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Nutrients ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 4317
Author(s):  
Yan-Xi Chen ◽  
Phuong Thu Nguyen Le ◽  
Tsai-Teng Tzeng ◽  
Thu-Ha Tran ◽  
Anh Thuc Nguyen ◽  
...  

Declines in physiological functions are the predominant risk factors for age-related diseases, such as cancers and neurodegenerative diseases. Therefore, delaying the aging process is believed to be beneficial in preventing the onset of age-related diseases. Previous studies have demonstrated that Graptopetalum paraguayense (GP) extract inhibits liver cancer cell growth and reduces the pathological phenotypes of Alzheimer’s disease (AD) in patient IPS-derived neurons. Here, we show that GP extract suppresses β-amyloid pathology in SH-SYS5Y-APP695 cells and APP/PS1 mice. Moreover, AMP-activated protein kinase (AMPK) activity is enhanced by GP extract in U87 cells and APP/PS1 mice. Intriguingly, GP extract enhances autophagy in SH-SYS5Y-APP695 cells, U87 cells, and the nematode Caenorhabditis elegans, suggesting a conserved molecular mechanism by which GP extract might regulate autophagy. In agreement with its role as an autophagy activator, GP extract markedly diminishes mobility decline in polyglutamine Q35 mutants and aged wild-type N2 animals in C. elegans. Furthermore, GP extract significantly extends lifespan in C. elegans.


2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Mohammad Amin Vaezi ◽  
Banafsheh Safizadeh ◽  
Amir Reza Eghtedari ◽  
Seyedeh Sara Ghorbanhosseini ◽  
Mostafa Rastegar ◽  
...  

Abstract15-lipoxygenase is one of the key enzymes for the metabolism of unsaturated fatty acids that its manipulation has been proposed recently as a new molecular target for regulating cancer cell growth. Aberrant expression of 15-lipoxygenase enzyme seems to play an indicative role in the pathology of different cancer types, tumor progression, metastasis, or apoptosis. Based on the fact that breast cancer is one of the most common cancers that imposes a burden of mortality in women also, on the other hand, evidence in experimental models and human studies indicate the emerging role of the 15-lipoxygenase pathway in breast cancer pathogenesis, we present a review of recent findings related to the role of 15- lipoxygenase enzyme and metabolites in breast cancer growth, apoptosis, metastasis, and invasion as well as their local and circulating expression pattern in patients with breast cancer. Our review supports the emerging role of 15- lipoxygenase in molecular and cellular processes regulating breast tumor cell fate with both positive and negative effects.


Molecules ◽  
2021 ◽  
Vol 26 (23) ◽  
pp. 7166
Author(s):  
Nigel Vicker ◽  
Helen V. Bailey ◽  
Joanna M. Day ◽  
Mary F. Mahon ◽  
Andrew Smith ◽  
...  

17β-Hydroxysteroid dehydrogenase type 3 (17β-HSD3) is expressed at high levels in testes and seminal vesicles; it is also present in prostate tissue and involved in gonadal and non-gonadal testosterone biosynthesis. The enzyme is membrane-bound, and a crystal structure is not yet available. Selective aryl benzylamine-based inhibitors were designed and synthesised as potential agents for prostate cancer therapeutics through structure-based design, using a previously built homology model with docking studies. Potent, selective, low nanomolar IC50 17β-HSD3 inhibitors were discovered using N-(2-([2-(4-chlorophenoxy)phenylamino]methyl)phenyl)acetamide (1). The most potent compounds have IC50 values of approximately 75 nM. Compound 29, N-[2-(1-Acetylpiperidin-4-ylamino)benzyl]-N-[2-(4-chlorophenoxy)phenyl]acetamide, has an IC50 of 76 nM, while compound 30, N-(2-(1-[2-(4-chlorophenoxy)-phenylamino]ethyl)phenyl)acetamide, has an IC50 of 74 nM. Racemic C-allyl derivative 26 (IC50 of 520 nM) was easily formed from 1 in good yield and, to determine binding directionality, its enantiomers were separated by chiral chromatography. Absolute configuration was determined using single crystal X-ray crystallography. Only the S-(+)-enantiomer (32) was active with an IC50 of 370 nM. Binding directionality was predictable through our in silico docking studies, giving confidence to our model. Importantly, all novel inhibitors are selective over the type 2 isozyme of 17β-HSD2 and show <20% inhibition when tested at 10 µM. Lead compounds from this series are worthy of further optimisation and development as inhibitors of testosterone production by 17β-HSD3 and as inhibitors of prostate cancer cell growth.


2021 ◽  
Vol 22 (23) ◽  
pp. 12686
Author(s):  
Tsuyoshi Waku ◽  
Akira Kobayashi

NRF3 (NFE2L3) belongs to the CNC-basic leucine zipper transcription factor family. An NRF3 homolog, NRF1 (NFE2L1), induces the expression of proteasome-related genes in response to proteasome inhibition. Another homolog, NRF2 (NFE2L2), induces the expression of genes related to antioxidant responses and encodes metabolic enzymes in response to oxidative stress. Dysfunction of each homolog causes several diseases, such as neurodegenerative diseases and cancer development. However, NRF3 target genes and their biological roles remain unknown. This review summarizes our recent reports that showed NRF3-regulated transcriptional axes for protein and lipid homeostasis. NRF3 induces the gene expression of POMP for 20S proteasome assembly and CPEB3 for NRF1 translational repression, inhibiting tumor suppression responses, including cell-cycle arrest and apoptosis, with resistance to a proteasome inhibitor anticancer agent bortezomib. NRF3 also promotes mevalonate biosynthesis by inducing SREBP2 and HMGCR gene expression, and reduces the intracellular levels of neural fatty acids by inducing GGPS1 gene expression. In parallel, NRF3 induces macropinocytosis for cholesterol uptake by inducing RAB5 gene expression. Finally, this review mentions not only the pathophysiological aspects of these NRF3-regulated axes for cancer cell growth and anti-obesity potential but also their possible role in obesity-induced cancer development.


2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Yueling Wu ◽  
Ning Li ◽  
Chengfeng Ye ◽  
Xingmei Jiang ◽  
Hui Luo ◽  
...  

AbstractKinases are the ideal druggable targets for diseases and especially were highlighted on cancer therapy. Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase and its aberrant signaling extensively implicates in the progression of most cancer types, involving in cancer cell growth, adhesion, migration, and tumor microenvironment (TME) remodeling. FAK is commonly overexpressed and activated in a variety of cancers and plays as a targetable kinase in cancer therapy. FAK inhibitors already exhibited promising performance in preclinical and early-stage clinical trials. Moreover, substantial evidence has implied that targeting FAK is more effective in combination strategy, thereby reversing the failure of chemotherapies or targeted therapies in solid tumors. In the current review, we summarized the drug development progress, chemotherapy strategy, and perspective view for FAK inhibitors.


Cells ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 3219
Author(s):  
Magdalena Rudzinska-Radecka ◽  
Łukasz Janczewski ◽  
Anna Gajda ◽  
Marlena Godlewska ◽  
Malgorzata Chmielewska-Krzesinska ◽  
...  

Isothiocyanates (ITCs) show strong activity against numerous human tumors. Five structurally diverse ITCs were tested in vivo using the zebrafish embryos 6 and 48 h post-fertilization (hpf). The survival rate, hatching time, and gross morphological changes were assessed 24, 48, and 72 h after treatment with all compounds in various doses (1–10 µM). As a result, we selected a phosphonate analog of sulforaphane (P-ITC; 1–3 µM) as a non-toxic treatment for zebrafish embryos, both 6 and 48 hpf. Furthermore, the in vivo anti-cancerogenic studies with selected 3 µM P-ITC were performed using a set of cell lines derived from the brain (U87), cervical (HeLa), and breast (MDA-MB-231) tumors. For the experiment, cells were labeled using red fluorescence dye Dil (1,1′-Dioctadecyl-3,3,3′,3′-Tetramethylindocarbocyanine, 10 μg/mL) and injected into the hindbrain ventricle, yolk sac region and Cuvier duct of zebrafish embryos. The tumor size measurement after 48 h of treatment demonstrated the significant inhibition of cancer cell growth in all tested cases by P-ITC compared to the non-treated controls. Our studies provided evidence for P-ITC anti-cancerogenic properties with versatile activity against different cancer types. Additionally, P-ITC demonstrated the safety of use in the living organism at various stages of embryogenesis.


Author(s):  
Jang Hyuk Bang ◽  
Kyung Ah Kim ◽  
Yeong Chae Ryu ◽  
Byoung Choul Kim ◽  
BYEONG HEE HWANG

Breast cancer is one of the serious diseases and has the second-highest mortality in women worldwide. RNA interference has been developed as a promising way of specific cancer treatment by silencing oncogenes efficiently. However, small RNAs exhibits difficulties in specific cellular uptake and instability. Therefore, we designed novel fusion peptides (RS and RT) for an efficient, stable, and specific delivery of small RNAs. Both RS and RT peptides could form self-assembled nanocomplexes via electrostatic attraction. RS nanocomplexes exhibited prolonged stability, enhanced cellular uptake, and target gene silencing by siRNAs to MDA-MB-231 breast cancer cells. Moreover, RS nanocomplexes successfully inhibited breast cancer cell growth via specific and efficient siRNA delivery. Furthermore, in vitro and in vivo safety tests showed negligible cytotoxicity and neither tissue damage nor significant inflammatory cytokine release. Therefore, the RS nanocomplexes could be expected to become a promising siRNA delivery platform for the treatment of breast cancer or other cancers.


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