the Brief Psychiatric Rating Scale and 583 ng/mL for dopamine D2 receptor occupancy. Both treatment duration and quetiapine exposure were associated with weight gain. CONCLUSIONS: Concurrent administration of potent or moderate CYP3A4 inducers and inhibitors need to be avoided in quetiapine-treated patients. When co-medication is required, it is recommended to adjust the dosage based on therapeutic drug monitoring. Additional research is warranted to delineate the dose-exposure-response relationships of quetiapine and active metabolite norquetiapine in pediatrics, geriatrics, hepatically-impaired patients, and women using contraceptives or are pregnant or menopausal. PROSPERO REGISTRATION: CRD42023446654.

Assessing perceived participation among older adults total hip arthroplasty and total knee arthroplasty patients six months post-surgery: a cross-sectional study.

Aims: This research sought to assess the perceived levels of participation and autonomy in senior patients who had received total hip arthroplasty (THA) or total knee arthroplasty (TKA) in Hangzhou, China. Furthermore, the study aimed to identify the factors linked to these outcomes. Study design: This investigation will utilize a cross-sectional study design to assess perceived participation and autonomy among older adults total hip arthroplasty (THA) and total knee arthroplasty (TKA) patients. The research was conducted in Hangzhou, China, at a tertiary hospital. Methods: Convenient sampling was utilized to select 139 patients who underwent THA or TKA between March 2022 and March 2023 and met the inclusion criteria at a tertiary hospital in Hangzhou. The Impact on Participation and Autonomy Questionnaire, Hip/Knee Injury and Osteoarthritis Outcome Score (HOOS/KOOS), 5-Item Geriatric Depression Scale, Multidimensional Scale of Perceived Social Support, and Elders Health Empowerment Scale were used to assess perceived participation, hip/knee-related symptoms and functional restrictions, depression symptoms, social support, and health empowerment. Results: The mean score for perceived participation and autonomy was 22.554 (SD: 13.042). The mean scores for participation in indoor autonomy, outdoor autonomy, family roles, and social relations were 0.654 (SD: 0.608), 1.324 (SD: 0.792), 1.053 (SD: 0.657), and 0.664 (SD: 0.542), respectively. Negative correlations were observed between perceived participation/autonomy scores and HOOS/KOOS, social support, and health empowerment scores. Conversely, a positive correlation was found between perceived participation/autonomy scores and depression scores. The detrimental effect of HOOS/KOOS, social support, and health empowerment scores on perceived participation and autonomy was notable, while the impact of depressive symptoms was comparatively minor. Conclusion: Older Chinese patients, at first six months post THA/TKA surgery, reported higher levels of perceived participation compared to individuals with other conditions, such as stroke patients. Functional limitations resulting from hip/knee-related symptoms, as well as social support and health empowerment, emerged as significant influencing factors for perceived participation and autonomy. This research enhances our comprehension of the elements influencing perceived participation among older adults individuals who have undergone THA/TKA procedures.

Corrigendum: Comparison of the effectiveness and safety of perampanel and oxcarbazepine as monotherapy in children and adolescents with newly diagnosed focal epilepsy.

[This corrects the article DOI: 10.3389/fphar.2023.1189058.].

Comparison of the effectiveness and safety of perampanel and oxcarbazepine as monotherapy in children and adolescents with newly diagnosed focal epilepsy.

Objective: This study aims to compare the effectiveness and safety of perampanel and oxcarbazepine as monotherapy in children with focal epilepsy (FE). Methods: This is an ambispective, single-center, non-inferiority study comparing the effectiveness and safety of perampanel (PER) monotherapy and oxcarbazepine (OXC) monotherapy in children with newly diagnosed FE. The primary endpoint was a six-month seizure freedom rate. The secondary endpoints included retention, responder, and seizure freedom rates at 3, 6, and 12 months, respectively. Adverse events (AEs) were also recorded for both groups. Results: One hundred and thirty children and adolescents aged from 4 to 18years newly diagnosed with FE between May 2020 and November 2022 in Wuhan Children's Hospital were included. There were 71 patients in the PER group and 59 patients in the OXC group. In the per protocol set (PPS), 50 (78.1%) in the PER group and 43 (78.2%) in the OXC group completed six months of treatment without seizures. The lower 95% CI (66.0%-87.5%) limit of PER was higher than the non-inferiority margin of 62.4% (80% of the 6-month seizure freedom rate in the OXC group); PER was non-inferior to OXC. The 3-month and 12-month seizure freedom rates were 77.1% and 82.9% for the PER group, respectively, while they were 80.4% and 75.8% for the OXC group. There were no serious adverse events in both groups. Conclusion: PER showed comparable effectiveness and safety compared with OXC in children with newly diagnosed focal epilepsy, which might be an effective and safe treatment for children and adolescents with newly diagnosed FE. Clinical Trial Registration: Identifier ChiCTR2300074696.

Targeting abnormal lipid metabolism of T cells for systemic lupus erythematosus treatment.

Systemic lupus erythematosus (SLE) is an autoimmune disease in which the immune system attacks its own tissues and organs. However, the causes of SLE remain unknown. Dyslipidemia is a common symptom observed in SLE patients and animal models and is closely correlated to disease activity. Lipid metabolic reprogramming has been considered as a hallmark of the dysfunction of T cells in patients with SLE, therefore, manipulating lipid metabolism provides a potential therapeutic target for treating SLE. A better understanding of the underlying mechanisms for the metabolic events of immune cells under pathological conditions is crucial for tuning immunometabolism to manage autoimmune diseases such as SLE. In this review, we aim to summarize the cross-link between lipid metabolism and the function of T cells as well as the underlying mechanisms, and provide light on the novel therapeutic strategies of active compounds from herbals for the treatment of SLE by targeting lipid metabolism in immune cells.

Clinical application of a body area network-based smart bracelet for pre-hospital trauma care.

Objective: This study aims to explore the efficiency and effectiveness of a body area network-based smart bracelet for trauma care prior to hospitalization. Methods: To test the efficacy of the bracelet, an observational cohort study was conducted on the clinical data of 140 trauma patients pre-admission to the hospital. This study was divided into an experimental group receiving smart bracelets and a control group receiving conventional treatment. Both groups were randomized using a random number table. The primary variables of this study were as follows: time to first administration of life-saving intervention, time to first administration of blood transfusion, time to first administration of hemostatic drugs, and mortality rates within 24 h and 28 days post-admission to the hospital. The secondary outcomes included the amount of time before trauma team activation and the overall length of patient stay in the emergency room. Results: The measurement results for both the emergency smart bracelet as well as traditional equipment showed high levels of consistency and accuracy. In terms of pre-hospital emergency life-saving intervention, there was no significant statistical difference in the mortality rates between both groups within 224 h post-admission to the hospital or after 28-days of treatment in the emergency department. Furthermore, the treatment efficiency for the group of patients wearing smart bracelets was significantly better than that of the control group with regard to both the primary and secondary outcomes of this study. These results indicate that this smart bracelet has the potential to improve the efficiency and effectiveness of trauma care and treatment. Conclusion: A body area network-based smart bracelet combined with remote 5G technology can assist the administration of emergency care to trauma patients prior to hospital admission, shorten the timeframe in which life-saving interventions are initiated, and allow for a quick trauma team response as well as increased efficiency upon administration of emergency care.

Application of rectal balloon ice water stimulation for the rehabilitation of stroke patients with neurogenic bowel dysfunction.

BACKGROUND: Neurogenic bowel dysfunction (NBD) is a common complication in stroke patients. OBJECTIVE: To investigate the effect of rectal balloon ice water stimulation on the rehabilitation of patients with NBD after a cerebral stroke. METHODS: Forty stroke patients with NBD were selected between March and August 2022 and randomly divided into a study group (n = 20) and a control group (n = 20). Based on routine rehabilitation training, rectal balloon ice water stimulation or finger rectal stimulation were performed on the study or control group, respectively. After two weeks, the changes in the NBD, self-rating depression scale (SDS) and self-rating anxiety scale (SAS) scores were compared between the two groups. RESULTS: Before the intervention, there were no significant differences in age, sex ratio, and NBD, SDS and SAS scores between the two groups (p > 0.05). The NBD, SDS and SAS scores of both groups were significantly decreased following intervention (p < 0.05). After 2 weeks of intervention, the NBD score of the study group was significantly lower than that of the control group (5.50±1.28 vs 6.45±1.05; p = 0.014). The SDS score of the study group was lower than that of the control group, and the difference was statistically significant (32.30±2.81 vs 44.05±2.19; p = 0.014). The study group also had significantly lower SAS scores than the control group (p = 0.024). In addition, the incidence of dizziness, headaches, nausea, vomiting and abdominal pain and distension in the study group was significantly lower than in the control group (p < 0.05). CONCLUSION: Rectal balloon ice water stimulation can significantly improve stroke patients with NBD's intestinal function and psychological status.

PRMT5 activates KLF5 by methylation to facilitate lung cancer.

The highly expressed oncogenic factor Krüppel-like factor 5 (KLF5) promotes various cancerous processes, such as cell growth, survival, anti-apoptosis, migration and metastasis, particularly in lung cancer. Nevertheless, the modifications to KLF5 after translation are poorly understood. Protein arginine methyltransferase 5 (PRMT5) is considered as an oncogene known to be involved in different types of carcinomas, including lung cancer. Here, we show that the expression levels of PRMT5 and KLF5 are highly expressed lung cancer. Moreover, PRMT5 interacts with KLF5 and facilitates the dimethylation of KLF5 at Arginine 41 in a manner that depends on methyltransferase activity. Downregulation or pharmaceutical suppression of PRMT5 reduces the expression of KLF5 and its downstream targets both in vitro and in vivo. Mechanistically, the dimethylation of KLF5 by PRMT5 promotes the maintenance and proliferation of lung cancer cells at least partially by stabilising KLF5 via regulation of the Akt/GSK3ß signalling axis. In summary, PRMT5 methylates KLF5 to prevent its degradation, thereby promoting the maintenance and proliferation of lung cancer cells. These results suggest that targeting PRMT5/KLF5 axis may offer a potential therapeutic strategy for lung cancer.

Sinomenine ameliorates collagen-induced arthritis in mice by targeting GBP5 and regulating the P2X7 receptor to suppress NLRP3-related signaling pathways.

Sinomenine (SIN) is an isoquinoline alkaloid isolated from Sinomenii Caulis, a traditional Chinese medicine used to treat rheumatoid arthritis (RA). Clinical trials have shown that SIN has comparable efficacy to methotrexate in treating patients with RA but with fewer adverse effects. In this study, we explored the anti-inflammatory effects and therapeutic targets of SIN in LPS-induced RAW264.7 cells and in collagen-induced arthritis (CIA) mice. LPS-induced RAW264.7 cells were pretreated with SIN (160, 320, 640 µM); and CIA mice were administered SIN (25, 50 and 100 mg·kg-1·d-1, i.p.) for 30 days. We first conducted a solvent-induced protein precipitation (SIP) assay in LPS-stimulated RAW264.7 cells and found positive evidence for the direct binding of SIN to guanylate-binding protein 5 (GBP5), which was supported by molecular simulation docking, proteomics, and binding affinity assays (KD = 3.486 µM). More importantly, SIN treatment markedly decreased the expression levels of proteins involved in the GBP5/P2X7R-NLRP3 pathways in both LPS-induced RAW264.7 cells and the paw tissue of CIA mice. Moreover, the levels of IL-1ß, IL-18, IL-6, and TNF-α in both the supernatant of inflammatory cells and the serum of CIA mice were significantly reduced. This study illustrates a novel anti-inflammatory mechanism of SIN; SIN suppresses the activity of NLRP3-related pathways by competitively binding GBP5 and downregulating P2X7R protein expression, which ultimately contributes to the reduction of IL-1ß and IL-18 production. The binding specificity of SIN to GBP5 and its inhibitory effect on GBP5 activity suggest that SIN has great potential as a specific GBP5 antagonist.