DNA methylation-mediated repression of microRNA-410 promotes the growth of human glioma cells and triggers cell apoptosis through its interaction with STAT3.

This study's purpose was to confirm the observed underexpression of miRNA-410 in glioma tissues and several glioma cells by Quantitative RT-PCR. Our findings suggest that epigenetic alterations occurring at the promoter region of miR-410 may be responsible for the reduced expression of miR-410 in glioma. The occurrence of DNA methylation in the miR-410 promoter was verified to be more prevalent through glioma tissues contrasted to adjacent non-tumor brain tissues through the utilization of methylation-specific PCR and CpG bisulfite sequencing sites in the miR-410 promoter region. Accordantly, miR-410 expression in glioma cell lines was observed to be significantly lesser in comparison to that of the human fetal glial cell line. In addition, it was demonstrated through gain- and loss-of-function investigations that miR-410 exerts significant regulation over cell growth, cell cycle development, and glioma cell apoptosis. The findings of the Luciferase reporter assay and western blot analysis indicate that miR-410 has a direct effect on the 3'-UTR of signal transducer and activator of transcription 3 (STAT3), thereby inhibiting its expression within glioma cells. Besides, our clinical investigation indicates a negative association between miR-410 expression and STAT3 within the glioma tissues of humans. In aggregate, the data provided in this investigation indicates that miR-410 is subjected to underexpression via DNA methylation. Furthermore, it has been observed to perform its function as a tumor suppressor in glioma cells through direct targeting of STAT3. The previously mentioned results could potentially have significant implications for the advancement of a new therapeutic approach for treating glioma.

Effect of Modified Cangfu Daotantang on Glucose and Lipid Metabolism in Simple Obese Children with Phlegm Dampness and Stagnation / 中国实验方剂学杂志

ObjectiveTo observe and compare the intervention effect of modified Cangfu Daotantang on glucose and lipid metabolism in simple obese children with phlegm dampness and stagnation. MethodA total of 60 children with simple obesity were randomly divided into two groups according to the simple randomization method of the random number table. The odd number was included in the test group， and the even number was included in the basic treatment group， with 30 cases in each group. On the basis of signing the informed consent notice， the treatment group was given modified Cangfu Daotantang combined with basic treatment， while the control group was only given basic treatment. After three months of treatment， the body mass index （BMI）， glucose and lipid metabolism level ［total cholesterol （TC）， triglyceride （TG）， low-density lipoprotein cholesterol （LDL-C）， fasting plasma glucose （FPG）， fasting insulin （FINS）， and homeostasis model assessment-insulin resistance （HOMA-IR）］， the change in the total score of traditional Chinese medicine （TCM） syndromes， and the effective rate of treatment were observed and compared. ResultAfter treatment， the BMI of the observation group and the control group decreased significantly （P<0.01）. Compared with the control group， the BMI level in the observation group decreased significantly （P<0.05）. After treatment， the levels of TC， TG， and LDL-C in the observation group and the control group decreased significantly （P<0.01）. Compared with the control group， the levels of TC， TG， and LDL-C in the observation group decreased significantly （P<0.05）. In addition， the level of TC in the observation group improved significantly compared with that in the control group （P<0.01）. The levels of FPG， FINS， and HOMA-IR in the observation group and the control group were significantly lower than those before treatment （P<0.05）. After treatment， compared with the control group， the levels of FPG， FINS， and HOMA-IR in the observation group were significantly reduced （P<0.05）. The level of FPG in the observation group was significantly improved compared with that in the control group （P<0.01）. After treatment， the total score of TCM syndromes in the two groups decreased significantly （P<0.01）. Compared with the control group， the total score of TCM syndromes in the observation group was lower （P<0.01）. After treatment， the total effective rate of treatment was 86.67% （26/30） in the observation group and 73.33% （22/30） in the control group. By rank sum test， the total effective rate of the observation group was better than that of the control group （Z=-2.100， P<0.05）. ConclusionModified Cangfu Daotantang combined with basic treatment can effectively reduce the BMI of obese children and improve their glucose and lipid metabolism. It has good clinical effects and high clinical application value， which is worth further in-depth research and promotion.

Traditional Chinese Medicine constitution among patients with allergic rhinitis and its correlation with anxiety and depression.

OBJECTIVE: To preliminary investigate the distribution of Traditional Chinese Medicine (TCM) constitution among patients with allergic rhinitis (AR) and reveal the related factors with anxiety and depression. METHODS: Between July 2020 and June 2021, specialist doctor recruited AR patients in Beijing and Shanghai. A total of 630 patients admitted to participate in the survey, and 516 (81.9%) (male 54.3%, female 45.7%) participants completed the questionnaires. Three scales including Constitution in Chinese Medicine Questionnaire (CCMQ), Generalized Anxiety Disorder Questionnaire (GAD-7) and The Patient Health Queationaire-9 (PHQ-9) were applied. The χ2 and the Fisher's exact test were used to evaluate the classification data, multivariate logistic regression was used to explore the related factors of anxiety and depression. RESULTS: According to 516 AR patients, the most commonly first-constitution was Yang-deficiency (22.1%) and frequent of all constitutions was inherited-special (21.6%). One third of AR patients (33.5%) suffered from anxiety, nearly half of AR patients (46.5%) were found to be depressive. Inherited-special (27.7%) was the most common constitution in patients with anxiety whereas Yang-deficiency (26.7%) was most common constitution in patients with depression. Sex, duration of symptoms, balanced, Qi-deficiency, phlegm-dampness, Qi-stagnation, and inherited-special constitutions were related with anxiety; Sex, income, duration of symptoms, balanced, Qi-deficiency, Yang-deficiency, phlegm-dampness, Qi-stagnation, and inherited-special constitutions were related with depression. CONCLUSIONS: According to our study, the commonly constitution types of AR were Yang-deficiency and inherited-special. We found that the prevalence value of anxiety and depression were high. People with Qi-deficiency, phlegm-dampness, Qi-stagnation, and inherited-special constitutions were more likely to have mental problems than the others. Controlling these influential factors might be beneficial for clinical health management of AR patients, and the government should apply appropriate mental health treatment services to offer psychiatric support.

The effect of robot-assisted gait training for patients with spinal cord injury: a systematic review and meta-analysis.

Background: With the aging of the global population, Spinal injuries are often prone to occur and affect human health. The development of technology has put robots on the stage to assist in the treatment of spinal injuries. Methods: A comprehensive literature search were carried out in multiple databases, including PubMed, Medline (Ovid), Web of Science, Cochrane, Embase, Scopus, CKNI, Wang fang, VIP database, Sino Med, Clinical Trails until 20th, June, 2023 to collect effect of robot-assisted gait training for patients with spinal cord injury patients. Primary outcome includes any changes of gait distance and gait speed. Secondary outcomes include any changes in functions (Such as TUG, Leg strength, 10 MWT) and any advent events. Data were extracted from two independent individuals and Cochrane Risk of Bias tool version 2.0 was assessed for the included studies. Systematic review and meta-analysis were performed by RevMan 5.3 software. Results: 11 studies were included in meta-analysis. The result showed that gait distance [WMD = 16.05, 95% CI (-15.73, 47.83), I2 = 69%], gait speed (RAGT vs. regular treatment) [WMD = 0.01, 95% CI (-0.04, 0.05), I2 = 43%], gait speed (RAGT vs. no intervention) [WMD = 0.07, 95% CI (0.01, 0.12), I2 = 0%], leg strength [WMD = 0.59, 95% CI (-1.22, 2.40), I2 = 29%], TUG [WMD = 9.25, 95% CI (2.76, 15.73), I2 = 74%], 10 MWT [WMD = 0.01, 95% CI (-0.15, 0.16), I2 = 0%], and 6 MWT [WMD = 1.79, 95% CI (-21.32, 24.90), I2 = 0%]. Conclusion: Robot-assisted gait training seems to be helpful for patients with spinal cord to improve TUG. It may not affect gait distance, gait speed, leg strength, 10 MWT, and 6 MWT.

Membrane anatomy in right colon cancer: definition and identification of mesocolic completeness / 中华胃肠外科杂志

Complete mesocolic excision (CME) and D3 resection of right colon cancer have been widely implemented, but the definition and identification of the completeness of the mesentery have not been fully agreed, especially the dorsal and medial borders. In this paper, we proposed the dorsal fascia of the colonic mesentery as the dorsal border of the mesocolon and the line connecting the roots of the ileocolic artery and the middle colic artery (ICA-MCA line) as the medial border of the CME by systematically studying the relationship between the mesentery and the mesenteric bed from the theory of membrane anatomy, combined with surgical experience and in-depth review of ontogenetic anatomy. We also proposed the visible "superior mesenteric vein notch" and "middle colic artery triangle" on surgical specimens as identifiers of mesocolic completeness.

Discovery of novel phosphodiesterase-1 inhibitors for curing vascular dementia: Suppression of neuroinflammation by blocking NF-κB transcription regulation and activating cAMP/CREB axis

Vascular dementia (VaD) is the second commonest type of dementia which lacks of efficient treatments currently. Neuroinflammation as a prominent pathological feature of VaD, is highly involved in the development of VaD. In order to verify the therapeutic potential of PDE1 inhibitors against VaD, the anti-neuroinflammation, memory and cognitive improvement were evaluated in vitro and in vivo by a potent and selective PDE1 inhibitor 4a. Also, the mechanism of 4a in ameliorating neuroinflammation and VaD was systematically explored. Furthermore, to optimize the drug-like properties of 4a, especially for metabolic stability, 15 derivatives were designed and synthesized. As a result, candidate 5f, with a potent IC50 value of 4.5 nmol/L against PDE1C, high selectivity over PDEs, and remarkable metabolic stability, efficiently ameliorated neuron degeneration, cognition and memory impairment in VaD mice model by suppressing NF-κB transcription regulation and activating cAMP/CREB axis. These results further identified PDE1 inhibition could serve as a new therapeutic strategy for treatment of VaD.

cardiovascular safety of COVID-19 vaccines in real-world studies: a systematic review and meta-analysis

AimsTo assess the association between COVID-19 vaccines and the risk of major adverse cardiovascular events (MACE) in the real world and to provide a reliable evidence-based basis for the cardiovascular safety of COVID-19 vaccines. MethodsWe conducted a comprehensive search in databases from January 1, 2020 to June 15, 2022 for observational studies, that included reporting of MACE and COVID-19 vaccines were included. Random-effects or fixed-effects models were used to estimate the pooled incidence rate and risk ratio of MACE after vaccination. Meta-regression, subgroup analyses, publication bias, sensitivity analyses were performed to evaluate the process and quality of meta-analysis. ResultsThe analyses included data from 43 studies reporting of 16,978 cases, 28,451 cases, and 96,269 cases of myocarditis, myocardial infarction, and cardiac arrhythmia, respectively. The overall incidence rate was 14.8 events per million persons of myocarditis, and 1.73 and 9.6 events per 10,000 persons of myocardial infarction and cardiac arrhythmia after COVID-19 vaccination, respectively. Overall and subgroup analyses showed the increased risks of myocarditis associated with second dose (RR, 2.09; 95%CI: 1.59-2.58), third dose (RR, 2.02; 95%CI: 1.40-2.91), mRNA-1273 (RR, 3.13; 95%CI: 2.11-4.14), or BNT162b2 (RR, 1.57; 95%CI: 1.30-1.85) vaccination. The risk ratios of myocarditis events were more frequently in males than in females (3.44, 2.61-4.54), in younger than in older (2.20, 1.06-4.55). No significant increase risk of myocardial infarction (RR, 0.96; 95%CI: 0.84-1.08) or cardiac arrhythmia (RR, 0.98; 95%CI: 0.84-1.12) events was observed following vaccination. The risk of cardiovascular events (myocarditis, RR, 8.53; myocardial infarction, RR, 2.59; cardiac arrhythmia, RR, 4.47) after SARS-CoV-2 infection was much higher than after vaccination. ConclusionAlthough there is a risk of cardiovascular events following vaccination, the risk was much lower than that following SARS-CoV-2 infection. The benefits of COVID-19 vaccination to the population outweigh the risks in terms of cardiovascular safety assessment.

Metabolomic mechanism and pharmacodynamic material basis of Buxue Yimu pills in the treatment of anaemia in women of reproductive age.

Objective: To explore the pharmacological basis and mechanism of Buxue Yimu pills (BYP) in the treatment of anaemia in women from the perspective of metabolomics and network analysis. Materials and Methods: Forty-six women of reproductive age with haemoglobin 70-110 g/L were recruited. Blood samples were collected before and after 4 weeks of oral BYP treatment to assess the changes in haemoglobin, coagulation function, and iron metabolism indices. An integrated analysis of metabolomics (liquid chromatography mass spectrometry) and network analysis was performed to identify the potential pharmacodynamic mechanisms of BYP. Results: After BYP treatment, the haemoglobin level of patients significantly increased from 93.67 ± 9.77 g/L to 109.28 ± 12.62 g/L (p < 0.01), while no significant changes were found in iron metabolism and coagulation-related indicators. A total of 22 differential metabolites were identified after metabolomics analysis, which were mainly related to the inhibition of inflammation and oxidative stress. Integrating pharmacodynamics and metabolomics, a network of drug-active components-targets-metabolic pathways-metabolomics was established. Acetylcholinesterase, phospholipase A2 group IIA, and phospholipase A2 group IVA may be the most promising therapeutic targets. Conclusion: BYP can inhibit inflammation and oxidative stress as well as promote haematopoiesis, potentially improving anaemia.

Erianin inhibits oral cancer cell growth, migration, and invasion via the Nrf2/HO-1/ GPX4 pathway

Objective: To evaluate the effect of erianin on the viability, migration, and invasion of KB cells and elucidate its underlying mechanisms. Methods: Cell Counting Kit-8, colony formation, wound healing, and Transwell assays were used to determine the proliferation, migration, and invasion of oral cancer KB cells. Furthermore, malondialdehyde (MDA) and glutathione (GSH) levels were determined. Fluorescent probes were used to detect changes in intracellular reactive oxygen species and iron ions. Additionally, the expressions of ferroptosis-related proteins, NF-E2-related factor 2 (Nrf2), ferritin heavy chain 1 (FTH1), heme oxygenase 1 (HO-1), and glutathione peroxidase 4 (GPX4) were analyzed by Western blotting assays. Results: Erianin induced ferroptosis and inhibited the proliferation, migration, and invasion of KB cells. Moreover, erianin decreased GSH level, increased MDA level, elevated intracellular ROS and Fe

Jinfukang Inhibits Lung Cancer Metastasis by Regulating Immune Senescence / 肿瘤防治研究

Objective To explore the effect of immune senescence on lung cancer metastasis and reveal the mechanism of Fuzheng traditional Chinese medicine Jinfukang in the prevention and treatment of the metastasis. Methods A lung metastasis model of Lewis lung cancer cells was established in C57BL/6 mice with different ages (15 months, 6 months, and 2 months). Mice in the 6-month-old group were given Jinfukang intragastrically for 42 days. Pulmonary metastasis was analyzed by in vivo imaging, anatomical microscopic observation, and HE staining. The proportion of memory T cells and NK cells in peripheral blood was detected by flow cytometry. Results The lung metastatic tumor formation rate of 15-month-old and 6-month-old mice was significantly higher than that of 2-month-old mice (all P < 0.05). Abundance of CD4+T cells in peripheral blood was positively correlated with age (2-month-old vs. 6-month-old, P=0.041; 2-month-old vs.15-month-old, P=0.041; 6-month-old vs.15-month-old, P=0.953). The abundance of NK cells was negatively correlated with age (2-month-old vs. 6-month-old, P=0.009; 2-month-old vs.15-month-old, P=0.009; 6-month-old vs. 15-month-old, P=0.574). However, the survival time of mice in the Jinfukang group was longer (P > 0.05) and the level of NK cells in peripheral blood was significantly higher (P=0.029) than those in the normal saline group. Conclusion Immune senescence can promote the metastasis of lung cancer. The prolongation of the survival time of mice administered with Jinfukang may be related to delaying immune senescence and increasing the number of NK cells.

Distribution characteristics and ecological risk assessment of heavy metals in farmland around Changqing Oilfield / 环境与职业医学

Background With the change of the national energy development layout, Qingyang has seen a situation where oil exploitation and agriculture go hand in hand, which may lead to local soil pollution if not taken seriously. Objective To evaluate the distribution characteristics, possible sources, and ecological risks of heavy metals in farmland soils around the main production areas of Changqing Oilfield. Methods A total of 60 farmland soil samples were collected from Zhengning County, Zhenyuan County, and Qingcheng County of Qingyang City, and the contents of heavy metals such lead (Pb), mercury (Hg), chromium (Cr), cadmium (Cd), and arsenic (As) in farmland soil were detected according to GB 15618-2018 Soil environmental quality—Risk control standard for soil contamination of agricultural land (on trial). The soil background value of Gansu Province was used as the denominator in the calculation of pollution index, and the pollution characteristics and ecological characteristics of selected five heavy metals in farmland soil were evaluated by single-factor pollution index (Pi), Nemerow comprehensive pollution index (PN), and potential ecological risk index. Results The levels of Pb, As, and Hg in farmland soils around Changqing Oilfield, the levels of Cr and Cd in Qingcheng County, and the level of Cd in Zhengning County were higher than the corresponding soil background values of Gansu Province, but lower than the national soil environmental quality standard. The single-factor pollution indexes (Pi) were: Hg, 2.14; Pb, 1.24; As, 1.13; Cr, 0.78; Cd, 0.67, which indicated that Hg were graded as moderate pollution, Pb and As were slight pollution, and Cd and Cr were not polluted. The Nemerow comprehensive pollution indexes (PN) were: Cr, 0.92; Cd, 1.08; As, 1.20; Pb, 1.68; Hg, 3.85, which indicated that Cr was graded as no pollution, Cd, Pb and As were mild pollution, and Hg was severe pollution. The variation coefficients of Hg and Cd in Zhenyuan County and that of Hg in Qingcheng County were 60.00%, 50.00%, and 50.00%, respectively, which were all greater than 50%, indicating that the pollution of above heavy metals in the location was subject to human activities. The potential ecological risk indexes (Er) of Pb, Cr, Cd, As, and Hg were 6.20, 1.55, 20.05, 11.28, and 81.64, respectively, indicating that Hg was graded as strong ecological risk, and the other four heavy metals were mild ecological risk. The comprehensive potential ecological risk index (RRI) was 124.48. Combined with the potential ecological risk index of Hg, the comprehensive potential ecological risk of the five heavy metals in local farmland soils was considered to be at a strong ecological risk level. Conclusion Although the average values of selected five heavy metals in farmland soils surrounding the main production areas of Changqing Oilfield are qualified with the national soil environmental quality standards, they exceed corresponding soil background values of Gansu Province, and there are signs of human influence and potential ecological risks of different degrees.

Influencing factors of pulmonary ventilation function and its relationship with indoor air pollution in rural areas of Gansu Province / 环境与职业医学

Background Indoor air pollution is an important risk factor affecting health of the respiratory system. Studies on indoor air pollution in China are mostly limited to the central and eastern regions, and there are few studies in the rural areas of northwest China. Objective To explore the influencing factors of lung ventilation function and its relationship with indoor air pollution in rural areas of Gansu Province based on a cross-sectional investigation. Methods A total of 399 subjects were selected from four villages in Baiyin and Yuzhong of Gansu Province. Questionnaires were used to collect demographic information, lifestyle, disease history, fuel use, and other information, and physical and functional tests were ordered such as height, weight, and lung function. The Indoor Air Pollution (IAP) exposure index was calculated based on smoking, fuel type, and weekly ventilation. IAP > 5 was defined as a high level of indoor air pollution. Lung function indexes included forced vital capacity (FVC), forced expiratory volume in the first second (FEV1), FEV1/FVC, forced vital capacity as a percentage of predicted value (FVC%), and forced expiratory volume in the first second as a percentage of predicted value (FEV1%), which were used to determine pulmonary ventilation dysfunction. Logistic regression model was used to evaluate the relationship between indoor air pollution and pulmonary ventilation function, and subgroup analysis was further conducted according to home address and BMI , in order to identify the high-risk population of pulmonary ventilation dysfunction. Results The mean age of the subjects was (56.75±7.31) years old; 155 subjects (38.85%) had normal pulmonary ventilation function, and the other 244 subjects (61.14%) had impaired pulmonary ventilation function; about 89.97% of the subjects were exposed to high level of indoor air pollution (IAP > 5). We found that IAP > 5 (OR=2.327, 95%CI: 1.089-4.974) and use of bituminous coal as the main heating fuel in winter (OR=3.467, 95%CI: 1.197-10.037) increased the risk of pulmonary ventilation dysfunction after adjusting for age, BMI, residence, gender, smoking, drinking, and cardiovascular disease. The subgroup analysis results showed that no ventilation in the living room/bedroom (OR=3.460, 95%CI: 1.116-10.268) increased the risk of pulmonary ventilation dysfunction in Baiyin. Heating with coal stoves and Chinese Kang in the bedroom (OR=2.092, 95%CI: 1.030-4.247) and cooking in the bedroom in winter ( OR =2.954, 95% CI : 1.046-8.344) also increased the risk of pulmonary ventilation dysfunction in the residents with BMI≤24 kg·m−2. IAP > 5 (OR=3.739, 95%CI: 1.147-12.182) was associated with a significantly increased risk of pulmonary ventilation dysfunction in the BMI > 24 kg·m−2 subgroup. Conclusion The pulmonary ventilation function of rural residents in Gansu is poor, which is negatively correlated with indoor air pollution. Coal use, overweight, cooking in bedroom, and use of coal stoves and Chinese Kang for heating may increase the risk of pulmonary ventilation dysfunction, while room ventilation is a beneficial factor.

The role of Caspase-1/GSDMD-mediated cell pyroptosis in anti-tumor effect of cisplatin in triple-negative breast cancer / 中华内分泌外科杂志

Objective:To investigate the role of Caspase-1/gasdermin D (GSDMD) -mediated cell pyroptosis in anti-tumor effect of cisplatin (DDP) in triple-negative breast cancer (TNBC) .Methods:HE staining and immunohistochemical staining were performed to detect the morphological changes and the expression of pyroptosis/apoptosis pathway related proteins in TNBC tissues before and after DDP-based neoadjuvant chemotherapy (NACT) . The TNBC cell line MDA-MB-231 was treated with DDP and the morphological changes were observed. The type of cell death induced by DDP was analyzed by Annexin V-FITC/PI double staining and flow cytometry. Lactate dehydrogenase (LDH) release assay and ELISA were performed to detect the release of LDH and inflammatory factors (IL-18 and IL-1β) in cell culture supernatant after DDP treatment. Western blot (WB) was performed to detect the expression of pyroptosis/apoptosis pathway related proteins in cells after DDP treatment. MDA-MB-231 cells treated with DDP were co-treated with caspase-1 specific inhibitor to inhibit pyroptois or co-treated with caspase-3 specific inhibitor to inhibit apoptosis. The effect of caspase-1 inhibitor or caspase-3 inhibitor on the anti-tumor effect of DDP was detected by MTT assay, clone formation assay, transwell assay and would healing test.Results:Reactive changes in the breast surgical specimen after DDP-based NACT included cell swelling and inflammatory cell aggregation around the tumor bed, which were more similar to pyroptosis. The up-regulation of key molecules of pyroptosis pathway post-NACT was significantly higher than that of key molecules of apoptosis pathway. Further experiments in vitro showed that DDP could induce MDA-MB-231 cells to show pyroptosis-like changes characterized by large bubbles blowing from the cellular membrane. Flow-cytometry analyses showed that the death type of MDA-MB-231 cells caused by DDP was mainly Annexin V +PI + cells (mainly lytic cells, such as pyroptosis) . Additionally, DDP treatment induced significant activation of caspase-1 and GSDMD, increased the release of LDH, IL-18 and IL-1β, however, the activation level of caspase-3, which dominates the apoptosis pathway, was significantly lower than that of caspase-1/GSDMD. Moreover, caspase-1 inhibitors (blocking the classical pyroptosis pathway) had a significantly greater inhibitory effect on the anti-tumor effect of DDP than caspase-3 inhibitors (blocking the apoptosis pathway) . Conclusion:Caspase-1/GSDMD mediated pyroptosis may play a leading role in the anti-tumor effect of DDP in triple-negative breast cancer.

Structure-based discovery of orally efficient inhibitors via unique interactions with H-pocket of PDE8 for the treatment of vascular dementia

Our previous study demonstrated that phosphodiesterase 8 (PDE8) could work as a potential target for vascular dementia (VaD) using a chemical probe 3a. However, compound 3a is a chiral compound which was obtained by chiral resolution on HPLC, restricting its usage in clinic. Herein, a series of non-chiral 9-benzyl-2-chloro-adenine derivatives were discovered as novel PDE8 inhibitors. Lead 15 exhibited potent inhibitory activity against PDE8A (IC50 = 11 nmol/L), high selectivity over other PDEs, and remarkable drug-like properties (worthy to mention is that its bioavailability was up to 100%). Oral administration of 15 significantly improved the cAMP level of the right brain and exhibited dose-dependent effects on cognitive improvement in a VaD mouse model. Notably, the X-ray crystal structure of the PDE8A-15 complex showed that the potent affinity and high selectivity of 15 might come from the distinctive interactions with H-pocket including T-shaped π-π interactions with Phe785 as well as a unique H-bond network, which have never been observed in other PDE-inhibitor complex before, providing new strategies for the further rational design of novel selective inhibitors against PDE8.

Progress on the pathogenesis and treatment of IgG4-related disease / 药学学报

IgG4-related disease (IgG4-RD) is a newly recognized fibro-inflammatory condition of autoimmune etiology in recent twenty years, mainly manifesting as mass-forming lesions in single or multiple organs. In the past, it was often missed or misdiagnosed as inflammation or tumor. Patients may die from multiple organ failure due to end-stage fibrosis if they are not treated promptly. However, the number of clinically confirmed cases has gradually increased with the improvement of diagnostic level in recent years, and these patients have benefited greatly after receiving early treatment. Although patients generally respond well to traditional immunosuppressors including glucocorticoids and disease-modifying anti-rheumatic drugs, refractory and recurrent cases, even patients with glucocorticoid contraindication are common. Important mechanistic insights have been derived from studies of B-cell depletion therapy, but greater awareness of the pathophysiology of IgG4-RD is still badly needed to identify novel therapeutic targets. In this article, we reviewed the pathogenesis progress and promising therapy of IgG4-RD to seek better clinical management of IgG4-RD.

Effects of Suspension Exercise Therapy Combined with Soft Tissue Manipulation on Upper Limb Sensory Function in Patients with Radicular Cervical Spondylosis / 医用生物力学

bjective To observe the changes of upper extremity sensory function in patients with radicular cervical spondylosis and evaluate the treatment effect, by using the method of suspension exercise therapy (SET) and soft tissue manipulation. Methods A total of 72 patients with cervical spondylosis were divided into observation group (treated by SET combined with manipulation)and control group (treated by purely cervical traction) by simple random method. Both groups received 4-week continuous treatment for 6 times per week. The somatosensory evoked potential(SEP), current perception threshold (CPT) before and after the treatment in two groups were separatedly tested, and changes in visual analogue scale (VAS) pain scores of the affected limbs were examined, so as to determine the effective rate of treatment. Results After treatment, the latency of SEP was shortened mainly in brachial plexus potential N9 and cervical spinal potential N13 in two groups (P<0.05). The CPT levels and the VAS pain scores of the affected limbs were reduced in two groups (P<0.01), and the treatment effect in observation group was better that in control group (P<0.01)．Conclusion SET combined with soft tissue manipulation can effectively promote the repair of nerve sense function of cervical spondylotic radiculopathy.

Free energy perturbation (FEP)-guided scaffold hopping

Scaffold hopping refers to computer-aided screening for active compounds with different structures against the same receptor to enrich privileged scaffolds, which is a topic of high interest in organic and medicinal chemistry. However, most approaches cannot efficiently predict the potency level of candidates after scaffold hopping. Herein, we identified potent PDE5 inhibitors with a novel scaffold via a free energy perturbation (FEP)-guided scaffold-hopping strategy, and FEP shows great advantages to precisely predict the theoretical binding potencies ΔG FEP between ligands and their target, which were more consistent with the experimental binding potencies ΔG EXP (the mean absolute deviations | Δ G FEP - Δ G EXP |  < 2 kcal/mol) than those ΔG MM-PBSA or ΔG MM-GBSA predicted by the MM-PBSA or MM-GBSA method. Lead L12 had an IC50 of 8.7 nmol/L and exhibited a different binding pattern in its crystal structure with PDE5 from the famous starting drug tadalafil. Our work provides the first report via the FEP-guided scaffold hopping strategy for potent inhibitor discovery with a novel scaffold, implying that it will have a variety of future applications in rational molecular design and drug discovery.

A novel inhibitor of N 6-methyladenosine demethylase FTO induces mRNA methylation and shows anti-cancer activities

N 6-methyladenosine (m6A) modification is critical for mRNA splicing, nuclear export, stability and translation. Fat mass and obesity-associated protein (FTO), the first identified m6A demethylase, is critical for cancer progression. Herein, we developed small-molecule inhibitors of FTO by virtual screening, structural optimization, and bioassay. As a result, two FTO inhibitors namely 18077 and 18097 were identified, which can selectively inhibit demethylase activity of FTO. Specifically, 18097 bound to the active site of FTO and then inhibited cell cycle process and migration of cancer cells. In addition, 18097 reprogrammed the epi-transcriptome of breast cancer cells, particularly for genes related to P53 pathway. 18097 increased the abundance of m6A modification of suppressor of cytokine signaling 1 (SOCS1) mRNA, which recruited IGF2BP1 to increase mRNA stability of SOCS1 and subsequently activated the P53 signaling pathway. Further, 18097 suppressed cellular lipogenesis via downregulation of peroxisome proliferator-activated receptor gamma (PPARγ), CCAAT/enhancer-binding protein alpha (C/EBPα), and C/EBPβ. Animal studies confirmed that 18097 can significantly suppress in vivo growth and lung colonization of breast cancer cells. Collectively, we identified that FTO can work as a potential drug target and the small-molecule inhibitor 18097 can serve as a potential agent against breast cancer.

Radical surgery for colon cancer guided by membrane anatomy theory / 中华胃肠外科杂志

Like other solid tumors, colon cancer surgery has undergone a century-old journey from lumpectomy to organ resection and then to lymphadenectomy. From the Toldt fascia to complete mesenteric resection, and from local resection to D3 radical treatment, local recurrence rates have been reduced, but remain a nuisance to surgeons and patients. Based on the theory of membrane anatomy, radical surgery for colon cancer will focus more on removing the mesocolon from the mesentery bed while maintaining the integrity of the posterior fascia to avoid the occurrence of "fifth metastasis" as much as possible. Thanks to the membrane anatomy theory, its strong reproducibility and replicability, a new phase of colorectal surgery is on the horizon.

Forensic Analysis of 43 Medical Disputes Caused by Death after Cardiac Surgery / 法医学杂志

Objective To explore the causes and characteristics of medical disputes caused by death after cardiac surgery and to analyze the pathological changes after cardiac surgery and the key points of forensic anatomy, thus to provide pathological evidence for clinical diagnosis and treatment of cardiac surgery and judicial appraisal as well as reference for the prevention of medical disputes in such cases. Methods Forensic pathological cases of medical disputes caused by death after cardiac surgery which were accepted by the Center for Medicolegal Expertise of Sun Yat-Sen University from 2013 to 2018 were analyzed retrospectively from aspects such as causes of death, pathological diagnosis, surgery condition, medical misconduct, and so on. Results The causes of death after cardiac surgery of 43 patients were abnormal operation, low cardiac output syndrome, postoperative infection, postoperative thrombosis, and other diseases. Among the 43 cases, there were 18 cases without medical fault while 25 cases had medical fault. Conclusion The medical disputes caused by death after cardiac surgery are closely related to the operative technique and postoperative complications. The causes of medical faults include defects in diagnosis and treatment technique, as well as unfulfillment of duty of care.