Naringenin (4,5,7-trihydroxyflavonoid) is a naturally occurring bioflavonoid found in citrus fruits, which plays an important role in metabolic syndrome, neurological disorders, and cardiovascular diseases. However, the pharmacological mechanism and biological function of naringenin on anti-angiogenesis and anti-tumor immunity have not yet been elucidated. Our study firstly demonstrates that naringenin inhibits the growth of hepatocellular carcinoma (HCC) cells both in vivo and in vitro. Naringenin diminishes the ability of HCC cells to induce tube formation and migration of human umbilical vein endothelial cells (HUVECs) and suppresses neovascularization in chicken chorioallantoic membrane (CAM) assays. Meanwhile, in vivo results demonstrate that naringenin can significantly upregulate level of CD8⁺ T cells, subsequently increasing the level of immune-related cytokines in the tumor immune microenvironment. Mechanistically, we found that naringenin facilitate the K48-linked ubiquitination and subsequent protein degradation of vascular endothelial growth factor A (VEGFA) and mesenchymal-epithelial transition factor (c-Met), which reduces the expression of programmed death ligand 1 (PD-L1). Importantly, combination therapy naringenin with PD-L1 antibody or bevacizumab provided better therapeutic effects in liver cancer. Our study reveals that naringenin can effectively inhibit angiogenesis and anti-tumor immunity in liver cancer by degradation of VEGFA and c-Met in a K48-linked ubiquitination manner. This work enlightens the potential effect of naringenin as a promising therapeutic strategy against anti-angiogenesis and anti-tumor immunity in HCC.

OBJECTIVE To analyze the use status and development trend of proton pump inhibitors(PPIs) in 33 hospitals in Wuhan, Hubei Province after the implementation of the national centralized drug procurement(NCDP) policy, and to provide reference for promoting the subsequent rational use of NCDP drugs and improving related policies. METHODS To make statistics and analysis of purchasing amount of PPIs, defined daily dose system(DDDs), defined daily dose consumption(DDDc) and utilization rate of 33 hospitals in Wuhan in 2019 and 2022. RESULTS After the implementation of the NCDP policy, the total purchasing amount of PPIs decreased by 53.6%, DDDs decreased by 15.4%, DDDc decreased by 45.2%, and the utilization rate of PPIs injectable dosage forms decreased by 12.6%. After NCDP, the highest growth rate of oral dosage forms was omeprazole(5.7%), followed by rabeprazole(5.0%), while injectable dosage forms showed a significant difference in utilization rate, with a significant decline in NCDP varieties and a significant increase in non-NCDP varieties. The overall NCDP utilization rate of PPIs in Wuhan was 64.9%, with little difference among hospitals of different grades. CONCLUSION The NCDP policy achieves the purpose of reducing the drug cost of patients and improving the accessibility of drugs, and is more optimized in the selection of dosage forms, which is in line with the policy expectations overall; but the quantity and price of PPIs in Wuhan decreased after NCDP, and highlighted a certain tendency in the selection of varieties. In the future, we still need to optimize measures to guide clinical priority in the selection of NCDP drugs, to ensure and improve the implementation of NCDP policy.

Background and aim:Few studies have reported hepatitis B surface antigen(HBsAg)kinetics after nucleos(t)ide analog(NA)discontinuation in patients with noncirrhotic chronic hepatitis B(CHB).The study specifically investigated long-term HBsAg kinetics after NA discontinuation. Methods:Between January 2014 to January 2024,this study prospectively enrolled 106 outpatients with noncirrhotic CHB who met the discontinuation criteria after NA consolidation treatment.Demographic,clinical,and laboratory data were collected and analyzed after NA discontinuation. Results:Ninety-six patients who finished 5 years of follow-up were included.HBsAg remained unde-tectable in 29 patients with end of treatment(EOT)HBsAg negativity.Among 67 patients with EOT HBsAg positivity,HBsAg seroclearance occurred in 12(17.9％)patients with an estimated annual inci-dence of HBsAg seroclearance of 3.6％.Patients with EOT HBsAg levels of ≤1000 IU/mL had a higher HBsAg seroclearance rate than those with EOT HBsAg levels of＞1000 IU/mL(33.3％vs.5.4％).The pro-portion of patients with HBsAg ≤1000 IU/mL increased during follow-up.Logistic regression analysis indicated that the EOT HBsAg level was an independent factor for HBsAg seroclearance and an HBsAg level decline exceeding 1 log10 IU/mL.The optimal EOT HBsAg cutoff for both HBsAg seroclearance and an HBsAg level decline exceeding 1 log10 IU/mL was 359 IU/mL. Conclusions:Patients with EOT HBsAg negativity experienced no relapse and maintained HBsAg sero-clearance during 5 years of follow-up after NA discontinuation.A higher HBsAg seroclearance rate can be obtained in patients with EOT HBsAg levels of ≤1000 IU/mL during 5 years of follow-up after NA discontinuation.Close monitoring and proper NA retreatment are recommended to guarantee the safety of NA discontinuation.

Objective:To explore the safety and efficacy of radiofrequency in the treatment of overactive bladder(OAB).Methods:A prospective, multicenter, non-randomized controlled trial was conducted. Eligible patients were divided into test group and control group in Zhejiang Provincial People’Hospital, The First Affiliated Hospital of Wenzhou Medical University, and Sir Run Run Shaw Hospital affiliated to Zhejiang University School of Medicine from March 2019 to June 2020. Inclusion criteria: patients diagnosed with OAB, and bladder capacity>100ml. Exclusion criteria: pregnant and lactating women; patients with secondary OAB symptoms such as urinary tract obstruction; patients with uncontrolled urinary tract infection within 1 week; patients in stable stage by using other treatment methods; patients implanted with any nerve stimulator, cardiac pacemaker or implantable defibrillator; patients with malignant tumors, serious cardiovascular, cerebrovascular diseases, renal insufficiency or received BTX treatment in recent 12 months. The patients were allocated to test group and the control group in a ratio of 2∶1 according to the time sequence of the visit. The patients in the test group were treated with radiofrequency treatment. After entering the group, they were treated for 4 times at the 1st, 2nd, 7th and 8th week respectively. In the control group, the energy was turned off during the radiofrequency treatment. The patients were followed-up every week until the end of the 12th week. The treatment success rate [the average frequency of urination in 24 h was reduced more than 50% from the baseline or returned to the normal (≤8 times/day) or the average frequency of urgent urination in 24 h was reduced more than 50% from the baseline], the frequency of urination, urgent urination and nocturnal urination before and after treatment, the residual urine volume of the bladder, the quality of life (QOL) score and the occurrence of catheter related adverse events in two groups were compared.Results:114 patients were enrolled in the study, including 76 patients in the test group and 38 patients in the control group. There were no significant differences in the age [(44.2±12.8) vs. (41.7 ± 12.1) years old], male female ratio (13/63 vs. 4/34), average course of disease [2.0(1.2, 5.0) vs. 2.0 (1.0, 4.0) years], the frequency of urination[12.8 (10.6, 16.8) vs. 12.8 (10.3, 17.0) times], urgency urination [11.8(9.3, 15.8) vs. 11.8 (9.0, 17.0) times], nocturia [2.7 (1.3, 3.7) vs. 2.3(0.7, 3.3) times], residual urine volume of bladder [12.0 (3.0, 28.0) vs. 14.0 (3.7, 20.0) ml ] and the QOL score [5.0(4.0, 5.0) vs. 4.0(4.0, 5.0)]before the treatment between the two groups ( P>0.05). The treatment success rate in the test group was 76.3% (58/76), while 26.3% (10/38) in the control group, with a statistically significant difference ( P<0.01). There were significant differences between the test group and control group in the frequency of urination [9.7 (7.7, 12.0) vs. 12.9 (9.6, 15.7) times], urgent urination [7.3 (5.0, 10.0) vs. 11.7 (7.3, 15.3) times], nocturia [1.3 (0.7, 2.0) vs. 1.7 (1.0, 3.0) times] and the QOL score of the patients[3.0(1.0, 3.0) vs. 4.0(3.0, 4.5)]after the treatment(all P<0.05). The frequency of urination, urgency urination, nocturia, the residual urine volume and the QOL score in the test group were significantly improved ( P<0.05) after the treatment.The frequency of urination, nocturia, residual urine volume and the QOL score in the control group were improved ( P<0.05) after the treatment. 13 (11.4%) patients had catheter related adverse events. In the test group and the control group, there were 7 cases of macroscopic hemorrhage caused by the placement of instruments (5/76 vs. 2/38), 5 cases of acute urinary tract infection within 3 days (3/76 vs. 2/38), and 1 case of instrument breakage (catheter breakage) (0/76 vs. 1/38). There were no significant differences in the adverse events between the two groups ( P> 0.05). Conclusions:Radiofrequency treatment of OAB can effectively improve the symptoms of patients, improve the QOL of patients, and has low incidence of adverse events, with good efficacy and safety.

Aromatic compounds are a class of organic compounds with benzene ring(s). Aromatic compounds are hardly decomposed due to its stable structure and can be accumulated in the food cycle, posing a great threat to the ecological environment and human health. Bacteria have a strong catabolic ability to degrade various refractory organic contaminants (e.g., polycyclic aromatic hydrocarbons, PAHs). The adsorption and transportation are prerequisites for the catabolism of aromatic compounds by bacteria. While remarkable progress has been made in understanding the metabolism of aromatic compounds in bacterial degraders, the systems responsible for the uptake and transport of aromatic compounds are poorly understood. Here we summarize the effect of cell-surface hydrophobicity, biofilm formation, and bacterial chemotaxis on the bacterial adsorption of aromatic compounds. Besides, the effects of outer membrane transport systems (such as FadL family, TonB-dependent receptors, and OmpW family), and inner membrane transport systems (such as major facilitator superfamily (MFS) transporter and ATP-binding cassette (ABC) transporter) involved in the membrane transport of these compounds are summarized. Moreover, the mechanism of transmembrane transport is also discussed. This review may serve as a reference for the prevention and remediation of aromatic pollutants.
Humans ; Adsorption ; Bacteria/metabolism* ; Organic Chemicals ; Biological Transport ; ATP-Binding Cassette Transporters ; Polycyclic Aromatic Hydrocarbons/metabolism*

Objective:To explore the early predictors for clinical cure by sequential combined interferon therapy in nucleos(t)ide analogues (NAs) experienced patients with chronic hepatitis B(CHB).Methods:CHB patients received NAs treatment≥one year with hepatitis B surface antigen (HBsAg) ≤1 500 IU/mL, hepatitis B e antigen (HBeAg) negative and hepatitis B virus (HBV) DNA <100 IU/mL in the Third Affiliated Hospital of Sun Yat-sen University from June 2016 to September 2019 were included. According to the different treatment regimens, the patients were divided into interferon alone for 48 weeks group (group A), interferon combined with NAs for 12 weeks and continued NAs treatment for 48 weeks group (group B), interferon combined with NAs for 48 weeks group (group C). Basic data such as age and gender of patients were collected. HBsAg, hepatitis B surface antibody (anti-HBs) and alanine aminotransferase (ALT) were monitored at week 4, 8, 12, 24, 36 and 48. The decline of HBsAg from baseline, and the rates of clinical cure at 48 weeks were analyzed. The independent sample t test, chi-square test and rank sum test were used for statistical analysis. Logistic regression analysis was used to achieve the early prediction index of clinical cure at week 48. Results:A total of 1 020 CHB patients were followed up regularly for at least five time points. The rates of clinical cure at week 48 in group A, B and C were 34.6%(157/454), 32.7%(69/211) and 33.5%(119/355), respectively, with no statistical significance ( χ2=0.25, P=0.883). Patients were divided into the cured group (345 cases) and the uncured group (675 cases) according to the clinical outcomes at week 48. The age ((38±13) years old vs (43±12) years old), baseline HBsAg (131.00(359.80) IU/mL vs 437.60(531.50) IU/mL) and the proportion of male patients (81.7%(282/345) vs 89.5%(604/675)) of patients in the cured group were all lower than those of patients in the uncured group. The differences were all statistically significant ( t=6.32, Z=12.67, χ2=11.99, respectively, all P<0.050). There were 212 patients in the cured group who achieved clinical cure within 24 weeks of treatment. The rate of clinical cure at 48 weeks in patients whose HBsAg at week 4 decreased from baseline was higher than that in patients with increased HBsAg (41.6%(149/358) vs 28.2%(108/383)). The difference was statistically significant ( χ2=14.13, P<0.001). The rate of clinical cure at week 48 in patients with HBsAg at week 12 decreased ≤34.03% of baseline was only 6.9%(13/188). Multivariate logistic regression analysis showed that age (odds ratio ( OR)=0.962, 95% confidence interval ( CI) 0.936 to 0.989, P=0.006), HBsAg level at week 24 ( OR=0.950, 95% CI 0.934 to 0.966, P<0.001) and anti-HBs level at week 24 ( OR=1.012, 95% CI 1.005 to 1.019, P=0.001) were early predictors for clinical cure at week 48 of treatment in NAs experienced CHB patients. Conclusions:Clinical cure of NAs experienced CHB patients received sequential combined interferon therapy mostly occurs in the early stage (within 24 weeks). Age, HBsAg level at week 24, and anti-HBs level at week 24 are early predictors for clinical cure of 48-week sequential combined interferon treatment.

OBJECTIVE: To explore the clinical features and genetic basis for a patient diagnosed with creatine deficiency syndrome (CDS). METHODS: The patient was subjected to whole exome sequencing (WES). Candidate variant was verified by Sanger sequencing. The level of creatine was determined by using a magnetic resonance spectrum (MRS) method. RESULTS: The patient presented with development delay and poor response to stimuli. No obvious abnormality was found with his muscle tone and strength of his limbs. Borderline EEG was detected. MRI showed abnormal development of the white matter and dysplasia of corpus callosum. Urine organic acid screening has shown increased glycerin-3-phosphate. WES revealed that the patient has carried compound heterozygous variants of the GAMT gene, namely c.412C>T and IVS4-1G>A, which were respectively derived from his mother and father. MRS showed reduced creatine in bilateral basal ganglia. Functional study of the splicing site suggested that the IVS4-1G>A variant has resulted skipping of exon 5 upon splicing. CONCLUSION The compound variants of the GAMT gene probably underlay the disease in this child. Above finding has enriched the spectrum of GAMT gene variants.
Child ; Creatine ; Exons ; Humans ; Mutation ; Syndrome ; Whole Exome Sequencing

Aplastic anemia (AA) refers to a life-threatening bone marrow failure disorder.With respect to the precise pathophysiology of AA at present, it is still unclear.MicroRNA (miRNA), about 22 nucleotides in length, is a kind of small RNAs and it can regulate gene expression post-transcriptionally.According to domestic and foreign reports recently, there are abnormal expressions of several miRNAs in AA patients, suggesting that miRNAs may be involved in the development and progression of AA.This article reviews the study progress of miRNAs in AA.

Objective:To investigate the correlation between peripheral blood renal function indexes and brain frailty imaging score in patients with mild ischemic stroke or transient ischemic attack (TIA).Methods:Patients with mild ischemic stroke or transient ischemic attack (TIA) admitted to the Department of Neurology, the Second Affiliated Hospital of Soochow University from March 2018 to August 2019 were enrolled retrospectively. General clinical data and peripheral blood renal function indexes, including urea, uric acid and estimated glomerular filtration rate (eGFR), were collected. eGFR <60 ml/(min·1.73 m 2) was used to reflect chronic kidney disease. According to the findings of MRI examination, the imaging score of cerebral frailty was performed. When there were white matter lesions, brain atrophy and lacunar infarction/lacuna, 1 point was given, and the total score was 3. Ordinal multi-class logistic regression analysis was used to evaluate the relationship between renal function indexes and brain frailty imaging score in patients with mild ischemic stroke or TIA. Binary logistic regression analysis was used to evaluate the relationship between renal function indexes and brain frailty imaging score >1. Results:A total of 204 patients with mild ischemic stroke or TIA were enrolled during the study. Their average age was 64.82 years old and 78 (38.2%) were females. There were 28 cases (13.73%), 70 cases (34.31%), 63 cases (30.88%) and 43 cases (21.08%) with brain frailty imaging scores of 0, 1, 2, and 3, respectively. One hundred and six patients (51.96%) were in the brain frailty imaging score >1 group and 98 (48.04%) were in the ≤1 group. Univariate analysis showed that there were significant differences in age, diabetes mellitus, eGFR, eGFR classification, homocysteine, intracranial vascular stenosis, stroke etiology classification and vascular distribution between the group with brain frailty imaging score >1 and those with brain frailty imaging score ≤1 (all P<0.05). Ordinal multi-class logistic regression analysis showed that urea (odds ratio [ OR] 0.67, 95% confidence interval [ CI] 0.51-0.89, P=0.005) and eGFR ( OR 0.98, 95% CI 0.96-0.99; P=0.004) were significantly and independently correlated with brain frailty imaging score. Binary logistic regression analysis showed that eGFR was significantly and independently correlated with brain frailty imaging score >1 ( OR 0.98, 95% CI 0.96-1.00; P=0.016). However, urea, uric acid and eGFR classification were not independently correlated with brain frailty imaging score or brain frailty imaging score >1. Conclusion:Blood urea and eGFR are correlated with the brain frailty imaging score in patients with mild ischemic stroke or TIA.

Objective:To assess the efficacy and safety of 100 units of botulinum toxin A (BTX-A) intradetrusor injection in patients with overactive bladder.Methods:From April 2016 to December 2018, 17 tertiary hospitals were selected to participate in this prospective, multicenter, randomized, double-blind, placebo-controlled study. Two phases of study were conducted: the primary phase and the extended phase. This study enrolled patients aged 18 to 75 years who had been inadequately managed by anticholinergic therapy (insufficient efficacy or intolerable side effects) and had spontaneous voiding with overactive bladder. Exclusion criteria included patients with severe cardiac, renal and hepatic disorders, patients with previous botulinum toxin treatment for 6 months or allergic to BTX-A, patients with urinary tract infections, patients with urinary stones, urinary tract tumors, diabetes mellitus, and bleeding tendency. Eligible patients were randomly assigned to BTX-A group and placebo control group in a ratio of 2∶1. Two groups of patients received 20 intradetrusor injections of BTX-A 100U or placebo at the depth of the submucosal muscle layer respectively under cystoscope, including 5 injections at the base of the bladder, 3 injections to the bladder triangle, 5 injections each to the left and right walls and 2 injections to the top, sparing the bladder neck. As a placebo control group, patients received same volume of placebo containing no BTX-A and only adjuvant freeze-dried preparations for injection with the same method. A combination of gelatin, sucrose, and dextran served as adjuvants. Average micturition times per 24 hours, urinary incontinence (UI) episodes per day, average micturition volume per day, OAB symptom score(OABSS), and quality of life (QOL) score were recorded at baseline and the 2nd, 6th and 12th week after treatment. The primary efficacy endpoint was the change from baseline in the average micturition times per 24 hours at the 6th week after treatment. The secondary efficacy endpoints included the change from baseline in the average micturition times per 24 hours at 2nd and 12th week, as well as the change from baseline in the OABSS, QOL score, average frequency of urgency and UI episodes per day, urgency score, average micturition volume per day at 2nd, 6th and 12th week after treatment. Patients were followed for 12 weeks to assess adverse events (AEs). After assessed at week 12, if the micturition times has decreased less than 50% compared to baseline and the patient is willing to receive retreatment, then patients could enter the extended trial phase. In that phase, patients in both groups were injected with 100 units BTX-A from 12th week onwards and then followed up the same indicators for 12 weeks.Results:216 patients were enrolled in this trial (144 cases in the BTX-A group and 72 cases in the placebo control group). Baseline characteristics such as age (47.75±14.20 in the BTX-A group and 46.39±15.55 in the control group), sex (25 male/117 female in the BTX-A group and 10/61 in the control group), and disease duration (0.51 years in the BTX-A group and 0.60 years in the control group) were balanced between the two groups( P>0.05). A marked reduction from baseline in average micturition times per 24 hours was observed in all treatment groups at the 6th week and the reduction of the two groups was statistically different ( P<0.001 and P=0.008 respectively). Compared with the baseline, the average micturition times per 24 hours at the 6th week decreased from baseline by 2.40(0.70, 4.60)times for the BTX-A group and 0.70(-1.00, 3.30) times for the placebo control group respectively, and the difference between the two groups was considered to be statistically significant ( P=0.003). The change rates of average micturition times per 24 hours from baseline at the 6th week of the two groups were (16±22)% and (8±25)% respectively, and the difference between the two groups was statistically significant ( P=0.014). Compared with the baseline, the average micturition times per 24 hours at 2nd and 12th week decreased by 2.00(0.00, 4.00)and 3.30(0.60, 5.03)for the BTX-A group, 1.00(-1.00, 3.00)and 1.70(-1.45, 3.85)for the placebo control group respectively. The difference between two groups was considered to be statistically significant ( P=0.038 and P=0.012); the changes of average urgency times per day for the BTX-A group and the control group at the 2nd, 6th and 12th week were 2.00(0.00, 4.30)and 2.40(0.30, 5.00), 3.00(0.30, 5.70)and 0.70(-1.30, 2.70), 0.70(-1.30, 3.00) and 1.35(-1.15, 3.50), respectively. There were significant differences between two groups at the 2nd, 6th and 12th week, ( P=0.010, P=0.003 and P=0.025, respectively). The OABSS of the BTX-A group and the control group at the 6th week decreased by 1.00(0.00, 4.00)and 0.50(-1.00, 2.00) compared with the baseline, and the difference between the two groups was statistically significant ( P=0.003). 47 cases of BTX-A group and 34 cases of placebo control group entered the extended trial phase, and 40 and 28 cases completed the extended trial phase, respectively. The average micturition volume per 24 hours changed by -16.60(-41.60, -0.60)ml and -6.40(-22.40, 13.30)ml, (-35.67±54.41)ml and(-1.76±48.69)ml, (-36.14±41.51)ml and (-9.28±44.59)ml, (-35.85±43.35)ml and(-10.41±40.29)ml for two groups at the 12th, 14th, 18th and 24th week, and the difference between two groups was statistically significant at each follow-up time ( P=0.01, 0.006, 0.012 and 0.016, respectively). There was no significant difference in other parameters( P>0.05). However, adverse reactions after intradetrusor injection included increased residual urine volume (27 in the BTX-A group and 3 in the control group), dysuria (21 in the BTX-A group and 6 in the control group), urinary infection (19 in the BTX-A group and 6 in the control group), bladder neck obstruction (3 in the BTX-A group and 0 in the control group), hematuria (3 in the BTX-A group and 1 in the control group), elevated alanine aminotransferase (3 in the BTX-A group and 0 in the control group), etc. During the follow-up period, there was no significant difference in the other adverse events between two groups except the increase of residual urine volume( P<0.05). In the primary trial phase, among the 27 cases with increased residual urine volume in BTA group, only 1 case (3.70%) with PVR more than 300 ml; the PVR of 3 patients in the placebo group was less than 100 ml. The increase of residual urine volume caused by the injection could be improved or disappeared with the passage of time. Conclusions:Intradetrusor injection of Chinese BTX-A improved the average micturition times per 24 hours, the average daily urgent micturition times, OABSS, and average micturition volume per time, and reduced the adverse effects in patients with overactive bladder.Chinese BTX-A at dose of 100U demonstrated durable efficacy and safety in the management of overactive bladder.