Background: Triptolide (TPL) is an epoxytriptolide diterpenoid lactone isolated from the traditional Chinese medicinal herb Tripterygium wilfordii and exhibits broad pharmacological activities, including anti-inflammatory, immunomodulatory, and antitumor effects. Its water-soluble prodrug, minnelide, is currently undergoing clinical trials for the treatment of pancreatic cancer. Reactive oxygen species (ROS) regulate cellular fate by inducing oxidative damage and activating autophagy, which can promote cell survival under moderate stress but contribute to cell death when excessively or persistently activated. Although TPL has been reported to induce ROS accumulation, its mechanistic role in non-small cell lung cancer (NSCLC) remains incompletely understood. This study aimed to systematically investigate the role of ROS-mediated autophagy in TPL-induced cytotoxicity and to evaluate the therapeutic potential of combining TPL with autophagy inhibition in NSCLC. Methods: A series of in vitro experiments was performed to characterize TPL-mediated changes in NSCLC cell proliferation, migration, and ROS production. Autophagy- and apoptosis-related molecular alterations were analyzed using Western blotting and fluorescence microscopy with fluorescent reporter constructs. An H1299 xenograft mouse model was established to assess the antitumor efficacy of TPL in vivo and its combination effects with an autophagy inhibitor. Results: In this study, we demonstrated that TPL induces NSCLC cell death primarily through increased ROS levels. Mechanistic analyses further revealed that ROS accumulation simultaneously activates a protective autophagic response. Notably, in vivo experiments showed that co-administration of TPL with the autophagy inhibitor chloroquine resulted in significantly stronger tumor growth suppression than either treatment alone. Conclusions: Autophagy acts as a resistance mechanism against TPL-induced cytotoxicity in NSCLC, and pharmacological autophagy inhibition potentiates the antitumor activity of TPL. These findings clarify the ROS-autophagy interplay underlying TPL-mediated cell death and provide a preclinical rationale for combining TPL with autophagy inhibitors as a therapeutic strategy for NSCLC.

IntroductionMetabolic reprogramming is a central driver of malignant progression in non-small cell lung cancer (NSCLC). However, conventional targeted therapies face significant limitations due to drug resistance and narrow therapeutic windows. Triptolide, a natural tricyclic diterpenoid derived from Tripterygium wilfordii, exhibits potent antitumor activity, yet its precise mechanisms for modulating metabolic reprogramming in NSCLC remain elusive.MethodsUsing NSCLC cell models, we assessed TPL effects on proliferation, migration, and mitochondrial function via CCK-8, Transwell, ROS, and MMP assays. In vivo efficacy was evaluated in xenograft models. Untargeted metabolomics identified metabolic alterations, while DARTS proteomics screened for potential TPL-interacting proteins.ResultsTPL significantly inhibited NSCLC cell proliferation and induced metabolic alterations characterized by glycolytic suppression (HK2 downregulation) and concurrent disruption of mitochondrial oxidative phosphorylation (OXPHOS)-associated proteins. Metabolomics revealed systemic metabolic shifts, with pyruvate metabolism and glutathione pathways being most significantly altered. Mechanistically, multi-omics analysis identified PDHX as a key node within a broader metabolic network disrupted by TPL, associated with glycolytic suppression (via HK2 degradation) and mitochondrial dysfunction.ConclusionThese findings suggest that TPL exerts antitumor effects in NSCLC by disrupting both glycolysis and mitochondrial function, with PDHX identified as a candidate mediator. Further studies are warranted to explore its therapeutic potential.

Although perinatal depression (PND) has garnered increasing attention, few specific pharmacological treatments exist, particularly for breastfeeding mothers concerned about antidepressant safety. The misconception that “natural is harmless” merits caution; herbal remedies and dietary supplements should be regarded as supplementary interventions pending robust safety evidence. This review summarizes recent advances in PND pathogenesis (neurotransmitter dysregulation, inflammation, hormonal imbalance, and microbiota alterations) and emerging drug development strategies, alongside clinical evidence for herbal and dietary supplements. Randomized controlled trial (RCT) findings reveal that while interventions like saffron and vitamin D show promise, significant limitations persist, including inconsistent efficacy, limited long-term safety data, and potential interactions with perinatal physiology. Caution is warranted until comprehensive studies validate the safety and reliability of natural interventions. This review underscores the need for rigorous trials to identify safe, effective PND treatments, particularly for vulnerable populations.

The complex etiology and spectrum of kidney diseases necessitate vigilant attention; the focus on early diagnosis and intervention in kidney diseases remains a critical issue in medical research. Recently, with the expanding studies on extracellular vesicles, exosomes have garnered increasing interest as a promising tool for the diagnosis and treatment of kidney diseases. Exosomes are nano-sized extracellular vesicles that transport a diverse array of bioactive substances, which can influence various pathological processes associated with kidney diseases and exhibit detrimental or beneficial effects. Within the kidney, exosomes derived from the glomeruli and renal tubules possess the ability to enter systemic circulation or urine. The biomarkers they carry can reflect alterations in the pathological state of the kidneys, thereby offering novel avenues for early diagnosis. Furthermore, research studies have confirmed that exosomes originating from multiple cell types exhibit therapeutic potential in treating kidney disease; notably, those derived from mesenchymal stem cells (MSCs) have shown significant treatment efficacy. This comprehensive review summarizes the contributions of exosomes from different cell types within the kidneys while exploring their physiological and pathological roles therein. Additionally, we emphasize recent advancements in exosome applications for the diagnosis and treatment of various forms of kidney diseases over the past decades. We not only introduce the urinary and blood biomarkers linked to kidney diseases found within exosomes but also explore their therapeutic effects. Finally, we discuss existing challenges and future directions concerning the clinical applications of exosomes for diagnostic and therapeutic purposes.

Supervised learning typically dominates in PET image denoising, primarily focusing on 18F-FDG images due to the high expense of training data collection, particularly for non-FDG tracer and new tracers. To address this limitations, some researchers have suggested training the network by utilizing self-supervised approach such as deep image prior, noise2noise, and noise2self. While this approach eliminates the need of additional training data, it comes at the expense of low efficiency. This paper aims to investigate the generalization of deep learning-based methods across diverse PET tracers and introduces a novel plug-and-play self-supervision paradigm specifically designed for this task. Preliminary experimental results demonstrate its effectiveness.

Pediatric heart failure (HF) is an important clinical disease with high hospitalization rates, morbidity, mortality and medical costs. Sacubitril/valsartan (also known as Entresto), was approved for the treatment of adult HF and is recently used in pediatrics. However, clinical therapy on children is more challenging than adults, and the pharmacokinetics of Entresto in children are still largely unknown and urgently needed. Herein, we aim to develop a simple and sensitive analytic method to monitor Entresto in pediatric patients, which is of great importance for individualized safe medication in children. Specifically, a liquid chromatography tandem mass spectrometry method for simultaneously quantification of valsartan, sacubitril and its bio-active metabolite sacubitrilat in human plasma has been developed and validated in pediatric patients. Plasma samples were pretreated with acetonitrile for protein precipitation. Elution was performed on X Select HSS T3 column (2.1 x 100 mm, 5 mu m; Waters) column using an isocratic mobile phase process consisting of 0.1% formic acid aqueous solution and 0.1% formic acid acetonit rile with a total run time of 3.0 min. Valsartan-d3, sacubitrilin-d4 and sacubitrilat-d4 were used as the corresponding deuterium internal standards. According to the Bioanalytical Method Validation Guidance for Industry, the method was validated in the range of 0.5-5000 ng/mL. Intra- and inter-day accuracy of sacubitril,valsartan and sacubitrilat ranged from 93%- 108%, 98%- 109%, 91%- 102%, respectively, with relative standard deviation of precision ranging from 2.0% to 5.1%, 2.4%- 7.5%, 1,3%7.4%. The proposed method demonstrated good accuracy, precision and linearity. The matrix factors normalized by internal standard meet the acceptance criteria. The method was fully validated and applied in 39 children. Trough concentration of the three substances to be measured were: valsartan (11.3-938.0 ng/mL), sacubitril (0.5-395.5 ng/mL) and sacubitrilat (522.1-4890.0 ng/mL). Overall, this is the first study to simultaneously determined the plasma valsartan, sacubitril and sacubitrilat concentrations in children, which is believed to facilitate the clinical management of pediatric HF.

Head motion (HM) leads to a degradation in PET image quality and inaccurate quantification, which affects the results of clinical diagnosis. To solve this problem, both image-based and rawdata-based correction methods have been proposed. Image based-method is easy to implement, but it has two main drawbacks. Firstly, due to the uncertainty of motion, some very noisy frames will inevitably be discarded, which means that only a portion of all counts can be used during motion correction. Secondly, if the motion is frequent and irregular, HM correction is time-consuming because many motion-free frames must be reconstructed before motion correction. In the past few years, researchers have proposed various deep learning-based image enhancement/reconstruction methods, which can obtain good brain images even at low counts. In this work, we introduced a deep learning-based reconstruction method for HM correction. The ROI-based quantitative results demonstrated that the proposed method could get better signal-tonoise ratio and contrast without introducing quantification bias.

In recent decades, natural products derived from plants and their derivatives have attracted great interest in the field of disease treatment. Triptolide is a tricyclic diterpene extracted from Tripterygium wilfordii, a traditional Chinese medicine, which has shown excellent therapeutic potential in the fields of immune inflammation and cancer treatment. In this study, 1,106 Web-of-Science-indexed manuscripts and 1,160 Chinese-National-Knowledge-Infrastructure-indexed manuscripts regarding triptolide published between 2011 and 2021 were analyzed, mapping the co-occurrence networks of keywords and clusters using CiteSpace software. The research frontier and development trend were determined by keyword frequency and cluster analysis, which can be used to predict the future research development of triptolide. Non–small cell lung cancer (NSCLC) is most common in lung cancer patients, accounting for about 80% of all lung cancer patients. New evidence suggests that triptolide effectively inhibits the development and metastasis of NSCLC by the induction of apoptosis, reversion of EMT, and regulation of gene expression. Specifically, it acts on NF-κB, MAPKs, P53, Wnt/β-catenin, and microRNAs (miRNAs), signaling pathways and molecular mechanisms. Consequently, this article reviews the research progress of the anti-NSCLC effect of triptolide. In addition, attenuated studies on triptolide and the potential of tumor immunotherapy are also discussed.

We developed and optimized an RF-driven H-source at the China Spallation Neutron Source (CSNS) to achieve the requirement of project phase-II. At the beginning of 2019, the first uncesiated H-beam was produced, but 15% RF power was reflected when the forward power was 20 kW. To decrease the reflection of the RF power, the RF power matching network was optimized based on the measurement of the plasma equivalent impedance, and the reflected power was decreased to less than 200W at the same forward power. The plasma equivalent impedance is studied with different conditions (RF power, hydrogen flow rate, and frequency). The results show that the plasma equivalent resistance increases at first and then decreases as the RF power increase. Then the transformer model is adopted to derive the plasma impedance.

Introduction Operation target beam power of China Spallation Neutron Source (CSNS), as the China's first 100 kW beam power pulsed neutron source, is now larger than 80 kW. During the beam power upgrading process of CSNS to 50 kW from 2018 to 2019, many improvements have been made for the front end of CSNS. Results The improvements mainly focus on solving the problems of ion source instability and the radio frequency quadrupole (RFQ) sparking caused by the pre-chopped beam into RFQ.

Abstract Background With the knowledge of tumor immunobiology deepening among researchers, the breakthroughs in the field of tumor immunotherapy in recent years have provided new approaches for cancer therapy. While patients who receive treatment are all at risk of side effects, about one‐fifth of them have sustained responses. It is crucial to figure out the underlying mechanism of how the immune system regulates the nonsmall cell lung cancer (NSCLC) microenvironment to improve the benefit of immunotherapy. Regarding glucose metabolism, the initial step is to generate glucose‐6‐phosphate by phosphorylating glucose with hexokinases‐3 (HK3). According to a recent study, HK3 has a functional role in the treatment of acute promyelocytic leukemia and colorectal cancer. Results Here, we studied the co‐expression relationship between the glycolytic pathway gene and the immune checkpoint gene and found that the expression of HK3 in tumor tissues may be related to immune status. By analyzing The Cancer Genome Atlas (TCGA) data, we found that the expression of HK3 was closely related to the main clinical features as well as to molecular characteristics. We also predicted that cases with low expression of HK3 were usually malignant entities and were shown to be obvious genomic aberrations of driver oncogenes. At the same time, gene ontology analysis based on significantly related genes in HK3 expression showed that HK3 expression was linked to inflammatory activity and immune response. Additionally, HK3 showed a remarkable trend in predicting the efficacy of immunotherapy for patients receiving Keytruda (PD‐1 monoclonal antibody) treatment. Conclusions This is the first comprehensive study to characterize HK3 expression in NSCLC from molecular and clinical aspects.

Capsaicin (trans-8-methyl-N-vanillyl-6-nonenamide, CAP) is an important ingredient in spicy foods consumed throughout the world. Vinblastine (VBL) is a naturally occurring alkaloid prescribed to cancer patients. Many cancer patients treated with VBL were taking CAP at the same time. This study attempted to investigate the effect of CAP on the pharmacokinetics of VBL, which is the substrate of CYP3A, Pgp, and Mrp2. CAP, cyclosporine (CsA) or olive oil was given to rats for seven consecutive days, and on the seventh day, VBL (1.3 mg/kg) was administered intravenously. CsA was used as a CYP3A1/2 and transporter inhibitor, and olive oil was used as a vehicle. The results showed that pretreatment of rats with CAP (3.0 mg/kg) for seven consecutive days resulted in an increase in the AUC0- t of VBL of about 29.8% (P < 0.05) compared with the control group. Moreover, CAP decreased the CL of VBL to 75.5% (P < 0.05). At this time, CYP3A1/2 and Mrp2/ Abcc2 in the liver was decreased at the mRNA and protein levels. These results demonstrate that chronic ingestion of CAP will increase systemic exposure and reduce clearance of VBL in rats. The food-drug interaction between CAP and VBL appears to be due to modulation of CYP3A1/2 and Mpr2 expression by CAP.

Programmed death-ligand 1 (PD-L1) is a crucial target for lung cancer immunotherapy. In lung cancer patients with high PD-L1 expression, blocking or reducing its expression can inhibit tumor growth. PD-L1 is regulated by signaling pathways, transcription factors and epigenetic factors, such as the GSK3β/β-catenin pathway, P53 protein and EMT. In our previous study, succinate dehydrogenase 5 (SDH5) was reported to regulate ZEB1 expression, induce EMT and lead to lung cancer metastasis via the GSK3β/β-catenin pathway. It is possible that SDH5 is involved in the mechanisms of PD-L1 regulation.In the present study, we observed a negative correlation between the expression of PD-L1 and SDH5 in vivo and in vitro. The examination of patient tissues also confirmed our results. Furthermore, we also found that SDH5 could reverse PD-L1 expression by the GSK3β/β-catenin/ZEB1 pathways. All these results reveal that SDH5 regulates PD-L1 expression and suggest that SDH5 can be used as a marker to predict tumor immune micro-states and provide guidance for clinical immunotherapy.

Concerning fan systems with an air pipe connecting air intake and a closed outlet, aerodynamic noise cannot be directly transmitted from the fan inlet and outlet to the outside. At this moment, the volute vibrational radiation noise induced casing surface vibration is the major noise component. The main factors affecting the fan vibrational noise are analyzed through theoretical derivation, then a vibrational noise optimization control method for the volute casing is proposed that considered the influence of vibro-acoustic coupling, taking the panel thickness of the volute (front-panel thickness [FT], side-panel thickness [ST], and back-panel thickness [BT]) as design variables, and the acoustical power of the volute surface and the total mass of the volute as the optimal target function. The optimization method is mainly divided into three main parts: the first was based on the simulation of unsteady flow of the fan to obtain the vibrational noise source; the second, using the design of experimental (DOE) method and the proposed numerical simulation of fluid-structure-acoustic coupling method to obtain the designing space, then the radical-based function (RBF) method is used to construct the approximate surrogate model instead of the simulation model previously mentioned, which was used to provide the basic mathematical model for the optimization of the next part; the third part, implementing the low vibrational noise optimization for the fan volute, applied the single-target (taking volute radiated acoustical power as the target function) and the multi-target (taking the volute radiated acoustical power and volute total mass as the target function) methods. In addition, the fan aerodynamic performance, volute casing surface fluctuations, and vibration response were validated by experiments, showing good agreement. It is of utmost importance that the dynamic pressure measurements and vibrational tests on the volute casing verify the accuracy of the numerical calculation. The optimization results showed that the vibrational noise optimization method proposed in this study can effectively reduce the vibration noise of the fan, obtaining a maximum value of noise reduction of 7.3 dB. The optimization identified in this paper provides a significant reference for the design of a low-vibrational-noise volute.

The commissioning of CSNS front end has been finished. The 15 mA beam intensity is obtained at the end of RFQ. For CSNS ion source, it is a type of penning surface plasma ion source, similar to ISIS ion source. To improve the operation stability and reduce spark, sonic improvements have been made, including Penning field and extraction optics. The codes PBGUNS and CST are applied to simulate the beam extraction. With these simulation results, various extracted structures are modified, including the jaw gap of extractor and the gap of between plasma slit and extractor. The running results show the stability of ion source is improved further.

The commissioning of CSNS front end has been finished. Above 15 mA beam intensity is obtained at the end of RFQ. For CSNS ion source, it is a type of penning surface plasma ion source, similar to ISIS ion source. To improve the operation stability and reduce spark rate, some modifications have been performed, including Penning field, extraction optics and post acceleration. PBGUNS is applied to optimize beam extraction. The co-extraction electrons are considered at PBGUNS simulation and various extracted structure are simulated aiming to make the beam through the extracted electrode without loss. The stability of ion source is improved further.