It's not magic - Hsp90 and its effects on genetic and epigenetic variation.

Canalization, or phenotypic robustness in the face of environmental and genetic perturbation, is an emergent property of living systems. Although this phenomenon has long been recognized, its molecular underpinnings have remained enigmatic until recently. Here, we review the contributions of the molecular chaperone Hsp90, a protein that facilitates the folding of many key regulators of growth and development, to canalization of phenotype - and de-canalization in times of stress - drawing on studies in eukaryotes as diverse as baker's yeast, mouse ear cress, and blind Mexican cavefish. Hsp90 is a hub of hubs that interacts with many so-called 'client proteins,' which affect virtually every aspect of cell signaling and physiology. As Hsp90 facilitates client folding and stability, it can epistatically suppress or enable the expression of genetic variants in its clients and other proteins that acquire client status through mutation. Hsp90's vast interaction network explains the breadth of its phenotypic reach, including Hsp90-dependent de novo mutations and epigenetic effects on gene regulation. Intrinsic links between environmental stress and Hsp90 function thus endow living systems with phenotypic plasticity in fluctuating environments. As environmental perturbations alter Hsp90 function, they also alter Hsp90's interaction with its client proteins, thereby re-wiring networks that determine the genotype-to-phenotype map. Ensuing de-canalization of phenotype creates phenotypic diversity that is not simply stochastic, but often has an underlying genetic basis. Thus, extreme phenotypes can be selected, and assimilated so that they no longer require environmental stress to manifest. In addition to acting on standing genetic variation, Hsp90 perturbation has also been linked to increased frequency of de novo variation and several epigenetic phenomena, all with the potential to generate heritable phenotypic change. Here, we aim to clarify and discuss the multiple means by which Hsp90 can affect phenotype and possibly evolutionary change, and identify their underlying common feature: at its core, Hsp90 interacts epistatically through its chaperone function with many other genes and their gene products. Its influence on phenotypic diversification is thus not magic but rather a fundamental property of genetics.

Quercetin potentiates the chemosensitivity of MCF-7 breast cancer cells to 5-fluorouracil.

BACKGROUND: Breast cancer is one of the leading causes of cancer mortality worldwide. 5-fluorouracil (5-FU) is one of the chemotherapy drugs to treat breast cancer, but it is associated with several side effects. Combination therapy is a way to increase the effectiveness of chemo drugs and decrease their usage dose. Quercetin (Quer) is one of the natural polyphenols with anti-cancer properties. This study investigated the apoptotic effect of 5-FU in combination with Quer compared with 5-FU alone on MCF-7 breast cancer cells. METHOD AND RESULTS: Different single and combined concentrations of 5-FU and Quer were applied to MCF 7 cells for 48 h. Cell viability, apoptosis, gene expression of Bax, Bcl2, and p53, caspase activity, and colony number were assessed using MTT assay, flow cytometry, quantitative real-time PCR, enzyme-linked immunosorbent (ELISA), and Colony formation assay, respectively. The combination of 5-FU and Quer compared to 5-FU alone improved apoptosis by increasing the gene expression of Bax and p53 and caspase-9 activity and decreasing the Bcl2 gene expression. Colony formation in MCF-7 cells significantly decreased in the combined state compared to 5-FU alone. CONCLUSION: Quer potentiates the sensitivity of breast cancer to 5-FU so that this combination may be proposed as a treatment for breast cancer. Therefore, this combination can be suggested for future in vivo studies.

The potentiation of menadione on imatinib by downregulation of ABCB1 expression.

Imatinib was the first BCR-ABL inhibitor used in clinical practice to treat chronic myeloid leukaemia (CML) and significantly improve the life expectancy of CML patients in the chronic phase. However, a portion of CML patients are resistant to imatinib. This study aimed to determine whether menadione (Vitamin K3) can improve imatinib efficacy in CML and to thoroughly explore the combination regimen mechanism between imatinib and menadione. Menadione improved imatinib efficacy in K562 cells by downregulating ABCB1 expression and increased the intracellular concentration of imatinib, which confirmed that this combination regimen is more effective than imatinib monotherapy. The results demonstrate that menadione and imatinib combination therapy may be a promising approach to refractory CML.

Poly r(C) binding protein is post-transcriptionally repressed by MiR-490-3p to potentiate squamous cell carcinoma.

Squamous cell skin carcinoma remains a leading cause of cancer-related mortality with a huge cost of treatment, necessitating discovery and validation of potent therapeutic targets. Poly r(C) binding protein 1 (PCBP1) has been previously shown to function as a tumor suppressor. Previous work has shown that PCBP1 expression is inversely correlated to maintenance of cancer stem cells in squamous cell skin carcinoma and prostate cancer, respectively. However, the precise mechanism that regulates PCBP1 expression has not been elucidated. Here, we show that loss of PCBP1 protein expression observed in CD34+ COLO-16 cells is orchestrated by translational silencing. Translational silencing is caused by targeting of PCBP1 mRNA by miR-490-3p. Exogenous manipulation of miR-490-3p levels can accordingly modulate PCBP1 protein expression, thus suggesting that miR-490-3p as a potential biomarker in squamous cell skin cancer with therapeutic benefits.

Intrinsic antibiotic resistance: mechanisms, origins, challenges and solutions.

The intrinsic antibiotic resistome is a naturally occurring phenomenon that predates antibiotic chemotherapy and is present in all bacterial species. In addition to the intrinsic resistance mediated by the bacterial outer membrane and active efflux, studies have shown that a surprising number of additional genes and genetic loci also contribute to this phenotype. Antibiotic resistance is rife in both the clinic and the environment; novel therapeutic strategies need to be developed in order to prevent a major global clinical threat. The possibility of inhibiting elements comprising the intrinsic resistome in bacterial pathogens offers the promise for repurposing existing antibiotics against intrinsically resistant bacteria.

TP0586532, a Novel Non-Hydroxamate LpxC Inhibitor: Potentiating Effect on In Vitro Activity of Meropenem against Carbapenem-Resistant Enterobacteriaceae.

Carbapenem-resistant Enterobacteriaceae (CRE) are an urgent threat to public health requiring the development of novel therapies. TP0586532 is a novel non-hydroxamate LpxC inhibitor that inhibits the synthesis of lipopolysaccharides, which are components of the outer membranes of Gram-negative bacteria. Based on the mechanism of action of TP0586532, we hypothesized that it might enhance the antibacterial activity of other antibiotics by increasing the permeability of the outer bacterial membrane. The combination of TP0586532 with meropenem, amikacin, cefepime, piperacillin, and tigecycline showed synergistic and additive effects against carbapenem-susceptible Klebsiella pneumoniae and Escherichia coli. Checkerboard experiments against 21 carbapenem-resistant K. pneumoniae and E. coli strains (13 blaKPC+, 5 blaNDM-1+, 2 blaVIM+, and 1 blaIMP+) showed that the combination of TP0586532 with meropenem yielded synergistic and additive effects against 9 and 12 strains, respectively. In a time-kill assay examining 12 CRE strains, synergistic effects were observed when TP0586532 was combined with meropenem against many of the strains. A membrane permeability assay using ethidium bromide (EtBr) was performed to investigate the mechanism of the potentiating effect. TP0586532 increased the influx of EtBr into a CRE strain, suggesting that TP0586532 increased membrane permeability and facilitated intracellular access for the antibiotics. Our study demonstrates that TP0586532 potentiates the in vitro antibacterial activity of meropenem against CRE. Combination therapy consisting of TP0586532 and meropenem has potential as a treatment for CRE infections. IMPORTANCE Carbapenem-resistant Enterobacteriaceae (CRE) are an urgent public health threat, as therapeutic options are limited. TP0586532 is a novel LpxC inhibitor that inhibits the synthesis of lipopolysaccharides in the outer membranes of Gram-negative bacteria. Here, we demonstrated the potentiating effects of TP0586532 on the antibacterial activity of meropenem against CRE harboring various types of carbapenemase genes (blaKPC+, blaNDM-1+ blaVIM+, and blaIMP+). TP0586532 also augmented the bactericidal effects of meropenem against CRE strains, even against those with a high level of resistance to meropenem. The potentiating effects were suggested to be mediated by an increase in bacterial membrane permeability. Our study revealed that a combination therapy consisting of TP0586532 and meropenem has the potential to be a novel therapeutic option for CRE infections.

Fototerapia associada à técnica de microagulhamento no tratamento de cicatriz de acne / Phototherapy associated with microneedle technique in the acne scar

A acne é uma doença bem comum, que vem a causar transtornos estéticos e psicológicos nas pessoas acometidas por esta patologia, que atinge principalmente o público jovem, deixando cicatrizes como sequelas. Visando uma atenuação dessas cicatrizes, muitos métodos propõem uma associação de procedimentos, sendo bastante eficazes, porem uma das fontes mais utilizadas atualmente na estética é a fototerapia, que vem sendo aplicada em vários tratamentos como: estrias, manchas celulite, acne, alopecia, rejuvenescimento, cicatrização da pele entre outros, e que nada mais é que a interação da luz com a pele com o âmbito de potencializar e acelerar o processo de reparação da epiderme. O advento Lasers e LEDs mensuram entre diferentes comprimentos de onda ou cores, permitindo realizar de forma controlada com efetividade e segurança do tratamento almejado e associando-se à técnica de microagulhamento também promissora nesses casos, promovendo micro lesões no tecido através de um "roller", estimulando a produção de colágeno, que é fundamental no processo de cicatrização, sendo que a aplicação dessa técnica é dividida em sessões, que variam de acordo com a necessidade de cada indivíduo. Dessa forma, o objetivo foi constatar a eficácia da aplicação da fototerapia e a técnica de microagulhamento, aperfeiçoando os resultados de cicatriz de acne, esperando potencializar os efeitos, tendo uma melhora nítida no quadro da cicatriz de acne. (AU)

Acne is a very common disease, which causes aesthetic and psychological disorders in people affected by this pathology, which mainly affects the young public, leaving scars as sequels. Aiming at attenuating these scars, many methods propose an association of procedures, being quite effective, but one of the most commonly used sources in esthetics today is phototherapy, which has been applied in several treatments such as stretch marks, cellulite spots, acne, alopecia, rejuvenation , skin healing among others, and that is nothing more than the interaction of light with skin with the scope to potentiate and accelerate the process of repairing the epidermis, the advent Lasers and LEDs measure between different wavelengths or colors, allowing to perform in a controlled manner with the effectiveness and safety of the targeted treatment and associated with the microaggregation technique also promising in these cases, promoting micro-lesions in the tissue through a roller, stimulating the production of collagen, which is fundamental in the cicatrization process, being that the application of this technique is divided into sessions, which vary according to the of each individual. Thus, the objective was to verify the effectiveness of the application of phototherapy and the technique of microneedle, improving the results of acne scar, hoping to potentiate the effects, having a clear improvement in the framework of the acne scar. (AU)