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1.
Biomed Pharmacother ; 123: 109801, 2020 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-31901717

RESUMO

The aim of this study was to investigate the effect of Gotfried positive reduction (GPR) on repair of femoral neck fracture in rabbits and its underlying mechanisms. Male New Zealand white rabbits were employed to establish the model of femoral neck fracture. All the rabbits were randomly divided into four groups: control, open accurate reduction (OR), closed Gotfried negative support reduction (CR-N) and closed Gotfried positive support reduction (CR-P). At the 8th and 12th week after surgery, the anteroposterior and lateral radiographs of their hip joints were taken by X-ray, and local hemodynamics of their hip joints was detected by ultrasound. Histological examination was evaluated by HE staining and bone biological strength test was measured by testing machine, which was performed to study the repair of femoral neck fracture. Osteogenesis and angiogenesis-related proteins were measured by western blot in bone tissues and synovial tissues. The results revealed that the fracture healing intensity and blood supply in CR-P were better than those in CR-N and much more excellent than those in OR. In addition, the content of bone morphogenetic protein2 (BMP2), platelet derived growth factor (PDGF) and ocsteocalcin was higher in CR-P group than in CR-N, while lower in CR-P than OR. Furthermore, the expression of BMP2, COL-2 and angiopoietin (ANGPT) was upregulated in CR-P compared to CR-N and OR. Taken together, our results indicated that GPR was able to promote the repair of femoral neck fracture via enhancing osteogenesis and angiogenesis, which is valuable to us and shows good application prospect in bone tissue repair.

2.
Br Poult Sci ; 2020 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-31918572

RESUMO

1. Melanin content is considered an important indicator of meat quality in black-boned chickens, which have a high market value. To understand the complex physiological processes underlying muscle melanogenesis in this chicken, differentially expressed miRNAs (DEMs) were detected between black muscle (BM) and white muscle (WM) of chickens using high-throughput sequencing technology. Six small RNA libraries were constructed, and more than 16.75 million clean reads were obtained for each library.2. A total of 582 known miRNAs and 65 novel miRNAs were identified from the six chicken sequence libraries. A total of 19 DEMs were identified between the two groups, of which nine were upregulated and 10 were downregulated. Furthermore, the DEMs were predicted to target 572 genes.3. Certain DEMs (such as miR-204, miR-133b, and miR-12229-3p) and their target genes may play an important role in muscle melanogenesis of chickens. These findings provide a foundation for clarifying the miRNA regulatory mechanisms involved in muscle pigmentation in avian species.

3.
BMC Infect Dis ; 20(1): 11, 2020 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-31906870

RESUMO

BACKGROUND: Brucellosis is endemic in many areas in China. The current diagnosis of Brucellosis predominantly relies on the traditional bacterial culture and serum agglutination test. In this study, we aimed to explore the value of ELISA in the diagnosis of Brucellosis in Chinese population. METHODS: We recruited 235 patients with a diagnosis of Brucellosis at different clinical stages: 117 in acute, 78 in subacute, and 40 in chronic. We also recruited 248 control patients who presented with similar clinical symptoms but with a different diagnosis other than Brucellosis. In addition, 90 healthy volunteers were also recruited. Bacterial culture, agglutination test and ELISA assay were performed to detect Brucella spp. RESULTS: Among 235 patients with Brucellosis, 51 (21.7%) was positive for bacterial culture, 150 (63.8%) were positive by agglutination test, and 232 (98.7%) were positive by ELISA (IgG and/or IgM). When we stratified the patients based on the disease stages (acute, subacute and chronic), ELISA was the most sensitive method and showed a highest positive rate in all stages. By Receiver Operating Characteristic Curve analysis of ELISA results, we found that measurement of IgG level was superior to measurement of IgM level (AUC, 0.993 versus 0.877). Since the measurement of IgG itself missed rare cases in acute phase, we recommended measuring IgG and IgM simultaneously by ELISA for the diagnosis of Brucellosis. In term of the specificity of ELISA in the diagnosis of Brucellosis, our study showed that only 1.6% (4/248) non-Brucellosis patients were positive by ELISA; all positive cases were IgM only and none showed positive IgG. Similar results were found in healthy volunteers. In summary, our study concluded that ELISA is the most sensitive and specific method to detect Brucellosis in Chinese population. CONCLUSIONS: ELISA assay is sensitive, fast, and convenient to detect Brucellosis. It shows the high sensitivity and specifity and should be used as a routine lab test when Brucellosis is suspected in clinical practice.

5.
Biomed Pharmacother ; 122: 109707, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31918278

RESUMO

Osteosarcoma (OS) is the most common type of bone cancer in children and adolescents. LncRNA differentiation antagonizing nonprotein coding RNA (DANCR) has been reported to be aberrant expression in osteosarcoma and contribute to proliferation, migration and invasion of cancer cells. Here, we further explore the exacted molecular mechanism of DANCR in OS. The expression of DANCR, microRNA-216a-5p (miR-216a-5p) and SOX5 was analyzed by quantitative real-time polymerase chain reaction (qRT-PCR). Cells proliferation and apoptosis were analyzed by WST-1assay or flow cytometry, respectively. The migratory and invasion abilities were measured by transwell assay. Western blot was used to detect the level of SOX5 and autophagy-related protein of Beclin1, LC3-I and LC3-II. The interaction among DANCR, miR-216a-5p and SOX5 was explored by luciferase reporter assay, RIP assay or Pull-down assay. Murine xenograft model was established using 143B cells transfected with sh-DANCR. We found that a significantly elevated of DNACR was detected in osteosarcoma tissue and cell lines. Functional experiments suggested that down-regulation of DANCR inhibited cells proliferation, migration, invasion and autophagy but induced apoptosis in osteosarcoma in vitro. Additionally, we also determined knockdown of DANCR inhibited the growth and autophagy of osteosarcoma in vivo. DANCR was a sponge of miR-216a-5p activity. DANCR regulated survival of osteosarcoma through targeting miR-216a-5p. Additionally, SOX5 was a direct target of miR-216a-5p, overexpression miR-216a-5p exerted inhibition effects via down-regulating SOX5 expression. Furthermore, DANCR regulated SOX5 expression by sponging to miR-216a-5p. In conclusion, LncRNA DANCR silence inhibits SOX5-medicated progression and autophagy in osteosarcoma via regulating miR-216a-5p which indicating DANCR may act as a potential prognostic biomarker and therapeutic target for osteosarcoma.

6.
J Clin Lab Anal ; : e23173, 2020 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-31903640

RESUMO

BACKGROUND: Primary adrenal lymphoma (PAL) is an infrequent malignant disease and there is no consensus classification or specialized treatment for it. However, PAL has been observed to have worse prognosis compared with other extrarenal malignant lymphomas and diffuse large B-cell lymphoma presents as the most common subtype of PAL. METHODS: The current study reported two cases of adrenal diffuse large B-cell lymphoma with high PD-L1 expression and discussed the clinical significance of PD-L1 through literature review. KEY RESULTS: The PD-L1 expression rate of the two cases was 90% and 80%, respectively, which was significantly higher than those reported in the literature. CONCLUSION: PAL is a type of non-Hodgkin's lymphoma with low incidence and poor prognosis, and it is necessary to further explore the early use of immunological checkpoint inhibitors for patients with higher expression of PD-L1 and with rituximab-resistance.

7.
Environ Sci Technol ; 2020 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-31904230

RESUMO

The dry impinger method, the indirect dilution method, and the direct dilution method can be used to measure the condensable particulate matter (CPM) emissions. We tested these methods in determining the CPM emissions from typical stationary sources in China and found that the CPM concentrations measured by the dry impinger method are much higher than those measured by the two dilution methods, regardless of the type of stationary source. The soluble gases (e.g., SO2, HCl, and NH3) partially absorbed by the impinger solutions are the main reason for the overestimation of the CPM concentrations. This is supported by detecting more water-soluble ions (e.g., SO42-, Cl-, and NH4+) from the CPM collected using the dry impinger method. The positive biases of the CPM concentration and its water-soluble ions collected by the dry impinger method are larger under the conditions with high concentrations of soluble gases such as at the flue gas desulfurization inlet in coal-fired power plants. Comparing to the direct dilution method, the indirect dilution method can better capture the rapid dilution, cooling, and condensation of condensable gas precursors in the presence of filterable particulate matter and is recommended as the appropriate method for the CPM measurement in stationary sources.

8.
Medicine (Baltimore) ; 99(2): e18708, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31914078

RESUMO

Sarcopenia is a geriatric syndrome and it impairs physical function. Patients with type 2 diabetes mellitus (T2DM) are at a higher risk of sarcopenia. The purpose of this study is to explore characteristics of general information and metabolic factors of sarcopenia in patients with T2DM in the northeast of China, and provide information for the prevention and treatment of sarcopenia in clinical practice.Patients with T2DM aged ≥65 were recruited in Changchun from March 2017 to February 2018. Questionnaires of general information, physical examination, laboratory and imaging examination were conducted. The patients were assigned into sarcopenia group and non-sarcopenia group according to the diagnostic criteria proposed by Asian working group for sarcopenia (AWGS), and the differences between 2 groups were analyzed.A total of 132 participants were included in this study, of which, 38 (28.8%) were diagnosed with sarcopenia. 94 (71.2%) were with no sarcopenia. Logistic regression analysis showed that age (OR: 1.182, 95%CI: 1.038-1.346), trunk fat mass (TFM) (OR: 1.499, 95%CI: 1.146-1.960) and free thyroxine (FT4) (OR: 1.342, 95%CI: 1.102-1.635) were independent risk factors for sarcopenia. BMI (body mass index) (OR: 0.365, 95%CI: 0.236-0.661), exercise (OR: 0.016, 95%CI: 0.001-0.169), female (OR: 0.000, 95%CI: 0.00-0.012), metformin (OR: 0.159, 95%CI: 0.026-0.967) and TSM (trunk skeletal muscle mass) (OR: 0.395, 95%CI: 0.236-0.661) were protective factors for sarcopenia.Sarcopenia in patients with T2DM is associated with increased age, increased TFM and increased FT4 level. Regular exercise, female, metformin administrations, high BMI and increased TSM are associated with lower risk of sarcopenia.

9.
FASEB J ; 34(1): 1018-1037, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31914603

RESUMO

Recombinant antimicrobial peptide microcin J25 (MccJ25) causes potent antimicrobial activity against enterotoxigenic Escherichia coli (ETEC) in vitro; however, independently of this activity, its role in suppressing intestinal inflammation and epithelial barrier injury in vivo remains unclear. We investigated the therapeutic effects of MccJ25 on intestinal inflammation and epithelial barrier dysfunction and the underlying mechanism, using gentamicin for comparison. In a mouse model of intestinal inflammation, therapeutic administration of either MccJ25 or gentamicin after ETEC K88 infection attenuated clinical symptoms, reduced intestinal pathogen colonization, improved intestinal morphology, and decreased inflammatory pathologies and intestinal permeability, ultimately improving the hosts' health. MccJ25 also attenuated ETEC-induced mouse intestinal barrier dysfunction by enhancing tight junction proteins (TJPs). Using the human epithelial cell line Caco-2, we verified the epithelial barrier-strengthening and mucosal injury-alleviating effects of MccJ25 on ETEC infection: increased expression of TJPs by activating the p38/MAPK pathway, balancing the microbiota, and improving short-chain fatty acid concentrations in the cecum of ETEC-infected mice. Although gentamicin and MccJ25 had similar effects in the inflamed gut, MccJ25 was superior to gentamicin with regard to defending the host from ETEC infection. Overall, MccJ25 may be a promising therapeutic drug for treating enteric pathogen-induced intestinal inflammation diseases.

10.
Environ Pollut ; 259: 113924, 2020 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-31926396

RESUMO

Microalgal aggregation is a key to many ecosystem functions in aquatic environments. Yet mechanistic understanding of microalgae aggregation, especially the interactions with ubiquitous bacteria populations, remains elusive. We reported an experimental study illustrating how the emerging bacterial populations interacted with a model microalga (Chlamydomonas microsphaera) cells and the consequent aggregation patterns. Results showed that the emergence of bacterial populations significantly stimulated C. microsphaera aggregation. Both bacterial and C. microsphaera motilities were remarkably excited upon coculturing, with the mean cell velocity being up to 2.67 and 1.80 times of those of separate bacterial and C. microsphaera cultures, respectively. The stimulated bacterial and C. microsphaera cell velocity upon coculturing would likely provide a mechanism for enhanced probability of cell-cell collisions that led to amplified aggregation of C. microsphaera population. Correlation analysis revealed that bacterial resource foraging (for polysaccharides) was likely a candidate mechanism for stimulated cell motility in an organic carbon source-limited environment, whereby C. microsphaera-derived polysaccharides serve as the sole organic carbon source for heterotrophic bacteria which in turns facilitates bacteria-C. microsphaera aggregation. Additional analysis showed that bacterial populations capable of successive decomposing algal-derived organic matters dominated the cocultures, with the top five abundant genera of Brevundimonas (24.78%), Shinella (17.94%), Sphingopyxis (11.62%), Dongia (5.82%) and Hyphomicrobium (5.45%). These findings provide new insights into full understanding of microalgae-bacteria interactions and consequent microbial aggregation characteristics in aquatic ecosystems.

11.
World J Microbiol Biotechnol ; 36(1): 12, 2020 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-31897767

RESUMO

Superoxide dismutases (SODs) have been shown to exhibit high levels of conservation and exist in almost all aerobic organisms and even many strict anaerobes. There are four SODs in Bacillus cereus 0-9, and this coexistence of multiple homologous enzymes is of great significance in the evolution of bacteria. We hypothesized that the four sod genes in B. cereus 0-9 constituted non-redundant protection against oxidative damage in vivo and played unique roles in the pathogenicity of B. cereus 0-9 during different phases or growth environments. To test this hypothesis, we constructed four single-knockout mutants (∆sodA1, ∆sodA2, ∆sodS, and ∆sodC) and a mutant lacking all four sod genes (∆sod-4) of B. cereus 0-9 and assessed their various phenotypes. Our results indicated that sodA1 plays a major role in tolerance to intracellular oxidative stress and spore formation. The ∆sodA1 and ∆sod-4 mutants were very sensitive to oxidants. The spore formation of the ∆sodA1 mutant was dramatically delayed, and the ∆sod-4 mutant did not form any spores under our experimental conditions. The sodA2 gene may play an important role in negative regulation of swarming motility, pathogenicity, and phospholipase and haemolytic activity of B. cereus but also a role in positive regulation of biofilm formation under our experimental conditions. The other two genes, sodS and sodC, were key to the pathogenicity of B. cereus. The lethal rates of Helicoverpa armigera infected by the ∆sodS and ∆sodC mutants were only 26.67%, while wild-type B. cereus 0-9 caused lethality in up to 86.67% of the insects at 24 h after injection. Moreover, the ∆sod-4 mutant caused a reduced death rate of H. armigera of 46.70%, which was slightly higher than that caused by the ∆sodS and ∆sodC strains. Thus, these four sod genes were non-redundant for oxidative stress and may play different additional roles in B. cereus 0-9. These results can help us to further understand the biocontrol characteristics of B. cereus 0-9 and lay a theoretical foundation for further research.

12.
J Med Chem ; 2020 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-31910010

RESUMO

Dysregulation of translation initiation factor 4E (eIF4E) activity occurs in various cancers. Mitogen-activated protein kinase (MAPK) interacting kinases 1 and 2 (MNK1 and MNK2) play a fundamental role in activation of eIF4E. Structure-activity relationship-driven expansion of a fragment hit led to discovery of dual MNK1 and MNK2 inhibitors based on a novel pyridine-benzamide scaffold. The compounds possess promising in vitro and in vivo pharmacokinetic profiles and show potent on target inhibition of eIF4E phosphorylation in cells.

13.
Artigo em Inglês | MEDLINE | ID: mdl-31899611

RESUMO

Patients with cancer have reduced immune function and are susceptible to bacterial infection after surgery, chemotherapy or radiotherapy. Spherical nanoparticles formed by the self-assembled peptide V6K3 can be used as a carrier for poorly soluble antitumor drugs to effectively deliver drugs into tumor cells. V6K3 was designed to achieve nanoparticle-to-nanofiber geometric transformation under induction by plasma amine oxidase (PAO). PAO is commercially available and functionally similar to lysyl oxidase (LO), which is widely present in serum. After the addition of fetal bovine serum (FBS) or PAO, the secondary structure of the peptide changed while the spherical nanoparticles stretched and transformed into nanofibers. The conversion of the self-assembled morphology reveals the susceptibility of this amphiphilic peptide to subtle chemical modifications and may lead to promising strategies to control self-assembled architecture via enzyme induction. Enzymatically self-assembled V6K3 had bactericidal properties after PAO addition that were surprisingly superior to those before PAO addition, enabling this peptide to be used to prevent infection. The amphiphilic peptide V6K3 displayed antitumor properties and low toxicity in mammalian cells, demonstrating good biocompatibility, as well as bactericidal properties to prevent bacterial contamination. These advantages indicate that enzymatically self-assembled V6K3 has great biomedical application potential in cancer therapy.

14.
Int J Cancer ; 2020 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-31900925

RESUMO

To examine the associations between fasting blood glucose (FBG) trajectories, the changes in FBG over time, and the risk of cancer, particularly for gastrointestinal cancer, we enrolled 69 742 participants without diabetes from the Kailuan cohort. FBG trajectories (2006-2010) were modeled by group-based trajectory modeling, and five trajectories were identified: low-increasing (n=6275), moderate-stable (n=44 120), moderate-increasing (n=10 149), elevated-decreasing (n=5244), and elevated-stable (n=3954). A total of 1364 cancer cases were accumulated between 2010 and 2015, including 472 gastrointestinal cancer cases. We used Cox proportional hazards regression models to evaluate the associations between FBG trajectory patterns and the risk of cancer. We further assessed the associations while carefully controlling for initial body mass index (BMI) in 2006 and for changes in BMI during 2006-2010. Relative to the moderate-stable group, we found a higher hazard ratio (HR) for overall cancer in the low-increasing group (HR=1.26, 95% confidence interval (CI) 1.06-1.50); and for gastrointestinal cancer in the elevated-stable group (HR=1.66, 95% CI 1.22-2.26). Moreover, among participants with an initial BMI ≥25 kg/m2 , a positive association with the low-increasing group was observed for both overall cancer and gastrointestinal cancer (HR=1.54, 95% CI 1.17-2.04; HR=1.65, 95% CI 1.02-2.66; respectively); among participants with a stable BMI (4.40% loss-5.15% gain), a positive association with the elevated-stable group was observed both for overall cancer and gastrointestinal cancer (HR=1.43, 95% CI 1.10-1.87; HR=1.95, 95% CI 1.33-2.86; respectively). This study observed that FBG trajectories were associated with cancer risk among participants without diabetes, and BMI may modify the associations. This article is protected by copyright. All rights reserved.

15.
Sci Total Environ ; 698: 133860, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31514029

RESUMO

The correlation between long-term exposure to SRF-EMR and the decline in male fertility is gradually receiving increasing attention from the medical society. While male reproductive organs are often exposed to SRF-EMR, little is currently known about the direct effects of long-term SRF-EMR exposure on the testes and its involvement in the suppression of male reproductive potential. The present study was designed to investigate this issue by using 4G SRF-EMR in rats. A unique exposure model using a 4G smartphone achieved localized exposure to the scrotum of the rats for 6 h each day (the smartphone was kept on active talk mode and received an external call for 1 min over 10 min intervals). Results showed that SRF-EMR exposure for 150 days decreased sperm quality and pup weight, accompanied by testicular injury. However, these adverse effects were not evident in rats exposed to SRF-EMR for 50 days or 100 days. Sequencing analysis and western blotting suggested Spock3 overexpression in the testes of rats exposed to SRF-EMR for 150 days. Inhibition of Spock3 overexpression improved sperm quality decline and alleviated testicular injury and BTB disorder in the exposed rats. Additionally, SRF-EMR exposure suppressed MMP2 activity, while increasing the activity of the MMP14-Spock3 complexes and decreasing MMP14-MMP2 complexes; these results were reversed by Spock3 inhibition. Thus, long-term exposure to 4G SRF-EMR diminished male fertility by directly disrupting the Spock3-MMP2-BTB axis in the testes of adult rats. To our knowledge, this is the first study to show direct toxicity of SRF-EMR on the testes emerging after long-term exposure.


Assuntos
Radiação Eletromagnética , Smartphone , Testículo/efeitos da radiação , Animais , Masculino , Ondas de Rádio , Ratos , Reprodução
16.
ACS Nano ; 2020 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-31877019

RESUMO

The electrical conductivity and mechanical strength of fibers constructed from single-walled carbon nanotubes (CNTs) are usually limited by the weak interactions between individual CNTs. In this work, we report a significant enhancement of both of these properties through chemical cross-linking of individual CNTs. The CNT fibers are made by wet-spinning a CNT solution that contains 1,3,5-tris(2'-bromophenyl)benzene (2TBB) molecules as the cross-linking agent, and the cross-linking is subsequently driven by Joule heating. Cross-linking with 2TBB increases the conductivity of the CNT fibers by a factor of ∼100 and increases the tensile strength on average by 47%; in contrast, the tensile strength of CNT fibers fabricated without 2TBB decreases after the same Joule heating process. Symmetrical supercapacitors made from the 2TBB-treated CNT fibers exhibit a remarkably high volumetric energy density of ∼4.5 mWh cm-3 and a power density of ∼1.3 W cm-3.

17.
J Cancer ; 10(27): 6910-6914, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31839826

RESUMO

CCL18 is a cytokine secreted by M2 type tumor associated macrophages, which frequently over-expressed in diverse human cancers. However, the clinical significance of serum CCL18 in patients with laryngeal squamous cell carcinoma (LSCC) remains unknown. In this study, serum CCL18 was initially quantified by enzyme-linked immunosorbent assay (ELISA) in 146 patients with LSCC, 25 patients with precancerous lesions and 72 healthy volunteers. In addition, the correlations between serum CCL18 and clinicopathological parameters were analyzed. Our data revealed that serum CCL18 was obviously increased in patients with LSCC. Moreover, serum CCL18 level was significantly associated with primary tumor site (Glottic vs Others), T classification (T1+T2 vs T3+T4), clinical stage (I+II vs III+IV) and lymph node metastasis (N0 vs N+). Survival analysis demonstrated that patients with high serum CCL18 displayed a shorter survival time than those in patients with low serum CCL18. Importantly, serum CCL18 level and clinical stage were independent prognostic factors in patients with LSCC. Taken together, serum CCL18 could be used as a promising biomarker in patients with LSCC.

18.
J Nat Prod ; 2019 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-31804830

RESUMO

In a study of the potential anti-inflammatory constituents from Kalimeris shimadae, six new sesquiterpenes, kalshinoids A-F (1-6), together with 21 known compounds (7-27), were isolated. The structures and absolute configurations of the new compounds were discerned from extensive spectroscopic analysis, and the absolute configurations of kalshinoids A, B, E, and F were established by ECD calculations. Furthermore, the identified compounds were tested for anti-inflammatory activity as assessed by inhibition of tumor necrosis factor-alpha (TNF-α) in THP-1 cells. Three sesquiterpenes [kalshinoid F, 4(15)-eudesmen-1ß,7,11-triol, and 4α,10α,11-trihydroxy-1ßH,5ßH-guai-7(8)-ene] reduced levels of TNF-α in lipopolysaccharide-stimulated THP-1 cells in a concentration-dependent manner and were more potent than dexamethasone. These natural sesquiterpenes merit further investigation as possible anti-inflammatory agents.

19.
PLoS Biol ; 17(12): e3000563, 2019 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-31805036

RESUMO

Liver fibrosis, often associated with cirrhosis and hepatocellular carcinomas, is characterized by hepatic damage, an inflammatory response, and hepatic stellate cell (HSC) activation, although the underlying mechanisms are largely unknown. Here, we show that the transcriptional Mediator complex subunit 23 (MED23) participates in the development of experimental liver fibrosis. Compared with their control littermates, mice with hepatic Med23 deletion exhibited aggravated carbon tetrachloride (CCl4)-induced liver fibrosis, with enhanced chemokine production and inflammatory infiltration as well as increased hepatocyte regeneration. Mechanistically, the orphan nuclear receptor RAR-related orphan receptor alpha (RORα) activates the expression of the liver fibrosis-related chemokines C-C motif chemokine ligand 5 (CCL5) and C-X-C motif chemokine ligand 10 (CXCL10), which is suppressed by the Mediator subunit MED23. We further found that the inhibition of Ccl5 and Cxcl10 expression by MED23 likely occurs because of G9a (also known as euchromatic histone-lysine N-methyltransferase 2 [EHMT2])-mediated H3K9 dimethylation of the target promoters. Collectively, these findings reveal hepatic MED23 as a key modulator of chemokine production and inflammatory responses and define the MED23-CCL5/CXCL10 axis as a potential target for clinical intervention in liver fibrosis.

20.
iScience ; 22: 269-287, 2019 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-31805432

RESUMO

Studies of intermolecular interactions enhance our knowledge of chemistry across molecular and supramolecular levels. Here, we show that host-guest quadrupolar interaction has a profound influence on the molecular system. With covalently bonded dimolybdenum complex units as the electron donor (D) and acceptor (A) and a thienylene group (C4H2S) as the bridge (B), the mixed-valence D-B-A complexes are shaped with clefts in the middle of the molecule. Interestingly, in aromatic solvents, the D-A electronic coupling constants (Hab) and electron transfer rates (ket) are dramatically reduced. Theoretical computations indicate that an aromatic molecule is encapsulated in the cleft of the D-B-A array; quadrupole-quadrupole interaction between the guest molecule and the C4H2S bridge evokes a charge redistribution, which increases the HOMO-LUMO energy gap, intervening in the through-bond electron transfer. These results demonstrate that a supramolecular system is unified underlying the characteristics of the assembled molecules through constitutional, electronic, and energetic complementarities.

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