The Use Of Green Tea Polyphenols For Treating Residual Albuminuria In Diabetic Nephropathy: A Double-blind Randomised Clinical Trial

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Prior research has shown that in experimental diabetes mellitus, green tea reduces albuminuria by decreasing podocyte apoptosis through activation of the WNT pathway. We investigated the effect of green tea polyphenols (GTP) on residual albuminuria of diabetic subjects with nephropathy. We conducted a randomised, double-blind study in 42 diabetic subjects with a urinary albumin-creatinine ratio (UACR) > 30 mg/g, despite administration of the maximum recommended dose of renin-angiotensin (RAS) inhibition. Patients were randomly assigned to two equal groups to receive either GTP (containing 800 mg of epigallocatechin gallate, 17 with type 2 diabetes and 4 with type 1 diabetes) or placebo (21 with type 2 diabetes) for 12 weeks. Treatment with GTP reduced UACR by 41%, while the placebo group saw a 2% increase in UACR (p = 0.019). Podocyte apoptosis (p = 0.001) and in vitro albumin permeability (p < 0.001) were higher in immortalized human podocytes exposed to plasma from diabetic subjects compared to podocytes treated with plasma from normal individuals. In conclusion, GTP administration reduces albuminuria in diabetic patients receiving the maximum recommended dose of RAS. Reduction in podocyte apoptosis by activation of the WNT pathway may have contributed to this effect.6Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP) [2008/57560-0, 2014/22687-0]Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq) [304026/2013-1]Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq

Study of the combination of self-activating photodynamic therapy and chemotherapy for cancer treatment

Cancer is a very challenging disease to treat, both in terms of treatment eficiency and side-effects. To overcome these problems, there have been extensive studies regarding the possibility of improving treatment by employing combination therapy, and by exploring therapeutic modalities with reduced side-effects (such as photodynamic therapy (PDT)). Herein, this work has two aims: (i) to develop self-activating photosensitizers for use in light-free photodynamic therapy, which would eliminate light-related restrictions that this therapy currently possesses; (ii) to assess their co-treatment potential when combined with reference chemotherapeutic agents (Tamoxifen and Metformin). We synthesized three new photosensitizers capable of self-activation and singlet oxygen production via a chemiluminescent reaction involving only a cancer marker and without requiring a light source. Cytotoxicity assays demonstrated the cytotoxic activity of all photosensitizers for prostate and breast tumor cell lines. Analysis of co-treatment effects revealed significant improvements for breast cancer, producing better results for all combinations than just for the individual photosensitizers and even Tamoxifen. By its turn, co-treatment for prostate cancer only presented better results for one combination than for just the isolated photosensitizers and Metformin. Nevertheless, it should be noted that the cytotoxicity of the isolated photosensitizers in prostate tumor cells was already very appreciable.This research was co-funded by Fundação para a Ciência e Tecnologia (FCT) and FEDER through COMPETE-POFC, grant number PTDC/QEQ-QFI/0289/2014; funded by FEDER through COMPETE2020, grant POCI-01-0145-FEDER-006980; funded by FEDER through NORTE2020, grant number NORTE-01-0145-FEDER 000028; co-funded by Fundação para a Ciência e Tecnologia (FCT) and FEDER through COMEPETE2020-POCI, grant number POCI-01-0145-FEDER-007274; co-funded by Fundação para a Ciência e Tecnologia (FCT) and FEDER, grant number IF/00092/2014/CP1255/CT0004; funded by Fundação para a Ciência e Tecnologia (FCT), grant number SFRH/BD/140734/2018; funded by Fundação para a Ciência e Tecnologia (FCT), grant number UID/QUI/50006/2013; funded by Fundação para a Ciência e Tecnologia (FCT), grant number PTDC/BIA-MIA/29059/2017; funded by Fundação para a Ciência e Tecnologia (FCT), grant number CEECIND/01425/2017; funded by Fundação para a Ciência e Tecnologia (FCT), grant number SFRH/BD/143211/2019

Target-Oriented Synthesis of Marine Coelenterazine Derivatives with Anticancer Activity by Applying the Heavy-Atom Effect

Photodynamic therapy (PDT) is an anticancer therapeutic modality with remarkable advantages over more conventional approaches. However, PDT is greatly limited by its dependence on external light sources. Given this, PDT would benefit from new systems capable of a light-free and intracellular photodynamic effect. Herein, we evaluated the heavy-atom effect as a strategy to provide anticancer activity to derivatives of coelenterazine, a chemiluminescent single-molecule widespread in marine organisms. Our results indicate that the use of the heavy-atom effect allows these molecules to generate readily available triplet states in a chemiluminescent reaction triggered by a cancer marker. Cytotoxicity assays in different cancer cell lines showed a heavy-atom-dependent anticancer activity, which increased in the substituent order of hydroxyl < chlorine < bromine. Furthermore, it was found that the magnitude of this anticancer activity is also dependent on the tumor type, being more relevant toward breast and prostate cancer. The compounds also showed moderate activity toward neuroblastoma, while showing limited activity toward colon cancer. In conclusion, the present results indicate that the application of the heavy-atom effect to marine coelenterazine could be a promising approach for the future development of new and optimized self-activating and tumor-selective sensitizers for light-free PDT

A modified echocardiographic protocol with intrinsic plausibility control to determine intraventricular asynchrony based on TDI and TSI

<p>Abstract</p> <p>Background</p> <p>Established methods to determine asynchrony suffer from high intra- and interobserver variability and failed to improve patient selection for cardiac resynchronization therapy (CRT). Thus, there is a need for easy and robust approaches to reliably assess cardiac asynchrony.</p> <p>Methods and Results</p> <p>We performed echocardiography in 100 healthy subjects and 33 patients with left bundle branch block (LBBB). To detect intraventricular asynchrony, we combined two established methods, i.e., tissue synchronization imaging (TSI) and tissue Doppler imaging (TDI). The time intervals from the onset of aortic valve opening (AVO) to the peak systolic velocity (S') were measured separately in six basal segments in the apical four-, two-, and three-chamber view. Color-coded TSI served as an intrinsic plausibility control and helped to identify the correct S' measuring point in the TDI curves. Next, we identified the segment with the shortest AVO-S' interval. Since this segment most likely represents vital and intact myocardium it served as a reference for other segments. Segments were considered asynchronous when the delay between the segment in question and the reference segment was above the upper limit of normal delays derived from the control population. Intra- and interobserver variability were 7.0% and 7.7%, respectively.</p> <p>Conclusion</p> <p>Our results suggest that combination of TDI and TSI with intrinsic plausibility control improves intra- and interobserver variability and allows easy and reliable assessment of cardiac asynchrony.</p

Synchrotron-based FTIR evaluation of biochemical changes in cancer and noncancer cells induced by brominated marine coelenteramine

The mode of action toward gastric cancer cells of brominated Coelenteramine, an analogue of a metabolic product of a marine bioluminescent reaction, was investigated by synchrotron radiation-based Fourier Transform Infrared spectrocopy (FTIR). This method revealed that the anticancer activity of brominated Coelenteramine is closely connected with cellular lipids, by affecting their organization and composition. More specifically, there is an increasing extent of oxidative stress, which results in changes in membrane polarity, lipid chain packing and lipid composition. However, this effect was not observed in a noncancer cell line, helping to explain its selectivity profile. Thus, synchrotron radiation-based FTIR helped to identify the potential of this Coelenteramine analogue in targeting membrane lipids, while proving to be a powerful technique to probe the mechanism of anticancer drugs

Efficacy and safety of recruitment maneuvers in acute respiratory distress syndrome

Recruitment maneuvers (RM) consist of a ventilatory strategy that increases the transpulmonary pressure transiently to reopen the recruitable lung units in acute respiratory distress syndrome (ARDS). The rationales to use RM in ARDS are that there is a massive loss of aerated lung and that once the end-inspiratory pressure surpasses the regional critical opening pressure of the lung units, those units are likely to reopen. There are different methods to perform RM when using the conventional ICU ventilator. The three RM methods that are mostly used and investigated are sighs, sustained inflation, and extended sigh. There is no standardization of any of the above RM. Meta-analysis recommended not to use RM in routine in stable ARDS patients but to run them in case of life-threatening hypoxemia. There are some concerns regarding the safety of RM in terms of hemodynamics preservation and lung injury as well. The rapid rising in pressure can be a factor that explains the potential harmful effects of the RM. In this review, we describe the balance between the beneficial effects and the harmful consequences of RM. Recent animal studies are discussed