Publications by authors named "Ning-Ning Liu"

69 Publications

Genetically predicted obesity and risk of deep vein thrombosis.

Thromb Res 2021 Sep 5;207:16-24. Epub 2021 Sep 5.

Key Laboratory of Pulmonary Vascular Medicine, National Clinical Research Center of Cardiovascular Diseases, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, China. Electronic address:

Aims/hypothesis: An association between obesity and deep vein thrombosis (DVT) has been revealed by observational studies, but it is not clear if the observed associations are causal, caused by confounding bias or reverse causation.

Methods: We performed a two-sample Mendelian Randomization (MR) study by obtaining exposure and outcome data from separate published studies. We utilized data from Genetic Investigation of Anthropometric Traits (GIANT, 339,224 participants) consortium and FinnGen project (FinnGen, 1785 DVT case and 84,462 control participants) to determine the causal effect of BMI on DVT.

Results: All three MR methods provided a positive association between BMI and DVT. Using IVW, we found evidence of causal relationships between BMI and DVT. BMI is positively associated with DVT (IVW odds ratio [OR] per SD increase in BMI = 1.67 [95% CI, 1.16-2.40]; P = 0.006). MR Egger and weighted median regression also showed directionally similar estimates (MR-Egger OR per SD increase in BMI, 2.50 [95% CI, 1.07-5.84], P = 0.034; weighted median OR per SD increase in BMI, 2.02 [95% CI, 1.10-3.71], P = 0.023). Both funnel plots and MR-Egger intercepts suggest no directional pleiotropic effects observed between BMI and DVT.

Conclusions/interpretation: Our findings provide evidence of significant causal association between BMI and DVT in agreement with observational studies. Taking measures to reduce the proportion of obesity may help reduce the incidence of DVT.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.thromres.2021.08.026DOI Listing
September 2021

Genetic predisposition to COVID-19 may increase the risk of hypertension disorders in pregnancy: A two-sample Mendelian randomization study.

Pregnancy Hypertens 2021 Aug 19;26:17-23. Epub 2021 Aug 19.

Thrombosis Center, National Clinical Research Center of Cardiovascular Diseases, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, China. Electronic address:

Aims: The aim of this study was to apply the Mendelian randomization (MR) design to explore the potential causal association between COVID-19 and the risk of hypertension disorders in pregnancy.

Methods: Our primary genetic instrument comprised 8 single-nucleotide polymorphisms (SNPs) associated with COVID-19 at genome-wide significance. Data on the associations between the SNPs and the risk of hypertension disorders in pregnancy were obtained from study based on a very large cohort of European population. The random-effects inverse-variance weighted method was conducted for the main analyses, with a complementary analysis of the weighted median and MR-Egger approaches.

Results: Using IVW, we found that genetically predicted COVID-19 was significantly positively associated with hypertension disorders in pregnancy, with an odds ratio (OR) of 1.111 [95% confidence interval (CI) 1.042-1.184; P = 0.001]. Weighted median regression also showed directionally similar estimates [OR 1.098 (95% CI, 1.013-1.190), P = 0.023]. Both funnel plots and MR-Egger intercepts suggest no directional pleiotropic effects observed.

Conclusions: Our findings provide direct evidence that there is a shared genetic predisposition so that patients infected with COVID-19 may be causally associated with increased risk of hypertension disorders in pregnancy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.preghy.2021.08.112DOI Listing
August 2021

The Application of High-Throughput Technologies for the Study of Microbiome and Cancer.

Front Genet 2021 28;12:699793. Epub 2021 Jul 28.

State Key Laboratory of Oncogenes and Related Genes, Centre for Single-Cell Omics, School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Human gut microbiome research, especially gut microbiome, has been developing at a considerable pace over the last decades, driven by a rapid technological advancement. The emergence of high-throughput technologies, such as genomics, transcriptomics, and others, has afforded the generation of large volumes of data, and in relation to specific pathologies such as different cancer types. The current review identifies high-throughput technologies as they have been implemented in the study of microbiome and cancer. Four main thematic areas have emerged: the characterization of microbial diversity and composition, microbial functional analyses, biomarker prediction, and, lastly, potential therapeutic applications. The majority of studies identified focus on the microbiome diversity characterization, which is reaching technological maturity, while the remaining three thematic areas could be described as emerging.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fgene.2021.699793DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8355622PMC
July 2021

Evaluation of artemisinin derivative artemether as a fluconazole potentiator through inhibition of Pdr5.

Bioorg Med Chem 2021 Aug 25;44:116293. Epub 2021 Jun 25.

State Key Laboratory of Oncogenes and Related Genes, Center for Single-Cell Omics, School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China. Electronic address:

Antifungal development has gained increasing attention due to its limited armamentarium and drug resistance. Drug repurposing holds great potential in antifungal discovery. In this study, we explored the antifungal activity of artemisinin and its derivatives, dihydroartemisinin, artesunate and artemether. We identified that artemisinins can inhibit the growth of Candida albicans, and can enhance the activity of three commonly used antifungals, amphotericin B, micafungin and fluconazole (FLC), on Candida albicans growth and filamentation. Artemisinins possess stronger antifungal effect with FLC than with other antifungals. Among artemisinins, artemether exhibits the most potent antifungal activity with FLC and can recover the susceptibility of FLC-resistant clinical isolates to FLC treatment. The combinatorial antifungal activity of artemether and FLC is broad-spectrum, as it can inhibit the growth of Candida auris, Candida tropicalis, Candida parapsilosis, Saccharomyces cerevisiae and Cryptococcus neoformans. Mechanistic investigation revealed that artemether might enhance azole efficacy through disrupting the function of Pdr5, leading to intracellular accumulation of FLC. This study identified artemether as a novel FLC potentiator, providing potential therapeutic insights against fungal infection and antifungal resistance.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmc.2021.116293DOI Listing
August 2021

ANLN promotes carcinogenesis in oral cancer by regulating the PI3K/mTOR signaling pathway.

Head Face Med 2021 Jun 3;17(1):18. Epub 2021 Jun 3.

Oncological Department of Oral and Maxillofacial Surgery, Xinjiang Medical University Affiliated First Hospital, Stomatological School of Xinjiang Medical University, Stomatology Research Institute of Xinjiang Province, No.137 Liyushan South Road, 830054, Urumqi, PR China.

Background: Oral cancer is a malignant disease that threatenshuman life and greatly reducespatientquality of life. ANLN was reported to promote the progression of cancer. This study aims to investigate the role of ANLNin oral cancer and the underlying molecular mechanism.

Methods: ANLN expression was downregulated by RNAi technology. The effect of ANLN on cell behaviors, including proliferation, cell cycle progression, invasion, and apoptosis, was detected. Western blotting analysis was used to explore the mechanism by whichANLN functions in oral cancer.

Results: Data from TCGA database showed that ANLN was expressed at significantly higher levels in tumor tissues thanin normal control tissues. Patients with higher ANLN expression exhibitedshorter survivaltimes. ANLN was alsoabundantly expressedin the cancer cell lines CAL27 and HN30. When ANLN was knocked down in CAL27 and HN30 cells, cell proliferation and colony formation weredecreased. The cell invasion ability was also inhibited. However, the cell apoptosis rate was increased. In addition, the levels of critical members of the PI3K signaling pathway, includingPI3K, mTOR, Akt, and PDK-1, were significantlyreducedafter ANLN was knocked down in CAL27 cells.

Conclusions: ANLN contributes to oral cancerprogressionand affects activation ofthe PI3K/mTOR signaling pathway. This study providesa new potential targetfor drug development and treatment in oral cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13005-021-00269-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8173900PMC
June 2021

Identification of microbial markers across populations in early detection of colorectal cancer.

Nat Commun 2021 05 24;12(1):3063. Epub 2021 May 24.

Guangdong Institute of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Department of Colorectal Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China.

Associations between gut microbiota and colorectal cancer (CRC) have been widely investigated. However, the replicable markers for early-stage adenoma diagnosis across multiple populations remain elusive. Here, we perform an integrated analysis on 1056 public fecal samples, to identify adenoma-associated microbial markers for early detection of CRC. After adjusting for potential confounders, Random Forest classifiers are constructed with 11 markers to discriminate adenoma from control (area under the ROC curve (AUC) = 0.80), and 26 markers to discriminate adenoma from CRC (AUC = 0.89), respectively. Moreover, we validate the classifiers in two independent cohorts achieving AUCs of 0.78 and 0.84, respectively. Functional analysis reveals that the altered microbiome is characterized with increased ADP-L-glycero-beta-D-manno-heptose biosynthesis in adenoma and elevated menaquinone-10 biosynthesis in CRC. These findings are validated in a newly-collected cohort of 43 samples using quantitative real-time PCR. This work proves the validity of adenoma-specific markers across multi-populations, which would contribute to the early diagnosis and treatment of CRC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-021-23265-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8144394PMC
May 2021

Fingolimod Potentiates the Antifungal Activity of Amphotericin B.

Front Cell Infect Microbiol 2021 23;11:627917. Epub 2021 Apr 23.

State Key Laboratory of Oncogenes and Related Genes, Center for Single-Cell Omics, School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

() is an opportunistic human fungal pathogen that can cause severe infection in clinic. Its incidence and mortality rate has been increasing rapidly. Amphotericin B (AMB), the clinical golden standard antifungal agent, has severe side effects that limit its clinical application. Thus, lowering the concentration and increasing the efficacy of AMB in a combinatorial antifungal therapy have been pursued by both industry and academia. Here we identify that fingolimod (FTY720), an immunomodulatory drug used for oral treatment of relapsing-remitting multiple sclerosis, can potentiate the efficacy of AMB against growth synergistically. Furthermore, we observe an antifungal efficacy of FTY720 in combination with AMB against diverse fungal pathogens. Intriguingly, cells treated with both drugs are hypersensitive to endothelial endocytosis and macrophage killing. This is later found to be due to the hyperaccumulation of reactive oxygen species and the corresponding increase in activities of superoxide dismutase and catalase in the cells that received combinatorial treatment. Therefore, the combination of AMB and FTY720 provides a promising antifungal strategy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fcimb.2021.627917DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8102868PMC
July 2021

Repurposing the FDA-approved anticancer agent ponatinib as a fluconazole potentiator by suppression of multidrug efflux and Pma1 expression in a broad spectrum of yeast species.

Microb Biotechnol 2021 May 6. Epub 2021 May 6.

State Key Laboratory of Oncogenes and Related Genes, Center for Single-Cell Omics, School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.

Fungal infections have emerged as a major global threat to human health because of the increasing incidence and mortality rates every year. The emergence of drug resistance and limited arsenal of antifungal agents further aggravates the current situation resulting in a growing challenge in medical mycology. Here, we identified that ponatinib, an FDA-approved antitumour drug, significantly enhanced the activity of the azole fluconazole, the most widely used antifungal drug. Further detailed investigation of ponatinib revealed that its combination with fluconazole displayed broad-spectrum synergistic interactions against a variety of human fungal pathogens such as Candida albicans, Saccharomyces cerevisiae and Cryptococcus neoformans. Mechanistic insights into the mode of action unravelled that ponatinib reduced the efflux of fluconazole via Pdr5 and suppressed the expression of the proton pump, Pma1. Taken together, our study identifies ponatinib as a novel antifungal that enhances drug activity of fluconazole against diverse fungal pathogens.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/1751-7915.13814DOI Listing
May 2021

Microbiome dysbiosis in lung cancer: from composition to therapy.

NPJ Precis Oncol 2020 Dec 10;4(1):33. Epub 2020 Dec 10.

State Key Laboratory of Oncogenes and Related Genes, Center for Single-Cell Omics, School of Public Health, Shanghai Jiao Tong University School of Medicine, 200025, Shanghai, China.

The correlations between microbiota dysbiosis and cancer have gained extensive attention and been widely explored. As a leading cancer diagnosis worldwide, lung cancer poses a great threat to human health. The healthy human lungs are consistently exposed to external environment and harbor a specific pattern of microbiota, sharing many key pathological and physiological characteristics with the intestinal tract. Although previous findings uncovered the critical roles of microbiota in tumorigenesis and response to anticancer therapy, most of them were focused on the intestinal microbiota rather than lung microbiota. Notably, the considerable functions of microbiota in maintaining lung homeostasis should not be neglected as the microbiome dysbiosis may promote tumor development and progression through production of cytokines and toxins and multiple other pathways. Despite the fact that increasing studies have revealed the effect of microbiome on the induction of lung cancer and different disease status, the underlying mechanisms and potential therapeutic strategies remained unclear. Herein, we summarized the recent progresses about microbiome in lung cancer and further discussed the role of microbial communities in promoting lung cancer progression and the current status of therapeutic approaches targeting microbiome to alleviate and even cure lung cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41698-020-00138-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7730185PMC
December 2020

How to Understand "Herd Immunity" in COVID-19 Pandemic.

Front Cell Dev Biol 2020 24;8:547314. Epub 2020 Sep 24.

School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

The COVID-19 pandemic has been a global threat. Through rapid and effective surveillance and control, the newly confirmed patients have been fluctuated at a very low level and imported case explained most of them through March, 2020 to the present, indicating China's response has achieved a stage victory. By contrast, the epidemic of COVID-19 in other countries out of China is bursting. Different countries are adopting varied response strategy in terms of their public health system to prevent the spread. Herd immunity has been a hot topic since the outbreak of COVID-19 pandemic. Can it be a possible strategy to combat COVID-19? To fully interpret the knowledge regarding the term upon the background of COVID-19-related health crisis, we aim to systematically review the definition, describe the effective measures of acquiring herd immunity, and discuss its feasibility in COVID-19 prevention. Findings from this review would promote and strengthen the international cooperation and joint efforts when confronting with COVID-19.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fcell.2020.547314DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7543944PMC
September 2020

Glutamate dehydrogenase (Gdh2)-dependent alkalization is dispensable for escape from macrophages and virulence of Candida albicans.

PLoS Pathog 2020 09 16;16(9):e1008328. Epub 2020 Sep 16.

Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Sweden.

Candida albicans cells depend on the energy derived from amino acid catabolism to induce and sustain hyphal growth inside phagosomes of engulfing macrophages. The concomitant deamination of amino acids is thought to neutralize the acidic microenvironment of phagosomes, a presumed requisite for survival and initiation of hyphal growth. Here, in contrast to an existing model, we show that mitochondrial-localized NAD+-dependent glutamate dehydrogenase (GDH2) catalyzing the deamination of glutamate to α-ketoglutarate, and not the cytosolic urea amidolyase (DUR1,2), accounts for the observed alkalization of media when amino acids are the sole sources of carbon and nitrogen. C. albicans strains lacking GDH2 (gdh2-/-) are viable and do not extrude ammonia on amino acid-based media. Environmental alkalization does not occur under conditions of high glucose (2%), a finding attributable to glucose-repression of GDH2 expression and mitochondrial function. Consistently, inhibition of oxidative phosphorylation or mitochondrial translation by antimycin A or chloramphenicol, respectively, prevents alkalization. GDH2 expression and mitochondrial function are derepressed as glucose levels are lowered from 2% (~110 mM) to 0.2% (~11 mM), or when glycerol is used as primary carbon source. Using time-lapse microscopy, we document that gdh2-/- cells survive, filament and escape from primary murine macrophages at rates indistinguishable from wildtype. In intact hosts, such as in fly and murine models of systemic candidiasis, gdh2-/- mutants are as virulent as wildtype. Thus, although Gdh2 has a critical role in central nitrogen metabolism, Gdh2-catalyzed deamination of glutamate is surprisingly dispensable for escape from macrophages and virulence. Consistently, using the pH-sensitive dye (pHrodo), we observed no significant difference between wildtype and gdh2-/- mutants in phagosomal pH modulation. Following engulfment of fungal cells, the phagosomal compartment is rapidly acidified and hyphal growth initiates and sustained under consistently acidic conditions within phagosomes. Together, our results demonstrate that amino acid-dependent alkalization is not essential for hyphal growth, survival in macrophages and hosts. An accurate understanding of the microenvironment within macrophage phagosomes and the metabolic events underlying the survival of phagocytized C. albicans cells and their escape are critical to understanding the host-pathogen interactions that ultimately determine the pathogenic outcome.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1371/journal.ppat.1008328DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7521896PMC
September 2020

FDA Approved Drug Library Screening Identifies Robenidine as a Repositionable Antifungal.

Front Microbiol 2020 3;11:996. Epub 2020 Jun 3.

Center for Single-Cell Omics, School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Due to the increasing prevalence of pathogenic fungal infections, the emergence of antifungal resistant clinical isolates worldwide, and the limited arsenal of available antifungals, developing new antifungal strategies is imperative. In this study, we screened a library of 1068 FDA-approved drugs to identify hits that exhibit broad-spectrum antifungal activity. Robenidine, an anticoccidial agent which has been widely used to treat coccidian infections of poultry and rabbits, was identified in this screen. Physiological concentration of robenidine (8 μM) was able to significantly inhibit yeast cell growth, filamentation and biofilm formation of - the most extensively studied human fungal pathogen. Moreover, we observed a broad-spectrum antifungal activity of this compound against fluconazole resistant clinical isolates of , a wide range of other clinically relevant fungal pathogens. Intriguingly, robenidine-treated cells were hypersensitive to diverse cell wall stressors, and analysis of the cell wall structure by transmission electron microscopy (TEM) showed that the cell wall was severely damaged by robenidine, implying that this compound may target the cell wall integrity signaling pathway. Indeed, upon robenidine treatment, we found a dose dependent increase in the phosphorylation of the cell wall integrity marker Mkc1, which was decreased after prolonged exposure. Finally, we provide evidence by RNA-seq and qPCR that Rlm1, the downstream transcription factor of Mkc1, may represent a potential target of robenidine. Therefore, our data suggest that robenidine, a FDA approved anti-coccidiosis drug, displays a promising and broadly effective antifungal strategy, and represents a potentially repositionable candidate for the treatment of fungal infections.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fmicb.2020.00996DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7283467PMC
June 2020

Ranibizumab Pretreatment in Vitrectomy with Internal Limiting Membrane Peeling on Diabetic Macular Edema in Severe Proliferative Diabetic Retinopathy.

Diabetes Ther 2020 Jun 30;11(6):1397-1406. Epub 2020 Apr 30.

The Department of Ophthalmology, First Affiliated Hospital of China Medical University, Shenyang, Liaoning Province, China.

Aim: To evaluate the efficacy of intravitreal ranibizumab (IVR) pretreatment for pars plana vitrectomy (PPV) with internal limiting membrane (ILM) peeling in severe proliferative diabetic retinopathy (PDR) combined with macular edema (ME).

Methods: Sixty-three patients with ME and PDR were divided into IVR and control groups. Three days before PPV stripping, ranibizumab was injected into the patients in the IVR group. The patients were followed for 6 months. The best-corrected visual acuity (BCVA), visual acuity improvement, centre macular thickness (CMT), and intraoperative and postoperative complications were compared between the two groups.

Results: The BCVA of the IVR group was significantly improved at 1, 3 and 6 months compared with the preoperative BCVA (P < 0.01). The BCVA of the control group was significantly improved at 3 and 6 months compared with the preoperative BCVA (P < 0.01), but was not significantly improved at 1 month. At 1 and 3 months, the BCVA of the IVR group was significantly better than that of the control group after surgery, with no difference between the two groups at 6 months. The CMT of the IVR group was thinner than that of the control group at 1 and 3 months (P < 0.01), with no significant difference at 6 months after surgery. The surgical time, the risk of intraoperative bleeding, the incidence of iatrogenic retinal breaks, the frequency of endodiathermy and the rate of silicone oil tamponade were significantly different between the two groups (all P < 0.05). There was no significant difference between the two groups in terms of postoperative complications.

Conclusions: Ranibizumab pretreatment may improve the outcome of PPV with ILM peeling for severe PDR with ME by decreasing ME and intraoperative complications.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s13300-020-00822-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7261291PMC
June 2020

COVID-19 Pandemic: Experiences in China and Implications for its Prevention and Treatment Worldwide.

Curr Cancer Drug Targets 2020 ;20(6):410-416

Center for Single-Cell Omics, School of Public Health, Shanghai Jiao Tong University School of Medicine, 200025 Shanghai, China.

The outbreak of COVID-19 due to SARS-CoV-2 originally emerged in Wuhan in December 2019. As of March 22, 2020, the disease spread to 186 countries, with at least 305,275 confirmed cases. Although there has been a decline in the spread of the disease in China, the prevalence of COVID-19 around the world remains serious despite containment efforts undertaken by national authorities and the international community. In this article, we systematically review the brief history of COVID-19 and its epidemic and clinical characteristics, highlighting the strategies used to control and prevent the disease in China, which may help other countries respond to the outbreak. This pandemic emphasizes the need to be constantly alert to shifts in both the global dynamics and the contexts of individual countries, making sure that all are aware of which approaches are successful for the prevention, containment and treatment of new diseases, and being flexible enough to adapt the responses accordingly.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2174/1568009620666200414151419DOI Listing
July 2020

Phase- and epidemic region-adjusted estimation of the number of coronavirus disease 2019 cases in China.

Front Med 2020 Apr 31;14(2):199-209. Epub 2020 Mar 31.

School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.

The outbreak of the coronavirus disease 2019 was first reported in Wuhan in December 2019 and gradually spread to other areas in China. After implementation of prevention and control measures, the estimation of the epidemic trend is needed. A phase- and region-adjusted SEIR model was applied for modeling and predicting the number of cases in Wuhan, Hubei Province and regions outside Hubei Province in China. The estimated number of infections could reach its peak in late February 2020 in Wuhan and Hubei Province, which is 55 303-84 520 and 83 944-129 312, respectively, while the epidemic peaks in regions outside Hubei Province in China could appear on February 13, 2020 with the estimated 13 035-19 108 cases. According to the estimation, the outbreak would abate in March and April all over China. Current estimation provided evidence for planned work resumption under stringent prevention and control in China to further support the fight against the epidemic. Nevertheless, there is still possibility of the second outbreak brought by the work resumption and population migration, especially from Hubei Province and high intensity cities outside Hubei Province. Strict prevention and control measures still need to be considered in the regions with high intensity of epidemic and densely-populated cities.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11684-020-0768-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7148426PMC
April 2020

Phosphoric Metabolites Link Phosphate Import and Polysaccharide Biosynthesis for Candida albicans Cell Wall Maintenance.

mBio 2020 03 17;11(2). Epub 2020 Mar 17.

Division of Infectious Diseases, Boston Children's Hospital/Harvard Medical School, Boston, Massachusetts, USA

The high-affinity phosphate transporter Pho84 is required for normal Target of Rapamycin (TOR) signaling, oxidative stress resistance, and virulence of this fungal pathogen. It also contributes to ' tolerance of two antifungal drug classes, polyenes and echinocandins. Echinocandins inhibit biosynthesis of a major cell wall component, beta-1,3-glucan. Cells lacking Pho84 were hypersensitive to other forms of cell wall stress beyond echinocandin exposure, while their cell wall integrity signaling response was weak. Metabolomics experiments showed that levels of phosphoric intermediates, including nucleotides like ATP and nucleotide sugars, were low in mutant compared to wild-type cells recovering from phosphate starvation. Nonphosphoric precursors like nucleobases and nucleosides were elevated. Outer cell wall phosphomannan biosynthesis requires a nucleotide sugar, GDP-mannose. The nucleotide sugar UDP-glucose is the substrate of enzymes that synthesize two major structural cell wall polysaccharides, beta-1,3- and beta-1,6-glucan. Another nucleotide sugar, UDP--acetylglucosamine, is the substrate of chitin synthases which produce a stabilizing component of the intercellular septum and of lateral cell walls. Lack of Pho84 activity, and phosphate starvation, potentiated pharmacological or genetic perturbation of these enzymes. We posit that low substrate concentrations of beta-d-glucan- and chitin synthases, together with pharmacologic inhibition of their activity, diminish enzymatic reaction rates as well as the yield of their cell wall-stabilizing products. Phosphate import is not conserved between fungal and human cells, and humans do not synthesize beta-d-glucans or chitin. Hence, inhibiting these processes simultaneously could yield potent antifungal effects with low toxicity to humans. species cause hundreds of thousands of invasive infections with high mortality each year. Developing novel antifungal agents is challenging due to the many similarities between fungal and human cells. Maintaining phosphate balance is essential for all organisms but is achieved completely differently by fungi and humans. A protein that imports phosphate into fungal cells, Pho84, is not present in humans and is required for normal cell wall stress resistance and cell wall integrity signaling in Nucleotide sugars, which are phosphate-containing building block molecules for construction of the cell wall, are diminished in cells lacking Pho84. Cell wall-constructing enzymes may be slowed by lack of these building blocks, in addition to being inhibited by drugs. Combined targeting of Pho84 and cell wall-constructing enzymes may provide a strategy for antifungal therapy by which two sequential steps of cell wall maintenance are blocked for greater potency.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1128/mBio.03225-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7078483PMC
March 2020

Surgical repair of graft aneurysm following ascending-to-abdominal aortic bypass.

J Vasc Surg Cases Innov Tech 2019 Jun 25;5(2):183-186. Epub 2019 May 25.

Department of Cardiovascular Surgery, Beijing Anzhen Hospital, Capital Medical University, and Beijing Institute of Heart, Lung, and Blood Vessel Diseases, Beijing, China.

Graft aneurysm after ascending aorta to abdominal aorta bypass is a rare complication of repair of coarctation of the aorta. We present a case of an aneurysm measuring 75 mm in diameter at the midportion of the prosthetic graft in a 33-year-old man. To prevent aneurysm rupture, redo ascending-to-abdominal aortic bypass was performed through an upper ministernotomy and upper midline laparotomy. No postoperative complications occurred. The patient was successfully discharged on postoperative day 6. Although ascending-to-abdominal aortic bypass can achieve long-term patency, the prosthetic graft still has the rare risk of aneurysm formation, as highlighted in this case. Early diagnosis and timely management of this rare complication are essential in preventing aneurysm rupture.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jvscit.2018.12.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6536852PMC
June 2019

Concomitant adenosquamous carcinoma and cystadenocarcinoma of the extrahepatic bile duct: A case report.

World J Clin Cases 2019 Jan;7(2):215-220

Key Laboratory of Liver and Kidney Diseases, Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.

Background: Infiltrative adenosquamous carcinoma (ASC) of the extrahepatic bile duct is reported infrequently, which is an unusual variant of the ordinary adenocarcinoma. The simultaneous development of ASC and cystadenocarcinoma in the extrahepatic biliary tree is rare. In addition, the accurate preoperative diagnosis of concomitant carcinoma in the multiple biliary trees at an early stage is often difficult. Thus, awareness of the risk of the multiplicity of biliary tumors is perhaps the most important factor in identifying these cases.

Case Summary: Here, we report a case of a 63-year-old female with jaundice, who was referred to Shuguang Hospital because of abdominal pain for 1 mo. An abdominal contrast-enhanced computed tomography revealed a type I choledochal cyst and intraluminal masses suggestive of adenoma of the common bile duct. In addition, a preoperative diagnosis of a concomitant Klatskin tumor and type I choledochal cyst was made. The patient underwent anti-inflammatory therapy, followed by radical surgery due to hilar cholangiocarcinoma and resection of the choledochal cyst. Examination of the surgical specimen revealed a papillary tumor of the common bile duct, which arose from the malignant transformation of a pre-existing cystadenoma. Histologic examination confirmed a special type of cholangiocarcinoma; the tumor in the hilar bile duct was an ASC, whereas the tumor in the common bile duct was a moderately differentiated cystadenocarcinoma. The patient showed rapid deterioration 8 mo after surgery.

Conclusion: Although concomitant ASC and cystadenocarcinoma of the extrahepatic bile duct is difficult to diagnose before surgery, and the prognosis is poor after surgery, surgical resection is still the preferred treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.12998/wjcc.v7.i2.215DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6354090PMC
January 2019

Synthesis, Anti-Varicella-Zoster Virus and Anti-Cytomegalovirus Activity of 4,5-Disubstituted 1,2,3-(1H)-Triazoles.

Med Chem 2019 ;15(7):801-812

School of Chemistry and Chemical Engineering, Beijing Institute of Technology, Beijing 100081, China.

Background: Clinical drugs for herpesvirus exhibit high toxicity and suffer from significant drug resistance. The development of new, effective, and safe anti-herpesvirus agents with different mechanisms of action is greatly required.

Objective: Novel inhibitors against herpesvirus with different mechanisms of action from that of clinical drugs.

Methods: A series of novel 5-(benzylamino)-1H-1,2,3-triazole-4-carboxamides were efficiently synthesized and EC50 values against Human Cytomegalovirus (HCMV), Varicella-Zoster Virus (VZV) and Herpes Simplex Virus (HSV) were evaluated in vitro.

Results: Some compounds present antiviral activity. Compounds 5s and 5t are potent against both HCMV and VZV. Compounds 5m, 5n, 5s, and 5t show similar EC50 values against both TK+ and TK- VZV strains.

Conclusion: 5-(Benzylamino)-1H-1, 2,3-triazole-4-carboxamides are active against herpesviruses and their activity is remarkably affected by the nature and the position of substituents in the benzene ring. The results indicate that these derivatives are independent of the viral thymidine kinase (TK) for activation, which is indispensable for current drugs. Their mechanisms of action may differ from those of the clinic anti-herpesvirus drugs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2174/1573406414666181109095239DOI Listing
December 2019

MicroRNA-410 inhibition of the TIMP2-dependent MAPK pathway confers neuroprotection against oxidative stress-induced apoptosis after ischemic stroke in mice.

Brain Res Bull 2018 10 18;143:45-57. Epub 2018 Sep 18.

Department of Neurology, Cangzhou Central Hospital, Cangzhou, 061000, PR China.

Ischemic stroke (IS) is an acute cerebral event characterized by a high incidence rate, high disability rate as well as a high mortality. More recently, accumulative literature has provided evidence highlighting the role played by microRNAs (miRs) in the development of neurons. Hence, the aim of the present study was to investigate the neuroprotective role of miR-410 in IS. Microarray-based gene expression profiling of AMI was conducted in order to identify differentially expressed genes (DEGs) and the corresponding miRs regulating these genes. IS models were established to assess neurology on a scoring basis. Superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) activity and malondialdehyde (MDA) were all subsequently assessed. The functional role of miR-410 in IS was determined based on ectopic expression, knockdown and reporter assay experiments in hippocampal neurons. The expressions of microRNA-410, TIMP2, ERK, p38MAPK, JNK were all examined accordingly. The survival rate was assessed by MTT assay, and cell cycle and apoptosis by flow cytometry. After the loss of hippocampal neurons, infarct size as well as oxidative stress injury had been detected, microarray technology revealed that TIMP2 was differentially expressed in IS and that miR-410 regulated TIMP2. Initial observations revealed elevated levels of TIMP2 expression and MDA activity, in addition to evidence obtained indicated that the MAPK pathway had been activated along with decreased SOD, GSH-Px activity and miR-410 expression in IS mice. Ectopic expression of miR-410 was observed to inactivate the MAPK pathway, TIMP2 expression and hippocampal neuron apoptosis, while elevated hippocampal neuron survival rates and cell cycle entry were detected. Furthermore, TIMP2 as a direct target gene of miR-410, was determined to be negatively regulated by miR-410, while the MAPK pathway was found to be inhibited following TIMP2 knockdown. Our results revealed that the overexpression of miR-410 could ameliorate hippocampal neuron loss, reduce infarct size and oxidative stress injury in IS mice. Taken together, the key evidence of the current study elucidated the distinct nature of the inhibitory effect on IS as a result of overexpressed miR-410 whereby the conferral of neuroprotection was observed in oxidative stress-induced apoptosis post IS through the TIMP2-dependent repression of the MAPK pathway in mice.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.brainresbull.2018.09.009DOI Listing
October 2018

MERIT: Systematic Analysis and Characterization of Mutational Effect on RNA Interactome Topology.

Hepatology 2019 08 19;70(2):532-546. Epub 2019 Jan 19.

Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX.

The interaction between RNA-binding proteins (RBPs) and RNA plays an important role in regulating cellular function. However, decoding genome-wide protein-RNA regulatory networks as well as how cancer-related mutations impair RNA regulatory activities in hepatocellular carcinoma (HCC) remains mostly undetermined. We explored the genetic alteration patterns of RBPs and found that deleterious mutations are likely to occur on the surface of RBPs. We then constructed protein-RNA interactome networks by integration of target binding screens and expression profiles. Network analysis highlights regulatory principles among interacting RBPs. In addition, somatic mutations selectively target functionally important genes (cancer genes, core fitness genes, or conserved genes) and perturb the RBP-gene regulatory networks in cancer. These regulatory patterns were further validated using independent data. A computational method (Mutational Effect on RNA Interactome Topology) and a web-based, user-friendly resource were further proposed to analyze the RBP-gene regulatory networks across cancer types. Pan-cancer analysis also suggests that cancer cells selectively target "vulnerability" genes to perturb protein-RNA interactome that is involved in cancer hallmark-related functions. Specifically, we experimentally validated four pairs of RBP-gene interactions perturbed by mutations in HCC, which play critical roles in cell proliferation. Based on the expression of perturbed RBP and target genes, we identified three subtypes of HCC with different survival rates. Conclusion: Our results provide a valuable resource for characterizing somatic mutation-perturbed protein-RNA regulatory networks in HCC, yielding valuable insights into the genotype-phenotype relationships underlying human cancer, and potential biomarkers for precision medicine.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/hep.30242DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6538468PMC
August 2019

The effects of ginsenoside Rb1 on fatty acid β-oxidation, mediated by AMPK, in the failing heart.

Iran J Basic Med Sci 2018 Jul;21(7):731-737

Department of Cardiology, the People's Hospital of Liaoning Province, i.e. the People's Hospital of China Medical University, Shenyang, China.

Objectives: This study intended to investigate the effects of on fatty acid β-oxidation (FAO) in rat failing heart and to identify potential mechanisms of improving heart failure (HF) by FAO pathway dependent on AMP-activated protein kinase (AMPK).

Materials And Methods: Rats with chronic HF, induced by adriamycin (), were randomly grouped into 7 groups. Gs-Rb1, adenine 9-β-D-arabinofuranoside (, specific AMPK inhibitor), and 5'-aminoimidazole-4-carboxamide riboside (, specific AMPK activator) were administered to rats with HF, singly and/or combinedly. Myocardial high-energy phosphate (such as phosphocreatine, ADP, and ATP), free L-Carnitine, malonyl-CoA, and the activity of FAO-related enzymes in left ventricle from different groups were measured by using the corresponding molecular biological techniques.

Results: improved HF significantly, accompanied by a significant increase in phosphocreatine (PCr), ADP, ATP, PCr/ATP ratio, free carnitine, malonyl-CoA, mRNA, activity of carnitine palmitoyltransferase (Cpt), medium-chain Acyl-CoA Dehydrogenase (MCAD) and long-chain acyl-CoA Synthetase (ACSL) and a significant decrease of the ADP/ATP ratio in the left ventricular myocardium. However, all those effects were almost abolished by A and were not further improved by .

Conclusion: Taken together, it suggests that may modulate cardiac metabolic remodeling by improving myocardial fatty acid β-oxidation in failing heart. In addition, the effects of may be mediated via activating AMPK.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.22038/IJBMS.2018.24002.6016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6098964PMC
July 2018

Intersection of phosphate transport, oxidative stress and TOR signalling in Candida albicans virulence.

PLoS Pathog 2018 07 30;14(7):e1007076. Epub 2018 Jul 30.

Division of Infectious Diseases, Boston Children's Hospital/Harvard Medical School, Boston, Massachusetts, United States of America.

Phosphate is an essential macronutrient required for cell growth and division. Pho84 is the major high-affinity cell-surface phosphate importer of Saccharomyces cerevisiae and a crucial element in the phosphate homeostatic system of this model yeast. We found that loss of Candida albicans Pho84 attenuated virulence in Drosophila and murine oropharyngeal and disseminated models of invasive infection, and conferred hypersensitivity to neutrophil killing. Susceptibility of cells lacking Pho84 to neutrophil attack depended on reactive oxygen species (ROS): pho84-/- cells were no more susceptible than wild type C. albicans to neutrophils from a patient with chronic granulomatous disease, or to those whose oxidative burst was pharmacologically inhibited or neutralized. pho84-/- mutants hyperactivated oxidative stress signalling. They accumulated intracellular ROS in the absence of extrinsic oxidative stress, in high as well as low ambient phosphate conditions. ROS accumulation correlated with diminished levels of the unique superoxide dismutase Sod3 in pho84-/- cells, while SOD3 overexpression from a conditional promoter substantially restored these cells' oxidative stress resistance in vitro. Repression of SOD3 expression sharply increased their oxidative stress hypersensitivity. Neither of these oxidative stress management effects of manipulating SOD3 transcription was observed in PHO84 wild type cells. Sod3 levels were not the only factor driving oxidative stress effects on pho84-/- cells, though, because overexpressing SOD3 did not ameliorate these cells' hypersensitivity to neutrophil killing ex vivo, indicating Pho84 has further roles in oxidative stress resistance and virulence. Measurement of cellular metal concentrations demonstrated that diminished Sod3 expression was not due to decreased import of its metal cofactor manganese, as predicted from the function of S. cerevisiae Pho84 as a low-affinity manganese transporter. Instead of a role of Pho84 in metal transport, we found its role in TORC1 activation to impact oxidative stress management: overexpression of the TORC1-activating GTPase Gtr1 relieved the Sod3 deficit and ROS excess in pho84-/- null mutant cells, though it did not suppress their hypersensitivity to neutrophil killing or hyphal growth defect. Pharmacologic inhibition of Pho84 by small molecules including the FDA-approved drug foscarnet also induced ROS accumulation. Inhibiting Pho84 could hence support host defenses by sensitizing C. albicans to oxidative stress.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1371/journal.ppat.1007076DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6085062PMC
July 2018

Retraction Note: Nuclear factor of activated T cells 5 maintained by Hotair suppression of miR-568 upregulates S100 calcium binding protein A4 to promote breast cancer metastasis.

Breast Cancer Res 2018 07 25;20(1):77. Epub 2018 Jul 25.

State Key Laboratory of Cancer Biology, Department of Immunology, Fourth Military Medical University, Xi'an, 710032, Shaanxi, China.

The authors are retracting this article [1] after an investigation by the Ethics Committee of the Fourth Military Medical University (Xi'an, Shaanxi, China) of the following concerns that had been raised with respect to two of the figures.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13058-018-1021-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6058376PMC
July 2018

The Human Gut Microbial Metabolome Modulates Fungal Growth via the TOR Signaling Pathway.

mSphere 2017 Nov-Dec;2(6). Epub 2017 Dec 13.

Infectious Diseases Research Centre-CRI, CHU de Québec Research Center (CHUQ), Université Laval, Quebec City, Quebec, Canada.

is well known as a major human fungal pathogen, but it is also a permanent resident of healthy gastrointestinal tracts. Recent studies have shown that the human gut microbial metabolome represents an interesting source of bioactive molecules with a significant degree of chemical diversity. Some of these bioactive molecules may have useful antivirulence activities. For instance, intestinal bacterial species belonging to the family were found to secrete molecules that attenuate pathogenicity and repress the expression of virulence genes. Here, we have investigated whether the microbial gut metabolome (GM) contains molecules that might promote the commensal lifestyle and/or inhibit the expression of virulence of in the intestine. We found that metabolites from human feces inhibited the growth of and other opportunistic yeasts. A genetic screen in suggested that TOR is the molecular target of the antifungal molecule(s) of the GM. In addition, we found that the GM metabolites inhibit both hyphal growth and the invasion of human enterocytes. The antigrowth and antivirulence activities were partially recapitulated by secretions from spp. and strains, respectively. This study demonstrates that the antimicrobial activity of the GM can be extended to a eukaryotic pathogen, , illuminating the antagonistic interkingdom interactions between a fungus and intestinal commensal bacteria. is a natural component of the human microbiota but also an opportunistic pathogen that causes life-threatening infections. The human gastrointestinal tract is the main reservoir of , from where systemic infections originate as a consequence of the disruption of the intestinal mucosal barrier. Recent studies provided convincing evidence that overgrowth of and other related species in the gut is predominantly associated with chronic intestinal inflammatory bowel diseases. Here, we showed, for the first time, the antagonistic interkingdom interactions between and common intestinal commensal bacteria. From a therapeutic perspective, administering a defined bacterial community, such as the one described here with anti- activity, could provide potential therapeutic protection against gastrointestinal inflammatory diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1128/mSphere.00555-17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5729221PMC
December 2017

Celecoxib Down-Regulates the Hypoxia-Induced Expression of HIF-1α and VEGF Through the PI3K/AKT Pathway in Retinal Pigment Epithelial Cells.

Cell Physiol Biochem 2017 6;44(4):1640-1650. Epub 2017 Dec 6.

Background/aims: The goal of this study was to detect the expression of hypoxia-inducible factor 1α (HIF-1α) and vascular endothelial growth factor (VEGF) in human retinal pigmented epithelial (RPE) cells treated with celecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, under hypoxic and normoxic conditions and to explore the signaling mechanism involved in regulating the hypoxia-induced expression of HIF-1α and VEGF in RPE cells.

Methods: D407 cells were cultured in normoxic or hypoxic conditions, with or without celecoxib or a PI3K inhibitor (LY294002). The anti-proliferative effect of celecoxib was assessed using the MTT assay. RT-PCR, Western blotting and ELISA were performed to detect the levels of PI3K, phosphorylated AKT (p-AKT), HIF-1α, VEGF and COX-2.

Results: Celecoxib inhibited the proliferation of RPE cells in a dose-dependent manner. Celecoxib suppressed the expression of VEGF at both the mRNA and protein levels and decreased HIF-1α protein expression. HIF-1α activation was regulated by the PI3K/AKT pathway. The celecoxib-induced down-regulation of HIF-1α and VEGF required the suppression of the hypoxia-induced PI3K/AKT pathway. However, the down-regulation of COX-2 did not occur in cells treated with celecoxib.

Conclusions: The antiangiogenic effects of celecoxib in RPE cells under hypoxic conditions resulted from the inhibition of HIF-1α and VEGF expression, which may be partly mediated by a COX-2-independent, PI3K/AKT-dependent pathway.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000485764DOI Listing
January 2018

The TOR-Activating GTPases Gtr1 and Rhb1 Coregulate Starvation Responses and Biofilm Formation.

mSphere 2017 Nov-Dec;2(6). Epub 2017 Nov 15.

Division of Oral Biosciences, Dublin Dental University Hospital, University of Dublin, Trinity College Dublin, Dublin, Ireland.

Target of rapamycin complex 1 (TORC1) is an essential regulator of metabolism in eukaryotic cells and in the fungal pathogen regulates morphogenesis and nitrogen acquisition. Gtr1 encodes a highly conserved GTPase that in regulates nitrogen sensing and TORC1 activation. Here, we characterize the role of in TORC1 activation and compare it with the previously characterized GTPase Rhb1. A homozygous mutant exhibited impaired TORC1-mediated phosphorylation of ribosomal protein S6 and increased susceptibility to rapamycin. Overexpression of impaired nitrogen starvation-induced filamentous growth, expression, and growth in bovine serum albumin as the sole nitrogen source. Both and were shown to regulate genes involved in ribosome biogenesis, amino acid biosynthesis, and expression of biofilm growth-induced genes. The mutant exhibited a different pattern of expression of Sko1-regulated genes and increased susceptibility to Congo red and calcofluor white. The homozygous mutant exhibited enhanced flocculation phenotypes and, similar to the mutant, exhibited enhanced biofilm formation on plastic surfaces. In summary, Gtr1 and Rhb1 link nutrient sensing and biofilm formation and this connectivity may have evolved to enhance the competitiveness of in niches where there is intense competition with other microbes for space and nutrients. is the major fungal pathogen of humans and is responsible for a wide range of infections, including life-threatening systemic infections in susceptible hosts. Target of rapamycin complex 1 (TORC1) is an essential regulator of metabolism in this fungus, and components of this complex are under increased investigation as targets for new antifungal drugs. The present study characterized the role of , encoding a putative GTPase, in TORC1 activation. This study shows that encodes a protein required for activation of TORC1 activity in response to amino acids and regulation of nitrogen starvation responses. mutants show increased cell-cell adhesion and biofilm formation and increased expression of genes involved in these processes. This study demonstrates that starvation responses and biofilm formation are coregulated by and suggests that these responses are linked to compete with the microbiome for space and nutrients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1128/mSphere.00477-17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5687921PMC
November 2017

Base-resolution stratification of cancer mutations using functional variomics.

Nat Protoc 2017 Nov 5;12(11):2323-2341. Epub 2017 Oct 5.

Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

A complete understanding of human cancer variants requires new methods to systematically and efficiently assess the functional effects of genomic mutations at a large scale. Here, we describe a set of tools to rapidly clone and stratify thousands of cancer mutations at base resolution. This protocol provides a massively parallel pipeline to achieve high stringency and throughput. The approach includes high-throughput generation of mutant clones by Gateway, confirmation of variant identity by barcoding and next-generation sequencing, and stratification of cancer variants by multiplexed interaction profiling. Compared with alternative site-directed mutagenesis methods, our protocol requires less sequencing effort and enables robust statistical calling of allele-specific effects. To ensure the precision of variant interaction profiling, we further describe two complementary methods-a high-throughput enhanced yeast two-hybrid (HT-eY2H) assay and a mammalian-cell-based Gaussia princeps luciferase protein-fragment complementation assay (GPCA). These independent assays with standard controls validate mutational interaction profiles with high quality. This protocol provides experimentally derived guidelines for classifying candidate cancer alleles emerging from whole-genome or whole-exome sequencing projects as 'drivers' or 'passengers'. For ∼100 genomic mutations, the protocol-including target primer design, variant library construction, and sequence verification-can be completed within as little as 2-3 weeks, and cancer variant stratification can be completed within 2 weeks.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/nprot.2017.086DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6145840PMC
November 2017

Anti-angiogenic effect of rapamycin in mouse oxygen-induced retinopathy is mediated through suppression of HIF-1alpha/VEGF pathway.

Int J Clin Exp Pathol 2017 1;10(10):10167-10175. Epub 2017 Oct 1.

Department of Ophthalmology, The First Affiliated Hospital of China Medical University Shenyang, Liaoning Province, China.

Hypoxia-inducible factor-1alpha (HIF-1α)-vascular endothelial growth factor (VEGF) pathway, a downstream of mammalian target of rapamycin (mTOR), plays a major role in the formation of pathological retinal angiogenesis. Rapamycin (RAPA), a highly specific inhibitor of mTOR, is widely used in cancer studies for its antiangiogenic activity. However, the inhibitory effects of RAPA on the HIF-1α-VEGF pathway in retinal tissues were rarely researched. The study aimed to investigate the efficacy and potential mechanisms of RAPA in inhibiting retinal neovascularization. Human umbilical vein endothelial cells (HUVECs) were treated with hypoxia and in the presence of different concentrations of RAPA. RAPA was injected intraperitoneally in oxygen-induced retinopathy (OIR) C57BL/6 mice from postnatal day 12 (P12) to P17. The proliferation of HUVECs, the protein and mRNA expressions of HIF-1α and VEGF were evaluated in HUVECs or OIR mice using MTT assay, ELISA, immunohistochemistry, Western-blot and real-time PCR. Histological methods were used to count blood vessel profiles in the inner retina. RAPA inhibited HUVECs proliferation and retinal neovascularization by reducing protein and mRNA expressions of HIF-1α and VEGF. RAPA suppresses hypoxia-induced HUVECs cell proliferation and pathological ocular angiogenesis through a mechanism linked to the targeting of HIF-1α/VEGF signaling.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6965774PMC
October 2017
-->