Current Molecular Medicine - Volume 17, Issue 5, 2017

Over a few decades a strong interlink between oxidative damage and cancer has been investigated by various scientists across the world on the basis of epidemiological observations of the effects of fruits and vegetables used in the diet for cancer patients. Primarily, Vitamin C, Vitamin D and Vitamin E are reported to be involved in the amelioration of side effects which occur in chemotherapy and radiation therapy of lungs, stomach, prostate, colorectal, gastric head and neck cancers. The vitamins acting as antioxidant adjuvants are found to have apoptotic and antiangiogenesis potential as well as inhibitory effects against metastasis in cancer cells. This chapter explicitly discusses the key aspects concerned with the vitamins in relation to cancer prevention and treatment. It describes vitamins and their natural resources, role of vitamins in the body, and vitamins as prime ingredients in the diet and their effects on cancer biology with reference to recent research reports. Moreover, this paper also includes the emerging potential of pharmaceutical advances to enhance bioavailability of the vitamins to cancer patients with improved safety and efficacy. Clinicians and researchers must mull over the nutritional requirements of individual cancer patient so as to treat cancer and increase life expectancy.

Carcinoma-associated fibroblasts (CAFs) are activated fibroblasts during development of several cancer types, and therefore emerge as an attractive therapeutic target for cancer therapy. Drugs such as PT-100 and sibrotuzumab that block the functions of CAFs have already been in clinical trials. However, these drugs exhibit limited efficacy in patients, partially due to the fact that currently used biomarkers for determining efficacy are not CAF-specific. Furthermore, depletion of CAFs may promote carcinogenesis and accelerate cancer progression by inducing immunosuppression and hypoxia, leading to reduced survival. Accumulating evidence demonstrates that restoring the expression of key microRNA induces the functional conversion of CAFs into normal fibroblasts by targeting different signaling pathways and metabolic mechanisms. Therefore, reprograming CAFs into normal fibroblasts by altering specific expression of microRNAs, rather than targeted ablation, may be an effective, novel strategy for cancer treatment. This review focuses on specific microRNAs involved in the transformation of CAFs as well as their multiple roles during tumorigenesis and chemo-resistance.

Background and Objective: Aging can result in a progressive decline in cellular protection and physiological function. The physiological status and microbiota of the intestine are intensively linked to the aging process. Numerous studies have suggested that Sargassum fusiforme polysaccharides possess antioxidant and antiaging activities. However, it remains unclear as to whether S. fusiforme polysaccharides can prevent the insult of oxidant and aging through modulating the physiological status and microbiota of the intestine. Methods: To assess the cytoprotective effect of S. fusiforme polysaccharides (SFPS) in the small intestine of mice embarking on the aging process, we compared the expressions of Nrf2 and several representative markers (SOD-2, CAT, NQO1 and HO-1) of the Nrf2/ARE signaling pathway in the small intestine of male ICR mice fed with a control diet with those of mice fed with a SFPS-containing diet. In addition, the overall compositional changes in the small intestine microbiota were determined by 16s rDNA sequencing followed by alpha and beta diversity analyses. Results: The results showed that dietary intake of SFPS could ameliorate the declined cytoprotective capacity of the small intestine by upregulating the Nrf2/ARE signaling pathway. Moreover, SFPS could partially rejuvenate the overall status of the small intestine microbiota. Conclusion: The results suggested that dietary SFPS may promote the health condition of the small intestine, consequently leading to a healthy aging.

Background: Age-related macular degeneration (AMD) is the main cause of irreversible blindness in the elderly. Oxidative stress in retinal pigment epithelium (RPE) is deemed to play a pivotal role in the pathogenesis of AMD. miR-25 functions as an essential modulator in response to oxidative-stress in several cell types, but its function in RPE cells is poorly understood. Objective: To explore the roles of miR-25 in RPE cells and in the development of AMD. Methods: A rat model of retinal degeneration was induced by sodium iodate (SI). Subretinal injection of antagomiR-25 was performed for the intervention while the scramble as control. Visual responses were recorded with Electroretinogram (ERG). TUNEL assay was performed to detect apoptosis. Phagosome quantification in vivo was performed to evaluate RPE cell function. Oxygen-glucose deprivation treatment was performed to mimic in vitro oxidative stress. Gene expression at mRNA level and protein level were performed by quantitative polymerase chain reaction (qPCR) and Western Blot, respectively. The pigment epithelium derived factor (PEDF) level in the cultured medium was measured by Enzyme-linked immunosorbent assay (ELISA). The interaction between miR-25 and integrin αV (IGTAV) / PEDF 3’UTR was examined by dual luciferase assay. Chromatin immunoprecipitation (ChIP) assay was performed to examine its transcriptional regulation of miR-25. Results: Oxidative stress up-regulated miR-25 in RPE cells in very early stage, accompanied by decreased phagocytosis and reduced growth factor secretion in those cells. Such changes preceded RPE cell apoptosis and visual impairment in the SItreated rats. Furthermore, antagomiR-25 intervention effectively rescued RPE cells from degeneration in such model. The increased miR-25 was confirmed to mediate RPE degeneration through direct targeting IGTAV and PEDF. On the other hand, upstream, miR-25 was found to be up-regulated by STAT3 signaling under oxidative stress in both in vivo and in vitro models. Conclusion: Our findings demonstrate that, in SI-treated rats, oxidative stress activates STAT3 signaling which up-regulates miR-25 expression, in a very early stage. The increased miR-25 then inhibits ITGAV and PEDF expressions, resulting in RPE phagocytosis dysfunction and then RPE apoptosis and visual impairment as observed in patients with AMD. These findings lead us to a better understanding of AMD pathogenesis, and suggest that miR-25 could be a potential therapeutic target for oxidative stress related RPE diseases, like AMD.

Background: Rheumatoid arthritis (RA) is a complicated and heterogeneous chronic disease with the characteristic of progressive joint destruction, deformity and disability. It is associated with not only genetic but also environmental factors. Many studies suggest that RA-derived fibroblast-like synoviocyte (RA-FLS) is involved in the pathogenic process of RA. The apoptosis and proliferation of RA-FLS is of great importance in the development and progression in RA. Nowadays, more and more traditional Chinese medicine (TCM) or natural products are studied in the treatment of RA. Objective: To investigate the effects of several natural products and the apoptosisinduced effect of α-mangostin and its underlying mechanisms in RA-FLS MH7A cells. Methods: The effects of natural products on MH7A cells were detected by MTT assay. Annexin V-FITC/PI double labeling and DAPI staining were adopted to observe the apoptosis induced by α-mangostin. The apoptosis related proteins were measured with western blotting analysis. ROS accumulation was determined by DHE staining. Results: Xantones, including Garcinone C, α-mangostin and γ-mangostin, significantly inhibited the MH7A cell viability. And α-mangostin induces apoptosis in MH7A cells. Further study showed that α-mangostin increased the ratio of Bax/Bcl-2 and increased the ROS generation in MH7A cells. Conclusion: α-Mangostin induces the apoptosis of MH7A cells through increasing ROS accumulation and the ratio of Bax/Bcl-2, suggesting that α-mangostin should be benefit to the therapy of RA.

Rationale: Studies have implied the positive association of JAK2/STAT3 signaling with the onset and severity of acute pancreatitis (AP). However, definitive functional study of JAK2/STAT3 signaling in the pathogenesis of acute pancreatitis in vivo is missing and its potential as a therapeutic target and the underlying mechanisms remain to be determined. Objectives: The aim of this study was to explore the role of JAK2/STAT3 signaling in the pathogenesis of hyperlipidemia-intensified caerulin-induced AP and its potential as a therapeutic target. Methods and Results: Using the caerulin-induced acute pancreatitis rat model, we showed that JAK2/STAT3 signaling was activated in pancreas and systemic inflammation was increased during AP. Pharmacological suppression of JAK2 by its inhibitor AG490 robustly protected against tissue damage, attenuated JAK2/STAT3 signaling and inflammatory responses. Local pancreatic tissue damage and phosphor- JAK2 in the pancreatic tissue were enhanced in animals fed with high fat diet compared to chow-diet fed animals. Interestingly, JAK2 inhibitor AG490 significantly inhibited pancreas necrosis and systemic inflammation in animals fed with high fat or chow-diet, but did not affect STAT3 signaling. Conclusion: These results establish that JAK2 activation plays a significant role in the pathogenesis of caerulin-induced AP in animals on both chow and high-fat diets by regulating necrosis and systemic inflammation. Thus, our results not only clarify novel signaling mechanisms in AP but also suggest that JAK2 might constitute a target in the management of hyperlipidemia-intensified caerulin-induced AP.