mRNA-HPV vaccine encoding E6 and E7 improves therapeutic potential for HPV-mediated cancers via subcutaneous immunization.

The E6 and E7 proteins of specific subtypes of human papillomavirus (HPV), including HPV 16 and 18, are highly associated with cervical cancer as they modulate cell cycle regulation. The aim of this study was to investigate the potential antitumor effects of a messenger RNA-HPV therapeutic vaccine (mHTV) containing nononcogenic E6 and E7 proteins. To achieve this, C57BL/6j mice were injected with the vaccine via both intramuscular and subcutaneous routes, and the resulting effects were evaluated. mHTV immunization markedly induced robust T cell-mediated immune responses and significantly suppressed tumor growth in both subcutaneous and orthotopic tumor-implanted mouse model, with a significant infiltration of immune cells into tumor tissues. Tumor retransplantation at day 62 postprimary vaccination completely halted progression in all mHTV-treated mice. Furthermore, tumor expansion was significantly reduced upon TC-1 transplantation 160 days after the last immunization. Immunization of rhesus monkeys with mHTV elicited promising immune responses. The immunogenicity of mHTV in nonhuman primates provides strong evidence for clinical application against HPV-related cancers in humans. All data suggest that mHTV can be used as both a therapeutic and prophylactic vaccine.

Potential Therapeutic Targets in Ovarian Cancer: Autophagy and Metabolism.

Ovarian cancer (OC) is characterized by high mortality rates owing to late diagnosis and resistance to chemotherapy. Autophagy and metabolism play essential roles in the pathological process of cancer and have recently been proposed as potential targets for anticancer therapies. Autophagy is responsible for the catabolic clearance of functionally misfolded proteins and plays different roles depending on the stage and type of cancer. Thus, understanding and controlling autophagy is relevant for treating cancer. Autophagy intermediates can communicate with each other by providing substrates for glucose, amino acid, and lipid metabolism. Metabolites and metabolic regulatory genes modulate autophagy and influence the immune response. Therefore, autophagy and the functional manipulation of metabolism during starvation or overnutrition are being investigated as potential therapeutic targets. This review discusses the role of autophagy and metabolism in OC and highlights effective therapeutic strategies targeting these processes.

Epigenetic Regulation in Breast Cancer: Insights on Epidrugs.

Breast cancer remains a common cause of cancer-related death in women. Therefore, further studies are necessary for the comprehension of breast cancer and the revolution of breast cancer treatment. Cancer is a heterogeneous disease that results from epigenetic alterations in normal cells. Aberrant epigenetic regulation is strongly associated with the development of breast cancer. Current therapeutic approaches target epigenetic alterations rather than genetic mutations due to their reversibility. The formation and maintenance of epigenetic changes depend on specific enzymes, including DNA methyltransferases and histone deacetylases, which are promising targets for epigenetic-based therapy. Epidrugs target different epigenetic alterations, including DNA methylation, histone acetylation, and histone methylation, which can restore normal cellular memory in cancerous diseases. Epigenetic-targeted therapy using epidrugs has anti-tumor effects on malignancies, including breast cancer. This review focuses on the importance of epigenetic regulation and the clinical implications of epidrugs in breast cancer.

Breast Cancer Metastasis: Mechanisms and Therapeutic Implications.

Breast cancer is the most common malignancy in women worldwide. Metastasis is the leading cause of high mortality in most cancers. Although predicting the early stage of breast cancer before metastasis can increase the survival rate, breast cancer is often discovered or diagnosed after metastasis has occurred. In general, breast cancer has a poor prognosis because it starts as a local disease and can spread to lymph nodes or distant organs, contributing to a significant impediment in breast cancer treatment. Metastatic breast cancer cells acquire aggressive characteristics from the tumor microenvironment (TME) through several mechanisms including epithelial-mesenchymal transition (EMT) and epigenetic regulation. Therefore, understanding the nature and mechanism of breast cancer metastasis can facilitate the development of targeted therapeutics focused on metastasis. This review discusses the mechanisms leading to metastasis and the current therapies to improve the early diagnosis and prognosis in patients with metastatic breast cancer.

Oral administration of lactobacilli isolated from Jeotgal, a salted fermented seafood, inhibits the development of 2,4-dinitrofluorobenzene-induced atopic dermatitis in mice.

Certain strains of lactobacilli have been reported to exert favorable effects on atopic dermatitis (AD). Jeotgal, a traditional Korean food, is a salted fermented seafood known to harbor many lactic acid bacteria. In the present study, two novel lactobacillus strains were isolated from Jeotgal, and their anti-AD effects were investigated. Lactobacilli isolated from Jeotgal were identified, according to conjugated linoleic acid-producing activity, as Lactobacillus plantarum (JBCC105645 and JBCC105683). AD-like skin lesions were induced in BALB/c mice using dinitrofluorobenzene (DNFB). Ear swelling, histological analysis and serum immunoglobulin E (IgE) levels in mice were evaluated to investigate the anti-AD effects of lactobacilli. Cytokine production of ex vivo cluster of differentiation (CD)4+ T cells, and interleukin (IL)-12 production of in vitro macrophages were also evaluated to establish a putative mechanism of the action of lactobacilli. Administration of JBCC105645 or JBCC105683 suppressed ear swelling and serum IgE levels in DNFB-treated mice (P<0.05). Notably, JBCC105645 was more effective than JBCC105683 (P<0.05). Treatment with the lactobacilli also induced a significant decrease in IL-4 production with concomitant increase in interferon (IFN)-γ production in DNFB-exposed CD4+ T cells, and an increase in IL-12 production in macrophages (P<0.05). Taken together, the lactobacilli isolated from Jeotgal may suppress the development of AD-like skin inflammation in mice by modulating IL-4 and IFN-γ production in CD4+ T cells, presumably via enhancing IL-12 production by macrophages.

Amelioration of hyperglycemia by intestinal overexpression of glucagon-like peptide-1 in mice.

To investigate whether the local production of glucagon-like peptide-1 (GLP-1) in the intestine can differentiate intestinal stem/progenitor cells into insulin-producing cells, we intra-intestinally injected a recombinant adenovirus expressing GLP-1 (rAd-GLP-1) into diabetic mice. There were no significant differences in body weight or food intake between rAd-GLP-1- and rAd-betaGAL-treated control mice. rAd-GLP-1-treated mice showed intestinal insulin mRNA expression, insulin- and glucagon-positive cells in the intestine, and significantly increased serum insulin, but not glucagon. rAd-GLP-1 injection significantly reduced blood glucose levels and improved glucose tolerance compared with controls. Expression of transcription factors related to beta cell differentiation, neurogenin 3 (ngn3) and neurogenin differentiation factor (NeuroD), was detected in the intestine at 2 weeks after rAd-GLP-1 injection. We suggest that expression of GLP-1 in the intestine by intra-intestinal delivery of rAd-GLP-1 may induce differentiation of intestinal stem/progenitor cells into insulin-producing cells, mediated by ngn3 and NeuroD expression, contributing to lowered blood glucose levels in diabetic mice.