Diet Plus Inositols, α-Lactalbumin and Gymnema sylvestre: The Successful Combo to Restore Body Weight and Metabolic Profile in Obese and Dysmetabolic Patients.

The primary control of dysmetabolic patients is extremely challenging worldwide, with inadequate dietary habits and sporadic physical activity among the key risk factors for metabolic syndrome onset. Nowadays, there is no exclusive treatment for this condition, and considering that preventive measures usually fail, new therapeutic approaches need to be proposed and investigated. This present pilot study compared the effects of diet alone and in association with a combination of myo-inositol and d-chiro-inositol in their 40:1 ratio, α-lactalbumin, and Gymnema sylvestre on different metabolic parameters in obese dysmetabolic patients. To this purpose, 37 patients with BMI between 30 and 40 and fasting blood glucose between 100 and 125 mg/dL were divided into two groups: (i) the control group followed a hypocaloric Mediterranean diet, (ii) while the study group was also supplemented with a daily dosage of two sachets, each one containing 1950 mg myo-inositol, 50 mg d-chiro-inositol, 50 mg α-lactalbumin, and 250 mg Gymnema Sylvestre. After a 6-month treatment, all parameters improved in both groups. Nevertheless, the treated group experienced a greater improvement, especially concerning the variation from the baseline of HOMA index, triglycerides, BMI, body weight, and waist circumference. These findings support the supplementation with myo-inositol and d-chiro-inositol in the 40:1 ratio, α-lactalbumin, and Gymnema sylvestre as a therapeutical strategy to potentiate the beneficial effects induced via dietary programs in dysmetabolic patients.

Ketone Bodies and SIRT1, Synergic Epigenetic Regulators for Metabolic Health: A Narrative Review.

Ketone bodies (KBs) and Sirtuin-1 (SIRT1) have received increasing attention over the past two decades given their pivotal function in a variety of biological contexts, including transcriptional regulation, cell cycle progression, inflammation, metabolism, neurological and cardiovascular physiology, and cancer. As a consequence, the modulation of KBs and SIRT1 is considered a promising therapeutic option for many diseases. The direct regulation of gene expression can occur in vivo through histone modifications mediated by both SIRT1 and KBs during fasting or low-carbohydrate diets, and dietary metabolites may contribute to epigenetic regulation, leading to greater genomic plasticity. In this review, we provide an updated overview of the epigenetic interactions between KBs and SIRT1, with a particular glance at their central, synergistic roles for metabolic health.

Positive Effects of α-Lactalbumin in the Management of Symptoms of Polycystic Ovary Syndrome.

To date, the involvement of α-Lactalbumin (α-LA) in the management of polycystic ovary syndrome (PCOS) refers to its ability to improve intestinal absorption of natural molecules like inositols, overcoming the inositol resistance. However, due to its own aminoacidic building blocks, α-LA is involved in various biological processes that can open new additional applications. A great portion of women with PCOS exhibit gastrointestinal dysbiosis, which is in turn one of the triggering mechanisms of the syndrome. Due to its prebiotic effect, α-LA can recover dysbiosis, also improving the insulin resistance, obesity and intestinal inflammation frequently associated with PCOS. Further observations suggest that altered gut microbiota negatively influence mental wellbeing. Depressive mood and low serotonin levels are indeed common features of women with PCOS. Thanks to its content of tryptophan, which is the precursor of serotonin, and considering the strict link between gut and brain, using α-LA contributes to preserving mental well-being by maintaining high levels of serotonin. In addition, considering women with PCOS seeking pregnancy, both altered microbiota and serotonin levels can induce later consequences in the offspring. Therefore, a deeper knowledge of potential applications of α-LA is required to transition to preclinical and clinical studies extending its therapeutic advantages in PCOS.

A Nutritional Approach for the Management of Chemotherapy-Induced Diarrhea in Patients with Colorectal Cancer.

This study aimed to determine if dietary modifications using a nutritional regimen could prevent or reduce the incidence of cancer therapy-induced diarrhea in patients with metastatic colorectal cancer and to evaluate the relationship of Vitamin D blood levels with diarrhea severity. Patients with metastatic colorectal cancer were enrolled. A Mediterranean diet, containing some special limitations aiming to reduce the risk of diarrhea, was administered before and during the entire chemotherapy program. Enrolled patients numbering 60/137 (44%) had diarrhea during chemotherapy. Adherence to the diet was high in 36 (26.3%) patients, medium in 94 (68.6%), and low in 7 (5.1%). Mean adherence to the diet was significantly lower in patients who experienced diarrhea with maximum grade 2−3 compared to those who had no diarrhea or grade 1 diarrhea (score = 5.4 ± 1.9 vs. 7.1 ± 1.5, p < 0.001). Patients with higher adherence to the diet had a lower risk of grade 2−3 diarrhea (odds ratio: 0.5 (95% CI: 0.3−0.7, p < 0.001)). In addition, patients who completed a higher number of chemotherapy cycles had an increased risk of grade 2−3 diarrhea (odds ratio: 1.2 (95% CI: 1.0−1.5, p = 0.02)). Of note, a lower level of Vitamin D correlated with an increased risk of G2-G3 diarrhea (p = 0.03). A diet based on vegetables with a controlled fiber content, Mediterranean Modified Healthy Diet (MMHD), is useful to control the incidence of cancer therapy-induced diarrhea.

Obesity treatment within the Italian national healthcare system tertiary care centers: what can we learn?

INTRODUCTION: The prevalence of obesity is soaring all over the world, and Italy is reaching the same pace. Similar to other countries, the Italian healthcare system counts on a three-tier model for obesity care, and each region has freedom in the implementation of guidelines. No national record is currently available to monitor the actual situation throughout the country. PURPOSE: To provide a report of the current status on the availability of specialized public obesity care services in Italy. METHODS: Regional prevalence of obesity was extrapolated from publicly available data. Data on facilities for the management of obesity were retrieved from records provided by national scientific societies. Whenever possible, data was verified through online research and direct contact. RESULTS: We report a north-south and east-west gradient regarding the presence of obesity focused facilities, with an inverse correlation with the regional prevalence of obesity (R = 0.25, p = 0.03). Medical-oriented centers appear homogeneous in the multidisciplinary approach, the presence of a bariatric surgery division, the availability of support materials and groups, with no major difference on follow-up frequency. Surgery-oriented centers have a more capillary territorial distribution than the medically oriented, but not enough data was retrieved to provide a thorough description of their characteristics. CONCLUSION: Obtaining a clear picture of the situation and providing consistent care across the country is a challenging task due to the decentralized organization of regions. We provide a first sketch, reporting that the model is applied unevenly, and we suggest feasible actions to improve the situation in our country and elsewhere. LEVEL OF EVIDENCE: Level V, narrative review.

Scientific evidence underlying contraindications to the ketogenic diet: An update.

First identified as a feasible treatment for intractable epilepsy, the ketogenic diet (KD) has recently gained popularity thanks to growing evidence on applications such as weight loss, most importantly, but also NAFLD, cancer, neurologic conditions and chronic pain. As with any treatment, whether pharmacologic or not, the KD might not be an appropriate intervention for every individual, and a number of contraindications have been proposed, now deeply rooted into clinical practice, excluding de facto many patients that could benefit from its use. However, many of these concerns were expressed due to the absence of clinical studies conducted on fragile populations, and an assessment of lately emerged evidence relative to KD safety is currently lacking and much needed. We herein provide a critical revision of the literature behind each safety alert, in order to guide through the treatment options in the case of subjects with an indication to the KD and a borderline safe situation. Based on available evidence, the possible use of this diet as a therapeutic intervention should be assessed on a patient-to-patient basis by adequately skilled medical doctors, keeping in mind current recommendations, but reading them through the knowledge of the current state of the art.

Beneficial effects of the ketogenic diet on nonalcoholic fatty liver disease: A comprehensive review of the literature.

Nonalcoholic fatty liver disease (NAFLD) is a major cause of chronic liver disease, characterized by hepatic fat accumulation and possible development of inflammation, fibrosis, and cancer. The ketogenic diet (KD), with its drastic carbohydrate reduction, is a now popular weight loss intervention, despite safety concerns on a possible association with fatty liver. However, KDs were also reported to be beneficial on hepatic pathology, with ketone bodies recently proposed as effective modulators of inflammation and fibrosis. If the beneficial impact of weight loss on NAFLD is established, less is known on the effect of macronutrient distribution on such outcome. In a hypocaloric regimen, the latter seems not to be crucial, whereas at higher calorie intake, macronutrient ratio and, theoretically, ketosis, may become important. KDs could positively impact NAFLD for their very low carbohydrate content, and whether ketosis plays an additional role is unknown. Indeed, several mechanisms may directly link ketosis and NAFLD improvement, and elucidating these aspects would pave the way for new therapeutic strategies. We herein aimed at providing an accurate revision of current literature on KDs and NAFLD, focusing on clinical evidence, metabolic pathways involved, and strict categorization of dietary interventions.

Overweight and obese patients with nickel allergy have a worse metabolic profile compared to weight matched non-allergic individuals.

BACKGROUND: A lack of balance between energy intake and expenditure due to overeating or reduced physical activity does not seem to explain entirely the obesity epidemic we are facing, and further factors are therefore being evaluated. Nickel (Ni) is a ubiquitous heavy metal implied in several health conditions. Regarding this, the European Food Safety Authority has recently released an alert on the possible deleterious effects of dietary Ni on human health given the current levels of Ni dietary intake in some countries. Pre-clinical studies have also suggested its role as an endocrine disruptor and have linked its exposure to energy metabolism and glucose homeostasis dysregulation. Ni allergy is common in the general population, but preliminary data suggest it being even more widespread among overweight patients. OBJECTIVES: The aim of this study has been to evaluate the presence of Ni allergy and its association with the metabolic and endocrine profile in overweight and obese individuals. METHODS: We have evaluated 1128 consecutive overweight and obese outpatients. 784 were suspected of being allergic to Ni and 666 were assessed for it. Presence of Ni allergy and correlation with body mass index (BMI), body composition, metabolic parameters and hormonal levels were evaluated. RESULTS: We report that Ni allergy is more frequent in presence of weight excess and is associated with worse metabolic parameters and impaired Growth Hormone secretion. CONCLUSIONS: We confirm that Ni allergy is more common in obese patients, and we report for the first time its association with worse metabolic parameters and impaired function of the GH-IGF1 axis in human subjects.

Testicular histopathology, semen analysis and FSH, predictive value of sperm retrieval: supportive counseling in case of reoperation after testicular sperm extraction (TESE).

BACKGROUND: To provide indicators for the likelihood of sperm retrieval in patients undergoing testicular sperm extraction is a major issue in the management of male infertility by TESE. The aim of our study was to determine the impact of different parameters, including testicular histopathology, on sperm retrieval in case of reoperation in patients undergoing testicular sperm extraction. METHODS: We retrospectively analyzed 486 patients who underwent sperm extraction for intracytoplasmic sperm injection and testicular biopsy. Histology was classified into: normal spermatogenesis; hypospermatogenesis (reduction in the number of normal spermatogenetic cells); maturation arrest (absence of the later stages of spermatogenesis); and Sertoli cell only (absence of germ cells). Semen analysis and serum FSH, LH and testosterone were measured. RESULTS: Four hundred thirty patients had non obstructive azoospermia, 53 severe oligozoospermia and 3 necrozoospermia. There were 307 (63%) successful sperm retrieval. Higher testicular volume, lower levels of FSH, and better histological features were predictive for sperm retrieval. The same parameters and younger age were predictive factors for shorter time for sperm recovery. After multivariable analysis, younger age, better semen parameters, better histological features and lower values of FSH remained predictive for shorter time for sperm retrieval while better semen and histology remained predictive factors for successful sperm retrieval. The predictive capacity of a score obtained by summing the points assigned for selected predictors (1 point for Sertoli cell only, 0.33 points for azoospermia, 0.004 points for each FSH mIU/ml) gave an area under the ROC curve of 0.843. CONCLUSIONS: This model can help the practitioner with counseling infertile men by reliably predicting the chance of obtaining spermatozoa with testicular sperm extraction when a repeat attempt is planned.

Circulating SIRT1 Increases After Intragastric Balloon Fat Loss in Obese Patients.

BACKGROUND: Sirtuins (SIRTs), ubiquitous deacetylases, are main regulators of energy homeostasis and metabolism. SIRT1 has a positive impact on obesity, diabetes mellitus, liver steatosis, and other metabolic disorders. Lean subjects have higher expression of SIRT1 in the adipose tissue compared to obese. However, it is not known whether weight loss associates with changes in blood SIRT1. We evaluated the effect of weight loss on circulating SIRT1, metabolic parameters, and body composition. METHODS: Thirty-two obese subjects were studied before and 6 months after BioEnterics® Intragastric Balloon (BIB®) [22 patients, BMI 41.82 ± 6.28 kg/m(2)] or hypocaloric diet [10 patients, BMI 38.95 ± 6.90 kg/m(2)]. Plasma SIRT1, body composition, measures of metabolic syndrome (waist circumference, fasting plasma glucose, blood pressure, HDL cholesterol, triglycerides), and inflammation markers (ESR, CRP, fibrinogen) were recorded. RESULTS: SIRT1 levels showed a significant increase, together with a significant reduction of BMI, excess body weight, and total fat mass either after BIB or diet intervention. The percent excess body weight loss was 33.73 ± 19.06 and 22.08 ± 11.62 % after BIB and diet, respectively, a trend toward a metabolic and inflammatory amelioration was observed with both treatments. Negative correlation between SIRT1 and % fat mass (BIB, ρ = -0.537, p = 0.017; diet, ρ = -0.638, p = 0.047) was also seen. CONCLUSIONS: The reduction of fat mass associates with increased plasma SIRT1 indicating that, besides tissue levels, circulating SIRT1 is stimulated by a negative caloric balance. The rise of plasma SIRT1 may represent a parameter associating with fat loss rather than weight lowering regardless of the weight reduction system method used.

Leptin modification in chronic myeloid leukemia patients treated with imatinib: An emerging effect of targeted therapy.

We evaluated serum leptin levels in 9 young chronic myeloid leukemia (CML) patients under imatinib therapy during a long-term follow-up. Body mass index (BMI) and fat mass percentage (%FM) were also measured. Leptin was above the normal range in 8 out of 9 patients. In one case the hormone was below the reference value. All subjects showed a normal BMI, but 3 had a small increase of FM%. One patient recovered the leptin normal value after imatinib suspension. A tendency to leptin normalization in patients switched to an intermittent therapy was also found. This study suggests that imatinib therapy may result in leptin alteration.

Hypogonadism in a patient with two novel mutations of the luteinizing hormone ß-subunit gene expressed in a compound heterozygous form.

CONTEXT: LH gene mutations are rare; only four mutations have been described. The affected individuals are hypogonadal. PATIENT: We describe the clinical features of a 31-yr-old man who presented with delayed puberty and azoospermia and was found to have hypogonadism associated with an absence of circulating LH. MAIN OUTCOME MEASURES AND RESULTS: The patient had a 12-bp deletion in exon 2 in the LH ß-subunit gene and a mutation of the 5' splice site IVS2+1G→T in the same gene present in a compound heterozygous state. The first mutation predicts a deletion of four leucines of the hydrophobic core of the signal peptide. The second mutation disrupts the splicing of mRNA, generating a gross abnormality in the processing. The patient's heterozygous parents were clinically normal. The phenotype of a 16-yr-old sister of the proband, carrying the same mutations, was characterized by normal pubertal development and oligomenorrhea. CONCLUSION: This report unravels two novel mutations of the LH gene critical for synthesis and activity of the LH molecule. The insight gained from the study is that normal pubertal maturation in women can occur in a state of LH deficiency, whereas LH is essential for maturation of Leydig cells and thus steroidogenesis, puberty, and spermatogenesis in man. These mutations should be considered in girls and boys with selective deficiency of LH.

Severe oligozoospermia in a young man with chronic myeloid leukemia on long-term treatment with imatinib started before puberty.

OBJECTIVE: To report the effect of long-term treatment with the tyrosine kinase inhibitor imatinib started before the onset of puberty on semen parameters, bone mineral density, and hormone values. DESIGN: Case report. SETTING: University hospital. PATIENT(S): An 18-year-old man given treatment with imatinib for chronic myeloid leukemia. INTERVENTION(S): Clinical, biochemical and dual-energy X-ray absorptiometry evaluations. MAIN OUTCOME MEASURE(S): Semen analysis, serum levels of gonadotropins, inhibin-B, and testosterone, bone mineral density, markers of skeletal homeostasis. RESULT(S): Semen analyses showed severe oligozoospermia after long-term administration of imatinib started before puberty. The inhibin-B/FSH ratio was reduced. A low bone mineral density for chronologic age was observed. CONCLUSION(S): This case study documents the potential risk of an impairment of semen parameters in patients undergoing a treatment with tyrosine kinase inhibitors before the complete maturation of the testis.

Role of platelet-derived growth factors in the testis.

Normal development and function of the testis are controlled by endocrine and paracrine signaling pathways. Platelet-derived growth factors (PDGFs) are growth factors that mediate epithelial-mesenchymal interactions in various tissues during normal and abnormal processes such as embryo development, wound healing, tissue fibrosis, vascular disorders, and cancer. PDGFs and their receptors (PDGFRs) have emerged as key players in the regulation of embryonic and postnatal development of the male gonad. Cells that express PDGFs and PDGFRs are found in the testis of mammals, birds, and reptiles, and their distribution, regulation, and function vary across species. Testicular PDGFs and PDGFRs appear after the process of sex determination in animals that use either genetic sex determination or environmental sex determination. Sertoli cells are the main PDGF-producing cells during the entire period of prenatal and postnatal testis development. Fetal Leydig cells and their precursors, adult Leydig cells and their stem cell precursors, peritubular myoid cells, cells of the blood vessels, and gonocytes are the testicular cell types expressing PDGFRs. Genetically targeted deletions of PDGFs, PDGFRs, PDGFR target genes or pharmacological silencing of PDGF signaling produce profound damage on the target cells that, depending on the developmental period, are under direct or indirect control of PDGF. PDGF signaling may also serve diverse functions outside of the realm of testis development, including testicular tumors. In this review, we provide a framework of the current knowledge to clarify the useful information regarding how PDGFs function in individual cells of the testis.

Platelet-derived growth factor receptor beta-subtype regulates proliferation and migration of gonocytes.

Proliferation and migration of gonocytes, the precursors of spermatogonial stem cells, to the germline niche in the basal membrane of the seminiferous tubules, are two crucial events that take place between postnatal d 0.5 (P0.5) and P5.0 in the mouse and involve a selection of the cells that are committed to the germline stem cells lineage. Here we show that from embryonic d 18.0 (E18) and up to P5, the gonocytes express platelet-derived growth factor (PDGF) receptor beta-subtype (PDGFR-beta) and that during the same time period, the Sertoli cells express PDGF-B and PDGF-D, both ligands for PDGFR-beta. Inhibition of the PDGFR-beta tyrosine kinase activity during the first five postnatal days provokes a profound reduction of gonocyte number through inhibition of their proliferation and induction of apoptosis. Moreover, we found that PDGFR-beta ligands are chemotactic for gonocytes. These data suggest that PDGFR-beta activation has the remarkable capability to drive the selection, survival, and migration of the gonocytes from the center of the seminiferous tubules to the testicular germline niche on the basal membrane.

Imatinib interferes with survival of multi drug resistant Kaposi's sarcoma cells.

Multi drug resistance (MDR) is defined as the ability of tumor cells to become resistant to unrelated drugs. Tyrosine kinase inhibitor imatinib has been demonstrated to be effective in the treatment of certain tumors. In particular, imatinib inhibits Bcr-Abl kinase activity, c-kit and the phosphorylation of platelet-derived growth factor (PDGF) receptors. In this work, we show that imatinib inhibits PDGF phosphorylation not only in wt Kaposi sarcoma (KS) but also in multi drug resistant KS cells. This was associated with an increased apoptosis in wt cells and an increased autophagy in MDR-KS cells. These data add new insights to the possible use of imatinib in the overcoming of MDR in KS cells.

Osteoblast-conditioned medium promotes proliferation and sensitizes breast cancer cells to imatinib treatment.

Inhibition of platelet-derived growth factor receptor (PDGFR) signaling restricts the growth of human breast cancer in the bone of nude mice. We hypothesized that osteoblast-secreted substances may alter the response capacity of breast cancer cells to the PDGFRs tyrosine kinase inhibitor imatinib mesylate. We found that osteoblast-conditioned medium (OCM) increases the proliferation rate of the estrogen receptor negative (ER-) MDA-MB-231 and of the ER+ MCF-7 human breast cancer cell lines and the growth-promoting effect on ER+ cells is independent from estrogen. OCM significantly improved the dose- and the time-dependent sensitivity of the tumor cells to the anti-proliferative effect of imatinib. We also found that MDA-MB-231 and MCF-7 cells express the two PDGFRs subtypes, PDGFR-alpha and PDGFR-beta, and OCM treatment increases the expression of the PDGFRs. Furthermore, imatinib inhibited the phosphorylation rate of its target tyrosine kinase receptors. We conclude that bone microenvironment, through osteoblast-secreted substances may cause estrogen-independent proliferation of breast cancer cells by a mechanism mediated by the induction of PDGFRs expression. The enhanced sensitivity of OCM-treated breast cancer cells to imatinib would justify investigation on the efficacy of imatinib in bone breast cancer metastasis.