Ketoacidosis and SGLT2 Inhibitors: A Narrative Review.

An acute metabolic complication of diabetes mellitus, especially type 1, is diabetic ketoacidosis (DKA), which is due to an increase in blood ketone concentrations. Sodium/glucose co-transporter-2 inhibitor (SGLT2-i) drugs have been associated with the occurrence of a particular type of DKA defined as euglycemic (euDKA), characterized by glycemic levels below 300 mg/dL. A fair number of euDKA cases in SGLT2-i-treated patients have been described, especially in the last few years when there has been a significant increased use of these drugs. This form of euDKA is particularly insidious because of its latent onset, associated with unspecific symptomatology, until it evolves (progressing) to severe systemic forms. In addition, its atypical presentation can delay diagnosis and treatment. However, the risk of euDKA associated with SGLT2-i drugs remains relatively low, but it is essential to promptly diagnose and manage it to prevent its serious life-threatening complications. In this narrative review, we intended to gather current research evidence on SGLT2i-associated euDKA from randomized controlled trials and real-world evidence studies, its diagnostic criteria and precipitating factors.

Positive Effects of the Nutraceutical Association of Lycopene and Selenium in Experimental Varicocele.

Many natural substances commonly found in healthy diets have been studied for their potential to reduce male infertility associated with varicocele. A positive role of selenium (Se) or lycopene alone was demonstrated in experimental varicocele, while no data are available on their association. One group of male Sprague-Dawley rats was sham operated and daily treated with Se (3 mg/kg, i.p.), lycopene (1 mg/kg, i.p.), or their association. A second group underwent surgery to induce varicocele. Sham and half of the varicocele animals were sacrificed after twenty-eight days, while the residual animals were treated for one more month and then sacrificed. In varicocele animals, testosterone levels and testes weight were reduced, Hypoxia Inducible Factor-1α (HIF-1α) expression was absent in the tubules and increased in Leydig cells, caspare-3 was increased, seminiferous epithelium showed evident structural changes, and many apoptotic germ cells were demonstrated with TUNEL assay. The treatment with lycopene or Se alone significantly increased testis weight and testosterone levels, reduced apoptosis and caspase-3 expression, improved the tubular organization, decreased HIF-1α positivity of Leydig cells, and restored its tubular positivity. Lycopene or Se association showed a better influence on all biochemical and morphological parameters. Therefore, the nutraceutical association of lycopene plus Se might be considered a possible therapeutic tool, together with surgery, in the treatment of male infertility. However, long-term experimental and clinical studies are necessary to evaluate sperm quantity and quality.

Glutathione: Lights and Shadows in Cancer Patients.

In cases of cellular injury, there is an observed increase in the production of reactive oxygen species (ROS). When this production becomes excessive, it can result in various conditions, including cancerogenesis. Glutathione (GSH), the most abundant thiol-containing antioxidant, is fundamental to re-establishing redox homeostasis. In order to evaluate the role of GSH and its antioxi-dant effects in patients affected by cancer, we performed a thorough search on Medline and EMBASE databases for relevant clinical and/or preclinical studies, with particular regard to diet, toxicities, and pharmacological processes. The conjugation of GSH with xenobiotics, including anti-cancer drugs, can result in either of two effects: xenobiotics may lose their harmful effects, or GSH conjugation may enhance their toxicity by inducing bioactivation. While being an interesting weapon against chemotherapy-induced toxicities, GSH may also have a potential protective role for cancer cells. New studies are necessary to better explain the relationship between GSH and cancer. Although self-prescribed glutathione (GSH) implementation is prevalent among cancer patients with the intention of reducing the toxic effects of anticancer treatments and potentially preventing damage to normal tissues, this belief lacks substantial scientific evidence for its efficacy in reducing toxicity, except in the case of cisplatin-related neurotoxicity. Therefore, the use of GSH should only be considered under medical supervision, taking into account the appropriate timing and setting.

Nutraceuticals as Alternative Approach against Cadmium-Induced Kidney Damage: A Narrative Review.

Cadmium (Cd) represents a public health risk due to its non-biodegradability and long biological half-life. The main target of Cd is the kidney, where it accumulates. In the present narrative review, we assessed experimental and clinical data dealing with the mechanisms of kidney morphological and functional damage caused by Cd and the state of the art about possible therapeutic managements. Intriguingly, skeleton fragility related to Cd exposure has been demonstrated to be induced both by a direct Cd toxic effect on bone mineralization and by renal failure. Our team and other research groups studied the possible pathophysiological molecular pathways induced by Cd, such as lipid peroxidation, inflammation, programmed cell death, and hormonal kidney discrepancy, that, through further molecular crosstalk, trigger serious glomerular and tubular injury, leading to chronic kidney disease (CKD). Moreover, CKD is associated with the presence of dysbiosis, and the results of recent studies have confirmed the altered composition and functions of the gut microbial communities in CKD. Therefore, as recent knowledge demonstrates a strong connection between diet, food components, and CKD management, and also taking into account that gut microbiota are very sensitive to these biological factors and environmental pollutants, nutraceuticals, mainly present in foods typical of the Mediterranean diet, can be considered a safe therapeutic strategy in Cd-induced kidney damage and, accordingly, could help in the prevention and treatment of CKD.

Identification and Targeting of Mutant Neoantigens in Multiple Myeloma Treatment.

Multiple myeloma (MM) is malignant disease characterized by the clonal proliferation of plasma cells in the bone marrow, leading to anemia, immunosuppression, and other symptoms, that is generally hard to treat. In MM, the immune system is likely exposed to neoplasia-associated neoantigens for several years before the tumor onset. Different types of neoantigens have been identified. Public or shared neoantigens derive from tumor-specific modifications often reported in several patients or across diverse tumors. They are intriguing therapeutic targets because they are frequently observed, and they have an oncogenic effect. Only a small number of public neoantigens have been recognized. Most of the neoantigens that have been identified are patient-specific or "private", necessitating a personalized approach for adaptive cell treatment. It was demonstrated that the targeting of a single greatly immunogenic neoantigen may be appropriate for tumor control. The purpose of this review was to analyze the neoantigens present in patients with MM, and to evaluate the possibility of using their presence as a prognostic factor or as a therapeutic target. We reviewed the most recent literature on neoantigen treatment strategies and on the use of bispecific, trispecific, and conjugated antibodies for the treatment of MM. Finally, a section was dedicated to the use of CAR-T in relapsed and refractory patients.

Correction: Antonuccio et al. The Nutraceutical N-Palmitoylethanolamide (PEA) Reveals Widespread Molecular Effects Unmasking New Therapeutic Targets in Murine Varicocele. Nutrients 2021, 13, 734.

In the original publication [...].

Corrigendum: Polydeoxyribonucleotide, an adenosine-A2A receptor agonist, preserves blood testis barrier from cadmium-induced injury.

[This corrects the article DOI: 10.3389/fphar.2016.00537.].

Varicocele, Functional Foods and Nutraceuticals: From Mechanisms of Action in Animal Models to Therapeutic Application.

Varicocele is one of the main causes of infertility in men, thus representing an important clinical problem worldwide. Inflammation contributes mainly to its pathogenesis, even if the exact pathophysiological mechanisms that correlate varicocele and infertility are still unknown. In addition, oxidative stress, apoptosis, hypoxia, and scrotal hyperthermia seem to play important roles. So far, the treatment of varicocele and the care of the fertility-associated problems still represent an area of interest for researchers, although many advances have occurred over the past few years. Recent experimental animal studies, as well as the current epidemiological evidence in humans, demonstrated that many functional foods of natural origin and nutraceuticals that are particularly abundant in the Mediterranean diet showed anti-inflammatory effects in varicocele. The aim of the present narrative review is to mainly evaluate recent experimental animal studies regarding the molecular mechanisms of varicocele and the state of the art about possible therapeutic approaches. As the current literature demonstrates convincing associations between diet, food components and fertility, the rational intake of nutraceuticals, which are particularly abundant in foods typical of plant-based eating patterns, may be a reliable therapeutic supportive care against varicocele and, consequently, could be very useful in the cure of fertility-associated problems in patients.

Involvement of Hypoxia-Inducible Factor 1-α in Experimental Testicular Ischemia and Reperfusion: Effects of Polydeoxyribonucleotide and Selenium.

Polydeoxyribonucleotide (PDRN) is an agonist of the A2A adenosine receptor derived from salmon trout sperm. Selenium (Se) is a trace element normally present in the diet. We aimed to investigate the long-term role of PDRN and Se, alone or in association, after ischemia-reperfusion (I/R) in rats. The animals underwent 1 h testicular ischemia followed by 30 days of reperfusion or a sham I/R and were treated with PDRN or Se alone or in association for 30 days. I/R significantly increased hypoxia-inducible factor 1-α (HIF-1α) in Leydig cells, malondialdehyde (MDA), phosphorylated extracellular signal-regulated kinases 1/2 (pErk 1/2), and apoptosis decreased testis weight, glutathione (GSH), testosterone, nuclear factor erythroid 2-related factor 2 (Nrf2), induced testicular structural changes, and eliminated HIF-1α spermatozoa positivity. The treatment with either PDRN or Se significantly decreased MDA, apoptosis, and HIF-1α positivity of Leydig cells, increased testis weight, GSH, testosterone, and Nrf2, and improved the structural organization of the testes. PDRN and Se association showed a higher protective effect on all biochemical, structural, and immunohistochemical parameters. Our data suggest that HIF-1α could play important roles in late testis I/R and that this transcriptional factor could be modulated by PDRN and Se association, which, together with surgery, could be considered a tool to improve varicocele-induced damages.

Corrigendum: Update on genistein and thyroid: an overall message of safety.

[This corrects the article DOI: 10.3389/fendo.2012.00094.].

Mediterranean Diet and Soy Isoflavones for Integrated Management of the Menopausal Metabolic Syndrome.

The transition from premenopause to postmenopause is associated with the development of multiple elements of Metabolic Syndrome (MetS) [...].

Nutraceuticals: A New Challenge against Cadmium-Induced Testicular Injury.

Cadmium (Cd) is a widespread heavy metal and a ubiquitous environmental toxicant. For the general population, the principal causes of Cd exposure are cigarette smoking, air pollution and contaminated water and food consumption, whereas occupational exposure usually involves humans working in mines or manufacturing batteries and pigments that utilize Cd. The aim of the present review is to evaluate recent data regarding the mechanisms of Cd-induced testicular structural and functional damages and the state of the art of the therapeutic approaches. Additionally, as the current literature demonstrates convincing associations between diet, food components and men's sexual health, a coherent nutraceutical supplementation may be a new valid therapeutic strategy for both the prevention and alleviation of Cd-induced testicular injury. The toxic effects on testes induced by Cd include many specific mechanisms, such as oxidative stress, inflammation and apoptosis. As no specific therapy for the prevention or treatment of the morbidity and mortality associated with Cd exposure is available, the development of new therapeutic agents is requested. Dietary strategies and the use of nutraceuticals, particularly abundant in fresh fruits, beans, vegetables and grains, typical of the Mediterranean diet, are recommended against Cd-induced testicular injury.

Cadmium-Induced Kidney Injury in Mice Is Counteracted by a Flavonoid-Rich Extract of Bergamot Juice, Alone or in Association with Curcumin and Resveratrol, via the Enhancement of Different Defense Mechanisms.

Cadmium (Cd) represents a public health risk due to its non-biodegradability and long biological half-life. The main target of Cd is considered the kidney, where it accumulates. No effective treatment for Cd poisoning is available so that several therapeutic approaches were proposed to prevent damages after Cd exposure. We evaluated the effects of a flavonoid-rich extract of bergamot juice (BJe), alone or in association with curcumin (Cur) and resveratrol (Re), in the kidney of mice exposed to cadmium chloride (CdCl2). Male mice were administered with CdCl2 and treated with Cur, Re, or BJe alone or in combination for 14 days. The kidneys were processed for biochemical, structural and morphometric evaluation. Cd treatment significantly increased urea nitrogen and creatinine levels, along with tp53, Bax, Nos2 and Il1b mRNA, while reduced that of Bcl2, as well as glutathione (GSH) content and glutathione peroxidase (GPx) activity. Moreover, Cd caused damages to glomeruli and tubules, and increased Nrf2, Nqo1 and Hmox1 gene expression. Cur, Re and BJe at 40 mg/kg significantly improved all parameters, while BJe at 20 mg/kg showed a lower protective effect. After treatment with the associations of the three nutraceuticals, all parameters were close to normal, thus suggesting a new potential strategy in the protection of renal functions in subjects exposed to environmental toxicants.

A Flavonoid-Rich Extract from Bergamot Juice, Alone or in Association with Curcumin and Resveratrol, Shows Protective Effects in a Murine Model of Cadmium-Induced Testicular Injury.

It is known that cadmium damages testis structure and functionality. We examined the effects of nutraceuticals such as a flavonoid-rich extract of bergamot juice (BJe), alone or in association with curcumin (Cur) and resveratrol (Re), on mice testicular dysfunction caused by cadmium chloride (CdCl2). Controversial data on the protective effects of Cur and Re are available, while no evidence on the possible role of BJe exists. Adult male C57 BL/6J mice were administered with CdCl2 and treated with Cur, Re, or BJe alone or in combination for 14 days. Then, testes were removed and processed for molecular, structural, and immunohistochemical analyses. CdCl2 increased the mRNA of IL-1ß, TNF-α, p53, and BAX while reduced that of Bcl-2 and induced tubular lesions and apoptosis of germinal cells. Cur, Re, and BJe at 40 mg/kg significantly improved all of these parameters and events, although BJe at 20 mg/kg showed a lower protective effect. The association of Cur, Re, and BJe at both doses of 50/20/20 and 100/20/40 mg/kg brought each parameter close to those of the control. Our results indicate that the nutraceuticals employed in this study and their associations exert a positive action against Cd-induced testicular injury, suggesting a possible protection of testis functionality in subjects exposed to environmental toxicants.

The Nutraceutical N-Palmitoylethanolamide (PEA) Reveals Widespread Molecular Effects Unmasking New Therapeutic Targets in Murine Varicocele.

Varicocele is an age-related disease with no current medical treatments positively impacting infertility. Toll-like receptor 4 (TLR4) expression is present in normal testis with an involvement in the immunological reactions. The role of peroxisome proliferator-activated receptor-α (PPAR-α), a nuclear receptor, in fertility is still unclear. N-Palmitoylethanolamide (PEA), an emerging nutraceutical compound present in plants and animal foods, is an endogenous PPAR-α agonist with well-demonstrated anti-inflammatory and analgesics characteristics. In this model of mice varicocele, PPAR-α and TLR4 receptors' roles were investigated through the administration of ultra-micronized PEA (PEA-um). Male wild-type (WT), PPAR-α knockout (KO), and TLR4 KO mice were used. A group underwent sham operation and administration of vehicle or PEA-um (10 mg/kg i.p.) for 21 days. Another group (WT, PPAR-α KO, and TLR4 KO) underwent surgical varicocele and was treated with vehicle or PEA-um (10 mg/kg i.p.) for 21 days. At the end of treatments, all animals were euthanized. Both operated and contralateral testes were processed for histological and morphometric assessment, for PPAR-α, TLR4, occludin, and claudin-11 immunohistochemistry and for PPAR-α, TLR4, transforming growth factor-beta3 (TGF-ß3), phospho-extracellular signal-Regulated-Kinase (p-ERK) 1/2, and nucleotide-binding oligomerization domain-like receptor (NLR) family pyrin domain-containing 3 (NLRP3) Western blot analysis. Collectively, our data showed that administration of PEA-um revealed a key role of PPAR-α and TLR4 in varicocele pathophysiology, unmasking new nutraceutical therapeutic targets for future varicocele research and supporting surgical management of male infertility.

NLRP3 Inflammasome: A New Pharmacological Target for Reducing Testicular Damage Associated with Varicocele.

Many bioactive natural compounds are being increasingly used for therapeutics and nutraceutical applications to counteract male infertility, particularly varicocele. The roles of selenium and Polydeoxyribonucleotide (PDRN) were investigated in an experimental model of varicocele, with particular regard to the role of NLRP3 inflammasome. Male rats underwent sham operation and were daily administered with vehicle, seleno-L-methionine (Se), PDRN, and with the association Se-PDRN. Another group of rats were operated for varicocele. After twenty-eight days, sham and varicocele rats were sacrificed and both testes were weighted and analyzed. All the other rats were challenged for one month with the same compounds. In varicocele animals, lower testosterone levels, testes weight, NLRP3 inflammasome, IL-1ß and caspase-1 increased gene expression were demonstrated. TUNEL assay showed an increased number of apoptotic cells. Structural and ultrastructural damage to testes was also shown. PDRN alone significantly improved all considered parameters more than Se. The Se-PDRN association significantly improved all morphological parameters, significantly increased testosterone levels, and reduced NLRP3 inflammasome, caspase-1 and IL-1ß expression and TUNEL-positive cell numbers. Our results suggest that NLRP3 inflammasome can be considered an interesting target in varicocele and that Se-PDRN may be a new medical approach in support to surgery.

Conservative Management of Gestational Hypercalcemia Due to Primary Hyperparathyroidism with Lack of Complications.

INTRODUCTION: Primary hyperparathyroidism (PHPT) is rare in pregnancy. PHPT and hypercalcemia are associated with negative maternofetal outcomes. Therefore, an early diagnosis and adequate treatment are essential. CASE PRESENTATION: We described the case of a pregnant woman complaining of nausea, vomiting and weight loss. Diagnosis of gestational PHPT (GPHPT) was made based on elevated serum calcium and parathyroid hormone levels (3.4 mmol/L and 41.6 pmol/L). Neck ultrasound documented a nodule suggestive of enlarged parathyroid, whereas the abdomen ultrasound revealed renal microlithiasis. Conservative treatment was started with oral hydration and a low-calcium diet. Clinical and biochemical monitoring was weekly and multidisciplinary. Despite our suggestion, the patient refused parathyroidectomy in the second trimester. Additional intravenous fluid rehydration from the 15th to the 25th week of gestation ameliorated the symptoms rapidly, and reduced calcium levels progressively from the 23rd week. At week 40, the woman gave birth to a healthy girl. At month 8 postpartum, calcemia and PTH were still elevated, and accompanied by osteoporosis and nephrocalcinosis. Surgery was accepted, and a parathyroid adenoma was removed. CONCLUSION: In the absence of guidelines for GPHPT management, its treatment should be individualized. In our case, despite high calcium levels, conservative treatment with strict monitoring led to a positive outcome of pregnancy.

Nutraceutical Effects of Lycopene in Experimental Varicocele: An "In Vivo" Model to Study Male Infertility.

Varicocele is one of the main causes of infertility in men. Oxidative stress and consequently apoptosis activation contribute to varicocele pathogenesis, worsening its prognosis. Natural products, such as lycopene, showed antioxidant and anti-inflammatory effects in several experimental models, also in testes. In this study we investigated lycopene effects in an experimental model of varicocele. Male rats (n = 14) underwent sham operations and were administered with vehicle (n = 7) or with lycopene (n = 7; 1 mg/kg i.p., daily). Another group of animals (n = 14) underwent surgical varicocele. After 28 days, the sham and 7 varicocele animals were euthanized, and both operated and contralateral testes were weighted and processed. The remaining rats were treated with lycopene (1 mg/kg i.p., daily) for 30 days. Varicocele rats showed reduced testosterone levels, testes weight, Bcl-2 mRNA expression, changes in testes structure and increased malondialdehyde levels and BAX gene expression. TUNEL (Terminal Deoxynucleotidyl Transferase dUTP Nick End Labeling) assay showed an increased number of apoptotic cells. Treatment with lycopene significantly increased testosterone levels, testes weight, and Bcl-2 mRNA expression, improved tubular structure and decreased malondialdehyde levels, BAX mRNA expression and TUNEL-positive cells. The present results show that lycopene exerts beneficial effects in testes, and suggest that supplementation with the tomato-derived carotenoid might be considered a novel nutraceutical strategy for the treatment of varicocele and male infertility.

Protective Effects of Myo-Inositol and Selenium on Cadmium-Induced Thyroid Toxicity in Mice.

Cadmium (Cd) damages the thyroid gland. We evaluated the effects of myo-inositol (MI), seleno-L-methionine (Se) or their combination on the thyroids of mice simultaneously administered with Cd chloride (CdCl2). Eighty-four male mice were divided into 12 groups (seven mice each). Six groups (controls) were treated with 0.9% NaCl (vehicle), Se (0.2 mg/kg/day), Se (0.4 mg/kg/day), MI (360 mg/kg/day), MI+Se (0.2 mg/kg) and MI+Se (0.4 mg/kg). The other six groups were treated with CdCl2 (2 mg/kg), CdCl2+MI, CdCl2+Se (0.2 mg/kg), CdCl2+Se (0.4 mg/kg), CdCl2+MI+Se (0.2 mg/kg) and CdCl2+MI+Se (0.4 mg/kg). An additional group of CdCl2-challenged animals (n= 7) was treated with resveratrol (20 mg/kg), an effective and potent antioxidant. All treatments lasted 14 days. After sacrifice, the thyroids were evaluated histologically and immunohistochemically. CdCl2 reduced the follicular area, increased the epithelial height, stroma, and cells expressing monocyte chemoattractant protein-1 (MCP-1) and C-X-C motif chemokine 10 (CXCL10). CdCl2+Se at 0.2/0.4 mg/kg insignificantly reversed the follicular and stromal structure, and significantly decreased the number of MCP-1 and CXCL10-positive cells. CdCl2+MI significantly reversed the thyroid structure and further decreased the number of MCP-1 and CXCL10-positive cells. CdCl2+MI+Se, at both doses, brought all indices to those of CdCl2-untreated mice. MI, particularly in association with Se, defends mice from Cd-induced damage. The efficacy of this combination was greater than that of resveratrol, at least when using the follicular structure as a read-out for a comparison. We suggest that the use of these nutraceuticals, more specifically the combination of MI plus SE, can protect the thyroid of Cd-exposed subjects.

Myo-inositol in the protection from cadmium-induced toxicity in mice kidney: An emerging nutraceutical challenge.

Cadmium (Cd) induces functional and morphological changes in kidney. Therefore, the effects of a natural nutraceutical antioxidant, myo-inositol (MI), were evaluated in mice kidneys after Cd challenge. Twenty-eight C57 BL/6 J mice were divided into these groups: 0.9% NaCl; MI (360 mg/kg/day); CdCl2 (2 mg/kg/day) plus vehicle; CdCl2 (2 mg/kg/day) plus MI (360 mg/kg/day). After 14 days, kidneys were processed for structural, biochemical and morphometric evaluation. Treatment with CdCl2 increased urea nitrogen and creatinine in serum and augmented tumor necrosis factor-α (TNF-α) and inducible nitric oxide synthase (iNOS) expression. Furthermore, monocyte chemoattractant protein-1 (MCP-1), kidney injury molecule-1 (KIM-1) and myo-inositol oxygenase (MIOX) immunoreactivity, and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) positive cells number were significantly higher than control and MI groups. Glutathione (GSH) content and glutathione peroxidase (GPx) activity were reduced and structural changes were evident. The treatment with MI significantly lowered urea nitrogen and creatinine levels, TNF-α and iNOS expression, MCP-1, KIM-1 and MIOX immunoreactivity and TUNEL positive cells number, increased GSH content and GPx activity and preserved kidney morphology. A protection of MI against Cd-induced damages in mice kidney was demonstrated, suggesting a strong antioxidant role of this nutraceutical against environmental Cd harmful effects on kidney lesions.