Multidrug-resistant (MDR) bacterial infections have emerged as a serious challenge of global public health crisis. The overuse and misuse of conventional antibiotics have dramatically accelerated the emergence, evolution and worldwide spread of drug-resistant bacterial strains, necessitating urgent exploration of novel antibacterial strategies. Bacteriophages serve as natural bacterial predators offering distinct advantages including high host specificity, autonomous self-replication capabilities and cost-effective large-scale production. However, wild-type phages present significant clinical limitations due to their narrow host ranges, susceptibility to rapid immune clearance and poor penetration of bacterial biofilms, which severely restrict their therapeutic applications. The convergence of synthetic biology, nanotechnology and advanced gene editing technologies has accelerated the development of engineered bacteriophage platforms, providing programmable, scalable and clinically translatable pathways to overcome these inherent biological constraints. Here, we systematically delineate four fundamental strategies for engineered bacteriophage development. Chemical modification utilizes reactive functional groups such as amino, carboxyl and thiol moieties on capsid proteins through esterification, amidation or click chemistry reactions to achieve precise drug conjugation and surface functionalization. In vivo editing encompasses ultraviolet or chemical mutagenesis for random mutation induction, homologous recombination for targeted genetic alterations, recombineering methodologies including electroporation-mediated bacteriophage recombination engineering, and CRISPR-Cas systems for precise genome editing to enable exact genetic reconstruction and host range reprogramming. In vitro synthesis leverages genome engineering platforms where intact phage genomes are transferred into yeast or host bacteria to facilitate highly efficient homologous recombination, enabling large DNA fragment assembly and cross-gene host range expansion without bacterial toxicity constraints. Directed evolution combines artificial selection through mutation library screening with rational design approaches involving chimeric receptor binding protein construction or site-specific mutagenesis, effectively balancing the discovery of unknown adaptive pathways with targeted host specificity modification. Moreover, we comprehensively discuss therapeutic applications across diverse clinical scenarios. Engineered bacteriophage effectively disrupt bacterial biofilms through sophisticated functionalized delivery platforms including nanozyme-conjugated phages, phage-liposome nanoconjugates and bio-responsive hydrogels, demonstrating significantly enhanced bactericidal efficiency compared to unmodified free phages. These bioengineered vectors attenuate bacterial virulence and resensitize pathogens to antibiotics by delivering CRISPR-Cas systems or base editors to disrupt critical virulence factors such as pili, capsule synthesis machineries and quorum sensing systems, or by inactivating antibiotic resistance determinants including beta-lactamase genes. As an intelligent nanomedicine delivery platform, engineered bacteriophage enable precise pathogen elimination an through photocatalytic reactive oxygen species generation, immunomodulatory interventions, or controlled release of antibacterial drugs. Furthermore, oral administration of engineered bacteriophage facilitates microbiota modulation, which selectively eliminate intestinal pathogens while preserve beneficial commensal microbiota, thereby restoring microbial community balance and preventing complications associated with dysbiosis. Finally, we critically analyze persistent challenges including host strain matching complexity, evolution of bacterial resistance mechanisms, pharmacokinetic optimization requirements, optimal administration route selection, large-scale production quality control standards and clinical dosing determination protocols. Through multidisciplinary integration of synthetic biology, infectious disease medicine and immunology, future translational medicine studies of bacteriophage should establish comprehensive technical platforms encompassing rapid phage screening, intelligent rational design, rigorous in vivo evaluation and standardized clinical validation processes, ultimately advancing engineered bacteriophage from laboratory innovations to clinically approved therapeutics for effectively combating MDR bacterial infections.

Ferroptosis, a programmed cell death modality discovered and defined in the last decade, is primarily induced by iron-dependent lipid peroxidation. At present, it has been found that ferroptosis is involved in various physiological functions such as immune regulation, growth and development, aging, and tumor suppression. Especially its role in tumor biology has attracted extensive attention and research. Breast cancer is one of the most common female tumors, characterized by high heterogeneity and complex genetic background. Triple negative breast cancer (TNBC) is a special type of breast cancer, which lacks conventional breast cancer treatment targets and is prone to drug resistance to existing chemotherapy drugs and has a low cure rate after progression and metastasis. There is an urgent need to find new targets or develop new drugs. With the increase of studies on promoting ferroptosis in breast cancer, it has gradually attracted attention as a treatment strategy for breast cancer. Some studies have found that certain compounds and natural products can act on TNBC, promote their ferroptosis, inhibit cancer cells proliferation, enhance sensitivity to radiotherapy, and improve resistance to chemotherapy drugs. To promote the study of ferroptosis in TNBC, this article summarized and reviewed the compounds and natural products that induce ferroptosis in TNBC and their mechanisms of action. We started with the exploration of the pathways of ferroptosis, with particular attention to the System X_c^--cystine-GPX4 pathway and iron metabolism. Then, a series of compounds, including sulfasalazine (SAS), metformin, and statins, were described in terms of how they interact with cells to deplete glutathione (GSH), thereby inhibiting the activity of glutathione peroxidase 4 (GPX4) and preventing the production of lipid peroxidases. The disruption of the cellular defense against oxidative stress ultimately results in the death of TNBC cells. We have also our focus to the realm of natural products, exploring the therapeutic potential of traditional Chinese medicine extracts for TNBC. These herbal extracts exhibit multi-target effects and good safety, and have shown promising capabilities in inducing ferroptosis in TNBC cells. We believe that further exploration and characterization of these natural compounds could lead to the development of a new generation of cancer therapeutics. In addition to traditional chemotherapy, we discussed the role of drug delivery systems in enhancing the efficacy and reducing the toxicity of ferroptosis inducers. Nanoparticles such as exosomes and metal-organic frameworks (MOFs) can improve the solubility and bioavailability of these compounds, thereby expanding their therapeutic potential while minimizing systemic side effects. Although preclinical data on ferroptosis inducers are relatively robust, their translation into clinical practice remains in its early stages. We also emphasize the urgent need for more in-depth and comprehensive research to understand the complex mechanisms of ferroptosis in TNBC. This is crucial for the rational design and development of clinical trials, as well as for leveraging ferroptosis to improve patient outcomes. Hoping the above summarize and review could provide references for the research and development of lead compounds for the treatment for TNBC.

The European Society of Cardiology (ESC) released the "2024 ESC guidelines for the management of elevated blood pressure and hypertension" on August 30, 2024. This guideline updates the 2018 "Guidelines for the management of arterial hypertension." One notable update is the introduction of the concept of "elevated blood pressure" (120-139/70-89 mm Hg). Additionally, a new systolic blood pressure target range of 120-129 mm Hg has been proposed for most patients receiving antihypertensive treatment. The guideline also includes numerous additions or revisions in areas such as non-pharmacological interventions and device-based treatments for hypertension. This article interprets the guideline's recommendations on definition and classification of elevated blood pressure and hypertension, and cardiovascular disease risk assessment, diagnosing hypertension and investigating underlying causes, preventing and treating elevated blood pressure and hypertension. We provide a comparison interpretation with the 2018 "Guidelines for the management of arterial hypertension" and the "2017 ACC/AHA guideline on the prevention, detection, evaluation, and management of high blood pressure in adults."

OBJECTIVE: To investigate the regulatory effects of two traditional mineral medicines (TMMs), Gypsum Fibrosum (Shigao, GF) and Terra Flava Usta (Zaoxintu, TFU), on gut-beneficial bacteria in mice, and preliminarily explore their mechanisms of action. METHODS: Mice were randomly divided into 3 groups (n=10 per group): the control group (standard diet), the GF group (diet supplemented with 2% GF), and the TFU group (diet supplemented with 2% TFU). After 4-week intervention, 16S rRNA gene sequencing was used to analyze the changes in the gut microbiota (GM). Scanning electron microscopy, in combination with coumarin A tetramethyl rhodamine conjugate and Hoechst stainings, was used to observe the bacteria and biofilm formation. RESULTS: Principal coordinate analysis revealed that GF and TFU significantly altered the GM composition in mice. Further analysis revealed that GF and TFU affected different types of gut bacteria, suggesting that different TMMs may selectively modulate specific bacterial populations. For certain bacteria, such as Faecalibaculum and Ileibacterium, both GF and TFU exhibited growth-promoting effects, implying that they may be sensitive to TMMs and that different TMMs can increase their abundance through their respective mechanisms. Notably, Lactobacillus reuteri, a widely recognized and used probiotic, was significantly enriched in the GF group. Random forest analysis identified Ileibacterium valens as a potential indicator bacterium for TMMs' impact on GM. Further mechanistic studies showed that gut bacteria formed biofilm structures on the TFU surface. CONCLUSIONS This study provides new insights into the interaction between TMMs and GM. As safe and effective natural clays, GF and TFU hold promise as potential candidates for prebiotic development.
Animals ; Gastrointestinal Microbiome/drug effects* ; Bacteria/growth & development* ; Mice ; Biofilms/drug effects* ; Male ; RNA, Ribosomal, 16S/genetics*

The ventral anterior (VA) nucleus of the thalamus is a major target of the basal ganglia and is closely associated with the pathogenesis of Parkinson's disease (PD). Notably, the VA receives direct innervation from the hypothalamic histaminergic system. However, its role in PD remains unknown. Here, we assessed the contribution of histamine to VA neuronal activity and PD motor deficits. Functional magnetic resonance imaging showed reduced VA activity in PD patients. Optogenetic activation of VA neurons or histaminergic afferents significantly alleviated motor deficits in 6-OHDA-induced PD rats. Furthermore, histamine excited VA neurons via H1 and H2 receptors and their coupled hyperpolarization-activated cyclic nucleotide-gated channels, inward-rectifier K⁺ channels, or Ca²⁺-activated K⁺ channels. These results demonstrate that histaminergic afferents actively compensate for Parkinsonian motor deficits by biasing VA activity. These findings suggest that targeting VA histamine receptors and downstream ion channels may be a potential therapeutic strategy for PD motor dysfunction.
Animals ; Histamine/metabolism* ; Male ; Oxidopamine/toxicity* ; Rats ; Ventral Thalamic Nuclei/physiopathology* ; Rats, Sprague-Dawley ; Disease Models, Animal ; Parkinson Disease/metabolism* ; Neurons/physiology* ; Humans ; Optogenetics

OBJECTIVES: The study of medicine formulas is a core component of traditional Chinese medicine (TCM), yet traditional learning methods often lack interactivity and contextual understanding, making it challenging for beginners to grasp the intricate composition rules of formulas. To address this gap, we introduce Formula-S, a situated visualization method for TCM formula learning in augmented reality (AR) and evaluate its performance. This study aims to evaluate the effectiveness of Formula-S in enhancing TCM formula learning for beginners by comparing it with traditional text-based formula learning and web-based visualization. METHODS: Formula-S is an interactive AR tool designed for TCM formula learning, featuring three modes (3D, Web, and Table). The dataset included TCM formulas and herb properties extracted from authoritative references, including textbook and the SymMap database. In Formula-S, the hierarchical visualization of the formulas as herbal medicine compositions, is linked to the multidimensional herb attribute visualization and embedded in the real world, where real herb samples are presented. To evaluate its effectiveness, a controlled study (n=30) was conducted.Participants who had no formal TCM knowledge were tasked with herbal medicine identification, formula composition, and recognition. In the study, participants interacted with the AR tool through HoloLens 2. Data were collected on both task performance (accuracy and response time) and user experience, with a focus on task efficiency, accuracy, and user preference across the different learning modes. Results The situated visualization method of Formula-S had comparable accuracy to other methods but shorter response time for herbal formula learning tasks. Regarding user experience, our new approach demonstrated the highest system usability and lowest task load, effectively reducing cognitive load and allowing users to complete tasks with greater ease and efficiency. Participants reported that Formula-S enhanced their learning experience through its intuitive interface and immersive AR environment, suggesting this approach offers usability advantages for TCM education. CONCLUSIONS The situated visualization method in Formula-S offers more efficient and accurate searching capabilities compared to traditional and web-based methods. Additionally, it provides superior contextual understanding of TCM formulas, making it a promising new solution for TCM learning.
Medicine, Chinese Traditional/methods* ; Humans ; Learning ; Drugs, Chinese Herbal

Nonobstructive azoospermia (NOA), one of the most severe types of male infertility, etiology often remains unclear in most cases. Therefore, this study aimed to detect four biallelic detrimental variants (0.5%) in the minichromosome maintenance domain containing 2 ( MCMDC2 ) genes in 768 NOA patients by whole-exome sequencing (WES). Hematoxylin and eosin (H&E) demonstrated that MCMDC2 deleterious variants caused meiotic arrest in three patients (c.1360G>T, c.1956G>T, and c.685C>T) and hypospermatogenesis in one patient (c.94G>T), as further confirmed through immunofluorescence (IF) staining. The single-cell RNA sequencing data indicated that MCMDC2 was substantially expressed during spermatogenesis. The variants were confirmed as deleterious and responsible for patient infertility through bioinformatics and in vitro experimental analyses. The results revealed four MCMDC2 variants related to NOA, which contributes to the current perception of the function of MCMDC2 in male fertility and presents new perspectives on the genetic etiology of NOA.
Humans ; Male ; Azoospermia/genetics* ; Meiosis/genetics* ; Spermatogenesis/genetics* ; Adult ; Exome Sequencing ; Microtubule-Associated Proteins/genetics* ; Alleles ; Infertility, Male/genetics*

OBJECTIVE To deeply explore the in vivo pharmacodynamic substance basis of Zhigancao Decoction,a classic tradi-tional Chinese medicine formula,and provide scientific evidence for its rational application and development in modern clinical practice.METHODS Wistar rats were treated with 12.15 g·kg-1 Zhigancao Decoction by gavage.Rat plasma samples were collect-ed at 10 time points(5,15,30,60,120,240,360,480,600 and 720 min after administration)and rat heart(atrial and ventricu-lar)tissue samples were collected at 12 h after administration.Components in the plasma and heart samples were qualitatively identi-fied by ultra-performance liquid chromatography-quadrupole-time-of-flight mass spectrometry(UPLC-Q-TOF/MS),and the distri-bution characteristics of Zhigancao Decoction in vivo were analyzed.At the same time,the time-concentration curve of the prototype components and metabolites in Zhigancao Decoction was drawn to observe the changes of blood drug concentration.RESULTS A total of 11 prototype components(Ajugol,Nicotiflorin,Isoschaftoside,4-Hydroxycinnamic acid,Rehmapicrogenin,4-Hydroxybenzoic acid,4′,7-Dihydroxyflavone,Calycosin,3′,4′,7-Trihydroxyflavone,Pinellic acid,Truxillic acid)and 7 metabolites were identified from the plasma samples of Zhigancao Decoction,mainly including flavonoids(flavonoids glycosides),organic acids,and iridoid glyco-sides,etc.Additionally,6 prototype components(Ajugol,Isoschaftoside,Rehmapicrogenin,4′,7-Dihydroxyflavone,Liquiritigenin,3′,4′,7-Trihydroxyflavone)and 3 metabolites were identified from the cardiac samples(the atrium and the ventricle showed the same results).The metabolic pathways mainly involved Phase Ⅰ metabolism and glucuronidation.CONCLUSION The prototype compo-nents and metabolites in plasma and heart tissue of Zhigancao Decoction is preliminarily determined,providing a reference for analyzing the active components of Zhigancao Decoction in heart tissue.

Objective:To explore the safety and efficacy of intraosseous regional administration (IORA) of vancomycin for preventing infection in primary total knee arthroplasty (TKA).Methods:A total of 124 patients with knee osteoarthritis undergoing TKA between February 2024 and May 2024 at nine hospitals were enrolled. Preoperative infection prophylaxis involved either IORA (0.5 g vancomycin administered via intraosseous regional infusion before incision) or intravenous infusion (1 g vancomycin via peripheral vein). The IORA group included 15 males and 47 females with a median age of 66.5 years (range, 60.0-70.0 years), while the intravenous group included 14 males and 48 females with a median age of 66.0 years (range, 61.8-70.3 years) years. Intraoperative samples were collected including fat and synovium tissues after incision, before prosthesis placement, and after tourniquet release; distal femoral cancellous bone during femoral osteotomy; proximal tibial cancellous bone during tibial osteotomy; proximal intercondylar cancellous bone before prosthesis placement; and peripheral blood from non-infused arms at surgery initiation and after tourniquet release. Vancomycin concentrations were measured using liquid chromatography-tandem mass spectrometry. Vital sign changes were recorded from admission to 5~10 minutes post-IORA (IORA group) or post-incision (intravenous group). Follow-ups were conducted on postoperative day 1 and 3, and at 1 and 3 months, to document complications including IORA-related adverse events, periprosthetic joint infections, surgical site infections, red man syndrome, acute kidney injury, deep vein thrombosis and so on.Results:Vancomycin concentrations in bone, fat, and synovial tissue samples were significantly higher in the IORA group than in the intravenous group ( P<0.05), while vancomycin concentrations in blood samples were significantly lower in the IORA group than in the intravenous group ( P<0.05). Only 7.3%(41/558) of tissue samples in the IORA group had vancomycin concentrations below 2.0 μg/g (the minimum inhibitory concentration of vancomycin against coagulase-negative staphylococcus), compared to 59.3%(331/558) in the intravenous group (χ 2=11.285, P<0.001). In the intravenous group, 16.9%(21/124) of blood samples had vancomycin concentrations exceeding 15.0 mg/L (the threshold associated with a significantly increased risk of nephrotoxicity), while all concentrations in the IORA group were below this threshold, the difference was statistically significant (χ 2=22.943, P<0.001). There were no statistically significant difference ( P>0.05) in vital signs changes before and after vancomycin administration between the two groups. Two patients in the intravenous group experienced incision exudate, while no other related complications occurred in either group. Conclusions:Compared to the traditional intravenous infusion of 1 g vancomycin, intraosseous injection of a low dose (0.5 g) of vancomycin achieves higher local tissue concentrations in the knee joint with a lower incidence of adverse reactions and is safe for infection prophylaxis. Despite guidelines not recommending the routine use of vancomycin for preventing infection after primary TKA, intraosseous injection of 0.5 g vancomycin may be considered intraoperatively for primary TKA in the following scenarios: patients in medical institutions with a high prevalence of methicillin-resistant staphylococcus aureus (MRSA) infections, patients with potential preoperative MRSA colonization, or patients with cephalosporin allergy.

Objective To compare the clinical efficacies of extrapleural internal fixation and transthoracic internal fixation in the treat-ment of thoracic tuberculosis.Methods A total of 70 patients with thoracic tuberculosis(T4 to T10)who were admitted to our hospital from June 2018 to June 2023 were enrolled,and their clinical data were retrospectively analyzed.The 35 patients treated with extrapleural internal fixation were included in the extrapleural group,and the other 35 patients treated with transthoracic internal fixation were included in the transthoracic group.The operation time,intraoperative blood loss,bone graft fusion time,kyphotic angle before and after operation,visual analogue scale(VAS)and Oswestry disability index(ODI)scores after operation,postoperative complications and recurrence were compared between the two groups.Results Compared with the transthoracic group,the operation time and bone graft fusion time were significantly shortened,and the intraoperative blood loss was significantly reduced in the extrapleural group,with statistically significant differences(P<0.05).The postoperative kyphotic angles of the two groups were smaller than those before operation,the postoperative kyphotic angle of the extrapleural group was smaller than that of the transthoracic group,and the differences were statistically significant(P<0.05).The VAS score 7 days after operation of the extrapleural group was lower than that of the transthoracic group,and the difference was statistically significant(P<0.05).The ODI score 1 month after operation of the extrapleural group was lower than that of the transthoracic group,and the difference was statistically significant(P<0.05).The incidence of postoperative complications in the extrapleural group(0)was lower than that in the transthoracic group(34.28%),and the difference was statistically significant(P<0.05).Conclusion Extrapleural internal fixation has the advantages of short time,less bleeding and less trauma in the treatment of thoracic tuberculosis,but it is difficult to completely remove the lesions.Transthoracic internal fixation can completely remove the lesion,but the surgical trauma is large.The choice of clinical operation plan should be comprehensively considered according to the specific condition of the patients,the location of the lesion,and the condition of the lung,so as to achieve the best treatment effect.