Nebulized myo-inositol increases mucus clearance in patients with Bronchiectasis: a retrospective study.

OBJECTIVE: This retrospective study aimed at ascertaining the clinical usefulness of nebulized myo-inositol in the management of patients affected by bronchiectasis. PATIENTS AND METHODS: 19 patients, aged between 63 and 73 years old, with bronchiectasis, were treated for 15 days with nebulized myo-inositol or placebo. Lung functionality [forced expiratory volume in the 1st second (FEV1)], solid content of expectorate, and surfactant tension were analyzed. RESULTS: All patients treated with nebulized myo-inositol had a significant decrease in the percentage of solid content in the expectorate (T0 7.9±2.8% vs. T1 5.2±2.7%; p<0.001) and surfactant tension (T0 81.5±6.9 mN/m vs. T1 77.4±7.2 mN/m; p<0.001). Among treated patients, these variations correlated with FEV1 (rs=- 0.79; p<0.01) and forced expiratory flow at 25-75% of FVC (FEF25-75%) (rs=-0.81; p<0.01) scores. Also, variation of surfactant tension correlated with FEV1 (rs= -0.74; p<0.05) score. CONCLUSIONS: Nebulized myo-inositol increases lung functionality and mucus clearance in patients affected by bronchiectasis.

Does Alpha-lipoic acid improve effects on polycystic ovary syndrome?

Alpha-lipoic acid (ALA) plays a key role in many physiological processes, exerting anti-inflammatory, immunomodulatory, antioxidant, detoxifying, and insulin sensitizing activities. Since ALA improves insulin resistance (IR), it has been suggested that ALA could be beneficial it in the treatment of PCOS. The natural polyol myo-Inositol (myo-Ins) and its isomers (D-Chiro-Inositol, D-Chiro-Ins) has proven to improve PCOS features and clinical outcome, according to a compelling body of available studies. Few studies have proposed to strengthen the inositol effect by associating ALA. ALA does not seem to influence significantly reproductive hormones, while its beneficial effects are presumably restricted to the metabolic features of insulin resistant PCOS women. Therefore, ALA usefulness in improving inositol activity still awaits convincingly confirmation.  Experimental studies as well as proper randomized clinical trials, should be specifically tailored to assess this hypothesis. In absence of reliable evidence, ALA should not be recommended in the routinary clinical management of PCOS, even if associated to myo-Ins.

Zebrafish embryo extracts enhance 5-FU anti-cancer effects upon breast cancer cells.

OBJECTIVE: The inhibition of the metastatic capability of cancer cells is a pivotal aim of current anticancer strategies. We investigated herein the anti-migrating and anti-invasive properties of Zebrafish embryo extracts (SL) - an integrative formula comprising morphogenetic factors extracted from zebrafish embryos - alone or in association with 5-Fluoro-Uracil (5-FU), when added to metastatic breast cancer cells (MDA-MB-231) and in normal epithelial breast cells (MCF10A) committed toward an inflammatory phenotype upon TGF-ß1 stimulation. MATERIALS AND METHODS: Invasiveness, migrating capability, cytoskeleton architecture and related molecular factors involved in the epithelial-mesenchymal transition were studied after treatment with 5-FU, with and without SL. RESULTS: Remarkably, in both circumstances, embryo extracts amplify the migratory inhibition triggered by the anticancer drug 5-Fu. The fact that such an effect is noticed in normal as well as in cancerous cells suggests that the critical target of embryo extracts is specifically represented by the migrating/invasive phenotype. However, while 5-FU was unable in antagonizing the invasiveness of cancerous cells, the association with SL can significantly impair the invasive capability of tumor cells. These findings are noticeably associated with the reversion of the EMT phenotype in SL-treated cells, as documented by the contemporary downregulation of TCTP and some EMT-related molecular effectors, like α-SMA and Vimentin. CONCLUSIONS: Embryo fish extracts significantly counteract the migrating and invasive phenotype of cancerous and inflammatory breast cells treated with the chemotherapeutic drug 5-FU. The availability of a compound able to amplify 5-Fu activity while significantly hampering the invasive phenotype of breast cancer should provide invaluable benefits, namely if we consider that this compound is substantially deprived of side-effects.

The use of D-chiro-Inositol in clinical practice.

OBJECTIVE: D-chiro-Inositol has been widely used in clinical practice to induce ovulation in women with polycystic ovary syndrome. Only recent evidence established that this molecule acts through two different mechanisms, with potentially different outcomes. On the one hand, under a metabolic perspective, D-chiro-Inositol improves insulin signaling, thus restoring physiological insulin levels in resistant subjects. On the other hand, at a cellular level, it downregulates the expression of steroidogenic enzyme aromatase, which is responsible for the conversion of androgens to estrogens. MATERIALS AND METHODS: We reviewed current literature in different databases, searching for D-chiro-Inositol in relation with one of the following keywords: myo-inositol, PCOS, infertility, insulin resistance, aromatase, androgen and inositol, testosterone, estrogen and inositol, estradiol, hypogonadotropic hypogonadism, fat tissue, estrogens and cancer, anovulation, uterine myoma, endometriosis, endometrial hyperplasia. RESULTS: D-Chiro-Inositol treatment may be helpful in restoring physiological hormonal levels in various clinical disorders. However, D-Chiro-Inositol intervention should be carefully designed to avoid possible undesired side effects stemming from its multiple mechanisms of action. CONCLUSIONS: We evaluated the optimal D Chiro-Inositol administration for different pathologies, defining dosages and timing. Even though further studies are required to validate our preliminary results, this paper is primarily intended to guide researchers through some of the pathways of D-Chiro-Inositol.

Inhibitory effects of Vitamin D on inflammation and IL-6 release. A further support for COVID-19 management?

The ongoing worldwide pandemic of Coronavirus disease 2019 (COVID-19), raised the urgency to address knowledge gaps and to establish evidence for improving management and control of this viral infection. Throughout a keen analysis of the World Health Organization (WHO) most updated data, a gender-specific difference in the occurrence of infection was determined, which seems to correlate with patient's vitamin D status. Therefore, our purpose is to provide insights into the nutritional importance of vitamin D for its immunomodulatory effect, in order to help counteracting the COVID-19 pandemic. Novel interesting findings suggest that vitamin D, by inducing progesterone-induced blocking factor (PIBF), might regulate the immune response and also modulate cytokine IL-6, which appears to be increased in COVID-19 infections. Therefore, in addition to the standard recommendations to prevent the infection, supplementation of vitamin D might be considered an approach to help counteracting this global epidemic.

Inositol and pulmonary function. Could myo-inositol treatment downregulate inflammation and cytokine release syndrome in SARS-CoV-2?

The outbreak of Sars-CoV-2 (COVID-19) poses serious challenges to people's health worldwide. The management of the disease is mostly supportive, and respiratory failure from acute respiratory distress syndrome is the leading cause of death in a significant proportion of affected patients. Preliminary data point out that dramatic increase in IL-6 and subsequent cytokine release syndrome may account for the development of fatal interstitial pneumonia. Inhibition of IL-6 by blocking its specific receptor with monoclonal antibodies has been advocated as a promising attempt. Here we assess the potential utility of myo-Inositol, a polyol already in use for treating the newborn Respiratory Distress Syndrome, in downregulating the inflammatory response upon Sars-CoV-2 infection. Myo-Inositol proved to reduce IL-6 levels in a number of conditions and to mitigate the inflammatory cascade, while being devoid of any significant side effects. It is tempting to speculate that inositol could be beneficial in managing the most dreadful effects of Sars-CoV-2 infection.

Natural products - alpha-lipoic acid and acetyl-L-carnitine - in the treatment of chemotherapy-induced peripheral neuropathy.

OBJECTIVE: Cancer patients frequently experience Chemotherapy-Induced Peripheral Neuropathy (CIPN), as a typical side effect related to time of administration and dose of anticancer agents. Yet, CIPN pathophysiology is poorly understood, and there is a lack of well-tolerated pharmacological remedies helpful to prevent or treat it. Therefore, new safe and effective compounds are highly warranted, namely if based on an adequate understanding of the pathogenic mechanisms. MATERIAL AND METHODS: Herein we reviewed and discussed scientific data related to the beneficial role of some non-conventional treatments able to counteract CIPN, focusing our attention on alpha-lipoic acid (ALA) and L-acetyl-carnitine (LAC), two natural products that have been demonstrated to be promising preventive drugs. RESULTS: Although a growing body of in vitro and in vivo studies support ALA as a molecule able to counteract CIPN symptoms, mostly due to its antioxidant and anti-inflammatory properties, only two randomized clinical trials evaluated ALA usefulness in preventing chemotherapy-related neuropathy. Unfortunately, these studies were inconclusive and clinical outcomes showed to be highly dependent on the route of administration (oral versus or intravenous injection). LAC has demonstrated beneficial effects on both in vitro and in animal studies. Yet, some controversies aroused from randomized clinical trials. Indeed, while CIPN-patients treated with Taxane showed no benefit from LAC treatment, CIPN-patients treated with platinum compounds exhibit significant improvement of CIPN-related symptoms. Therefore, LAC treatment should be used, and thoroughly investigated only in patients treated with chemotherapy protocols Taxanes-free. CONCLUSIONS: Mechanisms of toxicity triggered by each single drug need to be deeply explored to better identify effective compounds to prevent or treat them. Moreover, additional experiments are mandatory to establish effective doses and length of treatment for each clinical situation in order to perform large and long-term randomized studies.

Inositol hexaphosphate (InsP6) as an effective topical treatment for patients receiving adjuvant chemotherapy after breast surgery.

OBJECTIVE: Oral treatment with inositol hexaphosphate (InsP6) has shown to be efficient in decreasing adverse effects in patients with breast cancer under chemotherapy. This study was aimed at evaluating and comparing the efficacy of topical InsP6 in improving quality of life in women treated with anticancer drugs. PATIENTS AND METHODS: The study was a double-blind, randomized controlled trial (RCT) with allocation concealment of 20 patients in two groups, one (experimental) applied 4% topical formulation of InsP6 once a day, whereas the second one (control) a gel containing hyaluronic acid. InsP6 therapy started 6 weeks after lumpectomy. Blood tests were monitored in both groups and quality of life was assessed using standardized QLQ-C30 and QLQ-BR23. RESULTS: Patients who applied InsP6 on the breast significantly improved their quality of life and functional status reducing side effects compared to control group; moreover, after treatment, a significant difference between the two groups was observed in the white blood cells and platelets count values. CONCLUSIONS: Topical InsP6 treatment has demonstrated to be effective and safe in preventing and/or mitigating chemotherapy-induced side effects as well as the preserving quality of life in women with ductal breast cancer.

A randomized trial of Boswellia in association with betaine and myo-inositol in the management of breast fibroadenomas.

OBJECTIVE: Breast fibroadenoma is a common finding in young women and actually accounts for the majority of benign breast lumps. Fibroadenoma does not require any treatment unless clinical symptoms (mostly mastalgia) or histological markers of cancer risk (atypia) impose specific medical or surgical intervention. In symptomatic fibroadenoma, anti-estrogenic treatments provided evidence of success. Yet, these therapies are often associated with relevant side effects that lead to drug treatment discontinuation. Additionally, in such cases, relapse is a frequent issue. Therefore, an optimal strategy is still warranted. Boswellia, betaine and myo-inositol have already been proved to modulate different pathways - inflammatory, metabolic, oxidative and endocrine processes - in a wide array of human tissues. Based on that background, we hypothesized that these substances can effectively synergize in inducing the regression of fibroadenoma. PATIENTS AND METHODS: We included 64 patients ≤ 30 years of age with fibroadenoma. The patients were randomized into two groups. The experimental group was treated with an association of Boswellia, betaine, myo-inositol, B-group vitamins and N-acetylcysteine for 6 months; otherwise, the placebo group was treated only with B-group vitamins and N-acetylcysteine. Patients were monitored at the enrollment and the end of the study for evaluating the clinical response. RESULTS: A significant clinical improvement was observed in the experimental arm. Fibroadenoma median volume reduction averaged 17.86% in the experimental group and 5.96% in the placebo group. Moreover, 14 out of 36 (38.88%) patients showed a reduction of fibroadenoma volume compared to 5/28 (17.85%) observed in the placebo group (p = 0.005). CONCLUSIONS: A supplementation with Boswellia, betaine and myo-inositol reduces fibroadenoma dimension in young women. No relevant side effects have been recorded.

An association of boswellia, betaine and myo-inositol (Eumastós) in the treatment of mammographic breast density: a randomized, double-blind study.

OBJECTIVE: Mammographic breast density is a recognized risk factor for breast cancer. The causes that lead to the proliferation of the glandular breast tissue and, therefore, to an increase of breast density are still unclear. However, a treatment strategy to reduce the mammary density may bring about very relevant clinical outcomes in breast cancer prevention. Myo-inositol is a six-fold alcohol of cyclohexane, has already been proved to modulate different pathways: inflammatory, metabolic, oxidative and endocrine processes, in a wide array of human diseases, including cancer and the genesis of mammary gland and breast diseases, like fibrosis, as well as metabolic and endocrine cues. Similarly, boswellic acid and betaine (three-methyl glycine) both inhibit inflammation and exert protective effects on breast physiology. Based on this scientific background, we hypothesized that a combination including, boswellic acid, betaine and myo-inositol would be able to reduce breast density working on different pathways. PATIENTS AND METHODS: In this study, seventy-six premenopausal women were randomly assigned to the placebo and the experimental drug arms (Eumastós) for six months. RESULTS: After 6 months of treatment, statistically significant difference between the two groups was recorded on the breast density reduction (60% vs. 9%), using mammographic as well as ultrasound examination. CONCLUSIONS: Preliminary data collected here with support the starting assumptions, that the association comprising boswellic acid, betaine and myo-inositol significantly reduces mammary density, providing the first evidence for a new and safe approach for the management of mammographic density treatment.

Precision Measurement of the Helium Flux in Primary Cosmic Rays of Rigidities 1.9 GV to 3 TV with the Alpha Magnetic Spectrometer on the International Space Station.

Knowledge of the precise rigidity dependence of the helium flux is important in understanding the origin, acceleration, and propagation of cosmic rays. A precise measurement of the helium flux in primary cosmic rays with rigidity (momentum/charge) from 1.9 GV to 3 TV based on 50 million events is presented and compared to the proton flux. The detailed variation with rigidity of the helium flux spectral index is presented for the first time. The spectral index progressively hardens at rigidities larger than 100 GV. The rigidity dependence of the helium flux spectral index is similar to that of the proton spectral index though the magnitudes are different. Remarkably, the spectral index of the proton to helium flux ratio increases with rigidity up to 45 GV and then becomes constant; the flux ratio above 45 GV is well described by a single power law.

Precision Measurement of the Proton Flux in Primary Cosmic Rays from Rigidity 1 GV to 1.8 TV with the Alpha Magnetic Spectrometer on the International Space Station.

A precise measurement of the proton flux in primary cosmic rays with rigidity (momentum/charge) from 1 GV to 1.8 TV is presented based on 300 million events. Knowledge of the rigidity dependence of the proton flux is important in understanding the origin, acceleration, and propagation of cosmic rays. We present the detailed variation with rigidity of the flux spectral index for the first time. The spectral index progressively hardens at high rigidities.

Hyaluronic acid and vitamins are effective in reducing vaginal atrophy in women receiving radiotherapy.

AIM: During the last decades, therapies targeting cervical cancer have been considerably improved. Surgery and radiotherapy (RT) represent the main common therapeutic approach in cervical cancer. In order to minimize the side effects of radiotherapy approach, several protocols have been developed such as brachytherapy (BRT). Among the side effects associated with RT, the vaginal atrophy is the most important and common one. Vaginal atrophy, in turn, leads to additional alterations like inflammation, associated to relevant symptoms such as itching, burning and dyspareunia. All these alterations heavily affect the quality of women's life. The aim of our study was to evaluate the toxicity induced by RT on vaginal mucosa, and the adjuvant action of a product containing LMWHA, vitamin A, and Vitamin E (Santes®, Lo.Li. Pharma, Rome, Italy). The introduction of adjuvant therapies may have likely had a relevant place in providing that result. METHODS: A prospective randomized study was designed. From October 2006 to October 2008, 45 women with a mean age 38 ± 6 years were enrolled. After surgery, all patients were treated with 4 weeks of RT and 4 weeks of BRT, concomitantly with chemiotherapy. They were randomly assigned in two groups: 23 women were treated with two suppositories (Santes®) per day for 4 months. For the first two months the preventive treatment was simultaneous to RT and BRT. Instead the control groups for composed by 22 patients and they did not undergo any treatment during RT. To evaluate the efficacy of Santes® treatment three biopsies were performed. RESULTS: At the second biopsy, after the BRT therapy, the treated group showed a statistically significant improvement (P<0.05 vs. control) on inflammation, cell atypia, fibrosis, mucositis and bleeding. At the third biopsy, two months after BRT, further statistically improvement were observed for all RT/BRT associated side effects. The treatment showed an efficacy also in terms of pain severity. CONCLUSION: Our data suggest that low molecular weight HA shows good performances in treating RT-damaged tissue and plays a key role in all steps of the healing process. Indeed the results shows that women exposed to RT treatments and simultaneously treated with Santes®, had an optimal resolution of vaginal atrophy and related symptoms.

Precision Measurement of the (e

We present a measurement of the cosmic ray (e^{+}+e^{-}) flux in the range 0.5 GeV to 1 TeV based on the analysis of 10.6 million (e^{+}+e^{-}) events collected by AMS. The statistics and the resolution of AMS provide a precision measurement of the flux. The flux is smooth and reveals new and distinct information. Above 30.2 GeV, the flux can be described by a single power law with a spectral index γ=-3.170±0.008(stat+syst)±0.008(energy scale).

Electron and positron fluxes in primary cosmic rays measured with the alpha magnetic spectrometer on the international space station.

Precision measurements by the Alpha Magnetic Spectrometer on the International Space Station of the primary cosmic-ray electron flux in the range 0.5 to 700 GeV and the positron flux in the range 0.5 to 500 GeV are presented. The electron flux and the positron flux each require a description beyond a single power-law spectrum. Both the electron flux and the positron flux change their behavior at ∼30 GeV but the fluxes are significantly different in their magnitude and energy dependence. Between 20 and 200 GeV the positron spectral index is significantly harder than the electron spectral index. The determination of the differing behavior of the spectral indices versus energy is a new observation and provides important information on the origins of cosmic-ray electrons and positrons.

High statistics measurement of the positron fraction in primary cosmic rays of 0.5-500 GeV with the alpha magnetic spectrometer on the international space station.

A precision measurement by AMS of the positron fraction in primary cosmic rays in the energy range from 0.5 to 500 GeV based on 10.9 million positron and electron events is presented. This measurement extends the energy range of our previous observation and increases its precision. The new results show, for the first time, that above ∼200 GeV the positron fraction no longer exhibits an increase with energy.

Inositol: history of an effective therapy for Polycystic Ovary Syndrome.

Inositol is a physiological compound belonging to the sugar family. The two inositol stereoisomers, myo-inositol and D-chiroinositol are the two main stereisomers present in our body. Myo-inositol is the precursor of inositol triphosphate, a second messenger regulating many hormones such as TSH, FSH and insulin. D-chiroinositol is synthetized by an insulin dependent epimerase that converts myo-inositol into D-chiro-inositol. Polycistic Ovary Syndrome (PCOS) is a metabolic and hormonal disorder and a common cause of infertility. Insulin resistance and the consequent hyperinsulinaemia contribute to hyperandrogenism development, typical marker of PCOS. In these patients myo and/or D-chiro-inositol administration improves insulin sensivity while only myo-inositol is a quality marker for oocytes evaluation. Myo-inositol produces second messengers for FSH and glucose uptake, while D-chiroinositol provides second messengers promoting glucose uptake and glycogen synthesis. The physiological ratio of these two isomers is 40:1 (MI/DCI) and seems to be an optimal approach for the treatment of PCOS disorders.

Reprogramming cancer cells in endocrine-related tumors: open issues.

Reprogramming technologies have been developed to revert somatic differentiated cells into pluripotent stem cells that can be differentiated into different lineages potentially useful in stem cell therapy. Reprogramming methods have been progressively refined to increase their efficiency, to obtain a cell population suitable for differentiation, and to eliminate viral plasmid which could be responsible for many unwanted side-effects when used in personalized medicine. All these methods are aimed to introduce into the cell genes or mRNAs encoding a set of four transcription factors (OCT- 4, SOX-2, KLF-4 and c-MYC) or a set of three lincRNAs (large intragenic non-coding RNAs) acting downstream of the reprogramming transcription factors OCT-4, SOX-2 and NANOG. Translational clinical applications in human pathologies and in developmental, repair and cancer biology have been numerous. Cancer cells can be, at least in principle, reprogrammed into a normal phenotype. This is a recently raised issue, rapidly advancing in many human tumors, especially endocrine-related cancers, such as breast, prostate and ovarian ca. The present review aims to describe basic phenomena observed in reprogramming tumor cells and solid tumors and to discuss their meaning in human hormone-related cancers. We will also discuss the fact that some of the targeted transcription factors are "normally" activated in a number of physiological processes, such as morphogenesis, hypoxia and wound healing, suggesting an in vivo role of reprogramming for development and homeostasis. Finally, we will review concerns and warnings raised for in vivo reprogramming of human tumors and for the use of induced pluripotent stem cells (iPSCs) in human therapy.

Physical forces and non linear dynamics mould fractal cell shape: quantitative morphological parameters and cell phenotype.

Cell shape is mainly determined by biophysical constraints, interacting according to non-linear dynamics upon the basic units provided by the genome. In turn, the specific configuration a cell acquires plays a fundamental, permissive role in modulating gene expression and many other complex biological functions. Cell shape is tightly connected to cell activity and can be considered the most critical determinant of cell function. As a consequence, measurable parameters describing shape could be considered as 'omics' descriptors of the specific level of observation represented by the cell-stroma system. Such an approach promises to formalize some of the underlying basic mechanisms and, ultimately, provide a holistic understanding of the biological processes.