Novel therapeutic strategies for spinal osteosarcomas.

At the dawn of the third millennium, cancer has become the bane of twenty-first century man, and remains a predominant public health burden, affecting welfare and life expectancy globally. Spinal osteogenic sarcoma, a primary spinal malignant tumor, is a rare and challenging neoplastic disease to treat. After the conventional therapeutic modalities of chemotherapy, radiation and surgery have been exhausted, there is currently no available alternative therapy in managing cases of spinal osteosarcoma. The defining signatures of tumor survival are characterised by cancer cell ability to stonewall immunogenic attrition and apoptosis by various means. Some of these biomarkers, namely immune-checkpoints, have recently been exploited as druggable targets in osteosarcoma and many other different cancers. These promising strides made by the use of reinvigorated immunotherapeutic approaches may lead to significant reduction in spinal osteosarcoma disease burden and corresponding reciprocity in increase of survival rates. In this review, we provide the background to spinal osteosarcoma, and proceed to elaborate on contribution of the complex ecology within tumor microenvironment giving arise to cancerous immune escape, which is currently receiving considerable attention. We follow this section on the tumor microenvironment by a brief history of cancer immunity. Also, we draw on the current knowledge of treatment gained from incidences of osteosarcoma at other locations of the skeleton (long bones of the extremities in close proximity to the metaphyseal growth plates) to make a case for application of immunity-based tools, such as immune-checkpoint inhibitors and vaccines, and draw attention to adverse upshots of immune-checkpoint blockers as well. Finally, we describe the novel biotechnique of CRISPR/Cas9 that will assist in treatment approaches for personalized medication.

Salvia fruticosa Induces Vasorelaxation In Rat Isolated Thoracic Aorta: Role of the PI3K/Akt/eNOS/NO/cGMP Signaling Pathway.

Salvia fruticosa (SF) Mill. is traditionally used for its antihypertensive actions. However, little is known about its pharmacologic and molecular mechanisms of action. Here we determined the effects of an ethanolic extract of SF leaves on rings of isolated thoracic aorta from Sprague-Dawley rats. Our results show that SF extract increased nitric oxide production and relaxed endothelium-intact rings in a dose-dependent (0.3 µg/ml-1 mg/ml) manner, and the maximum arterial relaxation (Rmax) was significantly reduced with endothelium denudation. Pretreatment of endothelium-intact rings with L-NAME (a non-selective inhibitor of nitric oxide synthase, 100 µM), or ODQ (an inhibitor of soluble guanylyl cyclase, 10 µM) significantly diminished SF-mediated vasorelaxation. Furthermore, SF induced Akt phosphorylation as well as increased cGMP levels in rings treated with increasing doses of SF. Prior exposure to PI3K inhibitors, wortmannin (0.1 µM) or LY294002 (10 µM), decreased cGMP accumulation and attenuated the SF-induced vasorelaxation by approximately 50% (Rmax). SF-evoked relaxation was not affected by indomethacin, verapamil, glibenclamide, tetraethylammonium, pyrilamine or atropine. Taken together, our results indicate that SF induces endothelium-dependent vasorelaxation through the PI3K/Akt/eNOS/NO/sGC/cGMP signaling pathway. Our data illustrate the health-orientated benefits of consuming SF which may act as an antihypertensive agent to reduce the burden of cardiovascular complications.

Inflammogenesis of Secondary Spinal Cord Injury.

Spinal cord injury (SCI) and spinal infarction lead to neurological complications and eventually to paraplegia or quadriplegia. These extremely debilitating conditions are major contributors to morbidity. Our understanding of SCI has certainly increased during the last decade, but remains far from clear. SCI consists of two defined phases: the initial impact causes primary injury, which is followed by a prolonged secondary injury consisting of evolving sub-phases that may last for years. The underlying pathophysiological mechanisms driving this condition are complex. Derangement of the vasculature is a notable feature of the pathology of SCI. In particular, an important component of SCI is the ischemia-reperfusion injury (IRI) that leads to endothelial dysfunction and changes in vascular permeability. Indeed, together with endothelial cell damage and failure in homeostasis, ischemia reperfusion injury triggers full-blown inflammatory cascades arising from activation of residential innate immune cells (microglia and astrocytes) and infiltrating leukocytes (neutrophils and macrophages). These inflammatory cells release neurotoxins (proinflammatory cytokines and chemokines, free radicals, excitotoxic amino acids, nitric oxide (NO)), all of which partake in axonal and neuronal deficit. Therefore, our review considers the recent advances in SCI mechanisms, whereby it becomes clear that SCI is a heterogeneous condition. Hence, this leads towards evidence of a restorative approach based on monotherapy with multiple targets or combinatorial treatment. Moreover, from evaluation of the existing literature, it appears that there is an urgent requirement for multi-centered, randomized trials for a large patient population. These clinical studies would offer an opportunity in stratifying SCI patients at high risk and selecting appropriate, optimal therapeutic regimens for personalized medicine.

Anti-Hypertensive Herbs and Their Mechanisms of Action: Part II.

Traditional medicine has a history extending back to thousands of years, and during the intervening time, man has identified the healing properties of a very broad range of plants. Globally, the use of herbal therapies to treat and manage cardiovascular disease (CVD) is on the rise. This is the second part of our comprehensive review where we discuss the mechanisms of plants and herbs used for the treatment and management of high blood pressure. Similar to the first part, PubMed and ScienceDirect databases were utilized, and the following keywords and phrases were used as inclusion criteria: hypertension, high blood pressure, herbal medicine, complementary and alternative medicine, endothelial cells, nitric oxide (NO), vascular smooth muscle cell (VSMC) proliferation, hydrogen sulfide, nuclear factor kappa-B (NF-κB), oxidative stress, and epigenetics/epigenomics. Each of the aforementioned keywords was co-joined with plant or herb in question, and where possible with its constituent molecule(s). This part deals in particular with plants that are used, albeit less frequently, for the treatment and management of hypertension. We then discuss the interplay between herbs/prescription drugs and herbs/epigenetics in the context of this disease. The review then concludes with a recommendation for more rigorous, well-developed clinical trials to concretely determine the beneficial impact of herbs and plants on hypertension and a disease-free living.

Glucocorticoid-induced fetal origins of adult hypertension: Association with epigenetic events.

Hypertension is a predominant risk factor for cardiovascular diseases and a major health care burden. Accumulating epidemiological and experimental evidence suggest that adult-onset hypertension may have its origins during early development. Upon exposure to glucocorticoids, the fetus develops hypertension, and the offspring may be programmed to continue the hypertensive trajectory into adulthood. Elevated oxidative stress and deranged nitric oxide system are not only hallmarks of adult hypertension but are also observed earlier in life. Endothelial dysfunction and remodeling of the vasculature, which are robustly associated with increased incidence of hypertension, are likely to have been pre-programmed during fetal life. Apparently, genomic, non-genomic, and epigenomic factors play a significant role in the development of hypertension, including glucocorticoid-driven effects on blood pressure. In this review, we discuss the involvement of the aforementioned participants in the pathophysiology of hypertension and suggest therapeutic opportunities for targeting epigenome modifiers, potentially for personalized medicine.

Anti-hypertensive Herbs and their Mechanisms of Action: Part I.

The use of herbal therapies for treatment and management of cardiovascular diseases (CVDs) is increasing. Plants contain a bounty of phytochemicals that have proven to be protective by reducing the risk of various ailments and diseases. Indeed, accumulating literature provides the scientific evidence and hence reason d'etre for the application of herbal therapy in relation to CVDs. Slowly, but absolutely, herbal remedies are being entrenched into evidence-based medical practice. This is partly due to the supporting clinical trials and epidemiological studies. The rationale for this expanding interest and use of plant based treatments being that a significant proportion of hypertensive patients do not respond to Modern therapeutic medication. Other elements to this equation are the cost of medication, side-effects, accessibility, and availability of drugs. Therefore, we believe it is pertinent to review the literature on the beneficial effects of herbs and their isolated compounds as medication for treatment of hypertension, a prevalent risk factor for CVDs. Our search utilized the PubMed and ScienceDirect databases, and the criterion for inclusion was based on the following keywords and phrases: hypertension, high blood pressure, herbal medicine, complementary and alternative medicine (CAM), nitric oxide, vascular smooth muscle cell (VSMC) proliferation, hydrogen sulfide, nuclear factor kappa-B, oxidative stress, and epigenetics/epigenomics. Each of the aforementioned keywords was co-joined with herb in question, and where possible with its constituent molecule(s). In this first of a two-part review, we provide a brief introduction of hypertension, followed by a discussion of the molecular and cellular mechanisms. We then present and discuss the plants that are most commonly used in the treatment and management of hypertension.

Colorectal and Prostate Cancer Risk in Diabetes: Metformin, an Actor behind the Scene.

Both diabetes and cancer are prevalent diseases whose incidence rates are increasing worldwide, especially in countries that are undergoing rapid industrialization changes. Apparently, lifestyle risk factors including diet, physical inactivity and obesity play pivotal, yet preventable, roles in the etiology of both diseases. Epidemiological studies provide strong evidence that subjects with diabetes are at significantly higher risk of developing many forms of cancer and especially solid tumors. In addition to pancreatic and breast cancer, the incidence of colorectal cancer and prostate cancer is increased in type 2 diabetes. While diabetes (type 2) and cancer share many risk factors, the biological links between the two diseases are poorly characterized. In this review, we highlight the mechanistic pathways that link diabetes to colorectal and prostate cancer and the use of Metformin, a diabetes drug, to prevent and/or treat colorectal and prostate cancer. We review the role of AMPK activation in autophagy, oxidative stress, inflammation, apoptosis, and cell cycle progression.

Signal transduction and modulating pathways in tryptamine-evoked vasopressor responses of the rat isolated perfused mesenteric bed.

Tryptamine is an endogenous and dietary indoleamine-based trace amine implicated in cardiovascular pathologies, including hypertension, migraine and myocardial infarction. This study aimed at identifying the signalling pathways for the vasoconstrictor response to tryptamine in rat isolated perfused mesenteric arterial beds and co-released vasodilator modulators of tryptamine-mediated vasoconstriction. Tryptamine caused concentration-dependent vasoconstriction of the mesenteric bed, measured as increases in perfusion pressure. These were inhibited by the 5-HT(2A) receptor antagonist, ritanserin, indicating mediation via 5-HT(2A) receptors. The response was inhibited by the phospholipase C (PLC) and phospholipase A(2) (iPLA(2)) inhibitors, U-73122 and PACOCF(3), suggesting involvement of phospholipase pathways. Activation of these pathways by tryptamine releases cyclooxygenase (COX) products since indomethacin (non-selective inhibitor of COX-1/2) and nimesulide (selective COX-2 inhibitor) reduced the vasoconstriction. The most likely COX vasoconstrictor product was prostaglandin PGE(2) since the responses to tryptamine were reduced by AH-6809, a non-selective EP(1) receptor antagonist. Involvement of the Rho-kinase pathway in the tryptamine-evoked vasoconstriction was also indicated by its reduction by the Rho-kinase inhibitors, Y-27,632 and fasudil. The tryptamine vasoconstriction is modulated by the co-released endothelial vasodilator, nitric oxide. Thus, circulating tryptamine can regulate mesenteric blood flow through a cascade of signalling pathways secondary to stimulation of 5-HT(2A) receptors.

Erythrocyte hyper-aggregation in a patient undergoing orthotopic transplantation for primary sclerosing cholangitis complicated by biliary stricture.

We report on the hemorheological profile of a 16 year old school girl in whom liver transplant was performed due to primary sclerosing cholangitis complicated by biliary stricture. This patient turned out to be of particular hemorheological interest, displaying pre-transplant grossly increased hematocrit-standardized (45%) blood viscosity due to hyperaggregation and elevated plasma viscosity, which is a reflection of elevated immunoglobulins (IgG, IgA and IgM) and alpha-2-macroglobulin. Post-transplant values of rheological parameters were within the normal range for healthy controls.

Abnormal hemorheological properties in patients with compensated and decompensated hepatic cirrhosis.

In this study the hemorheological profiles of blood samples from cirrhotic patients (compensated and decompensated) were determined, along with 18 normal healthy volunteers for comparison. Both groups of patients were anaemic, and as a consequence had a lower native blood viscosity by comparison with the healthy control group. However, after adjusting the hematocrit to 45% the high shear rate (128 s(-1)) viscosity was within the normal range, while that at low shear rate (0.277 s(-1)) exhibited a significant increase in both groups of patients over that of the control group. This was partly due to the elevated plasma viscosities in the patients, but in the main is explained by exaggerated red blood cell aggregation. In spite of normal total plasma protein concentration in the patients, the concentration of rouleaugenic proteins was altered, and this particularly applied to the immunoglobulins (IgG, IgA and IgM). These results demonstrate that the hemorheology of the cirrhotics is disturbed from normal.