[Correlation analysis of age and microbial characteristics in saliva and feces of high-risk population of upper gastrointestinal cancer].

Objective: To explore the correlation between age and diversity and microbial composition in saliva and feces microbiota in high-risk population of upper gastrointestinal cancer. Methods: Based on the national project on early diagnosis and early treatment of upper gastrointestinal cancer, 38 participants were enrolled in Linzhou in Henan province in August 2019. The participant information was collected by questionnaire. Saliva and feces specimens were collected from each participant for 16S rRNA sequencing and bioinformatics analysis. Spearman rank correlation was used to analyze the correlation between age and α diversity (Observed ASVs and Shannon index) and relative abundance of microbiota (phyla, genera, and species) in saliva and feces. Results: The median age (age range) of 38 participants was 54 (43-60) years old, and there were 16 males (42.1%). The Observed ASVs of saliva was negatively correlated with age (rs=-0.35, P<0.05), but the observed ASVs of feces was not correlated with age. In saliva, the relative abundance of Treponema (rs=‒0.44, P<0.05), Alloprevotella (rs=‒0.42, P<0.05), and Porphyromonas (rs=‒0.41,P<0.05) were significantly negatively correlated with age. At the species level, the relative abundance of Porphyromonas endodontalis, Alloprevotella tannerae, Haemophilus influenza, Moraxella bovoculi, Prevotella sp.oral clone ID019, and Prevotella sp.oral clone ASCG10 in saliva were significantly negatively correlated with age, and the rs values were -0.50, -0.40, -0.38, -0.35, -0.33 and -0.33 (P<0.05), respectively. In feces, the relative abundance of Enterobacteria (rs=-0.35, P<0.05), Escherichia (rs=-0.33, P<0.05), and Bifidobacteria (rs=0.33, P<0.05) were correlated with age. At the species level, the relative abundance of Romboutsia sedimentorum, Citrobacter murliniae, and bacteroides uniformis in feces were correlated with age, and the rs values were -0.42, -0.37 and 0.36 (P<0.05), respectively. Conclusion: Age of the high-risk population of upper gastrointestinal cancer is correlated with the relative abundance of microbiota in saliva and feces.

[Arthroscopic evaluation of tibial plateau fractures combined with meniscal tears and cruciate ligamentous injuries].

Objectives: To investigate the types of meniscal tears and cruciate ligamentous injuries in patients with tibial plateau fracture(TPF) following arthroscopic examination. Methods: The clinical data of 216 patients with TPF who underwent closed reduction and internal fixation (CRIF) from January 2016 to January 2019 at Trauma Emergency center, the Third Hospital of Hebei Medical University were analyzed retrospectively. There were 147 males (147 knees) and 69 females (69 knees),aged 46.3 years (range: 18 to 80 years). All patients underwent closed reduction for the displaced fracture fragment with the use of bidirectional rapid redactor,and minimally invasive percutaneous plate osteosynthesis. Intra-operative arthroscopic examination was performed to exam the stability of meniscus and the continuity of cruciate ligamentous after CRIF. The percentages and types of meniscal tears and cruciate ligamentous injuries were recorded. Results: The overall percentages of meniscal tears associated with TPFs was 48.6%(105/216). The most common pattern of meniscal tears was longitudinal tears, accounting for 43.8% (46/105), and it occurred most frequently in Schatzker type Ⅱ (58.7%, 27/46). Furthermore, the percentage of meniscal complex tears was 17.1% (18/105), occurring most frequently in Schatzker type Ⅴ (9/18). The overall percentage of cruciate ligamentous injuries associated with TPFs was 17.1% (37/216), and the percentages of anterior cruciate ligament (ACL) injuries was 64.9%(24/37), the percentage of posterior cruciate ligament injuries was 35.1%(13/37). Avulsion fracture was the most common pattern in ACL injuries, accounting for 41.7% (13/24), and all occurred in the tibial insertion site. Conclusions: In the present study, the percentages of meniscal tears and ligamentous injuries in TPFs are 48.6% and 17.1%, respectively. The most common types are meniscal longitudinal tears and ACL injury, occurring most frequently in Schatzker type Ⅱ and Ⅳ, respectively. Recognition of concomitant meniscal tears and cruciate ligamentous injuries in TPFs is helpful for trauma physicians to choose the best surgical treatment.

Applications of microbial co-cultures in polyketides production.

Polyketides are a large group of natural biomolecules that are normally produced by bacteria, fungi and plants. These molecules have clinical importance due to their anti-cancer, anti-microbial, anti-oxidant and anti-inflammatory properties. Polyketides are biosynthesized from units of acyl-CoA by different polyketide synthases (PKSs), which display wide diversity of functional domains and mechanisms of action between fungi and bacteria. Co-culture of different micro-organisms can produce novel products distinctive from those produced during single cultures. This study compared the new polyketides produced in such co-culture systems and discusses aspects of the cultivation systems, product structures and identification techniques. Current results indicate that the formation of new polyketides may be the result of activation of previously silent PKSs genes induced during co-culture. This review indicated a potential way to produce pure therapeutic polyketides by microbial fermentation and a potential way to develop functional foods and agricultural products using co-co-culture of different micro-organisms. It also pointed out a new perspective for studies on the process of functional foods, especially those involving multiple micro-organisms.

Efficacy of repetitive transcranial magnetic stimulation for post-stroke depression: a systematic review and meta-analysis of randomized clinical trials

We aimed to conduct a meta-analysis to evaluate the efficacy of repetitive transcranial magnetic stimulation (rTMS) in patients with post-stroke depression (PSD). Six relevant electronic databases (PubMed, CENTRAL, Embase, Web of Science, CINAHL, and PsycINFO) were searched. Randomized controlled trials (RCTs) that compared rTMS with control condition for PSD were included. The mean change in depression symptom scores was defined as the primary efficacy outcome. Secondary outcomes included the remission rate of depression, stroke recovery, and cognitive function recovery. In total, 7 RCTs with 351 participants were included. At post-treatment, rTMS was significantly more effective than the control condition, with a standardized mean difference (SMD) of -1.15 (95%CI: -1.62 to -0.69; P<0.001, I2=71%) and remission with an odds ratio (OR) of 3.46 (95%CI: 1.68 to 7.12; P<0.001; I2=11%). As for stroke recovery, rTMS was also better than the control condition (SMD=-0.67, 95%CI: -1.02 to -0.32; P<0.001). However, no significant difference was found for cognitive function recovery between the two groups (SMD=4.07, 95%CI: -1.41 to 9.55; P=0.15). To explore the potential moderators for the primary outcome, a series of subgroup and sensitivity analyses were performed. The results implied that rTMS may be more effective in Asian samples than in North American samples (P=0.03). In conclusion, from the current evidence in this study, rTMS could be an effective treatment for patients with PSD. Further clinical studies with larger sample sizes and clearer subgroup definitions are needed to confirm these outcomes.

[Progress in research of Fusobacterium nucleatum and upper gastrointestinal cancer].

With the development of multi-omics and high throughput sequencing technology, studies have shown that the disorder of microbiota is related to various cancers. Nevertheless, the research on the relationship between upper digestive tract cancer or precancerous lesions and gastrointestinal microecology is still less. Fusobacterium nucleatum, one of the oral symbiotic bacteria, is also an opportunistic pathogen, which can promote the formation of tumor microenvironment and can be used as a new biomarker for the early detection and early diagnosis of cancer. In this study, by searching CNKI, Wanfang data, PubMed and Embase databases, it was found that the abundance of F. nucleatum in cancer tissues is higher than that in paracancerous tissues and associated with poor prognosis. The research of relationship between F. nucleatum and precancerous lesions needs to be carried out urgently. In addition, the types of specimens, sequencing technology, strain subtypes, carcinogenic mechanism and other directions still need to be explored.

[Detection and comparison of fiber count concentration in processing environment of asbestos and man-made mineral fiber].

Objective: To connect with the measurement data of asbestos dust fiber concentration in foreign countries, improve the accuracy of asbestos fiber detection in China, and understand the dust exposure in the working environment of asbestos and man-made mineral fiber production and processing sites in Zhejiang Province. The fiber count concentrations of working environment in glass fiber, ceramic fiber and asbestos processing plants were measured and compared. Methods: The dust concentration in the working environment of two glass fiber factories, one ceramic fiber factory and eight asbestos products processing factories was measured. The total dust mass concentration was measured according to GBZ/T 192.1-2007, and the fiber count concentration was measured by phase contrast microscope. Kruskal Wallis was used to test and compare the dust concentration in the working environment of each post. The correlation between asbestos mass concentration and fiber count concentration was analyzed by Spearman correlation. Results: Under the phase contrast microscope, there were many short and fine asbestos fibers in the field of vision, and there were many impurities around. The average dust concentration of asbestos processing plant was 3.2 f/ml, and the dust concentration of cotton ginning was the highest (6.68 f/ml) . There was a significantly positive correlation between asbestos fiber count concentration and mass concentration (r=0.535, P=0.033) . The average fiber count concentration of glass fiber factory was 0.001 f/ml, and the highest was 0.005 f/ml. The average fiber count concentration of ceramic fiber factory was 0.001 f/ml, and the highest was 0.006 f/ml. Conclusion: The fiber count concentration in the working environment of asbestos factory in Zhejiang Province is obviously over the standard, which is one of the important reasons for the high incidence of mesothelioma in this area. Short and small asbestos fibers are easy to be ignored when counting. It is necessary to improve the actual operation process of fiber counting to form a laboratory standard in China.

[Progress in research of influencing factors of oral microbiome and association between oral microbiome and upper gastrointestinal cancer].

The composition of human oral microorganism is numerous and complex and is easily affected by many factors. With the development of metagenomic technology, the important role of oral microbiome in the development of tumor has attracted extensive attention. A literature retrieval was conducted through PubMed, Embase, CNKI and WanFang database for an analysis on the characteristics of oral bacteria and its association with oral cancer, esophageal cancer and gastric cancer. The results indicated that oral microbiome can be influenced by age, gender, race, and lifestyle. Specific oral bacteria were associated with high risk of upper gastrointestinal cancer, indicating a potential role of oral microbiota to be the biomarker for upper gastrointestinal cancer. This paper summarizes the progress in the research of the association between oral microbiome and upper gastrointestinal cancer, showing a new direction for the exploration of microbiological etiology of upper gastrointestinal cancer and providing scientific evidence for the optimization of early detection and treatment of upper gastrointestinal cancer.

[Status of non-steroidal anti-inflammatory drugs use in areas with a high incidence of upper gastrointestinal cancer in China: a multi-center cross-sectional survey].

Objective: To describe the status of non-steroidal anti-inflammatory drugs (NSAIDs) use in areas with a high incidence of upper gastrointestinal cancer in China. Methods: This study was based on the National Key Research and Development Program of "National Precision Medicine Cohort of Esophageal Cancer" and "Study on Identification and Prevention of High-risk Populations of Gastrointestinal Malignancies (Esophageal cancer, Gastric cancer and Colorectal cancer)" . From January 2017 to August 2018, 212 villages or communities with a high incidence of esophageal cancer or gastric cancer were selected from 12 regions in 6 provinces. A total of 35 910 residents aged between 40 and 69 years old who met the inclusion criteria and signed the informed consent were investigated and enrolled in this study. The use of NSAIDs, demographic characteristics, health-related habits, height, weight, and blood pressure were collected by the questionnaire and physical examination. The status of main NSAIDs (aspirin, acetaminophen and ibuprofen) use with the difference varying in genders, age groups and regions were analyzed by using χ(2) test and Cochran-Armitage trend analysis method. Results: Of 35 910 subjects, the mean age was (54.6±7.1) years old and males accounted for 43.42% (15 591). The overall prevalence of NSAIDs intake was 4.56% (1 638), but it significantly varied in different provinces (P<0.001). The overall prevalence of NSAIDs intake was 4.87% (1 750) in females, which was significantly higher than that in males 4.24% (1 524) (P<0.001). The prevalence of NSAIDs intake increased with age (P for trend <0.001). As the frequency of NSAIDs intake increased, the incidence of gastrointestinal symptoms, gastrointestinal ulcers and black stools increased (P for trend <0.05 for all). Conclusion: The use of NSAIDs is prevalent in some areas with a high incidence of upper gastrointestinal cancer in China. The increased use of NSAIDs may lead to more adverse effects related to the gastrointestinal tract.

Efficacy of continuous renal replacement on acute renal injury developed in severe sepsis.

Sepsis is a systemic inflammatory response that can further develop into severe sepsis (septic shock), which eventually leads to multiple organ dysfunction syndrome (MODS). This study aimed to assess the effects of continuous renal replacement therapy (CRRT) on acute renal injury caused by severe sepsis by monitoring biochemical parameters. A total of 60 patients with septic shock and acute kidney injury were included. The control group (30 cases) was treated with routine treatment and intermittent renal replacement therapy (IRRT). The experimental group (30 cases) was treated with routine treatment and continuous renal replacement therapy CRRT. The changes in inflammation and biochemical indexes and APACHE- II score were evaluated before the treatment and 1, 3, and 7days after the treatment. The inflammatory markers (neutrophil percentage, C-reactive protein (CRP) and procalcitonin (PCT) levels) in the experimental group decreased significantly after treatment. In the control group, the index of inflammation still increased one day after treatment and decreased on day 3 of treatment. After treatment, blood lactate, serum creatinine and urea nitrogen levels decreased, but the urine volume increased. After treatment, the vasoactive dose in the experimental group was significantly lower than that of the control group (P less than 0.05). CRRT is a good treatment for septic shock-related acute kidney injury, which improves biochemical indicators and protects kidney function.

Vacuolar protein sorting 4 is required for silkworm metamorphosis.

Vacuolar protein sorting 4 (Vps4) not only functions with its positive regulator vacuolar protein sorting 20-associated 1 (Vta1) in the multivesicular body (MVB) pathway but also participates alone in MVB-unrelated cellular processes. However, its physiological roles at the organism level remain rarely explored. We previously identified their respective homologues Bombyx mori Vps4 (BmVps4) and BmVta1 from the silkworm, a model organism for insect research. In this study, we performed fluorescence quantitative real-time PCR and Western blot to globally characterize the transcription and protein expression profiles of BmVps4 and BmVta1 during silkworm development and in different silkworm tissues and organs. The results showed that they were significantly up-regulated in metamorphosis, adulthood and embryogenesis relative to larval stages, and displayed a roughly similar tissue-and-organ specificity for transcriptions in silkworm larvae. Importantly, BmVps4 was down-regulated during the early period of the fifth instar, reaching the lowest level of transcription on Day 6, then up-regulated from Day 7 to the wandering, spinning and pupal stages, and down-regulated again in adulthood. Moreover, knocking down BmVps4 by RNA interference significantly inhibited silk gland growth, shortened spinning time, prolonged pupation, reduced pupal size and weight, and increased moth wing defects. Together, our data demonstrate the critical and broad requirements for BmVps4 in silkworm metamorphosis.

Genistein increases progesterone secretion by elevating related enzymes in chicken granulosa cells.

Genistein, a biologically active isoflavone, exists in many soy products. It is well known that genistein binds to both oestrogen receptor alpha (ERα) and oestrogen receptor beta (ERß), but it has a higher affinity to ERß. Genistein can also bind to the G protein-coupled receptor 30 (GPR30, also known as G protein-coupled oestrogen receptor 1 or GPER). Furthermore, weak oestrogenic activity has been found in genistein, but the mechanism of action remains unknown. The aim of this study was to investigate the in vitro effects of genistein on the secretion of progesterone (P4) and oestradiol (E2) in chicken granulosa cells harvested from follicles, as well as the mRNA expression of ERs in these cells. In addition, we examined the expression of key enzymes including steroidogenic acute regulatory protein (StAR), cytochrome P450 side-chain cleavage (P450scc), and 3ß-hydroxysteroid dehydrogenase (3ß-HSD) in the process of P4 synthesis. The results showed that genistein did not affect the viability of granulosa cells, nor was the proliferating cell nuclear antigen (PCNA) protein changed. Among the 1-, 10-, 100-, and 1,000-nM concentrations tested, treatment with 1 nM genistein for 48 h significantly increased P4 but did not affect E2 secretion. Real-time PCR results showed that the ERß gene expression in granulosa cells was markedly upregulated by 1 nM genistein treatment for 48 h, but there was no significant difference in ERα and GPR30 expression. Genistein also increased the gene expression of StAR, P450scc and 3ß-HSD in the cultured granulosa cells. These results indicate that genistein acts directly on chicken granulosa cells to increase P4 production by upregulating the gene expression of key enzymes through binding in ERß. It may exert positive effects on the reproduction of late-laying hens and act as an effective and safe feed additive for animals.

[Progress in research of human microbiota for upper gastrointestinal tumors and precancerous lesions].

With the widely application of the metagenomics, the relationship between microbiota and disease has become a hot research topic. Understanding the potential association between upper gastrointestinal cancer or precancerous lesions and microbiota may play an important role in the early detection, clinical diagnosis and treatment, and prognostic evaluation of upper gastrointestinal cancer. Therefore, a literature retrieval was conducted by using PubMed, Embase and wanfang databases to summarize the latest research progress in the microbiota of upper gastrointestinal cancer, including oral, esophageal, gastric cancer and precancerous lesions. Lower microbial diversity or richness in esophageal cancer and precancerous lesions and specific prognostic biomarkers for esophageal cancer were found. Lactobacillus richness showed an increase trend during the process from gastritis to gastric cancer. This paper summarizes the progress in the research of potential biological etiology of upper gastrointestinal cancer from the perspective of metagenomics in order to provide evidence on the, prevention and control of upper gastrointestinal cancer.

The significance of Akt/NF-κb signaling pathway in the posterior cataract animal model.

OBJECTIVE: To establish SD rat posterior capsular opacification (posterior capsular opacification- PCO) animal model, and to detect the expression of Akt/NF-kb signaling pathway in the PCO model. METHODS: 30 healthy SD rats were randomly divided into control group (0d) and the experimental groups (7d and 14 d), there were 10 rats at all time points. All rats (right eye) were treated with the lens capsule, and the inflammatory reaction of the anterior segment of the eye and the occurrence of PCO at different time points were observed under the microscope. The TGF-ß concentration of humor aquosus was measured at the different time points by ELISA method. Eyeballs were removed after the rats were killed. RT-PCR method was used to detect the gene expression levels of Akt and NF-κb and Westen Blot method to detect the protein expression of Akt, p-Akt, NF-κb and p-NF-κb. RESULTS: TGF-ß concentration, Akt and NF-κb gene expression, and Akt, p-Akt, NF-κb and p-NF-κb protein expression in humor aquosus, increased with the time and the time-dependence was significant. CONCLUSION: Akt/NF-κb signaling pathway may be closely related to the occurrence and development of PCO, which may be related to the role of protein phosphorylation (Fig. 5, Ref. 20).

Strategies to increase the efficacy of using gut microbiota for the modulation of obesity.

Obesity is one of the most serious global public health challenges of the 21st century. The adjustment of gut microbiota is often recommended as an efficient strategy to treat obesity. This modulation of gut microbiota can be performed by many methods, including dietary intervention, antibiotic application, the use of prebiotics and probiotics, bariatric surgery and faecal microbiota transplantation. In most cases, positive effects have been observed in response to treatment, but invalid and even contrary effects have also been observed in some cases due to factors that are unrelated to intervention methods, such as genetic factors, patient age or gender, environmental microbiota, climate, geography and lifestyle. These factors can cause variation of gut microbial populations and thus should also be taken into consideration when selecting modulation strategies.

TDAG8 activation attenuates cerebral ischaemia-reperfusion injury via Akt signalling in rats.

BACKGROUND: T-cell death-associated gene 8 (TDAG8), a member of the proton-sensitive G-protein-coupled receptor (GPCR) class with an immune-specific expression profile, was recently shown to be expressed in the rat brain; however, its role in ischaemic stroke remains unknown. METHODS: We initially confirmed the time-dependent expression of TDAG8 in rat brain tissue after ischaemic stroke and reperfusion. Further evaluations were performed to increase TDAG8 expression 6h prior to middle cerebral artery occlusion (MCAO) by injecting a specific agonist, BTB09089, into the lateral ventricle to increase TDAG8 expression. Twenty-four hours before MCAO, a specific small interfering RNA (siRNA) was introduced. The infarction volume, neurological deficit score and cleaved caspase-3 and Bcl-2 expression were used to assess the effects of TDAG8 on ischaemic stroke. Finally, the effects of TDAG8 on the development of primary cortical neurons exposed to oxygen-glucose deprivation (OGD) were investigated. RESULTS: TDAG8 expression increased both in vivo and in vitro. Pretreatment with BTB09089 up-regulated TDAG8 and Bcl-2 expression and down-regulated cleaved caspase-3 expression, while the infarction volume was reduced, and neurological deficits were ameliorated 24 and 72h after MCAO. However, the protective effects of TDAG8 were reversed when its level was reduced in TDAG8-deficient rats. More importantly, these findings are consistent with data from neurons subjected to OGD. CONCLUSIONS: TDAG8 plays an important neuroprotective role through inhibition of neuronal apoptosis and alleviation of neurological deficits by activating the Akt signalling pathway in rats.

[The efficacy of thyroid hormone replacement therapy in patients with hypothyroidism and OSAHS: a Meta analysis].

Objective:To systematically evaluate the impact of thyroid hormone replacement in patients with OSAHS and hypothyroidism.Method:The related case-control study of thyroid hormone replacement in patients with OSAHS and hypothyroidism had been searched from Cochrane Library, PubMed, CNKI, Chinese Biomedical Literature Database, Wanfang Resource Database.The case-control study which were in line with the condition need to be evaluated the quality and to be extracted in literature. The RevMan 5.3 and STATA softwares were applied to carry out the Meta analysis.Result:Seven literatures of case-control study were included. The Meta analysis showed that: After the thyroid hormone replacement, the patient's AHI index, TSH index, LSaO2 index were significantly improved (P< 0.05). The AHI index statistical results of the patients were [SMD= 3.15, 95%CI: (4.36-1.94), P< 0.000 01; I²= 96%], TSH index were [SMD= 4.15,95%CI: (1.15-7.15), P= 0.007; I²= 99%], LSaO2 index were [SMD=-1.08, 95%CI: (-1.46--0.70), P< 0.000 01, I²= 68%].Conclusion:The use of thyroid hormone replacement can effectively reduce the patient's hypothyroidism symptoms and AHI symptoms.

Analysis of gene expression identifies candidate markers and pathways in pre-eclampsia.

Pre-eclampsia is a serious multisystem disorder and causes significant increase in both maternal and foetal morbidity and perinatal mortality globally. Due to the limited understanding of the molecular mechanism of pre-eclampsia, the current study conducted bioinformatic analyses to screen key regulators involved in pre-eclampsia. The gene expression profiling dataset GSE44711 containing 8 early-onset pre-eclampsia placentas and 8 gestational-age-matched control placentas was downloaded from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) were screened by limma software package, which were then subjected to Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analysis on the Database for Annotation, Visualization, and Integrated Discovery website. Finally, protein-protein interaction network was constructed using the Search Tool for the Retrieval of Interacting Genes database. In total, 192 DEGs including 106 upregulated and 86 downregulated genes were obtained. Proteoglycan 2 and podoplanin were the most significantly up- and downregulated genes, respectively. In addition, three potential pathways and their related DEGs: spermidine/spermine N1-acetyltransferase 1, amiloride-binding protein 1 and adenosylmethionine decarboxylase 1 were associated with arginine and proline metabolism. Vascular endothelial growth factor C; phosphatidylinositol-4, 5-bisphosphate 3-kinase, catalytic subunit beta; collagen, type I, alpha 1 (COL1A1); and fibronectin 1 (FN1) were associated with focal adhesion. COL6A1 as well as COL1A1 and FN1 were involved in extra-cellular matrix-receptor interaction. The current study identified several potential genes and three pathways which may be considered as candidate targets for diagnosis and therapy of pre-eclampsia.

Dexamethasone reverses monocrotaline-induced pulmonary arterial hypertension in rats.

Pulmonary arterial hypertension (PAH) is associated with dysregulated bone morphogenetic protein receptor (BMPR)-II signaling and pulmonary vascular inflammation. We evaluated the effects of dexamethasone on monocrotaline (MCT)-induced PAH in rats for potential reversal of PAH at late time-points. Saline-treated control, MCT-exposed, MCT-exposed and dexamethasone-treated rats (5 mg·kg⁻¹·day⁻¹, 1.25 mg·kg⁻¹ and 2.5 mg·kg⁻¹·48 h⁻¹) were evaluated at day 28 and day 35 following MCT for haemodynamic parameters, right ventricular hypertrophy, morphometry, immunohistochemistry, and IL6 and BMPR2 expression. Dexamethasone improved haemodynamics and pulmonary vascular remodelling, preventing PAH development at early (day 1-14 and 1-28) and reversing PAH at late (day 14-28 and 21-35) time-points following MCT, as well as improving survival in MCT-exposed rats compared with controls. Both MCT-induced pulmonary IL6 overexpression and interleukin (IL)-6-expressing adventitial inflammatory cell infiltration were reduced with dexamethasone. This was associated with pulmonary BMPR2 downregulation following MCT, which was increased with dexamethasone, in whole lung and control pulmonary artery smooth muscle cells. Dexamethasone also reduced proliferation of rat pulmonary artery smooth muscle cells in vitro. Experimental PAH can be prevented and reversed by dexamethasone, and survival is improved. In this model, mechanisms may involve reduction of IL-6-expressing inflammatory cells, restoration of pulmonary BMPR2 expression and reduced proliferation of vascular smooth muscle cells.

Platonin inhibits LPS-induced NF-kappaB by preventing activation of Akt and IKKbeta in human PBMC.

OBJECTIVE: Platonin is a potent macrophage-activating agent and an immunomodulator. It has been used to treat trauma, ulcers and some acute inflammations. Although platonin has desirable anti-inflammatory effects, its mechanism of action is not clear. In the present study, we investigated the effect of lipopolysaccharide (LPS) on human peripheral blood mononuclear cells (PBMC) gene expression and determined the molecular mechanism of platonin action in the LPS-induced NF-kappaB signaling pathway. METHODS: In human PBMC, treatments with platonin (0.1 microg/ml) suppressed the production of pro-inflammatory cytokines (IL-1beta, TNF-alpha and IL-6), nitric oxide (NO) and multiple kinases (iNOS, COX-2) induced by LPS. We found that the effect of platonin on LPS-induced production of pro-inflammatory cytokines and multiple kinases was due to the inhibition of NF-kappaB activity. Additional work revealed that this inhibition was caused by a reduction in the phosphorylation and subsequent degradation of IkappaBalpha. Further investigation revealed that Akt and IkappaB kinase beta (IKKbeta) activity were also inhibited during platonin treatment, which may be what prevented NF-kappaB from entering the nucleus and activating gene transcription. CONCLUSIONS: These results suggest the anti-inflammatory activity of platonin is a result of reduced NF-kappaB activity due to inhibition of Akt and IKKbeta.

Arp2/3 complex-mediated actin polymerisation occurs on specific pre-existing networks in cells and requires spatial restriction to sustain functional lamellipod extension.

The classical Arp2/3-mediated dendritic network defines the cytoskeleton at the leading edge of crawling cells, and it is generally assumed that Arp2/3-mediated actin polymerization generates the force necessary to extend lamellipods. Our previous work suggested that successful lamellipod extension required not only free barbed ends for actin polymerization but also a proper ultrastructural organization of the cytoskeleton. To further explore the structural role of the Arp2/3 complex-mediated networks in lamellipod morphology and function, we performed a detailed analysis of the ultrastructure of the Arp2/3-mediated networks, using the WA domains of Scar and WASp to generate mislocalised Arp2/3 networks in vivo, and to reconstruct de novo Arp2/3-mediated actin nucleation and polymerization on extracted cytoskeletons. We present here evidence that spatially unrestricted Arp2/3-mediated networks are intrinsically three-dimensional and multilayered by nature and, as such, cannot sustain significant polarized extension. Furthermore, such networks polymerize only at preferred locations in extracted cells, corresponding to pre-existing Arp2/3 networks, suggesting that the specific molecular organization of the actin cytoskeleton, in terms of structure and/or biochemical composition, dictates the location of Arp2/3 complex-mediated actin polymerization. We propose that successful lamellipod extension depends not only on localized actin polymerization mediated through local signalling, but also on spatial restriction of the Arp2/3 complex-mediated nucleation of actin polymerization, both in terms of location within the cell and ultrastructural organization of the resulting network.