It is extensively verified that continued oxidative stress and oxidative damage may lead to chronic inflammation, which in turn can mediate most chronic diseases including cancer, diabetes, cardiovascular, neurological, inflammatory bowel disease and pulmonary diseases. Curcumin, a yellow coloring agent extracted from turmeric, shows strong anti-oxidative and anti-inflammatory activities when used as a remedy for the prevention and treatment of chronic diseases. How oxidative stress activates inflammatory pathways leading to the progression of chronic diseases is the focus of this review. Thus, research to date suggests that chronic inflammation, oxidative stress, and most chronic diseases are closely linked, and the antioxidant properties of curcumin can play a key role in the prevention and treatment of chronic inflammation diseases.

https://www.mdpi.com/1420-3049/20/5/9183/pdf

Curcumin, inflammation, and chronic diseases: how are they linked?

Spices have been widely used as food flavorings and folk medicines for thousands of years. Numerous studies have documented the antioxidant, anti-inflammatory and immunomodulatory effects of spices, which might be related to prevention and treatment of several cancers, including lung, liver, breast, stomach, colorectum, cervix, and prostate cancers. Several spices are potential sources for prevention and treatment of cancers, such as Curcuma longa (tumeric), Nigella sativa (black cumin), Zingiber officinale (ginger), Allium sativum (garlic), Crocus sativus (saffron), Piper nigrum (black pepper) and Capsicum annum (chili pepper), which contained several important bioactive compounds, such as curcumin, thymoquinone, piperine and capsaicin. The main mechanisms of action include inducing apoptosis, inhibiting proliferation, migration and invasion of tumors, and sensitizing tumors to radiotherapy and chemotherapy. This review summarized recent studies on some spices for prevention and treatment of cancers, and special attention was paid to bioactive components and mechanisms of action.

https://www.mdpi.com/2072-6643/8/8/495/pdf

Spices for Prevention and Treatment of Cancers.

The efficacy of current standard chemotherapy is suboptimal due to the poor solubility and short half-lives of chemotherapeutic agents, as well as their high toxicity and lack of specificity which may result in severe side effects, noncompliance and patient inconvenience. The application of nanotechnology has revolutionized the pharmaceutical industry and attracted increasing attention as a significant means for optimizing the delivery of chemotherapeutic agents and enhancing their efficiency and safety profiles. Nanostructured lipid carriers (NLCs) are lipid-based formulations that have been broadly studied as drug delivery systems. They have a solid matrix at room temperature and are considered superior to many other traditional lipid-based nanocarriers such as nanoemulsions, liposomes and solid lipid nanoparticles (SLNs) due to their enhanced physical stability, improved drug loading capacity, and biocompatibility. This review focuses on the latest advances in the use of NLCs as drug delivery systems and their preparation and characterization techniques with special emphasis on their applications as delivery systems for chemotherapeutic agents and different strategies for their use in tumor targeting.

Nanostructured Lipid Carriers for Delivery of Chemotherapeutics: A Review.

Curcumin use in pulmonary diseases: State of the art and future perspectives

MicroRNA (miRNA or miR) therapeutics in cancer are based on targeting or mimicking miRNAs involved in cancer onset, progression, angiogenesis, epithelial-mesenchymal transition and metastasis. Several studies conclusively have demonstrated that miRNAs are deeply involved in tumor onset and progression, either behaving as tumor-promoting miRNAs (oncomiRNAs and metastamiRNAs) or as tumor suppressor miRNAs. This review focuses on the most promising examples potentially leading to the development of anticancer, miRNA-based therapeutic protocols. The inhibition of miRNA activity can be readily achieved by the use of miRNA inhibitors and oligomers, including RNA, DNA and DNA analogues (miRNA antisense therapy), small molecule inhibitors, miRNA sponges or through miRNA masking. On the contrary, the enhancement of miRNA function (miRNA replacement therapy) can be achieved by the use of modified miRNA mimetics, such as plasmid or lentiviral vectors carrying miRNA sequences. Combination strategies have been recently developed based on the observation that i) the combined administration of different antagomiR molecules induces greater antitumor effects and ii) some anti-miR molecules can sensitize drug-resistant tumor cell lines to therapeutic drugs. In this review, we discuss two additional issues: i) the combination of miRNA replacement therapy with drug administration and ii) the combination of antagomiR and miRNA replacement therapy. One of the solid results emerging from different independent studies is that miRNA replacement therapy can enhance the antitumor effects of the antitumor drugs. The second important conclusion of the reviewed studies is that the combination of anti-miRNA and miRNA replacement strategies may lead to excellent results, in terms of antitumor effects.

/pdf/targeting-oncomirnas-and-mimicking-tumor-suppressor-mirnas-4rf73iud3x.pdf

Targeting oncomiRNAs and mimicking tumor suppressor miRNAs: Νew trends in the development of miRNA therapeutic strategies in oncology (Review).

Cdc42, a Rho GTPase family member, is involved in cell transformation, proliferation, survival, invasion and metastasis of human cancer cells. Overexpression of Cdc42 has been reported in several types of human cancer. However, the underlying mechanisms are not well understood. The present study showed that Cdc42 was overexpressed in 80 of 110 primary lung cancer patients, and overexpression of Cdc42 was significantly associated with high TNM stage and lymph node metastasis. Moreover, RNAi-mediated suppression of Cdc42 expression reduced actin ﬁlopodia formation, migration and invasion potential of a highly metastatic lung cancer cell line, 801D. In parallel, 801D cells were treated with curcumin and the effect on the expression of the Cdc42 gene at the transcriptional and translational levels was analyzed by RT-PCR and Western blotting. Curcumin inhibited cell migration, invasion and downregulated Cdc42 gene and Cdc42-related target gene expression in 801D cells. It also induced rearrangements of the actin cytoskeleton. These effects mimicked those of Cdc42 knockdown. Furthermore, xenograft experiments confirmed the suppression of tumor growth and invasion in vivo, which was due to the effect of curcumin and the inhibition of Cdc42 by curcumin. Our results showing the downregulation of Cdc42 expression by curcumin in lung cancer cells taken together with the clinical data suggest a potential therapeutic role for curcumin in inducing Cdc42-mediated inhibition of invasion of lung cancer cells.

/pdf/expression-analysis-of-cdc42-in-lung-cancer-and-modulation-32wf3m2hu4.pdf

Expression analysis of Cdc42 in lung cancer and modulation of its expression by curcumin in lung cancer cell lines.

Background
Curcumin (diferuloylmethane) has chemopreventive and therapeutic properties against many types of tumors, both in vitro and in vivo. Previous reports have shown that curcumin exhibits anti-invasive activities, but the mechanisms remain largely unclear.

Methods
In this study, both microRNA (miRNA) and messenger RNA (mRNA) expression profiles were used to characterize the anti-metastasis mechanisms of curcumin in human non-small cell lung cancer A549 cell line.

Results
Microarray analysis revealed that 36 miRNAs were differentially expressed between the curcumin-treated and control groups. miR-330-5p exhibited maximum upregulation, while miR-25-5p exhibited maximum downregulation in the curcumin treatment group. mRNA expression profiles and functional analysis indicated that 226 differentially expressed mRNAs belonged to different functional categories. Significant pathway analysis showed that mitogen-activated protein kinase, transforming growth factor-β, and Wnt signaling pathways were significantly downregulated. At the same time, axon guidance, glioma, and ErbB tyrosine kinase receptor signaling pathways were significantly upregulated. We constructed a miRNA gene network that contributed to the curcumin inhibition of metastasis in lung cancer cells. let-7a-3p, miR-1262, miR-499a-5p, miR-1276, miR-331-5p, and miR-330-5p were identified as key microRNA regulators in the network. Finally, using miR-330-5p as an example, we confirmed the role of miR-330-5p in mediating the anti-migration effect of curcumin, suggesting the importance of miRNAs in the regulation of curcumin biological activity.

Conclusion
Our findings provide new insights into the anti-metastasis mechanism of curcumin in lung cancer.

https://www.onlinelibrary.wiley.com/doi/pdf/10.1111/1759-7714.12467

Integrated microRNA and gene expression profiling reveals the crucial miRNAs in curcumin anti-lung cancer cell invasion.

MiRNAs associated with the metastasis of lung cancer remain largely unexplored. In this study, gene and miRNA expression profiling were performed to analyze the global expression of mRNAs and miRNAs in human high- and low-metastatic lung cancer cell strains. By developing an integrated bioinformatics analysis, six miRNAs (miR-424-3p, miR-450b-5p, miR-335-5p, miR-34a-5p, miR-302b-3p and miR-206) showed higher target gene degrees in the miRNA–gene network and might be potential metastasis-related miRNAs. Using the qRT-PCR method, the six miRNAs were further confirmed to show a significant expression difference between human lung cancer and normal tissue samples. Since miR-206 showed lower expression both in lung cancer tissues and cell lines, it was used as an example for further functional verification. The wound healing assay and transwell invasion assay showed that miR-206 mimics significantly inhibited the cell migration and invasion of the high-metastatic lung cancer 95D cell strain. One of its predicted targets in our miRNA–gene network, MET, was also obviously decreased at the protein level when miR-206 was overexpressed. Instead, miR-206 inhibitors increased MET protein expression, cell migration and invasion of the low-metastatic lung cancer 95C cell strain. Meanwhile, the luciferase assay showed that MET was a direct target of miR-206. Furthermore, MET gene silence showed a similar anti-migration and anti-invasion effect with miR-206 mimics in 95D cells and could partially attenuate the migration- and invasion-promoting effect of miR-206 inhibitors in 95C cells, suggesting that miR-206 targets MET in lung cancer metastasis. Finally, we also demonstrated that miR-206 can significantly inhibit lung cancer proliferation and metastasis in mouse models. In conclusion, our study provided a miRNA–gene regulatory network in lung cancer metastasis and further demonstrated the roles of miR-206 and MET in this process, which enhances the understanding of the regulatory mechanism in lung cancer metastasis.

Comprehensive gene and microRNA expression profiling reveals miR-206 inhibits MET in lung cancer metastasis.

LIM kinase 1 (LIMK1) is a member of a novel class of serine-threonine protein kinases, which plays an important role in malignant transformation. High expression of LIM kinase 1 (LIMK1) has been detected in various invasive cancers. Here, we showed that LIMK1 was overexpressed in non-small cell lung cancer tissues (NSCLC) and cell lines. Expression of LIMK1 was detected in 115 of 150 lung cancer tissues, the frequency being more significant than in lung tissues. In addition, overexpression of LIMK1 was also associated with high TNM stage and lymph node metastasis in NSCLC patients. Moreover, RNAi-mediated suppression of LIMK1 expression markedly inhibited migration and invasion of 801D lung cancer cells. Furthermore, silencing of LIMK1 sensitized 801D cells to chemotherapeutic drugs of cisplatin and gemcitabine. These results indicate that the overexpression of LIMK1 is tightly associated with an aggressive phenotype of lung cancer cells, knockdown of LIMK1 suppressed cell migration and invasion, enhanced chemosensitivity, suggesting a potential therapeutic target for lung cancer.

Downregulation of LIMK1 level inhibits migration of lung cancer cells and enhances sensitivity to chemotherapy drugs.

A microarray analysis of differential genes by curcumin treatment was performed and the crucial pathways associated with non-small cell lung cancer (NSCLC) were investigated. Total RNAs from 0, 10 or 20 μM curcumin treated NSCLC 95D cells were used to prepare microarray chips. The differentially expressed genes (DEGs) were identified using the RankProducts package and their function was predicted by DAVID and gene set enrichment analysis. The pathway crosstalk was analyzed by mapping the gene expression profiles into protein–protein interaction databases. Validation of the microarray results was performed by cell viability, cell migration and western blot analyses. A total of 486 (10 μM) and 264 (20 μM) DEGs were screened between the 95D cells in the presence and absence of curcumin. Function enrichment analysis indicated the DEGs were mainly involved in the steroid biosynthetic process and regulation of autophagy. Pathway crosstalk analysis suggested there was a significant interaction between NSCLC and adherens junctions (or Wnt signaling pathways, which are important for cancer cell proliferation and invasion) in both 10 μM and 20 μM curcumin treated 95D cells. Furthermore, early growth response (EGR-1) was demonstrated to regulate the crosstalk between adherens junctions and Wnt signaling pathways, indicating that EGR-1 may also regulate cell proliferation and migration. This hypothesis was validated by in vitro experiments: EGR-1 was decreased after curcumin treatment. Curcumin exhibited a significant anti-proliferation and anti-migration activity in NSCLC 95D cells, possibly by steering the crosstalk between the Wnt signaling pathway and adherens junction via EGR-1.

De-min Jiao

Papers

Expression analysis of Cdc42 in lung cancer and modulation of its expression by curcumin in lung cancer cell lines.

Integrated microRNA and gene expression profiling reveals the crucial miRNAs in curcumin anti-lung cancer cell invasion.

Comprehensive gene and microRNA expression profiling reveals miR-206 inhibits MET in lung cancer metastasis.

Downregulation of LIMK1 level inhibits migration of lung cancer cells and enhances sensitivity to chemotherapy drugs.

Curcumin inhibits proliferation–migration of NSCLC by steering crosstalk between a Wnt signaling pathway and an adherens junction via EGR-1