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1.
Bioorg Med Chem ; 37: 116107, 2021 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-33735799

RESUMO

Triple-negative breast cancer (TNBC) is one of the most aggressive cancer with high mortality and recurrence rates. Hecogenin, a steroidal sapogenin, is reported as a potential anti-tumor agent against breast cancer. However, the moderate activity limits its further application in clinical. With the aim to identify novel analogues that are especially efficacious in therapy of TNBC, a series of novel hecogenin thiosemicarbazone and semicarbazone derivatives were designed, synthesized and biologically evaluated. Screening of cytotoxicity revealed that 4c could potently inhibit the proliferation of breast cancer cells (MCF-7 and MDA-MB-231 cells), lung cancer cells (A549) and colon cancer cells (HT-29) at low µM level. Importantly, further mechanism studies indicated the ability of 4c in inducing apoptosis of MDA-MB-231 cells by arresting the cell cycle. Moreover, 4c notably suppressed the migration and invasion of MDA-MB-231 cells compared to its parent hecogenin at the equal concentration.

2.
Arch Microbiol ; 2021 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-33651169

RESUMO

A haloalkaliphilic strain JWXQ-INN-674T was isolated from the water sample of a soda lake in Inner Mongolia Autonomous Region, China. Cells of the strain were coccoid, motile, and strictly aerobic. The strain was able to grow in presence of 2.6-5.4 M NaCl (optimum concentration is 3.4 M) at 30-50 °C (optimum temperature is 42 °C) and pH 7-9.5 (optimum pH is 9.0). The 16S rRNA gene sequence of strain JWXQ-INN-674T showed 95.3-96.6% similarity to members of the genus Natronorubrum of the family Natrialbaceae. The whole genome sequencing of strain JWXQ-INN-674T revealed a genome size of 4.56 M bp and a DNA G + C content of 62.5 mol%. Genome relatedness of strain JWXQ-INN-674T and other species in the genus Natronorubrum was analyzed by average nucleotide identity and digital DNA-DNA hybridization with the values of 76.8-90.6 and 23.1-39.3%, respectively. The strain possessed the polar lipids phosphatidylglycerol and methylated phosphatidylglycerol phosphate lipid. No glycolipids were detected. Based on phylogenetic analysis, phenotypic characteristics, chemotaxonomic properties and genome relatedness, the isolate was proposed as the type strain of a novel species of genus Natronorubrum, Natronorubrum halalkaliphilum sp. nov. (type strain JWXQ-INN-674T = CGMCC 1.17283T = JCM 34245T).

3.
Bioorg Chem ; 109: 104714, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33618254

RESUMO

Selective estrogen receptor degraders (SERDs) not only block ERα activity but degrade this receptor at the same time and are effective in relapsed ERα positive breast cancer patients who have accepted other endocrine therapies. Herein, through scaffold hopping of coumarin skeleton, a series of 2H-chromene-3-carbonyl-based SERDs with phenyl acrylic acid group as the side chain were designed and synthesized. Compound XH04 containing 7-hydroxy-2H-chromene-3-carbonyl skeleton exhibited the most potent activities in 2D (IC50 = 0.8 µM) and 3D cells culture models (MCF-7) and had the best ERα binding affinity as well. Furthermore, the significant antiestrogen property of compound XH04 was confirmed by inhibiting the expression of progesterone receptor (PgR) mRNA in MCF-7 cells. On the other hand, the outgoing ERα degradation property of compound XH04 was qualitatively and quantificationally verified by immunofluorescence analysis and Western blot assay in MCF-7 cells. Besides, compound XH04 repressed the expression level of Ki67 in MCF-7 cells and induced the apoptosis increase of this tumor cells in a dose-dependent manner like approved-SERD fulvestrant (2), while compound XH04 exhibited better preliminary pharmacokinetics in human and rat liver microsomes in vitro and a lower LogD7.4 value than fulvestrant. And further molecular docking study revealed that compound XH04 possessed a proverbial and typical binding model with ERα like other reported SERD. All these results confirmed that 7-hydroxy-2H-chromene-3-carbonyl structure could be a feasible skeleton for design of ERα antagonists including SERDs and compound XH04 is a promising candidate for further development of ERα + breast cancer therapy agents.

4.
J Bone Joint Surg Am ; 2021 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-33587512

RESUMO

BACKGROUND: Rotator cuff repair site failure is a well-established clinical concern. Tendon-to-bone healing is initiated by inflammatory mediators followed by matrix synthesis by fibroblasts. The kinetics of fibroblast accumulation and activity are currently poorly understood. METHODS: Ninety-six mice underwent supraspinatus tendon repair. Six were used for imaging using a novel 68Gallium (Ga)-labeled fibroblast activation protein alpha (FAP-α) inhibitor and positron emission tomography-computed tomography (PET/CT) at days 0 (before surgery), 3, 7, 14, and 28. Sixty-eight animals were divided into 4 groups to be evaluated at 3, 7, 14, or 28 days. Twenty-two native shoulders from mice without surgery were used as the control group (intact tendon). Six animals from each group were used for histological analysis; 6 from each group were used for evaluation of fibroblastic response-related gene expression; and 10 mice each from the intact, 14-day, and 28-day groups were used for biomechanical testing. RESULTS: There was minimal localization of 68Ga-labeled FAP-α inhibitor in the shoulders at day 0 (before surgery). There was significantly increased uptake in the shoulders with surgery compared with the contralateral sides without surgery at 3, 7, and 14 days. 68Ga-labeled FAP-α inhibitor uptake in the surgically treated shoulders increased gradually and peaked at 14 days followed by a decrease at 28 days. Gene expression for smooth muscle alpha (α)-2 (acta2), FAP-α, and fibronectin increased postsurgery followed by a drop at 28 days. Immunohistochemical analysis showed that FAP-α-positive cell density followed a similar temporal trend, peaking at 14 days. All trends matched closely with the PET/CT results. Biomechanical testing demonstrated a gradual increase in failure load during the healing process. CONCLUSIONS: 68Ga-labeled FAP-α inhibitor PET/CT allows facile, high-contrast in vivo 3-dimensional imaging of fibroblastic activity in a mouse rotator cuff repair model. CLINICAL RELEVANCE: Noninvasive imaging of activated fibroblasts using labeled radiotracers may be a valuable tool to follow the progression of healing at the bone-tendon interface.

5.
Artigo em Inglês | MEDLINE | ID: mdl-33579684

RESUMO

Halolysins, which are subtilisin-like serine proteases of haloarchaea, are usually secreted into the extracellular matrix via the twin-arginine translocation pathway. A small number of activated molecules can greatly affect cell growth owing to their proteolytic activity. It is, however, unclear as to whether this proteolysis-based growth inhibition by halolysins conveys antagonistic or defensive effects against other resident abd potentially competitive microorganisms. Here, we report that halolysin R4 (HlyR4), encoded by the hlyR4 gene, is the key enzyme in the initial steps of extracellular protein utilization in Haloferax mediterranei HlyR4 shows significant antagonistic activity against other haloarchaeal strains. Deletion of hlyR4 completely halts the inhibition activity of Hfx. mediterranei towards other haloarchaea, while correspondingly, complementation of hlyR4 almost completely restores the inhibition activity. Furthermore, Hfx. mediterranei strains containing hlyR4 showed a certain amount of resistance to halocins and halolysins in milieu, and this function of hlyR4 is reproducible in Haloarcula hispanica The versatility of HlyR4 enables its host to outcompete other haloarchaea living in the same hypersaline environment. Intriguingly, unlike the growth phase-dependent halolysins SptA and Nep, it is likely that HlyR4 may be secreted independent of growth phase. This study provides a new peptide antibiotics candidate in haloarchaea, as well as new insight towards a better understanding of the ecological roles of halolysins.Importance: This study shows that halolysin R4 from Haloferax mediterranei provides its host antagonistic and defensive activities against other haloarchaea, which expands our knowledge on the traditional function of haloarchaeal extracellular proteases. Haloarchaeal extracellular serine proteases have been previously discussed as growth-phase-dependent proteins, whereas our study reports constitutive expression of halolysin R4. This work also clearly reveals a hidden diversity of extracellular proteases from haloarchaea. Studies on multifunctional halolysins reveal that they play an important ecological role in shaping microbial community composition and provide a new perspective towards understanding the intricate interactions between haloarchaeal cells in hypersaline environments. HlyR4 can lyse competing cells living in the same environment, and the cell debris may probably be utilized as nutrients, which may constitute an important part of nutrient cycling in extremely hypersaline environments.

6.
Chin Med J (Engl) ; 134(2): 200-205, 2021 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-33443938

RESUMO

BACKGROUND: It has been a global trend that increasing complications related to pelvic floor surgeries have been reported over time. The current study aimed to outline the development of Chinese pelvic floor surgeries related to pelvic organ prolapse (POP) over the past 14 years and investigate the potential influence of enhanced monitoring conducted by the Chinese Association of Urogynecology since 2011. METHODS: A total of 44,594 women with POP who underwent pelvic floor surgeries between October 1, 2004 and September 30, 2018 were included from 22 tertiary academic medical centers. The data were reported voluntarily and obtained from a database. We compared the proportion of each procedure in the 7 years before and 7 years after September 30, 2011. The data were analyzed by performing Z test (one-sided). RESULTS: The number of different procedures during October 1, 2011-September 30, 2018 was more than twice that during October 1, 2004-September 30, 2011. Regarding pelvic floor surgeries related to POP, the rate of synthetic mesh procedures increased from 38.1% (5298/13,906) during October 1, 2004-September 30, 2011 to 46.0% (14,107/30,688) during October 1, 2011-September 30, 2018, whereas the rate of non-mesh procedures decreased from 61.9% (8608/13,906) to 54.0% (16,581/30,688) (Z = 15.53, P < 0.001). Regarding synthetic mesh surgeries related to POP, the rates of transvaginal placement of surgical mesh (TVM) procedures decreased from 94.1% (4983/5298) to 82.2% (11,603/14,107) (Z = 20.79, P < 0.001), but the rate of laparoscopic sacrocolpopexy (LSC) procedures increased from 5.9% (315/5298) to 17.8% (2504/14,107). CONCLUSIONS: The rate of synthetic mesh procedures increased while that of non-mesh procedures decreased significantly. The rate of TVM procedures decreased while the rate of LSC procedures increased significantly. TRIAL REGISTRATION NUMBER: NCT03620565, https://register.clinicaltrials.gov.

8.
Oncol Rep ; 45(3): 1011-1022, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33469672

RESUMO

High expression of δ­like ligand 4 (Dll4) is reportedly related to the invasion, metastasis, and clinical prognosis of various malignant tumours. Our previous study revealed that collective cell invasion was a common pattern in salivary adenoid cystic carcinoma (SACC). However, the roles of the Dll4/Notch1 signalling pathway in the collective invasion of SACC remain unclear. The present study revealed that Dll4 expression was higher at the invasive front of SACC, and that this upregulation was associated with solid tumour type, high TNM grade, and high rates of metastasis and recurrence. Furthermore, the expression levels of Notch1 and Dll4 were positively correlated at the invasive front, and a three­dimensional (3D) culture model revealed that leader cells showed high expression of Dll4, while follower cells showed high expression of Notch1. Moreover, silencing of Dll4 expression using small interfering RNA reduced the migration, invasion, and collective invasion of SACC cells, and these abilities were rescued by Notch1 overexpression. Finally, SACC collective invasion was increased via the Dll4/Notch1 signalling pathway in experiments that involved a stiff 3D gel, hypoxia and co­culture with human endothelial cells. These findings indicated that the Dll4/Notch1 signalling pathway may be involved in the collective invasion of SACC, which may help to provide possible targets for the treatment of SACC.

9.
Antonie Van Leeuwenhoek ; 114(1): 83-94, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33389352

RESUMO

A novel extremely halophilic archaeon, strain N1521T, was isolated from a saline lake in Tibet, China. Cells of the strain were pleomorphic and Gram-stain-negative. It produced red pigments. Growth was observed at 4-42 °C (optimum, 37 °C), pH 7.0-10.5 (optimum, 8.0-9.5), NaCl 11%-25% (optimum, 15%) and in the presence of 0-0.1 M MgCl2 (optimum, 0.05 M) in aerobic conditions. The minimum NaCl concentration that prevented cell lysis was 2% (w/v). The major polar lipids of strain N1521T were phosphatidylglycerol sulfate, phosphatidylglycerol phosphate methyl ester, phosphatidylglycerol and an unidentified glycolipid. The DNA G + C content was 58.37 mol%. According to 16S rRNA gene sequence comparisons, strain N1521T revealed the highest sequence similarity to Haloprofundus halophilus NK23T (91.38%) and Halogranum amylolyticum TNN58T (91.00%), and low sequence similarities (< 91%) with other genera in the order Haloferacales. Phylogenetic analysis based on the 16S rRNA gene and rpoB' gene sequence showed that strain N1521T was distinct from the members of the order Haloferacales. The digital DNA-DNA hybridization, average nucleotide identity and average amino acid identity values calculated from whole genome-sequence comparison between strain N1521T and the members of the order Haloferacales were in the ranges of 15.1-18.2%, 68.8-73.0%, and 58.4-63.9%, respectively. Phylogenetic tree reconstructions based on the whole-genome sequences revealed that strain N1521T was closer to the members of the family Halorubraceae. Based on the data obtained, strain N1521T is thus considered to represent a novel species of a new genus within the family Halorubraceae, for which the name Halalkalirubrum salinum gen. nov., sp. nov. is proposed. The type strain is N1521T (= CGMCC 1.16693 = JCM 33785).

10.
Artigo em Inglês | MEDLINE | ID: mdl-33275091

RESUMO

A haloalkaliphilic strain XQ-INN 246T was isolated from the sediment of a salt pond in Inner Mongolia Autonomous Region, China. Cells of the strain were rods, motile and strictly aerobic. The strain was able to grow in the presence of 2.6-5.3 M NaCl (optimum concentration is 4.4 M) at 30-50 °C (optimum temperature is 42 °C) and pH 7.0-10.0 (optimum pH is 8.0-8.5). The whole genome sequencing of strain XQ-INN 246T revealed a genome size of 4.52 Mbp and a DNA G+C content of 62.06 mol%. Phylogenetic tree based on 16S rRNA gene sequences and concatenated amino acid sequences of 122 single-copy conserved proteins revealed a robust lineage of the strain XQ-INN 246T with members of related genera of the family Natrialbaceae. The strain possessed the polar lipids of phosphatidylglycerol and phosphatidylglycerol phosphate methyl ester. No glycolipids were detected. Based on phylogenetic analysis, phenotypic characteristics, chemotaxonomic properties and genome relatedness, the isolate was proposed as the type strain of a novel species of a new genus within the family Natrialbaceae, for which the name Salinadaptatus halalkaliphilus gen. nov., sp. nov. is proposed. The type strain is XQ-INN 246T (=CGMCC 1.16692T=JCM 33751T).

11.
Medicine (Baltimore) ; 99(51): e23662, 2020 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-33371103

RESUMO

BACKGROUND: 18 previous meta-analyses have been published on the methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms with male infertility risk. However, results of the previous meta-analyses were still inconsistent. Moreover, their meta-analyses did not assess false-positive report probabilities except one study. Furthermore, many new studies have been published, and therefore an updated meta-analysis and re-analysis of systematic previous meta-analyses were performed to further explore these issues. OBJECTIVES: To determine the association between MTHFR C677T and A1298C polymorphisms and male infertility risk. METHODS: Crude odds ratios and their 95% confidence intervals were used to assess the association between MTHFR C677T and A1298C polymorphisms and male infertility risk. We used the Bayesian false discovery probability (BFDP) to assess the credibility of statistically significant associations. RESULTS: Fifty-nine studies were included concerning the MTHFR C677T and 28 studies were found on the MTHFR A1298C with male infertility risk. Overall, the MTHFR C677T was associated with increased male infertility risk in overall populations, Africans, East Asians, West Asians, South Asians, azoospermia, and Oligoasthenoteratozoospermia (OAT). In further sensitivity analysis and BFDP test, the positive results were only considered as "noteworthy" in the overall population (TT vs CC: BFDP = 0.294, CT + TT vs CC: BFDP = 0.300, T vs C: BFDP = 0.336), East Asians (TT vs CC: BFDP = 0.089, TT vs CT + CC: BFDP = 0.020, T vs C: BFDP < 0.001), West Asians (TT vs CC: BFDP = 0.584), hospital-based studies (TT vs CC: BFDP = 0.726, TT vs CT + CC: BFDP = 0.126), and OAT (TT vs CT + CC: BFDP = 0.494) for MTHFR C677T. In addition, a significantly increased male infertility risk was found in East Asians and population-based studies for MTHFR A1298C. However, we did not find that the positive results were considered as "noteworthy" in the overall and all subgroup analyses for MTHFR A1298C. CONCLUSIONS: In summary, this study indicates that the MTHFR C677T is associated with increased male infertility risk in East Asians, West Asians, and OAT. No significant association was observed on the MTHFR A1298C with male infertility risk.


Assuntos
Infertilidade Masculina/genética , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Teorema de Bayes , Predisposição Genética para Doença , Humanos , Masculino , Polimorfismo Genético
12.
J Orthop Res ; 2020 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-33336819

RESUMO

Muscle atrophy and fatty infiltration have been directly correlated with higher rates of incomplete or failed healing following surgical repair of the rotator cuff. The purpose of this study was to evaluate clinically relevant functional and morphological changes in the supraspinatus muscle at various time points in this model of rotator cuff tendinopathy. Subacromial impingement was induced in 47, male C57BL/6 mice (total 94 limbs) by implantation of a metal clip in the subacromial space. Specimens were evaluated at 4, 6, and 12 weeks postoperatively. Gait analysis was used to measure various kinematic parameters. Supraspinatus muscle wet weight, histology, and quantitative reverse-transcription polymerase chain reaction analysis of genes related to muscle atrophy and adipogenesis were performed to characterize the structural, cellular, and molecular changes. Muscle atrophy and fatty infiltration was evident beginning at 6 weeks, with progression out to 12 weeks. Gait analysis identified significant functional changes in many aspects of gait and abnormal stance tracing as early as 4 weeks, verifying alterations in upper extremity function. We have demonstrated that clinically relevant changes to the supraspinatus muscle are seen starting 6 weeks after induction of subacromial impingement. Furthermore, the gait analysis provides key functional outcome measurements that may be useful for future evaluation of new therapeutic strategies.

13.
Shanghai Kou Qiang Yi Xue ; 29(3): 304-307, 2020 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-33043349

RESUMO

PURPOSE: To evaluate the impact of health education with children popular oral science short drama on 10-year-old children's oral health knowledge, attitude, practice (KAP), and provide evidence for oral health education methods for children. METHODS: A oral health education short drama for children was filmed. 10-year-old children from a primary school in Minhang district, Shanghai were selected as the study subjects. The groups were asked to watch the drama on campus at enrollment and the first month for health education. Self-made questionnaires were used to conduct corresponding oral health KAP surveys at the time of enrollment, the first month and the sixth month. The survey results were compared using SPSS 21.0 software package for t test and Chi-square test, to compare the changes in oral health KAP scores and the accuracy of each question before and after oral health education. RESULTS: One hundred and seventy-four children were followed-up. Before the intervention, the subjects' oral health knowledge, attitude, and behavior scores were (21.02±12.54), (74.48±19.87), (31.90±22.39), and (57.05±17.56), (85.06±14.97), (55.03±29.32) at the first month; and (71.76±16.27), (91.49±12.40), (73.99±27.46) at the 6th month, respectively. Compared with those before the intervention, significant increases were observed (P<0.001). Before the intervention, there was no significant difference in KAP scores between different genders, but there were significant differences in knowledge and behavior scores at 1 and 6 months after intervention between different genders(P<0.05). CONCLUSIONS: School oral health education through children oral science short drama has a good effect on improving the knowledge, attitude and behavior of oral health care for 10-year-old children, and it is more effective when repeat.


Assuntos
Conhecimentos, Atitudes e Prática em Saúde , Saúde Bucal , Criança , China , Feminino , Educação em Saúde , Educação em Saúde Bucal , Humanos , Masculino
14.
Eur J Med Chem ; 209: 112910, 2020 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-33049605

RESUMO

Farnesoid X receptor (FXR) agonists are emerging as potential therapeutics for the treatment of various metabolic diseases, as they display multiple effects on bile acid, lipid, and glucose homeostasis. Although the steroidal obeticholic acid, a full FXR agonist, was recently approved, several side effects probably due to insufficient pharmacological selectivity impede its further clinical application. Activating FXR in a partial manner is therefore crucial in the development of novel FXR modulators. Our efforts focusing on isoxazole-type FXR agonists, common nonsteroidal agonists for FXR, led to the discovery a series of novel FXR agonists bearing aryl urea moieties through structural simplification of LJN452 (phase 2). Encouragingly, compound 11k was discovered as a potent FXR agonist which exhibited similar FXR agonism potency but lower maximum efficacy compared to full agonists GW4064 and LJN452 in cell-based FXR transactivation assay. Extensive in vitro evaluation further confirmed partial efficacy of 11k in cellular FXR-dependent gene modulation, and revealed its lipid-reducing activity. More importantly, orally administration of 11k in mice exhibited desirable pharmacokinetic characters resulting in promising in vivo FXR agonistic activity.

15.
Mol Genet Genomic Med ; : e1522, 2020 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-33016646

RESUMO

BACKGROUND: Atypical clinical symptoms of juvenile hereditary hemochromatosis (JHH) often leads to misdiagnosis and underdiagnosis bringing ominous outcomes, even death. METHODS: The whole exome was sequenced and interpreted. A literature review assisted to analyze and verify the phenotype-genotype relationships. We revealed the entire process of diagnosis, treatments, and outcome of two diabetic onset of JHH families to provide new insights for genotype-phenotype relation with novel compound heterozygous mutations in the hepcidin antimicrobial peptide (HAMP, OMIM: 606464). RESULTS: Two probands were diagnosed and treated as type 1 diabetes initially because of specific symptoms and positive islet autoantibodies. Poor control of hyperglycemia and progressive symptoms occurred. Sequencing informed that the compound heterozygous and homozygous mutations c.166C>G and c.223C>T in HAMP caused type 1 diabetic-onset JHH. The two patients accessed irregular phlebotomy treatments, and then, experienced poor prognosis. We summarized the process of overall clinical management of reported 26 cases comparing to our novel atypical diabetic onsets Juvenile Hereditary Hemochromatosis cases. CONCLUSION: It was first reported that positive pancreatic islet autoantibodies diabetes onset of JHH resulted from loss-of-function mutations of HAMP, of which the atypical JHH should be differentially diagnosed with type 1 diabetes at the onset. Early administration of phlebotomy and vital organs protection and surveillance might be important for the treatment of atypical JHH.

16.
Eur J Med Chem ; 208: 112865, 2020 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-32987316

RESUMO

Inhibition of PI3Kδ has been proved to be an efficacious strategy for the treatment of hematological malignancies where the PI3K/Akt signaling pathway is hyperactive. Herein, a series of quinazoline derivatives bearing acrylamide fragment were prepared using skeleton-deconstruction strategy. The preliminary bioactivity evaluation resulted in the discovery of lead compound 15c. Compound 15c exhibited excellent enzyme activity against PI3Kδ (IC50 = 27.5 nM) compared with BEZ235 as well as the significant anti-proliferation activities. With the high selectivity over other PI3K isoforms and potent effects on PI3K/Akt pathway, 15c can be identified as a promising PI3Kδ inhibitor worthy of further profiling.

17.
Biosci Rep ; 40(9)2020 09 30.
Artigo em Inglês | MEDLINE | ID: mdl-32945337

RESUMO

BACKGROUND: Many studies have been performed to explore the combined effects of glutathione-S-transferase M1 (GSTM1) present/null and cytochrome P4501A1 (CYP1A1) MspI polymorphisms with lung cancer (LC) risk, but the results are contradictory. Two previous meta-analyses have been reported on the issue in 2011 and 2014. However, several new articles since then have been published. In addition, their meta-analyses did not valuate the credibility of significantly positive results. OBJECTIVES: We performed an updated meta-analysis to solve the controversy following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. METHODS: False-positive report probability (FPRP), Bayesian false discovery probability (BFDP), and the Venice criteria were used to verify the credibility of meta-analyses. RESULTS: Twenty-three publications including 5734 LC cases and 7066 controls met the inclusion criteria in the present study. A significantly increased risk of LC was found in overall analysis, Asians and Indians. However, all positive results were considered as 'less-credible' when we used the Venice criteria, FPRP, and BFDP test to assess the credibility of the positive results. CONCLUSION: These positive findings should be interpreted with caution and results indicate that significant associations may be less-credible, there are no significantly increased LC risk between the combined effects of GSTM1 present/null and CYP1A1 MspI polymorphisms.

18.
Bioorg Med Chem ; 28(23): 115763, 2020 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-32992255

RESUMO

A series of novel steroidal-chalcone derivates were designed and synthesized based on the molecular hybridization strategy and further evaluated for their growth inhibitory activity against three human cancer cell lines. The MTT results indicated that most compounds were apparently more sensitive to human breast cancer cells MDA-MB-231. Compounds 8 and 18 exerted the best cytotoxic activity against triple-negative MDA-MB-231 cells with the IC50 values of 0.42 µM and 0.52 µM respectively, which were 23-fold increase or more compared with 5-Fu. Further mechanism studies demonstrated that compound 8 could induce cells apoptosis through regulating Bcl-2/Bax proteins and activating caspase-3 signaling pathway. Moreover, compound 8 could upregulate the cellular ROS levels which accelerated the apoptosis of MDA-MB-231 cells. In addition, interestingly, cell cycle assay showed that compound 8 could arrest MDA-MB-231 cells at S phase but not commonly anticipated G2/M phase. These evidences fully confirmed that compound 8 could be a potential candidate that deserves further development as an antitumor agent against triple-negative breast cancer.

19.
J Bone Joint Surg Am ; 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32941310

RESUMO

BACKGROUND: The purpose of this study was to assess mitochondrial dysfunction in a murine model of supraspinatus tendinopathy. METHODS: Eighty-four mice (168 limbs) were included in the study. Supraspinatus tendinopathy was induced by inserting a microsurgical clip in the subacromial space of 63 mice bilaterally (126 limbs). Forty-two of these limbs were harvested at 4 weeks postoperatively, 42 underwent clip removal at 4 weeks after the initial procedure and were harvested at 2 weeks, and 42 underwent clip removal at 4 weeks and were harvested at 4 weeks. Forty-two limbs in the remaining 21 mice did not undergo surgical intervention and were utilized as the control group. Outcomes included biomechanical, histological, gene expression, superoxide dismutase (SOD) activity, and transmission electron microscopy (TEM) analyses. RESULTS: Radiographs confirmed stable clip position in the subacromial space at 4 weeks. Biomechanical testing demonstrated a 60% decrease in failure force of the supraspinatus tendons at 4 weeks compared with the control group. The failure force gradually increased at 2 and 4 weeks after clip removal. Histological analysis demonstrated inflammation surrounding the tendon with higher modified Bonar scores at 4 weeks after clip placement followed by gradual improvement following clip removal. The expression of mitochondrial-related genes was decreased at 4 weeks after clip placement and then significantly increased after clip removal. SOD activity decreased significantly at 4 weeks after clip placement but increased following clip removal. TEM images demonstrated alterations in morphology and the number of mitochondria and cristae at 4 weeks after clip placement with improvement after clip removal. CONCLUSIONS: Mitochondrial dysfunction appears to be associated with the development of tendinopathy. CLINICAL RELEVANCE: Mitochondrial protection may offer a potential strategy for delaying the development of tendinopathy and promoting tendon healing.

20.
Int J Clin Oncol ; 25(11): 1936-1944, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32959231

RESUMO

BACKGROUND: Accumulating evidences have indicated that human cytomegalovirus (HCMV) may link to multiple human malignancies, including gastric cancer. However, the mechanistic role of HCMV in GC remains largely unknown. METHODS: In this study, we have successfully established HCMV latent gene UL-136-expressing gastric cancer cells. We measured cell proliferation of GC cells, MNK-45 and SGC-7901, with stable UL136 expression or paired control cells by using CCK-8 assay. We have showed that GC cells with stable UL136 expression had a rapid cell growth. Furthermore, our data from matrigel-coated transwell assay have demonstrated that UL136 expressing GC cells showed an enhanced invasion capacity compared to control cells. Furthermore, ectopic expression of UL136 inhibits tumorigenicity in an animal model. RESULTS: We observed that IL-6/STAT3 was stimulated by UL136 overexpression. Also, miR-138 is consistently up-regulated, while miR-34 down-regulated by UL136 in either MNK-45 or SGC-7901 cells. Our mechanistic study showed that treatment of miR-138 mimics in MNK-45 cells indeed inhibited SIRT1 expression to increase phosphorylation level of STAT3. MiR-34c suppressed expression of IL6R through direct binding with the putative 3'UTR binding sites of this gene. UL136 regulate IL6/STAT3 pathway, at least in part, through down-regulation of miR-34c in GC cells. CONCLUSION: In conclusion, HCMV-induced miR-34c or miR-138 involves in the activation of IL6/STAT3 signaling. Targeting the IL6-STAT3 axis or miRNAs represent a promising strategy for HCMV-related tumor formation.

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