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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.

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]

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.

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]

Objective The purpose of this study was to determine whether basic manual dexterity (BMD) could be an important parameter in selecting students for the Degree in Dentistry (CLOPD) and to assess whether initial manual dexterity in students admitted to the CLOPD can improve with training in pre-clinical and clinical practice. Design Observational study. Setting The study was carried out at the Catholic University of Rome, in five consecutive academic years. Subjects and methods Four hundred and thirty-three subjects (262 males and 171 females) were tested (10 different exercises) in five consecutive years. Two retests were performed after three and five years respectively from the beginning of the experimentation. Main outcome measures The scores of individual exercises were averaged for each candidate, assessing the mean value of basic manual dexterity score (BMDS). Results It was possible to observe some differences among candidates coming from different types of high schools, since those having a prior university degree or a scientific high school degree proved better than those with classical or vocational high school qualifications (p < 0.05). A statistically significant improvement of BMDS has been observed in students who attended the CLOPD for at least 32 months. Conclusions Data obtained revealed that basic manual dexterity is not essential in the selection of dental students. Students who could follow training significantly improved in their manual ability. [ABSTRACT FROM AUTHOR]

In the last years, the use of tests with predictive value for scholastic progress has become widespread. While there is an aptitude test already in use for admission to our Dental School, we have also been conducting, without consequence to their admission, an investigation into the manual dexterity of candidate students. The aim of this test is to investigate basic manual dexterity, not ability following exercise. As previous, no such specific test had been formulated; the choice of test criteria we made was new. The tests investigated over five consecutive Academic years the ability to discern characteristics of a surface, to distinguish between different types of consistency, hand–eye co-ordination, the graphic activities, laterality and muscular strength. A re-test for some years was conducted afterwards. The results provided an overall evaluation: insufficient; sufficient; good; very good; excellent. Students who came from non-technical high schools showed a good comprehension of questions put to them, use of strategy, description of procedures; and final checking but a certain clumsiness in the hand–eye co-ordination test and a tendency to use one hand only. Students coming from technical high schools showed a less immediate grasp of questions put to them, sometimes requiring their repetition, disorganised behaviour in blind-fold tests, insufficient use of strategies and little checking but notable ability in hand–eye co-ordination tests and dextrous simultaneous use of both hands. These results were then correlated with the result of the aptitude test. In conclusion, a notable correspondence between student selection based on the aptitude test and the experimental manual dexterity test was verified. This correspondence outlines that manual dexterity is not only a ‘manual’ but a ‘mental’ ability . [ABSTRACT FROM AUTHOR]

Epithelial-mesenchymal transition (EMT) is a trans-differentiating and reversible process that leads to dramatic cell phenotypic changes, enabling epithelial cells in acquiring mesenchymal phenotypes and behaviors. EMT plays a crucial role during embryogenesis, and occurs in several para-physiologic and pathological conditions, as during fibrosis or cancer development. EMT displays some hallmarks of critical transitions, as a sudden change in the overall configuration of a system in correspondence of specific tipping point around which a "catastrophic bifurcation" happens. The transition occurs when external conditions breach specific thresholds. This definition helps in highlighting two main aspects: (1) the change involves the overall system, rather than single, discrete components; (2) cues from the microenvironment play an irreplaceable role in triggering the transition. This evidence implies that critical transition should be ascertained focusing the investigation at the system level (rather than investigating only molecular parameters) in a well-defined context, as the transition is strictly dependent on the microenvironment in which it occurs. Therefore, we need a systems biology approach to investigate EMT across the Waddington-like epigenetic landscape wherein the participation of both internal and external cues can be studied to follow the extent and the main characteristics of the phenotypic transition. Herein, we suggest a set of systems parameters (motility, invasiveness) altogether with specific molecular/histological markers to identify those critical observables, which can be integrated into a comprehensive mechanistic model., (© 2024. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)