Nuclear factor (NF)-kappaB has been reported to be constitutively activated in various human neoplasms. However, its clinical significance in bladder urothelial carcinoma (UC) remains an unresolved issue. We conducted this study trying to elucidate the role of NFkappaB in bladder UC and its potential prognostic significance, by quantifying immunohistochemically the levels of p65/RelA expression in paraffin-embedded tissue from 116 patients. Some of the cases had previously been stained for cellular FLICE-like inhibitory protein (c-FLIP) and bcl-2. Seventy-four cases displayed concurrent cytoplasmic and nuclear immunoreactivity, whereas 18 only nuclear immunoexpression and 21 only cytoplasmic immunoexpression, and the remaining three cases were negative for p65/RelA. Nuclear p65/RelA expression was positively associated with tumour grade and T-category (p=0.0001 in both cases). In addition, cytoplasmic p65/RelA expression was lower in advanced T-category (p=0.0030). Moreover, p65/RelA nuclear expression was positively correlated with c-FLIP (p=0.0109) and bcl-2 (p=0.0452). p65/RelA nuclear expression adversely affected survival in both univariate and multivariate analysis in superficial (Ta-T1; p=0.0010 and p=0.0008) as well as in muscle-invasive carcinomas (T2-T4; p=0.0004 and p=0.0003). Our results demonstrate that NF-kappaB nuclear expression is correlated with histologic grade and T category in bladder UC. Moreover, NF-kappaB nuclear expression emerges as an independent prognosticator of adverse significance, conveying information beyond that obtained by standard clinicopathological prognosticators.
Aims Levosimendan (LEVO) a clinically-used inodilator, exerts multifaceted cardioprotective effects. Case-studies indicate protection against doxorubicin (DXR)-induced cardiotoxicity, but this effect remains obscure. We investigated the effect and mechanism of different regimens of levosimendan on sub-chronic and chronic doxorubicin cardiotoxicity. Methods and results Based on preliminary in vivo experiments, rats serving as a sub-chronic model of doxorubicin-cardiotoxicity and were divided into: Control (N/S-0.9%), DXR (18 mg/kg-cumulative), DXR+LEVO (LEVO, 24 μg/kg-cumulative), and DXR+LEVO (acute) (LEVO, 24 μg/kg-bolus) for 14 days. Protein kinase-B (Akt), endothelial nitric oxide synthase (eNOS), and protein kinase-A and G (PKA/PKG) pathways emerged as contributors to the cardioprotection, converging onto phospholamban (PLN). To verify the contribution of PLN, phospholamban knockout (PLN−/−) mice were assigned to PLN−/−/Control (N/S-0.9%), PLN−/−/DXR (18 mg/kg), and PLN−/−/DXR+LEVO (ac) for 14 days. Furthermore, female breast cancer-bearing (BC) mice were divided into: Control (normal saline 0.9%, N/S 0.9%), DXR (18 mg/kg), LEVO, and DXR+LEVO (LEVO, 24 μg/kg-bolus) for 28 days. Echocardiography was performed in all protocols. To elucidate levosimendan’s cardioprotective mechanism, primary cardiomyocytes were treated with doxorubicin or/and levosimendan and with N omega-nitro-L-arginine methyl ester (L-NAME), DT-2, and H-89 (eNOS, PKG, and PKA inhibitors, respectively); cardiomyocyte-toxicity was assessed. Single bolus administration of levosimendan abrogated DXR-induced cardiotoxicity and activated Akt/eNOS and cAMP-PKA/cGMP-PKG/PLN pathways but failed to exert cardioprotection in PLN−/− mice. Levosimendan’s cardioprotection was also evident in the BC model. Finally, in vitro PKA inhibition abrogated levosimendan-mediated cardioprotection, indicating that its cardioprotection is cAMP-PKA dependent, while levosimendan preponderated over milrinone and dobutamine, by ameliorating calcium overload. Conclusion Single dose levosimendan prevented doxorubicin cardiotoxicity through a cAMP-PKA-PLN pathway, highlighting the role of inotropy in doxorubicin cardiotoxicity.
The phenolic component Oleuropein (OLEU), a bioactive natural product, has recently shown antiproliferative properties. Doxorubicin (DXR) is an anthracycline present in many chemotherapeutic schemes, although limited due to its cardio-toxic effects. Important research effort has been devoted therefore, to reducing DXR toxicity without compromising its antitumor efficacy. The anticancer actions of DXR and OLEU were assessed, on PC-3 prostate cancer cells, while cell cycle distribution and rate of apoptosis were assessed by flow cytometry. The autophagic process was determined via immunoblotting and immunofluorescent staining. Finally, cell extracts were analyzed by NMR spectroscopy. The present study showed that both DXR and OLEU inhibited PC-3 cells proliferation, while the co-treatment with DXR and OLEU resulted in an additive inhibition. Although the addition of OLEU to DXR did not alter significantly the cell cycle distribution, exhibited by each treatment alone, and produced a marginal increase on the rate of apoptosis, both compounds produced a remarkable induction of autophagy. In addition, treated cells exhibited significant metabolite alterations. This study demonstrates that OLEU, a basic component of the everyday diet, is capable of lowering significantly the cytotoxic dose of DXR, while obtaining an important anti-proliferative effect in prostate cancer cells.
Apoptosis is a form of programmed death that has also been observed in cells infected by several viruses. It is considered one of the most critical innate immune mechanisms that limits pathogen proliferation and propagation before the initiation of the adaptive immune response. Recent studies investigating the cellular responses to SARS-CoV and SARS-CoV-2 infection have revealed that coronaviruses can alter cellular homeostasis and promote cell death, providing evidence that the modulation of apoptotic pathways is important for viral replication and propagation. Despite the genetic diversity among different coronavirus clades and the infection of different cell types and several hosts, research studies in animal coronaviruses indicate that apoptosis in host cells is induced by common molecular mechanisms and apoptotic pathways. We summarize and critically review current knowledge on the molecular aspects of cell-death regulation during animal coronaviruses infection and the viral–host interactions to this process. Future research is expected to lead to a better understanding of the regulation of cell death during coronavirus infection. Moreover, investigating the role of viral proteins in this process will help us to identify novel antiviral targets related to apoptotic signaling pathways.
Introduction !Prostate cancer (PCa) is one of the most common malignancies in men and a leading cause of death worldwide for men. Taking into consideration that chemotherapy has severe side effects and usually a poor outcome, there is an intensive need for the development of safer and more effective agents. Since plants have been used by traditional medicine for the treatment of various diseases, in the last decades, many natural products have been isolated from plants and tested for their tumor selectivity and cytotoxic efficacy. Several of these naturally occurring compounds have been found to inhibit PCa growth and metastasis and are thus a promising approach for the treatment of this malignancy. Laboratory studies in different in vitro and in vivo systems have shown that these natural products modulate cellular processes, exhibit chemopreventive and/or chemotherapeutic effects, and induce apoptosis and autophagy. Accordingly, the antiproliferative and autophagic effects of nontoxic dietary agents could be of additional significance for the prevention, control, and management of PCa, specifically for the advanced and androgen-independent stage of the malignancy [1][2][3]. As there is increasing data on how natural compounds interfere with diverse molecular pathways in cancer cells, this review discusses the mechanism of action of bioactive natural products in the field of PCa and emphasizes the implicated molecular pathways of apoptosis and autophagy as important processes that control cellular homeostasis and that have been highlighted as promising targets for novel cancer therapies.Apigenin ! Apigenin (4′,5,7-trihydroxyflavone) is a flavone found in plants of the Asteraceae family, such as Anthemis sp., and many fruits and vegetables [4]. Apigenin has been tested in various types of cancer cell lines (breast, colon, liver, lung) showing promising results [5]. In prostate cancer in particular, apigenin administered in various concentrations (1-20 μΜ) for 24, 48, and 72 h not only causes G1 cell cycle arrest both in androgen-dependent (LNCaP) and -independent (DU145 and PC-3) PC cell lines through the decreased expression of cyclins D1, D2, and E, but also induces apoptosis through a shift in the Bax/Bcl-2 ratio [6,7]. Further studies in PC-3 cells have also demonstrated that apigenin (5-40 μΜ), delivered for 24 h, suppresses cell proliferation and induces apoptosis by inhibiting IGF-IGF-IR signaling and inactivating the PI3k/Akt pathway [8]. Apigenin Abstract ! Prostate cancer is one of the leading causes of death worldwide for men. There is increasing evidence that diet and lifestyle play a crucial role in prostate cancer biology and tumorigenesis. Due to the fact that conventional chemotherapy is not adequately effective against prostate cancer and has severe side effects, numerous in vitro studies have been conducted in order to identify the potent cytotoxic or chemopreventive activity of naturally occurring compounds and their respective molecular mechanisms of action. In this context, many natural compo...
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