Risk Factors of Depression Screened by Two-Sample Mendelian Randomization Analysis: A Systematic Review / 生物医学与环境科学（英文）

OBJECTIVE@#This study explored the potentially modifiable factors for depression and major depressive disorder (MDD) from the MR-Base database and further evaluated the associations between drug targets with MDD.@*METHODS@#We analyzed two-sample of Mendelian randomization (2SMR) using genetic variant depression ( n = 113,154) and MDD ( n = 208,811) from Genome-Wide Association Studies (GWAS). Separate calculations were performed with modifiable risk factors from MR-Base for 1,001 genomes. The MR analysis was performed by screening drug targets with MDD in the DrugBank database to explore the therapeutic targets for MDD. Inverse variance weighted (IVW), fixed-effect inverse variance weighted (FE-IVW), MR-Egger, weighted median, and weighted mode were used for complementary calculation.@*RESULTS@#The potential causal relationship between modifiable risk factors and depression contained 459 results for depression and 424 for MDD. Also, the associations between drug targets and MDD showed that SLC6A4, GRIN2A, GRIN2C, SCN10A, and IL1B expression are associated with an increased risk of depression. In contrast, ADRB1, CHRNA3, HTR3A, GSTP1, and GABRG2 genes are candidate protective factors against depression.@*CONCLUSION@#This study identified the risk factors causally associated with depression and MDD, and estimated 10 drug targets with significant impact on MDD, providing essential information for formulating strategies to prevent and treat depression.

Research progress of nitrobenzoyl sesquiterpenoids as marine characteristic natural products / 药学学报

Sesquiterpenoids are widely found in nature, while nitrobenzoyl sesquiterpenoids are relatively rare. Twelve natural nitrobenzoyl sesquiterpenoids were all derived from marine Aspergillus fungi, which are typical natural products with marine characteristics. These natural products exhibit good antitumor, antiviral, and inhibition of osteoclast differentiation activity, especially in the treatment of osteoclast-related diseases, showing good medicinal development value. This article reviews the natural product sources, chemical structure, chemical synthesis, biosynthesis, bioactivity, and pharmacological mechanisms of nitrobenzoyl sesquiterpenoids and predicts and discusses their absorption, distribution, metabolism, excretion, toxicity (ADME/T), and drug-likeness, providing a comprehensive understanding of the natural products of nitrobenzoyl sesquiterpenoids from marine sources and their potential for pharmaceutical development.

Enhancement of tropane alkaloids biosynthesis in Atropa belladonna hariy root by overexpression of HnCYP82M3 and DsTRI genes / 药学学报

Tropane alkaloids (TAs) are a class of anticholinergic drugs widely used in clinical practice and mainly extracted from plant, among which Atopa belladonna is the main commercial drug source. It is of great industrial value to obtain TAs in large quantities by plant metabolic engineering. In TAs pathway, cytochrome oxidase CYP82M3 catalyze the synthesis of tropinone and then tropinone reductase I (TRI) compete with TRII for tropinone to form tropine leading to the TAs synthesis (drainage). In this study, based on the "increasing flow and drainage" metabolic engineering strategy, two genes, namely HnCYP82M3 and DsTRI from Hyoscyamus niger and Datura stramonium, respectively, were overexpressed in the hair roots of A. belladonna, with a view to promote the TAs accumulation. The HnCYP82M3 gene was cloned from the root of H. niger, and it encoded amino acid with 91.7% sequence identity with AbCYP82M3 from A. belladonna. Overexpression of HnCYP82M3 alone did not affect the content of TAs in hair roots of A. belladonna, indicating that CYP82M3 was not a key enzyme in TAs biosynthesis. Simultaneous overexpression of HnCYP82M3 and DsTRI greatly promoted the accumulation of the three TAs, and the contents of hyoscyamine, anisodamine and scopolamine were 4.97 times, 2.83 times and 2.19 times that of the control, respectively, and the increase amplitude was greater than that of single overexpression of DsTRI. This study showed that the "increasing flow and drainage" strategy of enzyme genes co-expression at branch points was a promising metabolic engineering method to effectively improve the biosynthesis of TAs in A. belladonna, and laid a theoretical and technical foundation for the large-scale industrial acquisition of TAs.

Mechanism of ellagic acid improving cognitive dysfunction in APP/PS double transgenic mice based on PI3K/AKT/GSK-3β signaling pathway / 中国药理学通报

Aim To investigate the effect of ellagic acid (EA) on cognitive function in APP/PS 1 double- transgenic mice, and to explore the regulatory mechanism of ellagic acid on the level of oxidative stress in the hippocampus of double-transgenic mice based on the phosphatidylinositol 3-kinase/protein kinase B/glycogen synthase kinase-3 (PI3K/AKT/GSK-3 β) signaling pathway. Methods Thirty-two SPF-grade 6-month-old APP/PS 1 double transgenic mice were randomly divided into four groups, namely, APP/PS 1 group, APP/PS1 + EA group, APP/PS1 + LY294002 group, APP/PS 1 + EA + LY294002 group, with eight mice in each group, and eight SPF-grade C57BL/6J wild type mice ( Wild type) were selected as the blank control group. The APP/PS 1 + EA group was given 50 mg · kg

Colonoscopy follow-up in patients with simultaneous multiple primary colorectal cancer and patients with sporadic colorectal cancer: a matched-pair study / 中华消化杂志

Objective:To investigate the incidences of metachronous advanced adenoma (MAA) in patients with simultaneous multiple primary colorectal cancer (CRC) and patients with sporadic CRC.Methods:From January 1, 2008 to September 30, 2022, at Beijing Shijitan Hospital, Capital Medical University, CRC patients who underwent surgery and 3 years follow-up with endoscopy were enrolled. The patients completed colonoscopy at least 2 times during follow-up in 6 to 36 months after surgery, and the interval between the 2 times colonoscopies was over 6 months. Clinical data including age, gender, and tumor location, stage, pathological features, combined underlying diseases, preoperative carcinoembryonic antigen, hemoglobin and other laboratory results, baseline colonoscopy results, and detection of MAA were collected. According to age (±2 years old), gender, location of primary lesion and stage of tumor, patients with simultaneous CRC or sporadic CRC were matched at 1∶1 ratio by propensity score matching. The cumulative risks of MAA in patients with simultaneous multiple primary CRC and patients with sporadic CRC were calculated. Cox proportional hazard regression was used to analyze the influencing factors in the occurrence of MAA.Results:A total of 814 CRC patients were enrolled and matched. After paired matching, there were 36 cases of simultaneous multiple primary CRC (78 lesions) and 78 cases of sporadic CRC (78 lesions). The cumulative incidences of MAA at 1, 2 and 3 years of simultaneous CRC group were 11.1%(4/36), 22.2%(8/36) and 33.3%(12/36), respectively. The cumulative incidences of MAA at 1-, 2- and 3-year of sporadic CRC group were 3.8%(3/78), 12.8%(10/78) and 20.5%(16/78), respectively.Simultaneous CRC was correlated with an increase in the 3-year cumulative incidence of MAA ( HR=4.163, 95% confidence interval(95% CI) 1.032 to 4.721, P=0.047). Especially in left-sided CRC, the risk of MAA in simultaneous CRC increased ( HR=7.186, 95% CI 1.602 to 20.787, P=0.010). The results of multivariate cox-regression analysis indicated that detection of simultaneous advanced adenoma at baseline endoscopy was an independent risk factor of MAA ( HR=3.175, 95% CI 1.411 to 7.142, P=0.005). Conclusion:Colouoscopy follow-up should be strengthened in patients with simultaneous multiple primary CRC and simultaneous advanced adenomas.

Treatment strategy of calciphylaxis in dialysis patients / 中华肾脏病杂志

Calciphylaxis is a vascular disease caused by a combination of multiple factors, and the calcified ischemic lesion results in the severe skin damage accompanied by unbearable pain. Calciphylaxis tends to occur in patients with end-stage renal disease, and the treatment of this disease faces enormous challenges. Current treatment recommendations are mainly based on clinical experience and observational research reports, and there is still a lack of clinical practice standards or consensus for managing calciphylaxis. Therefore, this paper will review the effective treatment methods and off-label use of calciphylaxis based on literature reports, providing reference for the clinical treatment of the disease.

Clinical features of POEMS syndrome initially diagnosed as pulmonary hypertension / 中华全科医师杂志

Objective:To analyze the clinical characteristics, diagnosis and treatments of patients with POEMS syndrome initially diagnosed as pulmonary hypertension (PH).Methods:Clinical data of 7 patients who were initially diagnosed as PH and finally diagnosed as POEMS syndrome in Shanghai Pulmonary Hospital from May 2013 to November 2021 were retrospectively reviewed. Clinical manifestations, laboratory tests, echocardiography, hemodynamic findings, treatment and prognosis of patients were analyzed.Results:Seven patients, including 4 males and 3 female, aged (55±9) (44-62) years were presented with elevated pulmonary artery pressure by echocardiography at admission. Chest tightness and shortness of breath (7/7), fatigue (6/7) and lower limb edema (4/7) were the most common symptoms in the first-episode. Meanwhile, patients also presented symptoms associated with POEMS syndrome, including multiple peripheral neuropathy (7/7), multiserosal cavity effusion (6/7), organomegaly (5/7), skin changes (5/7), and endocrine lesions (4/7). Serum levels of vascular endothelial growth factor (VEGF) were significantly increased in all patients. The pulmonary arterial systolic blood pressure was (66±21)mmHg (1 mmHg=0.133 kPa) estimated by echocardiography. Six patients underwent right heart catheterization and significantly increased mean pulmonary artery pressure((35±9) mmHg) was confirmed; and their pulmonary vascular resistance was (4.00±2.10) Wood U. All patients received corresponding treatment for POEMS syndrome. The excise tolerance was improved in 5 patients after successful treatment with stable or reversed WHO functional class. One patient received hemodialysis treatment for uncontrolled POEMS. One patient died during follow-up. The echocardiography was followed up in 4 patients, and 2 of whom had a complete reversal of PH, 1 had a partial reversal, and 1 had not yet reversed.Conclusions:In patients with PH who have multisystem manifestations, such as multiple peripheral neuropathy, multiserosal cavity effusion, organomegaly and skin changes, POEMS syndrome should be considered, and proper and active treatment of POEMS may reverse PH and improve the prognosis of patients.

Multi-disciplinary open comprehensive training program in improving the post competency of medical imaging students / 中华医学教育探索杂志

Objective:To evaluate the teaching effect of multi-disciplinary integrated training program on the open comprehensive training room to improve the post competency of medical imaging students.Methods:A total of 122 residential students of five-year medical imaging from Batch 2014 of The First Affiliated Hospital of Chengdu Medical College were divided into experimental group and control group. The experimental group carried out the multi-disciplinary open comprehensive training program, and the control group carried out open-ended exercises. The comprehensive discipline theory examination, assessment of clinical thinking and comprehensive skill appraisal, and satisfaction questionnaire results were compared between the two groups. SPSS 23.0 was used for t test. Results:①Comprehensive discipline theory examination scores were higher in experimental group than the control group [(80.33±3.70) vs. (74.56±5.09)], with statistical differences ( P<0.05). ②Experimental group scored higher in clinical thinking and comprehensive skills than the control group did, and the difference was statistically significant [(87.58±3.15) vs. (74.52±3.66), P<0.05]. ③The questionnaire investigation showed that the experimental group students did better in improving autonomous learning ability, expression ability, the team cooperation ability, the ability to find and fix problems and the degree of self-esteem than control group, with statistically significant differences ( P<0.05). Conclusion:The multi-disciplinary open comprehensive training program has a good effect on optimizing the open-ended exercises. Students' knowledge of multi-disciplinary comprehensive theoretical knowledge and imaging skills have been improved, and the ability of teamwork, problem-solving ability, self-learning ability and innovation ability required by the core competence of the profession have been developed and improved, which meets the modern medical treatment of education "to create an educational platform of medical education collaboration and multi-disciplinary integration, and to cultivate students' innovative and autonomous learning."

Inhibitory effect of blue light intervention on lens-induced myopia development in guinea pigs and the mechanism of cone density change / 中华实验眼科杂志

Objective:To observe the effects of blue light intervention on the development of optical defocus-induced myopia in guinea pigs and investigate its underlying mechanisms.Methods:Forty-eight normal-grade two-week-old tricolor guinea pigs were randomly divided into a blue light group and a white light group, with 24 animals in each group.The right eye of guinea pigs was fitted with a -5.00 D lens to establish an optical defocus model as the experimental eye, while the left eye served as the control without any covering.Before the experiment and after 8-week intervention, the refractive power of guinea pigs was measured by streak retinoscopy.The anterior chamber depth, lens thickness, and axial length were measured by A-scan ultrasonography.Corneal curvature radius was determined using a keratometer.After 8-week intervention, the guinea pigs were euthanized through overanesthesia, and the right eyeballs were enucleated and the retinas were isolated.The density of S and M cone cells of the guinea pig retinal sections were observed via immunofluorescence staining.The expression of retinal retinoic acid was assessed by high-performance liquid chromatography.The expressions of retinoic acid receptor (RAR-β) in the retina and matrix metalloproteinase-2 (MMP-2), tissue inhibitor of metalloproteinase-2 (TIMP-2), and type Ⅰ collagen in the sclera were detected by real-time fluorescence quantitative PCR.Changes in scleral thickness were observed through hematoxylin-eosin staining.The use and care of the animals complied with Regulations for the Administration of Affair Concerning Experimental Animals by State Science and Technology Commission.The study protocol was approved by the Ethics Committee of Eye and ENT Hospital of Fudan University (No.2022ETKLD10032).Results:After 8 weeks of intervention, guinea pigs in the blue light group showed (0.63±0.12)D of relative hyperopia and a deceleration of axial elongation by (0.08±0.00)mm compared with the white light group in the right eye.In the left eye, guinea pigs in the blue light group showed (0.42±0.09)D of relative hyperopia and a deceleration of axial elongation by (0.08±0.00)mm compared with the white light group.The guinea pigs in blue light group showed (1.52±0.09)D of myopia in the right eye compared with the left eye, with an increase in axial elongation of (0.06±0.00)mm.The guinea pigs in white light group showed (1.66±0.07)D of myopia in the right eye compared with the left eye, with an increase in axial elongation of (0.13±0.00)mm, and the differences were statistically significant (all at P<0.05). The density of M cone cells was lower and density of S cone cells was higher in the blue light group in the dorsal and ventral sides of the retinal sections compared with the white light group, showing statistically significant differences ( t=32.33, 52.23, 42.09, 25.02; all at P<0.05). The deceleration of myopia progression in the blue light group was strongly positively correlated with the increase in S cone cell density on the ventral side ( r=0.95, P<0.01). The expression levels of retinoic acid, RAR-β, and MMP-2 were decreased, and expression levels of TIMP-2 and type Ⅰ collagen were increased in blue light group compared with the white light group, showing statistically significant differences ( t=18.73, 7.45, 3.72, 6.19, 9.03; all at P<0.05). The scleral thickness in the blue light group was (125.0±7.8)μm, which was significantly thicker than (102.0±6.3)μm in the white light group ( t=26.93, P<0.05). Conclusions:Blue light intervention can inhibit the progression of defocus-induced myopia in guinea pigs.Refractive power changes in guinea pigs may be influenced by alterations in retinal cone cell density, retinoic acid expression, and scleral collagen expression.

Detection of aqueous humor cytokines in diabetic retinopathy and its clinical significance / 中华实验眼科杂志

Objective:To detect the concentration of various cytokines in aqueous humor of patients with diabetes retinopathy (DR) with Luminex liquid chip, and analyze the relationship between the cytokines and the occurrence and development of DR.Methods:A cross-sectional study was conducted.Sixty-three DR patients (97 eyes) treated with anti-vascular endothelial growth factor (VEGF) drugs in the First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine from March 1, 2019 to December 31, 2019 were enrolled as DR group, including 38 nonproliferative DR (NPDR) eyes in NPDR group and 59 proliferative DR (PDR) eyes in PDR group, 39 eyes in photocoagulation group and 58 eyes in non-photocoagulation group.Twenty-seven patients (31 eyes) hospitalized for cataract surgery at the same time were collected as the control group.Aqueous humor was extracted during the operation, and Luminex liquid chip was used to detect the concentrations of vascular endothelial growth factor-A (VEGF-A), placental growth factor (PLGF), platelet-derived growth factor (PDGF)-AA, PDGF-BB, angiopoietin-like protein 4 (ANGPTL4), interleukin-6 (IL-6), IL-8, IL-1β, monocyte chemotactic protein-1 (MCP-1), intercellular cell adhesion molecule-1 (ICAM-1) and tumor necrosis factor-α (TNF-α) in aqueous humor.The concentrations of various cytokines of different groups were compared, and the correlation among various aqueous humor cytokines was analyzed by Spearman rank correlation analysis.This study adhered to the Declaration of Helsinki.The study protocol was approved by the Ethics Committee of First Affiliated Hospital of Guangzhou University of Chinese Medicine (No.Y[2019]230). Written informed consent was obtained from each patient.Results:The concentrations of VEGF-A, PLGF, PDGF-AA, ANGPTL4, IL-6, IL-8, MCP-1 and ICAM-1 in DR group were significantly higher and the concentration of IL-1β was significantly lower than those of control group ( Z=-4.747, -5.164, -3.373, -8.062, -4.535, -5.954, -5.098, -3.228, -5.954, all at P<0.01). The concentrations of VEGF-A, PLGF, PDGF-AA, ANGPTL4, IL-6, IL-8 and MCP-1 of the photocoagulation and non-photocoagulation groups were higher and the concentration of IL-1β was significantly lower than those in the control group (all at P<0.017). The concentration of ICAM-1 in the photocoagulation group was significantly higher than that in the control group ( P<0.017). The concentrations of PLGF, PDGF-AA and ANGPTL4 of PDR group were higher than those of NPDR group, and the differences were statistically significant ( Z=-2.291, -3.396, -2.276, all at P<0.05). VEGF-A was positively correlated with the other cytokines except ICAM-1 ( rs=0.237-0.540, all at P<0.05). ANGPTL4 was positively correlated with the other cytokines except IL-1β ( rs=0.361-0.733, all at P<0.01). Conclusions:The occurrence and development of DR are closely related to VEGF family, PDGF family, ANGPTL family and inflammatory factors.The concentrations of PLGF, PDGF-AA and ANGPTL4 are higher in PDR eyes.There are close and complex relationships among a variety of cytokines in the eyes of DR patients.

Normative wideband absorbance measures in children: a cross-sectional study / 中华耳鼻咽喉头颈外科杂志

Objective: This study was to investigate the main characteristics and related factors of wideband absorbance (WBA) in children with normal hearing and to obtain age-specific reference range of WBA. Methods: 384 children between 0-12 years old (615 ears) who visited the Beijing Children's Hospital, Capital Medical University from October 2019 to February 2021 were enrolled, including 230 males (376 ears) and 154 females (239 ears), with totally 306 left ears and 309 right ears. Wideband tympanometry (WBT) was performed and normative WBA data were analyzed by SPSS 24.0 statistical software. Repeated measures and multivariate analysis of variance were applied to the data from 16 points at 1/3-octave frequencies (226, 324, 408, 500, 667, 841, 1 000, 1 297, 1 682, 2 000, 2 670, 3 364, 4 000, 5 339, 6 727 and 8 000 Hz) to evaluate the effects of frequency, age, external auditory canal pressures, gender and ear on WBA. Results: According to the WBT frequency-absorbance curve, the subjects were divided into seven groups: 1-month old group, 2-month old group, 3-month old group, 4-5 month old group, 6-24 month old group,>2-6 year old group and>6-12 year old group. The WBA of normal-hearing children underwent a series of developmental changes with age at both ambient pressure and tympanometric peak pressures. WBA results for 1-month group and 2-month old group exhibited a multipeaked pattern, with the peaks occurring around 2 000 and 4 897 Hz, and a notch around 3 886 Hz. WBA results for 3-month group and 4-5 month old group exhibited a single broad-peaked pattern, with the peak occurring between 2 000-4 757 Hz. The WBA of 1-month old group to 4-5 month old group decreased gradually at low frequency (226-408 Hz) and 6 727 Hz, and increased at middle to high frequency (2 670-4 000 Hz). The WBA of 6-24 month old group were significantly lower than that of 2-month old group to 4-5 month old group at all frequencies except 3 364 and 4 000 Hz. WBA results for 6-24 month old group,>2-6 year old group and>6-12 year old group exhibited a single-peaked pattern, and the peak frequency of WBA moved to the lower frequency successively. From 6-24 month old group to>6-12 year old group, the WBA gradually increased at low to middle frequencies (667-2 670 Hz) and 8 000 Hz, and decreased at middle to high frequencies (3 364-5 339 Hz). Among the 16 frequencies of all age groups, the difference between WBA under ambient pressure and tympanometric peak pressure were -0.09-0.06, and 43.75%-81.25% frequency points had statistically significant difference, which was mainly manifested in that WBA under ambient pressure were lower than that under tympanometric peak pressure at 226-1 682 Hz. There was no significant ear effect on all of the age groups. Similarly, there was no significant gender effect except for 3-month old group and 4-5 month old group. Conclusions: The WBA of normal-hearing children measured at ambient pressure and tympanometric peak pressure varied across the frequencies with age from 1 month to 12 years old, and different frequencies followed different change patterns (increase vs. decrease) in WBA. There was also significant external auditory canal pressures effect on all of the age groups. The establishment of age-specific reference range of WBA for 0-12 years old normal-hearing children in this study would be useful for clinical practice of determining normative data regarding WBT.

Danhong Injection Up-regulates miR-125b in Endothelial Exosomes and Attenuates Apoptosis in Post-Infarction Myocardium / 中国结合医学杂志

OBJECTIVE@#To investigate the involvement of endothelial cells (ECs)-derived exosomes in the anti-apoptotic effect of Danhong Injection (DHI) and the mechanism of DHI-induced exosomal protection against postinfarction myocardial apoptosis.@*METHODS@#A mouse permanent myocardial infarction (MI) model was established, followed by a 14-day daily treatment with DHI, DHI plus GW4869 (an exosomal inhibitor), or saline. Phosphate-buffered saline (PBS)-induced ECs-derived exosomes were isolated, analyzed by miRNA microarray and validated by droplet digital polymerase chain reaction (ddPCR). The exosomes induced by DHI (DHI-exo), PBS (PBS-exo), or DHI+GW4869 (GW-exo) were isolated and injected into the peri-infarct zone following MI. The protective effects of DHI and DHI-exo on MI hearts were measured by echocardiography, Masson's trichrome staining, and TUNEL apoptosis assay. The Western blotting and quantitative reverse transcription PCR (qRT-PCR) were used to evaluate the expression levels of miR-125b/p53-mediated pathway components, including miR-125b, p53, Bak, Bax, and caspase-3 activities.@*RESULTS@#DHI significantly improved cardiac function and reduced infarct size in MI mice (P<0.01), which was abolished by the GW4869 intervention. DHI promoted the exosomal secretion in ECs (P<0.01). According to the results of exosomal miRNA microarray assay, 30 differentially expressed miRNAs in the DHI-exo were identified (28 up-regulated miRNAs and 2 down-regulated miRNAs). Among them, DHI significantly elevated miR-125b level in DHI-exo and DHI-treated ECs, a recognized apoptotic inhibitor impeding p53 signaling (P<0.05). Remarkably, treatment with DHI and DHI-exo attenuated apoptosis, elevated miR-125b expression level, inhibited capsase-3 activity, and down-regulated the expression levels of proapoptotic effectors (p53, Bak, and Bax) in post-MI hearts, whereas these effects were blocked by GW4869 (P<0.05 or P<0.01).@*CONCLUSION@#DHI and DHI-induced exosomes inhibited apoptosis, promoted the miR-125b expression level, and regulated the p53 apoptotic pathway in post-infarction myocardium.

Emodin Ameliorates High Glucose-Induced Podocyte Apoptosis via Regulating AMPK/mTOR-Mediated Autophagy Signaling Pathway / 中国结合医学杂志

OBJECTIVE@#To investigate the effect of emodin on high glucose (HG)-induced podocyte apoptosis and whether the potential anti-apoptotic mechanism of emodin is related to induction of adenosine-monophosphate-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR)-mediated autophagy in podocytes (MPC5 cells) in vitro.@*METHODS@#MPC5 cells were treated with different concentrations of HG (2.5, 5, 10, 20, 40, 80 and 160 mmol/L), emodin (2, 4, 8 µ mol/L), or HG (40 mmol/L) and emodin (4 µ mol/L) with or without rapamycin (Rap, 100 nmol/L) and compound C (10 µ mol/L). The viability and apoptosis of MPC5 cells were detected using cell counting kit-8 (CCK-8) assay and flow cytometry analysis, respectively. The expression levels of cleaved caspase-3, autophagy marker light chain 3 (LC3) I/II, and AMPK/mTOR signaling pathway-related proteins were determined by Western blot. The changes of morphology and RFP-LC3 fluorescence were observed under microscopy.@*RESULTS@#HG at 20, 40, 80 and 160 mmol/L dose-dependently induced cell apoptosis in MPC5 cells, whereas emodin (4 µ mol/L) significantly ameliorated HG-induced cell apoptosis and caspase-3 cleavage (P<0.01). Emodin (4 µ mol/L) significantly increased LC3-II protein expression levels and induced RFP-LC3-containing punctate structures in MPC5 cells (P<0.01). Furthermore, the protective effects of emodin were mimicked by rapamycin (100 nmol/L). Moreover, emodin increased the phosphorylation of AMPK and suppressed the phosphorylation of mTOR. The AMPK inhibitor compound C (10 µ mol/L) reversed emodin-induced autophagy activation.@*CONCLUSION@#Emodin ameliorated HG-induced apoptosis of MPC5 cells in vitro that involved induction of autophagy through the AMPK/mTOR signaling pathway, which might provide a potential therapeutic option for diabetic nephropathy.

Different frequency of acupoint thread-embedding for overweight/obesity of spleen deficiency and dampness retention: a randomized controlled trial / 中国针灸

OBJECTIVES@#To compare the effect of different frequency of acupoint thread-embedding on weight loss in subjects with overweight/obesity of spleen deficiency and dampness retention.@*METHODS@#A total of 126 subjects with overweight/obesity of spleen deficiency and dampness retention were randomized into a 2-week group(63 cases, 13 cases dropped out)and a 3-week group(63 cases, 11 cases dropped out, 1 case was eliminated). The two groups were treated with acupoint thread-embedding once every 2 weeks and once every 3 weeks respectively, Zhongwan(CV 12), Shuifen(CV 9), Qihai(CV 6), Guanyuan(CV 4) and bilateral Zhangmen(LR 13), Tianshu(ST 25), Liangmen(ST 21), Daheng(SP 15), Fujie(SP 14), Pishu(BL 20), Yinlingquan(SP 9)were selected. Four times were required in the two groups. Before and after treatment, follow-up after 2 months of treatment completion, the body mass index(BMI), body weight, waist circumference, hip circumference, waist-to-hip ratio, obesity degree, fat percentage(F%), skin fold thickness were observed in the two groups.@*RESULTS@#After treatment and in follow-up, the BMI, body weight, waist circumference, hip circumference, waist-to-hip ratio, obesity degree, F%, skin fold thickness in the two groups were decreased compared with those before treatment (P<0.001, P<0.01), the changes of BMI, body weight, obesity degree, F%, skin fold thickness in the 2-week group were larger than those in the 3-week group(P<0.05, P<0.01, P<0.001).@*CONCLUSIONS@#The effect of acupoint thread-embedding once every 2 weeks on weight loss in subjects with overweight/obesity of spleen deficiency and dampness retention is superior to that once every 3 weeks.

Clinical research progress on drugs for non-alcoholic steatohepatitis treatment / 药学学报

Nonalcoholic steatohepatitis (NASH) is the leading chronic liver disease worldwide. NASH is commonly associated with metabolic risk factors, including obesity, hypertension, and diabetes. Hepatic glucose and lipid metabolism disorder, bile acid toxicity, oxidative stress, inflammation, fibrosis, intestinal dysbacteriosis, and susceptibility gene variation are involved in the pathogenesis of NASH. Drug development for NASH has been slow, this article focuses on the clinical research and development of several promising NASH drugs and their mechanisms, such as drugs targeting gut-liver axis, improving metabolism, inhibiting inflammation and fibrosis.

Effects of the national centralized drug procurement policy on drug availability and the structure of hospital drug use / 中国药房

OBJECTIVE To analyze the effects of the national centralized drug procurement （NCDP） policy on drug availability and the structure of drug use in public hospitals. METHODS Using hypoglycemic， lipid-lowering， antiviral drugs， and psychiatric drugs for the treatment of mental illness and depression as objects， the interrupted time series model was used to quantitatively evaluate the changes in consumption sum of drugs， consumption amount and daily cost of the target drugs in national sample hospitals as well as the changes in per capita medication frequency， outpatient prescription amount， and medical insurance surplus of target drugs in a third grade class A hospital before and after the implementation of NCDP policy. RESULTS After the implementation of the NCDP policy， the volume for the four bid-winning drugs increased significantly （P＜0.01 for the remaining three categories except for hypoglycemic drugs）， but DDDc （P＜0.01） and the amount of related drugs （P＜0.001） decreased significantly. The volume for the non-winning drugs （except for lipid-lowering drugs） decreased significantly （P＜0.05）， and DDDc also decreased significantly （P＜0.05 for other 3 categories except for psychiatric drugs）； the volume （P＜0.01） and DDDc （P＜0.01 only for psychiatric drugs） for alternative drugs all increased except for antiviral drugs. The structure of drug use for different drugs was affected differently by the NCDP policy，and that of hypoglycemic drugs was affected obviously； the proportion of alternative drugs increased after centralized procurement. The outpatient prescription amount of each hospital significantly decreased after centralized procurement，and the decrease in the cost paid by the patients using lipid-lowering and antiviral drugs related to centralized procurement was greater than 0.60； the remaining medical insurance amount for bid-winning drugs was approximately 1.252 5 million yuan. CONCLUSIONS NCDP policy effectively alleviates the burden of medical expenditure and also drives the structure changes of drug use such as the substitution of generic drugs for original drugs， the growth of the volume of alternative drugs.

Efficacy analysis of anti-thymocyte globulin regimens with different timing strategies for matched sibling donor hematopoietic stem cell transplantation / 中华血液学杂志

Objective: To compare the effects of two administration time strategies for rabbit antihuman thymocyte immunoglobulin (rATG) of 5mg/kg total dose in matched sibling donor hematopoietic stem cell transplantation (MSD-HSCT) . Methods: This study retrospectively analyzed the clinical data of 32 patients who received MSD-HSCT with 5 mg/kg rATG conditioning regimen at the Department of Hematology of the First Medical Center of the People's Liberation Army General Hospital from October 2020 to April 2022. The patients were classified into two groups: the 4d-rATG group (16 cases), who received antithymocyte globulin (ATG) from day -5 to day -2, and the 2d-rATG group (16 cases), who received ATG from day -5 to day -4. Between the two groups, the transplantation outcomes, serum concentrations of active antithymocyte globulin (ATG) in patients from -4 days to 28 days after graft infusion (+28 days), and the reconstitution of lymphocyte subsets on days +30, +60, and +90 were compared. Results: The cumulative incidences of acute graft-versus-host disease at 100 days after graft infusion were 25.0% (95% CI 7.8% -47.2% ) and 18.8% (95% CI 4.6% -40.2% ) (P=0.605) in the 4d-rATG group and 2d-rATG group, respectively. The 1-year cumulative incidences of chronic graft-versus-host disease were 25.9% (95% CI 8.0% -48.6% ) and 21.8% (95% CI 5.2% -45.7% ) (P=0.896). The 1-year cumulative incidence of relapse was 37.5% (95% CI 18.9% -65.1% ) and 14.6% (95% CI 3.6% -46.0% ) (P=0.135), and the 1-year probabilities of overall survival were 75.0% (95% CI 46.3% -89.8% ) and 100% (P=0.062). The total area under the curve (AUC) of serum active ATG was 36.11 UE/ml·d and 35.89 UE/ml·d in the 4d-rATG and 2d-rATG groups, respectively (P=0.984). The AUC was higher in the 4d-rATG group than that in the 2d-rATG group (20.76 UE/ml·d vs 15.95 UE/ml·d, P=0.047). Three months after graft infusion, the average absolute count of CD8(+) T lymphocytes in the 4d-rATG group was lower than that in the 2d-rATG group (623 cells/μl vs 852 cells/μl, P=0.037) . Conclusion: The efficiencies of GVHD prophylaxis in MSD-PBSCT receiving 4d-ATG regimen and the 2d-rATG regimen were found to be similar. The reconstruction of CD8(+)T lymphocytes in the 2d-rATG group was better than that in the 4d-rATG group, which is related to the lower AUC of active ATG after transplantation.

Structure-based drug discovery of novel fused-pyrazolone carboxamide derivatives as potent and selective AXL inhibitors

As a novel and promising antitumor target, AXL plays an important role in tumor growth, metastasis, immunosuppression and drug resistance of various malignancies, which has attracted extensive research interest in recent years. In this study, by employing the structure-based drug design and bioisosterism strategies, we designed and synthesized in total 54 novel AXL inhibitors featuring a fused-pyrazolone carboxamide scaffold, of which up to 20 compounds exhibited excellent AXL kinase and BaF3/TEL-AXL cell viability inhibitions. Notably, compound 59 showed a desirable AXL kinase inhibitory activity (IC50: 3.5 nmol/L) as well as good kinase selectivity, and it effectively blocked the cellular AXL signaling. In turn, compound 59 could potently inhibit BaF3/TEL-AXL cell viability (IC50: 1.5 nmol/L) and significantly suppress GAS6/AXL-mediated cancer cell invasion, migration and wound healing at the nanomolar level. More importantly, compound 59 oral administration showed good pharmacokinetic profile and in vivo antitumor efficiency, in which we observed significant AXL phosphorylation suppression, and its antitumor efficacy at 20 mg/kg (qd) was comparable to that of BGB324 at 50 mg/kg (bid), the most advanced AXL inhibitor. Taken together, this work provided a valuable lead compound as a potential AXL inhibitor for the further antitumor drug development.

Analysis and evaluation of bioactive constituents from different parts of Epimedium brevicornum / 中国中药杂志

A comprehensive analytical method based on ultra-fast liquid chromatography coupled with triple quadrupole/linear ion trap tandem mass spectrometry(UFLC-QTRAP-MS/MS) was established for simultaneous determination of the content of 45 bioactive constituents including flavonoids, alkaloids, amino acids, phenolic acids, and nucleosides in Epimedium brevicornum. The multiple bioactive constituents in leaves, petioles, stems and rhizomes of E. brevicornum were analyzed. The gradient elution was performed at 30 ℃ in an XBridge~® C_(18) column(4.6 mm×100 mm, 3.5 μm) with 0.4% formic acid aqueous solution-acetonitrile as the mobile phase at a flow rate of 0.8 mL·min~(-1). Single factor experiment and response surface methodology were employed to optimize the extraction conditions. Multivariate statistical analyses including systematic cluster analysis(SCA), principal component analysis(PCA), partial least squares discriminant analysis(PLS-DA), and one-way analysis of variance(One-way ANOVA) were carried out to classify the samples from different parts and identify different constituents. Grey relation analysis(GRA) and entropy weight-TOPSIS analysis were performed to build a multi-index comprehensive evaluation model for different parts of E. brevicornum. The results showed that there was a good relationship between the mass concentrations of 45 constituents and the corresponding peak areas, with the correlation coefficients(r) not less than 0.999 0. The precision, repeatability, and stability of the established method were good for all the target constituents in this study, with the relative standard deviations(RSDs) less than 5.0%(0.62%-4.9%) and the average recovery of 94.51%-105.7%. The above results indicated that the bioactive constituents varied in different parts of E. brevicornum, and the overall quality followed the trend of leaves > petioles > rhizomes > stems. This study verified the rationality of the Chinese Pharmacopoeia(2020 edition) stipulating that the medicinal part of E. brevicornum is the leaf. Moreover, our study indicated that the rhizome had the potential for medicinal development. The established method was accurate and reliable, which can be used to comprehensive evaluate and control the quality of E. brevicornum. This study provides data reference for clarifying the medicinal parts and rationally utilizing the resources of E. brevicornum.

Risk assessment of dietary lead exposure in Shanghai residents over 15 years old / 上海预防医学

ObjectiveTo investigate the risk of dietary lead exposure in residents aged 15 years and above in Shanghai. MethodsBased on the dietary consumption survey of residents aged 15 years and above in spring 2012 and the monitoring data of food lead contamination in Shanghai from 2020 to 2021， the dietary exposure level was assessed using the point assessment method and compared with the provisional weekly tolerable intake （PTWI） to assess the exposure risk. ResultsThe overall detection rate of lead in 9 commonly consumed food categories by residents in Shanghai was 56.82%， with a total excess rate of 0.23%. The average weekly dietary lead exposure （by body weight） of residents was 2.979 4 μg·kg⁻¹. The top three dietary lead contributing factors were vegetables （30.69%）， cereals （28.88%）， and aquatic products （11.12%）. The average weekly dietary lead exposure （by body weight） of residents in urban， suburban， and rural areas were 3.282 5， 2.979 5 and 2.478 0 μg·kg⁻¹， respectively. The food with the highest contribution rate of dietary lead exposure in these regions was vegetables， with contribution rates of 33.65%， 29.69%， and 25.22%， respectively. The average weekly dietary lead exposure （by body weight） of male and female residents was 3.077 7 and 2.881 5 μg·kg⁻¹， respectively， with vegetables being the main source of dietary lead， contributing 30.03% and 31.39%， respectively. The average weekly dietary lead exposure （by body weight） of residents aged 15‒， 45‒， and ≥60 years old was 3.084 2，3.009 9 and 2.874 4 μg·kg⁻¹， respectively. The food with the highest contribution rate of dietary lead exposure in these groups was vegetables， contributing 27.12%， 32.10%， and 32.26%， respectively. ConclusionThe dietary lead exposure of Shanghai residents aged 15 years and above is at an acceptable level， and the vegetables， cereals， and aquatic products with high contribution rates need to be supervised more closely.