Noscapine modulates hypoxia-induced angiogenesis and hemodynamics: Insights from a zebrafish model investigation.

We investigated the angiogenesis-modulating ability of noscapine in vitro using osteosarcoma cell line (MG-63) and in vivo using a zebrafish model. MTT assay and the scratch wound healing assay were performed on the osteosarcoma cell line (MG-63) to analyze the cytotoxic effect and antimigrative ability of noscapine, respectively. We also observed the antiangiogenic ability of noscapine on zebrafish embryos by analyzing the blood vessels namely the dorsal aorta, and intersegmental vessels development at 24, 48, and 72 h postfertilization. Real-time polymerase chain reaction was used to analyze the hypoxia signaling molecules' gene expression in MG-63 cells and zebrafish embryos. The findings from the scratch wound healing demonstrated that noscapine stopped MG-63 cancer cells from migrating under both hypoxia and normoxia. Blood vessel development and the heart rate in zebrafish embryos were significantly reduced by noscapine under both hypoxia and normoxia which showed the hemodynamics impact of noscapine. Noscapine also downregulated the cobalt chloride (CoCl2) induced hypoxic signaling molecules' gene expression in MG-63 cells and zebrafish embryos. Therefore, noscapine may prevent MG-63 cancer cells from proliferating and migrating, as well as decrease the formation of new vessels and the production of growth factors linked to angiogenesis in vivo under both normoxic and hypoxic conditions.

Role of berberine on angiogenesis and blood flow hemodynamics using zebrafish model.

Angiogenesis and hemodynamic instability created by the irregular blood vessels causes hypoperfusion and angiogenesis-mediated diseases. Therefore, therapies focusing on controlling angiogenesis will be a valuable approach to treat a broad spectrum of diseases. In this study, we explored the anti-angiogenic potential of berberine (BBR) and also analyzed blood flow hemodynamics using zebrafish embryos. Zebrafish embryos treated with BBR (0.01-0.75 mM) at various doses at 1 hour post-fertilization (hpf) developed a variety of phenotypic variations including aberrant blood vessels, tail bending, edema, and hemorrhage. Survival rates were much lower at higher dosages, and hatching rates were almost 99%, whereas control group appeared normal. Heart rate is an essential measure that has a strong association with hemodynamics. We used ImageJ software to study the heart rate of embryos treated with BBR, preceded by video processing. The resultant graph shows a significant decrease in heart rate of embryos treated with BBR in dose-dependent manner. Also, RBC staining using o-Dianisidine confirms the anti-angiogenic potential of BBR by indicating the decrease in the intersegmental vessels at 0.5 and 0.75 mM treated embryos. Further, the gene expression study determined that the transcripts (vegf, vegfr2, nrp1a, hif-1α, nos2a, nos2b, cox-2a, and cox-2b) measured were found to be downregulated by BBR at 0.5 mM concentration, from which we conclude that enos/vegf signaling could play an important role in modulating angiogenesis. Our data imply that BBR may be an effective compound for suppressing angiogenesis in vivo, which might be helpful in the treatment of vascular disorders like cancer and diabetic retinopathy in future.

Impact of nutraceuticals on immunomodulation against viral infections-A review during COVID-19 pandemic in Indian scenario.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) originated in Wuhan, China, in early December 2019 is a censorious global emergency after World War II. Research on the coronavirus uncovered essential information that aided in the development of the vaccine, and specific coronavirus disease 2019 (COVID-19) vaccines were later developed and were approved for usage in humans. But then, mutations in the coronavirus gave rise to new variants and questioned the vaccine's efficacy against them. On the other hand, the investigation of traditional medicine was also on its path to find a novel outcome against COVID-19. On a comparative analysis between India and the United States, India had low death rate and high recovery rate than the latter. The dietary regulation of immunity may be the factor that makes the above difference. The immunity gained from the regular diet of Indian culture nourishes Indian people with essential phytochemicals that support immunity and metabolism. Dietary phytochemicals or nutraceuticals possess antioxidant, anti-inflammatory, and anticancer properties, out of which our concern will be on immune-boosting phytochemicals from our daily nutritional supplements. In several case studies, dietary substance like lemon, ginger, and spinach was reported in the recovery of COVID-19 patients. Thus in this review, we discuss coronavirus and its available variants, vaccines, and the effect of nutraceuticals against the coronavirus. Further, we denote that the immunity of the Indian population may be high because of their diet, which adds natural phytochemicals to boost their immunity and metabolism.

Pharmacotherapeutic values of berberine: A Chinese herbal medicine for the human cancer management.

Berberine (BBR), a traditional Chinese phytomedicine extracted from various parts of Berberis plants, is an isoquinoline alkaloid used for centuries to treat diabetes, hypercholesterolemia, hypertension, and so forth. It has recently received immense attention worldwide to treat cancer due to its potent pro-apoptotic, antiproliferative, and anti-inflammatory properties. BBR efficiently induces tumor apoptosis, replicative quiescence and abrogates cell proliferation, epithelial-mesenchymal transition, tumor neovascularization, and metastasis by modulating diverse molecular and cell signaling pathways. Furthermore, BBR could also reverse drug resistance, make tumor cells sensitive to current cancer treatment and significantly minimize the harmful side effects of cytotoxic therapies. This review comprehensively analyzed the pharmacological effects of BBR against the development, growth, progression, metastasis, and therapy resistance in wide varieties of cancer. Also, it critically discusses the significant limitations behind the development of BBR into pharmaceuticals to treat cancer and the future research directions to overcome these limitations.

Studying molecular signaling in major angiogenic diseases.

The growth of blood vessels from already existing vasculature is angiogenesis and it is one of the fundamental processes in fetal development, tissue damage or repair, and the reproductive cycle. In a healthy person, angiogenesis is regulated by the balance between pro- and anti-angiogenic factors. However, when the balance is disturbed, it results in various diseases or disorders. The angiogenesis pathway is a sequential cascade and differs based on the stimuli. Therefore, targeting one of the factors involved in the process can help us find a therapeutic strategy to treat irregular angiogenesis. In the past three decades of cancer research, angiogenesis has been at its peak, where an anti-angiogenic agent inhibiting vascular endothelial growth factor acts as a promising substance to treat cancer. In addition, cancer can be assessed based on the expression of angiogenic factors and its response to therapies. Angiogenesis is important for all tissues, which might be normal or pathologically changed and occur through ages. In clinical therapeutics, target therapy focusing on discovery of novel anti-angiogenic agents like bevacizumab, cetuximab, sunitinib, imatinib, lenvatinib, thalidomide, everolimus etc., to block or inhibit the angiogenesis pathway is well explored in recent times. In this review, we will discuss about the molecular signaling pathways involved in major angiogenic diseases in detail.

Efficacy of marine biomolecules on angiogenesis by targeting hypoxia inducible factor/vascular endothelial growth factor signaling in zebrafish model.

Marine resources are notably explored for their unique biomolecules that have been designed to be drug targets for their immense potential against various pathologies. These biomolecules are mostly secondary metabolites from different species that include sponges, tunicates, echinoderms, ascidians, algae, and marine symbionts. Among the various biological activities of the marine biomolecules, antiangiogenic property has gained much significance in alternate therapy for treatment against cancer. Hypoxia inducible factor (HIF) and vascular endothelial growth factor (VEGF) are the prime signaling pathways related to angiogenesis that are exclusively designated as markers for critical selection of novel inhibitors. This is mainly due to their importance in tumor induction and regulatory control over other interlinked pathways involved in cancer. Small molecular drug screening using the zebrafish model has been an advantage in cancer research in recent times. This review addresses the importance of marine biomolecules and their antiangiogenic efficacy by targeting HIF/VEGF pathways experimented in the zebrafish model in the last decade. Thus, it would provide more clear insights into the role of biomolecules in alternative cancer therapy.

Antiangiogenic molecules from marine actinomycetes and the importance of using zebrafish model in cancer research.

Blood vessel sprouting from pre-existing vessels or angiogenesis plays a significant role in tumour progression. Development of novel biomolecules from marine natural sources has a promising role in drug discovery specifically in the area of antiangiogenic chemotherapeutics. Symbiotic actinomycetes from marine origin proved to be potent and valuable sources of antiangiogenic compounds. Zebrafish represent a well-established model for small molecular screening and employed to study tumour angiogenesis over the last decade. Use of zebrafish has increased in the laboratory due to its various advantages like rapid embryo development, optically transparent embryos, large clutch size of embryos and most importantly high genetic conservation comparable to humans. Zebrafish also shares similar physiopathology of tumour angiogenesis with humans and with these advantages, zebrafish has become a popular model in the past decade to study on angiogenesis related disorders like diabetic retinopathy and cancer. This review focuses on the importance of antiangiogenic compounds from marine actinomycetes and utility of zebrafish in cancer angiogenesis research.

Expression of adenosine receptors and vegf during angiogenesis and its inhibition by pentoxifylline-A study using zebrafish model.

Angiogenesis, formation of new blood vessels is an important process involved in neovascular diseases and tumor progression. Understanding and defining novel therapeutic targets of neovascular diseases like retinopathy of prematurity, diabetic retinopathy and age-related macular degeneration have been hindered by a lack of appropriate animal models. Zebrafish provides an excellent vertebrate model to study above disorders since its circulatory system and retinal layers are similar to mammals. Adenosine is a known mediator of angiogenesis in hypoxic condition and adenosine receptor antagonists such as theophylline, theobromine are known to exert antiangiogenic properties. We evaluated the anti-angiogenic potential of a methylxanthine pentoxifylline (PTX) with various concentrations (0.1-1mM) at 50% epiboly stage (5.2 hpf) of zebrafish embryos and studied the mRNA expression of major angiogenic factors like vegfaa and its receptors under normal conditions and when treated with an adenosine analog NECA (5'-N-ethylcarboxamidoadenosine). Upregulation of adenosine receptors, hif-1α and vegfaa by NECA could possibly mimic hypoxic condition, but PTX downregulated vegfaa and other growth factors at 1mM concentration. Vegfa protein expression was also downregulated by PTX in the retina and the compound did not damage the retinal cells. Embryos treated with PTX generated abnormal phenotypic variants with poor vasculature, tail bending and developmental delay at 1mM. Survival rates, heart rate and hatching rates were also significantly lower. Targeting the vegf signaling pathway with small molecules inhibiting adenosine receptors in addition to antagonizing vegf might be a promising approach to treat neovascular diseases of the retina and also tumors.