Cardiovascular Complications in Patients with Prostate Cancer: Potential Molecular Connections.

Cardiovascular diseases (CVDs) and complications are often seen in patients with prostate cancer (PCa) and affect their clinical management. Despite acceptable safety profiles and patient compliance, androgen deprivation therapy (ADT), the mainstay of PCa treatment and chemotherapy, has increased cardiovascular risks and metabolic syndromes in patients. A growing body of evidence also suggests that patients with pre-existing cardiovascular conditions show an increased incidence of PCa and present with fatal forms of the disease. Therefore, it is possible that a molecular link exists between the two diseases, which has not yet been unraveled. This article provides insight into the connection between PCa and CVDs. In this context, we present our findings linking PCa progression with patients' cardiovascular health by performing a comprehensive gene expression study, gene set enrichment (GSEA) and biological pathway analysis using publicly available data extracted from patients with advanced metastatic PCa. We also discuss the common androgen deprivation strategies and CVDs most frequently reported in PCa patients and present evidence from various clinical trials that suggest that therapy induces CVD in PCa patients.

Neuropeptide Y, a paracrine factor secreted by cancer cells, is an independent regulator of angiogenesis in colon cancer.

BACKGROUND: Resistance to anti-angiogenic therapies targeting vascular endothelial growth factor-A (VEGF-A) stems from VEGF-A independent angiogenesis mediated by other proangiogenic factors. Therefore identifying these factors in colon adenocarcinoma (CA) will reveal new therapeutic targets. METHODS: Neuropeptide Y (NPY) and Y2 receptor (Y2R) expressions in CA were studied by immunohistochemical analysis. Orthotopic HT29 with intact VEGF-A gene and VEGF-A knockdown (by CRISPR/Cas9 gene-editing technique) HT29 colon cancer-bearing mice were treated with specific Y2R antagonists, and the effects on angiogenesis and tumour growth were studied. The direct effect of NPY on angiogenesis and the underlying molecular mechanism was elucidated by the modulation of Y2R receptors expressed on colonic endothelial cells (CEC). RESULTS: The results demonstrated that NPY and Y2R are overexpressed in human CA, orthotopic HT29, and most interestingly in VEGF-A-depleted orthotopic HT29 tumours. Treatment with Y2R antagonists inhibited angiogenesis and thereby HT29 tumour growth. Blocking /silencing Y2R abrogated NPY-induced angiogenic potential of CEC. Mechanistically, NPY regulated the activation of the ERK/MAPK signalling pathway in CEC. CONCLUSIONS: NPY derived from cancer cells independently regulates angiogenesis in CA by acting through Y2R present on CEC. Targeting NPY/Y2R thus emerges as a novel potential therapeutic strategy in CA.

VEGF-A controls the expression of its regulator of angiogenic functions, dopamine D2 receptor, on endothelial cells.

We have previously demonstrated significant upregulation of dopamine D2 (DAD2) receptor (DRD2) expression on tumor endothelial cells. The dopamine D2 receptors, upon activation, inhibit the proangiogenic actions of vascular endothelial growth factor-A (VEGF-A, also known as vascular permeability factor). Interestingly, unlike tumor endothelial cells, normal endothelial cells exhibit very low to no expression of dopamine D2 receptors. Here, for the first time, we demonstrate that through paracrine signaling, VEGF-A can control the expression of dopamine D2 receptors on endothelial cells via Krüppel-like factor 11 (KLF11)-extracellular signal-regulated kinase (ERK) 1/2 pathway. These results thus reveal a novel bidirectional communication between VEGF-A and DAD2 receptors.

Racial differences in prostate tumor microenvironment: implications for disparate clinical outcomes and potential opportunities.

Disparities in cancer incidence and outcome are common among the racial and ethnical minorities in the United States and are of significant social and clinical concern. Prostate cancer is the most commonly diagnosed non-cutaneous malignancy in American men and exhibits substantial racial disparities with African American men bearing the highest burden in terms of incidence and mortality. A multitude of factors, including socioeconomic, behavioral, and access to healthcare, have been implicated as the underlying causes of such disparities. More recent data also suggest that there are inherent molecular and biological differences in prostate tumors of patients having distinct racial backgrounds. Tumor microenvironment has tremendous impact on the course of cancer progression and clinical outcome and may also contribute to the racial disparities observed in prostate cancer. Therefore, a better understanding of critical differences in the tumor microenvironment components may provide newer directions to study the biological causes of prostate cancer health disparities and may identify novel therapeutic targets. This review discusses the findings related to the tumor microenvironment differences between African American and Caucasian American prostate cancer patients and makes suggestion regarding their potential significance in prostate cancer disparities.

Lignin: Drug/Gene Delivery and Tissue Engineering Applications.

Lignin is an abundant renewable natural biopolymer. Moreover, a significant development in lignin pretreatment and processing technologies has opened a new window to explore lignin and lignin-based bionanomaterials. In the last decade, lignin has been widely explored in different applications such as drug and gene delivery, tissue engineering, food science, water purification, biofuels, environmental, pharmaceuticals, nutraceutical, catalysis, and other interesting low-value-added energy applications. The complex nature and antioxidant, antimicrobial, and biocompatibility of lignin attracted its use in various biomedical applications because of ease of functionalization, availability of diverse functional sites, tunable physicochemical and mechanical properties. In addition to it, its diverse properties such as reactivity towards oxygen radical, metal chelation, renewable nature, biodegradability, favorable interaction with cells, nature to mimic the extracellular environment, and ease of nanoparticles preparation make it a very interesting material for biomedical use. Tremendous progress has been made in drug delivery and tissue engineering in recent years. However, still, it remains challenging to identify an ideal and compatible nanomaterial for biomedical applications. In this review, recent progress of lignin towards biomedical applications especially in drug delivery and in tissue engineering along with challenges, future possibilities have been comprehensively reviewed.

Catecholamines in the regulation of angiogenesis in cutaneous wound healing.

Angiogenesis involves the formation of new blood vessels from preexisting ones, and it is an essential step during cutaneous wound healing, which supports cells at the wound site with nutrition and oxygen. Impaired angiogenesis in the wound tissues results in delayed wound closure and healing. Among the regulators of angiogenesis, the role of catecholamines (epinephrine, norepinephrine, and dopamine) is of interest due to their diverse roles in the process of wound healing. While both norepinephrine and epinephrine mostly inhibit the angiogenic process in cutaneous wounds, dopamine, the other member of the catecholamine family, has interesting and contradictory roles in the regulation of angiogenesis in the wound beds, depending on the type of dopamine receptor involved. The stimulation of dopamine D2 receptors negatively regulates the angiogenic process in normal dermal wounds and thereby delays healing, whereas the stimulation of dopamine D1 receptors promotes angiogenesis and expedites healing in diabetic wounds. Importantly, catecholamines also play important roles in other pathological conditions, and specific agonists and antagonists of catecholamines are available for the treatment of some disorders. Therefore, such drugs may be utilized for the management of angiogenesis to promote the healing of dermal wounds. This review provides a broad overview of the angiogenic process during cutaneous wound healing and the regulatory roles played by catecholamines during the process.

Angiogenesis Inhibition in Prostate Cancer: An Update.

Prostate cancer (PCa), like all other solid tumors, relies on angiogenesis for growth, progression, and the dissemination of tumor cells to other parts of the body. Despite data from in vitro and in vivo preclinical studies, as well as human specimen studies indicating the crucial role played by angiogenesis in PCa, angiogenesis inhibition in clinical settings has not shown significant benefits to patients, thus challenging the inclusion and usefulness of antiangiogenic agents for the treatment of PCa. However, one of the apparent reasons why these antiangiogenic agents failed to meet expectations in PCa can be due to the choice of the antiangiogenic agents, because the majority of these drugs target vascular endothelial growth factor-A (VEGFA) and its receptors. The other relevant causes might be inappropriate drug combinations, the duration of treatment, and the method of endpoint determination. In this review, we will first discuss the role of angiogenesis in PCa growth and progression. We will then summarize the different angiogenic growth factors that influence PCa growth dynamics and review the outcomes of clinical trials conducted with antiangiogenic agents in PCa patients and, finally, critically assess the current status and fate of antiangiogenic therapy in this disease.

Facile synthesis of carbon fiber reinforced polymer-hydroxyapatite ternary composite: A mechanically strong bioactive bone graft.

Carbon fiber reinforced carboxymethyl cellulose-hydroxyapatite ternary composites have been synthesized by a simple wet precipitation method for weight bearing orthopedic application. Composites were synthesized with the incorporation of chemically functionalized carbon fibers. The functional groups onto the surface of fibers induced the formation of hydroxyapatite at the bridging position through which fibers were effectively bound with matrix. Consequently, the flexural strength and compressive strength of composite have reached to 140 MPa and 118 MPa, respectively. The flexural modulus of the composite is in the range of 9-22 GPa. In-vitro cell study showed that the composite possesses excellent cell proliferation and differentiation ability. With these excellent mechanical and biological properties, synthesized composite exhibits potential to be used as a mechanically compatible bioactive bone graft.

One pot synthesis of carbon dots decorated carboxymethyl cellulose- hydroxyapatite nanocomposite for drug delivery, tissue engineering and Fe3+ ion sensing.

In this work, carbon dots conjugated carboxymethyl cellulose-hydroxyapatite nanocomposite has been synthesized by one-pot synthesis method and used for multiple applications like metal ion sensing, osteogenic activity, bio-imaging and drug carrier. The structure and morphology of the nanocomposite were systematically characterized by FTIR, XRD, TGA, FESEM, TEM and DLS. Results clearly demonstrated the formation of fluorescent enabled carbon dots conjugated nanocomposite from carboxymethyl cellulose-hydroxyapatite nanocomposite by a simple thermal treatment. The synthesized nanocomposite is smaller than 100 nm and exhibits fluorescence emission band around 440 nm upon excitation with 340 nm wavelength. In the meantime, the nanocomposite was loaded with a chemotherapeutic drug, doxorubicin to evaluate the drug loading potential of synthesized nanocomposite. Moreover, the as-synthesized nanocomposite showed good osteogenic properties for bone tissue engineering and also exhibited excellent selectivity and sensitivity towards Fe3+ ions.

Enhanced peripheral dopamine impairs post-ischemic healing by suppressing angiotensin receptor type 1 expression in endothelial cells and inhibiting angiogenesis.

Increased circulating catecholamines have been linked with cardiovascular anomalies as well as with peripheral vascular diseases. Although the roles of epinephrine and norepinephrine have received considerable attention, the role of the other catecholamine, dopamine, has been less studied. Since dopamine is a potent endogenous inhibitor of angiogenesis and as angiogenesis is essential for ischemic healing, we therefore studied the role played by dopamine during ischemic healing using dopamine D2 receptor knockout (KOD2) mice. Although concentration of dopamine and its rate-limiting enzyme, tyrosine hydroxylase, was considerably high in the muscle tissues of wild-type and KOD2 mice with unilateral hind limb ischemia (HLI), recovery was significantly faster in the KOD2 mice compared to the wild-type controls, thereby indicating that peripheral dopamine might have a role in this healing process. In addition, we observed significant differences in post-ischemic angiogenesis between these two groups. Our study further revealed that elevated dopamine independently suppressed activation of local tissue-based renin-angiotensin system (RAS), a critical growth factor system stimulating angiogenesis in ischemia. Angiotensin II (ATII) and its receptor, angiotensin receptor type 1 (AT1R), are the key players in RAS-mediated angiogenesis. Dopamine acting through its D2 receptors in endothelial cells inhibited ATII-mediated angiogenesis by suppressing the expression of AT1R in these cells. This study thus for the first time demonstrates the role played by dopamine in prolonging post-ischemic recovery. Therefore, pharmacological intervention inhibiting the action of dopamine holds promise as future therapeutic strategy for the treatment of HLI and other peripheral arterial diseases.

Activation of Dopamine D1 Receptors in Dermal Fibroblasts Restores Vascular Endothelial Growth Factor-A Production by These Cells and Subsequent Angiogenesis in Diabetic Cutaneous Wound Tissues.

In wound beds, fibroblasts are rich sources of vascular endothelial growth factor A, a cytokine necessary for promoting angiogenesis and thereby the healing of wound tissues. However, in diabetes mellitus, these cells are functionally impaired and produce reduced amounts of vascular endothelial growth factor A, resulting in deficient angiogenesis and delayed wound healing. We here for the first time demonstrate that stimulation of D1 dopamine receptors present in dermal fibroblasts restores vascular endothelial growth factor A production by these cells, resulting in adequate angiogenesis and subsequent healing of cutaneous wounds in both type 1 and type 2 diabetic mice. This action of D1 dopamine receptors was mediated through the protein kinase A pathway. As delayed wound healing or chronic wounds are one of the major health problems in diabetic patients, D1 dopamine receptor agonists, which are already in clinical use for the treatment of other disorders, may be of translational value in the treatment of chronic, nonhealing diabetic wounds.

Dopamine is a safe antiangiogenic drug which can also prevent 5-fluorouracil induced neutropenia.

The role of vascular endothelial growth factor A (VEGFA) in tumor angiogenesis is well established and accordingly, molecules targeting VEGFA or its receptors are being presently used in the clinics for treatment of several types of cancer. However, these antiangiogenic agents are expensive and have serious side effects. Thus identification of newer drugs with manageable systemic side effects or toxicities is of immense clinical importance. Since we have reported earlier that dopamine (DA) inhibits VEGFA induced angiogenesis in experimental tumor models, we therefore sought to investigate whether DA treatment results in similar toxicities like other antiangiogenic agents. Our results indicated that unlike sunitinib, another commonly used antiangiogenic agent in the clinics which targets VEGF receptors, DA [50 mg/kg/days × 7days intraperitoneally (i.p.)] not only could inhibit tumor angiogenesis and growth of HT29 human colon cancer and LLC (Lewis lung carcinoma) in mice, it also did not cause hypertension, hematological, renal and hepatic toxicities in normal, HT29 and LLC tumor bearing animals. Furthermore and interestingly, in contrast to the currently used antiangiogenic agents, DA also prevented 5-fluorouracil (5FU) induced neutropenia in HT29 colon cancer bearing mice. This action of DA was through inhibition of 5FU mediated suppression of colony forming unit-granulocyte macrophage colony forming units in the bone marrow. Thus our results indicate that DA may be safely used as an antiangiogenic drug for the treatment of malignant tumors.

Retention of stemness and vasculogenic potential of human umbilical cord blood stem cells after repeated expansions on PES-nanofiber matrices.

Despite recent advances in cardiovascular medicine, ischemic diseases remain a major cause of morbidity and mortality. Although stem cell-based therapies for the treatment of ischemic diseases show great promise, limited availability of biologically functional stem cells mired the application of stem cell-based therapies. Previously, we reported a PES-nanofiber based ex vivo stem cell expansion technology, which supports expansion of human umbilical cord blood (UCB)-derived CD133(+)/CD34(+) progenitor cells ∼225 fold. Herein, we show that using similar technology and subsequent re-expansion methods, we can achieve ∼5 million-fold yields within 24 days of the initial seeding. Interestingly, stem cell phenotype was preserved during the course of the multiple expansions. The high level of the stem cell homing receptor, CXCR4 was expressed in the primary expansion cells, and was maintained throughout the course of re-expansions. In addition, re-expanded cells preserved their multi-potential differential capabilities in vitro, such as, endothelial and smooth muscle lineages. Moreover, biological functionality of the re-expanded cells was preserved and was confirmed by a murine hind limb ischemia model for revascularization. These cells could also be genetically modified for enhanced vasculogenesis. Immunohistochemical evidences support enhanced expression of angiogenic factors responsible for this enhanced neovascularization. These data further confirms that nanofiber-based ex-vivo expansion technology can generate sufficient numbers of biologically functional stem cells for potential clinical applications.

Neurotransmitters as regulators of tumor angiogenesis and immunity: the role of catecholamines.

The growing tumor employs various strategies to establish its growth, progression and spread in the host. Angiogenesis or formation of new blood vessels from existing ones and escape from immune surveillance are the two critical steps that ensure proper establishment and growth of the newly formed tumor. Thus understanding the novel pathways associated with tumor angiogenesis and immunity may lead to the development of newer therapeutic strategies using the regulators of these pathways to improve patient outcomes. These two pivotal steps in the process of tumorigenesis are governed by plethora of endogenous factors. The neuroendocrine molecules, which include the catecholamine neurotransmitters, dopamine, norepinephrine and epinephrine are of growing interest considering their varied and diverse regulatory roles both in the process of tumor angiogenesis and tumor immunity. This review focuses on the emerging roles of catecholamines in modulating tumor angiogenesis and immunity, and also discusses the probable molecular mechanisms of their actions. Understanding of this new group of endogenous regulators of tumor growth may lead to the development of newer therapeutic approaches for the treatment of cancer.

Triphala and its active constituent chebulinic acid are natural inhibitors of vascular endothelial growth factor-a mediated angiogenesis.

Triphala churna (THL) is a combination of three fruits that has been used for many years in India for the treatment of various diseases. There are now reports which indicate that THL can inhibit growth of malignant tumors in animals. However, the mechanisms by which THL mediates its anti-tumor actions are still being explored. Because vascular endothelial growth factor-A (VEGF) induced angiogenesis plays a critical role in the pathogenesis of cancer, we therefore investigated whether tumor inhibitory effects of THL or its active constituents are through suppression of VEGF actions. We herein report that THL and chebulinic (CI) present in THL can significantly and specifically inhibit VEGF induced angiogenesis by suppressing VEGF receptor-2 (VEGFR-2) phosphorylation. These results are of clinical significance as these inexpensive and non-toxic natural products can be used for the prevention and treatment of diseases where VEGF induced angiogenesis has an important role.

Dopamine stabilizes tumor blood vessels by up-regulating angiopoietin 1 expression in pericytes and Kruppel-like factor-2 expression in tumor endothelial cells.

Impaired blood flow in the tumor vascular bed caused by structurally and functionally abnormal blood vessels not only hinders the delivery of chemotherapeutic agents but also aggravates tumor hypoxia, making the tumor cells further resistant to antineoplastic drugs. Therefore, normalization of tumor blood vessels may be an important approach to increase therapeutic efficacy in the treatment of cancer patients. As blood vessels are supplied by sympathetic nerves containing dopamine (DA), and DA regulates functions of normal blood vessels through its receptors present in these vessels, we investigated the effect of DA on tumor vasculature. Here we report loss of sympathetic innervation and endogenous DA in abnormal and immature tumor blood vessels in malignant colon and prostate tumor tissues. In contrast, exogenous administration of DA normalizes the morphology and improves the functions of these vessels by acting on pericytes and endothelial cells, the two major cellular components of blood vessels. DA acts through its D(2) receptors present in these cells to up-regulate directly the expression of angiopoietin 1 (Ang1) in pericytes and the expression of the zinc finger transcriptional factor, Krüppel-like factor-2 (KLF2) in tumor endothelial cells. Importantly, this vessel stabilization by DA also significantly increases the concentration of anticancer drug in tumor tissues. These results show a relationship between vascular stabilization and a neurotransmitter and indicate that DA or its D(2) receptor-specific agonists can be an option for the treatment of cancer and disorders in which normalization of blood vessels may have therapeutic benefits.

Dopamine regulates angiogenesis in normal dermal wound tissues.

Cutaneous wound healing is a normal physiological process and comprises different phases. Among these phases, angiogenesis or new blood vessel formation in wound tissue plays an important role. Skin is richly supplied by sympathetic nerves and evidences indicate the significant role of the sympathetic nervous system in cutaneous wound healing. Dopamine (DA) is an important catecholamine neurotransmitter released by the sympathetic nerve endings and recent studies have demonstrated the potent anti-angiogenic action of DA, which is mediated through its D(2) DA receptors. We therefore postulate that this endogenous catecholamine neurotransmitter may have a role in the neovascularization of dermal wound tissues and subsequently in the process of wound healing. In the present study, the therapeutic efficacy of D(2) DA receptor antagonist has been investigated for faster wound healing in a murine model of full thickness dermal wound. Our results indicate that treatment with specific D(2) DA receptor antagonist significantly expedites the process of full thickness normal dermal wound healing in mice by inducing angiogenesis in wound tissues. The underlined mechanisms have been attributed to the up-regulation of homeobox transcription factor HoxD3 and its target α5ß1 integrin, which play a pivotal role in wound angiogenesis. Since D(2) DA receptor antagonists are already in clinical use for other disorders, these results have significant translational value from the bench to the bedside for efficient wound management along with other conventional treatment modalities.

D1 and D2 dopamine receptor-mediated inhibition of activated normal T cell proliferation is lost in jurkat T leukemic cells.

Dopamine is a catecholamine neurotransmitter, which plays an important role in the regulation of T cell functions. In activated T cells from normal volunteers, stimulation of D(1) and D(2) dopamine receptors inhibit cell proliferation and cytokine secretion. However, there is no report yet regarding the regulatory role of D(1) and D(2) dopamine receptors in abnormally proliferating T cells. The present study investigates the expression and effect of activation of these dopamine receptors in Jurkat cells, a leukemic T cell line showing uncontrolled proliferation. Like normal human T cells, in Jurkat cells, D(1) and D(2) dopamine receptors are also expressed; however, unlike activated normal T cells, stimulation of these dopamine receptors in Jurkat cells fails to inhibit their T cell receptor-induced proliferation. This alteration is due to failure of D(1) dopamine receptor-mediated activation of cyclic AMP signaling and a missense mutation at the third cytoplasmic loop of D(2) dopamine receptors affecting inhibition of phosphorylation of ZAP-70, an important downstream protein transducing signal from the T cell receptor. These results help to understand the biology of abnormal proliferation of T cells in pathophysiological conditions where dopamine plays an important role.

The immunoregulatory role of dopamine: an update.

The neurotransmitter dopamine (DA) is an important molecule bridging the nervous and immune systems. DA through autocrine/paracrine manner modulates the functions of immune effector cells by acting through its receptors present in these cells. DA also has unique and opposite effects on T cell functions. Although DA activates naïve or resting T cells, but it inhibits activated T cells. In addition, changes in the expression of DA receptors and their signaling pathways especially in T cells are associated with altered immune functions in disorders like schizophrenia and Parkinson's disease. These results suggest an immunoregulatory role of DA. Therefore, targeting DA receptors and their signaling pathways in these cells by using DA receptor agonists and antagonists may be useful for the treatment of diseases where DA induced altered immunity play a pathogenic role.