OBJECTIVE: To explore short-term effectiveness of floating island laminectomy surgery in treating thoracic spinal stenosis and myelopathy caused by ossification of the ligamentum flavum. METHODS: A total of 31 patients with thoracic spinal stenosis and myelopathy caused by ossification of the ligamentum flavum between January 2019 and April 2022 were managed with floating island laminectomy surgery. The patients comprised 17 males and 14 females, aged between 36 and 78 years, with an average of 55.9 years. The duration of symptoms of spinal cord compression ranged from 3 to 62 months (mean, 27.2 months). The lesions affected T _1-6 in 4 cases and T _7-12 in 27 cases. The preoperative neurological function score from the modified Japanese Orthopaedic Association (mJOA) was 4.7±0.6. Surgical duration, intraoperative blood loss, and complications were recorded. The thoracic MRI was conducted to reassess the degree of spinal cord compression and decompression after operation. The mJOA score was employed to evaluate the neurological function and calculate the recovery rate at 12 months after operation. RESULTS: The surgical duration ranged from 122 to 325 minutes, with an average of 204.5 minutes. The intraoperative blood loss ranged from 150 to 800 mL (mean, 404.8 mL). All incisions healed by first intention after operation. All patients were followed up 12-14 months, with an average of 12.5 months. The patients' symptoms, including lower limb weakness, gait disorders, and pain, significantly improved. The mJOA scores after operation significantly increased when compared with preoperative scores ( P<0.05), gradually improving with time, with significant differences observed among 1, 3, and 6 months ( P<0.05). The recovery rate at 12 months was 69.76%±11.38%, with 10 cases exhibiting excellent neurological function and 21 cases showing good. During the procedure, there were 3 cases of dural tear and 1 case of dural defect. Postoperatively, there were 2 cases of cerebrospinal fluid leakage. No aggravated nerve damage, recurrence of ligamentum flavum ossification, or postoperative thoracic deformity occurred. CONCLUSION The floating island laminectomy surgery is safe for treating thoracic spinal stenosis and myelopathy caused by ossification of the ligamentum flavum, effectively preventing the exacerbation of neurological symptoms. Early improvement and recovery of neurological function are achieved.
Humans ; Male ; Spinal Stenosis/diagnostic imaging* ; Female ; Laminectomy/methods* ; Ligamentum Flavum/pathology* ; Middle Aged ; Aged ; Thoracic Vertebrae/surgery* ; Adult ; Decompression, Surgical/methods* ; Treatment Outcome ; Ossification, Heterotopic/surgery* ; Spinal Cord Compression/etiology* ; Spinal Cord Diseases/etiology* ; Magnetic Resonance Imaging

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*

The interaction between m⁶A-methylated RNA and chromatin modification remains largely unknown. We found that targeted inhibition of bromodomain-containing protein 4 (BRD4) by siRNA or its inhibitor (JQ1) significantly decreases mRNA m⁶A levels and suppresses the malignancy of breast cancer (BC) cells via increased expression of demethylase AlkB homolog 5 (ALKBH5). Mechanistically, inhibition of BRD4 increases the mRNA stability of ALKBH5 via enhanced binding between its 3' untranslated regions (3'UTRs) with RNA-binding protein RALY. Further, BRD4 serves as a scaffold for ubiquitin enzymes tripartite motif containing-21 (TRIM21) and ALKBH5, resulting in the ubiquitination and degradation of ALKBH5 protein. JQ1-increased ALKBH5 then demethylates mRNA of extra spindle pole bodies like 1 (ESPL1) and reduces binding between ESPL1 mRNA and m⁶A reader insulin like growth factor 2 mRNA binding protein 3 (IGF2BP3), leading to decay of ESPL1 mRNA. Animal and clinical studies confirm a critical role of BRD4/ALKBH5/ESPL1 pathway in BC progression. Further, our study sheds light on the crosstalks between histone modification and RNA methylation.

Pharmacokinetics of traditional Chinese medicine(TCM)is a discipline that adopts pharmacokinetic research methods and techniques under the guidance of TCM theories to elucidate the dynamic changes in the absorption,distribution,metabolism and excretion of active ingredients,active sites,single-flavour Chinese medicinal and compounded formulas of TCM in vivo.However,the sources and components of TCM are complex,and the pharmacodynamic substances and mechanisms of action of the majority of TCM are not yet clear,so the pharmacokinetic study of TCM is later than that of chemical medicines,and is far more complex than that of chemical medicines,and its development also confronts with challenges.The pharmacokinetic study of TCM originated in the 1950s and has experienced more than 70 years of development from the initial in vivo study of a single active ingredient,to the pharmacokinetic and pharmacodynamic study of active ingredients,to the pharmacokinetic study of compound and multi-component of Chinese medicine.In recent years,with the help of advanced extraction,separation and analysis technologies,gene-editing animals and cell models,multi-omics technologies,protein purification and structure analysis technologies,and artificial intelligence,etc.,the pharmacokinetics of TCM has been substantially applied in revealing and elucidating the pharmacodynamic substances and mechanisms of action of Chinese medicines,research and development of new drugs of TCM,scientific and technological upgrading of large varieties of Chinese patent medicines,as well as guiding the rational use of medicines in clinics.Pharmacokinetic studies of TCM have made remarkable breakthroughs and significant development in theory,methodology,technology and application.In this paper,the history of the development of pharmacokinetics of TCM and the progress of cutting-edge research was reviewed,with the aim of providing ideas and references for the pharmacokinetics of TCM and related research.

OBJECTIVE: Jiedu Recipe (JR), a Chinese herbal remedy, has been shown to prolong overall survival time and decrease recurrence and metastasis rates in patients with hepatocellular carcinoma (HCC). This work investigated the mechanism of JR in HCC treatment. METHODS: The chemical constituents of JR were detected using liquid chromatography-mass spectrometry. The potential anti-HCC mechanism of JR was screened using network pharmacology and messenger ribonucleic acid (mRNA) microarray chip assay, followed by experimental validation in human HCC cells (SMMC-7721 and Huh7) in vitro and a nude mouse subcutaneous transplantation model of HCC in vivo. HCC cell characteristics of proliferation, migration and invasion under hypoxic setting were investigated using thiazolyl blue tetrazolium bromide, wound healing and Transwell assays, respectively. Image-iT™ Hypoxia Reagent was added to reveal hypoxic conditions. Stem cell sphere formation assay was used to detect the stemness. Epithelial-mesenchymal transition (EMT) markers like E-cadherin, vimentin and α-smooth muscle actin, and pluripotent transcription factors including nanog homeobox, octamer-binding transcription factor 4, and sex-determining region Y box protein 2 were analyzed using Western blotting and real-time polymerase chain reaction. Western blot was performed to ascertain the anti-HCC effect of JR under hypoxia involving the Wnt/β-catenin pathway. RESULTS: According to network pharmacology and mRNA microarray chip analysis, JR may potentially act on hypoxia and inhibit the Wnt/β-catenin pathway. In vitro and in vivo experiments showed that JR significantly decreased hypoxia, and suppressed HCC cell features of proliferation, migration and invasion; furthermore, the hypoxia-induced increases in EMT and stemness marker expression in HCC cells were inhibited by JR. Results based on the co-administration of JR and an agonist (LiCl) or inhibitor (IWR-1-endo) verified that JR suppressed HCC cancer stem-like properties under hypoxia by blocking the Wnt/β-catenin pathway. CONCLUSION JR exerts potent anti-HCC effects by inhibiting cancer stemness via abating the Wnt/β-catenin pathway under hypoxic conditions. Please cite this article as: Guo BJ, Ruan Y, Wang YJ, Xiao CL, Zhong ZP, Cheng BB, Du J, Li B, Gu W, Yin ZF. Jiedu Recipe, a compound Chinese herbal medicine, inhibits cancer stemness in hepatocellular carcinoma via Wnt/β-catenin pathway under hypoxia. J Integr Med. 2023; 21(5): 474-486.
Animals ; Mice ; Humans ; Carcinoma, Hepatocellular/genetics* ; beta Catenin/pharmacology* ; Liver Neoplasms/genetics* ; Drugs, Chinese Herbal/therapeutic use* ; RNA, Messenger/therapeutic use* ; Cell Line, Tumor ; Cell Proliferation ; Cell Movement ; Gene Expression Regulation, Neoplastic

Humans ; Neoplasms, Second Primary/epidemiology* ; Neoplasms/epidemiology* ; Risk Factors ; Prognosis

BACKGROUND: Butylphthalide (NBP) and edaravone (EDV) injection are common acute ischemic stroke medications in China, but there is a lack of large real-world safety studies on them. This study aimed to determine the incidence of adverse events, detect relevant safety signals, and assess the risk factors associated with these medications in real-world populations. METHODS: In this study, data of acute ischemic stroke patients were extracted from the electronic medical record database of six tertiary hospitals between January 2019 and August 2021. Baseline confounders were eliminated using propensity score matching. The drugs' safety was estimated by comparing the results of 24 laboratory tests standards on liver function, kidney function, lipid level, and coagulation function. The drugs' relative risk was estimated by logistic regression. A third group with patients who did not receive NBP or EDV was constructed as a reference. Prescription sequence symmetry analysis was used to evaluate the associations between adverse events and NBP and EDV, respectively. RESULTS: 81,292 patients were included in this study. After propensity score matching, the NBP, EDV, and third groups with 727 patients in each group. Among the 15 test items, the incidence of adverse events was lower in the NBP group than in the EDV group, and the differences were statistically significant. The multivariate logistic regression equation revealed that NBP injection was not a promoting factor for abnormal laboratory test results, whereas EDV had statistically significant effects on aspartate transaminase, low-density lipoprotein cholesterol and total cholesterol. Prescription sequence symmetry analysis showed that NBP had a weak correlation with abnormal platelet count. EDV had a positive signal associated with abnormal results in gamma-glutamyl transferase, alanine aminotransferase, aspartate aminotransferase, prothrombin time, and platelet count. CONCLUSIONS In a large real-world population, NBP has a lower incidence of adverse events and a better safety profile than EDV or other usual medications.

Humans ; Otitis Media, Suppurative ; Chronic Disease ; Biofilms ; Otitis Media

Objective:To observe the effect of percutaneous auricular vagus nerve stimulation on myocardial structural remodeling, electrical remodeling and apoptosis in rats of heart failure with preserved ejection fraction, and to explore the relationship between this effect and oxidative stress.Methods:The arteriovenous fistula was closed by ligation two weeks after establishment in SD rat.By increasing cardiac volume load in the short term, a rat model of heart failure with preserved ejection fraction was constructed.Forty rats were randomly divided into four groups, with 10 rats in each group: sham operation group(S), abdominal aorta-inferior vena cava fistula + closure group(AVF+ L), abdominal aorta-inferior vena cava fistula + closure+ percutaneous auricular vagus nerve stimulation group(AVF+ L+ tVNS)and abdominal aorta-inferior vena cava fistula + closure+ percutaneous auricular vagus nerve stimulation + acetylcholine M 2 receptor antagonist group(AVF+ L+ tVNS+ M -). Rats in the AVF+ L+ tVNS group received percutaneous vagal nerve stimulation on the basis of those in the AVF+ L group.Rats in the AVF+ L+ tVNS+ M - group received daily injection of acetylcholine M 2 receptor antagonist mesotramine(0.5mg/Kg)into tail vein on the basis of those in the AVF+ L+ tVNS group.The parameters of cardiac structural remodeling and electrical remodeling in each group were obtained by cardiac ultrasound and cardiac electrophysiological stimulator.Enzyme-linked immunosorbent assay(ELISA)was used to detect the values of B-type natriuretic peptide precursor(NT-proBNP)and oxidative stress-related indicators in each group.hematoxylin-eosin(HE)staining was used to observe the damage of myocardial structure, disorder of cell arrangement and infiltration of inflammatory cells.Cardiomyocyte apoptosis was observed by TdT-mediated dUTP nick end labeling(TUNEL)staining and apoptosis index was calculated.reverse transcription-polymerase chain reaction(RT-PCR)and Western blotting were used to detect the mRNA and protein expression of B cell lymphoma / leukemia-2(BCL-2)and apoptosis promoting gene(BAX)in BCL-2 gene family. Results:The rats in the AVF + L group developed heart failure characterized by ventricular wall hypertrophy and diastolic dysfunction, and the left ventricular ejection fraction(LVEF)was >50 %.The rat heart failure model with preserved ejection fraction was successfully established.HE staining showed that the myocardial tissue structure damage, cell arrangement disorder and inflammatory cell infiltration were obvious in AVF+ L group, while the pathological changes of myocardial tissue in AVF+ L+ tVNs were significantly less than those in AVF+ L group.Compared with AVF+ L group, in the AVF+ L+ tVNs, the value of NT-proBNP decreased[(301.25 ± 16.07)ng/L vs.(79.33±5.63)ng/L, P<0.05], the value of E/A increased(1.28 ± 0.06 vs.1.66 ±0.05, P<0.05), the expression of BCL-2 mRNA[0.08(0.07, 0.08) vs.0.70(0.64, 0.76), P<0.05]and BCL-2 protein(0.19±0.03 vs.0.46±0.04, P<0.05)both increased, the expression of BAX mRNA(5.00±0.32 vs.2.14±0.36, P<0.05)and BAX protein(0.76±0.04 vs.0.43±0.05, P<0.05)both decreased, while the apoptotic index was also decreased(16.26±0.32 vs.7.04±0.24, P<0.05). Compared with AVF + L group, the indexes of myocardial structural remodeling, electrical remodeling and oxidative stress were decreased in AVF + L + tVNs group(P<0.05). Compared with AVF + L group, there was no significant difference in the above indexes in AVF + L + tVNS + M - group( P>0.05). Conclusions:tVNS can alleviate myocardial structural remodeling, electrical remodeling and apoptosis in HFpEF rats, which may be related to the reduction of oxidative stress response activity.

OBJECTIVE: To observe the effect of acupotomy on the fat infiltration degree of lumbar multifidus muscle (LMM) in patients with lumbar disc herniation after percutaneous transforaminal endoscopic discectomy (PTED). METHODS: A total of 104 patients with lumbar disc herniation treated with PTED were randomly divided into an observation group (52 cases, 3 cases dropped off) and a control group (52 cases, 4 cases dropped off). Patients of both groups received rehabilitation training of two weeks 48 h after PTED treatment. The observation group was treated with acupotomy (L₃-L₅ Jiaji [EX-B 2]) once within 24 h after PTED. In the two groups, the fat infiltration cross sectional area (CSA) of LMM was compared before and 6 months after PTED, the visual analogue scale (VAS) score and Oswestry disability index (ODI) score were observed before and 1, 6 months after PTED. The correlation between fat infiltration CSA of LMM in each segment and VAS score was analyzed. RESULTS: Six months after PTED, the fat infiltration CSA of LMM in L₄/L₅ and the total L₃-S₁ segments of the observation group was lower than that before PTED (P<0.05), and the fat infiltration CSA of LMM in L₄/L₅ of the observation group was lower than the control group (P<0.01). One month after PTED, the ODI and VAS scores of the two groups were lower than those before PTED (P<0.01), and those in the observation group were lower than the control group (P<0.05). Six months after PTED, the ODI and VAS scores of the two groups were lower than those before PTED and 1 month after PTED (P<0.01), and those in the observation group were lower than the control group (P<0.01). There was a positive correlation between the fat infiltration CSA of LMM in the total L₃-S₁ segments and VAS scores in the two groups before PTED (r = 0.64, P<0.01). Six months after PTED, there was no correlation between the fat infiltration CSA of LMM in each segment and VAS scores in the two groups (P>0.05). CONCLUSION Acupotomy can improve the fat infiltration degree of LMM, pain symptoms and activities of daily living in patients with lumbar disc herniation after PTED.
Humans ; Intervertebral Disc Displacement ; Activities of Daily Living ; Paraspinal Muscles ; Treatment Outcome ; Lumbar Vertebrae ; Retrospective Studies ; Endoscopy ; Diskectomy ; Acupuncture Therapy