Research advances of small molecule inhibitors in the treatment of mixed lineage leukemia / 药学学报

Acute leukemia (AL) is a kind of malignant clonal disease of hematopoietic stem cells. Rearrangement of mixed lineage leukemia (MLL) gene can be observed in about 5%-10% of AL patients. Currently, AL patients with MLL-rearrangements (MLL-r) lack effective treatment and are usually associated with poor prognoses. Recent studies have shown that many epigenetic regulators are directly or indirectly involved in the occurrence and development of AL carrying MLL-r (MLL), which provides a biological basis for the use of epigenetic regulation strategies to treat MLL. In this review, we start from the epigenetic regulation mechanism of MLL, and select representative drug targets to briefly analyze the relationship between each target and MLL and summarize the development progress of their inhibitors, hoping to provide reference for the subsequent research and development of drugs for the treatment of MLL.

Effect of Electro-acupuncture on Expression of IRS-1/PI3K/GLUT4 Pathway in Ovarian Granulosa Cells of Infertile Patients with Polycystic Ovary Syndrome-Insulin Resistance of Phlegm-Dampness Syndrome / 中国结合医学杂志

OBJECTIVE@#To evaluate the effect of electro-acupuncture (EA) in infertile patients with phlegm-dampness polycystic ovary syndrome-insulin resistance (PCOS-IR).@*METHODS@#Seventy-six PCOS-IR patients who underwnet in vitro fertilization and embryo transfer (IVF-ET) were equally assigned to two groups according to a random digital table: the EA group and the control group, with 38 cases in each group. Before undergoing IVF, the two groups were treated with EA or pseudo-acupuncture, respectively, for 3 menstrual cycles. The intervention was 25 min twice a week until the day of oocyte collection. The selected acupoints were Zhongwan (RN 12), Tianshu (ST 25), Daheng (SP 15), Daimai (GB 26), Qihai (CV 6), Guanyuan (CV 4), and bilateral points including Xuehai (SP 10), Fenglong (ST 40), Zusanli (ST 36), and Yinlingquan (SP 9). Evaluation of phlegm-dampness syndrome score and IR score were carried out before and after treatment. Additionally, the number of oocytes retrieved, transplantable embryo rate, high-quality embryo rate, clinical pregnancy rate and live birth rate were compared between the two groups. Real-time polymerase chain reaction analysis was used to monitor the mRNA expression of the insulin receptor substrate (IRS-1), phosphatidylinositiol 3-kinase (PI3K) and glucose transport factor 4 (GLUT4) in ovarian granulosa cells.@*RESULTS@#EA treatment reduced the phlegm-dampness syndrome score as well as the IR scores compared with the control group (P0.05). Moreover, the transplantable embryo rate [49.0% (284/580) vs. 41.9% (273/652)], high-quality embryo rate [36.6% (104/284) vs. 27.8% (76/273)], and live birth rate [50% (19/38) vs. 26.3% (10/38)] in the EA group were significantly higher than in the control group (P<0.05). Gene expression analyses revealed significantly elevated IRS-1, PI3K and GLUT4 mRNA in ovarian granulosa cells of the EA group compared with the control group (P<0.05).@*CONCLUSIONS@#EA may ameliorate the effects of phlegm-dampness syndrome and ovarian IR in PCOS-IR patients. Mechanistically, this effect might be through an upregulation of the IRS-1/PI3K/GLUT4 signaling pathway, which may result in improved oocyte quality and embryonic development potential. (Registration No. ChiCTR1800015453).

Research Strategies and Key Problems Analysis over Substance Benchmark of Famous Classical Formulas / 中国实验方剂学杂志

With continuous introduction of relevant national policies on famous classical formulas, the research of famous classical formulas is popular all over the country. Different from other new drugs, in the research and development process of famous classical formulas, substance benchmark is earlier than the product, suggesting that the research and development of substance benchmark is of great significance. Based on previous work of the authors, content of substance benchmark of famous classical formulas was analyzed, which was included in the document <italic>The Management Regulation of Simplified Registration and Approval over Chinese Herbal Medicine Compound Preparations of Ancient Famous Classical Formulas</italic> released by the National Medical Products Administration in May 2018. In this paper, the significance of substance benchmark development was described, a five-stage of research strategy was proposed, covering the prescription textual research and historical evolution, the collection and quality evaluation of medicinal materials, the processing method and quality evaluation of decoction pieces, the preparation and quality research of substance benchmark, the drafting and formulating of quality standard over substance benchmark. At the same time, some suggestions were put forward to the feasibility of compound preparations development over famous classical formulas, the implementation difficulty of resource evaluation over Chinese medicinal materials, and the irrationality on the quality correlation of Chinese medicinal materials. All of these are expected to provide reference and enlightenment for the development and policy officially landed over ancient famous classical formulas.

A double-blind, randomized, placebo- and positive-controlled phase III trial of 1% benvitimod cream in mild-to-moderate plaque psoriasis / 中华医学杂志(英文版)

BACKGROUND@#Benvitimod cream, a novel synthetic small molecule, was effective in treating mild-to-moderate plaque psoriasis. We conducted a phase III clinical trial to assess the efficacy and safety of benvitimod cream in patients with mild-to-moderate plaque psoriasis.@*METHODS@#We randomly assigned 686 patients (2:1:1) to receive 1% benvitimod cream, 0.005% calcipotriol ointment or placebo twice a day for 12 weeks. The primary efficacy end points were the percentage of patients with a 75% or greater reduction from baseline in the psoriasis area and severity index (PASI 75) score and with a score of 0 or 1 in static physician's global assessment (sPGA) at week 12.@*RESULTS@#The results showed that 50.4% of patients in the benvitimod group achieved PASI 75, which was significantly higher than that in the calcipotriol (38.5%, P < 0.05) and placebo (13.9%, P < 0.05) groups. The proportion of patients achieving an sPGA score 0 or 1 was 66.3% in the benvitimod group and 63.9% in the calcipotriol group, which were both significantly higher than that in the placebo group (34%, P < 0.05). In the long-term follow-up study, 50.8% of patients experienced recurrence. After retreatment with 1% benvitimod, 73.3% of patients achieved an sPGA score of 0 or 1 again at week 52. Adverse events included application site irritation, follicular papules, and contact dermatitis. No systemic adverse reactions were reported.@*CONCLUSION@#During this 12-week study, benvitimod cream was demonstrated with high effectiveness and safety in patients with mild-to-moderate plaque psoriasis.@*TRIAL REGISTRATION@#Chinese Clinical Trial Registry (ChiCTR), ChiCTR-TRC-13003259; http://www.chictr.org.cn/showprojen.aspx?proj=6300.

Genipin inhibits oxidative stress and apoptotic damage in high glucose-induced H9c2 cardiomyocytes / 中国病理生理杂志

AIM:To explore the effects of genipin (GEN) on high glucose (HG) -induced oxidative stress injury and apoptosis in H9c2 cardiomyocytes.METHODS:H9c2 cells were cultured in vitro and HG-induced injury model was established.H9c2 cells were divided into 4 groups:normal control (NC) group (glucose at 5.6 mmol/L) , HG group (glucose at 50 mmol/L) , NG+GEN group and HG+GEN group.The concentration of genipin was used at 10μmol/L.The viability of the H9c2 cells was measured by CCK-8 assay.The intracellular malondialdehyde (MDA) content and superoxide dismutase (SOD) activity were determined by enzyme labeling and WST-1 methods, respectively.The activity of lactate dehydrogenase (LDH) in the cell culture supernatant was detected by microplate method.Fluorescent probe DCF was used to detect intracellular levels of reactive oxygen species (ROS).Nucleosome fragments was measured to evaluate cell apoptosis by ELISA.The intracellular mitochondrial membrane potential was detected by JC-1 method.The protein levels of Mn-SOD, cytochrome C (Cyt C) , Bax and cleaved caspase-3 were determined by Western blot.RESULTS:Compared with HG group, the cell viability in HG+GEN group was increased significantly (P<0.05) , the levels of MDA and LDH were decreased (P<0.05) , SOD activity was increased (P<0.05) , the levels of ROS and nucleosome fragments in HG+GEN group were decreased (P<0.05) , and the mitochondrial membranes potential was notably increased (P<0.05).Compared with NG group, the activation of Mn-SOD was decreased, but the protein levels of Cyt C, Bax and cleaved caspase-3 were increased in HG group (P<0.05).Compared with HG group, the activation of Mn-SOD was increased, and the protein levels of Cyt C, Bax and cleaved caspase-3 were decreased in HG+GEN group (P<0.05).CONCLUSION:Genipin protects HG-induced H9c2 cardiomyocytes against oxidative stress injury and apoptosis.

The clinical value of intracranial translucency (IT) in open spina bifida at 11-13 +6 weeks of gestation / 中国医师杂志

Objective To explore the clinical value of intracranial translucency (HT) in open spina bifida at 11-13 +6 weeks of gestation.Methods Abdominal ultrasound was performed in 200 cases of normal fetus and 6 cases of confirmed open spina bifida at 11-13 +6 weeks of gestation to compare the morphology of IT,diencephalon and midbrain.Results Fetal IT was readily recognized in all 200 normal cases,with diencephalons and midbrain showing number "8" shape.In 6 cases of open spina bifida,fetal IT cannot be identified,and the expected " 8" shape of diencephalon and midbrain was distorted.During 11-13 +6 weeks of pregnancy,the fetal brain is caused by intracranial negative pressure,resulting in morphological changes in the intracranial hyaline,diencephalon and mesencephalon.Conclusions Fetal brain characteristics including intracranial translucency and the shape of diencephalon and midbrain in 11-13 +6 weeks gestation are valuable ultrasound screening indicators for opens pina bifida.

Hp infection and expression of TGF-βR II,IL-6 and TNF-α in patients with chronic atrophic gastritis / 中国免疫学杂志

Objective:To investigate the effect of Helicobacter pylori(Hp) infection in patients with chronic atrophic gastritis (CAG) and the expression of transforming growth factor-β receptorⅡ,interleukin 6 and tumor necrosis factor-α in gastric mucosa.Methods:76 cases of gastroscope biopsy specimens were collected in the CAG patients,the infection of Hp was detected by PCR fluorescence,and immunohistochemical staining was used to determine the expression of TGF-βRⅡ,IL-6 and TNF-α in gastric foveolar epithelium and stromal inflammatory cells.Results:There were significant differences in chronic inflammation between Hp-positive and Hp-negative group (P<0.05).Expression of IL-6 in stromal inflammatory cells was significantly different between Hp-positive and Hp-negative group (P<0.05).Expression of TGF-βRⅡ and TNF-α was not significantly different in two groups(P>0.05).IL-6 expressed instromal inflammatory cells were correlated with chronic inflammation (r=0.249,P=0.03).The degree of intestinal metaplasia and dysplasia were correlated with the atrophic severity respectively(r=0.697,0.366).Conclusion:IL-6 is related to the chronic inflammation in patients with CAG who has Hp infection.The chronic atroplic severity promotes the development of intestinal metaplasia and dysplasia.

The clinical value and significance of thyroid hormone changes in patients with acute cerebral infarction / 中华地方病学杂志

Objective To observe the thyroid hormone (TH) changes in patients with acute cerebral infarction in acute phase and convalescence,and to explore its clinical value.Methods Fifty cases of acute cerebral infarction patients from March 2015 to May 2016 in Heilongjiang Provincial Hospital were selected as observation group,at the same time 30 cases of healthy check-up people as control group.Serum levels of triiodothyronine (T3),thyroxine (T4),free triiodothyronine (FT3),free thyroxine (FT4) and thyroid stimulating hormone (TSH) were measured in 50 cases of acute cerebral infarction patients on the 2nd day (acute phase) and the 14th day (recovery) after onset of the disease,by using chemiluminescence method,and 30 cases of people underwent healthy physical check-up were treated the same way.Neurological injury and recovery of patients with cerebral infarction were evaluated using NIHSS.According to the recovery level of FT3,patients with cerebral infarction were divided into low FT3 group (FT3 ＜ 3.10 pmol/L) and normal FT3 group (FT3 ≥ 3.10 pmol/L).Prognosis of the patients was judged according to the NIHSS scores 90 days after discharged from the hospital,and NIHSS score improving acuity of 2 was judged as good prognosis.Results The T3 and FT3 levels in patients with acute cerebral infarction were significantly lower than those of people underwent healthy physical examination,the differences were statistically significant [(0.68 ± 0.22) vs(1.82 ± 0.31) nmol/L,(2.08 ± 0.31) vs (4.19 ± 0.75) pmol/L,all P ＜ 0.05].The T4,FT4 and TSH levels in patients with acute cerebral infarction were increased significantly,the differences were statistically significant [(142.56 ± 20.78) vs (109.89 ± 12.37) nmol/L,(12.88 ± 1.15) vs (9.77 ± 0.96) pmol/L,(5.15 ± 1.16) vs (2.95 ± 1.31) mU/L,all P ＜ 0.05].Compared with the acute phase,convalescence of cerebral infarction patients' serum T3 and FT3 levels [(1.75 ± 0.19) nmol/L,(3.97 ± 0.61) pmol/L] increased significantly,the differences were statistically significant (all P ＜ 0.05),and T4,FT4 and TSH [(115.64 ± 14.38) nmol/L,(10.05 ± 1.02) pmol/L,(3.16 ± 0.98) mU/L] obviously decreased,the differences were statistically significant (all P ＜ 0.05).Compared with control group,convalescence of cerebral infarction patients' serum T3,T4,FT3,FT4 and TSH were not statistically different (all P ＞ 0.05).There was a negative correlation between FT3 levels and NIHSS scores on admission (r =-0.586,P ＜ 0.05).Ninety days after discharge,7 cases (38.89％) of the patients had a good prognosis in low FT3 group,and normal FT3 group had 22 cases (68.75％) of patients with good prognosis,and the difference was statistically significant (x2 =7.186,P ＜ 0.05).Conclusions The thyroid hormone has a protective stress reaction in patients with acute cerebral infarction.The thyroid hormone level has changed significantly in the acute phase,and returned to normal level with improvement of the patients.As a biochemical indicator thyroid hormone detection can be used to estimate the prognosis of patients with acute cerebral infarction.

Interpretation in American Institute of Ultrasound in Medicine practice guideline for the performance of neurosonography in neonates and infants (2014) / 中华实用儿科临床杂志

This guideline was published by the American Institute of Ultrasound in Medicine,which has been developed to assist physicians performing sonographic studies of the brain in neonates and infants.Neurosonography should be performed only when there is a valid medical reason,and gain the necessary diagnostic information.Although it is not possible to detect every abnormality,adherence to the following guideline will maximize the detection of most abnormalities of the brain in neonates and infants that can be imaged with ultrasound.

Clinical Features of Adult/Adolescent Atopic Dermatitis and Chinese Criteria for Atopic Dermatitis / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Atopic dermatitis (AD) is an inflammatory skin disease characterized by chronic recurrent dermatitis with profound itching. Most patients have personal and/or family history of atopic diseases. Several criteria have been proposed for the diagnosis of AD. Although the clinical features of childhood AD have been widely studied, there has been less large-scale study on adult/adolescent AD. The aim of this study was to investigate the clinical features of adult/adolescent patients with chronic symmetrical eczema/AD and to propose Chinese diagnostic criteria for adult/adolescent AD.</p><p><b>METHODS</b>A hospital-based study was performed. Forty-two dermatological centers participated in this study. Adult and adolescent patients (12 years and over) with chronic symmetrical eczema or AD were included in this study. Questionnaires were completed by both patients and investigators. The valid questionnaires were analyzed using EpiData 3.1 and SPSS 17.0 software.</p><p><b>RESULTS</b>A total of 2662 valid questionnaires were collected (1369 male and 1293 female). Of all 2662 patients, 2062 (77.5%) patients had the disease after 12 years old, while only 600 (22.5%) patients had the disease before 12 years old, suggesting late-onset eczema/AD is common. Two thousand one hundred and thirty-nine (80.4%) patients had the disease for more than 6 months. One thousand one hundred and forty-four (43.0%) patients had a personal and/or family history of atopic diseases. One thousand five hundred and forty-eight (58.2%) patients had an elevated total serum IgE and/or eosinophilia and/or positive allergen-specific IgE. Based on these clinical and laboratory features, we proposed Chinese criteria for adult/adolescent AD. Of all 2662 patients, 60.3% were satisfied with our criteria, while only 48.2% satisfied with Hanifin Rajka criteria and 32.7% satisfied with Williams criteria, suggesting a good sensitivity of our criteria in adult/adolescent AD patients.</p><p><b>CONCLUSION</b>Late-onset of eczema or AD is common. The clinical manifestations of AD are heterogeneous. We have proposed Chinese diagnostic criteria for adolescent and adult AD, which are simple and sensitive for diagnosis of adult/adolescent AD.</p>

Remarks on the relationship between deqi and effect of acupuncture / 中国针灸

Acupuncturists have always paid high attention to deqi (needling sensation) in clinical. However, relationship between deqi and curative effect has not been elucidated yet. In order to have a further understanding on effect of deqi on clinical effect, through study on literature associated with deqi since the establishment of People's Republic of China in 1949, it is held that various factors can influence therapeutic effect of acupuncture treatment, including whether needling sensation appears or not, the speed of deqi, the intensity of deqi, different types of sensations as well as propagated sensation along meridians (PSM). Joint launched multidisciplinary researches should be carried out to reveal the influence principle of deqi on acupuncture effect, and to lay foundations for the further studies on mechanism of deqi.

Effect of Notch signaling on the activation of hepatic stellate cells / 中华肝脏病杂志

<p><b>OBJECTIVE</b>To investigate whether Notch signaling is activated in hepatic stellate cells (HSCs), and to determine whether manipulation of the Notch signaling pathway can effect the activation of HSCs.</p><p><b>METHODS</b>The expression of Notch signaling components in unactivated or TGF-b1-activated HSC-T6 cells was detected by Taqman Probe-based gene expression analysis. Differential expression of Notch3 and Jagged1 was detected by immunofluorescence analysis. Notch3-mediated expression of the myofibroblastic markers, a-SMA and collagen I, was detected in HSC-T6 cells transfected with pcDNA3.1-N3ICD or Notch3 siRNA by Western blotting.</p><p><b>RESULTS</b>Notch signaling components were expressed in both unactivated and activated HSC-T6 cells, but the TGF-b1-treated cells showed significantly higher expression levels of Jagged1 (3.9-fold, F = 2543.482), Notch3 (4.2-fold, F = 287.982), and HES1 (3.2-fold, F = 1719.851). Transfection-mediated over-expression of Notch3 led to significantly increased expression of a-SMA (6.8-fold, t = 13.157) and collagen I (5.5-fold, t = 9.810) (both P less than 0.01). Transient knock-down of Notch3 expression by siRNA decreased expression of the myofibroblastic markers (a-SMA by approximately 90%, t = 19.863 and collagen I by 84%, t = 10.376; both, P less than 0.01). Moreover, knock-down of Notch3 antagonized the TGF-b1-induced expression of a-SMA and collagen I.</p><p><b>CONCLUSION</b>Notch signaling may participate in liver fibrogenesis by regulating HSC activation. Selective interruption of Notch3 may represent a new anti-fibrotic strategy to treat liver fibrosis.</p>

Effect of the combination of bushen xuguan recipe and ruanjian huayu recipe on the MMP-2 expression in endometriosis rats / 中国中西医结合杂志

<p><b>OBJECTIVE</b>To observe the effect of the combination of Bushen Xuguan Recipe (BXR) and Ruan-jian Huayu Recipe (RHR) on the matrix metalloproteinases-2 (MMP-2) expression of rats with endometriosis (EMS), and to study the pathogenesis and mechanism of EMS.</p><p><b>METHODS</b>The EMS rat model was established. Successfully modeled female SD rats were randomly divided into the combination group (BXR+RHR), the RHR group, and the model group. And a normal control group was set up. After 4 weeks of medicinal treatment, rats were sacrificed in the oestrus cycle. MMP-2 distribution and the staining density in ectopic and eutopic endometrium of the rats were observed under microscope. The MMP-2 expression was determined by immunohistochemical assay (SP method).</p><p><b>RESULTS</b>The MMP-2 expression in the ectopic endometrial tissues of rats in the model group were significantly higher than that of the normal control group (P<0.01). Compared with the model group, the MMP-2 expression decreased in the combination group and the RHR group (P<0.05). The therapeutic effect of the combination group was most obvious by observing the distribution of MMP-2 and changes of positive staining.</p><p><b>CONCLUSIONS</b>The occurrence of EMS was correlated with increased activities of MMP-2. The combination method could inhibit the activities of MMP-2 in the ectopic endometrial tissues of EMS rats more effectively than RHR alone, which might be achieved through improving the endocrine environment, and reducing the "invasion" capability of the ectopic endometrium.</p>

The cross-sectional and longitudinal association of the BODE index with quality of life in patients with chronic obstructive pulmonary disease / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>The body mass index, airflow obstruction, dyspnea, and exercise capacity (BODE) index was shown at predicting the risk of death, exacerbation and disease severity among patients with COPD, but few studies verified relationship between BODE index and health related quality of life (HRQoL) among Chinese COPD patients. The objective of this study was to evaluate the relationship between BODE index and HRQoL in cross-sectional and longitudinal association analyses.</p><p><b>METHODS</b>A multi-center prospective cohort study was initially conducted in 491 stable COPD patients in Beijing, China. Health status (HRQoL) was assessed by St. George's Respiratory Questionnaire (SGRQ); the BODE index was calculated for each patient; dyspnea was assessed using the 5-grade Medical Research Council dyspnea scale. Other measurements included socio-demographic, body mass index (BMI), lung function test and 6-minute-walk test (6MWT). Patients were then followed monthly for 12 months.</p><p><b>RESULTS</b>Only 450 patients completed the 1-year follow up and were enrolled in our present analyses. Mean age was (65.2 +/- 10.6) years, men 309 (68.7%). The BODE index was categorized into 4 subgroups: 0 - 2, 3 - 4, 5 - 6 and 7 - 10. At baseline BODE index was gradually increased with baseline total SGRQ and SGRQ subscales (P trend < 0.001). For individual components of BODE index, with the decrease of airflow limitation, and 6MWD, and with the increase of Medical Research Council (MRC) dyspnea grade, total SGRQ and SGRQ subscales were increased correspondingly, P trend < 0.05, respectively. Similar association patterns were found between baseline BODE index and its individual components and mean SGRQ scores at the end of 1-year follow up. By multiple linear regression analyses, baseline BODE index was not only significantly associated with SGRQ score at baseline but also with SGRQ score at the end of 1-year follow up after adjustment for age, male, current smoking, betas being 0.434 and 0.378, respectively.</p><p><b>CONCLUSIONS</b>BODE index is associated with SGRQ score cross-sectionally and longitudinally among stable COPD patients. BODE index might have potential to be used as a sensitive tool to assess the status of quality of life and to monitor disease progression among stable COPD patients.</p>