Apoptotic Switch in Cancer Stem Cells: A Potential Approach for Cancer Treatment.

Cancer diseases account for about 15% of deaths globally right now, and the percentage may increase in the future. There are more than 100 types of cancer, and each of them is distinct in its origin, microenvironment, growth, metastasis, and signalling pathways. Cancer stem cells are the specialised cells that make cancer more aggressive and difficult to treat. Moreover, cancer aetiology may exist at the genomic, proteomic, or habitat level in any combination. Hence, a unanimous treatment protocol for the different cancers is an uphill task at the present juncture. In this context, this review aims to provide a comprehensive reappraisal concisely of anti-apoptotic proteins, which are shown to be overexpressed in most cancers, if not all, and to forthrightly rationalise the apoptotic proteins as potential biomarkers and druggable targets of the cancers by effectively killing cancer stem cells.

Dysregulation of miRISC Regulatory Network Promotes Hepatocellular Carcinoma by Targeting PI3K/Akt Signaling Pathway.

Hepatocellular carcinoma (HCC) remains the third leading malignancy worldwide, causing high mortality in adults and children. The neuropathology-associated gene AEG-1 functions as a scaffold protein to correctly assemble the RNA-induced silencing complex (RISC) and optimize or increase its activity. The overexpression of oncogenic miRNAs periodically degrades the target tumor suppressor genes. Oncogenic miR-221 plays a seminal role in the carcinogenesis of HCC. Hence, the exact molecular and biological functions of the oncogene clusters miR-221/AEG-1 axis have not yet been examined widely in HCC. Here, we explored the expression of both miR-221 and AEG-1 and their target/associate genes by qRT-PCR and western blot. In addition, the role of the miR-221/AEG-1 axis was studied in the HCC by flow cytometry analysis. The expression level of the AEG-1 did not change in the miR-221 mimic, and miR-221-transfected HCC cells, on the other hand, decreased the miR-221 expression in AEG-1 siRNA-transfected HCC cells. The miR-221/AEG-1 axis silencing induces apoptosis and G2/M phase arrest and inhibits cellular proliferation and angiogenesis by upregulating p57, p53, RB, and PTEN and downregulating LSF, LC3A, Bcl-2, OPN, MMP9, PI3K, and Akt in HCC cells.

The absence of cellular glucose triggers oncogene AEG-1 that instigates VEGFC in HCC: A possible genetic root cause of angiogenesis.

BACKGROUND AND OBJECTIVE: Astrocyte Elevated Gene-1 (AEG-1) is the master and multi-regulator of the various transcriptional factor primarily regulating chemoresistance, angiogenesis, metastasis, and invasion under the pathological condition, including liver cancer. This study was focused on investigating the process of tumor angiogenesis in liver carcinoma by studying the role of AEG-1 under GD/2DG conditions. METHOD AND RESULTS: The PCR and western blot analysis revealed that glucose depletion (GD) induces the overexpression of AEG-1. Further, it leads to the constant expression of VEGFC through the activation of HIF-1α/CCR7 via the stimulations of PI3K/Akt signaling pathways. GLUT2 is the major transporter of a glucose molecule that is highly participating under GD through the expression of AEG-1 and constantly expresses glucokinase (GCK). The obtained data suggest that AEG-1 act as an angiogenesis and glycolysis regulator by modulating the expression of GCK through HIF-1α and GLUT2. 2-deoxy-D-glucose (2DG) is a glycolysis inhibitor that induces impaired glycolysis and cellular apoptosis by cellular oxidative stress. The administration of 2DG has led to the chemoresistance of AEG-1. CONCLUSION: The total findings of the study judged that disruption of cellular energy metabolism induced by the absence of glucose or the presence of mutant glucose moiety (2DG) promotes the overexpression of AEG-1. The GD/2DG activates the VEGFC by inducing the HIF-1α and CCR7. Moreover, AEG-1 induces the expression of OPN, which regulates metastasis, angiogenesis, and actively participates in protective autophagy by promoting LC3 a/b.

p-Coumaric acid attenuates alcohol exposed hepatic injury through MAPKs, apoptosis and Nrf2 signaling in experimental models.

Overconsumption of alcohol could lead to severe liver injury that connects with oxidative stress, apoptosis, and inflammatory response. Previously, we proved that p-coumaric acid prevents ethanol induced reproductive toxicity; however, p-coumaric acid (PCA) on ethanol mediated hepatotoxicity has not been examined yet. In our work, we sought to study the potential of PCA in contradiction of ethanol induced hepatoxicity which linking with MAPKs, apoptosis, oxidative stress, and Nrf2 signaling. Foremost, we found that PCA could protect ethanol induced both L-02 and HepG2 hepatic cells by inhibiting cytotoxicity, ROS production, mitochondrial depolarization, and nuclear fragmentation. Also, in vivo experiments showed that the ethanol increasing the lipid markers (TBARS, CD) and depletes the antioxidants thereby increased phosphorylation of JNK, ERK, and p38 in rat liver tissues. Interestingly, PCA treatments inhibit ethanol exposed lipid markers and depletion of antioxidants, which directs the inhibition of MAPKs activation in rat liver tissues. We also noticed that the PCA protected ethanol induced apoptosis and liver markers by inhibiting the expression of Bax, caspases; AST, ALT, ALS, and LDH in liver tissue. Overall, the ameliorative consequence of PCA on ethanol induced oxidative stress and apoptosis was achieved by suppressing the expression of CYP2E1 and overexpressing Nrf2 and its target protein HO-1 in rat liver tissue. As a result, PCA was marked to be an effective antioxidant with notable hepatoprotection by inhibiting MAPKs and apoptosis signaling via enhancing Nrf2 signaling.

AEG-1/miR-221 Axis Cooperatively Regulates the Progression of Hepatocellular Carcinoma by Targeting PTEN/PI3K/AKT Signaling Pathway.

Hepatocellular carcinoma (HCC) is the third leading malignancy worldwide, causing mortality in children and adults. AEG-1 is functioned as a scaffold protein for the proper assembly of RNA-induced silencing complex (RISC) to optimize or increase its activity. The increased activity of oncogenic miRNAs leads to the degradation of target tumor suppressor genes. miR-221 is an oncogenic miRNA, that plays a seminal role in carcinogenesis regulation of HCC. However, the molecular mechanism and biological functions of the miR-221/AEG-1 axis have not been investigated extensively in HCC. Here, the expression of miR-221/AEG-1 and their target/associate genes was analyzed by qRT-PCR and Western blot. The role of the miR-221/AEG-1 axis in HCC was evaluated by proliferation assay, migration assay, invasion assay, and flow cytometry analysis. The expression level of miR-221 decreased in AEG-1 siRNA transfected HCC cells. On the other hand, there were no significant expression changes of AEG-1 in miR-221 mimic and miR-221 inhibitor transfected HCC cells and inhibition of miR-221/AEG-1 axis decreased cell proliferation, invasion, migration, and angiogenesis and induced apoptosis, cell cycle arrest by upregulating p57, p53, PTEN, and RB and downregulating LSF, MMP9, OPN, Bcl-2, PI3K, AKT, and LC3A in HCC cells. Furthermore, these findings suggest that the miR-221/AEG-1 axis plays a seminal oncogenic role by modulating PTEN/PI3K/AKT signaling pathway in HCC. In conclusion, the miR-221/AEG-1 axis may serve as a potential target for therapeutics, diagnostics, and prognostics of HCC.

p-Coumaric acid ameliorates ethanol-induced kidney injury by inhibiting inflammatory cytokine production and NF-κB signaling in rats

Objective: To examine the effects of p-coumaric acid on ethanol-induced kidney injury in Swiss Wistar rats. Methods: Ethanol (25％ v/v) was used to induce nephrotoxicity in rats. p-Coumaric acid was orally administered at 50, 100, or 200 mg/kg body weight. The levels of oxidative parameters were determined; pro-inflammatory biomarkers were analyzed by Western blotting and apoptotic protein was analyzed by immunohistochemistry. Results: Ethanol treated rats showed decreased levels of antioxidants and aberrant production of pro-inflammatory cytokines (IL-6, IL1β, TNF-α), NF-κB activation and imbalance of pro-and anti-apoptotic proteins (Bcl-2, Bax, caspase 3). Meanwhile, p-coumaric acid restored antioxidant levels and decreased the levels of inflammatory cytokines, NF-κB, and pro-apoptotic proteins and increased Bcl-2 expression. Conclusions: p-Coumaric acid ameliorates ethanol-induced kidney injury by restoring antioxidant production and suppressing cellular apoptosis and inhibiting NF-κB expression. p-Coumaric acid should be further investigated as a promising candidate for ethanol-induced kidney toxicity.

Protective effects of p­coumaric acid on ethanol induced male reproductive toxicity.

Alcohol, a psychoactive drug is one of the lifestyle factors responsible for male infertility. Present study was carried out to investigate the ameliorative effect of p­coumaric acid (PCA), a plant derived bioactive phenolic compound on alcohol induced chronic reproductive toxicity in male rats. Thirty male Wistar rats were divided into five groups, each with six animals. Group I as control received vehicle (distilled water) alone. And the following Group II, III, IV, V were treated orally with sequentially (per week) increased dose of ethanol 25% v/v (5, 8, 10 and 12 g/kg b wt per week in each group) for 28 days. On the 3rd and 4th week, the groups III, IV, V were administered with p­coumaric acid orally at three different concentrations (Low 50 mg/kg b wt; Medium 100 mg/kg b wt; High 200 mg/kg b wt). The rats treated with ethanol showed abnormal sperm characteristics, reduced anti-oxidant level, reduced testosterone level and abnormal testicular histoarchitecture while the rats treated with PCA in addition to ethanol were found to have protective effects on sperm parameters and apoptosis. The increased caspase-3, caspase-7, p21 immunoreactivity and reduced Cdk4 immunoreactivity in ethanol treated rats confirmed that ethanol increases the apoptosis in testis and a reduced expression in the rats treated with PCA in addition to ethanol indicates a protective role of PCA. Overall, our results showed that PCA mitigates alcohol induced male reproductive toxicity and improves reproductive health in male Wistar rats.

Doxorubicin-induced female reproductive toxicity: an assessment of ovarian follicular apoptosis, cyclicity and reproductive tissue histology in Wistar rats.

Doxorubicin is a widely used chemotherapeutic agent for various cancers, particularly for the female breast cancer patients. Although the rate of young female cancer patients is increasing every year, conversely the lack of knowledge of adverse effects of doxorubicin on female reproductive system insisted us to assess the toxic effects of doxorubicin on the female reproductive tissue histoarchitecture, cyclicity, and mammary glands in Wistar rats. The rats were divided into two groups depending on the treatment period, i.e., 24 h and 28 d and further subdivided into three subgroups and administered with doxorubicin at 3 mg/kg bw (subgroup I), 6 mg/kg bw (subgroup II), and equal volume of normal saline (subgroup III) intraperitoneally once during the whole treatment period. We observed a significantly altered estrous cycle with a prolonged diestrous and short proestrous in higher dose group and dose-dependent significant changes in the uteri and mammary gland histoarchitecture in 28 days treated rats as compared to control. Moreover, the micronuclei and chromosomal aberration frequency were increased significantly in both treatment groups. A significant increase in follicular atresia in ovaries of the 28 days treated rats was observed. The immunohistochemical analysis of ovarian tissues showed an increased p53 and caspase 3 expression and apoptosis in primordial follicles of treated rats. The results suggest that though doxorubicin is a potential chemotherapeutic drug for many tumors, but the risk of adverse effects on the female reproductive system is there even at low doses.

Inverse correlation of ribosomal protein S27A and multifunctional protein YB-1 in hepatocellular carcinoma.

OBJECTIVE: The detection of possible correlation between ribosomal protein RPS27A and multifunctional YB-1 expression in hepatocellular carcinoma (HCC). DESIGN AND METHODS: Tissue microarray slides containing totally 80 cores with 19 tissues of HCC, 1 tissue of hepatocholangiocarcinoma, 10 tissues of liver cirrhosis and 10 normal liver tissues in duplicates were analyzed for expression of RPS27A and YB-1 by immunohistochemistry. RESULTS: Among each of 10 LC and normal liver tissues all (100%) showed RPS27A positive expression but only 11 out of 19 HCC tissues (57.89%) showed RPS27A positive expression with significant difference compared (P<0.05) with both LC and normal tissues. We found positive expression of YB-1 in 17 tissues out of 19 HCC tissues (89.47%) but only 4 tissues out of each 10 LC as well as normal liver tissues showed positive expression with significant (P<0.01) difference compared to HCC tissues. A statistically significant inverse weak correlation (rho=-0.293) between YB-1 expression and RPS27A expression was found. CONCLUSION: The present investigation concludes that the ribosomal protein RPS27A was down-regulated in viral induced HCC patients. RPS27A expression was found to have a weak inverse correlation with overexpression of multifunctional protein YB-1 in HCC tissues. This study opens up a new window for YB-1-RPS27A axis in HCC.