[Altered dynamics of brain spontaneous activity in betel quid dependence chewers].

Objective: To investigate the dynamic characteristics of brain spontaneous activity in betel quid dependence (BQD) chewers and its relationship with clinical indexes. Method: This study was conducted in Hainan General Hospital from April to December 2019 and the data of 53 BQD chewers (37 males and 16 females, aged 20 to 58(38±11) years) and 37 healthy controls (HC) (24 males and 13 females, aged 23-57(42±12) years) were collected. All these subjects underwent resting-state functional magnetic resonance imaging (rs-fMRI) scan. The dynamic characteristics of resting fMRI indexes, including dynamic amplitude of low-frequency fluctuations (ALFF), regional homogeneity (ReHo) and degree centrality (DC) of these subjects were calculated using the sliding time window method, parameters such as age and dynamic local consistency were analyzed and compared between the two groups. Pearson correlation was used to analyze the relationship between dynamic indexes, betel quid dependence score (BQDS) and disease duration in BQD group. Results: BQD chewers showed decreased dynamic ALFF in the left orbital prefrontal cortex (0.138±0.041 vs 0.171±0.070), the right temporal pole superior temporal gyrus (0.277±0.070 vs 0.319±0.086) and the right inferior parietal lobule (0.223±0.052 vs 0.259±0.088) than HC (all P<0.05). For regional homogeneity, BQD chewers showed a decrease dynamic ReHo in the right inferior temporal gyrus (0.055±0.008 vs 0.061±0.009), the orbital prefrontal cortex (0.058±0.005 vs 0.063±0.008), the right inferior frontal gyrus (0.081±0.006 vs 0.087±0.011), the right superior occipital gyrus (0.056±0.007 vs 0.062±0.008), the left precentral gyrus (0.068±0.008 vs 0.074±0.008), and the left superior frontal gyrus (0.058±0.008 vs 0.064±0.009) than HC (all P<0.05). BQD chewers showed an increase dynamic ReHo in the right precuneus (0.095±0.009 vs 0.089±0.008) (P<0.05). There was no significant difference in DC between the two groups (all P>0.05). The relationships between three dynamic ALFF and BQDS (r=-0.104, -0.015, -0.119), seven dynamic ReHo and BQDS (r=-0.099, -0.141, -0.055, -0.078, -0.027, -0.111, -0.090), three dynamic ALFF and disease duration (r=-0.122, -0.095, -0.171), and seven dynamic ReHo and disease duration (r=0.242, -0.252, 0.035, 0.056, 0.047, 0.081, 0.169) were not statistically significant (all P>0.05). Conclusions: BQD chewers showed a decrease dynamic ReHo and/or ALFF in multiple brain regions dominated by prefrontal cortex, and an increase dynamic ReHo in the right precuneus.

[Investigate developmental coordination disorder of kindergarten children in Zhejiang Province].

In order to investigate developmental coordination disorder (DCD) of kindergarten children in Zhejiang province, 200 ordinary kindergartens were randomly selected by stratified random sampling in 11 prefecture-level cities of Zhejiang Province, and 38 900 children from 1 000 classes in each grade were then randomly selected into the study from June 2019 to December 2019. The Little DCD Questionnaire and a self-designed questionnaire were used to screen the DCD of those children. There were 36 807 valid questionnaires, and 6.50% (2 391/36 807) of them were positive results. The results showed that boy, age ≤5 years, overweight or obesity, left handedness, comorbidity with motor or developmental disorders and premature infants were risk factors of DCD in children. As for parents and families, maternal gestational age<20 years, maternal overweight or obesity before pregnancy, low-middle level education of parents, direct family and low income of family were also associated with DCD in children. Therefore, it is necessary to conduct early prevention and intervention strategies targeting on identified risk factors among relevant population.

[Clinicopathological features of verrucous hemangioma].

Objective: To investigate the clinicopathological features, and differential diagnosis of verrucous hemangioma (VH). Methods: Twenty-eight VH cases diagnosed from 2005 to 2020 in Henan Provincial People's Hospital, Zhengzhou, China were analyzed retrospectively. Immunohistochemical studies were used to detect diagnostic markers. The mutation status of PIK3CA (exons 9 and 20) was detected using fluorescence PCR. Results: There were 13 males and 15 females in 28 cases, with the male to female ratio of 1.0∶1.2. There were 25 patients under the age of 18 years. The age range was from 10 months to 56 years (mean, 9.7 years; median, 4.5 years). There were 17 cases occurred in the lower extremities, 7 in the upper extremities and 4 in the trunk. All 28 cases were irregular red patches on the skin, which grew slowly. Some of them were thickened with uneven surface, which was light pink or red-white. Skin lesions of the 7 cases ranged from dark red and reddish brown, with a rough and hard surface. Satellite foci were present. Microscopically, 28 cases had a wide range of pathological features. Dilated, malformed vessels were observed from dermal papilla to deep soft tissue. Among them, the dermal papillary layer was mainly composed of many proliferating and expanding thin-walled capillaries and cavernous blood vessels. Thin-walled small vessels were found in the dermal reticular layer and subcutaneous fascia layer, with no obvious endothelial cell proliferation, occasional papillary hyperplasia, and lobular distribution of the malformed vessels in the fascia layer mixed with the fibroadipose tissue. There was epidermal papillary hyperplasia with hyperkeratosis and parakeratosis, lengthening and mutual fusion of epithelial horns. Immunohistochemistry showed that CD31, CD34, ERG and WT-1 were diffusely and strongly positive. The expression of GLUT-1 was present in superficial dermal vascular endothelial cells, but undetectable in the deep layer. The PIK3CA tests of 13 cases showed that no somatic mutations were found in exons 9 and 20. Twenty-five patients were followed up for 5 months to 10 years. Seven patients underwent multiple surgical resections and plastic surgeries due to the large size, and 8 patients had recurrence. Conclusions: VH is a rare congenital vascular malformation and more commonly occurs in infants and children. It tends to appear in limbs, especially lower limbs and distal limbs. Its morphology and immunophenotype are characteristic and should be distinguished from other vascular malformations and the resolution phase of infant hemangiomas. In about one third of the cases, postoperative recurrence may occur and long-term follow-up is often required.

[An analysis of the status quo of ground-level ozone pollution research].

Objective: To analyze the research status of ground-level ozone pollution, explore research trends and hot spots, and provide references for future research on air pollution. Methods: Papers on ground-level ozone pollution research published before December 31, 2019 had been retrieved in SCI-E database of the "Web of Science Core Collection" in January 2020. The retrieval strategies were set as follows: TS= ( ("Tropospheric Ozone" OR "Low Level Ozone" OR "Ground Level Ozone") AND ("Air pollution*" OR "Air quality") ) . The survey included 2084 articles. By using bibliometric research and visual analysis tools, the research status of global ground-level ozone pollution was revealed from the aspects of time, discipline, journal, financing, institution, country and key words. Results: Cumulative publications increased in a cubic function of y=0.05x(3)+0.80x(2)+0.74x+4.55 (R(2)=0.999, P<0.01) . The most studied subject was Environmental sciences ecology (1401 articles, 67.23%) . Atmospheric Environment was the journal with the most articles (332 articles, 15.93%) . The United States was the country with the most publications (44.67%, 931/2084) , while China ranked second (17.13%, 357/2084) . 80.39% (287/357) of Chinese papers had funding information. Among the top 10 research institutions, 7 and 2 were affiliated to the United States and China respectively. Source apportionment and human health were high frequency keywords that had appeared in the last 5 years. Conclusion: The research on ground-level ozone pollution is in a good period of development. The United States has a leading position in this area, and China has a good prospect in this field. Pollution source apportionment and human health effects are new research directions.

[Analysis of five children with acquired thrombotic thrombocytopenic purpura].

Objective: To investigate the clinical characteristics, treatment and prognosis of children with acquired thrombotic thrombocytopenic purpura (TTP). Methods: The clinical manifestations, laboratory examination, treatment and prognosis of 5 children with acquired TTP hospitalized in Beijing Children's Hospital, Capital Medical University from January 2016 to July 2019 were analyzed retrospectively. Results: There were 5 children with acquired TTP including 2 males and 3 females, with the onset age of 8.9(0.8-14.5) years, while 11 children with TTP in the same period. Thrombocytopenia and microangiopathic hemolytic anemia were found in all 5 patients. Only one patient had typical pentalogy of TTP, 3 patients had nervous system symptoms and 3 patients had fever, while renal impairment was relatively rare (1 case). Laboratory examination showed severe thrombocytopenia (7(4-14) ×109/L) and low level of hemoglobin (70(58-100)g/L) in all 5 children. Blood biochemical examination showed that total bilirubin (mainly indirect bilirubin) increased in 3 patients, lactate dehydrogenase increased in 5 patients, and urea nitrogen increased in 1 patient. Bone marrow smear showed megakaryocyte did not decrease. Plasma ADAMTS13 activity was 0 in all 5 patients while ADAMTS13 inhibitor was positive in 4 patients and negative in 1 patient. All 5 children received glucocorticoid therapy, rituximab was added in the early stage of the disease, and 3 children received plasma exchange. The time of platelet recovery to normal was 19 (9-29) days. One child had TTP recurrence after 9 months of treatment. The condition was stable after being treated with glucocorticoid and rituximab again. This case was finally diagnosed as systemic lupus erythematosus after more than 3 years followed up. By December 1, 2020, the follow-up time was 24(16-57) months.The clinical symptoms of all patients disappeared and the platelet level was stable at 159(125-269) ×109/L. Conclusions: Childhood acquired TTP is relatively rare, which can occur in all age groups. The clinical manifestations are mainly thrombocytopenia and microangiopathic hemolytic anemia, the plasma ADAMTS 13 activity and inhibitor test are helpful for the diagnosis of acquired TTP. Plasma exchange and rituximab are effective treatment. This disease requires long-term follow-up.

[A bibliometric analysis of research on occupational asthma during 1998 to 2017].

Objective: To understand the research status of occupational asthma and provide information for related research on occupational asthma in the future. Methods: Papers on occupational asthma published from January 1998 to December 2017 had been retrieved in Web of Science core collection database on 9 October 2018. The data retrieval strategies were set as follows: #1 TS=(occupational AND asthma), #2 TS=(occupational AND asthmas), #3 TS=(occupational asthma OR occupational asthmas), #1 OR #2 OR #3. Three thousand two hundred and twelve publications were analyzed by bibliometric and visualizer. Results: Yearly output of articles in this field had been at a stable high level and annual total citations had been increasing. A significant positive correlation was found between the year and annual total citations (r=0.97, P<0.05). The most productive countries were European countries except the United States and Canada. Our country had few literatures accounting for 1.21 percent of the total and the research on occupational asthma in our country started relatively late which were published mainly from 2013 to 2017. The most studied category and journal were public environmental occupational health and Am J Ind Med respectively. "occupational exposure", "allergy" and "rhinitis" were key words with high frequency. Conclusion: Yearly output of publications of occupational asthma has been at a stable high level. Our country should do more research to provide a scientific basis for further prevention and management of occupational asthma.

[Analysis of 5 children with congenital thrombotic thrombocytopenic purpura].

Objective: To explore the clinical features and points of diagnosis and treatment for congenital thrombotic thrombocytopenic purpura (TTP) in children. Methods: The clinical manifestations, laboratory tests, genetic analysis and treatments of 5 children with congenital TTP hospitalized in Beijing Children's Hospital, Capital Medical University from February 2015 to July 2017 were analyzed retrospectively. Results: Among the 5 children with congenital TTP diagnosed by genetic monitoring and enzymology, there were 1 male and 4 females, 3 cases had suspicious positive family history, the age of onset was several hours after birth (range several hours after birth to 28 months). The main clinical manifestations were recurrent moderate to severe thrombocytopenia in 5 cases, mild to moderate hemolytic anemia in 4 cases, proteinuria or hematuria in 2 cases, and nervous system involvement in 1 case. The recurrence time was 1.5 (range 1.0 to 5.0) times per year and most of the inducing factors were respiratory and (or) digestive tract infections. Laboratory test showed that ADMATS13 enzyme activity were 0 in 4 cases, the enzyme activity was 100% in 1 case due to plasma infusion before examination. ADMATS13 enzyme antibody detection of all 5 cases were negative. Genetic analysis of all 5 children showed complex heterozygous mutations at different loci of ADAMTS13 gene, among which 8 loci were previously unreported, details are as follows: missense mutations in 4 cases (c.1564T>C(p.522C>R), c.1510G>T(p.504D>Y), c.4154A>C(p.1385Q>P) and c.G3854C (P.R1285P)); frameshift mutations in 3 cases(c.2875_2876insT (p.959Lfs29), c.2362_2363delGG (p.788G>Gfs56) and c.1335delC (p.F445fs)), shear mutation in one case(IVS21+1A>G). The patients in the acute phase were all treated with fresh frozen plasma infusion (10 ml/(kg·d)), continuous application for 7-14 days). Platelets gradually returned to normal and clinical symptoms improved. The follow-up time was 27 months (range 11-35 months). All the children survived, among whom 2 cases were treated with prophylaxis and monitoring platelet stability above 200×10(9)/L, 3 cases were treated on-demand only when platelet decreased and monitoring platelet stability above 100×10(9)/L. Conclusions: The main clinical manifestation of congenital TTP is recurrent thrombocytopenia with or without hemolytic anemia. The key point of treatment is plasma infusion. Genetic testing is helpful for early diagnosis.

[Analysis on influencing factors of unprotected sexual behavior among men who have sex with men based on structural equation model].

Objective: To analyze the influencing factors and mechanism for unprotected sexual behavior of men who have sex with men (MSM) in China. Methods: MSM who are more than 16 years old and have had homosexual sexual behaviors in recent years were recruited from five cities (Tianjin, Harbin, Nanjing, Chongqing and Xi'an) with active MSM population during 2013-2014 through network, site recruitment and peer recommendation using convenient sampling method. 3 519 subjects were included in this study. The sexual behavior related information of MSM in five cities was investigated using questionnaires. The confirmatory factor analysis was used to construct the measurement model by using the robust estimation method based on the weighted least square method to estimate parameters, and the final model was determined through evaluation and modification. Results: A total of 3 519 subjects were (29.9±8.76) years old, with a clear sexual orientation of 3 223 (91.6%), and 2 287 (65.0%) were aware of free HIV/AIDS treatment policies. The proportion of using condom last time was 77.2% (n=2 718), and the proportion of using condom every time was 36.9% (n=1 299) and 43.2% (n=1 521) respectively for the past six months with fixed and temporary partners. Structural equation model provided a good fit, the root mean square error of approximation, comparative fit index and non-normed fit index was 0.07, 0.97, 0.95, respectively. Knowing AIDS knowledge, educational level and sexual orientation had direct effects on unprotected sexual behavior, and the path coefficients were 0.179,-0.049 and -0.159, respectively. While the role of interventions was indirect, the path coefficient was 0.147. Conclusion: Lower education and unclear sexual orientation are disadvantages for reducing unprotected sexual behavior. Interventions mainly affect the unprotected sexual behavior by improving the level of HIV/AIDS knowledge. Increasing the comprehensive knowledge of MSM through intervention should be highly valued.

Effects of testosterone supplementation therapy on lipid metabolism in hypogonadal men with T2DM: a meta-analysis of randomized controlled trials.

Testosterone supplementation may be effective for the treatment of hypogonadism in men with type 2 diabetes mellitus (T2DM), but the evidence from randomized controlled trials (RCTs) is inconclusive. We aimed to systematically summarize results from intervention studies and assess the effects of testosterone supplementation therapy (TST) on lipid metabolism in RCTs of hypogonadal men with T2DM by meta-analysis. PubMed, Embase, and Cochrane Library databases were searched for studies reporting the effect of TST on lipid metabolism in hypogonadal men with T2DM until December 31, 2016. Seven RCTs from 252 trials, enrolling a total of 612 patients in the experimental and control groups with a mean age of 58.5 years, were included in this study. The pooled results of the meta-analysis demonstrated that TST significantly decreased TC and TG levels in hypogonadal men with T2DM compared with the control group, with mean differences (MDs) of -6.44 (95% CI: -11.82 to -1.06; I2  = 28%; p = 0.02) and -27.94 (95% CI: -52.33 to -3.54; I2  = 76%; p = 0.02). Subgroup analyses revealed that the heterogeneity (I2  = 76%) of TG originated from different economic regions, in which economic development, genetic and environmental factors, and dietary habits affect lipid metabolism of human, with a decrease (I2  = 45%) in developed countries. Additionally, subgroup analyses showed that TST increased HDL-C level in developing countries compared with the control group (MD = 2.79; 95% CI: 0.73 to 4.86; I2  = 0%; p = 0.008), but there was no improvement in developed countries (MD = 1.02; 95% CI: -4.55 to 6.60; I2  = 91%; p = 0.72). However, LDL-C levels were not improved consistently. Because the relationship between lipid metabolism and atherosclerosis is unequivocal, TST, which ameliorates lipid metabolism, may decrease the morbidity and mortality of cardiovascular disease in hypogonadal men with T2DM by preventing atherogenesis.

[Clinical study of pulsed high- dose dexamethasone treatment in 38 children with primary immune thrombocytopenic purpura].

Objective: To evaluate the efficacy and safety of pulsed high- dose dexamethasone(HDD)treatment in children with primary immune thrombocytopenic purpura(ITP). Method: ITP children who failed to first-line therapy from September 2013 to September 2014 were given pulsed HDD treatment, dexamethasone was administered at a dosage of 0.6 mg ·kg-1·d-1(maximum 40 mg/d)for 4 consecutive days. The cycle was repeated every 28 days for 6 months. Results: ①A total of 38 cases were enrolled, 26 boys and 12 girls, median age was 54(6-151)months, median duration of disease was 6(1- 72)months, 9 cases was newly diagnosed ITP, 13 cases with persistent ITP, 16 cases with chronic ITP. Median platelet count before treatment was 16.3(1.0- 30.0)× 109/L. ②A median follow- up time was 180(90- 554)days. Treatment response was obtained in 17 cases(44.7%), including 7 cases(18.4%)with complete response(CR), 10 cases(26.3%)response(R); the median time to response was 80.5(23-245)days. Of 17 CR/R cases, 3 turned to no response, with a median duration of response 63(37-67)days. Of 38 cases, 21(55.3%)was no response, but the bleeding symptoms in 85.7% of this group improved. ③ Only 1 patient had mild reversible side effects during treatment. ④ The percentage of CD4 +CD25 +Foxp3+T cells is higher in effective group than that in ineffective group[(7.54±1.50)% vs(5.69±1.95)%, P=0.049]. Univariate analyses suggested that the efficacy of HDD treatment in children with megakaryocyte count <300/slide is better than that >300/slide(P=0.049). Conclusion: Pulsed HDD treatment is a comparatively safe and effective choice for children with ITP who failed to first-line therapy. Children with less than 300 megakaryocytes or higher CD4+CD25+Foxp3+T cells may be more suitable for the therapy.

Retina Is Protected by Neuroserpin from Ischemic/Reperfusion-Induced Injury Independent of Tissue-Type Plasminogen Activator.

The purpose of the present study was to investigate the potential neuroprotective effect of neuroserpin (NSP) on acute retinal ischemic/reperfusion-induced (IR) injury. An IR injury model was established by elevating intraocular pressure (IOP) for 60 minutes in wild type and tPA-deficient (tPA-/-) mice. Prior to IR injury, 1 µL of 20 µmol/L NSP or an equal volume of bovine serum albumin (BSA) was intravitreally administered. Retinal function was evaluated by electroretinograph (ERG) and the number of apoptotic neurons was determined via TUNEL labeling. Caspase-3, -8, -9,poly (ADP-ribose) polymerase (PARP)and their cleaved forms were subsequently analyzed. It was found that IR injury significantly damaged retinal function, inducing apoptosis in the retina, while NSP attenuated the loss of retinal function and significantly reduced the number of apoptotic neurons in both wild type and tPA-/- mice. The levels of cleaved caspase-3, cleaved PARP (the substrate of caspase-3) and caspase-9 (the modulator of the caspase-3), which had increased following IR injury, were significantly inhibited by NSP in both wild type and tPA-/- mice. NSP increased ischemic tolerance in the retina at least partially by inhibiting the intrinsic cell death signaling pathway of caspase-3. It was therefore concluded that the protective effect of neuroserpin maybe independent from its canonical interaction with a tissue-type plasminogen activator.

In silico analysis and experimental validation of active compounds from fructus Schisandrae chinensis in protection from hepatic injury.

OBJECTIVES: The aim of this study was to explore mechanisms by which fructus Schisandrae chinensis (Wuweizi) is able to reveal its protective capacity against hepatocyte injury. MATERIALS AND METHODS: Identification of candidate small molecular compounds was performed by text-mining, extraction and isolation, reverse-docking, network construction, molecular docking and molecular dynamics (MD) simulation. In vitro cytological examination and western blotting were used to validate efficacy of selected compounds. RESULTS: We analyzed chemical composition of fructus Schisandrae chinensis and constructed protein-protein networks of key targets. Networks of miRNA-protein were constructed. Molecular docking and MD simulation results supported good interaction between selected compound 11/12 and GBA3/SHBG. Further in vitro examination divulged molecular mechanisms involved. CONCLUSIONS: In silico analysis and experimental validation together demonstrated that compound 11/12 of fructus Schisandrae chinensis targetted GBA3/SHBG in hepatocytes. Hopefully this will shed light on exploration of its complex molecular mechanisms.

Eukaryotic elongation factor-2 kinase (eEF2K): a potential therapeutic target in cancer.

Eukaryotic elongation factor-2 kinase (eEF2K), encoded by the EEF2K gene, is well-known to be a Ca(2+)/calmodulin (CaM)-dependent kinase which can negatively modulate protein synthesis. It is highly conserved among eukaryotes from mammals to invertebrates, of which human and mouse may have 99 % overall amino acid identity. This kinase can phosphorylate eukaryotic elongation factor-2 (eEF2) or undergo the process of autophosphorylation at multiple sites to inhibit its function in translation elongation. Due to the fact that regulation of eEF2 by eEF2K is an evolutionarily conserved mechanism, eEF2K activity may confer tumor cell adaption to metabolic stress under acute nutrient depletion, and the high expressed level of eEF2K has been found in several types of malignancies. eEF2K may modulate the expression of some apoptotic proteins such as XIAP, c-FLIPL, Bcl-XL, PI3KCI and p70(S6K) to inhibit apoptotic process in cancer. On the other hand, it plays a regulatory role in autophagy involved in mTORC1, AMPK and Atg8, thereby promoting cancer cell survival. Additionally, eEF2K may play a crucial role in the crosstalk between apoptosis and autophagy in cancer. Collectively, these findings have led to the conclusions that eEF2K may contribute to carcinogenesis, and thus being utilized as a potential target for future cancer therapy.

In silico analysis and experimental validation of azelastine hydrochloride (N4) targeting sodium taurocholate co-transporting polypeptide (NTCP) in HBV therapy.

OBJECTIVES: The aim of this study was to explore sodium taurocholate co-transporting polypeptide (NTCP) exerting its function with hepatitis B virus (HBV) and its targeted candidate compounds, in HBV therapy. MATERIALS AND METHODS: Identification of NTCP as a novel HBV target for screening candidate small molecules, was used by phylogenetic analysis, network construction, molecular modelling, molecular docking and molecular dynamics (MD) simulation. In vitro virological examination, q-PCR, western blotting and cytotoxicity studies were used for validating efficacy of the candidate compound. RESULTS: We used the phylogenetic analysis of NTCP and constructed its protein-protein network. Also, we screened compounds from Drugbank and ZINC, among which five were validated for their authentication in HepG 2.2.15 cells. Then, we selected compound N4 (azelastine hydrochloride) as the most potent of them. This showed good inhibitory activity against HBsAg (IC50 = 7.5 µm) and HBeAg (IC50 = 3.7 µm), as well as high SI value (SI = 4.68). Further MD simulation results supported good interaction between compound N4 and NTCP. CONCLUSIONS: In silico analysis and experimental validation together demonstrated that compound N4 can target NTCP in HepG2.2.15 cells, which may shed light on exploring it as a potential anti-HBV drug.

Oncogenic and tumor suppressive roles of microRNAs in apoptosis and autophagy.

MicroRNAs (miRNAs), small and non-coding endogenous RNAs ∼22 nucleotides (nt) in length, have been known to regulate approximately 30 % of human gene expression at the post-transcriptional and translational levels. Accumulating data have demonstrated that certain miRNAs could exert an oncogenic and/or tumor suppressive function and might play essential roles in the regulation of apoptosis and autophagy in cancer. In this review, we summarize that certain oncogenic and tumor suppressive miRNAs could modulate apoptotic pathways in different types of cancer. Subsequently, we demonstrate that other miRNAs might play regulatory roles in the autophagic pathways of cancer. A limited number of oncogenic/tumor suppressive miRNAs could regulate apoptosis and autophagy, respectively, and cooperatively. Taken together, these findings would provide a new clue to elucidate more apoptotic and/or autophagic mechanisms of miRNAs for designing potential novel therapeutic strategies in cancer.

Sirtuin-3 (SIRT3), a therapeutic target with oncogenic and tumor-suppressive function in cancer.

Sirtuin-3 (SIRT3), a major mitochondria NAD+-dependent deacetylase, may target mitochondrial proteins for lysine deacetylation and also regulate cellular functions. And, SIRT3 is an emerging instrumental regulator of the mitochondrial adaptive response to stress, such as metabolic reprogramming and antioxidant defense mechanisms. Accumulating evidence has recently demonstrated that SIRT3 may function as either oncogene or tumor suppressor on influencing cell death by targeting a series of key modulators and their relevant pathways in cancer. Thus, in this review, we present the structure, transcriptional regulation, and posttranslational modifications of SIRT3. Subsequently, we focus on highlighting the Janus role of SIRT3 with oncogenic or tumor-suppressive function in cancer, which may provide more new clues for exploring SIRT3 as a therapeutic target for drug discovery.

Identification of novel caspase/autophagy-related gene switch to cell fate decisions in breast cancers.

OBJECTIVES: Caspases, a family of cysteine proteases with unique substrate specificities, contribute to apoptosis, whereas autophagy-related genes (ATGs) regulate cytoprotective autophagy or autophagic cell death in cancer. Accumulating evidence has recently revealed underlying mechanisms of apoptosis and autophagy; however, their intricate relationships still remain to be clarified. Identification of caspase/ATG switches between apoptosis and autophagy may address this problem. MATERIALS AND METHODS: Identification of caspase/ATG switches was carried out using a series of elegant systems biology & bioinformatics approaches, such as network construction, hub protein identification, microarray analyses, targeted microRNA prediction and molecular docking. RESULTS: We computationally constructed the global human network from several online databases and further modified it into the basic caspase/ATG network. On the basis of apoptotic or autophagic gene differential expressions, we identified three molecular switches [including androgen receptor, serine/threonine-protein kinase PAK-1 (PAK-1) and mitogen-activated protein kinase-3 (MAPK-3)] between certain caspases and ATGs in human breast carcinoma MCF-7 cells. Subsequently, we identified microRNAs (miRNAs) able to target androgen receptor, PAK-1 and MAPK-3, respectively. Ultimately, we screened a range of small molecule compounds from DrugBank, able to target the three above-mentioned molecular switches in breast cancer cells. CONCLUSIONS: We have systematically identified novel caspase/ATG switches involved in miRNA regulation, and predicted targeted anti-cancer drugs. These findings may uncover intricate relationships between apoptosis and autophagy and thus provide further new clues towards possible cancer drug discovery.

Naloxone inhibition of lipopolysaccharide-induced activation of retinal microglia is partly mediated via the p38 mitogen activated protein kinase signalling pathway.

OBJECTIVES: To investigate the effects and underlying mechanism of action of naloxone on lipopolysaccharide (LPS)-induced activation of retinal microglia in vitro. METHODS: Rat retinal microglia primary cultures were divided into four treatment groups: untreated; 1 µg/ml LPS for 12 h; 0.5, 1.0 or 2.0 µM naloxone for 30 min before LPS; 2.5 or 5.0 µM SB203580 for 12 h before LPS and naloxone. Levels of tumour necrosis factor (TNF)-α and interleukin (IL)-1ß were determined by enzyme-linked immuno sorbent assay. Western blot analysis and double immunofluorescence were used to examine activation of the mitogen activated protein kinase (MAPK) signalling pathway. RESULTS: LPS induced an increase in TNF-α and IL-1ß in culture supernatants, which was dose-dependently inhibited by naloxone. Naloxone also dose-dependently inhibited LPS-induced increases in phosphorylated p38 MAPK. Pretreatment of cells with SB203580 attenuated the inhibitory effect of naloxone on TNF-α and IL-1ß production. CONCLUSIONS: Naloxone suppressed LPS-induced activation of cultured retinal microglia and this suppression appeared to occur partly through the p38 MAPK signalling pathway. Naloxone may have therapeutic potential in neuro degenerative diseases characterized by the activation of microglia.