Identification of Hydrolyzable Tannins (Punicalagin, Punicalin and Geraniin) as Novel inhibitors of Hepatitis B Virus Covalently Closed Circular DNA

The development of new agents to target HBV cccDNA is urgently needed because of the limitations of current available drugs for treatment of hepatitis B. By using a cell-based assay in which the production of HBeAg is in a cccDNA-dependent manner, we screened a compound library derived from Chinese herbal remedies for inhibitors against HBV cccDNA. Three hydrolyzable tannins, specifically punicalagin, punicalin and geraniin, emerged as novel anti-HBV agents. These compounds significantly reduced the production of secreted HBeAg and cccDNA in a dose-dependent manner in our assay, without dramatic alteration of viral DNA replication. Furthermore, punicalagin did not affect precore/core promoter activity, pgRNA transcription, core protein expression, or HBsAg secretion. By employing the cell-based cccDNA accumulation and stability assay, we found that these tannins significantly inhibited the establishment of cccDNA and modestly facilitated the degradation of preexisting cccDNA. Collectively, our results suggest that hydrolyzable tannins inhibit HBV cccDNA production via a dual mechanism through preventing the formation of cccDNA and promoting cccDNA decay, although the latter effect is rather minor. These hydrolyzable tannins may serve as lead compounds for the development of new agents to cure HBV infection

NEDD4L facilitates granulosa cell ferroptosis by promoting GPX4 ubiquitination and degradation

Background: Polycystic ovary syndrome (PCOS) is an androgen disorder and ovarian dysfunction disease in women of reproductive age. The cell death of granulosa cells (GCs) plays an important role in the development of PCOS. However, the mechanism of GC death is still unclear. Methods: In the current study, NEDD4L was found to be elevated in PCOS GEO (Gene Expression Omnibus) databases and mouse models. The cell viability was analyzed by CCK-8 and FDA staining. The expression of ferroptosis markers was assessed by ELISA and immunofluorescence. The direct interaction of GPX4 and NEDD4L was verified by co-immunoprecipitation assay. Result: Functionally, results from CCK-8 and FDA staining demonstrated that NEDD4L inhibited the cell viability of KGN cells and NEDD4L increased the levels of iron, malonyldialdehyde, and reactive oxygen species and decreased glutathione levels. Moreover, the cell death of KGN induced by NEDD4L was blocked by ferroptosis inhibitor, suggesting that NEDD4L regulates KGN cell ferroptosis. Mechanistically, NEDD4L directly interacts with GPX4 and promotes GPX4 ubiquitination and degradation. Conclusion: Taken together, our study indicated that NEDD4L facilitates GC ferroptosis by promoting GPX4 ubiquitination and degradation and contributes to the development of PCOS

Passivation mechanism of thermal atomic layer-deposited Al2O3 films on silicon at different annealing temperatures

Thermal atomic layer-deposited (ALD) aluminum oxide (Al(2)O(3)) acquires high negative fixed charge density (Q(f)) and sufficiently low interface trap density after annealing, which enables excellent surface passivation for crystalline silicon. Q(f) can be controlled by varying the annealing temperatures. In this study, the effect of the annealing temperature of thermal ALD Al(2)O(3) films on p-type Czochralski silicon wafers was investigated. Corona charging measurements revealed that the Q(f) obtained at 300°C did not significantly affect passivation. The interface-trapping density markedly increased at high annealing temperature (>600°C) and degraded the surface passivation even at a high Q(f). Negatively charged or neutral vacancies were found in the samples annealed at 300°C, 500°C, and 750°C using positron annihilation techniques. The Al defect density in the bulk film and the vacancy density near the SiO(x)/Si interface region decreased with increased temperature. Measurement results of Q(f) proved that the Al vacancy of the bulk film may not be related to Q(f). The defect density in the SiO(x) region affected the chemical passivation, but other factors may dominantly influence chemical passivation at 750°C

Advances of DNA Damage Repair and Cisplatin Resistance Mechanisms in Lung Cancer

Lung cancer is the most common cause of death from cancer worldwide per year. Platinum-based combination chemotherapy is a main treatment of lung cancer. Cisplatin is adopted widely and used effectively in the first-line chemotherapy. Unfortunately, development of cisplatin resistance is a major obstacle to the success of lung caner. Cisplatin is a cell-cycle-non-specific cytotoxic drugs and its main target is DNA. Thus, defective DNA damage repair is one of the main mechanisms of cisplatin resistance. In this review, we will focus on the defective DNA damage repair in cisplatin resistance of lung cancer including nucleotide excision repair, DNA mismatch repair, DNA double-strand break repair and translesion synthesis

Overexpressing Sonic Hedgehog Peptide Restores Periosteal Bone Formation in a Murine Bone Allograft Transplantation Model

The article describes the results of a theoretical study on the issue of Teacher Education and its social interplay. It develops a broad analysis of the structural conditions which, at the globalization level, impinge upon the regional-local political configuration. Adopting the viewpoint of the regulations, the text then interprets how the decisions of educational policies promote or stabilize the functions, profiles and actions performed by the teacher. The reflection about this issue is the object of study of research projects carried out in Salta, Argentina. The methodology employed includes a survey of the historical evolution since the 1960s and 1970s up to this day, arguing and comparing conceptual and interpretive sources which - in that region - give support to the function assigned to the teacher. The period analysis is supplemented by the consideration of social, historical, and cultural factors that are gradually incorporated along the changes in the profile of the professional teacher. This kind of immutability of teacher education would be consistent with the regulation policy imposed by the government. However, the power of the social movement resulting from the recent globalization process has triggered profound changes in teacher education in the shape of reforms and transformations. Despite the government's interest in modifying teacher education, it continues to practice a politically-oriented policy with repercussions to the spheres of institutional management and practice of teacher education. Finally, principles are put forward for consideration with a view to face the challenges of the transformations of local teacher education.El artículo expone los resultados de un estudio teórico sobre el tema Formación Docente (FD) en relación con el juego de lo social. Se efectúa un análisis general de las condiciones estructurales que, a nivel de globalización, inciden en la configuración política regional-local. Luego, asumiendo el enfoque de la regulación, se interpreta cómo las decisiones de la política educacional promocionan o estabilizan las funciones, perfil y actuación que el docente desempeña. La reflexión sobre el tema es objeto de estudio en proyectos de investigación que se llevan a cabo en Salta, Argentina. La metodología de abordaje incluye un rastreo histórico evolutivo desde los '60-'70 a la actualidad, argumentando y comparando fuentes conceptuales e interpretativas que - en la región - fundamentan la función asignada al maestro y al profesor. Se complementa el análisis epocal considerando factores sociales, históricos, culturales que lentamente se asumen en el cambio del perfil profesional docente. Esta suerte de inmutabilidad formativa docente resultaría coherente con la política de regulación que impone el gobierno. Sin embargo, la potencia del movimiento social que origina la globalización en los últimos tiempos, conduce a cambios profundos en la preparación de los docentes, bajo la modalidad de reformas y transformaciones. Pese al interés del gobierno por modificar la formación docente, continúa efectuándose un manejo político coactivo e interesado, que repercute en los órdenes de la gestión y la práctica institucional de la formación. Finalmente se postulan principios a considerar para asumir el reto de las transformaciones en la formación docente local

Analytical Techniques and Pharmacokinetics of Gastrodia elata Blume and Its Constituents

Gastrodia elata Blume (G. elata), commonly called Tianma in Chinese, is an important and notable traditional Chinese medicine (TCM), which has been used in China as an anticonvulsant, analgesic, sedative, anti-asthma, anti-immune drug since ancient times. The aim of this review is to provide an overview of the abundant efforts of scientists in developing analytical techniques and performing pharmacokinetic studies of G. elata and its constituents, including sample pretreatment methods, analytical techniques, absorption, distribution, metabolism, excretion (ADME) and influence factors to its pharmacokinetics. Based on the reported pharmacokinetic property data of G. elata and its constituents, it is hoped that more studies will focus on the development of rapid and sensitive analytical techniques, discovering new therapeutic uses and understanding the specific in vivo mechanisms of action of G. elata and its constituents from the pharmacokinetic viewpoint in the near future. The present review discusses analytical techniques and pharmacokinetics of G. elata and its constituents reported from 1985 onwards

The Changes in Guilin Paddy Soil Organic Matter and Rice Yield under Long-Term Fertilization

Rational fertilization is an important measure to increase crop yield and soil fertility. Through analysis, this paper aims to master the change characteristics of soil organic matter and rice yield under different fertilizer treatments, in order to provide an important reference for the sustainable use of soil and effective fertilization. Long-term (19 years) rice crop rotation experiments in waterloggogenic paddy soil were conducted to investigate the change trend of crop grain yield and soil organic matter with time, reveal the dynamic characteristics and relationship between main fertility factors and crop yields using comparative analysis at three sites with conventional fertilization and non-fertilization in Guilin. The results showed that compared with previous years, the rice yield increased by 53% under the fertilization treatment and degreased by 66% under the control. Over the years, the average soil organic matter (SOM) content under fertilization treatment was 23% higher than under CK treatment. This indicates that chemical fertilizer and organic manure application can increase the rice yield and soil organic matter, and high rice yield can be attributed to the SOM increase

Kaposi's sarcoma-associated herpesvirus ORF6 gene is essential in viral lytic replication.

Kaposi's sarcoma associated herpesvirus (KSHV) is associated with Kaposis's sarcoma (KS), primary effusion lymphoma and multicentric Castleman's disease. KSHV encodes at least 8 open reading frames (ORFs) that play important roles in its lytic DNA replication. Among which, ORF6 of KSHV encodes an ssDNA binding protein that has been proved to participate in origin-dependent DNA replication in transient assays. To define further the function of ORF6 in the virus life cycle, we constructed a recombinant virus genome with a large deletion within the ORF6 locus by using a bacterial artificial chromosome (BAC) system. Stable 293T cells carrying the BAC36 (wild type) and BACΔ6 genomes were generated. When monolayers of 293T-BAC36 and 293T-BACΔ6 cells were induced with 12-O-tetradecanoylphorbol-13-acetate (TPA) and sodium butyrate, infectious virus was detected from the 293T-BAC36 cell supernatants only and not from the 293T- BACΔ6 cell supernatants. DNA synthesis was defective in 293T-BACΔ6 cells. Expression of ORF6 in trans in BACΔ6-containing cells was able to rescue both defects. Our results provide genetic evidence that ORF6 is essential for KSHV lytic replication. The stable 293T cells carrying the BAC36 and BACΔ6 genomes could be used as tools to investigate the detailed functions of ORF6 in the lytic replication of KSHV

Marine Antitumor Peptide Dolastatin 10: Biological Activity, Structural Modification and Synthetic Chemistry

Dolastatin 10 (Dol-10), a leading marine pentapeptide isolated from the Indian Ocean mollusk Dolabella auricularia, contains three unique amino acid residues. Dol-10 can effectively induce apoptosis of lung cancer cells and other tumor cells at nanomolar concentration, and it has been developed into commercial drugs for treating some specific lymphomas, so it has received wide attention in recent years. In vitro experiments showed that Dol-10 and its derivatives were highly lethal to common tumor cells, such as L1210 leukemia cells (IC50 = 0.03 nM), small cell lung cancer NCI-H69 cells (IC50 = 0.059 nM), and human prostate cancer DU-145 cells (IC50 = 0.5 nM), etc. With the rise of antibody-drug conjugates (ADCs), milestone progress was made in clinical research based on Dol-10. A variety of ADCs constructed by combining MMAE or MMAF (Dol-10 derivatives) with a specific antibody not only ensured the antitumor activity of the drugs themself but also improved their tumor targeting and reduced the systemic toxicity. They are currently undergoing clinical trials or have been approved for marketing, such as Adcetris®, which had been approved for the treatment of anaplastic large T-cell systemic malignant lymphoma and Hodgkin lymphoma. Dol-10, as one of the most medically valuable natural compounds discovered up to now, has brought unprecedented hope for tumor treatment. It is particularly noteworthy that, by modifying the chemical structure of Dol-10 and combining with the application of ADCs technology, Dol-10 as a new drug candidate still has great potential for development. In this review, the biological activity and chemical work of Dol-10 in the advance of antitumor drugs in the last 35 years will be summarized, which will provide the support for pharmaceutical researchers interested in leading exploration of antitumor marine peptides

Novel Strategies Using Total Gastrodin and Gastrodigenin, or Total Gastrodigenin for Quality Control of Gastrodia elata

Gastrodia elata Blume (G. elata), a traditional Chinese medicine, is widely used for treatment of various neuro dysfunctions. However, its quality control is still limited to the determination of gastrodin. In the present study, two novel strategies based on quantitative evaluation of total gastrodin and gastrodigenin with base hydrolysis and total gastrodigenin with base-enzymatic hydrolysis followed by HPLC-FLD were put forward and successfully applied to evaluate the quality of 47 batches of G. elata from eight localities. Meanwhile, a systematic comparison of the novel strategy with the multiple markers and the Pharmacopeia method was performed. The results showed that the parishins category could be completely hydrolyzed to gastrodin by sodium hydroxide solution, and gastrodin could further utterly hydrolyze to gastrodigenin with β-d-glucosidase buffer solution. The contents of total gastrodin and gastrodigenin ranged from 1.311% to 2.034%, and total gastrodigenin from 0.748% to 1.120% at the eight localities. From the comparison, we can conclude that the two novel strategies can comprehensively reveal the characteristics of overall active ingredients in G. elata for quality control. The present study provides a feasible and credible strategy for the quality control of G. elata, suggesting a revision of the latest Chinese Pharmacopoeia or European Pharmacopoeia methods for the modernization of G. elata use