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Androgen excess is a key feature of several clinical phenotypes of polycystic ovary syndrome (PCOS). However, the presence of FSH receptor (FSHR) and aromatase (CYP19A1) activity responses to physiological endocrine stimuli play a critical role in the pathogenesis of PCOS. Preliminary data suggest that myo-Inositol (myo-Ins) and D-Chiro-Inositol (D-Chiro-Ins) may reactivate CYP19A1 activity. We investigated the steroidogenic pathway of Theca (TCs) and Granulosa cells (GCs) in an experimental model of murine PCOS induced in CD1 mice exposed for 10 weeks to a continuous light regimen. The effect of treatment with different combinations of myo-Ins and D-Chiro-Ins on the expression of Fshr, androgenic, and estrogenic enzymes was analyzed by real-time PCR in isolated TCs and GCs and in ovaries isolated from healthy and PCOS mice. Myo-Ins and D-Chiro-Ins, at a ratio of 40:1 at pharmacological and physiological concentrations, positively modulate the steroidogenic activity of TCs and the expression of Cyp19a1 and Fshr in GCs. Moreover, in vivo, inositols (40:1 ratio) significantly increase Cyp19a1 and Fshr. These changes in gene expression are mirrored by modifications in hormone levels in the serum of treated animals. Myo-Ins and D-Chiro-Ins in the 40:1 formula efficiently rescued PCOS features by up-regulating aromatase and FSHR levels while down-regulating androgen excesses produced by TCs. [ABSTRACT FROM AUTHOR]

Simple Summary: Inflammatory conditions can enact the emergence of cancer, especially by promoting an epithelial-mesenchymal transition (EMT). Furthermore, EMT is a critical requirement for the dissemination of cancerous cells. The discovery of pharmacological agents able to inhibit EMT has become a critical issue in recent times. Herein we demonstrate that myo-inositol (myo-Ins), can efficiently rescue normal breast cells committed to an inflammatory phenotype upon the addition of the inflammatory TGF-β1 stimulus. Myo-Ins was able to almost completely inhibit the resulting invasive–migrating phenotype, namely by reverting EMT. A critical step is the reconstitution of proper E-cadherin-based cell-to-cell junctions, which are instrumental in the recovery of a tissue-like structure. Moreover, myo-Ins re-established a normal gene expression pattern, while normalizing the microenvironment by reducing collagen and metalloproteinase release. These results highlight the relevance of inflammation in promoting a precancerous state and provide useful new perspectives in cancer treatment and prevention with natural compounds. Epithelial-Mesenchymal Transition (EMT), triggered by external and internal cues in several physiological and pathological conditions, elicits the transformation of epithelial cells into a mesenchymal-like phenotype. During EMT, epithelial cells lose cell-to-cell contact and acquire unusual motility/invasive capabilities. The associated architectural and functional changes destabilize the epithelial layer consistency, allowing cells to migrate and invade the surrounding tissues. EMT is a critical step in the progression of inflammation and cancer, often sustained by a main driving factor as the transforming growth factor-β1 (TGF-β1). Antagonizing EMT has recently gained momentum as an attractive issue in cancer treatment and metastasis prevention. Herein, we demonstrate the capability of myo-inositol (myo-Ins) to revert the EMT process induced by TGF-β1 on MCF-10A breast cells. Upon TGF-β1 addition, cells underwent a dramatic phenotypic transformation, as witnessed by structural (disappearance of the E-cadherin–β-catenin complexes and the emergence of a mesenchymal shape) and molecular modifications (increase in N-cadherin, Snai1, and vimentin), including the release of increased collagen and fibronectin. However, following myo-Ins, those changes were almost completely reverted. Inositol promotes the reconstitution of E-cadherin–β-catenin complexes, decreasing the expression of genes involved in EMT, while promoting the re-expression of epithelial genes (keratin-18 and E-cadherin). Noticeably, myo-Ins efficiently inhibits the invasiveness and migrating capability of TGF-β1 treated cells, also reducing the release of metalloproteinase (MMP-9) altogether with collagen synthesis, allowing for the re-establishment of appropriate cell-to-cell junctions, ultimately leading the cell layer back towards a more compact state. Inositol effects were nullified by previous treatment with an siRNA construct to inhibit CDH1 transcripts and, hence, E-cadherin synthesis. This finding suggests that the reconstitution of E-cadherin complexes is an irreplaceable step in the inositol-induced reversion of EMT. Overall, such a result advocates for the useful role of myo-Ins in cancer treatment. [ABSTRACT FROM AUTHOR]

Polycystic ovarian syndrome (PCOS) is the most common endocrinological disorder in women, in which, besides chronic anovulation/oligomenorrhea and ovarian cysts, hyperandrogenism plays a critical role in a large fraction of subjects. Inositol isomers—myo-Inositol and D-Chiro-Inositol—have recently been pharmacologically effective in managing many PCOS symptoms while rescuing ovarian fertility. However, some disappointing clinical results prompted the reconsideration of their specific biological functions. Surprisingly, D-Chiro-Ins stimulates androgen synthesis and decreases the ovarian estrogen pathway; on the contrary, myo-Ins activates FSH response and aromatase activity, finally mitigating ovarian hyperandrogenism. However, when the two isomers are given in association—according to the physiological ratio of 40:1—patients could benefit from myo-Ins enhanced FSH and estrogen responsiveness, while taking advantage of the insulin-sensitizing effects displayed mostly by D-Chiro-Ins. We need not postulate insulin resistance to explain PCOS pathogenesis, given that insulin hypersensitivity is likely a shared feature of PCOS ovaries. Indeed, even in the presence of physiological insulin stimulation, the PCOS ovary synthesizes D-Chiro-Ins four times more than that measured in control theca cells. The increased D-Chiro-Ins within the ovary is detrimental in preserving steroidogenic control, and this failure can easily explain why treatment strategies based upon high D-Chiro-Ins have been recognized as poorly effective. Within this perspective, two factors emerge as major determinants in PCOS: hyperandrogenism and reduced aromatase expression. Therefore, PCOS could no longer be considered a disease only due to increased androgen synthesis without considering the contemporary downregulation of aromatase and FSH receptors. Furthermore, these findings suggest that inositols can be specifically effective only for those PCOS phenotypes featured by hyperandrogenism. [ABSTRACT FROM AUTHOR]

The currently accepted theory on the influence of DNA mutations on carcinogenesis (the Somatic Mutation Theory, SMT) is facing an increasing number of controversial results that undermine the explanatory power of mutated genes considered as "causative" factors. Intriguing results have demonstrated that several critical genes may act differently, as oncogenes or tumor suppressors, while phenotypic reversion of cancerous cells/tissues can be achieved by modifying the microenvironment, the mutations they are carrying notwithstanding. Furthermore, a high burden of mutations has been identified in many non-cancerous tissues without any apparent pathological consequence. All things considered, a relevant body of unexplained inconsistencies calls for an in depth rewiring of our theoretical models. Ignoring these paradoxes is no longer sustainable. By avoiding these conundrums, the scientific community will deprive itself of the opportunity to achieve real progress in this important biomedical field. To remedy this situation, we need to embrace new theoretical perspectives, taking the cell–microenvironment interplay as the privileged pathogenetic level of observation, and by assuming new explanatory models based on truly different premises. New theoretical frameworks dawned in the last two decades principally focus on the complex interaction between cells and their microenvironment, which is thought to be the critical level from which carcinogenesis arises. Indeed, both molecular and biophysical components of the stroma can dramatically drive cell fate commitment and cell outcome in opposite directions, even in the presence of the same stimulus. Therefore, such a novel approach can help in solving apparently inextricable paradoxes that are increasingly observed in cancer biology. [ABSTRACT FROM AUTHOR]