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BIOLOGICAL COMPLEX FUNCTIONS TRIGGERED BY GRAPE SEED EXTRACT IN HUMAN COLON CANCER CELLS
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Pharmacodynamics and pharmacokinetics of inositol(s) in health and disease
No full textINTRODUCTION:
Inositol and its derivatives comprise a huge field of biology. Myo-inositol is not only a prominent component of membrane-incorporated phosphatidylinositol, but participates in its free form, with its isomers or its phosphate derivatives, to a multitude of cellular processes, including ion channel permeability, metabolic homeostasis, mRNA export and translation, cytoskeleton remodeling, stress response.
AREAS COVERED:
Bioavailability, safety, uptake and metabolism of inositol is discussed emphasizing the complexity of interconnected pathways leading to phosphoinositides, inositol phosphates and more complex molecules, like glycosyl-phosphatidylinositols.
EXPERT OPINION:
Besides being a structural element, myo-inositol exerts unexpected functions, mostly unknown. However, several reports indicate that inositol plays a key role during phenotypic transitions and developmental phases. Furthermore, dysfunctions in the regulation of inositol metabolism have been implicated in several chronic diseases. Clinical trials using inositol in pharmacological doses provide amazing results in the management of gynecological diseases, respiratory stress syndrome, Alzheimer's disease, metabolic syndrome, and cancer, for which conventional treatments are disappointing. However, despite the widespread studies carried out to identify inositol-based effects, no comprehensive understanding of inositol-based mechanisms has been achieved. An integrated metabolomics-genomic study to identify the cellular fate of therapeutically administered myo-inositol and its genomic/enzymatic targets is urgently warranted
Anticancer Effects of Grape Seed Extract on Human Cancers: A Review
No full textGrape seed extract (GSE) is a complex mixture of several compounds, mostly represented by polyphenols
and phenolic acids. Their consumption is safe and is recognized to exert several and meaningful health benefits.
In particular, grape-related anti-tumoral activity encompasses a wide array of biological mechanisms and cellular
targets, eventually leading to inhibition of cell growth and to enhanced apoptosis in several cancer cell lines, including
lung, colon, breast, bladder, leukemia and prostate tumors. Those effects are likely modulated at the molecular
level through selectively modulating the redox balance and displaying anti-oxidant as well as pro-oxidant actions,
according to the specific context. GSE-related anti-cancer activity mostly relies on the induced increase in reactive
oxygen species, followed by the orchestrated down- and up-regulation of several key-molecular pathways, including
MAPK kinases, PI3K/Akt, NF-kB, cytoskeleton proteins and metalloproteinases. Promising results obtained in vitro as
well as on animal studies suggest that GSE may have a great relevance as source of potential new pharmacological
molecules, and could represent an important opportunity for clinical research
Soft gel capsules improve melatonin's bioavailability in humans.
No full textObjective: Oral bioavailability is one of the most important properties in drug design and development. A poor oral bioavailability can result in low efficacy and unpredictable response to a drug. Several dosages of melatonin have been used for various investigations to clarify its bioavailability in humans. Aiming to search for a pharmaceutical form, which is better absorbed, the pharmacokinetic (PK) profile of the new manufactured melatonin soft gelatin (soft gel) capsule form has been evaluated and compared with the commercially available melatonin powder. Research design and methods: A total of 60 healthy volunteers received 1, 3 mg of melatonin powder and 1 mg of melatonin in soft gel capsules. PK profiles were obtained by analysis of melatonin plasma concentration, and the respective melatonin bioavailability was compared. Results: Melatonin soft gel capsule form showed similar PK parameters compared with the highest doses of melatonin in powder form, but its bioavailability was improved. Conclusions: Soft gel capsules improved the bioavailability of melatonin in humans even when administered dose was reduced. Considering the number of conditions in which melatonin supplementation is recommended, this evidence could support a broader use of melatonin in clinical practice. © 2014 Informa UK, Ltd
Modulation of both insulin resistance and cancer growth by inositol
No full textInsulin resistance indicates a deregulated set of biochemical pathways and physiological functions
involved in the pathogenesis of a number of diseases, including type 2 diabetes and cancer. Conversely, a number
of synthetic and natural insulin sensitizers, including inositol, have been recognized to exert both anti-diabetic as
well as anti-cancer properties. Inositol participates in insulin transduction signaling, and deregulated inositol
metabolism has been ascertained in several conditions associated with insulin resistance. Two distinct inositolphosphoglycans
released upon insulin stimulation act as insulin-mimetic by counteracting hyperinsulinemia,
hyperglycemia and their metabolic complications. Additionally, inositol may directly interfere with both glucose
metabolism and carcinogenesis by modulating a number of critical processes downstream of insulin stimulation,
including anti-oxidant defenses, oxidative glucose metabolism and endocrine modulation. A selected cluster of
biochemical factors (PI3K/Akt, PDH and AMPK-related pathways), that are presently considered putative targets
for anticancer treatments, are also specifically modulated by inositol or its derivatives. What is more, studies on
inositol mechanism of action paved the way in understanding that both insulin resistance and cancer share a few
perturbed, critical biochemical pathways. Asides from the basic investigations, preliminary studies in vivo demonstrated
the beneficial effect of inositol in fostering glucose homeostasis as well as in antagonizing cancer
growth. Thereby, inositol fulfills the requirement to target both insulin resistance and cancer, and its clinical
usefulness deserves to be adequately addressed by specific, randomized trials
Systems Biology approach to metabolomics in cancer studies
No full textThe astonishing development of high-throughput techniques in the last decades has fostered a renewed, dynamical comprehension of cell and tissue metabolism, giving unexpected insights into the ‘systemic aspects’ of cancer, namely pointing out that metabolism should be considered a truly “systems property. Both internal and microenvironmental cues tightly cooperate in shaping tissue metabolomic fingerprint. tumour metabolome hardly could be mechanistically linked to the linear dynamics of few gene regulatory networks; otherwise it is likely to be the complex end point of several interacting non-linear pathways, involving both cells and their microenvironment. As such, tumour metabolism might be considered an emerging, “systems property”, arising at the integrated scale of the whole system and behaving like an “attractor” in a specific space phase defined by thermodynamic constraints . Therefore, metabolomics ‘strategies’ are settled in order to understand complex biological systems from an integrated (‘holistic’) point of view. Metabolomics measurements are hence correlated with the time-dependent changes in concentrations of other components (proteins, gene-expression data), in order to obtain an integrated model of the gene-protein-metabolite interactions. Such framework represents a meaningful discontinuity with respect to the reductionist and qualitative molecular biology, and discloses new perspective to scientific researc
Broad spectrum anticancer activity of myo-inositol and inositol hexakisphosphate
Full text linkInositols (myo-inositol and inositol hexakisphosphate) exert a wide range of critical activities in both physiological and pathological settings. Deregulated inositol metabolism has been recorded in a number of diseases, including cancer, where inositol modulates different critical pathways. Inositols inhibit pRB phosphorylation, fostering the pRB/E2F complexes formation and blocking progression along the cell cycle. Inositols reduce PI3K levels, thus counteracting the activation of the PKC/RAS/ERK pathway downstream of PI3K activation. Upstream of that pathway, inositols disrupt the ligand interaction between FGF and its receptor as well as with the EGF-transduction processes involving IGF-II receptor and AP-1 complexes. Additionally, Akt activation is severely impaired upon inositol addition. Downregulation of both Akt and ERK leads consequently to NF-kB inhibition and reduced expression of inflammatory markers (COX-2 and PGE2). Remarkably, inositol-induced downregulation of presenilin-1 interferes with the epithelial-mesenchymal transition and reduces Wnt-activation, β-catenin translocation, Notch-1, N-cadherin, and SNAI1 release. Inositols interfere also with the cytoskeleton by upregulating Focal Adhesion Kinase and E-cadherin and decreasing Fascin and Cofilin, two main components of pseudopodia, leading hence to invasiveness impairment. This effect is reinforced by the inositol-induced inhibition on metalloproteinases and ROCK1/2 release. Overall, these effects enable inositols to remodel the cytoskeleton architecture
Altered Ovarian Inositol Ratios May Account for Pathological Steroidogenesis in PCOS
No full textThe presence of abnormal ovarian ratios of myo-inositol (MI) to D-chiro-inositol (DCI) is a recurrent feature in PCOS. Available evidence suggests that MI and DCI may modulate steroid biosynthesis, likely in an opposite manner. Specifically, MI seems to induce estrogen production, while DCI has a role in the synthesis of androgens. Elevated insulin levels, generally associated with PCOS, alter the physiological MI/DCI ratio, increasing MI-to-DCI conversion through activation of a specific epimerase enzyme. DCI directly increases testosterone biosynthesis in thecal cells and reduces its conversion to estradiol by downregulating aromatase enzyme in granulosa cells. This manuscript reviews the literature that supports the connection between altered MI/DCI ratios and pathological steroidogenesis observed in PCOS women. Furthermore, it discusses the application of inositol-based treatment protocols in managing PCOS symptoms and improving the quality of patients’ life
Does myo-inositol effect on PCOS follicles involve cytoskeleton regulation?
No full textInositol metabolism is severely impaired in follicles obtained from cystic ovaries, leading to deregulated insulin transduction and steroid synthesis. On the contrary, inositol administration to women suffering from polycystic ovary syndrome (PCOS) has been proven to efficiently counteract most of the clinical hallmarks displayed by PCOS patients, including insulin resistance, hyperandrogenism and oligo-amenorrhea. We have recently observed that myo-inositol induces significant changes in cytoske- letal architecture of breast cancer cells, by modulating different biochemical pathways, eventually mod- ulating the epithelial–mesenchymal transition. We hypothesize that inositol and its monophosphate derivatives, besides their effects on insulin transduction, may efficiently revert histological and functional features of cystic ovary by inducing cytoskeleton rearrangements. We propose an experimental model that could address not only whether inositol modulates cytoskeleton dynamics in both normal and cystic ovary cells, but also whether this effect may interfere with ovarian steroidogenesis. A more compelling understanding of the mechanisms of action of inositol (and its derivatives) would greatly improve its therapeutic utilization, by conferring to current treatments a well-grounded scientific rationale
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