New Chemical Strategies for prodrug preparations: from sulfide to doxorubicin

Prodrug is an often-used approach to facilitate the delivery of an active drug to an appropriate site with targeted release whenever possible. Proper prodrug design often relies on a few essential requirements: prodrug stability, triggered release, and selectivity. In the last few decades, there have been impressive progress in prodrug development. However, the delivery of gasotransmitters and ensuring linker stability while allowing drug release at the desired site of action are among remaining challenges. The dissertation work focuses on developing new chemical strategies to address these two issues using hydrogen sulfide (H2S) as a model for gasotransmitters and doxorubicin as a model for anticancer compounds. In the gasotransmiter part of the project, we developed a “trimethyl lock”-lactonization based approach to deliver pure H2S, an esterase-sensitive acetal approach to deliver persulfide, and an enrichment-triggered release method to deliver doxorubicin. The therapeutic effects of these prodrugs were evaluated in a combination of in vitro and in vivo models. The concepts described should be generally applicable and should be very useful to those interested in prodrug design

Hydrogen Sulfide Prodrugs—A review

Abstract Hydrogen sulfide (H2S) is recognized as one of three gasotransmitters together with nitric oxide (NO) and carbon monoxide (CO). As a signaling molecule, H2S plays an important role in physiology and shows great potential in pharmaceutical applications. Along this line, there is a need for the development of H2S prodrugs for various reasons. In this review, we summarize different H2

Should chronic hepatitis B mothers breastfeed? a meta analysis

<p>Abstract</p> <p>Background</p> <p>Hepatitis B virus (HBV) exists in the breast milk of chronic hepatitis B (CHB) mothers. The authors use a meta-analytic technique to quantify the evidence of an association between breastfeeding and risk of CHB infection among the infants vaccinated against HBV.</p> <p>Methods</p> <p>Literature search is performed up to 2010 on the relationship between infantile CHB infection within one-year follow up after immunization with the third-dose hepatitis B vaccine and breastfeeding. Two reviewers independently extract the data and evaluate the methodological quality. A random-effects model is employed to systematically combine the results of all included studies.</p> <p>Results</p> <p>Based on data from 32 studies, 4.32% (244/5650) of infants born of CHB mothers develop CHB infection. The difference in risk of the infection between breastfed and formula-fed infants (RD) is -0.8%, (95% confidence interval [CI]: -1.6%, 0.1%). Analysis of the data from 16 of the studies finds that RD for mothers who are positive for the HBeAg and/or the HBV DNA, 0.7% (95%CI: -2.0%, 3.5%), is similar to that for those who are negative for these infectivity markers, -0.5% (95%CI: -1.7%, 0.6%).</p> <p>Conclusions</p> <p>Breast milk is infectious; yet, breastfeeding, even by mothers with high infectivity, is not associated with demonstrable risk of infantile CHB infection, provided that the infants have been vaccinated against HBV at birth.</p

Assessment of proteolytic degradation of the basement membrane: a fragment of type IV collagen as a biochemical marker for liver fibrosis

<p>Abstract</p> <p>Background</p> <p>Collagen deposition and an altered matrix metalloproteinase (MMP) expression profile are hallmarks of fibrosis. Type IV collagen is the most abundant structural basement membrane component of tissue, which increases 14-fold during fibrogenesis in the liver. Proteolytic degradation of collagens by proteases produces small fragments, so-called neoepitopes, which are released systemically. Technologies investigating MMP-generated fragments of collagens may provide more useful information than traditional serological assays that crudely measure total protein. In the present study, we developed an ELISA for the quantification of a neoepitope generated by MMP degradation of type IV collagen and evaluated the association of this neoepitope with liver fibrosis in two animal models.</p> <p>Methods</p> <p>Type IV collagen was degraded <it>in vitro </it>by a variety of proteases. Mass spectrometric analysis revealed more than 200 different degradation fragments. A specific peptide sequence, 1438'GTPSVDHGFL'1447 (CO4-MMP), in the α1 chain of type IV collagen generated by MMP-9 was selected for ELISA development. ELISA was used to determine serum levels of the CO4-MMP neoepitope in two rat models of liver fibrosis: inhalation of carbon tetrachloride (CCl₄) and bile duct ligation (BDL). The levels were correlated to histological findings using Sirius red staining.</p> <p>Results</p> <p>A technically robust assay was produced that is specific to the type IV degradation fragment, GTPSVDHGFL. CO4-MMP serum levels increased significantly in all BDL groups compared to baseline, with a maximum increase of 248% seen two weeks after BDL. There were no changes in CO4-MMP levels in sham-operated rats. In the CCl₄model, levels of CO4-MMP were significantly elevated at weeks 12, 16 and 20 compared to baseline levels, with a maximum increase of 88% after 20 weeks. CO4-MMP levels correlated to Sirius red staining results.</p> <p>Conclusion</p> <p>This ELISA is the first assay developed for assessment of proteolytic degraded type IV collagen, which, by enabling quantification of basement membrane degradation, could be relevant in investigating various fibrogenic pathologies. The CO4-MMP degradation fragment was highly associated with liver fibrosis in the two animal models studied.</p

Como a edição de genes na prática médica e de saúde pública poderia apoiar o teste da bioética

In recent years, gene editing is increasingly used as one of the technical means to solve public health problems. The great progress made in the field of life science and gene-editing technology has made it possible for humans to control and alter human physiological characteristics through gene-editing technology and created a broad application prospect for this technology. However, gene-editing technology has faced with many significant ethical risks, and human gene editing experiments have been banned for a long time in the past. Realistic technological breakthroughs and the emergence of real cases force the ethics circle to re-examine this issue. Through the analysis and trade-off of the potential benefits and ethical risks of human gene-editing technology, it can be found that different applications of human gene editing for different purposes are considered to have different acceptability. Among them, human gene editing for medical purposes has no fundamental moral barriers, human gene editing for purposes of enhancement cannot be allowed by ethics and reality in the current social environment, and human gene editing for purposes of transformation fundamentally violates ethical norms. Therefore, gene editing can be allowed if it is only used to solve human medical and public health problems.En años recientes, se usa cada vez más la edición génica como medio técnico para resolver problema de salud pública. El gran progreso realizado en el campo de las ciencias de la vida y la tecnología de edición génica ha hecho posible que el ser humano controle y altere las características fisiológicas humanas, usando esta tecnología y abriéndose una amplia perspectiva de aplicación. Sin embargo, esta tecnología enfrenta problemas éticos significativos, y los experimentos de edición génica en humanos han sido prohibidos por mucho tiempo en el pasado. Los avances tecnológicos realistas y la emergencia de casos reales ejerce presión sobre el círculo de reflexión ética para volver a examinar el tema. Mediante el análisis y balance de los potenciales beneficios y riesgos éticos de la tecnología de edición génica, se puede encontrar que las diferentes aplicaciones de ésta tecnología, para propósitos diferentes, tienen distinta aceptabilidad. Entre ellos, el uso de edición génica para propósitos médicos no tiene barreras morales fundamentales; la edición génica humana para propósitos de mejoramiento no debería permitirse en la realidad social actual, y la edición génica humana para propósitos de transformación viola fundamentalmente las normas éticas. Por lo tanto, la edición génica podría permitirse solamente para resolver problemas médicos y de salud pública en humanos.Em anos recentes, a edição de genes é cada vez mais usada como um recurso técnico para resolver problemas de saúde pública. O grande progresso feito no campo das ciências da vida e da tecnologia de edição de genes tornou possível para os humanos controlarem e alterarem as características fisiológicas humanas através da tecnologia da edição de genes e criou uma ampla perspectiva de aplicação para esta tecnologia. Entretanto, a tecnologia de edição de genes enfrentou muitos riscos éticos significativos e os experimentos de edição de genes humanos foram banidos por muito tempo no passado. Avanços tecnológicos realísticos e a emergência de casos reais forçaram o círculo ético a reexaminar esta questão. Através da análise e do equilíbrio entre os benefícios potenciais e riscos éticos da tecnologia de edição de genes humanos, pode ser encontrado que diferentes aplicações da edição de genes humanos para diferentes propósitos são consideradas ter diferentes aceitações. Dentre elas, a edição de genes humanos com objetivos médicos não tem barreiras morais fundamentais, edição de genes humanos objetivando aprimoramento não pode ser permitida pela ética e realidade do ambiente social atual, e edição de genes humanos objetivando transformação fundamentalmente viola normas éticas. Portanto, edição de genes pode ser permitida somente se usada para resolver problemas médicos humanos e de saúde pública