OBJECTIVE To analyze the specific risks and long-term toxicities of four BCR-ABL1 tyrosine kinase inhibitors （TKIs）（imatinib， dasatinib， nilotinib， and bosutinib） in pediatric patients with hematological malignancies. METHODS Adverse drug event （ADE） reports submitted to the the United States FDA Adverse Event Reporting System （FAERS） from January 2012 to December 2024， with imatinib， dasatinib， nilotinib， and bosutinib as the primary suspect drugs， were collected. Data mining was performed using the reporting odds ratio method and proportional reporting ratio method. ADE terms were classified and summarized by system organ class （SOC） and preferred term （PT） according to the Medical Dictionary for Drug Regulatory Activities （MedDRA， version 26.0）. Meanwhile， the ADE reports were divided by age into the adult group （≥18 years） and the pediatric group （＜18 years） to compare the differences in ADE between the two groups. RESULTS A total of 1 512 pediatric ADE reports were included： 993 for imatinib， 391 for dasatinib， 112 for nilotinib， and 16 for bosutinib. Among the reported ADEs， the patients were mainly aged 12-＜18 years； the reports mainly originated from the United States， France， and Japan； and the primary indications were chronic myeloid leukemia and acute lymphoblastic leukemia. A total of 5 256 ADE signals were mined， among which 235 were positive signals， involving 1 103 PT across 27 SOC. The top five PT ranked by the number of positive signals were nausea， febrile neutropenia， abdominal pain， neutropenia， and anemia. The top two SOC were general disorders and administration site conditions， and gastrointestinal disorders. Compared with the adult group， the pediatric group had relatively higher proportions of events related to infections and infestations as well as blood and lymphatic system disorders. Pediatric long-term toxicity signals primarily included growth retardation， accompanied by signals related to endocrine system abnormalities and bone metabolism abnormalities. Specific signals included imatinib-associated septic shock， dasatinib-associated chylothorax， and nilotinib-associated electrocardiographic QT interval prolongation. CONCLUSIONS When pediatric patients use BCR-ABL1 TKIs， priority monitoring of infection risk and hematologic parameters is required， along with long-term follow-up of height， endocrine， and bone metabolism parameters. Targeted screening and management of drug-specific signals should be performed to ensure the long-term safety of pediatric medication.

ObjectiveThis study employed the scoping review method to systematically retrieve and analyze the basic information and clinical research evidence of expensive Chinese patent medicines （CPMs）， aiming to provide a basis for future related research and clinical applications. MethodsEight Chinese and English databases were systematically searched for the clinical research evidence on expensive CPMs. ResultsEleven expensive CPMs （Angong Niuhuang Wan， Jufang Zhibao Wan， Suhexiang Wan， Pien Tze Huang， Niuhuang Qingxin Wan， Qinggong Shoutao Wan， Compound Realgar Natural Indigo Tablets， Xihuang Wan， Dingkun Wan， Babao Wan， and Guilingji Capsules） were selected. A total of 365 related studies were included in this review， comprising 331 clinical studies （of which 291 were randomized controlled trials）， 30 systematic reviews and Meta-analyses， 3 expert consensus， and 1 rapid health technology assessment. Among the 11 CPMs， 2（Angong Niuhuang Wan and Jufang Zhibao Wan） had a daily price over 500 yuan. The famous and precious Chinese medicinal materials involved included Moschus （frequency of 7）， Bovisc Alculus （7）， and Borneol （5）. The dosage forms included pills， capsules， oral liquid， tablets， and lozenges. The diseases treated by these CPMs mainly included malignant tumors， cerebrovascular diseases， gynecological diseases， and hepatobiliary system diseases. The sample sizes of the clinical studies were mainly concentrated within the range of 51-100 cases， and the main control form was CPM + basic Western medicine treatment vs. basic Western medicine treatment. The 331 clinical studies reported a total of 44 adverse events occurred， of which 36 were determined to be adverse reactions. ConclusionThe scarcity of raw materials leads to the high prices of expensive CPMs. The difficulty of conducting clinical research and the critical and severe cases treated lead to a lack of clinical research evidence with large sample sizes. The uneven distribution of existing studies， incomplete information on medicine package， and non-standard clinical research designs remain to be addressed in the future.

Objective To comparatively evaluate the diagnostic value of metagenomic next-generation sequencing(mNGS)versus conventional microbial culture in spinal infections.Methods A cross-section design was conducted on 82 consecutive patients with suspected spinal infections treated between February 2022 and January 2024 at Jiangbei Branch of First Affiliated Hospital of Army Medical University(Third Military Medical University).Microbiological culture,histopathological examination,and mNGS results from infected specimens were analyzed.Clinical diagnosis,primarily based on clinical manifestations,laboratory tests and radiologic features combined with medical history,was defined as the gold standard,and then the diagnostic performance,including sensitivity and specificity,were compared between mNGS and microbial culture.Results Among the 82 patients,definitive microbiological evidence was identified in 70 cases,and mNGS demonstrated a significantly higher detection rate than microbial culture(64 vs 36 cases,78.05％vs 43.9％,P<0.05).mNGS also obtained obviously higher sensitivity,accuracy,and negative predictive value(NPV),and notably lower positive predictive value(PPV)when compared to conventional microbial culture(all P<0.05).When stratified by infection type,mNGS obtained significantly higher sensitivity and accuracy compared to microbial culture in tuberculous spinal infections(P<0.05).For non-tuberculous spinal infections,mNGS also showed superior sensitivity to microbial culture(P<0.05).Conclusion In patients with spinal infections,mNGS demonstrates a significantly higher pathogen detection rate than conventional microbial culture.This technique can provide early and broad-spectrum pathogenic microbiological evidence for spinal infection.

Liquiritigenin(LG)is a flavone of pharmacological importance,however,its application potential is severely limited due to its poor water solubility.LG could be disassociated slightly in water to form phenolate anion,therefore,better solubilization effect is expected by inclusion with cationic cyclodextrins(CCDs).In this work,four kinds of CCDs modified with amino groups at the primary face were synthesized,and their solid inclusion complexes with LG were successfully prepared by preparing their saturated solutions.The formation of the solid inclusion complexes was confirmed by scanning electron microscopy(SEM)and powder X-ray diffraction(PXRD),and their supramolecular binding behavior in solution was studied using multiple techniques.A 1∶1 inclusion stoichiometry of inclusion complexation was defined using Job plot by ultraviolet-visible(UV-vis)spectroscopy,and their binding stability constants(Ks)were determined as 2862.77,3494.70,6521.85 and 9599.48 L/mol using UV-vis spectroscopic titration,far more superior to that of nativeβ-CD(Ks=236.79 L/mol).This indicated that the amino side chains on CCDs could actively participate in the inclusion complexation through anion-cation interactions,significantly strengthening the host-guest binding between CCDs and LG.The inclusion modes were further elucidated based on proton and two-dimensional rotating-frame overhauser enhancement spectroscopy(2D-ROESY)nuclear magnetic resonance(NMR)experiments and molecular docking.Water solubility of LG was dramatically promoted up to 4.9 mg/mL,which was 70-fold higher than that of native LG.This study could draw inspiration for the binding and solubilization of phenols such as flavones by design of cationic macrocyclic molecules.

Objective To observe the therapeutic effect and mechanism of allicin on uremic-induced myocardial injury in rats.Methods Twenty-four rats were randomly divided into sham-operated group,model group,and low-,and high-dose allicin groups,with six rats in each group.Except for the sham-operated group,the uremic-induced myocardial injury model was constructed using the 5/6 nephrectomy method in all other groups of rats.After successful modeling,corresponding interventions were carried outed.At the end of the intervention,the renal function of rats was observed,the cardiac mass index was calculated,the levels of serum high-sensitive cardiac troponinⅠ(hs-cTnI)and creatine kinase isoenzyme(CK-MB)were detected by enzyme-linked immunosorbent assay(ELISA),the pathological changes of rat cardiac tissues were observed by hematoxylin-eosin(HE)staining,the changes of autophagosomes and autolysosomes were observed by transmission electron microscopy,and the protein expressions of PTEN-induced putative kinase 1(PINK1)and E3 ubiquitin protein ligase(Parkin)in myocardial tissues were detected by Western Blot.Results Compared with the sham-operated group,the serum creatinine(SCr),blood urine nitrogen(BUN),cardiac mass index,CK-MB and hs-cTnI in rats in the model group were elevated(P<0.05),the pathological damage of cardiac tissues were obvious,and the autophagosomes and autolysosomes were decreased,and PINK1 and Parkin protein expressions in myocardial tissues were decreased(P<0.05);compared with the model group,SCr,BUN,cardiac mass index,CK-MB and hs-cTnI in allicin low-and hogh-dose groups were decreased,the changes of pathological damage of cardiac tissues were relieved,the autophagosomes and autolysosomes were increased,and PINK1 and Parkin protein expressions in myocardial tissues were increased(P<0.05).Conclusion Allicin can reduce myocardial injury in uremic rats,and its mechanism may be related to the up-regulation of PINK1/Parkin-mediated mitochondrial autophagy.

Methods: This retrospective study analyzed 32 consecutive IDS patients who underwent UEDD surgery. Clinical features, laboratory data (erythrocyte sedimentation rate and C-reactive protein), and treatment outcomes were analyzed. Results: Definite microorganisms were identified in 27 patients (84.3%), with 24 (88.9%) meeting cure criteria. The cure rate was significantly higher in the detected pathogen group compared to the undetected pathogen group (88.9% vs. 80%; χ²=19.36, p<0.0001). Metagenomic next generation sequencing (mNGS) provided faster diagnosis (41.72±6.81 hours) compared to tissue culture (95.74±35.47 hours, p<0.05). The predominant causative pathogen was Mycobacterium tuberculosis, followed by Staphylococcus aureus. Significant improvements were observed in Visual Analog Scale pain scores, from a mean of 7.9 preoperatively to 1.06 at 1 year postoperatively. The Oswestry Disability Index revealed a similar trend, showing significant improvement (p<0.05). Conclusions UEDD is a viable alternative to traditional open surgery for managing IDS in high-risk patients. UEDD offers a dual therapeutic-diagnostic advantage during the initial admission phase, enabling simultaneous debridement, neurological decompression, and targeted biopsy in a single intervention. Compared with traditional tissue culture, mNGS enables rapid microbiological diagnosis and extensive pathogen coverage.

Myocardial injury is the leading cause of death in uremic patients.PINK 1/Parkin-mediated mitochondrial autophagy is involved in the progression of myocardial injury.In recent years,pathogenic turbidity has been gradually accepted as a representative of a new type of toxic pathogens by the researchers of traditional Chinese medicine(TCM).This paper sorts out literature about pathogenic turbidity,analyzes the etiological and pathogenic characteristics of pathogenic turbidity,and suggests that the pathogenesis of uremia-induced myocardial injury can be more comprehensively clarified from the perspective of healthy-qi deficiency resulting in latent pathogenic turbidity.In the patients with uremia,the down-regulation of PINK1/Parkin causes the weakening of mitochondrial autophagy,which leads to the elevation of levels of reactive oxygen species(ROS)and inflammatory factors,and eventually causes the injury of myocardial cell.The above pathogenic mechanism is similar to the process of traditional Chinese medicine(TCM)in which the deficiency of the healthy-qi(in particular kidney deficiency)results in the production of the pathogenic turbidity(showing as dampness,blood stasis,phlegm,toxin and so on)and then causes the pathogenic turbidity hide in vessels and collaterals and gradually injure the heart vessels,and eventually results in the deficiency of heart vessels.The mitochondrial autophagy mechanism mediated by the PINK1/Parkin pathway is suitalbe for explaining the TCM pathogenesis of uremia-induced myocardial injury,characterized by healthy-qi deficiency resulting in latent pathogenic turbidity,and also is suitable for interpretating the principle of supporting healthy-qi to eliminate pathogenic turbidity for treating uremia-induced myocardial injury.Under the guidance of the theory of health y-qi deficiency and turbid pathogens in TCM,the development of specific PINK 1/Parkin agonists may expand the approach for the treatment of uremia-induced myocardial injury.

The study was conducted to investigate the mechanism of Xinyang Tablets( XYP) in modulating the fat mass and obesity-associated protein(FTO)/N6-methyladenosine(m6A) signaling pathway to ameliorate ventricular remodeling in heart failure(HF). A mouse model of HF was established by transverse aortic constriction(TAC). Mice were randomized into sham, model, XYP(low, medium, and high doses), and positive control( perindopril) groups(n= 10). From day 3 post-surgery, mice were administrated with corresponding drugs by gavage for 6 consecutive weeks. Following the treatment, echocardiography was employed to evaluate the cardiac function, and RT-qPCR was employed to determine the relative m RNA levels of key markers, including atrial natriuretic peptide( ANP), B-type natriuretic peptide( BNP), β-myosin heavy chain(β-MHC), collagen type I alpha chain(Col1α), collagen type Ⅲ alpha chain(Col3α), alpha smooth muscle actin(α-SMA), and FTO. The cardiac tissue was stained with Masson's trichrome and wheat germ agglutinin(WGA) to reveal the pathological changes. Immunohistochemistry was employed to detect the expression levels of Col1α, Col3α, α-SMA, and FTO in the myocardial tissue. The m6A modification level in the myocardial tissue was measured by the m6A assay kit. An H9c2 cell model of cardiomyocyte injury was induced by angiotensin Ⅱ(AngⅡ), and small interfering RNA(siRNA) was employed to knock down FTO expression. RT-qPCR was conducted to assess the relative m RNA levels of FTO and other genes associated with cardiac remodeling. The m6A modification level was measured by the m6A assay kit, and Western blot was employed to determine the phosphorylated phosphatidylinositol 3-kinase(p-PI3K)/phosphatidylinositol 3-kinase(PI3K) and phosphorylated serine/threonine kinase(p-Akt)/serine/threonine kinase(Akt) ratios in cardiomyocytes. The results of animal experiments showed that the XYP treatment significantly improved the cardiac function, reduced fibrosis, up-regulated the m RNA and protein levels of FTO, and lowered the m6A modification level compared with the model group. The results of cell experiments showed that the XYP-containing serum markedly up-regulated the m RNA level of FTO while decreasing the m6A modification level and the p-PI3K/PI3K and p-Akt/Akt ratios in cardiomyocytes. Furthermore, FTO knockdown reversed the protective effects of XYP-containing serum on Ang Ⅱ-induced cardiomyocyte hypertrophy. In conclusion, XYP may ameliorate ventricular remodeling by regulating the FTO/m6A axis, thereby inhibiting the activation of the PI3K/Akt signaling pathway.
Animals ; Ventricular Remodeling/drug effects* ; Heart Failure/physiopathology* ; Signal Transduction/drug effects* ; Mice ; Male ; Alpha-Ketoglutarate-Dependent Dioxygenase FTO/genetics* ; Drugs, Chinese Herbal/administration & dosage* ; Mice, Inbred C57BL ; Humans ; Adenosine/analogs & derivatives* ; Myocytes, Cardiac/metabolism* ; Disease Models, Animal

Cardiac fibrosis(CF) is a cardiac pathological process characterized by excessive deposition of extracellular matrix(ECM). When the heart is damaged by adverse stimuli, cardiac fibroblasts are activated and secrete a large amount of ECM, leading to changes in cardiac fibrosis, myocardial stiffness, and cardiac function declines and accelerating the development of heart failure. There is a close relationship between heart yin deficiency and cardiac fibrosis, which have similar pathogenic mechanisms. Heart Yin deficiency, characterized by insufficient Yin fluids, causes the heart to lose its nourishing function, which acts as the initiating factor for myocardial dystrophy. The deficiency of body fluids leads to stagnation of blood flow, resulting in blood stasis and water retention. Blood stasis and water retention accumulate in the heart, which aligns with the pathological manifestation of excessive deposition of ECM, as a tangible pathogenic factor. This is an inevitable stage of the disease process. The lingering of blood stasis combined with water retention eventually leads to the generation of heat and toxins, triggering inflammatory responses similar to heat toxins, which continuously stimulate the heart and cause the ultimate outcome of CF. Considering the syndrome of heart Yin deficiency, traditional Chinese medicine capable of nourishing Yin, activating blood, and promoting urination can reduce myocardial cell apoptosis, inhibit fibroblast activation, and lower the inflammation level, showing significant advantages in combating CF.
Humans ; Fibrosis/drug therapy* ; Animals ; Yin Deficiency/metabolism* ; Myocardium/metabolism* ; Medicine, Chinese Traditional ; Drugs, Chinese Herbal/therapeutic use*

This study investigates the effect and underlying mechanism of Guizhi Tongluo Tablets(GZTL) in treating atherosclerosis(AS) in a mouse model. Apolipoprotein E-knockout(ApoE~(-/-)) mice were randomly assigned to the following groups: model, high-, medium-, and low-dose GZTL, and atorvastatin(ATV), and age-matched C57BL/6J mice were selected as the control group. ApoE~(-/-) mice in other groups except the control group were fed with a high-fat diet for the modeling of AS and administrated with corresponding drugs via gavage for 8 weeks. General conditions, signs of blood stasis, and body mass of mice were monitored. Aortic plaques and their stability were assessed by hematoxylin-eosin, Masson, and oil red O staining. Serum levels of total cholesterol(TC), triglycerides(TG), and low-density lipoprotein cholesterol(LDL-C) were measured by biochemical assays, and those of interleukin-1β(IL-1β), tumor necrosis factor-α(TNF-α), and interleukin-6(IL-6) were determined via enzyme-linked immunosorbent assay. Apoptosis was assessed by terminal deoxynucleotidyl transferase dUTP nick end labeling(TUNEL). Single-cell RNA sequencing(scRNA-seq) was employed to analyze the differential expression of CD72hi macrophages(CD72hi-Mφ) in the aortas of AS patients and mice. The immunofluorescence assay was employed to visualize CD72hi-Mφ expression in mouse aortic plaques, and real-time fluorescence quantitative PCR was utilized to determine the mRNA levels of IL-1β, TNF-α, and IL-6 in the aorta. The results demonstrated that compared with the control group, the model group exhibited significant increases in body mass, aortic plaque area proportion, necrotic core area proportion, and lipid deposition, a notable decrease in collagen fiber content, and an increase in apoptosis. Additionally, the model group showcased elevated serum levels of TC, TG, LDL-C, IL-1β, TNF-α, and IL-6, alongside marked upregulations in the mRNA levels of IL-1β, TNF-α, and IL-6 in the aorta. In comparison with the model group, the GZTL groups and the ATV group showed a reduction in body mass, and the medium-and high-dose GZTL groups and the ATV group demonstrated reductions in aortic plaque area proportion, necrotic core area proportion, and lipid deposition, an increase in collagen fiber content, and a decrease in apoptosis. Furthermore, the treatment goups showcased lowered serum levels of TC, TG, LDL-C, IL-1β, TNF-α, and IL-6. The data of scRNA-seq revealed significantly elevated CD72hi-Mφ signaling in carotid plaques of AS patients compared with that in the normal arterial tissue. Animal experiments confirmed that CD72hi-Mφ expression, along with several pro-inflammatory cytokines, was significantly upregulated in the aortas of AS mice, which were downregulated by GZTL treatment. In conclusion, GZTL may alleviate AS by inhibiting CD72hi-Mφ activity.
Animals ; Drugs, Chinese Herbal/administration & dosage* ; Atherosclerosis/immunology* ; Mice ; Mice, Inbred C57BL ; Macrophages/immunology* ; Male ; Humans ; Apolipoproteins E/genetics* ; Tablets ; Tumor Necrosis Factor-alpha/genetics* ; Apoptosis/drug effects* ; Interleukin-1beta/genetics* ; Interleukin-6/genetics* ; Disease Models, Animal ; Mice, Knockout