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Testosterone signaling in spermatogenesis, male fertility and infertility
Published in Rajender Singh, Molecular Signaling in Spermatogenesis and Male Infertility, 2019
Arijit Chakraborty, Vertika Singh, Kiran Singh, Rajender Singh
Androgen insensitivity syndrome (AIS) is a disorder in which there is alteration in the androgen function due to a nonfunctional androgen receptor (AR). This is an X-linked recessive disorder with a 46,XY karyotype. We previously reported a number of mutations in the AR gene that cause AIS (51). Hundreds of such mutations have been tabulated in the Androgen Receptor Gene Mutations Database (52). There are mechanistic studies demonstrating that S-AR−/y mice have defects in the expression of anti-Müllerian hormone, androgen-binding protein, cyclin A1 and sperm-1, which play important roles in the control of spermatogenesis and/or steroidogenesis. Hence, it was shown that Sertoli cell–specific AR knockout mice provide in vivo evidence of the need for functional AR in the Sertoli cells to maintain normal spermatogenesis and testosterone production and to ensure normal male fertility (53). In certain diseases like AIS, spinal bulbar muscular atrophy (SBMA), benign prostatic hyperplasia (BPH) and prostate cancer, abnormalities in the function of androgen receptor have been identified. Recently, novel therapeutic interventions using miRNAs in prostate cancer have been proposed that specifically target the transactivation function of the AR at post-transcriptional stages (54).
The Anticancer Potential of the Bacterial Protein Azurin and Its Derived Peptide p28
Published in Ananda M. Chakrabarty, Arsénio M. Fialho, Microbial Infections and Cancer Therapy, 2019
Ana Rita Garizo, Nuno Bernardes, Ananda M. Chakrabarty, Arsénio M. Fialho
Experiments with isothermal calorimetry demonstrated that azurin binds to the NH2-terminal domain of p53 with nanomolar affinity in a 4:1 stoichiometry, as well to the DNA-binding domain of this protein [28]. A few studies, supported by site-directed mutagenesis, suggest that a specific region of azurin has been implicated in this complex formation. This region (Met-44 to Met-64) forms a hydrophobic patch and is located within the p28 peptide [32]. Thus, with the inhibition of proteasomal degradation of p53 occurs a raise of the cytoplasmic and nuclear levels of this protein, and consequently, increased DNA binding activity. The levels of the cyclin-dependent kinase inhibitors p21 and p27 also increase, which in turn reduces the intracellular levels of cyclin-dependent kinase 2 (CDK2) and cyclin A1, essential proteins in the mitotic process, as well as Forkhead box M1 (FOXM1), a transcription factor for G2/M progression. Since these components are involved in controlling the cell cycle, the reduction in their levels interrupts this process at the G2/M phase, thus leading to apoptosis (Fig. 9.2; [16]). With this, it was possible to understand that the use of azurin/p28 can be a good therapeutic option for the regression of tumors.
Alantolactone induces apoptosis through ROS-mediated AKT pathway and inhibition of PINK1-mediated mitophagy in human HepG2 cells
Published in Artificial Cells, Nanomedicine, and Biotechnology, 2019
Xing Kang, Hijuan Wang, Yanwei Li, Ying Xiao, Lili Zhao, Tingting Zhang, Shaohe Zhou, Xiaolun Zhou, Yi Li, Zhexing Shou, Chao Chen, Bin Li
G2/M phase cell cycle arrest was firstly observed in HepG2 cells exposed to Ala as compared to the control group (Figure 2(A)). Furthermore, Ala induced G2/M cell cycle arrest in a dose-dependent manner and the percentage of cells accumulated in the G2/M phase was enhanced by 13.45%, 34.65% and 42.41% in the 4, 6 and 8 μM groups, respectively, as compared to that in the control group (7.42%, p < .001). Additionally, we performed western blot analysis to determine the cell cycle regulatory proteins involved in the action of Ala in HepG2 cells. As shown in Figure 2(B), the expression of cyclin A1 and cyclin B1 decreased, whereas p21 expression significantly increased. These results suggested that Ala effectively blocked proliferation by inducing G2/M phase arrest in HepG2 cells.
Biomarkers of drug resistance in ovarian cancer – an update
Published in Expert Review of Molecular Diagnostics, 2019
Huang and co-workers performed cDNA microarray analysis of OC cell lines and clinical specimens comparing patient-matched primary ovarian tumors and recurrent tumors, as well as tumors from patients who responded to standard chemotherapy versus resistant tumors, and 2 CCC cell lines characterized by different chemoresponse. A group of 10 genes was shown to be overexpressed in the recurrent/resistant tumors, with the most pronounced differences observed for CCNA1, TGM2, and PEA15. In vitro analysis of 24 OC cell lines showed significant association between higher CCNA1 levels and response to paclitaxel, doxorubicin and 5-fluorouracil, and modulation of cyclin A1 expression affected proliferation and apoptosis. Cyclin A1 expression was significantly related to shorter time to relapse in analysis of a small series of clinical specimens of different histotype [11].
A Novel Compound Plumercine from Plumeria alba Exhibits Promising Anti-Leukemic Efficacies against B Cell Acute Lymphoblastic Leukemia
Published in Nutrition and Cancer, 2022
Aaheli Chatterjee, Amrita Pal, Santanu Paul
ALL is prevalent among approximately 80% of children and 20% of adults, making it the most perennial malignancy among the children (6,7). In 2019, there were around 5930 cases and 1500 deaths observed in the United States (8). From 1990 to 2017 there was a drastic peak of 15.02 × 103 ALL cases around the world. Whereas the mortality rate increased from 37.26 × 103 to 52.22 × 103 (4). ALL incidences in India vary according to the region and age-adjusted rates that lead to around 62.3 per million and 101.4 per million cases for girls and boys, respectively (9,10) ALL is a bit more common for boys of 2–5 yr. 15–20% of pediatric ALL falls under T ALL. Although, a much higher proportion (20-50%) has been reported in India (11). Many genes and their products have been reported to be involved in leukemogenesis due to genetic translocations (12). Research has shown that quite a number of these have direct or indirect contribution in the regulation of the cell cycle and differentiation processes (13). In the transformation of a normal cell to a malignant one, deregulation of the cell cycle plays a salient role and hence the genes and the proteins involved serve as major therapeutic agents. Each phase of the cell cycle and the transitions from one phase to another are minutely controlled by proteins like cyclin or cyclin-dependent kinase and their inhibitors. Deregulations of these different molecules may prevent the normal cell cycle process. Therefore, these proteins can serve as key targets to control the abnormal proliferation of cells (14). In ALL, alteration in cyclins like Cyclin A1, E1, D1, D3 (CCNA1, CCNE1, CCND1, CCND3, respectively) and cyclin-dependent kinase-like CDK6 have been reported to show evident differential expression in control of cell cycle checkpoints. Hence, they act as excellent drug targets to perform in-silico therapeutic docking study which has been performed here (15–17).