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.

Diabetic microvascular complications （DMC） are major chronic complications of diabetes，primarily including diabetic kidney disease （DKD），diabetic retinopathy （DR），diabetic cardiomyopathy （DCM），and diabetic peripheral neuropathy （DPN）. These complications significantly impact patients' quality of life and prognosis. Modern medicine primarily focuses on symptomatic control in the treatment of DMC，with limited ability to reverse the disease progression. Endoplasmic reticulum stress （ERS），as a central event under hyperglycemic toxicity，is not only a key cause of pancreatic β-cell dysfunction （reduced insulin synthesis and secretion） but also a core driver of damage in various target organs of DMC. It activates three signaling pathways of the unfolded protein response （UPR）-inositol-requiring enzyme 1 （IRE1），activating transcription factor 6 （ATF6），and protein kinase R-like endoplasmic reticulum kinase （PERK），intertwining processes such as autophagy，apoptosis，oxidative stress，and calcium homeostasis imbalance. Traditional Chinese medicine （TCM） offers multi-target and multi-pathway therapeutic advantages and can curb the pathological progression of DMC by regulating ERS. This article systematically reviews the relationships of ERS with pancreatic β-cell function，insulin synthesis，and insulin secretion，and elucidates the core signaling pathways through which ERS mediates DMC. Furthermore，it categorizes and summarizes experimental evidence and mechanisms of single medicinal herbs and their extracts，TCM compound formulas，and modern TCM preparations in regulating ERS for the treatment of various DMC subtypes. Finally，this article proposes ERS as a molecular bridge for integrating traditional Chinese and Western medicine in DMC treatment. Future research should leverage emerging technologies such as network pharmacology，multi-omics analysis，and nano-formulations to establish a synergistic network combining modern hypoglycemic drugs and TCM regulation of ERS. This approach is expected to achieve dual efficacy，enhance drug targeting and bioavailability，deepen the understanding of scientific connotation of TCM，and pave new avenues for the prevention and treatment of DMC.

Diabetic microvascular complications （DMC） are major chronic complications of diabetes，primarily including diabetic kidney disease （DKD），diabetic retinopathy （DR），diabetic cardiomyopathy （DCM），and diabetic peripheral neuropathy （DPN）. These complications significantly impact patients' quality of life and prognosis. Modern medicine primarily focuses on symptomatic control in the treatment of DMC，with limited ability to reverse the disease progression. Endoplasmic reticulum stress （ERS），as a central event under hyperglycemic toxicity，is not only a key cause of pancreatic β-cell dysfunction （reduced insulin synthesis and secretion） but also a core driver of damage in various target organs of DMC. It activates three signaling pathways of the unfolded protein response （UPR）-inositol-requiring enzyme 1 （IRE1），activating transcription factor 6 （ATF6），and protein kinase R-like endoplasmic reticulum kinase （PERK），intertwining processes such as autophagy，apoptosis，oxidative stress，and calcium homeostasis imbalance. Traditional Chinese medicine （TCM） offers multi-target and multi-pathway therapeutic advantages and can curb the pathological progression of DMC by regulating ERS. This article systematically reviews the relationships of ERS with pancreatic β-cell function，insulin synthesis，and insulin secretion，and elucidates the core signaling pathways through which ERS mediates DMC. Furthermore，it categorizes and summarizes experimental evidence and mechanisms of single medicinal herbs and their extracts，TCM compound formulas，and modern TCM preparations in regulating ERS for the treatment of various DMC subtypes. Finally，this article proposes ERS as a molecular bridge for integrating traditional Chinese and Western medicine in DMC treatment. Future research should leverage emerging technologies such as network pharmacology，multi-omics analysis，and nano-formulations to establish a synergistic network combining modern hypoglycemic drugs and TCM regulation of ERS. This approach is expected to achieve dual efficacy，enhance drug targeting and bioavailability，deepen the understanding of scientific connotation of TCM，and pave new avenues for the prevention and treatment of DMC.

ObjectiveTo observe the clinical efficacy of modified Yuejuwan in the treatment of thyroid cysts after microwave ablation. MethodsA total of 90 patients with thyroid cysts who met the inclusion criteria and treated in the First Affiliated Hospital of Hebei University of Chinese Medicine from September 2022 to December 2023 were randomly assigned to either the control group or the observation group， with 45 patients in each group. The control group received conventional postoperative drug treatment and was followed up regularly. The observation group was additionally administrated with modified Yuejuwan for one month and followed up regularly. The alterations in volume， thyroid function parameters ［thyroid-stimulating hormone （TSH）， free triiodothyronine （FT₃）， and free thyroxine （FT₄）］， quality of life scores， and clinical efficacy were monitored and compared between the two groups. Additionally， the safety profile was appraised. ResultsAfter treatment， both the observation group and the control group showed a reduction in cyst volume （P<0.05）， and the observation group exhibited a more significant reduction in cyst volume than the control group （P<0.05）. After treatment， both the observation group and the control group showed a decrease in TSH level and increases in FT₃ and FT₄ levels （P<0.05）， and the changes were more significant in the observation group （P<0.05）. In addition， both groups exhibited elevations in the quality of life scores （P<0.05）. Moreover， the observation group showed more increments in physiological， psychological， and social scores than the control group （P<0.05）. The total response rate of the observation group was higher than that of the control group （Z=-2.516， P<0.05）. The incidence of adverse reactions was similar between the two groups， with no statistically significant difference. ConclusionModified Yuejuwan is effective in the treatment of thyroid cysts after microwave ablation. It can promote the absorption of cysts， improve the thyroid function and quality of life， and has high safety.

ObjectiveTo observe the clinical efficacy of modified Yuejuwan in the treatment of thyroid cysts after microwave ablation. MethodsA total of 90 patients with thyroid cysts who met the inclusion criteria and treated in the First Affiliated Hospital of Hebei University of Chinese Medicine from September 2022 to December 2023 were randomly assigned to either the control group or the observation group， with 45 patients in each group. The control group received conventional postoperative drug treatment and was followed up regularly. The observation group was additionally administrated with modified Yuejuwan for one month and followed up regularly. The alterations in volume， thyroid function parameters ［thyroid-stimulating hormone （TSH）， free triiodothyronine （FT₃）， and free thyroxine （FT₄）］， quality of life scores， and clinical efficacy were monitored and compared between the two groups. Additionally， the safety profile was appraised. ResultsAfter treatment， both the observation group and the control group showed a reduction in cyst volume （P<0.05）， and the observation group exhibited a more significant reduction in cyst volume than the control group （P<0.05）. After treatment， both the observation group and the control group showed a decrease in TSH level and increases in FT₃ and FT₄ levels （P<0.05）， and the changes were more significant in the observation group （P<0.05）. In addition， both groups exhibited elevations in the quality of life scores （P<0.05）. Moreover， the observation group showed more increments in physiological， psychological， and social scores than the control group （P<0.05）. The total response rate of the observation group was higher than that of the control group （Z=-2.516， P<0.05）. The incidence of adverse reactions was similar between the two groups， with no statistically significant difference. ConclusionModified Yuejuwan is effective in the treatment of thyroid cysts after microwave ablation. It can promote the absorption of cysts， improve the thyroid function and quality of life， and has high safety.

OBJECTIVE: To observe the effect of electroacupuncture (EA) on the intestinal flora in rats with chronic obstructive pulmonary disease (COPD) and explore its possible mechanism based on the gut-lung axis theory. METHODS: A total of 30 male SD rats of SPF grade were randomly divided into a normal control (NC) group, a model group and an EA group, 10 rats in each one. In the model group and the EA group, COPD model was established by intratracheal instillation of lipopolysaccharide combined with cigarette fumigation. In the EA group, EA was applied at bilateral "Feishu" (BL13) and "Zusanli" (ST36), with disperse-dense waves, in frequency of 4 Hz/20 Hz, current of 1-3 mA, 20 min a time, once a day for 14 days continuously. Before and after modeling, as well as after intervention, body weight was observed; after intervention, the lung function indexes (forced expiratory volume in 0.1 second [FEV_0.1], FEV_0.1/forced vital capacity [FVC]%, forced expiratory volume in 0.3 second [FEV_0.3] and FEV_0.3/FVC%) were measured, serum levels of inflammatory factors (tumor necrosis factor-α[TNF-α], interleukin-6[IL-6], interleukin-1β[IL-1β] and interleukin-10[IL-10]) were detected by ELISA, histopathology of lung and colon tissues was observed by HE staining, the intestinal flora were analyzed by 16S rRNA, and the correlations between lung function and intestinal flora were analyzed. RESULTS: Compared with the NC group, in the COPD group, the body weight and lung function indexes were reduced (P<0.01); the lung and colon tissues were damaged, the mean linear intercept (MLI) of alveolus and inflammatory cell numbers of 100 μm² in lung tissue were increased (P<0.01); the serum levels of TNF-α, IL-6 and IL-1β were increased (P<0.01, P<0.05), and the serum level of IL-10 was decreased (P<0.01); α-diversity indexes of intestinal flora were increased (P<0.01); the relative abundance of Bacteroidetes, Proteobacteria and Oscillospira, Bacteroides, Coprococcus was increased (P<0.01), the relative abundance of Firmicutes, Actinobacteria, Tenericutes, TM7 and Lactobacillus, Allobaculum, Bifidobacterium, YRC22 was decreased (P<0.01, P<0.05); 31 different expressed metabolic pathways were identified between the two groups. Compared with the COPD group, in the EA group, the body weight and lung function indexes were increased (P<0.01); the damage of lung and colon tissues was improved, the MLI of alveolus was decreased (P<0.05); the serum levels of TNF-α, IL-6 and IL-1β were decreased (P<0.05), and the serum level of IL-10 was increased (P<0.05); α-diversity indexes of intestinal flora were decreased (P<0.01); the relative abundance of Bacteroidetes, Proteobacteria and Oscillospira, Bacteroides, Coprococcus was decreased (P<0.01, P<0.05), the relative abundance of Firmicutes, Actinobacteria, Tenericutes, TM7 and Lactobacillus, Allobaculum, Bifidobacterium, YRC22 was increased (P<0.01); 35 different expressed metabolic pathways were identified between the two groups. The lung function was positive related with Actinobacteria, Tenericutes, TM7 and YRC22, and was negative related with Bacteroidetes, Proteobacteria and Oscillospira, Bacteroides, Coprococcus. CONCLUSION EA may ameliorate lung function and tissue injury of COPD by regulating intestinal flora dysbiosis and inflammatory response, suggesting an anti-inflammatory effect mediated via "gut-lung" axis.
Animals ; Pulmonary Disease, Chronic Obstructive/genetics* ; Male ; Electroacupuncture ; Rats ; Rats, Sprague-Dawley ; Lung/metabolism* ; Gastrointestinal Microbiome ; Humans ; Interleukin-6/immunology* ; Tumor Necrosis Factor-alpha/immunology* ; Intestines/microbiology* ; Interleukin-10/immunology*

BACKGROUND: Oral squamous cell carcinoma (OSCC) is a prevalent type of cancer with a high mortality rate in its late stages. One of the major challenges in OSCC treatment is the resistance to epidermal growth factor receptor (EGFR) inhibitors. Therefore, it is imperative to elucidate the mechanism underlying drug resistance and develop appropriate precision therapy strategies to enhance clinical efficacy. METHODS: To evaluate the efficacy of the combination of the Ca 2+ /calmodulin-dependent protein kinase II (CAMK2) inhibitor KN93 and EGFR inhibitors, we performed in vitro and in vivo experiments using two FAT atypical cadherin 1 ( FAT1 )-deficient (SCC9 and SCC25) and two FAT1 wild-type (SCC47 and HN12) OSCC cell lines. We assessed the effects of EGFR inhibitors (afatinib or cetuximab), KN93, or their combination on the malignant phenotype of OSCC in vivo and in vitro . The alterations in protein expression levels of members of the EGFR signaling pathway and SRY-box transcription factor 2 (SOX2) were analyzed. Changes in the yes-associated protein 1 (YAP1) protein were characterized. Moreover, we analyzed mitochondrial dysfunction. Besides, the effects of combination therapy on mitochondrial dynamics were also evaluated. RESULTS: OSCC with FAT1 mutations exhibited resistance to EGFR inhibitors treatment. The combination of KN93 and EGFR inhibitors significantly inhibited the proliferation, survival, and migration of FAT1 -mutated OSCC cells and suppressed tumor growth in vivo . Mechanistically, combination therapy enhanced the therapeutic sensitivity of FAT1 -mutated OSCC cells to EGFR inhibitors by modulating the EGFR pathway and downregulated tumor stemness-related proteins. Furthermore, combination therapy induced reactive oxygen species (ROS)-mediated mitochondrial dysfunction and disrupted mitochondrial dynamics, ultimately resulting in tumor suppression. CONCLUSION Combination therapy with EGFR inhibitors and KN93 could be a novel precision therapeutic strategy and a potential clinical solution for EGFR-resistant OSCC patients with FAT1 mutations.
Humans ; ErbB Receptors/metabolism* ; Mouth Neoplasms/metabolism* ; Cell Line, Tumor ; Animals ; Drug Resistance, Neoplasm/genetics* ; Cadherins/metabolism* ; Carcinoma, Squamous Cell/metabolism* ; Mice ; Mutation/genetics* ; Mice, Nude ; Protein Kinase Inhibitors/therapeutic use* ; Cetuximab/pharmacology* ; Afatinib/therapeutic use* ; Cell Proliferation/drug effects* ; Signal Transduction/drug effects*

INTRODUCTION: Lecanemab has shown promise in treating early Alzheimer's disease (AD), but its safety and efficacy in Chinese populations remain unexplored. This study aimed to evaluate the safety and 6-month clinical outcomes of lecanemab in Chinese patients with mild cognitive impairment (MCI) or mild AD. METHODS: In this single-arm, real-world study, participants with MCI due to AD or mild AD received biweekly intravenous lecanemab (10 mg/kg). The study was conducted at Hainan Branch, Ruijin Hospital Shanghai Jiao Tong University School of Medicine. Patient enrollment and baseline assessments commenced in November 2023. Safety assessments included monitoring for amyloid-related imaging abnormalities (ARIA) and other adverse events. Clinical and biomarker changes from baseline to 6 months were evaluated using cognitive scales (mini-mental state examination [MMSE], montreal cognitive assessment [MoCA], clinical dementia rating-sum of boxes [CDR-SB]), plasma biomarker analysis, and advanced neuroimaging. RESULTS: A total of 64 patients were enrolled in this ongoing real-world study. Safety analysis revealed predominantly mild adverse events, with infusion-related reactions (20.3%, 13/64) being the most common. Of these, 69.2% (9/13) occurred during the initial infusion and 84.6% (11/13) did not recur. ARIA-H (microhemorrhages/superficial siderosis) and ARIA-E (edema/effusion) were observed in 9.4% (6/64) and 3.1% (2/64) of participants, respectively, with only two symptomatic cases (one ARIA-E presenting with headache and one ARIA-H with visual disturbances). After 6 months of treatment, cognitive scores remained stable compared to baseline (MMSE: 22.33 ± 5.58 vs . 21.27 ± 4.30, P = 0.733; MoCA: 16.38 ± 6.67 vs . 15.90 ± 4.78, P = 0.785; CDR-SB: 2.30 ± 1.65 vs . 3.16 ± 1.72, P = 0.357), while significantly increasing plasma amyloid-β 42 (Aβ42) (+21.42%) and Aβ40 (+23.53%) levels compared to baseline. CONCLUSIONS: Lecanemab demonstrated a favorable safety profile in Chinese patients with early AD. Cognitive stability and biomarker changes over 6 months suggest potential efficacy, though high dropout rates and absence of a control group warrant cautious interpretation. These findings provide preliminary real-world evidence for lecanemab's use in China, supporting further investigation in larger controlled studies. REGISTRATION ClinicalTrials.gov , NCT07034222.
Humans ; Alzheimer Disease/drug therapy* ; Male ; Female ; Aged ; Middle Aged ; Cognitive Dysfunction/drug therapy* ; Aged, 80 and over ; Amyloid beta-Peptides/metabolism* ; Biomarkers ; East Asian People