Medicinal plants serve as a lead source of bioactive compounds and have been an integral part of day-to-day life in treating various disease conditions since ancient times. Withaferin A (WFA), a ...bioactive ingredient of Withania somnifera, has been used for health and medicinal purposes for its adaptogenic, anti-inflammatory, and anticancer properties long before the published literature came into existence. Nearly 25% of pharmaceutical drugs are derived from medicinal plants, classified as dietary supplements. The bioactive compounds in these supplements may serve as chemotherapeutic substances competent to inhibit or reverse the process of carcinogenesis. The role of WFA is appreciated to polarize tumor-suppressive Th1-type immune response inducing natural killer cell activity and may provide an opportunity to manipulate the tumor microenvironment at an early stage to inhibit tumor progression. This article signifies the cumulative information about the role of WFA in modulating antitumor immunity and its potential in targeting prostate cancer.
Epigenetic alterations such as DNA methylation and histone modifications are implicated in repressing several tumor suppressor genes in prostate cancer progression. In this study, we determined the ...anti-prostate cancer effect of a small molecule drug guadecitabine (gDEC) that inhibits/depletes the DNA methylation writer DNA methyltransferase 1 (DNMT1). gDEC inhibited prostate cancer cell growth and proliferation in vitro without activating the apoptotic cascade. Molecular studies confirmed DNMT1 depletion and modulated epithelial-mesenchymal transition markers E-cadherin and β-catenin in several prostate cancer cell lines (LNCaP, 22Rv1, and MDA PCa 2b). gDEC treatment also significantly inhibited prostate tumor growth in vivo in mice (22Rv1, MDA PCa 2b, and PC-3 xenografts) without any observed toxicities. gDEC did not impact the expression of androgen receptor (AR) or AR-variant 7 (AR-V7) nor sensitize the prostate cancer cells to the anti-androgen enzalutamide in vitro. In further investigating the mechanism of cytoreduction by gDEC, a PCR array analyses of 84 chromatin modifying enzymes demonstrated upregulation of several lysine-specific methyltransferases (KMTs: KMT2A, KMT2C, KMT2E, KMT2H, KMT5A), confirmed by additional expression analyses in vitro and of harvested xenografts. Moreover, gDEC treatment increased global histone 3 lysine 4 mono-and di-methylation (H3K4me1 and H3K4me2). In sum, gDEC, in addition to directly depleting the corepressor DNMT1, upregulated KMT activating epigenetic enzymes, activating terminal epithelial program activation, and prostate cancer cell cycling exits independent of apoptosis.
Immunomodulatory activity of Seabuckthorn (SBT) leaf extract was evaluated in adjuvant induced arthritis (AIA) rat model. Inflammation was induced by injecting Complete Freund's Adjuvant (CFA) in the ...right hind paw of rats. SBT extract was administered intraperitoneally to treat the inflammation. The extent of inflammation and treatment response was evaluated by clinical analysis, scintigraphic visualization using technitium-99m-glutathione (Tc99m-GSH) and lymphocyte proliferation. Serial evaluation was carried out on days 1, 7, 14, 21 and 28 after creation of inflammation. The Tc99m-GSH uptake in the inflamed leg was compared with the normal contralateral leg of the same animal. The measurements were done by obtaining scintigraphic images using gamma camera and an online computer. Both qualitative and quantitative evaluation of radiotracer accumulation was considered to evaluate the anti-inflammatory response. The lymphocyte proliferation study revealed cellular immunosuppression during the early phase of the disease. Administration of SBT extract on the same day or 5 days prior to inflammatory insult into the joint, significantly reduced the inflammation as compared to the untreated animals in a dose dependent manner. These observations suggest that the SBT leaf extract has a significant anti-inflammatory activity and has the potential for the treatment of arthritis.
In this paper, we discuss the inducibility problem for automorphisms of multiplicative Lie algebra extensions and show that obstruction to the inducibility of pairs lies in the second cohomology ...group of multiplicative Lie algebras. We also establish the Wells type exact sequence for multiplicative Lie algebras, which relates automorphism groups with the second cohomology group of multiplicative Lie algebras.
This paper aims to introduce and explore the concept of Lie perfect multiplicative Lie algebras, with a particular focus on their connections to the central extension theory of multiplicative Lie ...algebras. The primary objective is to establish and provide proof for a range of results derived from Lie perfect multiplicative Lie algebras. Furthermore, the study extends the notion of Lie nilpotency by introducing and examining the concept of local nilpotency within multiplicative Lie algebras. The paper presents an innovative adaptation of the Hirsch-Plotkin theorem specifically tailored for multiplicative Lie algebras.
In this paper, we discuss the capable and isoclinic properties of the tensor square in the context of multiplicative Lie algebras. We also developed the concept of isoclinic extensions and proved ...several results for multiplicative Lie algebras. Consequently, we demonstrate that covers of a multiplicative Lie algebra are mutually isoclinic.
As a part of the study to identify genes associated with hormone-refractory stage of human prostate cancer, we have recently identified several genetic and epigenetic changes that seem to be ...associated with the progression of androgen-sensitive to androgen-independent prostate tumor cells. In the present study, we report a novel gene, macrophage inhibitory cytokine-1 (
MIC-1) also known as prostate derived factor (
PDF), that was highly expressed in androgen-independent LNCaP-C81 cells and its metastatic variant LNCaP-Ln3 compared to androgen-sensitive LNCaP-C33 cells. The MIC-1/PDF expression was dysregulated (very low to non-detectable) in the androgen-independent PC3 and DU145 cells. Interestingly, serum factors demonstrated a differential regulation of MIC-1/PDF in the androgen-sensitive and the androgen-independent cells of LNCaP cells. Immunohistochemical analysis on 15 prostatic adenocarcinomas showed a weak staining in the benign prostatic glandular area (intensity score 2.38
±
0.25;
n=13), while the immunoreactivity was significantly stronger (
p<0.05) in areas of adenocarcinoma (score 7.33
±
0.88;
n=15). Altogether, these data suggest that the serum factors (including androgens and cytokines) might contribute to the regulation of the
MIC-1/PDF gene that seems to be associated with the progression of prostate cancer.
The androgen receptor (AR) is the main driver in the development of castration‐resistant prostate cancer, where the emergence of AR splice variants leads to treatment‐resistant disease. Through ...detailed molecular studies of the marine alkaloid manzamine A (MA), we identified transcription factor E2F8 as a previously unknown regulator of AR transcription that prevents AR synthesis in prostate cancer cells. MA significantly inhibited the growth of various prostate cancer cell lines and was highly effective in inhibiting xenograft tumor growth in mice without any pathophysiological perturbations in major organs. MA suppressed the full‐length AR (AR‐FL), its spliced variant AR‐V7, and the AR‐regulated prostate‐specific antigen ( PSA ; also known as KLK3 ) and human kallikrein 2 ( hK2 ; also known as KLK2 ) genes. RNA sequencing (RNA‐seq) analysis and protein modeling studies revealed E2F8 interactions with DNA as a potential novel target of MA, suppressing AR transcription and its synthesis. This novel mechanism of blocking AR biogenesis via E2F8 may provide an opportunity to control therapy‐resistant prostate cancer over the currently used AR antagonists designed to target different parts of the AR gene.
The androgen receptor (AR) is the main driver in the development of castration‐resistant prostate cancer, where the emergence of AR splice variants leads to treatment‐resistant disease. Through ...detailed molecular studies of the marine alkaloid manzamine A (MA), we identified transcription factor E2F8 as a previously unknown regulator of AR transcription that prevents AR synthesis in prostate cancer cells. MA significantly inhibited the growth of various prostate cancer cell lines and was highly effective in inhibiting xenograft tumor growth in mice without any pathophysiological perturbations in major organs. MA suppressed the full‐length AR (AR‐FL), its spliced variant AR‐V7, and the AR‐regulated prostate‐specific antigen (PSA; also known as KLK3) and human kallikrein 2 (hK2; also known as KLK2) genes. RNA sequencing (RNA‐seq) analysis and protein modeling studies revealed E2F8 interactions with DNA as a potential novel target of MA, suppressing AR transcription and its synthesis. This novel mechanism of blocking AR biogenesis via E2F8 may provide an opportunity to control therapy‐resistant prostate cancer over the currently used AR antagonists designed to target different parts of the AR gene.
This study used a marine sponge product, Manzamine A (MA), and identified E2F8 as a novel regulator of androgen receptor (AR) transcription. MA abrogated AR biogenesis and inhibited prostate tumor growth in mice. These findings demonstrated that as a small molecule inhibitor of E2F8, MA may serve as a potential lead compound to overcome therapy resistance to prostate cancer caused by AR remodeling.
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