Designing Potent Anticancer Peptides by Aurein 1.2 Key Residues Mutation and Catenate Cell-Penetrating Peptide.

Purpose: Aurein 1.2 (Aur) peptide is known for possessing anticancer characteristics devoid of conventional therapeutics side effects. For improving Aur peptide anticancer functionality, different anticancer peptides were constructed based on Aur peptide through targeting two separate strategies, including (1) sequence-based mutations and (2) adding a cell-penetrating peptide linker. Methods: The study was approached by designing three different analogs of Aur, including (a) Aur mutant (Aurm), (b) Aur with N-terminal polyarginine linker (R5-Aur), and (c) Aurm with R5 (R5-Aurm). Computational molecular dynamics simulations clearly showed higher structural stability of R5-Aur and R5-Aurm compared to Aur, solely. The α-helical properties of R5-Aur and R5-Aurm were protected during 500 ns simulations in water solution while no such structural conservation was seen for Aur in silico. Results: The results of the current study highlight response to one of the main challenges of cancer therapy through selective invasion of Aur to cancer cells without significant involvement of normal cells. This issue was confirmed by different assays, including: MTT assay, flow cytometry, qPCR, and nuclei morphological observations. Furthermore, this study intensifies exploiting in silico approaches for adjusting drug delivery. The results of different assessments on designed peptides reveal an anticancer activity pattern rising from Aur toward Aurm, and R5- Aur, consecutively. Conclusion: The designed structure of Aur shows improved anticancer activity through molecular changes which makes it suggestable for anticancer therapies.

Hydrogel nanocomposite based on alginate/zeolite for burn wound healing: In vitro and in vivo study.

Objectives: The main objective of the current assay was to evaluate the antibacterial and regenerative effects of hydrogel nanocomposite containing pure natural zeolite (clinoptilolite) integrated with alginate (Alg) as wound healing/dressing biomaterials. Materials and Methods: The zeolites were size excluded, characterized by SEM, DLS, XRD, FTIR, and XRF, and then integrated into Alg hydrogel followed by calcium chloride crosslinking. The Alg and alginate zeolite (Alg/Zeo) hydrogel was characterized by swelling and weight loss tests, also the antibacterial, hemocompatibility, and cell viability tests were performed. In animal studies, the burn wound was induced on the back of rats and treated with the following groups: control, Alg hydrogel, and Alg/Zeo hydrogel. Results: The results showed that the hydrodynamic diameter of zeolites was 367 ± 0.2 nm. Zeolites did not show any significant antibacterial effect, however, the hydrogel nanocomposite containing zeolite had proper swelling as well as hemocompatibility and no cytotoxicity was observed. Following the creation of a third-degree burn wound on the back of rats, the results indicated that the Alg hydrogel and Alg/Zeo nanocomposite accelerated the wound healing process compared with the control group. Re-epithelialization, granulation tissue thickness, collagenization, inflammatory cell recruitment, and angiogenesis level were not significantly different between Alg and Alg/Zeo nanocomposite. Conclusion: These findings revealed that although the incorporation of zeolites did not induce a significant beneficial effect in comparison with Alg hydrogel, using zeolite capacity in hydrogel for loading the antibiotics or other effective compounds can be considered a promising wound dressing.

Cell-based wound dressing: Bilayered PCL/gelatin nanofibers-alginate/collagen hydrogel scaffold loaded with mesenchymal stem cells.

Wound dressing is applied to promote the healing process, wound protection, and additionally regeneration of injured skin. In this study, a bilayer scaffold composed of a hydrogel and nanofibers was fabricated to improve the regeneration of injured skin. To this end, polycaprolactone/gelatin (PCL/Gel) nanofibers were electrospun directly on the prepared collagen/alginate (Col/Alg) hydrogel. The bilayer scaffold was characterized by scanning electron microscopy (SEM), Fourier transform infrared (FTIR), mechanical properties, and swelling/degradation time. Cytotoxicity assays were evaluated using MTT assay. Then, the nanofiber and bilayer scaffolds were seeded with Adipose-derived stem cells (ADSCs). ADSCs were isolated from rat adipose tissue and analyzed using flow cytometry, in advance. Full-thickness wounds on the backs of rats were dressed with ADSCs-seeded bilayer scaffolds and nanofibers. Histopathological evaluations were performed after 14 and 21 days using H&E (hematoxylin and eosin) staining. The results indicated that re-epithelialization, angiogenesis, and collagen remodeling were enhanced in ADSCs-seeded bilayer scaffolds and nanofibers in comparison with the control group. In conclusion, the best re-epithelialization, collagen organization, neovascularization, and low presence of inflammation in the wound area were observed in the ADSCs-seeded bilayer scaffolds.

Review article epithelial to mesenchymal transition­associated microRNAs in breast cancer.

Despite major advances, breast cancer (BC) is the most commonly diagnosed carcinoma and remains a deadly disease among women worldwide. Many researchers point toward an important role of an epithelial to mesenchymal transition (EMT) in BC development and promoting metastasis. Here, will be discussed that how functional changes of transcription factors, signaling pathways, and microRNAs (miRNA) in BC promote EMT. A thorough understanding the EMT biology can be important to determine reversing the process and design treatment approaches. There are frequent debates as to whether EMT is really relevant to BC in vivo, in which due to the intrinsic heterogeneity and tumor microenvironment. Nevertheless, given the importance of EMT in cancer progression and metastasis, the implementation of therapies against cancer-associated EMT will continue to help us develop and test potential treatments.

Let-7d and miR-185 Impede Epithelial-Mesenchymal Transition by Downregulating Rab25 in Breast Cancer.

OBJECTIVE: MicroRNAs (miRNAs) expression has deregulated in several cancer types including breast cancer (BC). The present study aims at investigating the role, mechanism, clinical value of let-7d and miR-185 in BC, and the possible correlation these miRNAs with Rab25. MATERIALS AND METHODS: Tumor samples as well adjacent normal tissues (ANT) were acquired from fresh surgical specimens from 110 patients and the expression levels of let-7d, miR-185, Rab25, and snail were evaluated using real-time PCR. The immunohistochemical (IHC) process and western blot were done to detect the level of Rab25 and Snail protein expression in BC samples. RESULTS: By comparing miRNAs expression profiles in clinical tissues of 110 patients using real-time PCR, let-7d, and miR-185 expression were dramatically downregulated in BC tissues (P < 0.05). Tumor size, stage, and lymph node metastasis were significantly related to miRNAs expression. Based on qRT-PCR and bioinformatics database analyses, we also recognized Rab25 as a possible target of miR-185 and let-7d. Rab25 expression was enhanced in BC cells and associated inversely with the expression level of mentioned miRNAs. qRT-PCR, immunohistochemistry, and western blot studies verified that Rab25 upregulation increased the levels of the snail, that key transcription factor of epithelial-mesenchymal transition (EMT). CONCLUSION: These findings demonstrated that let-7d and miR-185 inhibited EMT by targeting Rab25 expression in BC. Therefore, targeting the let-7d and miR-185/Rab25 interaction may offer new therapeutic opportunities for treating BC patients.
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miR-140 and miR-196a as Potential Biomarkers in Breast Cancer Patients.

OBJECTIVE: MiR-140 and miR-196a were known to be correlated with cancer diagnosis and prognosis. The current study aimed at the analysis of miR-140 and miR-196a expression patterns and their clinical significance for breast cancer (BC) patients. METHODS: Differentially expressed miR-140 and miR-196a were examined via quantitative PCR in 110 cases of BC and their adjacent non-tumor (ANT) tissues. RESULTS: The results indicated that miR-140 and miR-196a, respectively, notably decreased and increased expression in BC samples in comparison with ANT (p<0.001). Reduced miR-140 expression was also related to Lymph node metastasis (LNM, P= 0.023) and stage (P = 0.009). Additionally, Receiver Operating Characteristics (ROC) analysis illustrated that miR-140 had a significant diagnostic accuracy for stage and LNM of BC patients. We also discovered a strong negative correlation between miR-196a expression with histological grade (P = 0.038), LNM (P = 0.012) and stage (P = 0.001). CONCLUSION: Overall, exploring the miR-140 and miR-196a profiles not only can statistically different among BC and ANT samples, but it is also expected to become potential BC biomarkers.
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Pichia fermentans originates apoptosis in human oral squamous cell carcinoma by over-expressing BAX and CASP 9 genes.

Squamous cell carcinoma (SCC) is one of the most common malignant tumors of the oral cavity. Probiotics have often been considered as effective anti-tumoral candidates. This study aimed to investigate the role of Pichia fermentans YSH secretion metabolites on the induction of apoptosis in SCC. Cytotoxicity, apoptotic effects, and visualization DNA damage were evaluated by MTT, flow cytometry, and DAPI staining assays, respectively. Real-time PCR was employed for evaluation of the mechanism of cellular apoptosis. P. fermentans YSH secretions (IC50) showed cellular cytotoxicity in human tongue squamous carcinoma (HSC4, RRID:CVCL_1289) cells (85% apoptosis) similar to the cytotoxicity of cisplatin whereas only 21% apoptosis was observed in human epithelial normal (KDR, RRID:CVCL_9V14) cells. The prophylactic efficacy of reference yeast, which regarded as a reference, was not comparable to P. fermentans YSH illustrating strain-dependent properties of bioactivities on oral disease control and prevention. According to our result, the main cytotoxicity is related to apoptosis mechanisms induced by apoptosis genes inducing BAX and CASP. However, follow-up researches should be performed to recognize the compounds to be utilized as effective anticancer therapeutics.

Mummy Induces Apoptosis Through Inhibiting of Epithelial-Mesenchymal Transition (EMT) in Human Breast Cancer Cells.

BACKGROUND: Mummy (Iranian pure shilajit) is a remedy with possessing anti-inflammatory, antioxidant and anticancer activities. This study aimed to examine mummy effects on epithelial-mesenchymal transition (EMT) and invasiveness of MCF-7 and MDA-MB-231 breast cancer (BC) cell lines with underlying its mechanism. MATERIALS AND METHODS: The dose-dependent inhibitory effect of the mummy on cell proliferation in vitro was determined using the MTT assay. Flow cytometry and 4',6-diamidino-2-phenylindole dihydrochloride staining were respectively used for quantitative and qualitative analysis of cellular apoptosis, and gene expression analysis was conducted using real-time PCR. RESULTS: MDA-MB-231 showed more sensitivity than the MCF-7 cell line to the anticancer activity of mummy, while mummy did not exhibit significant cell cytotoxicity against human normal cells (MCF-10A). The gene expression profile demonstrated a significant decrease in TGF-ß1, TGF-ßR1, TWIST1, NOTCH1, CTNNB1, SRC along with an increase in E-cadherin mRNA levels in mummy treated cells compared to the untreated control group (P≤0.05). CONCLUSION: Mummy triggers inhibition of EMT and metastasis in breast cancer cells mainly through the downregulation of TGFß1 activity, and more studies required to find its specific anticancer activity with details.

The relationship between microRNAs and Rab family GTPases in human cancers.

microRNAs (miRNAs), as a group of noncoding RNAs, posttranscriptionally control gene expression by binding to 3'-untranslated region (3'-UTR). Ras-associated binding (Rab) proteins function as molecular switches for regulating vesicular transport, which mainly have oncogenic roles in cancer development and preventing the efficacy of chemotherapies. Increased evidence supported that miRNAs/Rabs interaction have been determined as potential therapeutics for cancer therapy. Nevertheless, instability and cross-targeting of miRNAs are main limitations of using miRNA-based therapeutic. The mutual interplay between Rabs and miRNAs has been poorly understood. In the present review, we focused on the essence and activity of these molecules in cancer pathogenesis. Also, numerous hindrances and potential methods in the expansion of miRNA as an anticancer therapeutics are mentioned.

Targeted cancer therapy through 17-DMAG as an Hsp90 inhibitor: Overview and current state of the art.

Heat shock protein 90 (Hsp90) is an evolutionary preserved molecular chaperone which mediates many cellular processes such as cell transformation, proliferation, and survival in normal and stress conditions. Hsp90 plays an important role in folding, maturation, stabilization and activation of Hsp90 client proteins which all contribute to the development, and proliferation of cancer as well as other inflammatory diseases. Functional inhibition of Hsp90 can have a massive effect on various oncogenic and inflammatory pathways, and will result in the degradation of their client proteins. This turns it into an interesting target in the treatment of different malignancies. 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG) as a semi-synthetic derivative of geldanamycin, has several advantages over 17-Allylamino-17-demethoxygeldanamycin (17-AAG) such as higher water solubility, good bioavailability, reduced metabolism, and greater anti-tumour capability. 17-DMAG binds to the Hsp90, and inhibits its function which eventually results in the degradation of Hsp90 client proteins. Here, we reviewed the pre-clinical data and clinical trial data on 17-DMAG as a single agent, in combination with other agents and loaded on nanomaterials in various cancers and inflammatory diseases.

A Systems Biology Approach Provides Deeper Insights into Differentially Expressed Genes in Taxane-Anthracycline Chemoresistant and Non-Resistant Breast Cancers

Objective: To date, numerous studies have been conducted to search for reasons for chemoresistance and differences in survival rates of patients receiving chemotherapy. We have sought to identify differentially expressed genes (DEGs) between predicted chemotherapy resistance and sensitive phenotypes by a network as well as gene enrichment approach. Methods: Functional modules were explored with network analysis of DEGs in predicted neoadjuvant taxane-anthracycline resistance versus sensitive cases in the GSE25066 dataset, including 508 samples. A linear model was created by limma package in R to establish DEGs. Results: A gene set related to phagocytic vesicle membrane was found to be up-regulated in chemoresistance samples. Also, we found GO_CYTOKINE_ACTIVITY and GO_GROWTH_FACTOR BINDING to be up-regulated gene sets with the chemoresistance phenotype. Growth factors and cytokines are two groups of agents that induce the immune system to recruit APCs and promote tolerogenic phagocytosis. Some hub nodes like S100A8 were found to be important in the chemoresistant tumor cell network with associated high rank genes in GSEA. Conclusions: Functional gene sets and hub nodes could be considered as potential treatment targets. Moreover, by screening and enrichment analysis of a chemoresistance network, ligands and chemical agents have been found that could modify significant gene sets like the phagocytic vesicle membrane functional gene set as a key to chemoresistance. They could also impact on down- or up-regulated hub nodes.