Deubiquitylase YOD1 regulates CDK1 stability and drives triple-negative breast cancer tumorigenesis.

BACKGROUND: Accumulating evidence has demonstrated that aberrant expression of deubiquitinating enzymes is associated with the initiation and progression of Triple-negative breast cancer (TNBC). The publicly available TCGA database of breast cancer data was used to analyze the OTUD deubiquitinating family members that were correlated with survival of breast cancer and ovarian tumor domain-containing 2 (OTUD-2), or YOD1 was identified. The aim of present study was to assess YOD1 expression and function in human TNBC and then explored the underlying molecular events. METHODS: We detected the expression of YOD1 in 32 TNBC and 44 NTNBC samples by qRT-PCR, Western blot and immunohistochemistry. Manipulation of YOD1 expression was assessed in vitro and in vivo for TNBC cell proliferation, migration, invasion, cell-cycle and drug resistance, using colony formation assay, transwell assay, CCK8 assay, TUNEL assay, flow cytometric analysis and xenograft tumor assay. Next, proteomic analysis, Western blot, proximity ligation assay, Immunoprecipitation, and Immunofluorescence were conducted to assess downstream targets. RESULTS: It was found that YOD1 was significantly upregulated in TNBC tissues compared with non-triple-negative breast cancer (NTNBC), which was positively correlated with poor survival in TNBC patients. Knockdown of YOD1 effectively inhibited TNBC cell migration, proliferation, cell cycle and resistance to cisplatin and paclitaxel. Mechanistically, YOD1 promoted TNBC progression in a manner dependent on its catalytic activity through binding with CDK1, leading to de-polyubiquitylation of CDK1 and upregulation of CDK1 expression. In addition, YOD1 overexpression was found to be correlated with CDK1 overexpression in human TNBC specimens. Finally, in vivo study demonstrated that YOD1 knockdown or YOD1 inhibitor could inhibit CDK1 expression and suppress the growth and metastasis of TNBC tumors. CONCLUSION: Our study highlights that YOD1 functions as an oncogene in TNBC via binding to CDK1 and mediated its stability and oncogenic activity. Interfering with YOD1 expression or YOD1 inhibitor could suppress TNBC cells in vitro and in vivo, suggesting that YOD1 may prove to be a promising therapeutic target for TNBC.

Transcriptome analysis of a newly established mouse model of Toxoplasma gondii pneumonia.

BACKGROUND: Toxoplasmosis is a zoonotic parasitic disease caused by Toxoplasma gondii. Toxoplasma gondii infection of the lungs can lead to severe pneumonia. However, few studies have reported Toxoplasma pneumonia. Most reports were clinical cases due to the lack of a good disease model. Therefore, the molecular mechanisms, development, and pathological damage of Toxoplasma pneumonia remain unclear. METHODS: A mouse model of Toxoplasma pneumonia was established by nasal infection with T. gondii. The model was evaluated using survival statistics, lung morphological observation, and lung pathology examination by hematoxylin and eosin (H&E) and Evans blue staining at 5 days post-infection (dpi). Total RNA was extracted from the lung tissues of C57BL/6 mice infected with T. gondii RH and TGME49 strains at 5 dpi. Total RNA was subjected to transcriptome analysis by RNA sequencing (RNA-seq) followed by quantitative real-time polymerase chain reaction (qRT-PCR) validation. Transcript enrichment analysis was performed using the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases to assess the biological relevance of differentially expressed transcripts (DETs). RESULTS: C57BL/6 mice infected with T. gondii via nasal delivery exhibited weight loss, ruffled fur, and respiratory crackles at 5 dpi. The clinical manifestations and lethality of RH strains were more evident than those of TGME49. H&E staining of lung tissue sections from mice infected with T. gondii at 5 dpi showed severe lymphocytic infiltration, pulmonary edema, and typical symptoms of pneumonia. We identified 3167 DETs and 1880 DETs in mice infected with the T. gondii RH and TGME49 strains, respectively, compared with the phosphate-buffered saline (PBS) control group at 5 dpi. GO and KEGG enrichment analyses of DETs showed that they were associated with the immune system and microbial infections. The innate immune, inflammatory signaling, cytokine-mediated signaling, and chemokine signaling pathways displayed high gene enrichment. CONCLUSION: In this study, we developed a new mouse model for Toxoplasma pneumonia. Transcriptome analysis helped to better understand the molecular mechanisms of the disease. These results provided DETs during acute T. gondii lung infection, which expanded our knowledge of host immune defenses and the pathogenesis of Toxoplasma pneumonia.

Prunus mira Koehne in Sichuan, China: Recorded History as a Medicine and Food, Modern Applications, Distribution, and Ethnobotanical Investigations.

Prunus mira Koehne, a Prunus plant in the Rosaceae family, is named ཁམབུ། in Tibetan and "Guang he tao" in Chinese. It is mainly distributed in Tibet Autonomous Region, Yunnan Province, and Sichuan Province in China. It is also a rare "living fossil group" of peach genetic resources in the world. It is used in traditional Chinese medicine for the treatment of dysmenorrhea, injury, intestinal dryness, constipation, and other diseases, and is used in Tibetan medicine for the treatment of hair, eyebrows, and beard shedding. In this article, the botanical characteristics, medicinal history, modern applied research, and ethnobotanical investigation of P. mira were recorded and evaluated. P. mira was first recorded in Dumu Materia Medica. P. mira in Sichuan Province is mainly distributed in Ganzi Tibetan Autonomous Prefecture, and has certain economic and medicinal value. P. mira has high nutritional composition. It is made into high-quality edible oil, cosmetic base oil, fruit juice, fruit wine, fruit vinegar, "Liang guo", and other products. Oleic acid and linoleic acid are the main fat-soluble components of P. mira, which has an anti-inflammatory medicinal value and promotes hair growth. Its longevity and cold resistance can bring great genetic value and play an important role in maintaining peach genetic diversity. At present, there are few studies on the pharmacological effects of specific active components of P. mira and there are also few clinical studies. We can continue to study these aspects in the future. At the same time, products of P. mira have great market potential. All in all, P. mira is very worthy of further research and development.

Multi-omics of the expression and clinical outcomes of TMPRSS2 in human various cancers: A potential therapeutic target for COVID-19.

Growing evidence has shown that Transmembrane Serine Protease 2 (TMPRSS2) not only contributes to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, but is also closely associated with the incidence and progression of tumours. However, the correlation of coronavirus disease (COVID-19) and cancers, and the prognostic value and molecular function of TMPRSS2 in various cancers have not been fully understood. In this study, the expression, genetic variations, correlated genes, immune infiltration and prognostic value of TMPRSS2 were analysed in many cancers using different bioinformatics platforms. The observed findings revealed that the expression of TMPRSS2 was considerably decreased in many tumour tissues. In the prognostic analysis, the expression of TMPRSS2 was considerably linked with the clinical consequences of the brain, blood, colorectal, breast, ovarian, lung and soft tissue cancer. In protein network analysis, we determined 27 proteins as protein partners of TMPRSS2, which can regulate the progression and prognosis of cancer mediated by TMPRSS2. Besides, a high level of TMPRSS2 was linked with immune cell infiltration in various cancers. Furthermore, according to the pathway analysis of differently expressed genes (DEGs) with TMPRSS2 in lung, breast, ovarian and colorectal cancer, 160 DEGs genes were found and were significantly enriched in respiratory system infection and tumour progression pathways. In conclusion, the findings of this study demonstrate that TMPRSS2 may be an effective biomarker and therapeutic target in various cancers in humans, and may also provide new directions for specific tumour patients to prevent SARS-CoV-2 infection during the COVID-19 outbreak.

Secreted Wnt6 mediates diabetes-associated centrosome amplification via its receptor FZD4.

We recently published that type 2 diabetes promotes cell centrosome amplification via upregulation of Rho-associated protein kinase 1 (ROCK1) and 14-3-3 protein-σ (14-3-3σ). This study further investigates the molecular mechanisms underlying diabetes-associated centrosome amplification. We found that treatment of cells with high glucose, insulin, and palmitic acid levels increased the intracellular and extracellular protein levels of Wingless-type MMTV integration site family member 6 (Wnt6) as well as the cellular level of ß-catenin. The treatment also activated ß-catenin and promoted its nuclear translocation. Treatment of cells with siRNA species for Wnt6, Frizzled-4 (FZD4), or ß-catenin as well as introduction of antibodies against Wnt6 or FZD4 to the cell culture medium could all attenuate the treatment-triggered centrosome amplification. Moreover, we showed that secreted Wnt6-FZD4-ß-catenin was the signaling pathway that was upstream of ROCK1 and 14-3-3σ. We found that advanced glycation end products (AGEs) were also able to increase the cellular and extracellular levels of Wnt6, the cellular protein level of ß-catenin, and centrosome amplification. Treatment of the cells with siRNA species for Wnt6 or FZD4 as well as introduction of antibodies against Wnt6 or FZD4 to the cell culture could all inhibit the AGEs-elicited centrosome amplification. In colon tissues from a diabetic mouse model, the protein levels of Wnt6 and 14-3-3σ were increased. In conclusion, our results showed that the pathophysiological factors in type 2 diabetes, including AGEs, were able to induce centrosome amplification. It is suggested that secreted Wnt6 binds to FZD4 to activate the canonical Wnt6 signaling pathway, which is upstream of ROCK1 and 14-3-3σ, and that this is the cell signaling pathway underlying diabetes-associated centrosome amplification.

Redox modulated fluorometric sensing of ascorbic acid by using a hybrid material composed of carbon dots and CoOOH nanosheets.

Carbon dots (CDs) were hydrothermally prepared from gelatin as the sole precursor. The CDs were hybridized with CoOOH nanosheets (NSs) to obtain a fluorescent probe (CD-CoOOH) for ascorbic acid (AA). The blue luminescence of the CDs, with excitation/emission maxima of 350/443 nm, is quenched by the NSs. If the NSs are reduced to Co2+ by addition of AA, the CD-CoOOH hybrid is disintegrated and fluorescence recovers. The hybrid nanoprobe has a linear response in the 0.8-12.5 µM and 12.5-690 µM AA concentration ranges and a 0.025 µM limit of detection. Compared to previously reported methods for detecting AA, this methods has a wider linear range and a lower detection limit. The nanoprobe was utilized to quantify AA in spiked human serum samples and gave satisfactory results. The strategy was also applied to the construction of an "AND" logic gate, which avoided perplexed material decorations and chemical tracking. Graphical abstract Scheme 1. Schematic illustrations of the preparation of CDs and of the working principle for determination of ascorbic acid (AA).

PPARγ promotes diabetes-associated centrosome amplification via increasing the expression of SKA1 directly at the transcriptional level.

We have recently published that type 2 diabetes can induce cell centrosome amplification due to the action of high glucose, palmitic acid, and insulin, and ROCK1 and 14-3-3σ are signal mediators. In this study, we further investigated the molecular mechanisms of the centrosome amplification in colon cancer HCT116 cells. Treatment of the cells with high glucose, palmitic acid, and insulin increased the expression of peroxisome proliferator-activated receptor γ (PPARγ) as well as the spindle and kinetochore associated protein 1 (SKA1), knockdown of each of which resulted in the inhibition of the treatment-triggered centrosome amplification. Knockdown of PPARγ inhibited the treatment-evoked increase in the SKA1 level, whereas knockdown of SKA1 did not modify the treatment-increased PPARγ level. We found a predicted binding site for PPARγ in the promoter region of the SKA1 gene from the JASPAR database. Experimental results showed that the treatment increased the messenger RNA level of SKA1, which could be inhibited by PPARγ chemical inhibitor or small interfering RNA. Moreover, we were able to show that PPARγ could bind to the binding site in the SKA1 gene promoter, which was increased by the experimental treatment. In conclusion, it is suggested that the pathophysiological factors in type 2 diabetes, high glucose, palmitic acid, and insulin, induce the cell centrosome amplification through the PPARγ-SKA1 pathway, in which PPARγ increases the expression of SKA1 via directly enhancing the SKA1 gene transcription.

Powder carbonization to synthesize novel carbon dots derived from uric acid for the detection of Ag(I) and glutathione.

This article first reported that a simple synthesis of carbon dots (UCDs) by pyrolysis of uric acid was proposed. The excitation wavelength was 350 nm and the emission wavelength was 402 nm for the synthesized UCDs. And the corresponding fluorescence quantum yield was 52.06%. The obtained UCDs could be served as a fluorescence probe to recognize Ag+ and glutathione (GSH), respectively. The fluorescence of UCDs was quenched after the addition of Ag+. The obtained UCDs had a linear relationship with Ag+ in the detection range of 0.1 µM to 2.0 µM, and the detection limit was 39 nM. The quenching fluorescence of this system could be restored after adding GSH. The fluorescence intensity increased linearly on increasing the concentration of glutathione in the range of 4 to 9 µM, and the detection limit was 66 nM. Based upon these phenomena, we proposed a novel fluorescence probe to detect Ag+ and detect GSH, respectively. In addition, the prepared UCDs were successfully applied to analyze Ag+ in mineral waters and GSH in blood serums.

Bright carbon dots via inner filter effect for the sensitive determination of the purine metabolic disorder in human fluids.

In this paper, the high performance fluorescent carbon dots were synthesized with maleic acid, tris and benzoic acid as raw materials by one-step hydrothermal method. The obtained carbon dots with uniform size emitted strong blue fluorescence, which the maximum excitation and emission wavelengths at 250 nm and 415 nm, respectively. Under the optimum condition, it was meaningfully founded that the reaction between the carbon dots and uric acid resulting in the fluorescence quenching of the carbon dots at the emission spectrum of 415 nm. The reason was that they had a synergistic effect between the fluorescence internal filtering effect and the static quenching effect. The fluorescence internal filter effect sensing system was constructed by using uric acid as the absorbable material and carbon dots as the luminophore. Hence, a fluorescence quenching method for the determination of uric acid was established in the concentration range from 5.0 to 400 µM with the detection limit (3σ/S) of 2.26 µM. Thus, a fluorescent sensing assay for the determination of uric acid was founded and confirmed in human fluids.

Controlled Construction of Supported Cu+ Sites and Their Stabilization in MIL-100(Fe): Efficient Adsorbents for Benzothiophene Capture.

Cu+-containing materials have drawn much attention in various applications because they are versatile, nontoxic, and low-cost. However, the difficulty of selective reduction and the poor stability of Cu+ species are now pretty much the agendas. Here, controlled construction of supported Cu+ sites in MIL-100(Fe) was realized under mild conditions (200 °C, 5 h) via a vapor-reduction strategy (VRS). Remarkably, the yield of Cu+ reaches 100%, which is quite higher than the traditional high-temperature autoreduction method with a yield less than 50% even at 700 °C for 12 h. More importantly, during the treatment via VRS some Fe3+ in MIL-100(Fe) are reduced to Fe2+, which prevent the frequently happened oxidation of Cu+ due to the higher oxidation potential of Fe2+. These properties make Cu+/MIL-100(Fe) efficient in the capture of typical aromatic sulfur, benzothiophene, with regard to both adsorption capacity and stability. To our knowledge, the stabilization of Cu+ using the oxidation tendency of supports is achieved for the first time, which may offer a new idea to utilize active sites with weak stability.

Vitamin D deficiency may predict a poorer outcome of IgA nephropathy.

BACKGROUND: Experimental studies showed that 25-hydroxy-vitamin D [25(OH)D] deficiency (defined as 25-hydroxy-vitamin D < 15 ng/ml) has been associated with CKD progression. Patients with IgA nephropathy have an exceptionally high rate of severe 25(OH)D deficiency; however, it is not known whether this deficiency is a risk factor for progression of IgA nephropathy. We conducted this study to investigate the relationship between the plasma level of 25(OH)D and certain clinical parameters and renal histologic lesions in the patients with IgA nephropathy, and to evaluate whether the 25(OH)D level could be a good prognostic marker for IgA nephropathy progression. METHODS: A total of 105 patients with biopsy-proven IgA nephropathy were enrolled between 2012 and 2015. The circulating concentration of 25(OH)D was determined using serum samples collected at the time of biopsy. The primary clinical endpoint was the decline of estimated glomerular filtration rate (eGFR; a 30 % or more decline compared to the baseline). RESULTS: Mean eGFR decreased and proteinuria worsened proportionally as circulating 25(OH)D decreased (P < 0.05). The 25(OH)D deficiency was correlated with a higher tubulointerstitial score by the Oxford classification (P = 0.008). The risk for reaching the primary endpoint was significantly higher in the patients with a 25(OH)D deficiency compared to those with a higher level of 25(OH)D (P = 0.001). As evaluated using the Cox proportional hazards model, 25(OH)D deficiency was found to be an independent risk factor for renal progression [HR 5.99, 95 % confidence intervals (CIs) 1.59-22.54, P = 0.008]. CONCLUSION: A 25(OH)D deficiency at baseline is significantly correlated with poorer clinical outcomes and more sever renal pathological features, and low levels of 25(OH)D at baseline were strongly associated with increased risk of renal progression in IgAN.

[Application of computer-aided diagnosis in early detection of pulmonary nodules based on digital chest radiograph].

This study aims to explore the clinical value of the computer-aided diagnosis (CAD) system for early detection of the pulmonary nodules on digital chest X-ray. A total of 100 cases of digital chest radiographs with pulmonary nodules of 5-20 mm diameter were selected from Pictures Archiving and Communication System (PACS) database in West China Hospital of Sichuan University were enrolled into trial group, and other 200 chest radiographs without pulmonary nodules as control group. All cases were confirmed by CT examination. Firstly, these cases were diagnosed by 5 different-seniority doctors without CAD, and after three months, these cases were re-diagnosed by the 5 doctors with CAD. Subsequently, the diagnostic results were analyzed by using SPSS statistical methods. The results showed that the sensitivity and specificity for detecting pulmonary nodules tended to be improved by using the CAD system, especially for specificity, but there was no significant difference before and after using CAD system.

[An 18-year follow-up study on the risk factors of deaths regarding chronic obstructive pulmonary disease in Xi'an, China].

OBJECTIVE: To examine risk factors of chronic obstructive pulmonary disease (COPD) deaths in Chinese military elderly men. METHODS: A cohort analytic study was carried out in Xi'an, China. A total of 1268 retired military males aged 55 or older were examined in 1987 and followed for 18 years. Main outcome measures were all causes and COPD deaths. RESULTS: The total person-years of follow-up from 1987 until June 2005 was 18 766.28. The mean follow-up time was 14.35 years; A total of 491 had died, with 748 alive and 29 lost of follow-up. COPD was the second cause of death in all deaths (16.90%). Results Univariate analysis of Cox model showed that age, number of smoking cigarettes per day, duration of smoking, negative affairs and existing COPD were risk factors of COPD deaths and the relative risks [95% confidence intervals (CI)] were 1.13 (1.09-1.17), 1.04 (1.02-1.06), 1.03 (1.01-1.04), 1.81 (2.85-6.77) and 4.39 (2.85-6.77) respectively. Data from Multivariate analysis of Cox model showed that age, number of smoking cigarettes per day and existing COPD were risk factors of COPD death with relative risks [95% confidence intervals (CI)] as 1.10 (1.06-1.15), 1.03 (1.01-1.06) and 3.07 (1.90-4.98) respectively. The risks for deaths increased significantly with increasing amount and duration of smoking resulting from all causes and COPD. Compared with current smokers, former smokers had lower risks of total mortality(excess risk reduction of 66.67%). CONCLUSION: COPD was the second cause among all deaths in this cohort. Age, number of smoking cigarettes per day and existing COPD were the risk factors of COPD deaths which called for further survey to examine the relationship between quitting smoking and COPD deaths in this cohort.

An 18-year follow-up study on the risk factors of deaths regarding chronic obstructive pulmonary disease in Xi'an, China / 中华流行病学杂志

<p><b>OBJECTIVE</b>To examine risk factors of chronic obstructive pulmonary disease (COPD) deaths in Chinese military elderly men.</p><p><b>METHODS</b>A cohort analytic study was carried out in Xi'an, China. A total of 1268 retired military males aged 55 or older were examined in 1987 and followed for 18 years. Main outcome measures were all causes and COPD deaths.</p><p><b>RESULTS</b>The total person-years of follow-up from 1987 until June 2005 was 18 766.28. The mean follow-up time was 14.35 years; A total of 491 had died, with 748 alive and 29 lost of follow-up. COPD was the second cause of death in all deaths (16.90%). Results Univariate analysis of Cox model showed that age, number of smoking cigarettes per day, duration of smoking, negative affairs and existing COPD were risk factors of COPD deaths and the relative risks [95% confidence intervals (CI)] were 1.13 (1.09-1.17), 1.04 (1.02-1.06), 1.03 (1.01-1.04), 1.81 (2.85-6.77) and 4.39 (2.85-6.77) respectively. Data from Multivariate analysis of Cox model showed that age, number of smoking cigarettes per day and existing COPD were risk factors of COPD death with relative risks [95% confidence intervals (CI)] as 1.10 (1.06-1.15), 1.03 (1.01-1.06) and 3.07 (1.90-4.98) respectively. The risks for deaths increased significantly with increasing amount and duration of smoking resulting from all causes and COPD. Compared with current smokers, former smokers had lower risks of total mortality(excess risk reduction of 66.67%).</p><p><b>CONCLUSION</b>COPD was the second cause among all deaths in this cohort. Age, number of smoking cigarettes per day and existing COPD were the risk factors of COPD deaths which called for further survey to examine the relationship between quitting smoking and COPD deaths in this cohort.</p>