Hypercalin B alleviates nonalcoholic steatohepatitis progression via suppressing mTORC1 signaling pathway / 药学学报

The global incidence rate of nonalcoholic steatohepatitis (NASH) continues to rise. The pathogenesis of NASH is complex, and there is no effective clinical treatment. Previous study has shown that DEAD box protein 5 (DDX5) can significantly alleviate the NASH process in mice. This study screened the natural product library of the research group and found that the active compound hypercalin B (HB) in Hypericum beanii N. Robson, a traditional Chinese medicine, can upregulate the expression of DDX5 protein in a dose-dependent manner. In this study, an in vitro model of NASH stimulated by palmitic acid (PA) and an animal model of NASH induced by the methionine- and choline-deficient diet (MCD) were constructed. Different concentrations of HB were used to investigate the effect and mechanism of HB in alleviating NASH progression. All animal experiments in this paper were approved by the Ethics Committee of China Pharmaceutical University (NO: 2021-02-003). In vitro model results showed that HB significantly reduced the intracellular lipid deposition induced by free fatty acid (FFA). Animal experiments showed that HB improved liver injury by significantly reducing lipid accumulation in the liver of NASH mice, and reducing serum aspartate transaminase (AST) and alanine transaminase (ALT) levels. Moreover, HB could inhibit liver inflammation by reducing the mRNA levels of liver pro-inflammatory cytokines including interleukin 6 (IL-6), interleukin 1β (IL-1β), and tumor necrosis factor α (TNFα). Further research showed that HB could reduce the phosphorylation level of the mechanical target of rapamycin (mTOR) and reduce the expression of sterol regulatory element binding protein 1 (SREBP1) and fatty acid synthase (FASN), thereby improving lipid metabolism and alleviating NASH progression, and the effects of HB against NASH were dependent on DDX5. In conclusion, HB can improve lipid metabolism and inhibit inflammatory activation by suppressing mTORC1 pathway via upregulating DDX5 protein, and showed promising anti-NASH activity in vitro and in vivo.

Long-term outcomes of lateral vocal fold autologous fat injection for unilateral vocal fold paralysis / 中华耳鼻咽喉头颈外科杂志

Objective: To investigate the long-term outcomes of patients with unilateral vocal fold paralysis resulting in dysphonia treated with lateral vocal fold autologous fat injection. To analyze the factors that may affect the long-term efficacy of the procedure. Methods: From July 2003 to June 2020, 163 patients (86 males and 77 females), aged 9-73 years (mean (34.50±12.94) years) with unilateral vocal fold paralysis resulting in dysphonia underwent transoral laryngoscopic injection of autologous fat into the lateral vocal folds. Subjective auditory perception assessment (GRBAS scale), objective acoustic assessment, voice handicap index (VHI) evaluation and stroboscopic laryngoscopy were compared before and after the surgery. Patients were followed up for 1 to 18 years, with median follow-up time of 6 years. SPSS 22.0 software was used for statistical analysis. Results: Of 163 patients, 17 patients (10.4%) had mild hoarseness (G1) and 146 patients (89.6%) had moderate to severe hoarseness (G2-3). Stroboscopic laryngoscopy revealed an arch-shaped vocal fold on the affected side, fixed in the paramedian position or abduction position, with obvious glottic closure fissure. Postoperatively, voice recovered to normal (G0) in 139 patients (85.3%), mild hoarseness (G1) in 18 patients (11.0%) and moderate hoarseness (G2) in 6 patients (3.7%). Of these, 131 patients (80.4%) showed significant improvement in hoarseness, 29 patients (17.8%) showed mild improvement and 3 patients (1.8%) showed no significant improvement in hoarseness. Objective acoustic parameters of Jitter, Shimmer, NHR and MPT improved significantly, as did VHI scores. Stroboscopic laryngoscopy showed medialization of the affected vocal folds, improved vocal fold closure and normal or nearly normal vocal fold mucosal waves. With a fat injection volume of 3.0-4.5 ml, the patient's subjective auditory perception scores of G, R, B and A improved more significantly within 3 months after surgery, and both VHI and MPT were significantly better since 1 year after surgery. With bilateral vocal fold injection, the B and A scores improved significantly from 1 month postoperatively compared to unilateral injections(unilateral vs. bilateral injection 1 month post-operation, tB scores=1.42,tA scores=1.51,P<0.05). Conclusions: The long-term efficacy of autologous fat injection in the paraglottic space for the treatment of unilateral vocal fold paralysis was stable. The efficacy of the surgery was related to the amount of fat injected, unilateral or bilateral of the injection.

Study on drug-target binding kinetics profiles of flavonoids in Chrysanthemum morifolium and xanthine oxidase / 中国中药杂志

Based on the target occupancy mathematical model, the binding kinetic process of potential active ingredients of lowering uric acid in Chrysanthemum morifolium with xanthine oxidase(XOD) was evaluated. The potential active ingredients of lowering uric acid in Ch. morifolium were screened by UPLC-Q-Exactivems MS technology, reference substance identification and in vitro enzymatic kinetics experiments. The binding kinetic parameters of xanthine oxidase and potential inhibitor in Ch. morifolium were determined by surface plasma resonance(SPR). The verified mathematical model of the XOD target occupancy evaluated the kinetic binding process of inhibitors and xanthine oxidase in vivo. According to UPLC-Q-Exactive MS and reference substance identification, 39 potential uric acid-lowering active ingredients in Ch. morifolium extracts were identified and the inhibitory activities of 23 compounds were determined. Three potential xanthine oxidase inhibitors were screened, namely genistein, luteolin, and apigenin. whose IC_(50 )were 1.23, 1.47 and 1.59 μmol·L~(-1), respectively. And the binding rate constants(K_(on)) were 1.26×10~6, 5.23×10~5 and 6.36×10~5 mol·L~(-1)·s~(-1), respectively. The dissociation rate constants(K_(off)) were 10.93×10~(-2), 1.59×10~(-2), and 5.3×10~(-2 )s~(-1), respectively. After evaluation by different administration methods, the three selected compounds can perform rapid and sustained inhibition of xanthine oxidase in vivo under combined administration. This study comprehensively evaluated the target occupancy process of three effective components in different ways of administration in vivo by UPLC-MS, concentration-response method, SPR technology and xanthine oxidase target occupancy model, which would provide a new research idea and method for screening active ingredients in traditional Chinese medicine.

Simulation Analysis of Occupancy Rates of Baicalein， Quercetin and Galangin on Target Sites of Xanthine Oxidase / 中国实验方剂学杂志

Objective:To simulate the occupancy rates of baicalein， quercetin and galangin on the target sites of xanthine oxidase <italic>in vivo</italic>. Method:In this experiment， the half inhibitory concentration （IC₅₀） of febuxostat， baicalein， quercetin and galangin against xanthine oxidase were determined by <italic>in vitro</italic> enzymatic reaction. Binding free energy was predicted by molecular docking technology and their association rate constant （k_on） and dissociation rate constant （k_off） were determined by surface plasmon resonance technology. Based on measured binding kinetic parameters （k_on and k_off） and extracted pharmacokinetic data， the target occupancy model <italic>in vivo</italic> was established. Result:The IC₅₀values of febuxostat， baicalein， quercetin and galangin were 0.002 7， 1.63， 0.38， 1.59 µmol·L^-1， respectively. The IC₅₀ of febuxostat was very close to that reported in the literature. The predicted curve of target occupancy rate <italic>in vivo</italic> of febuxostat was consistent with its duration of clinical efficacy. When single intragastric administration of long-circulating liposomes of quercetin with dose of 100 mg·kg^-1 in rats， the time of target occupancy rate >70% <italic>in vivo</italic> lasted for about 3.9 h. When rats were orally administered baicalein and galangin with dose of 200 mg·kg^-1， the time of target occupancy rate >50% <italic>in vivo </italic>lasted for about 10 h and 1.7 h， respectively. Conclusion:The prediction model of xanthine oxidase target occupancy constructed by drug target binding kinetics and <italic>in vivo</italic> pharmacokinetic curves can effectively evaluate the <italic>in vivo</italic> inhibitory activity of compounds against the target.

Detection of oropharyngeal sensory function in normal population / 中华耳鼻咽喉头颈外科杂志

Objective: To study the oropharyngeal sensory function by Current Perception Threshold(CPT) detection, to explore the detection method of oropharyngeal sensory function in normal population, and to analyze the possible influencing factors. Methods: Fifty-eight normal subjects were included prospectively in this study. Age, gender, body mass index (BMI) were collected. The age of the subjects ranged from 20 to 76 (43.27±13.52) years old. There were 34 females with 17 in childbearing period and 17 in menopause; and 24 males were included.In all the cases, 6 cases were in low BMI, 39 cases were in normal BMI, 10 cases were overweight and 3 cases were suffering from obesity. The CPT system of Neurometer was used to stimulate bilateral palatoglossal arch and tongue base.The current used was 2000 Hz, 250 Hz and 5 Hz respectively.The function of type Aβ, Aδ and C sensory nerve fibers were tested and the CPT values were recorded.The values were inversely proportional to pharyngeal sensation function.To evaluate the oropharyngeal sensory function of the subjects, the CPT values of each frequency at each testing point were compared. SPSS 25.0 software was used for statistical analysis. Results: The CPT value of palatoglossal arch was significantly lower than that of tongue base (t=-2.58,-2.65,-2.54,-2.47,-2.37,-2.77,P<0.05), 2 000 Hz>250 Hz>5 Hz, and there was no significant difference between left and right sides(t=-0.03,-0.51,-0.49,0.06,-0.16,0.13,P>0.05). The CPT value of male was slightly higher than that of female (t=0.92,1.55,0.27,0.78,1.44,1.26,0.35,0.77,1.27,0.24,0.78,0.96,P>0.05). The CPT values of women in childbearing period were significantly less than those in menopausal women (t=-3.90,-3.64,-2.14,-4.20,-4.28,-4.28,-3.52,-4.46,-3.41,-3.63,-4.66,-2.86,P<0.05). The CPT value increased with age, and the values of all frequency of 20 to 30 years old group was significantly lower than those of subjects over 40 years old at each point (The t values of bilateral palatoglossal arch at 2 000 Hz were -5.57,-6.22,-10.18,-11.00;the t values of bilateral palatoglossal arch at 250 Hz were -6.39,-8.79,-6.39,-15.61;the t values of bilateral palatoglossal arch at 5 Hz were -7.09, -5.57, -9.26, -15.23;the t values of tongue base at 2 000 Hz were -3.11,-3.88,-7.60,-8.55;the t values of tongue base at 250 Hz were -6.31,-10.59,-8.52,-10.60;the t values of tongue baseat 5 Hz were -6.69,-5.09,-8.70,-7.07,P<0.05).The values at all frequencies and testing points of 30-40 years old group were significantly lower than those of all subjects over 60 years old (The t values of bilateral palatoglossal arch at 2 000 Hz were -10.91,-12.42;the t values of bilateral palatoglossal arch at 250 Hz were -6.25,-10.87;the t values of bilateral palatoglossal arch at 5 Hz were -5.53,-11.01;the t values of tongue base at 2 000 Hz were -8.62,-10.12;the t values of tongue base at 250 Hz were -6.89,-7.82;the t values of tongue base at 5 Hz were -6.13,-6.48,P<0.05). Conclusions: CPT can be used to evaluate oropharyngeal sensory function. The sensitivity of tongue base is lower than that of palatoglossal arch, there is no significant difference in oropharyngeal sensory function between male and female,between left and right sides. There are many factors influencing oropharyngeal sensory function. Age, hormone level changes may affect the sensitivity of oropharyngeal sensory function.

Rac1 Modulates Excitatory Synaptic Transmission in Mouse Retinal Ganglion Cells / 神经科学通报·英文版

Ras-related C3 botulinum toxin substrate 1 (Rac1), a member of the Rho GTPase family which plays important roles in dendritic spine morphology and plasticity, is a key regulator of cytoskeletal reorganization in dendrites and spines. Here, we investigated whether and how Rac1 modulates synaptic transmission in mouse retinal ganglion cells (RGCs) using selective conditional knockout of Rac1 (Rac1-cKO). Rac1-cKO significantly reduced the frequency of AMPA receptor-mediated miniature excitatory postsynaptic currents, while glycine/GABA receptor-mediated miniature inhibitory postsynaptic currents were not affected. Although the total GluA1 protein level was increased in Rac1-cKO mice, its expression in the membrane component was unchanged. Rac1-cKO did not affect spine-like branch density in single dendrites, but significantly reduced the dendritic complexity, which resulted in a decrease in the total number of dendritic spine-like branches. These results suggest that Rac1 selectively affects excitatory synaptic transmission in RGCs by modulating dendritic complexity.

Analysis of clinical characteristics of paroxysmal laryngospasm / 临床耳鼻咽喉头颈外科杂志

OBJECTIVES@#To analyze the clinical characteristics of paroxysmal laryngospasm in adult.@*METHODS@#A retrospective analysis was performed on 149 patients with paroxysmal laryngospasm in adult. All patients underwent the strobolaryngoscopy, completed the reflux symptom index (RSI) or the reflux finding score (RFS). Partial patients underwent an ambulatory 24-hour pH measurement.@*RESULTS@#Laryngospasm was diagnosed in 76 females and 73 males. The average age was 55.4±11.4. The episode time of 149 (98%) patients last from several seconds tominutes, and 139 (93.3%) episodes could have a spontaneous remission. 84 (56.4%) episodes occurred only in the daytime, 28 (18.8%) only in the nighttime. There were 45.6% over weight/obesity patients, including 40 males and 28 females. The smokers were 28.9% (43/149) including 40 males and 3 females, and the drinkers were 29.5% (44/149) with 39 males and 5 females. 76 (51.0%) patients had no induced factor, while some caused by irritable cough/bucking (53,35.6%), cold (15, 10.1%), excitant food/smell (10, 6.7%), or regurgitation (6.5, 4.0%). Strobolaryngoscopy revealed laryngopharyngeal lesions in 46.3% (69/149) patients, including the glottic lesions with 40 (26.8%), unilateral vocal fold paralysis (21, 14.1%) and supraglottic lesions (8,5.4%). RSI/RFS showed 74.5% (111/149) patients had laryngopharyngeal reflux. Two patients treated with dietary and lifestyle modifications get improved, and 15/16 of the patients responded to antireflux treatment.@*CONCLUSIONS@#Episode of paroxysmal laryngospasm occurs more in the daytime, and could have a spontaneous resolution. Paroxysmal laryngospasm is much easier to occur in the male who are overweight or obesity, or with a long-term history of smoking or drinking. Almost half of the patients have an induced factor; partial may have laryngopharyngeal lesions simultaneously. Paroxysmal laryngopharyngeal reflux may be closely related to laryngospasm.

Influence of Guiqiyiyuan Ointment on the expression of caspase-3 and caspase-9 in rat lung tissues injured by heavy ion radiation-induced bystander effect / 解放军医学杂志

Objective To explore the influence of Guiqiyiyuan Ointment on the expressions of caspase-3 and caspase-9 in the lung and kidney of the rats damaged by heavy ion (12C6+) radiation-induced bystander effect.Methods The Wistar male rats were equally and randomly divided into seven groups,normal control group (NCG),radiation alone group (RAG) and Chinese medicine group (CMG),with the latter two groups being redivided into 6,12 and 24h groups according to the executing time.The Chinese medicine groups were given Guiqiyiyuan Ointment by gavage for two weeks in advance.The normal control group and the radiation alone groups were given the equal normal saline.Afterwards,the right lung of the rats in the radiation alone groups and Chinese medicine groups were radiated by 2Gy 12C6+ ion once.The rats in normal control group were not radiated.All groups of rats were executed 6,12,and 24h after radiation.The protein and mRNA expressions of caspase-3 and caspase-9 in the right lung,left lung and left kidney were examined with immunohistochemistry and Q-PCR.Results Compared with the normal control group,the mRNA expressions of caspase-3 and caspase-9 in the right lung,left lung and left kidney in the radiation alone groups obviously increased 6 and 24h after radiation.While the protein expressions of caspase-3 and caspase-9 in the radiation alone group obviously increased only 24h after radiation (P＜0.01).Compared with the radiation alone groups,the expressions of protein and mRNA ofcaspase-3 and caspase-9 were obviously down-regulated in the Chinese medicine groups (P＜0.01).Conclusion By controlling the up-regulation of the expression ofcaspase-3 and caspase-9,Guiqiyiyuan Ointment can prevent the lung and kidney cell apoptosis and alleviate the damage caused by heavy ion radiation-induced bystander effect in vivo.

Risk Factors and Perinatal Outcomes of Velamentous Umbilical Cord Insertion / 中国医学科学院学报

<p><b>OBJECTIVE</b>To explore the risk factors of velamentous umbilical cord insertion(VCI)and the impact of VCI on perinatal outcomes.</p><p><b>METHODS</b>The clinical data of 588 VCI patients who were treated in Beijing Gynecology and Obstetrics Hospital from January 2006 to January 2011 were retrospectively analyzed. In addition,61,143 non-VCI subjects were enrolled as the control group. The possible risk factors of VCI and the impact of VCI on perinatal outcomes were analyzed. In addition,the causes of perinatal deaths were analyzed.</p><p><b>RESULTS</b>The gemellary pregnancy,multiple pregnancy,in vitro fitilization(IVF),placenta praevia,and placenta succenturiata/placenta bipartite were found to be the risk factors of VCI. The incidences of low birth weight,intrauterine growth restriction,asphyxia of newborns,deaths of fetuses or neonates,and single umbilical artery in the VCI group were significantly higher than those in the control group(all P<0.05). In 678 perineonates with VCI,the total death toll of perineonates was 7(1.0%),among whom the death causes included angiorrhexis of placenta praevia(n=1),preterm birth and low birth weight(n=3),torsion of cord(n=1),prolapse of cord(n=1),and placental abruption(n=1).</p><p><b>CONCLUSIONS</b>The risk factors of VCI should be carefully monitored. A diagnosis of VCI,if any,should be correctly made by using modern ultrasound techniques before delivery,so as to lower the mortality of perineonates.</p>

Rare renal metastases from differentiated thyroid carcinoma: early clinical detection and treatment based on radioiodine / Metástases renais raras de carcinoma diferenciado da tireoide: detecção clínica precoce e tratamento com radioiodoterapia

Objective : The aim of this study was to explore the clinical characteristics of renal metastatic cancer, the methods for its detection by radioiodine (131I), and the response to 131I treatment in fourteen patients with renal metastases from differentiated thyroid carcinoma (DTC).Subjects and methods : DTC patients (n = 2,955) that received treatment with 131I were retrospectively analyzed. Scans (131I-WBS, 31I-SPECT/CT and/or 18F-FDG-PET/CT) were performed after an oral therapeutic dose of 131I. Therapeutic efficacy was evaluated based on changes in Tg and anatomical imaging changes at renal lesions.Results : Among these 14 patients, 11 had avidity for 131I, but three patients did not accumulate 131I after 131I treatment. In the 11 131I-positive renal lesions, 10 cases were detected by 131I-SPECT/CT combined with another imaging modality and one case by 131I-WBS combined with ultrasonography (US). In the three 131I-negative renal lesions, two cases were detected by 18F-FDG-PET/CT and one case by computed tomography (CT). In 11 patients with 131I-avid renal metastases, Serum Tg levels in 81.82% (9/11) patients showed a gradual decline, and 18.18% (2/11) of the patients showed a significant elevation. There was no marked difference in serum Tg before the last 131I treatment (Z = 0.157; p = 0.875). Only one patient presented partial response, eight patients exhibited stable disease, and renal metastases progressed in two patients showing progressive disease. No patients reached complete response.Conclusion : 131I-SPECT/CT, combined with another imaging modality after 131I-WBS, can contribute to the early detection of renal metastases of DTC. 131I therapy is a feasible and effective treatment for most DTC renal metastases with avidity for 131I. Arq Bras Endocrinol Metab. 2014;58(3):260-9.

Objetivo : O objetivo deste estudo foi analisar as características clínicas de metástases renais, os métodos para sua detecção por radioiodo (131I) e a resposta ao tratamento com 131I em 14 pacientes com metástases renais de carcinoma diferenciado da tireoide (DTC).Sujeitos e métodos Pacientes com DTC (n = 2.955) que receberam tratamento com 131I foram analisados retrospectivamente. 131I-PCI, 31I-SPECT/CT e/ou 18F-FDG-PET/CT foram feitos após uma dose terapêutica oral de 131I. A eficácia terapêutica foi baseada nas alterações da Tg e nas imagens anatômicas das lesões renais.Resultados : Dos 14 pacientes, 11 apresentaram lesões ávidas por 131I, mas três pacientes não acumularam 131I depois do tratamento com 131I. Nas 11 lesões renais positivas para 131I, 10 casos foram detectados por 131I-SPECT/CT combinado com outra modalidade de exame de imagem e um caso por 131I-WBS combinado com US. Nas três lesões renais negativas para 131I, dois casos foram detectados por 18F-FDG-PET/CT e um caso por tomografia computadorizada (TC). Em 11 pacientes com metástases renais ávidas por 131I, os níveis séricos de Tg em 81,82% (9/11) dos pacientes mostraram um declínio gradual e 18,18% (2/11) apresentaram uma elevação significativa. Não houve diferenças marcadas na Tg sérica antes do último tratamento com 131I (Z = 0,157; p = 0,875). Apenas um paciente apresentou resposta parcial, oito pacientes apresentaram doença estável e as metástases renais progrediram em dois pacientes que apresentaram doença progressiva. Nenhum dos pacientes apresentou resposta completa.Conclusão : 131I-SPECT/CT, combinada com outra modalidade de diagnóstico por imagem após 131I-PCI, pode contribuir para a detecção precoce de metástases renais de DTC. O tratamento ...