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

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.

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.

Clinicopathological features and prognostic factors of patients with lung metastasis of stage Ⅰa~Ⅲb cervical cancer / 中华肿瘤杂志

Objective: To investigate the clinicopathological features and prognostic factors of lung metastasis in patients with cervical cancer after treatment. Methods: The clinicopathological data of 191 patients with lung metastasis of stage Ⅰa-Ⅲb cervical cancer (FIGO 2009 stage) treated in Sichuan Cancer Hospital from January 2007 to December 2020 were analyzed retrospectively. Kaplan Meier method and Log rank test were used for survival analysis, and Cox regression model was used for prognostic factors analysis. Results: Among 191 patients with lung metastasis of cervical cancer, pulmonary metastasis was found in 134 patients (70.2%) during follow-up examination, and 57 patients (29.8%) had clinical symptoms (cough, chest pain, shortness of breath, hemoptysis, and fever). The time from the initial treatment of cervical cancer to the discovery of lung metastasis was 1-144 months in the whole group, with a median time of 19 months. Univariate analysis of the prognosis of lung metastasis after treatment of cervical cancer showed that the diameter of cervical tumor, lymph node metastasis, positive surgical margin, disease-free interval after treatment of cervical cancer, whether it is accompanied by other metastasis, the number, location and maximum diameter of lung metastasis, and the treatment method after lung metastasis are related to the prognosis of patients with lung metastasis of cervical cancer. Multivariate analysis showed that the number of lung metastases and other site metastases in addition to lung metastases were independent factors affecting the prognosis of patients with lung metastases of cervical cancer (P<0.05). Conclusions: For patients with cervical cancer, attention should be paid to chest CT examination during follow-up to guard against the possibility of lung metastasis after treatment. Besides lung metastasis, other site metastasis and the number of lung metastasis are independent factors affecting the prognosis of patients with lung metastasis of cervical cancer. For patients with lung metastasis after treatment of cervical cancer, surgical treatment is an effective treatment. It is necessary to strictly grasp the surgical indications, and some patients can achieve long-term survival. For patients with lung metastasis of cervical cancer who are not suitable for resection of lung metastasis, the remedial treatment of chemotherapy with or without radiotherapy is still a recommended choice.

Current status of diagnosis and treatment of chronic lymphocytic leukemia in China: A national multicenter survey research / 中华血液学杂志

Objective: To understand the current status of diagnosis and treatment of chronic lymphocytic leukemia (CLL) /small lymphocytic lymphoma (SLL) among hematologists, oncologists, and lymphoma physicians from hospitals of different levels in China. Methods: This multicenter questionnaire survey was conducted from March 2021 to July 2021 and included 1,000 eligible physicians. A combination of face-to-face interviews and online questionnaire surveys was used. A standardized questionnaire regarding the composition of patients treated for CLL/SLL, disease diagnosis and prognosis evaluation, concomitant diseases, organ function evaluation, treatment selection, and Bruton tyrosine kinase (BTK) inhibitor was used. Results: ①The interviewed physicians stated that the proportion of male patients treated for CLL/SLL is higher than that of females, and the age is mainly concentrated in 61-70 years old. ②Most of the interviewed physicians conducted tests, such as bone marrow biopsies and immunohistochemistry, for patient diagnosis, in addition to the blood test. ③Only 13.7% of the interviewed physicians fully grasped the initial treatment indications recommended by the existing guidelines. ④In terms of cognition of high-risk prognostic factors, physicians' knowledge of unmutated immunoglobulin heavy-chain variable and 11q- is far inferior to that of TP53 mutation and complex karyotype, which are two high-risk prognostic factors, and only 17.1% of the interviewed physicians fully mastered CLL International Prognostic Index scoring system. ⑤Among the first-line treatment strategy, BTK inhibitors are used for different types of patients, and physicians have formed a certain understanding that BTK inhibitors should be preferentially used in patients with high-risk factors and elderly patients, but the actual use of BTK inhibitors in different types of patients is not high (31.6%-46.0%). ⑥BTK inhibitors at a reduced dose in actual clinical treatment were used by 69.0% of the physicians, and 66.8% of the physicians had interrupted the BTK inhibitor for >12 days in actual clinical treatment. The use of BTK inhibitors is reduced or interrupted mainly because of adverse reactions, such as atrial fibrillation, severe bone marrow suppression, hemorrhage, and pulmonary infection, as well as patients' payment capacity and effective disease progression control. ⑦Some differences were found in the perceptions and behaviors of hematologists and oncologists regarding the prognostic assessment of CLL/SLL, the choice of treatment options, the clinical use of BTK inhibitors, etc. Conclusion: At present, a gap remains between the diagnosis and treatment of CLL/SLL among Chinese physicians compared with the recommendations in the guidelines regarding the diagnostic criteria, treatment indications, prognosis assessment, accompanying disease assessment, treatment strategy selection, and rational BTK inhibitor use, especially the proportion of dose reduction or BTK inhibitor discontinuation due to high adverse events.

Comparison of cytokine levels in prostatic secretion between the IIIa and IIIb subtypes of prostatitis / 亚洲男科学杂志(英文版)

Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS), also known as National Institutes of Health (NIH) type III prostatitis, is a common disorder with an unclear etiology and no known curative treatments. Based on the presence or absence of leukocytes in expressed prostatic secretion (EPS), CP/CPPS is classified further into IIIa (inflammatory) and IIIb (noninflammatory) subtypes. However, the severity of symptoms is not entirely consistent with the white blood cell (WBC) count. Following the preliminary finding of a link between inflammatory cytokines and CP/CPPS, we performed this clinical study with the aim of identifying cytokines that are differentially expressed according to whether the prostatitis subtype is IIIa or IIIb. We found that granulocyte colony-stimulating factor (G-CSF), interleukin-18 (IL-18), and monocyte chemoattractant protein-1 (MCP-1) levels were significantly elevated and interferon-inducible protein-10 (IP-10) and platelet-derived growth factor-BB (PDGF-BB) levels were downregulated in the EPS of patients with type IIIa prostatitis. In a word, it is a meaningful study in which we investigate the levels of various cytokines in EPS according to whether prostatitis is the IIIa or IIIb subtype. The combination of G-CSF, IL-18, MCP-1, IP-10, and PDGF-BB expression levels could form a basis for classification, diagnosis, and therapeutic targets in clinical CP/CPPS.

Quality evaluation of Lysimachiae Herba from different habitats based on simultaneous determination of multiple bioactive constituents combined with multivariate statistical analysis / 中国中药杂志

A method based on ultra-high performance liquid chromatography coupled with triple quadrupole linear ion trap-tandem mass spectrometry(UHPLC-QTRAP-MS/MS) was developed for the simultaneous determination of 41 bioactive constituents of flavonoids, organic acids, nucleosides, and amino acids in Lysimachiae Herba. The content of multiple bioactive constituents was compared among the samples from different habitats. The chromatographic separation was performed in a Waters XBridge®C_(18) column(4.6 mm×100 mm, 3.5 μm) at 30 ℃. The gradient elution was performed with 0.4% methanol(A)-formic acid water(B) as the mobile phase at a flow rate of 0.8 mL·min~(-1), and the multiple-reaction monitoring(MRM) mode was adopted. According to the content of 41 constituents, hierarchical cluster analysis(HCA), orthogonal partial least squares discriminant analysis(OPLS-DA), and gray relational analysis(GRA) were perfomed to comprehensively evaluate the samples from different habitats. The results showed that the 41 constituents exhibited good linear relationship within the tested concentration ranges, with the correlation coefficients(r) greater than 0.999 4. The method featured good precision, repeatability, and stability with the relative standard deviations(RSDs) less than 5.0%. The average recoveries of the 41 constituents ranged from 98.06% to 101.9%, with the RSDs of 0.62%-4.6%. HCA and OPLS-DA separated 48 batches of Lysimachiae Herba samples from different habitats into three categories: the producing areas in Sichuan and Chongqing, the producing areas in Jiangsu, Zhejiang, and Jiangxi, and the producing areas in Guizhou. The content of 41 constituents varied among the Lysimachiae Herba samples from different habitats. The GRA results revealed that the Lysimachiae Herba sample from Nanchong City, Sichuan Province had the best comprehensive quality. The method developed in this study was accurate and reliable and thus can be used for comprehensive evaluation of Lysimachiae Herba quality and provide basic information for the selection of habitats.

Risk assessment of dietary exposure to 3-monochloropropane-1,2-diol esters in infant formula powders in Shanghai / 环境与职业医学

Background Chloropropanol esters (MCPDE) have attracted much attention in recent years as a kind of new contaminant found in various refined oils. The pollution of 3-monochloropropane-1,2-diol esters (3-MCPDE) is the most prominent. 3-MCPDE is hydrolyzed in organisms to 3-monochloropropane-1,2-diol which has been shown to have reproductive toxicity, nephrotoxicity, and potential carcinogenicity. Infant formula powders can be polluted by 3-MCPDE when refined edible oils are added during production. Objective To assess the risk of exposure to 3-MCPDE related to the consumption of infant formula powders for children aged 0-3 years in Shanghai market using the food consumption data and the data of 3-MCPDE contamination in these foods. Methods Gas chromatography-mass spectrometry was used to determine 3-MCPDE in 133 samples of infant formula powders in Shanghai. Using a multistage stratified random sampling method, a total of 807 infants and toddlers aged 0-3 years were randomly selected from each district/rural/town in Shanghai, including 208 children aged 0-6 months, 276 children aged 6-12 months, and 323 children aged 12-36 months. The food consumption data was investigated using food frequency questionnaire (FFQ) distributed by combining telephone inquiries and face-to-face interviews among guardians. Population's probability distributions of 3-MCPDE exposure were assessed by @Risk 7.5 software and Monte Carlo simulation algorithm. According to the dietary intake assessment model and the tolerable daily intake (TDI) of 3-MCPDE of 2.00 μg·(kg·d)−1 proposed by the European Food Safety Authority (ESFA), a risk assessment of exposure to 3-MCPDE was conducted for infants and toddlers aged 0 to 3 years old in Shanghai who consumed 3-MCPDE via infant formula powders. Results The average concentration of 3-MCPDE in 133 samples of infant formula powders was 0.115 mg·kg−1 with a positive rate of 100.00%. Among different types of formula powders, infant formula powders for infants of 0-6 months had the highest concentrations of 3-MCPDE and fat [0.136 mg·kg−1 and 25.2 g (per 100 g sample) in average respectively]. There was a positive correlation between fat concentration and 3-MCPDE concentration in the samples (r=0.438, P<0.05). The average consumption of infant formula powders of 807 infants aged 0-3 years was 88.3 g·d−1. Among all investigated age groups, the average consumption of infant formula powders by infants aged 0-6, 6-12, and 12-36 months was 87.7, 98.3, and 80.1 g·d−1 respectively. The dietary exposure to 3-MCPDE from infant formula powders of infants aged 0-3 years averaged 0.83 μg·(kg·d)−1 for general intake level or valued 1.44 μg·(kg·d)−1 using the 95 percentile for high intake level. Exposure decreased with increasing age and was highest in infants 0-6 months of age, whose general and high intake levels were 1.41 and 2.34 μg·(kg·d)−1, respectively. The risk population defined with the exposure higher than the TDI proposed by EFSA were proportioned to be 13.90% and 0.50% in infants aged 0-6 months and 6-12 months respectively, indicating a risk that cannot be ignored, and no risk in infants aged 12-36 months. Conclusion Among the investigated infants aged 0-3 years in Shanghai, those aged 0-6 months are at a high risk of exposure to 3-MCPDE. In view of the sensitivity of infants to pollutant exposure, the risk of exposure to 3-MCPDE should be highly concerned.

Research progress of biomimetic nano drug delivery system in nervous system disease / 药学学报

Brain delivery of drugs remains challenging due to the presence of the blood-brain barrier (BBB). With advances in nanotechnology and biotechnology, new possibilities for brain-targeted drug delivery have emerged. Biomimetic nano drug delivery systems with high brain-targeting and BBB-penetrating capabilities, along with good biocompatibility and safety, can enable 'invisible' drug delivery. In this review, five different types of biomimetic strategies are presented and their research progress in central nervous system disorders is reviewed. Finally, the challenges and future prospects for biomimetic nano drug delivery systems in intracerebral drug delivery are summarized.

Anti-aging and mechanism of 2-O-cinnamic acid magnolol / 药学学报

Magnolol, a hydroquinone containing an allyl side chain, is one of the major active components of magnolia for antioxidation and anti-aging. To enhance the anti-aging activity and improve the intramolecular hydrogen bonding of magnolol, magnolol was reacted with cinnamic acid to obtain 2-O-cinnamic acid magnolol by esterification. The anti-aging activity of magnolol 2-O-cinnamate was investigated based on Caenorhabditis elegans model. The results showed that 2-O-cinnamic acid magnolol can reduce lipofuscin accumulation in the nematode body, and the effect is better than that of magnolol. 2-O-Cinnamic acid magnolol can extend nematode lifespan, reduce ROS levels in nematodes during normal aging and oxidative stress and improve nematode stress resistance under heat stress and oxidative stress. 2-O-Cinnamic acid magnolol could induce DAF-16 translocation from the cytoplasm to the nucleus and upregulate the expression of the sod-3 gene encoding superoxide dismutase in the nematode TJ356 expressing DAF-16 fused with GFP. 2-O-Cinnamic acid magnolol did not improve the survival rate of hsp-16.2 gene deficient nematodes under oxidative stress, indicating that 2-O-cinnamic acid magnolol improves stress resistance of nematodes under oxidative stress may be associated with sod-3 and hsp-16.2. Moreover, 2-O-cinnamic acid magnolol did not extend the lifespan of daf-16 and age-1 mutants, indicating that age-1 and daf-16 are required for 2-O-cinnamic acid magnolol to delay aging. It showed that magnolol 2-O-cinnamic acid has the potential to improve antioxidant capacity and delay aging, and the mechanism may be related to the insulin/insulin-like growth factor signaling pathway.

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.

Effect of processing method on chemical constituents of Rehmanniae Radix: based on UHPLC-LTQ-Orbitrap MS / 中国中药杂志

This study aims to explore the chemical composition of Rehmanniae Radix braised with mild fire and compare the effect of processing method on the chemical composition of Rehmanniae Radix. To be specific, ultra-high performance liquid chromatography with linear ion trap-orbitrap mass spectrometry(UHPLC-LTQ-Orbitrap MS) was used to screen the chemical constituents of Rehmanniae Radix. The chemical constituents were identified based on the relative molecular weight and fragment ions, literature information, and Human Metabolome Database(HMDB). The ion peak area ratio of each component before and after processing was used as the index for the variation. SIMCA was employed to establish principal component analysis(PCA) and orthogonal partial least squares discriminant analysis(OPLS-DA) models of different processed products. According to the PCA plot, OPLS-DA plot, and VIP value, the differential components before and after the processing were screened out. The changes of the content of differential components with the processing method were analyzed. A total of 66 chemical components were identified: 57 of raw Rehmanniae Radix, 55 of steamed Rehmanniae Radix, 55 of wine-stewed Rehmanniae Radix, 51 of repeatedly steamed and sundried Rehmanniae Radix Praeparata, 62 of traditional bran-braised Rehmanniae Radix, and 63 of electric pot-braised Rehmanniae Radix. Among them, the 9 flavonoids of braised Rehmanniae Radix were from Citri Reticulatae Pericarpium. PCA suggested significant differences in the chemical composition of Rehmanniae Radix Praeparata prepared with different processing methods. OPLS-DA screened out 32 chemical components with VIP value >1 as the main differential components. Among the differential components, 9 were unique to braised Rehmanniae Radix(traditional bran-braised, electric pot-braised) and the degradation rate of the rest in braised(traditional bran-braised, electric pot-braised) or repeatedly steamed and sundried Rehmanniae Radix was higher than that in the steamed or wine-stewed products. The results indicated the chemical species and component content of Rehmanniae Radix changed significantly after the processing. The 32 components, such as rehmapicrogenin, martynoside, jionoside D, aeginetic acid, hesperidin, and naringin, were the most important compounds to distinguish different processed products of Rehmanniae Radix. The flavonoids introduced by Citri Reticulatae Pericarpium as excipient may be the important material basis for the effectiveness of braised Rehmanniae Radix compared with other processed products.

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.