SMAC Mimetics as Therapeutic Agents in HIV Infection

Although combination antiretroviral therapy is extremely effective in lowering HIV RNA to undetectable levels in the blood, HIV persists in latently infected CD4+ T-cells and persistently infected macrophages. In latently/persistently infected cells, HIV proteins have shown to affect the expression of proteins involved in the apoptosis pathway, notably the inhibitors of apoptosis proteins (IAPs), and thereby influence cell survival. IAPs, which are inhibited by endogenous second mitochondrial-derived activators of caspases (SMAC), can serve as targets for SMAC mimetics, synthetic compounds capable of inducing apoptosis. There is increasing evidence that SMAC mimetics can be used to reverse HIV latency and/or kill cells that are latently/persistently infected with HIV. Here, we review the current state of knowledge of SMAC mimetics as an approach to eliminate HIV infected cells and discuss the potential future use of SMAC mimetics as part of an HIV cure strategy.

An atlas of inter- and intra-tumor heterogeneity of apoptosis competency in colorectal cancer tissue at single-cell resolution

Cancer cells’ ability to inhibit apoptosis is key to malignant transformation and limits response to therapy. Here, we performed multiplexed immunofluorescence analysis on tissue microarrays with 373 cores from 168 patients, segmentation of 2.4 million individual cells, and quantification of 18 cell lineage and apoptosis proteins. We identified an enrichment for BCL2 in immune, and BAK, SMAC, and XIAP in cancer cells. Ordinary differential equation-based modeling of apoptosis sensitivity at single-cell resolution was conducted and an atlas of inter- and intra-tumor heterogeneity in apoptosis susceptibility generated. Systems modeling at single-cell resolution identified an enhanced sensitivity of cancer cells to mitochondrial permeabilization and executioner caspase activation compared to immune and stromal cells, but showed significant inter- and intra-tumor heterogeneity.

MOLECULAR CHARACTERISTICS AND PROGNOSTIC MARKERS IN ENDOMETRIAL INTRAEPITHELIAL NEOPLASIA (CRITICAL REVIEW)

Endometrial carcinoma represents the most common gynaecologic malignancy, which frequently arises from malignant progression of endometrial intraepithelial neoplasia (EIN). Nowadays, there are no defined prognostic markers for the prognosis of the malignant progression of EIN and it still represents the subject of various investigations. Different studies indicate, that sex hormone receptors, DNA damage and apoptosis proteins, as well as epithelial-mesenchymal transformation markers play an important role in the progression of EIN. However, most of the published studies are full of contradictory results, which indicates that additional studies are necessary. In current review, we will discuss the current knowledge about the mentioned markers in terms of the prognosis of EIN.

Livin/BIRC7 gene expression as a possible diagnostic biomarker for endometrial hyperplasia and carcinoma

Background Livin/BIRC7 is a member of the inhibitors of apoptosis proteins family which are implicated in development of cancer through the inhibition of apoptosis process. This case-control study was intended to investigate livin/BIRC7 gene expression in endometrial hyperplasia and carcinoma and its correlation to some oxidative stress markers in addition to its possible diagnostic performance. Methods This study included 90 participants [30 endometrial hyperplasia patients, 30 endometrial carcinoma patients, and 30 healthy controls]. Livin/BIRC7 gene expression was analyzed using quantitative reverse transcriptase-polymerase chain reaction (RT-PCR). Serum catalase activity was assessed by enzyme-linked immunosorbent assay (ELISA) and malondialdehyde level was measured by the colorimetric method. Results Livin/BIRC7 gene expression was significantly (p < 0.001) higher in endometrial carcinoma from patients with endometrial hyperplasia when compared to controls. A positive correlation was found between livin/BIRC7 expression and serum catalase activity and malondialdehyde level in endometrial hyperplasia and carcinoma. The detection of livin/BIRC7 in endometrial carcinoma has excellent sensitivity and specificity. Conclusions Livin/BIRC7 was overexpressed in endometrial carcinoma with excellent power to differentiate endometrial carcinoma from endometrial hyperplasia or healthy subjects, suggesting that it might be a useful molecular marker for endometrial carcinoma diagnosis.

INFLUENCE OF VARIOUS SURGICAL INTERVENTIONS ON VASCULAR WALL APOPTOSIS INDICES IN PATIENTS WITH ATHEROSCLEROSIS OF PERIPHERAL ARTERIES

Objective. Assessment of apoptosis proteins Bcl-2 and Bax indices before and after the open vascular reconstructions and X-ray endovascular interventions in patients with the peripheral atherosclerosis of the arteries of the lower extremities. Methods. The study included patients (n=40) with the peripheral atherosclerosis of the lower extremities arteries (stage III-IV) disease who underwent open surgery - group A, and patients (n=40) who underwent endovascular interventions - group B. Two apoptosis proteins were analyzed in blood serum: Bax and Bcl-2 initially before surgery, on the 1^st day and after 1 month. The reference values of the studied parameters were determined in 40 healthy volunteers. Results. Initial Bax protein index - 27.1 ng / ml (р<0,001) were elevated in patients of group A and reduced Bax protein - 4.4 ng / ml (p=0.00008) in patients of group B compared with indices of healthy volunteers (16.5 ng / ml, 5.3 ng / ml, respectively). On the 1^st day after the interventions in the patients of the operative groups there was an increasing tendency for Bax index to 35.6 ng / ml (p<0.001) - group A, to 25.6 ng/ml (p<0.001) - group B. By the end of 1^st month, Bax was increased to 28 ng/ml (p<0.001) in patients of group A and Bcl-2 was reduced to 3.0 ng / ml (p=0.039) compared to the initial indices; in patients of group B, only protein Bax - 23.9 ng / ml (p<0.001) was increased. Conclusion. Open and endovascular intervention on the arteries of the lower extremities leads to the activation of the pro-apoptotic protein Bax on the 1^st day after surgery. In the postoperative period the open reconstruction leads to an evaluation of the pro-apoptotic potential in comparison with endovascular intervention in the form of increasing Bax protein and reducing Bcl-2 by the end of the first month. What this paper adds The dynamics of changes markers Bcl-2 and Bax in apoptosis at different periods after surgery has been firstly studied in patients with atherosclerosis of peripheral arteries (stage III-IV) of the lower extremities. It has been found that the open surgery leads to a sufficient evaluation of the proapoptotic potential, i.e. the increasing Bax protein index on the 1^st day and by the end of 1^st month with reducing Bcl-2 index by the end of 1^st month compared with the endovascular intervention.

Clinical stage drugs targeting inhibitor of apoptosis proteins purge episomal Hepatitis B viral genome in preclinical models

A major unmet clinical need is a therapeutic capable of removing hepatitis B virus (HBV) genome from the liver of infected individuals to reduce their risk of developing liver cancer. A strategy to deliver such a therapy could utilize the ability to target and promote apoptosis of infected hepatocytes. Presently there is no clinically relevant strategy that has been shown to effectively remove persistent episomal covalently closed circular HBV DNA (cccDNA) from the nucleus of hepatocytes. We used linearized single genome length HBV DNA of various genotypes to establish a cccDNA-like reservoir in immunocompetent mice and showed that clinical-stage orally administered drugs that antagonize the function of cellular inhibitor of apoptosis proteins can eliminate HBV replication and episomal HBV genome in the liver. Primary human liver organoid models were used to confirm the clinical relevance of these results. This study underscores a clinically tenable strategy for the potential elimination of chronic HBV reservoirs in patients.

Assessing risks caused by nickel-based nanomaterials: hazardous factor identification

Nanoparticles of nickel (Ni) and its compounds attract a lot of attention bearing in mind their promising innovative properties allowing their use as catalysts, components in electrical appliances, electronic devices and photonic appliances, and materials used in producing medications, diagnostic preparations, and pesticides. Production volumes of these materials in their nano-form are likely to grow rapidly in the nearest future and it involves greater loads created by these nanomaterials on a human body. And we should remember that Ni and its compounds are highly toxic for humans even in their traditional disperse forms. Their toxicity induces oxidative stress, cellular membranes and mitochondria dysfunction, expression of nuclear transcription factors that are responsible for apoptosis, caspases, as well as proto-oncogenes. Leading role in toxicity of Ni-containing nanomaterials obviously belongs to ions of heavy Ni++ being emitted from them since this heavy metal has pro-oxidant properties and influences enzyme activity and gene expression. Cytotoxic effects produced by Ni-containing nanomaterials were revealed in Model experiments in vitro performed with suing cellular cultures that were morphologically and functionally similar to epithelial cells of respiratory and gastrointestinal tract, liver, kidneys, and nervous system; these materials were able to stimulate oxidant stress, influence expression of apoptosis proteins and nuclear transcription factors, induce apoptosis and necrosis. There are data indicating that Ni-containing nanomaterials can produce malignant transforming effects in vitro. All the above mentioned proves that nickel compounds in their nanoform are a new hazardous factor that requires assessing related risks for workers, consumer, and population in general. Our review focuses on analyzing literature sources on cytotoxicity of Ni-containing nanomaterials and their effects produced on molecular-genetic and cellular levels taken over a period starting from 2011.