Review of lipoic acid: From a clinical therapeutic agent to various emerging biomaterials.

Lipoic acid (LA), an endogenous small molecule in organisms, has been extensively used for the highly efficient clinical treatment of malignant diseases, which include diabetes, Alzheimer's disease, and cancer over the past seven decades. Tremendous progresses have been made on the use of LA in nanomedicine for the development of various biomaterials because of its unique biological properties and highly adaptable structure since the first discovery. However, there are few reviews thus far, to our knowledge, summarizing this hot subject of research of LA and its derived biomaterials. For this purpose, we present herein the first comprehensive summary on the design and development of LA and its derived materials for biomedical applications. This review first discusses the therapeutic use of LA followed by the description of synthesis and preclinical study of LA-derived-small molecules. The applications of various LA and poly (lipoic acid) (PLA)-derived-biomaterials are next summarized in detail with an emphasis on the use of LA for the design of biomaterials and the diverse properties. This review describes the development of LA from a clinical therapeutic agent to a building unit of various biomaterials field, which will promote the further discovery of new therapeutic uses of LA as therapeutic agents and facile development of LA-based derivates with greater performance for biomedical applications.

Author Correction: Targeting Hsp90 with FS-108 circumvents gefitinib resistance in EGFR mutant non-small cell lung cancer cells.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Gastrointestinal toxicity induced by microcystins.

Microcystins (MCs) are produced by certain bloom-forming cyanobacteria that can induce toxicity in various organs, including renal toxicity, reproductive toxicity, cardiotoxicity, and immunosuppressive effects. It has been a significant global environmental issue due to its harm to the aquatic environment and human health. Numerous investigators have demonstrated that MC exposure can induce a widespread epidemic of enterogastritis with symptoms similar to food poisoning in areas close to lakes. Both in vivo and in vitro studies have provided evidence of positive associations between MC exposure and gastrointestinal toxicity. The toxicity of MCs on the gastrointestinal tract is multidimensional. MCs can affect gastrointestinal barrier function and shift the structure of gut microbiota in different gut regions. Furthermore, MCs can inhibit the secretion of gastrointestinal digestive enzymes and the release of inflammatory cytokines, which affects the expression of immune-related genes in the intestine. The damage of the intestine is closely correlated to MC exposure because the intestine is the main site for the digestion and absorption of nutrients. The damage to the gastrointestinal tract due to MCs was summarized from different aspects, which can be used as a foundation for further exploration of molecular damage mechanisms.

14, 15-EET induces breast cancer cell EMT and cisplatin resistance by up-regulating integrin αvß3 and activating FAK/PI3K/AKT signaling.

BACKGROUND: 14,15-epoxyeicosatrienoic acid (14,15-EET) is an important lipid signaling molecule involved in the regulation of tumor metastasis, however, the role and molecular mechanisms of 14,15-EET activity in breast cancer cell epithelial-mesenchymal transition (EMT) and drug resistance remain enigmatic. METHODS: The 14, 15-EET level in serum and in tumor or non-cancerous tissue from breast cancer patients was measured by ELISA. qRT-PCR and western blot analyses were used to examine expression of integrin αvß3. The role of 14, 15-EET in breast cancer cell adhesion, invasion was explored by adhesion and Transwell assays. The role of 14, 15-EET in breast cancer cell cisplatin resistance in vitro was determined by MTT assay. Western blot was conducted to detect the protein expressions of EMT-related markers and FAK/PI3K/AKT signaling. Xenograft models in nude mice were established to explore the roles of 14, 15-EET in breast cancer cells EMT and cisplatin resistance in vivo. RESULTS: In the present study, we show that serum level of 14, 15-EET increases in breast cancer patients and 14, 15-EET level of tumor tissue is higher than that of non-cancerous tissue. Moreover, 14, 15-EET increases integrin αvß3 expression, leading to FAK activation. 14, 15-EET induces breast cancer cell EMT via integrin αvß3 and FAK/PI3K/AKT cascade activation in vitro. Furthermore, we find that 14, 15-EET induces breast cancer cells EMT and cisplatin resistance in vivo, αvß3 integrin and the resulting FAK/PI3K/AKT signaling pathway are responsible for 14, 15-EET induced-breast cancer cells cisplatin resistance. CONCLUSIONS: Our findings suggest that inhibition of 14, 15-EET or inactivation of integrin αvß3/FAK/PI3K/AKT pathway could serve as a novel approach to reverse EMT and cisplatin resistance in breast cancer cells.

Targeting Hsp90 with FS-108 circumvents gefitinib resistance in EGFR mutant non-small cell lung cancer cells.

AIM: Inhibition of heat shock protein (Hsp90) has been proven to be effective in overriding primary and acquired resistance of kinase inhibitors. In this study, we investigated the role of FS-108, a newly developed Hsp90 inhibitor, to overcome gefitinib resistance in EGFR mutant non-small cell lung cancer cells. METHODS: Cell proliferation was assessed using the SRB assay. Cell cycle distribution and apoptosis were analyzed by flow cytometry. Protein expression was examined by Western blotting. The in vivo effectiveness of FS-108 was determined in an NCI-H1975 subcutaneous xenograft model. RESULTS: FS-108 triggered obvious growth inhibition in gefitinib-resistant HCC827/GR6, NCI-H1650 and NCI-H1975 cells through inducing G2/M phase arrest and apoptosis. FS-108 treatment resulted in a remarkable degradation of key client proteins involved in gefitinib resistance and further abrogated their downstream signaling pathways. Interestingly, FS-108 alone exerted an identical or superior effect on circumventing gefitinib resistance compared to combined kinase inhibition. Finally, the ability of FS-108 to overcome gefitinib resistance in vivo was validated in an NCI-H1975 xenograft model. CONCLUSION: FS-108 is a powerful agent that impacts the survival of gefitinib-resistant cells in vitro and in vivo through targeting Hsp90.

Identification of differentially expressed microRNAs between Bacillus thuringiensis Cry1Ab-resistant and -susceptible strains of Ostrinia furnacalis.

The Asian corn borer (ACB), Ostrinia furnacalis (Guenée), can develop strong resistance to Cry1Ab, the most widely commercialized Cry toxin for Bt maize worldwide. It is essential to understand the mechanism of resistance for management of this species, but information on the post-transcriptional regulation of Bt resistance in this target insect is limited. In the present study, RNA was extracted from the ACB in various larval stages (1-5 instar) from Cry1Ab-sensitive (ACB-BtS) and -resistant (ACB-AbR) strains, each of which included two biological replicates. Using Illumina sequencing, a total of 23,809,890 high-quality reads were collected from the four ACB libraries. The numbers of known microRNAs (miRNAs) were 302 and 395 for ACB-BtS and 268 and 287 for ACB-AbR. Using Mireap software, we identified 32 and 16 potential novel miRNAs for ACB-BtS and 18 and 22 for ACB-AbR. Among them, 21 known and 1 novel miRNAs had significantly different expression between ACB-BtS and ACB-AbR. Several miRNAs were observed to target potential Bt receptor genes, such as aminopeptidase N and cadherin-like protein. The glycosylphosphatidylinositol-anchor biosynthetic process and ABC transporters pathway were identified through Gene Ontology and KEGG pathway analysis of target genes of the differentially expressed miRNAs.

Transcriptome differences between Cry1Ab resistant and susceptible strains of Asian corn borer.

BACKGROUND: Asian corn borer (ACB), Ostrinia furnacalis (Guenée), is the major insect pest of maize in China and countries of East and Southeast Asia, the Pacific and Australasia. ACB can develop strong resistance to the transgenic Bt maize expressing Cry1Ab, the most widely commercialized Bt maize worldwide. However, the molecular basis for the resistance mechanisms of ACB to Cry1Ab remained unclear. Two biological replicates of the transcriptome of Bt susceptible (ACB-BtS) and Cry1Ab resistant (ACB-AbR) strains of ACB were sequenced using Solexa/Illumina RNA-Seq technology to identify Cry1Ab resistance-relevant genes. RESULTS: The numbers of unigenes for two biological replications were 63,032 and 53,710 for ACB-BtS and 57,770 and 54,468 for ACB-AbR. There were 35,723 annotated unigenes from ACB reads found by BLAST searching NCBI non-redundant, NCBI non-redundant nucleotide, Swiss-prot protein, Kyoto Encyclopedia of Genes and Genomes, Cluster of Orthologous Groups of proteins, and Gene Ontology databases. Based on the NOISeq method, 3,793 unigenes were judged to be differentially expressed between ACB-BtS and ACB-AbR. Cry1Ab resistance appeared to be associated with change in the transcription level of enzymes involved in growth regulation, detoxification and metabolic/catabolic process. Among previously described Bt toxin receptors, the differentially expressed unigenes associated with aminopeptidase N and chymotrypsin/trypsin were up-regulated in ACB-AbR. Whereas, other putative Cry receptors, cadherin-like protein, alkaline phosphatase, glycolipid, actin, V-type proton ATPase vatalytic, heat shock protein, were under-transcripted. Finally, GPI-anchor biosynthesis was found to be involved in the significantly enriched pathway, and all genes mapped to the pathway were substantially down-regulated in ACB-AbR. CONCLUSION: To our knowledge, this is the first comparative transcriptome study to discover candidate genes involved in ACB Bt resistance. This study identified differentially expressed unigenes related to general Bt resistance in ACB. The assembled, annotated transcriptomes provides a valuable genomic resource for further understanding of the molecular basis of ACB Bt resistance mechanisms.

Paeonol inhibits oxidized low density lipoprotein-induced monocyte adhesion to vascular endothelial cells by inhibiting the mitogen activated protein kinase pathway.

Atherosclerosis is a chronic inflammatory disease characterized by increased expression of adhesion molecules, which contribute to monocytes adhesion to vascular endothelial cells (VECs). Paeonol, an active compound isolated from cortex Moutan, has been shown to have therapeutic effects on atherosclerotic animals. The present study aims to investigate whether paeonol can inhibit monocyte adhesion to vascular endothelial cells induced by oxidized Low-Density Lipoprotein (ox-LDL) and its possible therapeutic molecular mechanism. Exposure to ox-LDL (50, 100 µg/mL) induced damaged to VECs leading to decreased survival rates (p<0.01). Paeonol (7.2-18.0 µM) partially restored survival and reduced lactate dehydrogenase (LDH) release in VECs in a concentration-dependent manner (p<0.01). Adhesion of monocytes to VECs was dramatically prevented by paeonol at 21.6 and 25.2 µM (p<0.01). In addition, paeonol (14.4-21.6 µM) repressed the expression of vascular cell adhesion molecule-1 (VCAM-1) and lowered the levels of phosphor-c-Jun N-terminal kinase (P-JNK)1/2, phosphor-extracellular signal-regulated kinase (P-ERK)1/2 and P-p38 in a dose-dependent manner. The molecular effects of paeonol were more pronouced when companied with mitogen activated protein kinases (MAPKs) inhibitors. These data suggest that paeonol (10.8-25.2 µM), at certain concentrations, prevents monocyte adhesion to VEC induced by ox-LDL, probably by means of blocking one or more target proteins on MAPKs signaling pathway. These results indicate that paeonol has potential protective effects on the development of atherosclerosis.