ObjectiveThis paper aims to analyze the damage degree of muscle tone in rats with spasticity of cerebral apoplexy （SCA） and the expression of Nestin and β-catenin in the M1 region of the cerebral cortex， thereby investigating the action mechanism of different doses of Shaoyao Gancaotang on rats with SCA. MethodsThe rats were randomly divided into a blank group， a model group， a positive control group （baclofen， 5.25 mg·kg^-1）， and low， medium， and high-dose groups of Shaoyao Gancaotang （2.1， 4.2， 8.4 g·kg^-1）， with nine rats in each group. A rat model with SCA was established by using a modified phrenic nerve block combined with intraventricular injection of anhydrous ethanol. Following behavioral scoring to confirm model validity， drug interventions were conducted. Neurological deficits and muscle tone were evaluated by behavioral assessments. The open field test was used to measure locomotor distance. Transmission electron microscopy was employed to examine the synaptic structures. Skeletal muscle adenosine triphosphate （ATP）ase staining was used to analyze myofibrillar changes. Hematoxylin and eosin （HE） staining was used to observe the histomorphological changes. Immunohistochemistry， Real-time polymerase chain reaction （Real-time PCR）， and Western blot were employed to detect mRNA levels and protein expressions of Nestin and β-catenin in the M1 region of the cerebral cortex. ResultsCompared with the blank group， rats in the model group exhibited significantly increased neurological deficit scores （P<0.01）， markedly elevated muscle tone scores （P<0.01）， substantially reduced locomotor distance （P<0.01）， prominent structural swelling and blurring， severe destruction of cerebral cortical cells， a significant increase in the proportion of skeletal muscle ATPase type Ⅰ fibers （P<0.01）， a significant decrease in mRNA levels and protein expression of Nestin （P<0.01）， and a significant increase in mRNA levels and protein expression of β-catenin （P<0.01）. Compared with the model group， the Shaoyao Gancaotang group exhibited reduced neurological deficit scores and muscle tone scores in rats with SCA （P<0.01） and increased locomotor distance （P<0.01）. Transmission electron microscopy revealed clearer and more intact synaptic structures in the rats from the Shaoyao Gancaotang group， with increased vesicle numbers and improved morphology. HE staining revealed intact neuronal cell structures with regular arrangement and reduced vacuolated cells in the rats from Shaoyao Gancaotang. ATPase staining result indicated a decreased proportion of type Ⅰ muscle fibers in the rats from the Shaoyao Gancaotang group （P<0.01）. Real-time PCR results demonstrated increased mRNA expressions of Nestin and β-catenin in the rats from the Shaoyao Gancaotang group （P<0.01）. Immunohistochemistry and western blot analyses indicated elevated protein expressions of Nestin and β-catenin in rats with SCA from the Shaoyao Gancaotang group （P<0.05， P<0.01）. ConclusionShaoyao Gancaotang may improve neurological function impairment and limb spasticity in model rats with SCA by regulating the proliferation and differentiation of neural stem cells in the cerebral cortex M1 region.

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.

BACKGROUND: Quantitative flow ratio (QFR) holds significant value in guiding drug-coated balloon (DCB) treatment and enhancing outcomes. However, the predictive capability of post-angioplasty QFR for long-term clinical events in patients with de novo lesions who receive DCB treatment remains uncertain. The aim of this study was to explore the potential significance of post-angioplasty QFR measurements in predicting clinical outcomes in patients underwent DCB treatment for de novo lesions. METHODS: Patients who underwent DCB-only intervention for de novo lesions were enrolled. QFR was conducted after DCB treatment. The patients were then categorized based on post-angioplasty QFR. The primary endpoint was major adverse cardiac events (MACE), encompassing all-cause death, cardiovascular death, nonfatal myocardial infarction, stroke, and target vessel revascularization. RESULTS: A total of 553 patients with 561 lesions were included. The median follow-up period was 505 days, during which 66 (11.8%) MACEs occurred. Based on post-procedural QFR grouping, there were 259 cases in the high QFR group (QFR > 0.93) and 302 cases in the low QFR group (QFR ≤ 0.93). Kaplan-Meier analysis revealed a significantly higher cumulative incidence of MACE in the low QFR group (log-rank P = 0.004). The multivariate Cox proportional hazards model demonstrated a significant inverse correlation between QFR and the occurrence of MACEs (HR = 0.522, 95%CI: 0.289-0.942, P = 0.031). Landmark analysis indicated that high QFR had a significant reducing effect on the cumulative incidence of MACEs within 1 year (log-rank P = 0.016) and 1-5 years (log-rank P = 0.026). CONCLUSIONS In patients who underwent DCB-only treatment for de novo lesions, higher post-procedural QFR values (> 0.93) were identified as an independent protective factor against adverse prognosis.

OBJECTIVE: To evaluate the efficacy and safety of a hospital-made resuscitation pack, a Chinese medicinal herbal compound formula designed to enhance recovery in post-bronchoscopy patients. METHODS: In this randomized, single-blind, placebo-controlled clinical trial, eligible patients were randomly assigned 1:1 to either the treatment or control groups. The patients in the treatment group applied the resuscitation pack, which contained aromatic compounded Chinese herbs. The patients in the control group applied a hospital-made, single herb placebo pack. Packs were placed on the Tiantu (CV 22) acupuncture point for 4 h as soon as the bronchoscopy finished. Efficacy indicators, such as recovery time, patients' symptoms including nausea and dizziness, and adverse events (AEs) were observed and compared. The outcome indices were evaluated at baseline, 1 and 24 h after the bronchoscopy. Subgroup analysis was further performed by patients' age and depth of sedation. RESULTS: When applying generalized estimating equations (GEE) to evaluate the intensity of post-bronchoscopy nausea and vomiting, the intensity was lower in the treatment group (163 cases) compared with the control group (162 cases; 95% CI: 0.004, 0.099, P=0.03]. Also, significantly lower intensity of nausea was observed in the 60-70 years of age subgroup (95% CI: 0.029, 0.169, P=0.006) and deep sedation subgroup (95% CI: 0.002, 0.124; P=0.04). There was no significant difference in dizziness between two groups by GEE (95% CI: -0.134, 0.297; P=0.459). In addition, no serious AEs were observed in either group. CONCLUSIONS Our study found that the resuscitation pack markedly improved patients' symptoms by reducing nausea and vomiting after bronchoscopy without AEs, compared with placebo in the perioperative period. (Trial registration No. ChiCTR2000038299).
Humans ; Male ; Middle Aged ; Female ; Bronchoscopy/adverse effects* ; Single-Blind Method ; Aged ; Drugs, Chinese Herbal/adverse effects* ; Treatment Outcome ; Resuscitation ; Adult ; Medicine, Chinese Traditional

The unique characteristics of the deep space environment, microgravity, cosmic radiation, and extreme temperature fluctuations, are emerging as major driving forces for pharmaceutical innovation. These factors provide new avenues for optimizing drug formulations, improving crystal structure quality, and accelerating the discovery of therapeutic targets. Advances in deep space research not only help overcome critical bottlenecks in terrestrial drug development but also promote progress in structure-based drug design and deepen understanding of cellular stress-response mechanisms. Current progress in space-based pharmaceutical research primarily includes the study of disease mechanisms under microgravity, protein crystallization in microgravity, and drug development utilizing deep space radiation and resources. However, the operational complexity, high costs, and limited data reproducibility of space experiments remain key challenges hindering widespread application. Looking ahead, with the integration of automation, artificial intelligence analysis, and on-orbit manufacturing, deep space drug development is expected to achieve greater scalability and precision, opening a new frontier in biopharmaceutical science.
Drug Design ; Drug Development/methods* ; Humans ; Weightlessness ; Space Flight ; Artificial Intelligence ; Extraterrestrial Environment

Targeting T-cell is a strategy to control allogeneic response disorders, such as acute graft-versus-host disease (GVHD) which is an important cause of therapy-failure after allogeneic hematopoietic cell transplants. Free fatty acid receptor-4 (FFAR4) is a regulator of obesity but its role in T-cell and allogeneic reactions is unknown. Here, we found knockout of Ffar4 in donor T-cells in a mouse allograft model increased acute GVHD whereas the natural FFAR4 ligands and the synthetic FFAR4 agonists decreased it. FFAR4 agonist-mediated anti-acute GVHD effects depended on FFAR4-expression in donor T-cells. The FFAR4 agonist CpdA suppressed donor T-cell-mediated alloreaction by activating an aryl hydrocarbon receptor (AhR) pathway. CpdA recruited β-Arrestin2 to FFAR4 which facilitated nuclear translocation of AhR and upregulation of IL-22. The CpdA-mediated anti-acute GVHD effect was absent in mice receiving Ahr-knockout or Il22-knockout T-cells. Recipient-expressing Ffar4 was also important for the anti-acute GVHD effect of CpdA which inhibited activation of antigen presenting cells. Importantly, CpdA decreased acute GVHD in obese mice, an effect also depended on Ffar4-expression in donor T-cells and recipients. Our study shows the immunoregulatory effect of FFAR4 in T-cell, and targeting FFAR4 might be a relative option for controlling allogeneic reactions in obese patients.

[This corrects the article DOI: 10.1016/j.apsb.2022.05.019.].

To investigate the protective effects and underlying mechanisms of Qin-Zhu-Liang-Xue decoction (QZLX) in atopic dermatitis (AD) and glucocorticoid resistance, we conducted a single-blinded, randomized controlled clinical trial to evaluate the efficacy and safety of this concoction. Network pharmacology analysis was performed and validated through clinical studies. The efficacy, safety, and mechanism of action of QZLX and glucocorticoid receptor (GR) α recombinant protein were assessed in AD mice induced by 2,4-dinitrofluorobenzene (DNFB). Correlation analysis was performed to determine the clinical relevance of GRα. The trial demonstrated that patients who received QZLX showed considerable improvements in their Scoring Atopic Dermatitis (SCORAD) and Dermatology Life Quality Index (DLQI) scores compared with those who received mizolastine at week 4. Network pharmacological analysis identified GRα as a key target for QZLX in AD treatment. QZLX administration increased the serum GRα expression in AD patients, alleviated AD symptoms in mice, decreased inflammatory cytokine expression, and increased GRα expression without affecting liver or kidney function. In addition, GRα recombinant protein improved AD-like skin lesions in DNFB-induced mice. A negative correlation was observed between GRα expression and clinical parameters, including SCORAD, DLQI, and serum IgE levels. QZLX alleviates AD symptoms through the upregulation of GRα and thus presents a novel therapeutic strategy for the prevention of glucocorticoid resistance in AD management.
Dermatitis, Atopic/drug therapy* ; Animals ; Drugs, Chinese Herbal/administration & dosage* ; Humans ; Mice ; Network Pharmacology ; Male ; Female ; Adult ; Receptors, Glucocorticoid/metabolism* ; Disease Models, Animal ; Single-Blind Method ; Middle Aged ; Young Adult

Combined with elastic network model (ENM), the perturbation response scanning (PRS) has emerged as a robust technique for pinpointing allosteric interactions within proteins. Here, we proposed the PRS analysis of drug-target networks (DTNs), which could provide a promising avenue in network medicine. We demonstrated the utility of the method by introducing a deep learning and network perturbation-based framework, for drug repurposing of multiple sclerosis (MS). First, the MS comorbidity network was constructed by performing a random walk with restart algorithm based on shared genes between MS and other diseases as seed nodes. Then, based on topological analysis and functional annotation, the neurotransmission module was identified as the "therapeutic module" of MS. Further, perturbation scores of drugs on the module were calculated by constructing the DTN and introducing the PRS analysis, giving a list of repurposable drugs for MS. Mechanism of action analysis both at pathway and structural levels screened dihydroergocristine as a candidate drug of MS by targeting a serotonin receptor of serotonin 2B receptor (HTR2B). Finally, we established a cuprizone-induced chronic mouse model to evaluate the alteration of HTR2B in mouse brain regions and observed that HTR2B was significantly reduced in the cuprizone-induced mouse cortex. These findings proved that the network perturbation modeling is a promising avenue for drug repurposing of MS. As a useful systematic method, our approach can also be used to discover the new molecular mechanism and provide effective candidate drugs for other complex diseases.

OBJECTIVE: To explore the efficacy and safety of human epidermal growth factor gel in the treatment of pin tract infections after surgery in patients with severe spinal deformity. METHODS: A retrospective case-control study was conducted to analyze the clinical data of 26 patients with pin tract infections after skull-pelvic ring traction for severe spinal deformity admitted from February 2019 to May 2022. Among them, 11 were male and 15 were female;the age ranged from 18 to 31 years, with an average of (24.1±4.3) years;the Cobb angle ranged 80.3° to 120.7°, with an average of (88.6±10.2)°;there were 52 iliac traction pins, 104 pin tract openings, and 38 pin tract infections. According to the Checketts-Otterbum classification, there were 11 infections of gradeⅠ, 13 infections of gradeⅡ, 10 infections of grade Ⅲ, and 4 infections of grade Ⅳ. The patients were divided into the conventional dressing change group (13 cases) and the growth factor group (13 cases) by coin flipping. Clinical efficacy was evaluated by recording the visual analogue scale(VAS) score during dressing change, duration of dressing change, cost of dressing change, positive rate of bacterial culture, wound improvement rate, and wound improvement time. RESULTS: There were no statistically significant differences in VAS or duration of dressing change between the two groups (P>0.05). The cost of dressing change was (800.0±59.5) yuan in the conventional dressing change group and (1 179.5±80.9) yuan in the growth factor group, with a statistically significant difference (P<0.05). There was no statistically significant difference in the positive rate of bacterial culture between the two groups (P>0.05). In the conventional dressing change group, within 20 pin tract infections, 2 infections achieved wound healing, 7 infections showed improvement, and 11 infections were ineffective;in the growth factor group, within 18 pin tract infections 5 infections achieved wound healing, 8 infections showed improvement, and 5 infections were ineffective, with a statistically significant difference between the two groups (P<0.05). The wound healing time was (22.8±4.9) days in the conventional dressing change group and (14.2±2.5) days in the growth factor group, with a statistically significant difference (P<0.05). No complications occurred in either group. CONCLUSION The application of human epidermal growth factor gel in the treatment of pin tract infections after skull-pelvic ring surgery in patients with severe spinal deformity is easy to operate, does not increase patient pain, and has significant efficacy. It shortens wound healing time, effectively promotes wound healing, and has good safety and high cost-effectiveness.
Humans ; Male ; Female ; Adult ; Adolescent ; Retrospective Studies ; Case-Control Studies ; Young Adult ; Epidermal Growth Factor/therapeutic use* ; Traction/adverse effects* ; Gels ; Bone Nails/adverse effects* ; Surgical Wound Infection/drug therapy*