Author Correction: Epigallocatechin gallate, folic acid, vitamin B12, and hyaluronic acid significantly increase apoptosis and p53 expression in HeLa cells.

Correction to: Eur Rev Med Pharmacol Sci 2023; 27 (11): 5240-5245-DOI: 10.26355/eurrev_202306_32642-PMID: 37318498-published online on June 13, 2023. After publication, the authors discovered that Prof. C. Gentili's affiliation was wrong as he has never been a member of the Italian Society of Colposcopy and Cervicovaginal Pathology (SICPCV). The authors never found the mistake during the review process nor requested a correction before publication. Therefore, the second affiliation has been corrected as follows: Pathologist, Independent Practitioner, Carrara, Italy. There are amendments to this paper. The Publisher apologizes for any inconvenience this may cause. https://www.europeanreview.org/article/32642.

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.

Risks and limits of bariatric surgery: old solutions and a new potential option.

The present review focuses on the side effects that ex-obese patients face following bariatric surgery. We searched through the principal medical indexes (SCOPUS, Web of Science, PubMed, MEDLINE) using the following words, both alone and in combinations: bariatrics; bariatric surgery; anemia; vitamin B12; cobalamin; folate; folic acid; iron; iron supplements; gut microbiota; lactalbumin; α-lactalbumin. To perform exhaustive research, we considered articles published since 1985. Bariatric surgery induces states of nutritional deficiencies. In particular, the surgery results in a drastic fall in the levels of iron, cobalamin, and folate. Despite the dietary supplements which can counteract such decrease, some limitations exist in the nutraceutical approach. Indeed, the gastrointestinal side effects of supplements, the alterations in the microbiota, and the reduced absorption induced by the surgery may impair the effect of dietary supplements, exposing the patients to the risk of developing nutritional deficiencies. Recent literature reports the effect of promising molecules to counteract such limitations, which include α-lactalbumin, a whey protein with prebiotic activities, and new pharmaceutical forms of iron supplements, namely micronized ferric pyrophosphate. If on the one hand, α-lactalbumin enhances intestinal absorption and helps in restoring a physiological microbiota, micronized ferric pyrophosphate has a high tolerability and low or null risk of gastrointestinal side effects. Bariatric surgery represents a valid solution to obesity and obesity-related disease. However, the procedure may induce deficiencies in micronutrients. Data exists on the promising activities of α-lactalbumin and micronized ferric pyrophosphate, which may help in preventing bariatric-induced anemia.

Epigallocatechin gallate, folic acid, vitamin B12, and hyaluronic acid significantly increase apoptosis and p53 expression in HeLa cells.

OBJECTIVE: The human papilloma virus (HPV) is the etiological agent of cervical cancer in more than 95% of cases worldwide. Although most HPV infections clear up on their own and most pre-cancerous lesions spontaneously resolve, in some cases, they can persist, leading to lesions which may progress towards invasive cervical cancer. MATERIALS AND METHODS: We evaluated the effects of the association of epigallocatechin gallate (EGCG) + folic acid (FA) + vitamin B12 (B12) + hyaluronic acid (HA) on HPV-positive cervical cancer cells (HeLa). RESULTS: The association of EGCG + FA + B12 + HA induced a significant increase of apoptosis and p53 gene expression with a concomitant decrease of E6/E7 gene expression, a marker of HPV infection. CONCLUSIONS: This study provides for the first-time evidence on the potential additive activity of EGCG + FA + B12 + HA in counteracting HPV infection, by increasing apoptosis and p53 expression in HPV-infected cervical HeLa cells.

Does high molecular weight-hyaluronic acid prevent hormone-induced preterm labor in rats?

OBJECTIVE: The aim of our study was to test if oral high hyaluronic acid (HMW-HA) administration was effective in contrasting induced preterm birth (PTB) in female Wistar rats. MATERIALS AND METHODS: A total of 24 pregnant rats were pretreated with placebo or low (2.5 mg/day)/high dose (5 mg/day) of HMW-HA (day 15) and then induced to delivery with mifepristone plus prostaglandin E2 (PGE2) (3 mg/100 µL + 0.5 mg/animal) on the 19th day of pregnancy. The delivery time was recorded and the messenger RNA (mRNA) levels of pro-inflammatory cytokines [tumor necrosis factor-α (TNF-α), interleukin (IL)1ß, IL-6] were detected in the uterine tissues by real-time polymerase chain reaction (real PCR). Immunohistochemistry was performed alongside. RESULTS: Oral HMW-HA was well absorbed in the body and was able to significantly delay the timing of delivery and decrease mRNA synthesis of pro-inflammatory cytokines. CONCLUSIONS: HMW-HA, by acting in the management of PTB, may represent a new approach to protecting physiological pregnancy.

Safety of inositol supplementation in patients taking lithium or valproic acid: a pilot clinical study.

OBJECTIVE: Mood stabilizers like lithium (Li) and valproic acid (VPA) act via cellular depletion of inositol in the central nervous system (CNS). However, such depletion also involves peripheral tissues, thus exposing patients to various side effects. Preclinical and clinical studies revealed the effectiveness of inositol supplementation to recover such pathological conditions. Nevertheless, the risk of reducing the effectiveness of pharmacological therapies by raising inositol levels in the CNS, still represents a matter of concern. This study adds new insights on this aspect, highlighting the safety of a tailored dosage of inositol in patients taking Li or VPA. PATIENTS AND METHODS: We enrolled 15 patients over 18 years of age taking Li and/or VPA. They assumed 2 gr of myo-inositol (myo-ins) and d-chiro-inositol (d-chiro-ins) in the combined 80:1 ratio, plus 50 mg of α-lactalbumin (α-LA), twice a day for a total period of 6 months (T1). Evaluating the interference of such dietary supplementation with pharmacological therapy was the primary outcome. Monitoring blood levels of thyroid (fT3, fT4, TSH) and metabolic markers (fasting insulin, glucose, HOMA-IR index, triglycerides, HDL, LDL) were secondary outcomes. The analysis was carried out by comparing values at baseline (T0) and T1 (6 months). RESULTS: After 6 months, pharmacological therapy was still suitable for patients, requiring no changes nor adjustments. Instead, inositol treatment improved those borderline values about thyroid functionality and glucose and lipid metabolism. CONCLUSIONS: This pilot study demonstrated that the dosage of 4 gr/daily of inositol is safe in patients taking Li/VPA, as we recorded no interference with the pharmacological therapy. Moreover, such treatment may counteract or even prevent side effects, thus improving patients' quality of life.

Unopposed estrogens: current and future perspectives.

Estrogens and progestogens act on female reproductive tissues in opposite ways. As they counteract each other actions, the correct balance between these two classes of hormones is pivotal to avoid dangerous states. Unopposed estrogens occur when progestogen levels do not balance estrogens, primarily deriving from overproduction of estrogens via aromatase enzyme. In the endometrium, unopposed estrogens induce proliferative or invasive phenomena, which represent the first step toward different diseases. These pathologies include endometrial hyperplasia, endometrial polyps, endometriosis and adenomyosis. Endometrial hyperplasia and polyps are proliferative pathologies, while endometriosis and adenomyosis are characterized by the invasion of other tissues by endometrial cells. Current pharmacological treatments include Gonadotropin-Releasing-Hormone analogs, aromatase inhibitors and progestogens, either alone or in combination with estrogens. As these drugs usually lead to burdensome undesired effects, researchers seek to find new therapeutical molecules. Recent literature highlights the positive effects of metformin, an insulin sensitizing drug that reduces the insulin proliferative stimulus on the endometrium. d-chiro-inositol is an insulin second messenger with insulin sensitizing and mimetic properties, recently described as an aromatase down-regulator. Based on current evidence, d-chiro-inositol may be useful to treat the pathologies responsive to unopposed estrogens.

Treatment of lean PCOS teenagers: a follow-up comparison between Myo-Inositol and oral contraceptives.

OBJECTIVE: Polycystic ovary syndrome (PCOS) is an endocrinological and metabolic disorder widely diffused and diagnosed in women of reproductive age. The pathology exhibits alteration of the reproductive functions, including conditions as hyperandrogenism, menstrual cycle irregularity, type 2 diabetes. These conditions are visible in the patients through phenotypical manifestations as hirsutism, acne, and obesity. Even if the syndrome is characterized by common features among both adult and adolescent women, the diagnostic criteria are different for the two age categories and to date still controversial. We investigated different treatments in PCOS adolescents with non-severe metabolic conditions, to evaluate which could be the appropriate therapeutical approach for these patients. PATIENTS AND METHODS: We enrolled lean teenagers with PCOS, and we divided the patients in two age ranges: 13-16 years old and 17-19 years old. They were treated for 3 months either with oral contraceptive pills (OCP) drospirenone/ethinylestradiol (group A), myo-Inositol (myo-Ins) (group B), or OCP plus myo-Ins (group C). Data were analyzed with a descriptive statistics summarizing quantitative variables including median, 25th and 75th percentiles. RESULTS: We pointed out that the group of 13-16 years old lean teenagers treated with myo-Ins exhibit a significant decrease of weight and body mass index (BMI), and an effective improvement the metabolic and hormonal parameters achieved with a non-pharmacological treatment. In the older teenagers aged 17-19 years, data highlights that myo-Ins treatment in combination with OCP prevents the increases of weight and BMI, improves the metabolic profile of the patients, and strongly ameliorates the hormonal parameters analyzed. CONCLUSIONS: The results indicate a different scenario in the two age ranges considered and interestingly suggest an important role of myo-Ins in the PCOS context. A therapy based on this natural compound alone or in combination with OCP seems effective to improve both metabolic and hormonal parameters of PCOS adolescents and thus could represent a novel and valid option to consider for the treatment of this syndrome.

A multicenter clinical study with myo-inositol and alpha-lactalbumin in Mexican and Italian PCOS patients.

OBJECTIVE: This open-label non-randomized clinical study aimed at evaluating the effects of myo-inositol plus alpha-lactalbumin in two groups of PCOS women, treated in Mexico and Italy. Alpha-lactalbumin was used being effective in increasing myo-inositol intestinal absorption. This effect is very useful in greatly reducing the therapeutic failure of myo-inositol in some patients (inositol resistant subjects). PATIENTS AND METHODS: The study involved 34 normal weight or overweight patients (14 in Mexico and 20 in Italy), aged 18 to 40 years, with anovulation and infertility > 1 year and insulin resistance diagnosed by HOMA-Index. Patients were administered orally with 2 g myo-inositol, 50 mg alpha-lactalbumin, and 200 µg of folic acid twice a day for 6 months. Controls were the same patients at t0 (baseline). The primary outcome was HOMA-index decrease after 3 and 6 months of treatment. Other parameters monitored were BMI, progesterone, LH, FSH, total testosterone, free testosterone, androstenedione, total cholesterol, HDL, LDL, triglycerides. RESULTS: Recovery was general, and its relevance was higher when the starting point was further away from the normal range. The most important results were obtained with insulin, HOMA-index, LH, and androstenedione. No significant adverse effects were detected in both groups of patients. CONCLUSIONS: This clinical trial demonstrated for the first time that myo-inositol and alpha-lactalbumin improve important parameters in PCOS patients characterized by different metabolic profiles.

Inositol treatment for psychological symptoms in Polycystic Ovary Syndrome women.

OBJECTIVE: PCOS women experience different discomfort as a consequence of the illness. During the years, several risk factors and treatments emerged. This review aims at underlining evidence on psychological symptoms in PCOS women and on the effectiveness of therapies. MATERIALS AND METHODS: We reviewed literature searching through different databases. We used different keywords, including: PCOS, PCOS and depression, PCOS and anxiety, PCOS and psychological, PCOS depression and risk factors, PCOS depression therapies, depression and inositol. RESULTS: Based on the collected evidence, PCOS women are more likely to develop psychological symptoms, like depression or anxiety disorders. Furthermore, several risk factors are associated with higher depression or worse psychological conditions. Particularly, the literature highlights BMI, hirsutism, insulin resistance, excess of androgens and lack of serum Vitamin D. Even though several pharmaceuticals find application in psychological symptoms, some of them can impair hormonal condition in PCOS women. Few molecules are able to improve psychological symptoms without impairing hormonal profiles. Among these, myo-inositol appears to be the most interesting, as it is also considered first-line therapy in PCOS women. CONCLUSIONS: Psychological symptoms affect PCOS women more than healthy subjects. Among the different treatments, inositol emerges as a safe approach, being the first-line therapy in PCOS for hormonal improvement and having putative effects also in psychiatrists.

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.

Enhancement of D-chiro-inositol transport across intestinal cells by alpha-Lactalbumin peptides.

OBJECTIVE: This study aims to characterize in vitro D-chiro-inositol intestinal absorption and identify factors able to improve its bioavailability. D-chiro-inositol, one of the natural occurring stereoisomer of myo-inositol, acts as a second messenger in insulin-regulated glucose metabolism in complementary mode with myo-inositol. Because of their insulin-mimetic activities and safety, both myo-inositol and D-chiro-inositol are often employed as supplements in insulin-resistance treatment. MATERIALS AND METHODS: Trans-epithelial passage of D-chiro-inositol was evaluated in the human intestinal Caco-2 cell line differentiated on filter, a widely established in vitro model to study intestinal absorption. D-chiro-inositol transport was assayed in a concentration range corresponding to an estimated in vivo concentration following oral supplementation. α-Lactalbumin peptides, obtained by in vitro simulated gastrointestinal digestion, were tested as possible modulators of the intestinal permeability of D-chiro-inositol. RESULTS: The absorption of this stereoisomer was relatively low and presumably due to passive diffusion, while it was greatly enhanced by the presence of α-Lactalbumin digest. α-Lactalbumin peptides induced an increase in paracellular permeability that was completely reversible, indicating lack of cytotoxicity. This effect involved temporary rearrangement of F-actin apical cytoskeleton and of the tight junction protein ZO-1. CONCLUSIONS: Although further studies are required to identify and characterize the most effective peptides, the ability of α-Lactalbumin digest to act as absorption enhancers may have very interesting and promising applications in the fields of nutritional supplements and pharmacology.

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.

Pheromone receptors and their putative ligands: possible role in humans.

Pheromones are ectohormones that play an important role in communication and behavior. Pheromones and pheromone receptor genes are important in mice and other mammals that rely heavily on pheromone cues to survive. Although there is controversy about whether pheromones and pheromone receptor genes have the same importance or are even active in humans, there are some hints that they might have roles in sociosexual behavior and mental disorders. The aim of this qualitative review was to provide an overview of the state of the art regarding pheromones and pheromone receptors in humans and their possible implications in human physiology and pathology. An electronic search was conducted in MEDLINE, PubMed and Scopus databases for articles published in English up to December 2018. The search concerned a possible role of pheromones and pheromone receptors in humans with implications for sociosexual behavior, mental disorders, the menstrual cycle and nutrition. Pheromone communication in humans has not been definitively demonstrated. However, the potential ability of putative pheromones to activate the hypothalamus, which controls the release of many hormones, suggests they could have a role in systemic functions in humans. Future confirmation of the effects of pheromones and pheromone receptors in humans could be useful in the prevention and treatment of various human disorders.

Genetics of lipedema: new perspectives on genetic research and molecular diagnoses.

OBJECTIVE: The aim of this qualitative review is to provide an update on the current understanding of the genetic determinants of lipedema and to develop a genetic test to differentiate lipedema from other diagnoses. MATERIALS AND METHODS: An electronic search was conducted in MEDLINE, PubMed, and Scopus for articles published in English up to March 2019. Lipedema and similar disorders included in the differential diagnosis of lipedema were searched in the clinical synopsis section of OMIM, in GeneCards, Orphanet, and MalaCards. RESULTS: The search identified several genetic factors related to the onset of lipedema and highlighted the utility of developing genetic diagnostic testing to help differentiate lipedema from other diagnoses. CONCLUSIONS: No genetic tests or guidelines for molecular diagnosis of lipedema are currently available, despite the fact that genetic testing is fundamental for the differential diagnosis of lipedema against Mendelian genetic obesity, primary lymphedema, and lipodystrophies.

Genetic background, nutrition and obesity: a review.

OBJECTIVE: To summarize the latest information on the relationship between genes and common forms of obesity, and to review genetic markers (SNPs and miRNA) that play a role in predisposing to common forms of obesity and related disorders. MATERIALS AND METHODS: We searched PubMed with the following keywords: (obesity[Title/Abstract]) AND predisposition[Title/Abstract]) AND miRNA[Title/Abstract]) OR polymorphism[Title/Abstract]. RESULTS: From the search we obtained a total of 44 gene loci and 48 miRNAs associated with common obesity. CONCLUSIONS: It is now widely accepted that obesity involves interactions between environmental risk factors (physical inactivity, excessive calorie intake, chronic stress, taste perception) and a genetic background of risk. Analysis of the genetic background of obese subjects is therefore an important way to determine the molecular mechanisms controlling the link between food intake and obesity, enabling a better understanding of how these interactions may differ from person to person.

Mendelian obesity, molecular pathways and pharmacological therapies: a review.

OBJECTIVE: In this qualitative review we analyze the major pathways and mechanisms involved in the onset of genetically-determined obesity (Mendelian obesity), identifying possible pharmacological treatments and trials. MATERIALS AND METHODS: We searched PubMed with the keywords (obesity[Title/Abstract]) AND mutation[Title/Abstract], and OMIM with the keyword "obesity". In both cases, we selected non-syndromic Mendelian obesity. We then searched ClinicalTrials.gov with the following criteria: "recruitment status: active, not recruiting and completed"; "study type: interventional (clinical trial)"; "study results: with results"; type of intervention: "drug or dietary supplement". RESULTS: From the PubMed and OMIM searches we obtained a total of 15 genes associated with monogenic Mendelian obesity. From ClinicalTrials.gov we retrieved 46 completed or active trials of pharmacological treatments. CONCLUSIONS: We summarized the molecular bases of Mendelian obesity and searched for any clinical trials completed or underway for the treatment of severe forms of obesity. Most Mendelian obesities are linked to dysfunctions in the leptin/melanocortin signaling pathway, and most of the possible drugs target this pathway in order to improve energy expenditure and reduce food intake.