Stretching effects on non-adiabatic electron dynamic behavior in poly(dG)-poly(dC) DNA upon the proton irradiation.

The electronic excitations caused by DNA when exposed to ion radiation is essential to DNA damage. In this paper, we investigated the energy deposition and electron excitation process of DNA with reasonable stretching range upon proton irradiation based on time-dependent density functional theory. Stretching changes the strength of hydrogen bonding between the DNA base pairs, which in turn affects the Coulomb interaction between the projectile and DNA. As a semi-flexible molecule, the way of energy deposition is weakly sensitive to the stretching rate of DNA. However, the increase of stretching rate causes the increase of charge density along the trajectory channel, sequentially resulting in an increase in proton resistance along the intruding channel. The Mulliken charge analysis indicates that the guanine base and guanine ribose are ionized, meanwhile the cytosine base and cytosine ribose are reduced at all stretching rates. In a few femtoseconds, there exists an electron flow passing through the guanine ribose, guanine, cytosine base and the cytosine ribose in turn. This electron flow increases electron transfer and DNA ionization, promoting the side chain damage of the DNA upon ion irradiation. Our results provide a theoretical insight for deciphering the physical mechanism of the early stage of the irradiation process, and are also of great significance for the study of particle beam cancer therapy in different biological tissues.

Dynamic interplay between thionine and DNA under carbon ion irradiation: a real-time first-principles study.

Understanding the interactions between deoxyribonucleic acid (DNA) and photosensitizer under ion irradiation benefits the development of aptasensors, DNA biosensors and cancer diagnosis. Using real-time time-depended density functional theory, by simulating high-energy C ion passing through DNA with poly(dG)·poly(dC) sequence and that with embedded thionine (3,7-diamino-5-phenothiazinium, TH), we compared the electronic stopping power (ESP), evolution of the structure and charge, and absorption spectrum. TH inserting leads the increase in space charge density, a larger electron de-excitation and a larger ESP, but the speed corresponding to the maximum ESP is almost same. When C ion passes through TH-DNA, the structure of TH slightly changes and there still exists noncovalent interaction between TH and DNA, but the absorption coefficient depends on the electron occupied state of TH when the ion passes through. These results indicate that at low radiation doses, TH still can be a DNA detector, although its response wavelength and intensity have been slightly changed, and provide a theoretical reference to improve the possible application of phenothiazine dye in DNA biosensor under ion irradiation.

An overview of pharmacological activities of baicalin and its aglycone baicalein: New insights into molecular mechanisms and signaling pathways.

The flavonoids, baicalin, and its aglycone baicalein possess multi-fold therapeutic properties and are mainly found in the roots of Oroxylum indicum (L.) Kurz and Scutellaria baicalensis Georgi. These flavonoids have been reported to possess various pharmacological properties, including antibacterial, antiviral, anticancer, anticonvulsant, anti-oxidant, hepatoprotective, and neuroprotective effects. The pharmacological properties of baicalin and baicalein are due to their abilities to scavenge reactive oxygen species (ROS) and interaction with various signaling molecules associated with apoptosis, inflammation, autophagy, cell cycle, mitochondrial dynamics, and cytoprotection. In this review, we summarized the molecular mechanisms underlying the chemopreventive and chemotherapeutic applications of baicalin and baicalein in the treatment of cancer and inflammatory diseases. In addition, the preventive effects of baicalin and baicalein on mitochondrial dynamics and functions were highlighted with a particular emphasis on their anti-oxidative and cytoprotective properties. The current review highlights could be useful for future prospective studies to further improve the pharmacological applications of baicalein and baicalin. These studies should define the threshold for optimal drug exposure, dose optimization and focus on therapeutic drug monitoring, objective disease markers, and baicalin/baicalein drug levels.

Association Between Variants of the Mannose-Binding Lectin 2 Gene and Susceptibility to Sepsis in the Hainan Island.

BACKGROUND Sepsis has emerged as a leading cause of death in the intensive care unit. A growing number of studies have shown that genetic variants, especially single nucleotide polymorphisms, are key determinants of inter-individual variation in sepsis response. Therefore, early prediction of the onset and progression of sepsis, along with early intervention in high-risk patients, should be performed to effectively reduce the morbidity and mortality of the disease. MATERIAL AND METHODS A total of 581 Chinese patients were enrolled in this study, including 271 patients with sepsis and 310 patients without. We measured gene polymorphisms of MBL2 and serum levels of MBL2, tumor necrosis factor (TNF-alpha), interleukin (IL)-6, IL-4, and IL-10 in all patients. The effects of site mutations on the binding of MBL2 to mannose-associated serine protease 1 (MASP1) and MASP2 were also analyzed. RESULTS Of 3 site mutations in the MBL2 gene (rs5030737, rs1800450, and rs1800451), only rs1800450 had a mutant (G/A) genotype. The frequency of the GA genotype and A allele in the sepsis group was higher than that in the non-sepsis group. Furthermore, rs1800450G/A was associated with decreased serum MBL2 and IL-10 levels and decreased MBL2-MASP1 and MBL2-MASP2 interactions. Bioinformatics analysis showed that rs1800450G/A reduced the structural stability of the MBL2 protein and affected its function. CONCLUSIONS MBL2 rs1800450G/A was associated with a higher risk of sepsis, which possibly involved a decreased level of serum MBL2 that broke the balance of inflammation and weakened the binding of MBL2 to MASP1 and MASP2.

A novel compact broadband and radiation efficient antenna design for medical IoT healthcare system.

This paper investigates and develops a novel compact broadband and radiation efficient antenna design for the medical internet of things (M-IoT) healthcare system. The proposed antenna comprises of an umbrella-shaped metallic ground plane (UsMGP) and an improved radiator. A hybrid approach is employed to obtain the optimal results of antenna. The proposed solution is primarily based on the utilization of etching slots and a loaded stub on the ground plane and rectangular patch. The antenna consists of a simple rectangular patch, a 50 Ƹ microstrip feed line, and a portion of the ground plane printed on a relatively inexpensive flame retardant material (FR4) thick substrate with an overall compact dimension of 22 × 28 × 1.5 mm3. The proposed antenna offers compact, broadband and radiation efficient features. The antenna is carefully designed by employing the approximate calculation formulae extracted from the transmission line model. Besides, the parameters study of important variables involved in the antenna design and its influence on impedance matching performance are analyzed. The antenna shows high performance, including impedance bandwidth of 7.76 GHz with a range of 3.65Ƀ11.41 GHz results in 103% wider relative bandwidth at 10 dB return loss, 82% optimal radiation efficiency in the operating band, reasonable gain performance, stable monopole-shaped radiation patterns and strong current distribution across the antenna lattice. The suggested antenna is manufactured, and simulation experiments evaluate its performance. The findings indicate that the antenna is well suited for medical IoT healthcare systems applications.

A framework for efficient brain tumor classification using MRI images.

A brain tumor is an abnormal growth of brain cells inside the head, which reduces the patient's survival chance if it is not diagnosed at an earlier stage. Brain tumors vary in size, different in type, irregular in shapes and require distinct therapies for different patients. Manual diagnosis of brain tumors is less efficient, prone to error and time-consuming. Besides, it is a strenuous task, which counts on radiologist experience and proficiency. Therefore, a modern and efficient automated computer-assisted diagnosis (CAD) system is required which may appropriately address the aforementioned problems at high accuracy is presently in need. Aiming to enhance performance and minimise human efforts, in this manuscript, the first brain MRI image is pre-processed to improve its visual quality and increase sample images to avoid over-fitting in the network. Second, the tumor proposals or locations are obtained based on the agglomerative clustering-based method. Third, image proposals and enhanced input image are transferred to backbone architecture for features extraction. Fourth, high-quality image proposals or locations are obtained based on a refinement network, and others are discarded. Next, these refined proposals are aligned to the same size, and finally, transferred to the head network to achieve the desired classification task. The proposed method is a potent tumor grading tool assessed on a publicly available brain tumor dataset. Extensive experiment results show that the proposed method outperformed the existing approaches evaluated on the same dataset and achieved an optimal performance with an overall classification accuracy of 98.04%. Besides, the model yielded the accuracy of 98.17, 98.66, 99.24%, sensitivity (recall) of 96.89, 97.82, 99.24%, and specificity of 98.55, 99.38, 99.25% for Meningioma, Glioma, and Pituitary classes, respectively.

Differences in survival of prostate cancer Gleason 8-10 disease and the establishment of a new Gleason survival grading system.

BACKGROUND: Although the latest Gleason grading system in 2014 has distinguished between Gleason 3 + 4 and 4 + 3, Gleason 8 and Gleason 9-10 are remained systemically classified. METHODS: A total of 261,125 patients diagnosed with prostate cancer (PCa) were selected between 2005 and 2015 from the Surveillance, Epidemiology, and End Results (SEER) database. We used propensity score matching to balance clinical variables and then compared overall survival (OS) and cancer-specific survival (CSS) between Gleason score subgroups. We further establish a new Gleason survival grading system based on the hazard ratio (HR) values of each Gleason subgroup. Cox proportional hazards models and Kaplan-Meier curves were used to compare patient survival. RESULTS: Among PCa patients with Gleason score 8 disease, patients with Gleason 5 + 3 had significantly worse OS and CSS than those with Gleason 3 + 5 (OS: HR = 1.26, p = 0.042; CSS: HR = 1.42, p = 0.005) and 4 + 4 (HR = 1.50 for OS and HR = 1.69 for CSS, p < 0.001 for all). PCa patients with Gleason 5 + 3 and Gleason 4 + 5 may have the similar OS and CSS (reference Gleason score <=6, 5 + 3: OS HR = 2.44, CSS HR = 7.63; 4 + 5: OS HR = 2.40, CSS HR = 8.92; p < 0.001 for all). The new Gleason survival grading system reclassified the grades 4 and 5 of the 2014 updated Gleason grading system into three hierarchical grades, which makes the classification of grades more detailed and accurate. CONCLUSION: PCa patients with Gleason 8-10 may have three different survival subgroups, Gleason 3 + 5 and 4 + 4, Gleason 5 + 3 and 4 + 5, and Gleason 5 + 4 and 5 + 5. Our results maximize risk stratification for PCa patients, provide guidance for clinicians to assess their survival and clinical management, and make a recommendation for the next Gleason grading system update.

Ribavirin sensitizes nasopharyngeal carcinoma to 5-fluorouracil through suppressing 5-fluorouracil-induced ERK-dependent-eIF4E activation.

Although overexpression of eukaryotic translation initiation factor 4E (eIF4E) is associated with enhanced growth and poor prognosis in nasopharyngeal carcinoma (NPC), the function of eIF4E in NPC response to chemotherapy has not been revealed. In this work, we demonstrate that eIF4E inhibition using both ribavirin and siRNA targets NPC cells and enhances the efficacy of 5-fluorouracil (5-FU). Mechanism studies indicate that 5-FU treatment increases phosphorylation of eIF4E in NPC cells, and this is dependent on ERK activation. eIF4E inhibition thus significantly sensitizes NPC cell response to 5-FU. Of note, ribavirin is a clinically available anti-viral drug. We show that ribavirin exhibits preferential toxicity to NPC with normal nasopharyngeal epithelial cells largely unaffected. Ribavirin acts on NPC cells via inhibiting eIF4E/Akt signaling, and the suppression of eIF4E by ribavirin are not the consequence of inhibition of eIF4E upstream signaling: Mnk and mTOR. In two independent NPC xenograft mouse models, ribavirin at well-tolerated dose that significantly inhibited NPC growth as single drug alone and its combination with 5-FU completely arrests tumor growth throughout the whole duration of treatment, without causing toxicity in mice. Our findings provide the better understanding on the role of eIF4E in NPC in response to 5-FU and preclinical rationale to explore ribavirin as a sensitizing strategy to treat NPC, particularly in those who develop 5-FU resistance.

Overexpression and Low Expression of Selenoprotein S Impact Ochratoxin A-Induced Porcine Cytotoxicity and Apoptosis in Vitro.

Our previous study demonstrated that selenium could alleviate ochratoxin A (OTA)-induced nephrotoxicity in PK15 cells. Selenoprotein S (SelS) has antioxidant activities, but it is unclear whether SelS plays a role in the alleviating effects of selenium on OTA-induced nephrotoxicity. We previously have stably transfected pig pCDNA3.1-SelS to PK15 cells to overexpress SelS. Here, we demonstrated that SelS overexpression alleviated OTA-induced cytotoxicity and apoptosis as demonstrated by cell viabilities, LDH activities, Annexin V-bing, caspase 3 activities, and apoptotic nuclei. SelS overexpression increased glutathione (GSH) levels and decreased reactive oxygen species (ROS) and malondialdehyde levels in PK15 cells, regardless of OTA treatment. SelS overexpression inhibited OTA-induced p38 phosphorylation. Adding buthionine sulfoximine reversed all of the above SelS-induced changes. In addition, the knockdown of SelS by SelS-specific siRNA decreased GSH levels, increased ROS levels, and aggravated OTA-induced p38 phosphorylation. The knockdown of SelS aggravated OTA-induced cytotoxicity and apoptosis in PK15 cells. These data indicate that pig SelS overexpression and lowexpression impact OTA-induced cytotoxicity and apoptosis by modulating the oxidative stress and p38 phosphorylation. Our work provides new insights into the relationship between SelS- and OTA-induced cytotoxicity and apoptosis and describes an antitoxic mechanism of action for Se.

Overexpression of pig selenoprotein S blocks OTA-induced promotion of PCV2 replication by inhibiting oxidative stress and p38 phosphorylation in PK15 cells.

Porcine circovirus type 2 (PCV2) is the primary cause of porcine circovirus disease, and ochratoxin A (OTA)-induced oxidative stress promotes PCV2 replication. In humans, selenoprotein S (SelS) has antioxidant ability, but it is unclear whether SelS affects viral infection. Here, we stably transfected PK15 cells with pig pCDNA3.1-SelS to overexpress SelS. Selenium (Se) at 2 or 4 µM and SelS overexpression blocked the OTA-induced increases of PCV2 DNA copy number and infected cell numbers. SelS overexpression also increased glutathione (GSH), NF-E2-related factor 2 (Nrf2) mRNA, and γ-glutamyl-cysteine synthetase mRNA levels; decreased reactive oxygen species (ROS) levels; and inhibited p38 phosphorylation in PCV2-infected PK15 cells, regardless of OTA treatment. Buthionine sulfoximine reversed all of the above SelS-induced changes. siRNA-mediated SelS knockdown decreased Nrf2 mRNA and GSH levels, increased ROS levels, and promoted PCV2 replication in OTA-treated PK15 cells. These data indicate that pig SelS blocks OTA-induced promotion of PCV2 replication by inhibiting the oxidative stress and p38 phosphorylation in PK15 cells.

Ochratoxin A promotes porcine circovirus type 2 replication in vitro and in vivo.

Ochratoxin A (OTA), a worldwide mycotoxin found in food and feeds, is a potent nephrotoxin in animals and humans. Porcine circovirus-associated disease (PCVAD), including porcine dermatitis and nephropathy syndrome, is a worldwide swine disease. To date, little is known concerning the relationship between OTA and porcine circovirus type 2 (PCV2), the primary causative agent of PCVAD. The effects of OTA on PCV2 replication and their mechanisms were investigated in vitro and in vivo. The results in vitro showed that low doses of OTA significantly increased PCV2 DNA copies and the number of infected cells. Maximum effects were observed at 0.05 µg/ml OTA. The results in vivo showed that PCV2 replication was significantly increased in serum and tissues of pigs fed 75 µg/kg OTA compared with the control group and pigs fed 150 µg/kg OTA. In addition, low doses of OTA significantly depleted reduced glutathione and mRNA expression of NF-E2-related factor 2 and γ-glutamylcysteine synthetase; increased reactive oxygen species, oxidants, and malondialdehyde; and induced p38 and ERK1/2 phosphorylation in PK15 cells. Adding N-acetyl-L-cysteine reversed the changes induced by OTA. Knockdown of p38 and ERK1/2 by their respective specific siRNAs or inhibition of p38 and ERK1/2 phosphorylation by their respective inhibitors (SB203580 and U0126) eliminated the increase in PCV2 replication induced by OTA. These data indicate that low doses of OTA promoted PCV2 replication in vitro and in vivo via the oxidative stress-mediated p38/ERK1/2 MAPK signaling pathway. This suggests that low doses of OTA are potentially harmful to animals, as they enhance virus replication, and partly explains why the morbidity and severity of PCVAD vary significantly in different pig farms.

Interaction of porcine circovirus type 2 replication with intracellular redox status in vitro.

OBJECTIVES: Redox status influences replication of some viruses but its effect on porcine circovirus type 2 (PCV2), the primary causative agent of the emerging swine disease post-weaning multisystemic wasting syndrome is not known. The interaction of PCV2 replication with intracellular redox status in PK15 cells was examined in this study. METHODS: Intracellular glutathione (GSH) was measured spectrophotometrically by reaction with 5, 5'-dithiobis (2-nitrobenzoic acid). Total superoxide dismutase activity (SOD) was assayed by inhibition of oxyamine oxidation by the xanthine oxidase system. Malondialdehyde (MDA) was assayed spectrophotometrically using the thiobarbituric acid reaction. Both quantification of PCV2 DNA by real-time polymerase chain reaction and indirect immunofluorescence of PCV2-infected cells were used to evaluate the replication of PCV2. RESULTS: Both GSH and SOD decreased significantly at 48 hours after PCV2 infection, whereas MDA concentration increased significantly after 48 hour post-infection. Furthermore, PCV2 replication in PK15 cells was significantly impaired after the elevation of intracellular GSH through treatment with the antioxidant N-acetyl-l-cysteine (NAC), a precursor in GSH synthesis. In contrast, PCV2 replication in PK15 cells was enhanced after reduction of GSH levels through H2O2-mediated oxidation. In addition, NAC treatment blocked the increase of virus replication induced by H2O2. CONCLUSIONS: This study suggests that PCV2 infection induces oxidative stress and that intracellular redox status influences PCV2 replication in PK15 cells.