Pulmonary fibrosis（PF） is a progressive and life-threatening disease with limited therapeutic options， highlighting the urgent need for innovative drug discovery strategies. To address this challenge， the authors propose the formula-originated rational intelligent screening&translation（FIRST）， a systematic framework for developing anti-fibrotic monomers derived from classical traditional Chinese medicine（TCM）. The strategy integrates three key dimensions， including tissue-oriented intelligent screening of active compounds， structural optimization based on drug-target spatial interactions and plant biosynthetic pathways， and cross-scale validation of drug. We further highlight its applications in discovering tissue-oriented novel drugs from clinically validated TCM， the development and mechanistic elucidation of anti-fibrotic therapeutics， as well as the clinical translation and secondary development of candidate drugs. This strategy paves the way for first-in-class， formula-derived monomeric drugs with defined structures， clarified mechanisms， and proven safety， offering a transformative avenue to meet the urgent therapeutic needs of PF and setting a new paradigm for TCM-based drug innovation.

Pulmonary fibrosis（PF） is a progressive and life-threatening disease with limited therapeutic options， highlighting the urgent need for innovative drug discovery strategies. To address this challenge， the authors propose the formula-originated rational intelligent screening&translation（FIRST）， a systematic framework for developing anti-fibrotic monomers derived from classical traditional Chinese medicine（TCM）. The strategy integrates three key dimensions， including tissue-oriented intelligent screening of active compounds， structural optimization based on drug-target spatial interactions and plant biosynthetic pathways， and cross-scale validation of drug. We further highlight its applications in discovering tissue-oriented novel drugs from clinically validated TCM， the development and mechanistic elucidation of anti-fibrotic therapeutics， as well as the clinical translation and secondary development of candidate drugs. This strategy paves the way for first-in-class， formula-derived monomeric drugs with defined structures， clarified mechanisms， and proven safety， offering a transformative avenue to meet the urgent therapeutic needs of PF and setting a new paradigm for TCM-based drug innovation.

Objective:Using graph theory analysis, this study compares the topological and node attributes of the brain network to explore the differences in gray matter structural and functional network topological properties between bipolar depression (BD) patients with and without obsessive-compulsive symptoms (OCS).Methods:A total of 90 BD patients (27 males, 63 females; median age 19.0(22.0, 25.0) years) were recruited from the psychiatric outpatient and inpatient departments of the First Affiliated Hospital of Jinan University between March 2018 and December 2022. Fifty healthy controls (19 males, 31 females; median age: 23.0 (20.0, 27.0) years) were also enrolled. The BD patients were divided into two groups based on the presence of OCS: 53 with OCS (OCS group) and 37 without OCS (NOCS group). Resting-state structural and functional MRI data were collected for all participants to construct gray matter structural and functional networks. Graph therory analysis was applied to calculate network topological metrics such as small-world properties. The structural and functional network topological properties were compared among the BD-OCS, BD-nOCS, and control groups. Partial correlation analysis was conducted to examine the association between network topological metrics with significant group differences and Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) scores. Support vector machines (SVM) were used with these metrics as classification feature values to improve diagnostic accuracy through pairwise group classification.Results:Structural network analysis of gray matter: compared to HC group, both OCS group and NOCS group showed increased shortest path length and standardized characteristic path length (shortest path length: 0.78 and 0.80 vs. 0.69; normalized characteristic path length: 0.48 and 0.49 vs. 0.43), and decreased global efficiency (0.21 and 0.21 vs. 0.24) compared to the HC group (permutation test, all P<0.05). Compared to NOCS and HC groups, the OCS group showed increased nodal centrality and betweenness centrality in the right rolandic operculum and left superior occipital gyrus (permutation test, all P<0.05). Functional network analysis of gray matter: compared to the NOCS group, the OCS group showed increased node efficiency and decreased betweenness centrality in the cerebellum ( t=2.15, -3.04; all P<0.05); compared to HC groups, the OCS group showed decreased betweenness centrality in the cerebellum and left inferior frontal gyrus, along with increased node centrality and nodal efficiency in the right transverse temporal gyrus ( t=-2.99, -3.61, 3.06, 3.10; all P<0.05). In the OCS group, betweenness centrality in the left inferior frontal gyrus positively correlated with Y-BOCS scale obsessive thinking score ( r=0.303, P=0.034). Nodal centrality and node efficiency of the right transverse temporal gyrus negatively correlated with Y-BOCS total score ( r=-0.301, -0.311) and Y-BOCS obsessional thinking scores ( r=-0.385, -0.380) separately(all P<0.05). SVM classification: the combined network features achieved an area under the curve of 0.80 in distinguising OCS from NOCS patients. Conclusion:BD-OCS and BD-nOCS patients both exhibit consistent changes in gray matter structural network topology, with the OCS group displaying more pronounced nodal topological abnormalities. Multi-network feature integration demostrates potential for diagnostic classfication.

Objective To evaluate the clinical efficacy of hip-knee-ankle active and passive exercise therapy in patients with early-to mid-stage knee osteoarthritis(KOA).Methods A total of 180 patients with early to mid-stage knee osteoarthritis(KOA)were recruited from the First Affiliated Hospital of Hebei University of Tradi-tional Chinese Medicine between March 2023 and March 2024.Patients were randomly assigned to one of four groups:active movement group,passive movement group,combined movement group,and control group,with 45 patients in each group.The active movement group received hip-knee-ankle active movement therapy daily until the end of follow-up.The passive movement group underwent hip-knee-ankle passive movement therapy three times per week for two weeks.The combined movement group received both active and passive therapies.The control group was administered oral celecoxib capsules(200 mg once daily for two weeks).Joint function was assessed in all four groups before treatment,at two weeks post-treatment,and at 14 weeks post-treatment.The primary outcome measure was the WOMAC joint function score,while secondary outcomes included the WOMAC pain score,stiffness score,and quality of life score(SF-12).Results A total of 160 patients completed the trial,with 39 in the active group,42 in the passive group,40 in the combined group,and 39 in the control group.There were no significant differences in baseline characteristics among the groups(P>0.05).Compared to baseline,the WOMAC scores for function,pain,and stiffness in the passive,combined,and control groups decreased significantly at both 2 and 14 weeks post-treatment(P<0.05),while the SF-12 scores increased significantly(P<0.05).Between 2 and 14 weeks post-treat-ment,the active and combined groups showed further significant decreases in WOMAC function,pain,and stiffness scores(P<0.05)and increases in SF-12 scores(P<0.05).At 2 weeks post-treatment,compared to the control group,the passive and combined groups exhibited significantly lower WOMAC function scores(P<0.05),with no significant difference between the passive and combined groups(P>0.05).By 14 weeks post-treatment,the active and combined groups demonstrated significantly lower WOMAC function scores(P<0.05),with the combined group showing a significantly lower score than the active group(P<0.05).Conclusion The four therapeutic approaches demonstrate a certain degree of efficacy in improving joint function for patients with early and mid-stage KOA.The passive therapy group exhibits superior short-term outcomes,while the active therapy group shows better long-term benefits.The combined therapy group presents notable advantages in both short-term and long-term effi-cacy,although its short-term effectiveness does not surpass that of the passive therapy group.It is recommended for patients with early and mid-stage KOA who have underlying gastrointestinal and cardiovascular conditions.

Genetic transformation is a fundamental tool in molecular biology research of medicinal plants. Tailoring transgenic technologies to each distinct medicinal plant would necessitate a substantial investment of time and effort. Here, we present a simple hairy root transformation method that does not require sterile conditions, utilizing Agrobacterium rhizogenes strain K599 and the visible RUBY reporter system. Transgenic hairy roots were obtained for six tested medicinal plant species, roots or rhizomes of which have recognized medicinal value, spanning four botanical families and six genera (Platycodon grandiflorus, Atractylodes macrocephala, Scutellaria baicalensis, Codonopsis pilosula, Astragalus membranaceus, and Glycyrrhiza uralensis). Furthermore, two previously identified Glycyrrhiza uralensis UGTs that convert liquiritigenin into liquiritin in heterologous systems were studied in planta using the method. Our results indicate that overexpression of GuUGT1 but not GuUGT10 and Cas9-mediated knockout of GuUGT1 profoundly influenced the accumulation of liquiritin and isoliquiritin in licorice roots. Therefore, the method described here represents a simple, rapid and widely applicable hairy root transformation method that enables fast gene functional study in medicinal plants.

Glioblastoma (GBM) is a highly aggressive primary brain tumor characterized by poor prognosis. Conventional chemo-radiotherapy demonstrates limited therapeutic efficacy and is often accompanied by significant side effects, largely due to factors such as drug resistance, radiation resistance, the presence of the blood-brain barrier (BBB), and the activation of DNA damage repair mechanisms. There is a pressing need to enhance treatment efficacy, with BRD4 identified as a promising target for increasing GBM sensitivity to therapy. Lacking small molecule inhibitors, BRD4 can be degraded using PROteolysis Targeting Chimera (PROTAC), thereby inhibiting DNA damage repair. To deliver PROTAC, SIAIS171142 (SIS) effectively, we designed a responsive nanocapsule, MPL_(SS)P@SIS, featuring GBM-targeting and GSH-responsive drug release. Modified with 1-methyl-l-tryptophan (MLT), nanocapsules facilitate targeted delivery of SIS, downregulating BRD4 and sensitizing GBM cells to radiotherapy and chemotherapy. After intravenous administration, MPL_(SS)P@SIS selectively accumulates in tumor tissue, enhancing the effects of radiotherapy and temozolomide (TMZ) by increasing DNA damage and oxidative stress. GSH activates the nanocapsules, triggering BRD4 degradation and hindering DNA repair. In mouse models, the nanosensitizer, combined with TMZ and X-ray irradiation, efficiently inhibited the growth of GBM. These findings demonstrate a novel PROTAC-based sensitization strategy targeting BRD4, offering a promising approach for effective GBM therapy.

OBJECTIVE: In Pakistan, traditional medicines are an important component of the medical system, with numerous varieties and great demands. However, due to the scattered resources and the lack of systematic collection and collation, adulteration of traditional Pakistani medicine (TPM) is common, which severely affects the safety of their medicinal use and the import and export trades. Therefore, it is urgent to systematically organize and unify the management of TPM and establish a set of standards and operable methods for the identification of TPM. METHODS: We collected and organized the information on 128 TPMs with regard to their medicinal parts, efficacy, usage, and genetic material, based on Pakistan Hamdard Pharmacopoeia of Eastern Medicine: Pharmaceutical Codex. The genetic information of TPM is summarized from national center for biotechnology information (NCBI) and global pharmacopoeia genome database (GPGD). Furthermore, we utilized bioinformatics technology to supplement the chloroplast genome (cp-genome) data of 12 TPMs. To build the web server, we used the Linux + Apache + MySQL + PHP (LAMP) system and constructed the webpage on a PHP: Hypertext Preprocessor (PHP) model view controller (MVC) framework. RESULTS: We constructed a new genomic database, the traditional Pakistani medicine genomic database (TPMGD). This database comprises five entries, namely homepage, medicinal species, species identification, basic local alignment search tool (BLAST), and download. Currently, TPMGD contains basic profiles of 128 TPMs and genetic information of 102 TPMs, including 140 cytochrome c oxidase subunit I (COI) sequences and 119 mitochondrial genome sequences from Bombyx mori, 1 396 internal transcribed spacer 2 (ITS2) sequences and 1 074 intergenic region (psbA-trnH) sequences specific to 92 and 83 plant species, respectively. Additionally, TPMGD includes 199 cp-genome sequences of 82 TPMs. CONCLUSION TPMGD is a multifunctional database that integrates species description, functional information inquiry, genetic information storage, molecular identification of TPM, etc. The database not only provides convenience for TPM information queries but also establishes the scientific basis for the medication safety, species identification, and resource protection of TPM.

OBJECTIVE: Benzylisoquinoline alkaloids (BIAs) have pharmacological functions and clinical use. BIAs are mainly distributed in plant species across the order Ranunculales and the genus Phellodendron from Sapindales. The BIA biosynthesis has been intensively investigated in Ranunculales species. However, the accumulation mechanism of BIAs in Phellodendron is largely unknown. The aim of this study is to unravel the biosynthetic pathways of BIAs in Phellodendron amurens. METHODS: The transcriptome and metabolome data from 18 different tissues of P. amurense were meticulously sequenced and subsequently subjected to a thorough analysis. Weighted gene co-expression network analysis (WGCNA), a powerful systems biology approach that facilitates the construction and subsequent analysis of co-expression networks, was utilized to identify candidate genes involved in BIAs biosynthesis. Following this, recombinant plasmids containing candidate genes were expressed in Escherichia coli, a widely used prokaryotic expression system. The purpose of this genetic engineering endeavor was to express the candidate genes within the bacteria, thereby enabling the assessment of the resultant enzyme activity. RESULTS: The synonymous substitutions per synonymous site for paralogs indicated that at least one whole genome duplication event has occurred. The potential BIA biosynthetic pathway of P. amurense was proposed, and two PR10/Bet v1 members, 14 CYP450s, and 33 methyltransferases were selected as related to BIA biosynthesis. One PR10/Bet v1 was identified as norcoclaurine synthase, which could catalyze dopamine and 4-hydroxyphenylacetaldehyde into (S)-norcoclaurine. CONCLUSION Our studies provide important insights into the biosynthesis and evolution of BIAs in non-Ranunculales species.

Traditional Chinese Medicine (TCM), as a treasure of the Chinese nation, plays a significant role in maintaining public health. In 2019, the Central Committee of the Communist Party of China and the State Council proposed for the first time the establishment of a TCM registration and evaluation evidence system that integrates TCM theory, "personal experience" and clinical trials (referred to as the "Three-in-One" System) to promote the inheritance and innovation of TCM. Subsequently, the National Medical Products Administration issued several guiding principles to advance the improvement and implementation of this system. Owing to the complexity of its implementation, there are still differing understandings within the TCM industry regarding the positioning of the "Three-in-One" Registration and Evaluation Evidence System, as well as the connotation and value orientation of the "personal experience." To address this, Academician WANG Qi, President of the TCM Association, China International Exchange and Promotion Association for Medical and Healthcare and TCM master, led a group of academicians, TCM masters, TCM pharmacology experts and clinical TCM experts to convene a "Seminar on Promoting the Implementation of the ′Three-in-One′ Registration and Evaluation Evidence System for Chinese Medicinals." Through extensive discussions, an expert consensus was formed, clarifying the different roles of the TCM theory, "personal experience" and clinical trials within the system. It was further emphasized that the "personal experience" is the core of this system, and its data should be derived from clinical practice scenarios. In the future, the improvement of this system will require collaborative efforts across multiple fields to promote the high-quality development of the Chinese medicinal industry.

Recent studies have shown that the physiological homeostasis of oral mucosal cells is regulated by the circadian clock.Dis-ruption or dysfunction of the circadian clock is closely associated with the development of oral squamous cell carcinoma(OSCC).Research based on the circadian clock offers a novel perspective on the pathogenesis and therapeutic strategies for OSCC.However,there is current-ly limited research on this topic,and people generally have insufficient understanding and recognition of the circadian clock.Given the complexity and challenges of circadian clock which is the fourth dimension of medical research,we organize relevant experts based on summarizing the current research results of circadian clock in the pathogenesis and precision diagnosis and treatment of OSCC,combining the scientific principles of the circadian clock's role and their long-term research experience,then summarizes and recommends the con-sensus opinions for the research of circadian clock in the pathogenesis mechanism and precision diagnosis and treatment of human OSCC,with the hope of providing guidance for the basic research and clinical application of circadian clock or circadian rhythm in the pathogene-sis mechanism and precision diagnosis and treatment of oral and maxillofacial squamous cell carcinoma.