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RCM-102 is a Chinese herbal medicine formulation derived from a formula which was shown to be effective in treating seasonal allergic rhinitis (SAR) in a randomized placebo-controlled trial. The aim of this study was to investigate the in vitro effect of RCM-102 on the formation of inflammatory mediators, histamine, prostaglandin and nitric oxide, which are known to be involved in the pathophysiology of SAR. The effect of RCM-102 on histamine release was tested in compound 48/80-stimulated rat peritoneal mast cells. The effects of RCM-102 on the release of NO and prostaglandins (PGE(2)) and the expression of inducible NO synthase (iNOS) and COX-2 were studied in lipopolysaccharide (LPS)-stimulated RAW 264.7 cells. In rat peritoneal mast cells, RCM-102 significantly reduced the compound 48/80-induced histamine release. It also significantly reduced NO and PGE(2) production as well as the expression of COX-2 and iNOS in RAW 264.7 cells. These findings indicate that RCM-102 inhibits the formation of several allergic/inflammatory mediators and thus may be used for treating related conditions such as SAR. The actions of RCM-102 are likely to be contributed by the synergistic actions of individual herbal ingredients. [ABSTRACT FROM AUTHOR]

Tanshinone IIB (TSB) is a major active constituent of the roots of Salvia miltiorrhiza (Danshen) widely used in the treatment of stroke and coronary heart disease in Asian countries. This study investigated the in vitro neuroprotective effects of TSB and the underlying mechanism. Co-treatment with TSB significantly inhibited the cytotoxicity and apoptosis of rat cortical neurons induced by staurosporine in a concentration-dependent manner. Consistently, TSB significantly reduced the DNA laddering caused by staurosporine in a concentration-dependent manner. TSB also suppressed the elevated Bax protein and decreased bcl-2 and caspase-3 proteins induced by staurosporine in rat cortical neurons. These findings indicated that TSB had a neuroprotective effect via inhibition of apoptosis. Further studies are warranted to investigate the role of other apoptosis-related signaling proteins and reperfusion-related mechanisms in the protective effect of TSB on neurons. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To investigate the efficacy of electroacupuncture, applied to distal acupoints only, for tension-type headache. BACKGROUND: Electroacupuncture is commonly used for tension-type headache, but when applied to distal acupoints only, evidence of its efficacy is lacking. DESIGN: A randomized, single-blinded, sham-controlled, crossover clinical trial. Methods.-The trial had 5 stages: baseline (2 weeks), phases I and II (each 4 weeks), washout period (2 weeks), and follow-up (3 months after phase II). Forty patients were randomly assigned to either group A or group B. Group A received real electroacupuncture during phase I, then sham electroacupuncture in phase II. Group B received the treatments in reverse order. Outcome measures were headache frequency and duration, pain intensity using a visual analog scale, mechanical pain threshold, headache disability, and sickness impact. Data were analyzed by univariate 2-way analysis of variance. RESULTS: Thirty-seven patients completed the trial. There were no significant differences between the 2 groups at baseline. At the end of phase I, group A, but not group B, demonstrated significant improvement in mean (standard error of the mean [SEM]) headache frequency (3.0 per month [0.3] versus 12.0 per month [1.7]), duration (13.3 hours [3.5] versus 32.0 hours [6.2]), pain intensity (32.8 mm [4.1] versus 47.5 mm [2.7]), pain threshold (right side, 2.9 kg/second [0.1] versus 0.9 kg/second [0.1]; left side, 2.4 kg/second [0.1] versus 1.1 kg/second [0.1]), headache disability score (6.0 [1.0] versus 16.3 [1.6]), and sickness impact score (288.7 [48.0] versus 687.1 [77.2]). For each parameter, significant differences also were demonstrated for both groups between baseline and phase II, and baseline and follow-up. There were no significant differences between the groups at the end of follow-up (P >.05). CONCLUSION: Electroacupuncture to distal points alone is effective for short-term symptomatic relief of tension-type headache. [ABSTRACT FROM AUTHOR]

The clinical efficacy and safety of acupuncture in the treatment of Seasonal Allergic Rhinitis (SAR) was evaluated by employing a two-phase crossover single-blind clinical trial. Thirty subjects were randomly assigned to two groups with 17 and 13 subjects respectively and treated with real or sham acupuncture (three times per week) for four consecutive weeks and then a crossover for treatments for a further four weeks without a washout period. The administration of real acupuncture treatment was guided by a syndrome differentiation according to Chinese Medicine Theory. Subjects were assessed by various criteria before, during and after the treatments. Outcome measures included subjective symptom scores using a five-point scale (FPS), relief medication scores (RMS) and adverse effect records. Twenty-six (26) subjects completed the study. There was a significant improvement in FPS (nasal and non-nasal symptoms) between the two types of acupuncture treatments. No significant differences were shown in RMS between the real acupuncture treatment group and the sham acupuncture treatment group. No side effects were observed for both groups. The results indicate that acupuncture is an effective and safe alternative treatment for the management of SAR. [ABSTRACT FROM AUTHOR]

Objectives.Necrotizing vasculitis and granuloma formation are the predominant features of Wegener's granulomatosis (WG). We have investigated the importance of vascular endothelial growth factor (VEGF) in monitoring disease activity in WG. [ABSTRACT FROM PUBLISHER]

CONTEXT: Chinese herbal medicine (CHM) is widely used to treat seasonal allergic rhinitis (SAR), however, evidence of efficacy is lacking. OBJECTIVE: To evaluate the efficacy of a Chinese herbal formulation for the treatment of SAR. DESIGN: Randomized, double blind, placebo controlled trial. SETTING: RMIT Chinese Medicine Clinic. PATIENTS: 55 patients with seasonal allergic rhinitis (active 28, placebo 27). INTERVENTIONS: CHM extract capsule (containing 18 herbs) or placebo, given daily for 8 weeks. MAIN OUTCOME MEASURES: The primary measure of efficacy were changes in severity of nasal and non-nasal symptoms using a Five Point Scale (FPS) measured by both patients and the practitioner. The secondary measure was the change in score for the domains measured in the Rhinoconjunctivitis and Rhinitis Quality of Life Questionnaire (RQLQ) assessed by patients. RESULTS: Forty-nine patients completed the study (active 24, placebo 25). After eight weeks, the severity of nasal symptoms and non-nasal symptoms were significantly less in the active treatment group than in the control group, both for measurements made by patients and those by the practitioner. Comparison of active and placebo treatment groups RQLQ scores also indicated significant beneficial effects of treatment (end point Section 1: P < 0.05; Section 2: P < 0.01). Intention-to-treat analyses of categorical items showed moderate to marked improvement rates were 60.7% and 29.6% for active and placebo respectively. Eleven patients reported mild adverse events including 1 withdrawn from the trial. CONCLUSIONS: This CHM formulation appears to offer symptomatic relief and improvement of quality of life for some patients with seasonal allergic rhinitis. [ABSTRACT FROM AUTHOR]

Objectives: To investigate the impact of different pretreatment strategies and cleaning methods on the cleaning efficacy of electrosurgical instruments, aiming to propose an optimal protocol., Methods: A total of 573 electrosurgical instruments were collected from three large-scale hospitals within two hours post-use from December 2023 to July 2024. The instruments were categorized into six group: medical alkaline or multi-enzyme cleaner, or instant foam-type multi-enzyme humectant, followed by either manual cleaning or vacuum boiling washer. Cleaning quality was assessed through visual estimation, residual protein detection and adenosine triphosphate (ATP) biological fluorescence detection., Results: Visual assessment indicated that different pretreatment and cleaning methods did not significantly affect cleaning quality (P>0.05). Residual protein detection analysis revealed that mechanical cleaning outperformed manual cleaning (adjusted odds ratio [AOR]=2.20, 95% confidence interval [CI]=1.18-4.11, P=0.013), with both the medical multi-enzyme cleaner (AOR=3.72, 95%CI=1.11-12.44, P=0.033) and the instant foam-type multi-enzyme humectant (AOR=3.27, 95% CI=1.07-10.03, P=0.038) combined with mechanical cleaning demonstrating superior performance. ATP detection confirmed that mechanical cleaning was more effective than manual cleaning (AOR=5.10, 95% CI=2.00-12.95, P<0.001), particularly when using medical alkaline (AOR=6.79, 95%CI=1.36-33.83, P=0.019) or multi-enzyme cleaner (AOR=6.77, 95% CI=1.43-31.95, P=0.016) combined with mechanical cleaning exhibiting enhanced efficacy., Conclusion: Vacuum boiling washer emerged as a critical factor for improving the cleaning efficacy of electrosurgical instruments while no significant differences were observed among three pretreatment strategies: medical alkaline cleaner, medical multi-enzyme cleaner and instant foam-type multi-enzyme humectant. Furthermore, even electrosurgical instruments with complex structures maintain adequate cleanliness after standardized pretreatment and cleaning protocols., Competing Interests: Declaration of Competing Interest None declared., (Copyright © 2025. Published by Elsevier Ltd.)

Allergic rhinitis (AR), a chronic airway inflammation, has witnessed a rising prevalence in recent decades. Recent research indicates that various EVs are released into plasma in allergic airway inflammation, correlating with impaired airway function and severe inflammation. However, the contribution of plasma EVs to AR pathogenesis remains incompletely understood. We isolated plasma EVs using differential ultracentrifugation or size exclusion chromatography (SEC) and obtained differential microRNA (miRNA) expression profiles through miRNA sequencing. Peripheral blood mononuclear cells (PBMCs) were exposed to plasma EVs and miRNA mimics and inhibitors to assess the effect of plasma EVs and the underlying mechanisms. We found that EVs from HC and AR patients exhibited comparable characteristics in terms of concentration, structure, and EV marker expression. AR-EVs significantly enhanced Th2 cell levels and promoted ILC2 differentiation and IL-13 + ILC2 levels compared to HC-EVs. Both HC-EVs and AR-EVs were efficiently internalized by CD4 + T cells and ILCs. miRNA sequencing of AR-EVs revealed unique miRNA signatures implicated in diverse biological processes, among which miR-150-5p, miR-144-3p, miR-10a-5p, and miR-10b-5p were identified as pivotal contributors to AR-EVs' effects on CD4 + T cells and ILC2s. MiR-150-5p exhibited the most pronounced impact on cell differentiation and was confirmed to be upregulated in AR-EVs by PCR. In total, our study demonstrated that plasma EVs from patients with AR exhibited a pronounced capacity to significantly enhance the differentiation of Th2 cells and ILC2, which was correlated with an elevated expression of miR-150-5p within AR-EVs. These findings contribute to the advancement of our comprehension of EVs in the pathogenesis of AR and hold the potential to unveil novel therapeutic targets for the treatment of AR., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Objective: To investigate the therapeutic effect of Xiangshao Granules (XSG) on post-stroke depression (PSD) and explore the underlying mechanisms., Methods: Forty-three C57BL/6J mice were divided into 3 groups: sham (n=15), PSD+vehicle (n=14), and PSD+XSG (n=14) groups according to a random number table. The PSD models were constructed using chronic unpredictable mild stress (CUMS) after middle cerebral artery occlusion (MCAO). The sham group only experienced the same surgical operation, but without MACO and CUMS stimulation. The XSG group received XSG (60 mg/kg per day) by gavage for 4 weeks. The mice in the sham and vehicle groups were given the same volume of 0.9% saline at the same time. The body weight and behavior tests including open field test, sucrose preference test, tail suspension test, and elevated plus-maze test, were used to validate the PSD mouse model. Real-time fluorescence quantitative polymerase chain reaction (RT-qPCR), enzyme-linked immunosorbent assay (ELISA), and immunofluorescence staining were used to evaluate the anti-inflammatory effects of XSG. The potential molecular mechanisms were explored and verified through network pharmacology analysis, Nissl staining, Western blot, ELISA, and RT-qPCR, respectively., Results: The body weight and behavior tests showed that MCAO combined with CUMS successfully established the PSD models. XSG alleviated neuronal damage, reduced the expressions of pro-apoptotic proteins Caspase-3 and B-cell lymphoma-2 (BCL-2)-associated X (BAX), and increased the expression of anti-apoptotic protein BCL-2 in PSD mice (P<0.05 or P<0.01). XSG inhibited microglial activation and the expressions of pro-inflammatory cytokines including tumor necrosis factor-α, interleukin (IL)-1 β, and IL-6 via the toll-like receptor 4/nuclear factor kappa-B signaling pathway in PSD mice (P<0.05 or P<0.01). Furthermore, XSG decreased the expression of indoleamine 2,3-dioxygenase1 (IDO1) and increased the concentration of 5-hydroxytryptamine in PSD mice (P<0.05 or P<0.01)., Conclusion: XSG could reverse the anxiety/depressionlike behaviors and reduce the neuronal injury in the hippocampus and prefrontal cortex of PSD mice, which may be a potential therapeutic agent for PSD., Competing Interests: Conflict of Interest. The authors declare that they have no conflicts of interest in this work., (© 2024. The Chinese Journal of Integrated Traditional and Western Medicine Press and Springer-Verlag GmbH Germany, part of Springer Nature.)

Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Previous studies showed that serum amyloid A (SAA) and macrophages were associated with allergic airway inflammation. However, the interaction between SAA1 and macrophages in allergic airway inflammation remains to be further elucidated. In this study, the levels of SAA1 were measured in nasal tissues from patients with eosinophilic chronic rhinosinusitis with nasal polyps (CRSwNP), house dust mite (HDM)-treated BEAS-2B cells and the tissues of mice of HDM-induced allergic airway inflammation. Human monocytes-derived macrophages and mouse bone marrow-derived macrophages (BMDMs) were exposed to SAA1, and CCL17 and the other M1/M2-related factors were evaluated using RT-PCR and/or ELISA. To test the effects of SAA1-treated BMDMs on chemotaxis and differentiation of CD4 + T cells, number of migrated cells and the levels of Th1 and Th2 were measured using flow cytometry. SAA1 receptors were examined in BMDMs and lung macrophages of model mice. CD36 neutralizing antibody was applied to explore the mechanisms of SAA1 in regulating BMDMs using RT-PCR and/or ELISA. We found that SAA1 was expressed in epithelial cells, and was increased in the nasal tissues of patients with eosinophilic CRSwNP and HDM-treated BEAS-2B- cells as well as the bronchoalveolar lavage fluid and lung tissues of mice exposed to HDM. We also found that the level of CCL17 was increased in M2 macrophages, more CD4 + T cells were recruited and proportion of Th2 was increased after the treatment of SAA1. The treatment of CD36 neutralizing antibody decreased CCL17 level in SAA1-treated M2 BMDMs. In summary, our results showed that SAA1 was increased in allergic airway inflammation, and the administration of SAA1 upregulated the expression of CCL17 in M2 macrophages via CD36 and promoted the chemotaxis of CD4 + T cells and differentiation of Th2. It may provide a new therapeutic strategy that could mediate allergic airway inflammation via suppressing SAA1 to reduce recruitment of CD4 + T cells and activation of Th2., (Copyright © 2024. Published by Elsevier B.V.)

Exercise activates autophagy and lysosome system in skeletal muscle, which are known to play an important role in metabolic adaptation. However, the mechanism of exercise-activated autophagy and lysosome system in obese insulin resistance remains covert. In this study, we investigated the role of exercise-induced activation of autophagy and lysosome system in improving glucose metabolism of skeletal muscle. Male C57BL/6 mice were randomly divided into five groups: the chow diet (CD) group, the high-fat diet (HFD) group, the high-fat diet plus exercise (HFD-E) group and the HFD-E treated with calcineurin inhibitor FK506 (HFD-E-F) or saline (HFD-E-S) groups. The mice in exercise groups (HFD-E, HFD-E-F and HFD-E-S) were subjected to aerobic treadmill exercise (speed at 12 m/min for 1 h per session, 0° slope, 5 days per week for 12 weeks). Mice of HFD-E-F group were intraperitoneally administered FK506 (1 mg/kg), once each day for 2 weeks before the end of exercise. Expressions pTFEB, T-TFEB and autophagy-lysosome markers, including Beclin1, LC3, ULK1, SQSTM1, LAMP1, CTSD and CTSL proteins in gastrocnemius muscle were analysed. We demonstrated that HFD induced insulin resistance and decreased autophagy-lysosomal proteins and the exercise significantly increased transcription factor EB (TFEB) translocation from the cytoplasm to the nucleus, restored the impaired autophagy-lysosomal-related protein expressions, and improved glucose metabolism. The increase in TFEB nuclear translocation was partly blocked by the calcineurin inhibitor FK506. Our results suggest that exercise promotes autophagy and lysosome restoration by regulating calcineurin-mediated TFEB nuclear translocation, ultimately alleviating HFD-induced insulin resistance in mice skeletal muscle., (© 2025 John Wiley & Sons Australia, Ltd.)

The fracture position of a friction plug welding (FPW) joint is typically located at or near the thermo-mechanically affected zone (TMAZ). Here, we found that microcracks in all FPW specimens initiate at the deformed plug center (DPC) zone and then propagate through the plug center along 45° shear surfaces, because the lowest hardness occurs at the DPC zone rather than the TMAZ or other zones, and the DPC zone presents a tilt fiber-like microstructure. Such a tilt microstructure stimulates formations and deformations of microvoids and propagation of microcracks along 45° shear surfaces. The ultimate tensile strength (237.7 MPa) and yield strength (220.8 MPa) of the FPW joint reach 78.8% and 85.7% of the base metal, respectively. These results indicate that 6061-T6 aluminum alloy can be effectively joined by the FPW technique.

Modeling the architecture search process on a supernet and applying a differentiable method to find the importance of architecture are among the leading tools for differentiable neural architectures search (DARTS). One fundamental problem in DARTS is how to discretize or select a single-path architecture from the pretrained one-shot architecture. Previous approaches mainly exploit heuristic or progressive search methods for discretization and selection, which are not efficient and easily trapped by local optimizations. To address these issues, we formulate the task of finding a proper single-path architecture as an architecture game among the edges and operations with the strategies "keep" and "drop" and show that the optimal one-shot architecture is a Nash equilibrium of the architecture game. Then, we propose a novel and effective approach for discretizing and selecting a proper single-path architecture, which is based on extracting the single-path architecture that associates the maximal coefficient of the Nash equilibrium with the strategy "keep" in the architecture game. To further improve the efficiency, we employ a mechanism of entangled Gaussian representation of mini-batches, inspired by the classic Parrondo's paradox. If some mini-batch formed uncompetitive strategies, the entanglement of mini-batches would ensure the games be combined and, thus, turn into strong ones. We conduct extensive experiments on benchmark datasets and demonstrate that our approach is significantly faster than the state-of-the-art progressive discretizing methods while maintaining competitive performance with higher maximum accuracy.

Background: Postoperative pain management remains a significant challenge for patients undergoing posterior urethroplasty (PU). In a previous study, we proposed a novel technique of combined pudendal nerve (PN) and spermatic cord (SC) block to manage pain after PU. The present trial was conducted to test the hypothesis that this technique is effective for pain control after PU and provides longer-lasting analgesia than caudal epidural block (CB)., Methods: Sixty patients undergoing PU were randomized into two groups: Group NB received combined PN and SC block, and Group CB received CB. General anesthesia with a laryngeal mask was performed. The primary outcome was the postoperative analgesic duration, and the secondary outcomes included the Numeric Rating Scale (NRS) scores for pain and the number of patients with different motor scores of the lower limb at 3, 6, 12, and 24 h postoperatively., Results: Two patients in Group CB were withdrawn due to block failure. The postoperative analgesic duration was statistically longer in Group NB compared with Group CB (mean difference [95% confidence interval], 115.78 min [17.80, 213.75]; P = 0.021). The NRS scores for pain at 12 and 24 h after surgery were statistically lower in Group NB compared with Group CB. Group NB had statistically more patients with motor score 0 at 3 h postoperatively than Group CB., Conclusions: PN combined with SC block is an effective technique for postoperative analgesia in PU. This technique can achieve a longer duration of analgesia and lower pain scores, especially 12 h after surgery, than a CB., Trial Registration: This study was registered in the Chinese Clinical Trial Register (registration no. ChiCTR2100042971, registration date on 2/2/2021)., (© 2024. The Author(s).)

Background: Accurate preoperative evaluation of microvascular invasion (MVI) in hepatocellular carcinoma (HCC) is crucial for surgeons to make informed decisions regarding appropriate treatment strategies. However, it continues to pose a significant challenge for radiologists. The integration of computer-aided diagnosis utilizing deep learning technology emerges as a promising approach to enhance the prediction accuracy. Methods: This experiment incorporated magnetic resonance imaging (MRI) scans with six different sequences. After a cross-sequence registration preprocess, a deep neural network was employed for the segmentation of hepatocellular carcinoma. The final prediction model was constructed by combining radiomics features with clinical features. The selection of clinical features for the final model was determined through univariate analysis. Results: In this study, we analyzed MRI scans obtained from a cohort of 420 patients diagnosed with HCC. Among them, 140 cases exhibited MVI, while the remaining 280 cases comprised the non-MVI group. The radiomics features demonstrated strong predictive capability for MVI. By extracting radiomic features from each MRI sequence and subsequently integrating them, we achieved the highest area under the curve (AUC) value of 0.794±0.033. Specifically, for tumor sizes ranging from 3 to 5 cm, the AUC reached 0.860±0.065. Conclusions: In this study, we present a fully automatic system for predicting MVI in HCC based on preoperative MRI. Our approach leverages the fusion of radiomics and clinical features to achieve accurate MVI prediction. The system demonstrates robust performance in predicting MVI, particularly in the 3-5 cm tumor group., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Objective: To investigate the independent effects of irisin on insulin resistance (IR) in ovary of polycystic ovary syndrome (PCOS) and explore possible pathways., Methods: We established PCOS medel using Poretsky L's method, then PCOS rats were randomly divided into model group (M) and irisin group (I), and normal rats (N) were used as the control. Then rats in the group I were injected with recombinant irisin. Then the levels of circulating fasting blood glucose (FBG), fasting insulin (FINS), homeostasis model assessment of IR (HOMA-IR) and PI3K/AKT and MAPK/ERK pathways in each group were observed, as well as the effects of irisin on the levels of circulating HOMA-IR and PI3K/AKT and MAPK/ERK pathways in ovary of PCOS rats were evaluated., Results: Compared with normal group, levels of FBG, FINS, and HOMA-IR of model group were significantly increased (p < 0.001, p < 0.001, and p < 0.001, respectively), levels of average optical density by IHC of p-PI3K, PI3K, p-AKT, and AKT (p = 0.015, p = 0.010, p = 0.005, and p = 0.009, respectively) and levels of mRNA concentration of PI3K and AKT (p = 0.001, and p = 0.005, respectively) were decreased, while the levels of average optical density of p-ERK, ERK (p = 0.011, and p = 0.013, respectively) and level of mRNA concentration of ERK (p < 0.001) were increased in ovary. After irisin intervention, compared with model group, levels of FBG, FINS, and HOMA-IR of rats in irisin group were significantly decreased (p = 0.001, p < 0.001, and p < 0.001, respectively), levels of average optical density by IHC of p-PI3K, PI3K, p-AKT, and AKT (p = 0.030, p = 0.024, p = 0.012, and p = 0.025, respectively) and levels of mRNA concentration of PI3K and AKT (p = 0.002, and p = 0.003, respectively) were significantly increased, while the levels of average optical density of p-ERK, ERK (p = 0.004, and p = 0.026, respectively) and level of mRNA concentration of ERK (p = 0.001) were significantly decreased., Conclusion: Our study demonstrated that irisin could not only improve circulating insulin resistance, but may also improve ovarian IR through an increase in the activity of PI3K/AKT signaling and a decrease of MAPK/ERK signaling., (© 2024 Japan Society of Obstetrics and Gynecology.)

Curcumin, as the main active component of turmeric ( Curcuma longa ), has been demonstrated with various bioactivities. However, its potential therapeutic applications are hindered by challenges such as poor solubility and bioavailability, rapid metabolism, and pan-assay interference properties. Recent advancements have aimed to overcome these limitations by developing novel curcumin analogues and modifications. This brief review critically assesses recent studies on synthesising different curcumin analogues, including metal complexes, nano particulates, and other curcumin derivatives, focused on the antioxidant, anti-inflammatory, and anticancer effects of curcumin and its modified analogues. Exploring innovative curcumin derivatives offers promising strategies to address the challenges associated with its bioavailability and efficacy and valuable insights for future research directions.

Mitochondria and lysosomes play a very important role in maintaining cellular homeostasis, and the dysfunction of these organelles is closely related to many diseases. Recent studies have revealed direct interactions between mitochondria and lysosomes, forming mitochondria-lysosome contact sites that regulate organelle network dynamics and mediate the transport of metabolites between them. Impaired function of these contact sites is not only linked to physiological processes such as glucose and cholesterol transport but also closely related to the pathological processes of metabolic diseases. Here, we highlight the recent progress in understanding the mitochondria-lysosome contact sites, elucidate their role in regulating metabolic homeostasis, and explore the potential implications of this pathway in metabolic disorders., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Chen, Li, Zhou, Zhu, Jin and Wang.)

Programmed cell death (PCD) is a fundamental biological process for maintaining cellular equilibrium and regulating development, health, and disease across all living organisms. Among the various types of PCD, apoptosis plays a pivotal role in numerous diseases, notably cancer. Cancer cells frequently develop mechanisms to evade apoptosis, increasing resistance to standard chemotherapy treatments. This resistance has prompted extensive research into alternative mechanisms of programmed cell death. One such pathway is oncosis, characterized by significant energy consumption, cell swelling, dilation of the endoplasmic reticulum, mitochondrial swelling, and nuclear chromatin aggregation. Recent research suggests that oncosis can impact conditions such as chemotherapeutic cardiotoxicity, myocardial ischemic injury, stroke, and cancer, mediated by specific oncosis-related proteins. In this review, we provide a detailed examination of the morphological and molecular features of oncosis and discuss various natural or small molecule compounds that can induce this type of cell death. Additionally, we summarize the current understanding of the molecular mechanisms underlying oncosis and its role in both normal physiology and pathological conditions. These insights aim to illuminate future research directions and propose innovative strategies for leveraging oncosis as a therapeutic tool against human diseases and cancer resistance., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Guo, Yang, Mai, Liang, Luo, Zhou, Yu, Wang and Li.)

Background: Low-density neutrophils are heterogeneous immune cells with immunosuppressive (such as polymorphonuclear myeloid-derived suppressor cells [PMN-MDSC]) or pro-inflammatory (such as low-density granulocytes [LDG]) properties that have been well described in multiple cancers and immune diseases. However, its role in allergic rhinitis (AR) is still unclear., Methods: In the present study, we defined low-density neutrophils as CD14 - CD11B + CD15 + LOX-1 + (LOX-1 + neutrophils), and their levels in the peripheral blood (PB) were evaluated and compared between patients with AR and healthy donors using flow cytometric analysis. LOX-1 expression on polymorphonuclear neutrophils was identified. Carboxyfluorescein succinimidyl ester (CFSE)-stained CD3 + T cells were cultured alone or with LOX-1 + neutrophils, T cell proliferation was assessed using flow cytometry, and pro-inflammatory cytokines in the supernatants were detected using enzyme-linked immunosorbent assay (ELISA). Clinicopathological analyses were performed to gain a thorough understanding of LOX-1 + neutrophils., Results: We determined that LOX-1 + neutrophils were significantly increased in the PB of patients with AR, and LOX-1 expression in neutrophils from patients with AR was elevated. Interestingly, LOX-1 + neutrophils derived from patients with AR, unlike PMN-MDSC, promoted T cell proliferation and pro-inflammatory cytokine production. Moreover, clinicopathological analysis revealed that there was no any relation between circulating LOX-1 + neutrophil levels and the levels of IgE, age and sex., Conclusion: These findings indicate that elevated circulating LOX-1 + neutrophils play a pro-inflammatory role in AR., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors. Published by Elsevier Ltd.)

Background: The Oka varicella vaccine strain remains neurovirulent and can establish lifelong latent infection, raising safety concerns about vaccine-related herpes zoster. In this study, we aimed to evaluate the immunogenicity and safety of a skin-attenuated and neuro-attenuated varicella vaccine candidate (v7D vaccine)., Methods: We did this randomised, double-blind, controlled, phase 2a clinical trial in Jiangsu, China. Healthy children aged 3-12 years with no history of varicella infection or vaccination were enrolled and randomly assigned (1:1:1:1) to receive a single subcutaneous injection of the v7D vaccine at 3·3 log 10 plaque forming units (PFU; low-dose v7D group), 3·9 log 10 PFU (medium-dose v7D group), and 4·2 log 10 PFU (high-dose v7D group), or the positive control varicella vaccine (vOka vaccine group). All the participants, laboratory personnel, and investigators other than the vaccine preparation and management staff were masked to the vaccine allocation. The primary outcome was assessment of the geometric mean titres (GMTs) and seroconversion rates of anti-varicella zoster virus immunoglobulin G (IgG) induced by different dose groups of v7D vaccine at 0, 42, 60, and 90 days after vaccination in the per-protocol set for humoral immune response analysis. Safety was a secondary outcome, focusing on adverse events within 42 days post-vaccination, and serious adverse events within 6 months after vaccination. This study was registered on Chinese Clinical Trial Registry, ChiCTR2000034434., Findings: On Aug 18-21, 2020, 842 eligible volunteers were enrolled and randomly assigned treatment. After three participants withdrew, 839 received a low dose (n=211), middle dose (n=210), or high dose (n=210) of v7D vaccine, or the vOka vaccine (n=208). In the per-protocol set for humoral immune response analysis, the anti-varicella zoster virus IgG antibody response was highest at day 90. At day 90, the seroconversion rates of the low-dose, medium-dose, and high-dose groups of v7D vaccine and the positive control vOka vaccine group were 100·0% (95% CI 95·8-100·0; 87 of 87 participants), 98·9% (93·8-100·0; 87 of 88 participants), 97·8% (92·4-99·7; 91 of 93 participants), and 96·4% (89·8-99·2; 80 of 83 participants), respectively; the GMTs corresponded to values of 30·8 (95% CI 26·2-36·0), 31·3 (26·7-36·6), 28·2 (23·9-33·2), and 38·5 (31·7-46·7). The v7D vaccine, at low dose and medium dose, elicited a humoral immune response similar to that of the vOka vaccine. However, the high-dose v7D vaccine induced a marginally lower GMT compared with the vOka vaccine at day 90 (p=0·027). In the per-protocol set, the three dose groups of the v7D vaccine induced a similar humoral immune response at each timepoint, with no statistically significant differences. The incidence of adverse reactions in the low-dose, medium-dose, and high-dose groups of v7D vaccine was significantly lower than that in the vOka vaccine group (17% [35 of 211 participants], 20% [41 of 210 participants], and 13% [27 of 210 participants] vs 24% [50 of 208 participants], respectively; p=0·025), especially local adverse reactions (10% [22 of 211 participants], 14% [30 of 210 participants] and 9% [18 of 210 participants] vs 18% [38 of 208 participants], respectively; p=0·016). None of the serious adverse events were vaccine related., Interpretation: The three dose groups of the candidate v7D vaccine exhibit similar humoral immunogenicity to the vOka vaccine and are well tolerated. These findings encourage further investigations on two-dose vaccination schedules, efficacy, and the potential safety benefit of v7D vaccine in the future., Funding: The National Natural Science Foundation of China, CAMS Innovation Fund for Medical Sciences, the Fundamental Research Funds for the Central Universities, and Beijing Wantai., Translation: For the Chinese translation of the abstract see Supplementary Materials section., Competing Interests: Declaration of interests J-ZJ, J-LH, and X-ZY are employees of and have stock options in Beijing Wantai. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Background: There is currently a shortage of accurate, efficient, and precise predictive instruments for rectal neuroendocrine neoplasms (NENs)., Aim: To develop a predictive model for individuals with rectal NENs (R-NENs) using data from a large cohort., Methods: Data from patients with primary R-NENs were retrospectively collected from 17 large-scale referral medical centers in China. Random forest and Cox proportional hazard models were used to identify the risk factors for overall survival and progression-free survival, and two nomograms were constructed., Results: A total of 1408 patients with R-NENs were included. Tumor grade, T stage, tumor size, age, and a prognostic nutritional index were important risk factors for prognosis. The GATIS score was calculated based on these five indicators. For overall survival prediction, the respective C-indexes in the training set were 0.915 (95% confidence interval: 0.866-0.964) for overall survival prediction and 0.908 (95% confidence interval: 0.872-0.944) for progression-free survival prediction. According to decision curve analysis, net benefit of the GATIS score was higher than that of a single factor. The time-dependent area under the receiver operating characteristic curve showed that the predictive power of the GATIS score was higher than that of the TNM stage and pathological grade at all time periods., Conclusion: The GATIS score had a good predictive effect on the prognosis of patients with R-NENs, with efficacy superior to that of the World Health Organization grade and TNM stage., Competing Interests: Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

The challenges of the COVID-19 pandemic have highlighted an increasing clinical demand for safe and effective treatment options against an overzealous immune defence response, also known as the "cytokine storm". Andrographolide is a naturally derived bioactive compound with promising anti-inflammatory activity in many clinical studies. However, its cytokine-inhibiting activity, in direct comparison to commonly used nonsteroidal anti-inflammatory drugs (NSAIDs), has not been extensively investigated in existing literature. The anti-inflammatory activities of andrographolide and common NSAIDs, such as diclofenac, aspirin, paracetamol and ibuprofen were measured on lipopolysaccharide (LPS) and interferon-γ induced RAW264.7 cells. The levels of PGE2, nitric oxide (NO), TNF-α & LPS-induced release of pro-inflammatory cytokines on differentiated human macrophage THP-1 cells were measured against increasing concentrations of andrographolide and aforementioned NSAIDs. The associated mechanistic pathway was examined on NFκB using flow cytometry on the human endothelial-leukocyte adhesion molecule (ELAM9) (E-selectin) transfected RAW264.7 cells with green fluorescent protein (GFP). Andrographolide exhibited broad and potent anti-inflammatory and cytokine-inhibiting activity in both cell lines by inhibiting the release of IL-6, TNF-α and IFN-γ, which are known to play a key role in the etiology of cytokine storm and the pathogenesis of inflammation. In comparison, the tested NSAIDs demonstrated weak or no activity against proinflammatory mediators except for PGE2, where the activity of andrographolide (IC50 = 8.8 μM, 95% CI = 7.4 to 10.4 μM) was comparable to that of paracetamol (IC50 = 7.73 μM, 95% CI = 6.14 to 9.73 μM). The anti-inflammatory action of andrographolide was associated with its potent downregulation of NFκB. The wide-spectrum anti-inflammatory activity of andrographolide demonstrates its therapeutic potential against cytokine storms as an alternative to NSAIDs., Competing Interests: NO authors have competing interests., (Copyright: © 2024 Low et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

In this study, a series of H-bonded arylamide foldamers bearing benzoselenadiazole ends with solvent-responsive properties have been synthesized. In dichloromethane or dimethyl sulfoxide solvents, the molecules exhibit meniscus or linear structures, respectively, which can be attributed to the unique intramolecular hydrogen bonding behavior evidenced by 1D 1 H NMR and 2D NOESY spectra. UV-vis spectroscopy experiments show that the absorption wavelength of H-bonded arylamide foldamers are significantly red-shifted due to the presence of benzoselenadiazole group. In addition, the crystal structures reveal that effective intermolecular dual Se ⋅ ⋅ ⋅ N interactions between benzoselenadiazole groups induce further assembly of the monomers. Remarkably, supramolecular linear and double helices structures are constructed under the synergistic induction of intramolecular hydrogen bonding and intermolecular chalcogen bonding. Additionally, 2D DOSY diffusion spectra and theoretical modelling based on density functional theory (DFT) are performed to explore the persistence of intermolecular Se ⋅ ⋅ ⋅ N interactions beyond the crystalline state., (© 2024 Wiley-VCH GmbH.)

Australian fruits such as native currant ( Acrotriche depressa ) and lemon aspen ( Acronychia acidula ) are under-examined in terms of their therapeutic potential. In this study, the in vitro antiproliferative activity of native currant and lemon aspen extracts (water and ethanol) against MCF7 breast adenocarcinoma cells was determined using the Alamar blue assay. The most potent extracts (native currant water, NC-W; native currant ethanol, NC-Et; lemon aspen ethanol, LA-Et) were further evaluated using flow cytometry to detect the potential induction of apoptosis in MCF7 cells whereas 2',7'-dichlorodihydrofluorescein diacetate (H2DCFDA) assay was implemented to understand the impact of the extracts on the intracellular reactive oxygen species (ROS) levels in MCF7 cells. Furthermore, the antioxidant activity of the extracts was assessed using ABTS [2,2'-azinobis-(3-ethylbenzothiazoline-6-sulfonate)], and CUPRAC (cupric reducing antioxidant capacity) assays. The antimicrobial susceptibility testing of NC-W, NC-Et, and LA-Et was carried out against Gram-positive ( Staphylococcus aureus ), Gram-negative ( Escherichia coli ), and yeast ( Candida albicans ) strains using a resazurin-based assay. Additionally, potential metabolites in the NC-W and NC-Et extracts were analysed with liquid chromatography-mass spectrometry (LC-MS) driven metabolomics and chemometrics to spot differential and major metabolites. A dose-dependent antiproliferative activity was conferred by the NC extracts against MCF7 cells. Of the two LA extracts, only LA-Et showed a dose-dependent antiproliferative activity at higher concentrations. Both NC extracts and LA-Et induced apoptosis in MCF7 cells. None of the extracts increased the production of ROS significantly in MCF7 cells compared to the untreated control. A dose-dependent antioxidant activity was observed in both antioxidant assays. Both NC and LA extracts showed a similar minimum inhibitory concentration (MIC) value against S. aureus . Only LA-Et showed activity against E. coli , while NC-W and NC-Et were less active. All extracts showed MIC values of >1500 μg mL -1 against C. albicans . The metabolomics analysis revealed an abundance of flavonoids, fatty acyl derivatives, carbohydrates, carboxylic acids and their derivatives, and alkaloid compounds as potential bioactive metabolites in the NC extracts. In conclusion, both NC and LA showed antiproliferative (against MCF7 breast adenocarcinoma cells through the induction of apoptosis), strong antioxidant and minimal antimicrobial properties.

Cerebral small vessel disease (CSVD) is the most common progressive vascular disease that causes vascular dementia. Aging and hypertension are major contributors to CSVD, but the pathophysiological mechanism remains unclear, mainly due to the lack of an ideal animal model. Our previous study revealed that vascular smooth muscle cell (VSMC)-specific myosin phosphatase target subunit 1 (MYPT1) knockout (MYPT1 SMKO ) leads to constant hypertension, prompting us to explore whether hypertensive MYPT1 SMKO mice can be considered a novel CSVD animal model. Here, we found that MYPT1 SMKO mice displayed age-dependent CSVD-like neurobehaviors, including decreased motion speed, anxiety, and cognitive decline. MYPT1 SMKO mice exhibited remarkable white matter injury compared with control mice, as shown by the more prominent loss of myelin at 12 months of age. Additionally, MYPT1 SMKO mice were found to exhibit CSVD-like small vessel impairment, including intravascular hyalinization, perivascular space enlargement, and microbleed and blood-brain barrier (BBB) disruption. Last, our results revealed that the brain of MYPT1 SMKO mice was characterized by an exacerbated inflammatory microenvironment, which is similar to patients with CSVD. In light of the above structural and functional phenotypes that closely mimic the conditions of human CSVD, we suggest that MYPT1 SMKO mice are a novel age- and hypertension-dependent animal model of CSVD., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Type 17 helper T cells (Th17)-dominant neutrophilic airway inflammation is critical in the pathogenesis of steroid-resistant airway inflammation such as severe asthma. Small extracellular vesicles (sEV) derived from human mesenchymal stem cells (MSCs) display extensive therapeutic effects and advantages in many diseases. However, the role of MSC-sEV in Th17-dominant neutrophilic airway inflammation and the related mechanisms are still poorly studied. Here we found that MSC-sEV significantly alleviated the infiltration of inflammatory cells in peribronchial interstitial tissues and reduced levels of inflammatory cells, especially neutrophils, in bronchoalveolar lavage fluids (BALF) of mice with neutrophilic airway inflammation. Consistently, MSC-sEV significantly decreased levels of IL-17A in BALF and Th17 in lung tissues. Furthermore, we found that labelled MSC-sEV were taken up by human CD4 + T cells most obviously at 12 h after incubation, and distributed mostly in mouse lungs. More importantly, potential signaling pathways involved in the MSC-sEV mediated inhibition of Th17 polarization were found using RNA sequencing. Using Western blot, JAK2-STAT3 pathway was identified as an important role in the inhibition of Th17 polarization by MSC-sEV. We found that proteins in MSC-sEV were mostly involved in the therapeutic effects of MSC-sEV. In total, our study suggested that MSC-sEV could be a potential therapeutic strategy for the treatment of neutrophilic airway inflammation., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Introduction: Macrophage-mediated inflammatory response may have crucial roles in the pathogenesis of a variety of human diseases. Growth differentiation factor 15 (GDF15) is a cytokine of the transforming growth factor-β superfamily, with potential anti-inflammatory activities. Previous studies observed in human lungs some macrophages which expressed a high level of GDF15., Methods: In the present study, we employed multiple techniques, including immunofluorescence, flow cytometry, and single-cell RNA sequencing, in order to further clarify the identity of such GDF15 high macrophages., Results: We demonstrated that macrophages derived from human peripheral blood mononuclear cells and rat bone marrow mononuclear cells by in vitro differentiation with granulocyte-macrophage colony stimulating factor contained a minor population (~1%) of GDF15 high cells. GDF15 high macrophages did not exhibit a typical M1 or M2 phenotype, but had a unique molecular signature as revealed by single-cell RNA sequencing. Functionally, the in vitro derived GDF15 high macrophages were associated with reduced responsiveness to pro-inflammatory activation; furthermore, these GDF15 high macrophages could inhibit the pro-inflammatory functions of other macrophages via a paracrine mechanism. We further confirmed that GDF15 per se was a key mediator of the anti-inflammatory effects of GDF15 high macrophage. Also, we provided evidence showing that GDF15 high macrophages were present in other macrophage-residing human tissues in addition to the lungs. Further scRNA-seq analysis in rat lung macrophages confirmed the presence of a GDF15 high sub-population. However, these data indicated that GDF15 high macrophages in the body were not a uniform population based on their molecular signatures. More importantly, as compared to the in vitro derived GDF15 high macrophage, whether the tissue resident GDF15 high counterpart is also associated with anti-inflammatory functions remains to be determined. We cannot exclude the possibility that the in vitro priming/induction protocol used in our study has a determinant role in inducing the anti-inflammatory phenotype in the resulting GDF15 high macrophage cells., Conclusion: In summary, our results suggest that the GDF15 high macrophage cells obtained by in vitro induction may represent a distinct cluster with intrinsic anti-inflammatory functions. The (patho)physiological importance of these cells in vivo warrants further investigation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Dai, Zhang, Zheng, Li, Ma, Gao, Zhang, Jiang and Cui.)