Antibiotic adjuvants offer a promising strategy for restoring antibiotic sensitivity, expanding antibacterial spectra, and reducing required dosages. Previously, compound 15 was identified as a potential adjuvant for Polymyxin B (PB) against multidrug-resistant (MDR) Pseudomonas aeruginosa DK2; however, its clinical utility was hindered by high cytotoxicity, uncertain in vivo efficacy, and an unclear synergetic mechanism. To address these challenges, we synthesized and evaluated a series of novel benzamide derivatives, with A22 emerging as a particularly promising candidate. A22 demonstrated potent synergistic activity to PB, minimal cytotoxicity, improved water solubility, and broad-spectrum synergism of polymyxins against various clinically isolated MDR Gram-negative strains. In vivo studies using Caenorhabditis elegans and mouse models further confirmed the efficacy of A22. Moreover, A22 effectively suppressed the development of PB resistance in Pseudomonas aeruginosa DK2. Mechanistic investigations revealed that A22 enhances polymyxins activity by inducing reactive oxygen species production, reducing ATP levels, increasing NOX activity, and inhibiting biofilm formation, leading to bacterial death. These findings position A22 as a highly promising candidate for the development of polymyxin adjuvants, offering a robust approach to combating MDR Gram-negative bacterial infections.

BACKGROUND: Chronic kidney disease (CKD) is associated with common pathophysiological processes, such as inflammation and fibrosis, in both the heart and the kidney. However, the underlying molecular mechanisms that drive these processes are not yet fully understood. Therefore, this study focused on the molecular mechanism of heart and kidney injury in CKD. METHODS: We generated an microRNA (miR)-26a knockout (KO) mouse model to investigate the role of miR-26a in angiotensin (Ang)-II-induced cardiac and renal injury. We performed Ang-II modeling in wild type (WT) mice and miR-26a KO mice, with six mice in each group. In addition, Ang-II-treated AC16 cells and HK2 cells were used as in vitro models of cardiac and renal injury in the context of CKD. Histological staining, immunohistochemistry, quantitative real-time polymerase chain reaction (PCR), and Western blotting were applied to study the regulation of miR-26a on Ang-II-induced cardiac and renal injury. Immunofluorescence reporter assays were used to detect downstream genes of miR-26a, and immunoprecipitation was employed to identify the interacting protein of LIM and senescent cell antigen-like domain 1 (LIMS1). We also used an adeno-associated virus (AAV) to supplement LIMS1 and explored the specific regulatory mechanism of miR-26a on Ang-II-induced cardiac and renal injury. Dunnett's multiple comparison and t -test were used to analyze the data. RESULTS: Compared with the control mice, miR-26a expression was significantly downregulated in both the kidney and the heart after Ang-II infusion. Our study identified LIMS1 as a novel target gene of miR-26a in both heart and kidney tissues. Downregulation of miR-26a activated the LIMS1/integrin-linked kinase (ILK) signaling pathway in the heart and kidney, which represents a common molecular mechanism underlying inflammation and fibrosis in heart and kidney tissues during CKD. Furthermore, knockout of miR-26a worsened inflammation and fibrosis in the heart and kidney by inhibiting the LIMS1/ILK signaling pathway; on the contrary, supplementation with exogenous miR-26a reversed all these changes. CONCLUSIONS Our findings suggest that miR-26a could be a promising therapeutic target for the treatment of cardiorenal injury in CKD. This is attributed to its ability to regulate the LIMS1/ILK signaling pathway, which represents a common molecular mechanism in both heart and kidney tissues.
Animals ; MicroRNAs/metabolism* ; Angiotensin II/toxicity* ; Mice ; Renal Insufficiency, Chronic/chemically induced* ; Mice, Knockout ; Disease Models, Animal ; Male ; Signal Transduction/genetics* ; LIM Domain Proteins/genetics* ; Mice, Inbred C57BL ; Cell Line ; Humans

ObjectiveTo characterize the changes in the overall chemical profile and key index components during nine-time repeating steaming and sun-drying processing of Rhei Radix et Rhizoma， and to reveal the change law of its material basis. MethodsHigh performance liquid chromatography（HPLC） was used to analyze the changes in the overall chemical profile of Rhei Radix et Rhizoma decoction pieces， and the contents of 15 main active components such as chrysophanol-8-O-β-D-glucoside， chrysophanol and gallic acid in the process of nine-time repeating steaming and sun-drying were determined. Combined with chemometrics， the contents and quantity ratio relationships of the glycosides， aglycones and tannins during the processing of Rhei Radix et Rhizoma were analyzed， and the partial least squares-discriminant analysis（PLS-DA） and cluster analysis of the main components in different steaming times were conducted， the statistically significant differential markers were selected with the variable importance in the projection（VIP） value>1. ResultsIn the nine-time repeating steaming and sun-drying process of Rhei Radix et Rhizoma， there were certain regularity in the number and peak area of characteristic peaks and the steaming and sun-drying times， the anthraquinone glycosides and aglycones could be roughly divided into three stages， including rapid change stage， fluctuation change stage and stable stage， and the total amount of tannins showed a decreasing trend. However， the ratios between the three components mentioned above tended to stabilize after five rounds of steaming and sun-drying. The results of PLS-DA and cluster heatmap showed that the content of each component in Rhei Radix et Rhizoma fluctuated greatly during the 1-4 steaming and sun-drying processes， while the content of each component was relatively close during the 5-9 steaming and sun-drying processes. After screening， it was found that chrysophanol， emodin， chrysophanol-8-O-β-D-glucoside， rhein， physcion and emodin-8-O-β-D-glucoside could be used as the index components for distinguishing the processed products of Rhei Radix et Rhizoma with different steaming and sun-drying times. ConclusionThe changes in the properties and efficacy of Rhei Radix et Rhizoma caused by the processing of nine-time repeating steaming and sun-drying are due to the changes in the composition and ratio of various glycosides and complex tannins in this herb， which is also the key to the formation of its characteristic of "purgation with supplement". This study can provide a basis for the research on the processing mechanism of Rhei Radix et Rhizoma and the establishment of processing specifications.

The persistent high prevalence and poor survival outcomes of lung cancer underscore the urgent need for innovative therapeutic modalities. Here, we present a novel multifunctional delivery platform for the synergistic treatment of lung malignancies, combining in situ-triggerable photodynamic therapy (PDT) with radiotherapy. The new platform CLL was developed by loading a new reactive oxygen species (ROS)-triggerable photosensitizer, luminol-conjugated chlorin e6 (Ce6), into liposomes. CLL can be activated through the bioluminescence resonance energy transfer effect under oxidative stress, thereby producing singlet oxygen for targeted tumor treatment without external irradiation. In vitro studies showed significant cytotoxic effects of CLL in both 4T1 and A549 tumor cells. Furthermore, a PDT-radiopharmaceutical combination nanotherapy CLL-¹⁷⁷Lu was engineered by incorporating the radionuclide ¹⁷⁷Lu into CLL. CLL-¹⁷⁷Lu demonstrated synergistic antitumor effects in 4T1 and A549 tumor cells, as well as in mouse models of 4T1 breast cancer lung metastasis or A549 tumor xenografts. Mechanistically, CLL-¹⁷⁷Lu can induce singlet oxygen/ROS generation, enhance tumor cell apoptosis, and promote M1 macrophage-mediated immunotherapy. Preliminary assessments showed a favorable profile for CLL-¹⁷⁷Lu, highlighting its potential as a promising nanotherapy for cancer treatment. Additionally, CLL can serve as a versatile platform for delivering a range of therapies to achieve synergistic antitumor effects.

Acute pancreatitis(AP)is an autopeptic disease,which can be accompanied by systemic inflammation and multiple organ failure.Mesenchymal stem cells(MSCs)have been used in the treatment of AP and have shown good application potential.MSCs can act through multiple mechanisms to reduce pancreatic inflammation and enhance tissue repair.These mechanisms include homing to injury sites,anti-inflammatory and immunomodulatory effects,oxidative stress reduction,inhibition of apoptosis and suppression of autophagy.Additionally,MSCs can mitigate multi-organ damage associated with AP,impacting lungs,intestines,heart and other organs.Research on the application of MSCs in treating AP is predominantly at the preclinical animal study stage,with limited clinical investigations reported.This article reviews the mechanisms and research progress of MSCs in the treatment of AP,aiming to provide references for basic research and clinical applications.

To understand the infection status of main intestinal protozoa in BALB/c mice and pro-vide a basis for further control of intestinal protozoa infection.Five hundred and forty BALB/c mice provided by four domestic suppliers of BALB/c mice were detected for intestinal protozoa,in which 140 from supplier A,130 from supplier B,135 from supplier C,and 135 from supplier D,re-spectively.Fresh faecal samples were collected from each mouse separately to extract the genome and amplified by nested PCR based on primers for the 18S rRNA gene sequences of Pent-atrichomonas hominis(P.hominis)and Cryptosporidium tyzzeri(C.tyzzeri),and the 16S-like rRNA gene sequence of Tritrichomonas muris(T.muris)and sequenced.The results showed that the total intestinal protozoan infection rate was 7.1％(10/140)in 140 mice faecal samples provided by supplier A.Among them,the positivity rate of T.muris was 7.1％(10/140),C.tyzzeri was 2.1％(3/140),and P.hominis was 7.1％(10/140),the co-infection rate of two intestinal protozoa was 7.1％(10 mice:T.muris+P.hominis),and three intestinal protozoa was 2.1％(3 mice:T.muris+P.hominis+C.tyzzeri).The total intestinal protozoan infection rate in 135 mice faecal samples provided by supplier C was 7.4％,in which,7.4％(10/135)was positive for T.muris.There are no intestinal protozoa to be detected in 130 mice faecal samples from supplier B and 135 mice faecal samples from supplier D.The homology analysis showed that the homology of ampli-fied sequence of T.muris,P.hominis and C.tyzzeri was 98.52％,98.27％and 99.87％compared with published sequence of GenBank No:AY886846.1,GenBank No:AF156964.1 and GenBank No:KJ000486.1,which was clustered as an independent branch by phylogenetic analysis respec-tively.In conclusion,there are intestinal protozoan infection in BALB/c mice in some animal sup-pliers.The co-infections of more than 3 parasites such as T.muris,P.hominis and C.tyzzeri has been found.It will provide a basis for control of intestinal protozoa infection in BALB/c mice in the future.

BACKGROUND:The plateau environment affects the immune function and metabolic status of patients with osteomyelitis,leading to acceleration or complication of the disease process.The construction of effective and stable animal models of chronic osteomyelitis is essential for experimental studies of chronic osteomyelitis.OBJECTIVE:To establish a sheep model of chronic osteomyelitis in plateau regions for toxicity assessment and therapeutic research.METHODS:Fifteen healthy sheep were selected in this study.Sodium morrhuate and Staphylococcus aureus suspension were injected into the medullary cavity of the middle segment of the tibia to establish the chronic osteomyelitis model.General observation,body mass and temperature monitoring,blood infection index detection,radiological scoring,and microbial culture were performed for evaluation and analysis.RESULTS AND CONCLUSION:(1)Local tissue swelling and lameness of the affected leg were observed in all sheep in the early stage after modeling,accompanied by varying degrees of anorexia.A slight decrease in body mass was observed in sheep 1 week after modeling,while no significant changes in body temperature were observed.(2)The erythrocyte sedimentation rate significantly accelerated 4 days after modeling(P<0.05)and gradually returned to normal levels after 1 month.The white blood cell count showed a significant increase within 4 days after modeling and returned to normal after 1 week.The level of C-reactive protein increased significantly after modeling(P<0.05)and remained significantly higher than normal until the end of the experiment(P<0.05).(3)Fifteen sheep exhibited typical radiological manifestations of osteomyelitis,including unclear boundaries,irregular osteolytic lesions,and low-density bright absorption areas with interspersed necrotic bone fragments of increased and uneven density.Different degrees of periosteal reaction were observed in the cortex near the lesion.(4)Thirteen sheep were cultured for a single strain of Staphylococcus aureus,while two sheep were cultured for Staphylococcus aureus and Escherichia coli.These findings indicate that a reliable chronic osteomyelitis animal model of sheep tibia can be successfully established in plateau regions by injecting an appropriate amount of Staphylococcus aureus suspension into the medullary cavity of sheep,combined with local implantation of foreign cotton thread and sodium morrhuate.

BACKGROUND:At present,the clinical application of gastrointestinal stents is relatively common.Conventional self-expanding metal and plastic stents have the problems of easy displacement,difficulty to remove,and postoperative restenosis.With the advantages of biodegradability and low postoperative restenosis rate,biodegradable drug-eluting stents have become the hot spot in the research of gastrointestinal stents.OBJECTIVE:To summarize the research progress of biodegradable drug-eluting gastrointestinal stents and to provide a forecast of biodegradable drug-eluting gastrointestinal stents.METHODS:Relevant articles were retrieved on CNKI,WanFang,PubMed,and Web of Science databases from January 1994 to March 2024.The Chinese and English search terms were"biodegradable,drug-eluting stent,esophageal stent,biliary stent,pancreatic duct stent,intestinal stent,gastrointestinal stent."Finally,64 articles were included for review and analysis.RESULTS AND CONCLUSION:(1)Biodegradable drug-eluting gastrointestinal stent is a medical device that uses biodegradable material as the main body of the stent,carries and locally elutes drugs for different therapeutic purposes,and plays the dual roles of physical support and drug therapy.By adjusting the properties of stent materials,improving manufacturing processes and auxiliary means,the degradation rate of stents can be accelerated or slowed down to meet clinical needs.Drug elution technology uses drug coatings,nanoparticles,and polymer drug-loaded films,as drug-loading platforms to accurately release drugs,increase local drug concentrations in lesions,and reduce drug loss and systemic absorption of toxic drugs.(2)The main structure of biodegradable drug-eluting gastrointestinal stent is one or more functional drugs combined with biodegradable polymers,metals or nanofiber materials.The available functional drugs are divided into anti-inflammatory and antiproliferative,antitumor,lithotripsy,and enzyme inhibitors.(3)Maintaining the stability of the mechanical properties of gastrointestinal stent and precise controlled drug release are the problems that need to be solved at this stage of biodegradable drug-eluting gastrointestinal stent.The development of new biodegradable materials and the continuous innovation of drug-carrying and drug-releasing methods,manufacturing processes and auxiliary means are the future research directions.

Objective:To deeply explore the thematic needs and characteristics of learners regarding course elements based on the review texts of nursing massive open online courses (MOOC), providing a reference for achieving effective alignment between digital nursing education content and learner needs.Methods:Data were collected from the review texts of 112 nursing courses on the Chinese University MOOC platform using a web crawler script written with Python′s Requests library. The collection period spanned from the course launch dates to December 31, 2023. Sentiment analysis and high-frequency words analysis were conducted using Chinese text Nature language processing library, and core themes of learners′ positive and negative reviews were extracted using the latent dirichlet allocation.Results:A corpus of 18 184 nursing MOOC review texts was constructed, with positive sentiment reviews accounting for 89.30% (16 238/18 184) and negative sentiment reviews making up 10.70% (1 946/18 184). Word frequency analysis revealed that most nursing MOOC serve as carriers for blended online and offline teaching models, with students being the primary target audience, though social participants were also involved. The reviews effectively mirrored real-world clinical nursing scenarios. The need of learners was categorized into three major themes: content design and assessment, course resources and teaching strategies, and software applications and platform functionality.Conclusions:This study, leveraging text mining technology, thoroughly investigated the three thematic characteristics of nursing MOOC needs of online learners and proposed targeted optimization recommendations. Future research could incorporate other online teaching platforms and comprehensively construct a sentiment lexicon for nursing online course reviews using big data modeling and machine learning algorithms. These would enable a holistic analysis of the digital nursing education landscape, allowing for precise improvements to address existing shortcomings.

Objective:To conduct a comprehensive review on the current research status of postpartum follow-up for patients with hypertensive disorders of pregnancy (HDP), and provide a basis and guidance for the management of postpartum follow-up for HDP patients.Methods:Guided by the methodological framework of the scoping review, the literatures on postpartum follow-up of HDP patients in Cochrane Library, PubMed, Web of Science, Embase, China Biomedical Literature Database, China National Knowledge Infrastructure, VIP and Wanfang databases were retrieved, and search for relevant literature by the snowballing method. The search time range is from the establishment of the database to February 1, 2025. The included literature was analyzed and summarized.Results:A total of 32 literatures were included, including 31 in English and 1 in Chinese. The participation rate of postpartum follow-up for HDP patients is generally low, and the disease has a significant impact on long-term health. In addition, there is considerable variation in the content, format and time of follow-up. The follow-up content includes the patient's physical health status, long-term health risks and the availability of medical resources, etc.Conclusions:There are still deficiencies in the current implementation of postpartum follow-up for HDP patients. Existing follow-up studies lack high-quality randomized controlled trials as evidence support, and the influencing factors are complex and diverse. In the future, it is necessary to strengthen cooperation among multiple disciplines, closely integrate clinical guidelines with practical needs, and systematically evaluate the effectiveness of follow-up in clinical practice to enhance the scientific and effectiveness of follow-up and provide better health management support for HDP patients.