Nature's Elixir for Cancer Treatment: Targeting Tumor-induced Neovascularization.

Angiogenesis, a multistep process, involves sprouting of new vessels from the pre-existing vessels in response to a stimulus in its microenvironment. Normally, angiogenesis is important for tissue maintenance and homeostasis, however it is also known to be associated with various pathologies, including cancer. Importantly, neovascularization is very crucial for tumors to grow and metastasize since it allows delivery of oxygen and nutrients as well as promotes tumor cell dissemination to distant sites. Activation of angiogenic switch is a consequence of imbalance in pro- as well as anti-angiogenic factors, that are immensely impacted by reactive oxygen species and epigenetic regulation. Several reports have suggested that angiogenic inhibitors significantly inhibit tumor growth. Therefore, anti-angiogenic therapy has gained substantial attention and has been considered a rational approach in cancer therapeutics. In this line, several anti- angiogenic drugs have been approved, however, their long term usage caused several side effects. In view of this, researchers switched to plant-based natural compounds for identifying safe and cost-effective anti-angiogenic drugs. Of note, various phytochemicals have been evaluated to reduce tumor growth by inhibiting tumor-induced angiogenesis. Moreover, the implication of nano-carriers to enhance the bioavailability of phytochemicals has proven to be more efficient anti-cancer agents. The present review highlights the existing knowledge on tumor-induced neovascularization and its regulation at the epigenetic level. Further, we emphasize the inhibitory effect of phytochemicals on tumor- induced angiogenesis that will open up new avenues in cancer therapeutics.

Melatonin modulates L-arginine metabolism in tumor-associated macrophages by targeting arginase 1 in lymphoma.

L-Arginine metabolism plays a crucial role in determining the M1/M2 polarization of macrophages. The M1 macrophages express inducible nitric oxide synthase (iNOS), while the M2 macrophages express arginase 1 and metabolize arginine into nitric oxide and urea, respectively. The tumor microenvironment promotes M2 macrophage polarization and consequently switches the metabolic fate of arginine from nitric oxide towards urea production. Importantly, infiltration of M2 macrophages or tumor-associated macrophages (TAMs) has been correlated with poor prognosis of various cancer types. Melatonin is well reported to have antitumor and immunomodulatory properties. However, whether and how it impacts the polarization of TAMs has not been elucidated. Considering the crucial role of arginine metabolism in macrophage polarization, we were interested to know the fate of L-arginine in TAMs and whether it can be reinstated by melatonin or not. We used a murine model of Dalton's lymphoma and established an in vitro model of TAMs. For TAMs, we used the ascitic fluid of tumor-bearing hosts to activate the macrophages in the presence and absence of lipopolysaccharide (LPS). In these groups, L-arginine metabolism was evaluated, and then the effect of melatonin was assessed in these groups, wherein the metabolic fate of arginine as well as the expression of iNOS and arginase 1 were checked. Furthermore, in the in vivo system of the tumor-bearing host, the effect of melatonin was assessed. The in vitro model of TAMs showed a Th2 cytokine profile, reduced phagocytic activity, and increased wound healing ability. Upon investigating arginine metabolism, we observed high urea levels with increased activity and expression of arginase 1 in TAMs. Furthermore, we observed reduced levels of LPS-induced nitric oxide in TAMs; however, their iNOS expression was comparable. With melatonin treatment, urea level decreased significantly, while the reduction in nitric oxide level was not as significant as observed in its absence in TAMs. Also, melatonin significantly reduced arginase activity and expression at the transcriptional and translational levels, while iNOS expression was affected only at the translational level. This effect was further investigated in the in vivo system, wherein melatonin treatment reversed the metabolic fate of arginine, from urea towards nitric oxide, within the tumor microenvironment. This effect was further correlated with pro-apoptotic tumor cell death in the in vivo system. Our results reinforced the immunomodulatory role of melatonin and offered a strong prospect for activating the anti-tumor immune response in cancer conditions.

The spatial frequency domain designated watermarking framework uses linear blind source separation for intelligent visual signal processing.

This paper develops a digital watermarking algorithm using an informed watermark retrieval architecture. The developed method uses the fractional Fourier transform to embed the watermark in the space-frequency domain and extracts the watermark using blind source separation techniques. The watermark embedding is further enhanced using a heuristic algorithm to increase the strength of the watermarking system. We use genetic algorithm to find the optimal fractional domain by minimizing the coefficient of RMSE between the input image and the watermarked image. The algorithm's performance against various common attacks, e.g., JPEG compression and Gaussian noise, is presented to estimate the algorithm's robustness.

Amelioration of Dalton's lymphoma-induced angiogenesis by melatonin.

For tumor to grow beyond 1-2 mm3 size, tumor recruits new blood vessels referred as angiogenesis; therefore, targeting angiogenesis can be a promising strategy to suppress cancer progression. In this study, in order to develop a good angiogenesis model, we investigated effect of Dalton's lymphoma on angiogenesis and further monitored the role of melatonin on regulation of angiogenesis. To evaluate angiogenesis, endothelial cells were isolated from main thoracic aorta and cultured in vitro in the presence or absence of Dalton's lymphoma supplemented with or without melatonin to monitor their role on its proliferation and migration, a hallmark of angiogenesis. Chick chorioallantoic membrane as well as mice mesentery which allows in vivo studies of tumor angiogenesis and testing of anti-angiogenic molecules was used to validate the in vitro analysis. To further extend our understanding about the regulation of the angiogenesis, we evaluated expression of tissue inhibitor of metalloproteinases 3, vascular endothelial growth factor, vascular endothelial growth factor receptor, and fibroblast growth factor in Dalton's lymphoma cells and mesentery by semiquantitative and quantitative reverse transcription polymerase chain reaction analysis. Dalton's lymphoma ascites induced significant increase in endothelial cell proliferation, migration, and sprouting of the tertiary branching in chorioallantoic membrane and mesentery of Dalton's lymphoma-bearing mice, whereas melatonin treatment led to their inhibition in a dose-dependent manner. Semiquantitative and quantitative reverse transcription polymerase chain reaction analysis of melatonin-treated Dalton's lymphoma cells and mesentery tissue clearly demonstrated restoration of angiogenesis-related genes tissue inhibitor of metalloproteinases 3 and reduction of vascular endothelial growth factor, vascular endothelial growth factor receptor, and fibroblast growth factor messenger RNA expression. Taken together, our results strongly demonstrate that Dalton's lymphoma provides pro-angiogenic environment leading to significant increase in angiogenesis, and further melatonin treatment reduced the Dalton's lymphoma ascites-induced angiogenesis implying that Dalton's lymphoma can serve as a very good model to study angiogenesis as well as for screening of drugs that can target angiogenesis.

Diabetic retinopathy in type II diabetics detected by targeted screening versus newly diagnosed in general practice.

INTRODUCTION: The aim of this study was to compare the occurrence of diabetic retinopathy in targeted screening diabetic patients (Group I) with newly diagnosed diabetic patients in general practice (Group II). MATERIALS AND METHODS: This was an observational cross-sectional study. Data were obtained from 25,313 subjects who participated in the diabetic screening camps, and 128 newly diagnosed diabetes who presented to the diabetic retinopathy screening camps in general practice in rural and urban south India. The study variables were collected from all patients who underwent eye examination from the target screening detected diabetics [(n = 173) Group I] and those newly diagnosed in general practice [(n = 128) Group II]. The variations in prevalence of diabetic retinopathy and sight-threatening diabetic retinopathy in Group I and Group II and the factors affecting it were identified. RESULTS: The occurrence of diabetic retinopathy was 6.35% (95% CI, 2.5-9.5) in Group I and 11.71% (95% CI, 5.6-16.4) in Group II. No significant difference was observed on occurrence of diabetic retinopathy, including sightthreatening retinopathy, in rural versus urban population and in Group I versus Group II. Patients diagnosed in general practice (Group II) with systolic blood pressure (BP) >140 were more likely to have retinopathy (P = 0.02). CONCLUSIONS: Diabetic retinopathy including sightthreatening complications was found at the time of diagnosis of diabetes in the targeted screening group as well as in newly diagnosed diabetics in the general practice group.