Inositol metabolism is severely impaired in follicles obtained from cystic ovaries, leading to de... more Inositol 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 cytoskeletal architecture of breast cancer cells, by modulating different biochemical pathways, eventually modulating 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.
Benign mammary lumps and mastalgia are the most common breast disorders; yet, there is no clear-c... more Benign mammary lumps and mastalgia are the most common breast disorders; yet, there is no clear-cut consensus about the best strategy for their treatment. We hypothesized that a combination, including boswellic acid, betaine, and myoinositol, would be beneficial in breast disorders by exerting a pleiotropic effect on multiple pathways. Indeed, myoinositol has already been proven to modulate some factors involved in the genesis of breast diseases, such as fibrosis and metabolic and endocrine cues. In our study, 76 women were randomly assigned to either the experimental or the placebo arm. After six months of treatment, statistically significant differences between the two groups were recorded for pain relief (56% vs 17%) and breast density reduction (60% vs 9%). Furthermore, benign breast mass dimension showed a reduction in the experimental group (40% vs 16%). The combination of boswellic acid, betaine, and myoinositol has been demonstrated to be effective in the treatment of breast pain and radiologically and histologically confirmed benign breast mass and in the reduction of breast density, one of the pivotal risk factors for the development of breast cancer, without any side effects.
Presenilin-1 (PS1), the main component of γ-secretase activity support a key role during Epitheli... more Presenilin-1 (PS1), the main component of γ-secretase activity support a key role during Epithelial-Mesenchymal Transition (EMT) and chemoresistance acquisition by triggering a complex sequence of molecular events, including E-cadherin down-regulation. However, we hypothesize that EMT and chemoresistance should be deemed separate processes in HCT-8 colon cancer cells. HCT-8 and HCT-8FUres invasion was evaluated by trans-well assay. uPA activity was detected by zymography. Prostaglandin E2 levels were quantified using an ELISA kit. E-cadherin FL and CTF2, PS1, Notch1, Cyclin D1, COX2, SNAI1 and α-SMA expression were determined using Western blot technique. β-Catenin localization was observed by confocal microscopy. Cell apoptosis was evaluated by cytofluorimetric assay, and measurement of caspase-3 and cl-PARP. γ-Secretase activity was inhibited by DAPT, a γ-secretase inhibitor. Chemoresistant HCT-8 underwent EMT that can be efficiently reversed by inhibiting PS1 activity, leading thus to a normalization of mostly of the pivotal features showed by the invasive cancer phenotype. Indeed, we observed decreased SNAI1 and Notch 1 activation, altogether with reduced E-cadherin cleavage. Concomitantly, resistant HCT-8 invasiveness was almost completely abolished. However, such reversion was not followed by any increase in apoptotic rate, not by changes in E-cadherin levels. Indeed, despite HCT-8FUres underwent an undeniable EMT, full-length E-cadherin levels were found remarkably higher than those observed in wild HCT-8. High E-cadherin concentration in presence of enhanced γ-secretase activity is incontestably a paradoxically result, highlighting that E-cadherin loss is not a pre-requisite for EMT. Additionally, EMT and chemoresistance acquisition in HCT-8 should be considered as distinct processes.
The importance of rosuvastatin at therapeutic dosage in regulating the release, activity, protein... more The importance of rosuvastatin at therapeutic dosage in regulating the release, activity, protein level, and expression of matrix metalloproteinases (MMP)-2 and MMP-9 was investigated. Human umbilical artery smooth muscle cells were stimulated, in vitro, in a serum-free medium with rosuvastatin at various concentrations (2, 4, 7, and 10 ng/mL, which correspond to the maximal plasma concentration observed in healthy men after a daily oral intake of 5, 10, 20, and 40 mg, respectively). The release of MMP-2 and MMP-9 in the conditioned medium was assessed by enzyme-linked immunosorbent assay and confirmed by Western blot, the activity and expression were determined by zymography and polymerase chain reaction, respectively. Human umbilical artery smooth muscle cells stimulated with rosuvastatin at 7 and 10 ng/mL had a significant lower release, activity, protein level, and expression of MMP-2 and MMP-9, when compared with those stimulated at 2 and 4 ng/mL (MMP-2 =p < 0.0001 and p <...
Background/Aim: Matrix metalloproteinases (MMPs) are involved in cancer biology. Expression of MM... more Background/Aim: Matrix metalloproteinases (MMPs) are involved in cancer biology. Expression of MMP7 (matrilysin) in colorectal cancer is associated with metastatic disease even though it is expressed in most tumour states. In the present study, our purpose was to analyze MMP7 in bowel and lymph nodes of different tumour stages and to evaluate its expression as a cancer biomarker. 28 patients surgically-treated for benign and malignant colorectal tumours were recruited and analyzed for MMP7 in tumoural tissue, lymph nodes and serum by histology, immunohistochemistry, ELISA and western blotting. Immunohistochemistry showed prevalent expression of MMP7 in advanced cancer. A significant increase (p<0.001) was evident in serum of stage III/IV cancers compared to both adenomas and non-metastatic disease. MMP7 was increased in cancer tissues with prevalence in stage I/II. Lymph nodes presented a significant increase of MMP7 (p<0.05 adenoma vs. stage I/II and p<0.001 vs. stage III/...
MWCNT buckypaper (BP) shows physico-chemical and mechanical properties that make it potentially u... more MWCNT buckypaper (BP) shows physico-chemical and mechanical properties that make it potentially useful as a substrate in nano-bio interface research including in tissue engineering. When used as a scaffold material, BP comes into contact with host cells and surrounding tissues; therefore it is critical to determine its biocompatibility and interaction with living systems. The aim of this study was to investigate BP effects on cell growth, apoptosis and reactive oxygen species (ROS) production in three human leukemia cell lines HL-60, U-937 and K-562. BP was able to induce both the reduction of cell proliferation, associated with an arrest in G0/G1 phase of cell cycle and the increase of apoptosis in leukemic cell lines, thus exerting both cytostatic and cytotoxic effects. The growth inhibitory effect was likely mediated by the decrease of cyclins D, E, A, B1 levels and CDK4 expression; meanwhile, the apoptotic effect, not mediated by ROS production, was presumably due to the combined action of the survival and pro-apoptotic AKT and MAPK signal transduction pathways. These results raised the issue of biocompatibility of MWCNT BP for the creation of carbon nanotubes based scaffolds to utilize as prostheses in tissue engineering.
Matrix metalloproteinases (MMPs) are involved in cancer biology. Expression of MMP7 (matrilysin) ... more Matrix metalloproteinases (MMPs) are involved in cancer biology. Expression of MMP7 (matrilysin) in colorectal cancer is associated with metastatic disease even though it is expressed in most tumour states. In the present study, our purpose was to analyze MMP7 in bowel and lymph nodes of different tumour stages and to evaluate its expression as a cancer biomarker. 28 patients surgically-treated for benign and malignant colorectal tumours were recruited and analyzed for MMP7 in tumoural tissue, lymph nodes and serum by histology, immunohistochemistry, ELISA and western blotting. Immunohistochemistry showed prevalent expression of MMP7 in advanced cancer. A significant increase (p<0.001) was evident in serum of stage III/IV cancers compared to both adenomas and non-metastatic disease. MMP7 was increased in cancer tissues with prevalence in stage I/II. Lymph nodes presented a significant increase of MMP7 (p<0.05 adenoma vs. stage I/II and p<0.001 vs. stage III/IV). MMP7 increa...
PCOS is one of the most common endocrine disorders affecting women and it is characterized by a c... more PCOS is one of the most common endocrine disorders affecting women and it is characterized by a combination of hyper-androgenism, chronic anovulation, and insulin resistance. While a significant progress has recently been made in the diagnosis for PCOS, the optimal infertility treatment remains to be determined. Two inositol isomers, myo-inositol (MI) and D-chiro-inositol (DCI) have been proven to be effective in PCOS treatment, by improving insulin resistance, serum androgen levels and many features of the metabolic syndrome. However, DCI alone, mostly when it is administered at high dosage, negatively affects oocyte quality, whereas the association MI/DCI, in a combination reproducing the plasma physiological ratio (40:1), represents a promising alternative in achieving better clinical results, by counteracting PCOS at both systemic and ovary level.
ABSTRACT Morphological changes have been reported to occur in cells exposed to microgravity, even... more ABSTRACT Morphological changes have been reported to occur in cells exposed to microgravity, even if quantitative (i.e., fractal) analysis has been never performed on cell shape. We investigated cell shape as well as cytoskeleton modifications induced by simulated microgravity on murine osteoblasts (MC3T3-E1) growing in vitro by means of fractal analysis. On average, after 48–72 h of exposition to microgravity, osteoblasts display significant changes in shape profile, recovering a more rounded phenotype characterized by larger surface area than controls. More specifically, microgravity enacted the emergence of two distinct morphological phenotypes, one of which characterized by an increase in membrane fractal values, surface area, and roundness. Moreover, osteoblasts exposed to microgravity undergo significant functional changes (inhibited growth proliferation, increased apoptosis, β1-integrin decrease, impaired Akt and Erk phosphorylation) that could likely concur in explaining the observed alteration in bone structure experienced by astronauts.
Expert Opinion on Drug Metabolism & Toxicology, 2014
Objective: Oral bioavailability is one of the most important properties in drug design and develo... more Objective: 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.
CAS 2012 (International Semiconductor Conference), 2012
ABSTRACT Treatment of the human breast adenocarcinoma cell line, MCF-7, with 0.1 mg/ml of MWCNTs,... more ABSTRACT Treatment of the human breast adenocarcinoma cell line, MCF-7, with 0.1 mg/ml of MWCNTs, MWCNTs-COOH, or MWCNTs-OH for 72 hours induced both a decrease in cell proliferation and a reduction of the percentage of cells in S-phase of cell cycle. Moreover, all types of MWCNTs induced an increase in apoptotic cells. Overall, these data indicated that the cytotoxic effects of all types of MWCNTs are mediated both from a decrease in the proliferation rate and from an increase of apoptotic cell death. The biological effects of all types of MWCNTs could be explained with their cellular internalization.
Inositol metabolism is severely impaired in follicles obtained from cystic ovaries, leading to de... more Inositol 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 cytoskeletal architecture of breast cancer cells, by modulating different biochemical pathways, eventually modulating 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.
Benign mammary lumps and mastalgia are the most common breast disorders; yet, there is no clear-c... more Benign mammary lumps and mastalgia are the most common breast disorders; yet, there is no clear-cut consensus about the best strategy for their treatment. We hypothesized that a combination, including boswellic acid, betaine, and myoinositol, would be beneficial in breast disorders by exerting a pleiotropic effect on multiple pathways. Indeed, myoinositol has already been proven to modulate some factors involved in the genesis of breast diseases, such as fibrosis and metabolic and endocrine cues. In our study, 76 women were randomly assigned to either the experimental or the placebo arm. After six months of treatment, statistically significant differences between the two groups were recorded for pain relief (56% vs 17%) and breast density reduction (60% vs 9%). Furthermore, benign breast mass dimension showed a reduction in the experimental group (40% vs 16%). The combination of boswellic acid, betaine, and myoinositol has been demonstrated to be effective in the treatment of breast pain and radiologically and histologically confirmed benign breast mass and in the reduction of breast density, one of the pivotal risk factors for the development of breast cancer, without any side effects.
Presenilin-1 (PS1), the main component of γ-secretase activity support a key role during Epitheli... more Presenilin-1 (PS1), the main component of γ-secretase activity support a key role during Epithelial-Mesenchymal Transition (EMT) and chemoresistance acquisition by triggering a complex sequence of molecular events, including E-cadherin down-regulation. However, we hypothesize that EMT and chemoresistance should be deemed separate processes in HCT-8 colon cancer cells. HCT-8 and HCT-8FUres invasion was evaluated by trans-well assay. uPA activity was detected by zymography. Prostaglandin E2 levels were quantified using an ELISA kit. E-cadherin FL and CTF2, PS1, Notch1, Cyclin D1, COX2, SNAI1 and α-SMA expression were determined using Western blot technique. β-Catenin localization was observed by confocal microscopy. Cell apoptosis was evaluated by cytofluorimetric assay, and measurement of caspase-3 and cl-PARP. γ-Secretase activity was inhibited by DAPT, a γ-secretase inhibitor. Chemoresistant HCT-8 underwent EMT that can be efficiently reversed by inhibiting PS1 activity, leading thus to a normalization of mostly of the pivotal features showed by the invasive cancer phenotype. Indeed, we observed decreased SNAI1 and Notch 1 activation, altogether with reduced E-cadherin cleavage. Concomitantly, resistant HCT-8 invasiveness was almost completely abolished. However, such reversion was not followed by any increase in apoptotic rate, not by changes in E-cadherin levels. Indeed, despite HCT-8FUres underwent an undeniable EMT, full-length E-cadherin levels were found remarkably higher than those observed in wild HCT-8. High E-cadherin concentration in presence of enhanced γ-secretase activity is incontestably a paradoxically result, highlighting that E-cadherin loss is not a pre-requisite for EMT. Additionally, EMT and chemoresistance acquisition in HCT-8 should be considered as distinct processes.
The importance of rosuvastatin at therapeutic dosage in regulating the release, activity, protein... more The importance of rosuvastatin at therapeutic dosage in regulating the release, activity, protein level, and expression of matrix metalloproteinases (MMP)-2 and MMP-9 was investigated. Human umbilical artery smooth muscle cells were stimulated, in vitro, in a serum-free medium with rosuvastatin at various concentrations (2, 4, 7, and 10 ng/mL, which correspond to the maximal plasma concentration observed in healthy men after a daily oral intake of 5, 10, 20, and 40 mg, respectively). The release of MMP-2 and MMP-9 in the conditioned medium was assessed by enzyme-linked immunosorbent assay and confirmed by Western blot, the activity and expression were determined by zymography and polymerase chain reaction, respectively. Human umbilical artery smooth muscle cells stimulated with rosuvastatin at 7 and 10 ng/mL had a significant lower release, activity, protein level, and expression of MMP-2 and MMP-9, when compared with those stimulated at 2 and 4 ng/mL (MMP-2 =p < 0.0001 and p <...
Background/Aim: Matrix metalloproteinases (MMPs) are involved in cancer biology. Expression of MM... more Background/Aim: Matrix metalloproteinases (MMPs) are involved in cancer biology. Expression of MMP7 (matrilysin) in colorectal cancer is associated with metastatic disease even though it is expressed in most tumour states. In the present study, our purpose was to analyze MMP7 in bowel and lymph nodes of different tumour stages and to evaluate its expression as a cancer biomarker. 28 patients surgically-treated for benign and malignant colorectal tumours were recruited and analyzed for MMP7 in tumoural tissue, lymph nodes and serum by histology, immunohistochemistry, ELISA and western blotting. Immunohistochemistry showed prevalent expression of MMP7 in advanced cancer. A significant increase (p<0.001) was evident in serum of stage III/IV cancers compared to both adenomas and non-metastatic disease. MMP7 was increased in cancer tissues with prevalence in stage I/II. Lymph nodes presented a significant increase of MMP7 (p<0.05 adenoma vs. stage I/II and p<0.001 vs. stage III/...
MWCNT buckypaper (BP) shows physico-chemical and mechanical properties that make it potentially u... more MWCNT buckypaper (BP) shows physico-chemical and mechanical properties that make it potentially useful as a substrate in nano-bio interface research including in tissue engineering. When used as a scaffold material, BP comes into contact with host cells and surrounding tissues; therefore it is critical to determine its biocompatibility and interaction with living systems. The aim of this study was to investigate BP effects on cell growth, apoptosis and reactive oxygen species (ROS) production in three human leukemia cell lines HL-60, U-937 and K-562. BP was able to induce both the reduction of cell proliferation, associated with an arrest in G0/G1 phase of cell cycle and the increase of apoptosis in leukemic cell lines, thus exerting both cytostatic and cytotoxic effects. The growth inhibitory effect was likely mediated by the decrease of cyclins D, E, A, B1 levels and CDK4 expression; meanwhile, the apoptotic effect, not mediated by ROS production, was presumably due to the combined action of the survival and pro-apoptotic AKT and MAPK signal transduction pathways. These results raised the issue of biocompatibility of MWCNT BP for the creation of carbon nanotubes based scaffolds to utilize as prostheses in tissue engineering.
Matrix metalloproteinases (MMPs) are involved in cancer biology. Expression of MMP7 (matrilysin) ... more Matrix metalloproteinases (MMPs) are involved in cancer biology. Expression of MMP7 (matrilysin) in colorectal cancer is associated with metastatic disease even though it is expressed in most tumour states. In the present study, our purpose was to analyze MMP7 in bowel and lymph nodes of different tumour stages and to evaluate its expression as a cancer biomarker. 28 patients surgically-treated for benign and malignant colorectal tumours were recruited and analyzed for MMP7 in tumoural tissue, lymph nodes and serum by histology, immunohistochemistry, ELISA and western blotting. Immunohistochemistry showed prevalent expression of MMP7 in advanced cancer. A significant increase (p<0.001) was evident in serum of stage III/IV cancers compared to both adenomas and non-metastatic disease. MMP7 was increased in cancer tissues with prevalence in stage I/II. Lymph nodes presented a significant increase of MMP7 (p<0.05 adenoma vs. stage I/II and p<0.001 vs. stage III/IV). MMP7 increa...
PCOS is one of the most common endocrine disorders affecting women and it is characterized by a c... more PCOS is one of the most common endocrine disorders affecting women and it is characterized by a combination of hyper-androgenism, chronic anovulation, and insulin resistance. While a significant progress has recently been made in the diagnosis for PCOS, the optimal infertility treatment remains to be determined. Two inositol isomers, myo-inositol (MI) and D-chiro-inositol (DCI) have been proven to be effective in PCOS treatment, by improving insulin resistance, serum androgen levels and many features of the metabolic syndrome. However, DCI alone, mostly when it is administered at high dosage, negatively affects oocyte quality, whereas the association MI/DCI, in a combination reproducing the plasma physiological ratio (40:1), represents a promising alternative in achieving better clinical results, by counteracting PCOS at both systemic and ovary level.
ABSTRACT Morphological changes have been reported to occur in cells exposed to microgravity, even... more ABSTRACT Morphological changes have been reported to occur in cells exposed to microgravity, even if quantitative (i.e., fractal) analysis has been never performed on cell shape. We investigated cell shape as well as cytoskeleton modifications induced by simulated microgravity on murine osteoblasts (MC3T3-E1) growing in vitro by means of fractal analysis. On average, after 48–72 h of exposition to microgravity, osteoblasts display significant changes in shape profile, recovering a more rounded phenotype characterized by larger surface area than controls. More specifically, microgravity enacted the emergence of two distinct morphological phenotypes, one of which characterized by an increase in membrane fractal values, surface area, and roundness. Moreover, osteoblasts exposed to microgravity undergo significant functional changes (inhibited growth proliferation, increased apoptosis, β1-integrin decrease, impaired Akt and Erk phosphorylation) that could likely concur in explaining the observed alteration in bone structure experienced by astronauts.
Expert Opinion on Drug Metabolism & Toxicology, 2014
Objective: Oral bioavailability is one of the most important properties in drug design and develo... more Objective: 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.
CAS 2012 (International Semiconductor Conference), 2012
ABSTRACT Treatment of the human breast adenocarcinoma cell line, MCF-7, with 0.1 mg/ml of MWCNTs,... more ABSTRACT Treatment of the human breast adenocarcinoma cell line, MCF-7, with 0.1 mg/ml of MWCNTs, MWCNTs-COOH, or MWCNTs-OH for 72 hours induced both a decrease in cell proliferation and a reduction of the percentage of cells in S-phase of cell cycle. Moreover, all types of MWCNTs induced an increase in apoptotic cells. Overall, these data indicated that the cytotoxic effects of all types of MWCNTs are mediated both from a decrease in the proliferation rate and from an increase of apoptotic cell death. The biological effects of all types of MWCNTs could be explained with their cellular internalization.
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Papers by Simona Dinicola
anovulation, and insulin resistance. While a significant progress has recently been made in the diagnosis for PCOS, the optimal infertility treatment
remains to be determined. Two inositol isomers, myo-inositol (MI) and D-chiro-inositol (DCI) have been proven to be effective in PCOS treatment,
by improving insulin resistance, serum androgen levels and many features of the metabolic syndrome. However, DCI alone, mostly when it is
administered at high dosage, negatively affects oocyte quality, whereas the association MI/DCI, in a combination reproducing the plasma
physiological ratio (40:1), represents a promising alternative in achieving better clinical results, by counteracting PCOS at both systemic and ovary
level.
anovulation, and insulin resistance. While a significant progress has recently been made in the diagnosis for PCOS, the optimal infertility treatment
remains to be determined. Two inositol isomers, myo-inositol (MI) and D-chiro-inositol (DCI) have been proven to be effective in PCOS treatment,
by improving insulin resistance, serum androgen levels and many features of the metabolic syndrome. However, DCI alone, mostly when it is
administered at high dosage, negatively affects oocyte quality, whereas the association MI/DCI, in a combination reproducing the plasma
physiological ratio (40:1), represents a promising alternative in achieving better clinical results, by counteracting PCOS at both systemic and ovary
level.