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Background/Objectives: The expression of oncogene zinc-finger protein 217 (ZNF217) has been reported to play a central role in cancer development, resistance, and recurrence. Therefore, targeting ZNF217 has been proposed as a possible strategy to fight cancer, and there has been much research on compounds that can target ZNF217. The present work investigates the chemo-preventive properties of cucurbitacin D, a compound with a broad range of anticancer effects, in hematological cancer cells, specifically with regard to its ability to modulate ZNF217 expression. Methods: Different cucurbitacins were isolated from the Vietnamese plant Elaeocarpus hainanensis. The purified compounds were tested on nucleophosmin-mutated acute myeloid leukemia and other hematological cancer cell lines to assess their effects on the cell cycle, cell viability and apoptosis, and the expression of ZNF217. Results: Cucurbitacin D resulted in a reduction in the number of acute myeloid leukemia cells by inducing an increase in apoptosis and blocking cell cycle progression. It also led to a significant decrease in ZNF217 expression in the nucleophosmin-mutated acute myeloid leukemia cell line but not in the other hematologic cancer cell lines. The reduction in ZNF217 expression contributed significantly to the blocking of cell cycle progression but did not affect apoptosis. Conclusions: The obtained results suggest that cucurbitacin D is a promising molecule for targeting mutated nucleophosmin or its pathway in acute myeloid leukemia cells, although further studies are needed for in-depth investigations into its specific mechanisms.

AbstractContext: Bergamot, mainly produced in the Ionian coastal areas of Southern Italy (Calabria), has been used since 1700 for its balsamic and medicinal properties. Phytochemical profiling has confirmed that bergamot juices are rich in flavonoids, including flavone and flavanone glycosides which are responsible for its beneficial effects.Objective: Recently, it was shown that the combination of natural compounds with conventional treatments improves the efficacy of anticancer therapies. Natural compounds with anticancer properties attack cancerous cells without being toxic to healthy cells. Bergamot can induce cytotoxic and apoptotic effects and prevent cell proliferation in various cancer cells.Methods: In this review, the antiproliferative, pro-apoptotic, anti-inflammatory, and antioxidant effects of bergamot are described. Information was compiled from databases such as PubMed, Web of Science, and Google Scholar using the key words ‘bergamot’ accompanied by ‘inflammation’ and, ‘cancer’ for data published from 2015–2021.Results: In vitro and in vivo studies provided evidence that different forms of bergamot (extract, juice, essential oil, and polyphenolic fraction) can affect several mechanisms that lead to anti-proliferative and pro-apoptotic effects that decrease cell growth, as well as anti-inflammatory and antioxidant effects.Conclusions: Considering the effects of bergamot and its new formulations, we affirm the importance of its rational use in humans and illustrate how bergamot can be utilized in clinical applications. Numerous studies evaluated the effect of new bergamot formulations that can affect the absorption and, therefore, the final effects by altering the therapeutic profile of bergamot and enhancing the scientific knowledge of bergamot.

IntroductionAutoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) syndrome is a rare monogenic disease determined by biallelic mutations in AIRE gene, which encodes a transcription factor essential for central immune tolerance. Classic diagnosis is determined by the presence of two of the main APECED clinical diseases: chronic mucocutaneous candidiasis, chronic hypoparathyroidism, and Addison’s disease. Non-endocrine autoimmunity, involving the liver, intestine, eyes, and kidneys, is generally reported in a minority of European patients, while American APECED patients have a higher tendency of developing organ-specific non-endocrine manifestations early in life. This observation led to the revision of the diagnostic criteria to permit earlier diagnosis based on the appearance of one classic triad symptom or one non-classical manifestation at a young age in the presence of IFNωAbs or AIRE mutations (Ferre-Lionakis criteria).Patients and methodsWe analyzed the clinical, genetic, and autoantibody (Ab) profiles in a series of 14 pediatric Italian APECED patients with gastrointestinal manifestations (seven male and seven female patients). Ten patients presented hepatitis (APECED-associated hepatitis (APAH)), while seven were affected by constipation, diarrhea, and malabsorption. Four patients had developed APAH before classic triad symptoms.ResultsBased on the age of appearance of non-endocrine manifestations including APAH and gastro-enteropathy, the Ferre-Lionakis criteria would have allowed an expedited diagnosis in 11/14 patients. Abs to tryptophan hydroxylase (TPHAb) and hepatic aromatic l-amino acid decarboxylase (AADC) were significantly associated with APECED patients of the present series. Abs to cP4501A2 were detectable in the serum of 4/8 patients with APAH, and Abs to cP4502A6 were detectable in 3/8 patients. AADC Abs tested positive in 5/7 patients, which is indicative of gastrointestinal dysfunction in APECED and TPHAb in 5/7 patients with gastrointestinal dysfunction. IFNAb was significantly associated with the syndrome.ConclusionAlthough Ferre-Lionakis expanded criteria applied to the American cohorts of APECED patients would require validation in independent large cohorts of European patients, the results of this study emphasize the importance to evaluate the presence and the age of appearance of APAH and autoimmune enteropathy even in European cohorts for an earlier APECED diagnosis. An earlier APECED diagnosis would also allow the prevention of episodes of life-threatening hypocalcemic seizures and adrenal crisis, which are the main manifestations of undiagnosed APECED.

Background/Objectives: The expression of oncogene zinc-finger protein 217 (ZNF217) has been reported to play a central role in cancer development, resistance, and recurrence. Therefore, targeting ZNF217 has been proposed as a possible strategy to fight cancer, and there has been much research on compounds that can target ZNF217. The present work investigates the chemo-preventive properties of cucurbitacin D, a compound with a broad range of anticancer effects, in hematological cancer cells, specifically with regard to its ability to modulate ZNF217 expression. Methods: Different cucurbitacins were isolated from the Vietnamese plant Elaeocarpus hainanensis. The purified compounds were tested on nucleophosmin-mutated acute myeloid leukemia and other hematological cancer cell lines to assess their effects on the cell cycle, cell viability and apoptosis, and the expression of ZNF217. Results: Cucurbitacin D resulted in a reduction in the number of acute myeloid leukemia cells by inducing an increase in apoptosis and blocking cell cycle progression. It also led to a significant decrease in ZNF217 expression in the nucleophosmin-mutated acute myeloid leukemia cell line but not in the other hematologic cancer cell lines. The reduction in ZNF217 expression contributed significantly to the blocking of cell cycle progression but did not affect apoptosis. Conclusions: The obtained results suggest that cucurbitacin D is a promising molecule for targeting mutated nucleophosmin or its pathway in acute myeloid leukemia cells, although further studies are needed for in-depth investigations into its specific mechanisms. [ABSTRACT FROM AUTHOR]

Abstract Background SARS-CoV-2 causes lesions, in addition to lung, in endocrine organs such as the pancreas through ACE2 receptor. Recently the relationship between SARS-CoV-2 exposition and the incidence or evolution of clinical autoimmune diabetes has attracted the attention of diabetologists. Case presentation We report the analysis of the clinical history of a child diagnosed for insulin-dependent diabetes mellitus (Type 1 diabetes) at the time a paucisymptomatic COVID-19 infection occurred, followed by well-controlled metabolic status. As opposite to previous findings SARS-CoV2 did not cause ketosis and ketoacidosis. Polydipsia was reported a few months and weight loss 4 weeks before SARS- CoV-2 infection suggesting that SARS-CoV-2 could not be the trigger of Type 1 diabetes in this patient. Conclusions SARS-CoV-2 in this patient was an unexpected event in the course of disease. We advance the hypothesis that the SARS-CoV-2 infection, even if paucisymptomatic could have acted in the present case report as a hypothetical downstream precipitating factor; whilst the inciting triggering event of the autoimmune disease, as confirmed by the presence of circulating autoantibodies, could have occurred even before, as generally assumed for this category of disorders. The precipitating mechanism could have been the acute interaction between virus and the ACE receptor on the beta cells, at the time that hyperglycemia and glycosuria were ascertained, and HbA1c levels confirmed a metabolic dysregulation over the previous 3 months in absence of ketoacidosis.

Abstract Background Autoimmune polyendocrinopathy-candidiasis-ectodermal-dystrophy (APECED) or autoimmune polyglandular syndrome Type 1 is a rare autosomal recessive syndrome. The disorder is caused by mutations in the AIRE (AutoImmune Regulator) gene. According to the classic criteria, clinical diagnosis requires the presence of at least two of three main components: chronic mucocutaneous candidiasis, hypoparathyroidism and primary adrenal insufficiency. Furthermore, patients are often affected by other endocrine or non-endocrine associated autoimmune conditions. The enrichment of the non-classical triad seems to occur differently in different cohorts. Screenings of the population revealed that homozygous AIRE mutations c.769C > T, c.415C > T and c.254A > G have a founder effect in Finnish, Sardinian and Iranian Jew populations respectively. Case presentation We report here the clinical and genetic characteristics of two new Serbian APECED siblings, one male and one female, actual age of 27 and 24 respectively, born from non-consanguineous parents. Addison’s disease was diagnosed in the male at the age of 3.5 and hypoparathyroidism at the age of 4. The female developed hypoparathyroidism at 4 years of age. She presented diffuse alopecia, madarosis, onychomycosis, teeth enamel dysplasia. She further developed Addison’s disease at the age of 11 and Hashimoto’s thyroiditis at the age of 13.5. She had menarche at the age of 14 but developed autoimmune oophoritis and premature ovarian failure at the age of 16. A treatment with hydrocortisone, fludrocortisone and alfacalcidiol was established for both siblings; L-T4 (levo-thyroxine) for thyroid dysfunction and levonorgestrel and etinilestradiol for POF were also administered to the female. Genetic screening revealed a homozygous c.769C > T (R257X (p.Arg257X)) AIRE mutation. We additionally reviewed the literature on 11 previously published Serbian patients and evaluated the frequency of their main diseases in comparison to Finnish, Sardinian, Turkish, Indian and North/South American cohorts. Conclusion A founder effect was discovered for the R257X genotype detected in the DNA of 10 homozygous and 2 heterozygous patients. Of note, all Serbian APECED patients were affected by adrenal insufficiency and 10 out of 13 patients presented CMC.

Autoimmune polyglandular syndrome (APS) comprises a complex association of autoimmune pathological conditions. APS Type 1 originates from loss-of-function mutations in the autoimmune regulator (AIRE) gene. APS2, APS3 and APS4 are linked to specific HLA alleles within the major histocompatibility complex, with single-nucleotide polymorphisms (SNPs) in non-HLA genes also contributing to disease. In general, variability in the AIRE locus and the presence of heterozygous loss-of-function mutations can impact self-antigen presentation in the thymus. In this study, whole-exome sequencing (WES) was performed on a sixteen-year-old female APS3A/B patient to investigate the genetic basis of her complex phenotype. The analysis identified two variants (p.Arg111Trp and p.Thr101Ile) of the hepatitis A virus cell receptor 2 gene (HAVCR2) encoding for the TIM-3 (T cell immunoglobulin and mucin domain 3) protein. These variants were predicted, through in silico analysis, to impact protein structure and stability, potentially influencing the patient's autoimmune phenotype. While confocal microscopy analysis revealed no alteration in TIM-3 fluorescence intensity between the PBMCs isolated from the patient and those of a healthy donor, RT-qPCR showed reduced TIM-3 expression in the patient's unfractionated PBMCs. A screening conducted on a cohort of thirty APS patients indicated that the p.Thr101Ile and p.Arg111Trp mutations were unique to the proband. This study opens the pathway for the search of TIM-3 variants possibly linked to complex autoimmune phenotypes, highlighting the potential of novel variant discovery in contributing to APS classification and diagnosis. [ABSTRACT FROM AUTHOR]

The C1858T variant of the protein tyrosine phosphatase N22 (PTPN22) gene is associated with pathophysiological phenotypes in several autoimmune conditions, namely, Type 1 diabetes and autoimmune thyroiditis. The R620W variant protein, encoded by C1858T, leads to a gain of function mutation with paradoxical reduced T cell activation. We previously exploited a novel personalized immunotherapeutic approach based on siRNA delivered by liposomes (lipoplexes, LiposiRNA) that selectively inhibit variant allele expression. In this manuscript, we functionalize lipoplexes carrying siRNA for variant C1858T with a high affinity ligand of Siglec-10 (Sig10L) coupled to lipids resulting in lipoplexes (LiposiRNA-Sig10L) that enhance delivery to Siglec-10 expressing immunocytes. LiposiRNA-Sig10L lipoplexes more efficiently downregulated variant C1858T PTPN22 mRNA in PBMC of heterozygous patients than LiposiRNA without Sig10L. Following TCR engagement, LiposiRNA-Sig10L more significantly restored IL-2 secretion, known to be paradoxically reduced than in wild type patients, than unfunctionalized LiposiRNA in PBMC of heterozygous T1D patients.

Carcinomas evade the host immune system by negatively modulating CD4+ and CD8+ T effector lymphocytes through forkhead box protein 3 (FOXP3) positive T regulatory cells’ increased activity. Furthermore, interaction of the programmed cell death 1 (PD1) molecule and its ligand programmed cell death ligand 1 (PDL1) inhibits the antitumor activity of PD1+ T lymphocytes. Immunotherapy has become a powerful strategy for tailored cancer patients’ treatment both in adult and pediatric patients aiming to generate potent antitumor responses. Nevertheless, immunotherapies can generate autoimmune responses. This study aimed to investigate the potential effect of the transformation-related protein 53 (p53) reactivation by a peptide-based inhibitor of the MDM2/MDM4 heterodimer (Pep3) on the immune response in a solid cancer, i.e., thyroid carcinoma frequently presenting with thyroid autoimmunity. In peripheral blood mononuclear cell of thyroid cancer patients, Pep3 treatment alters percentages of CD8+ and CD4+ T regulatory and CD8+ and CD4+ T effector cells and favors an anticancer immune response. Of note that reduced frequencies of activated CD8+ and CD4+ T effector cells do not support autoimmunity progression. In evaluating PD1 expression under p53 activation, a significant decrease of activated CD4+PD1+ cells was detected in thyroid cancer patients, suggesting a defective regulation in the initial activation stage, therefore generating a protective condition toward autoimmune progression.

The autoimmune polyglandular syndrome type 1 (APS1) is caused by pathogenic variants of the autoimmune regulator (AIRE) gene, located in the chromosomal region 21q22.3. The related protein, AIRE, enhances thymic self-representation and immune self-tolerance by localization to chromatin and anchorage to multimolecular complexes involved in the initiation and post-initiation events of tissue-specific antigen-encoding gene transcription. Once synthesized, the self-antigens are presented to, and cause deletion of, the self-reactive thymocyte clones. The clinical diagnosis of APS1 is based on the classic triad idiopathic hypoparathyroidism (HPT)—chronic mucocutaneous candidiasis—autoimmune Addison's disease (AAD), though new criteria based on early non-endocrine manifestations have been proposed. HPT is in most cases the first endocrine component of the syndrome; however, APS1-associated AAD has received the most accurate biochemical, clinical, and immunological characterization. Here is a comprehensive review of the studies on APS1-associated AAD from initial case reports to the most recent scientific findings.

Autoimmune diseases recognize a multifactorial pathogenesis, although the exact mechanism responsible for their onset remains to be fully elucidated. Over the past few years, the role of natural killer (NK) cells in shaping immune responses has been highlighted even though their involvement is profoundly linked to the subpopulation involved and to the site where such interaction takes place. The aberrant number and functionality of NK cells have been reported in several different autoimmune disorders. In the present review, we report the most recent findings regarding the involvement of NK cells in both systemic and organ-specific autoimmune diseases, including type 1 diabetes (T1D), primary biliary cholangitis (PBC), systemic sclerosis, systemic lupus erythematosus (SLE), primary Sjögren syndrome, rheumatoid arthritis, and multiple sclerosis. In T1D, innate inflammation induces NK cell activation, disrupting the Treg function. In addition, certain genetic variants identified as risk factors for T1D influenced the activation of NK cells promoting their cytotoxic activity. The role of NK cells has also been demonstrated in the pathogenesis of PBC mediating direct or indirect biliary epithelial cell destruction. NK cell frequency and number were enhanced in both the peripheral blood and the liver of patients and associated with increased NK cell cytotoxic activity and perforin expression levels. NK cells were also involved in the perpetuation of disease through autoreactive CD4 T cell activation in the presence of antigen-presenting cells. In systemic sclerosis (SSc), in addition to phenotypic abnormalities, patients presented a reduction in CD56hi NK-cells. Moreover, NK cells presented a deficient killing activity. The influence of the activating and inhibitory killer cell immunoglobulin-like receptors (KIRs) has been investigated in SSc and SLE susceptibility. Furthermore, autoantibodies to KIRs have been identified in different systemic autoimmune conditions. Because of its role in modulating the immune-mediated pathology, NK subpopulation could represent a potential marker for disease activity and target for therapeutic intervention.

Abstract Background Hypercholesterolemia is a major risk factor for cardiovascular disorders and requires specific intervention through an adequate lifestyle (diet and physical exercise) and, if necessary, an appropriate drug treatment. Lipid-lowering drugs, although generally efficacious, may sometimes cause adverse events. A growing attention has been devoted to the correction of dyslipidemias through the use of dietary supplements. The aim of this study was to assess the lipid-lowering activity and safety of a dietary supplement containing monacolin K, L-arginine, coenzyme Q10 and ascorbic acid, named Argicolina (A), compared to a commercially available product containing monacolin K and coenzyme Q10, Normolip 5 (N). Methods This was a single center, controlled, randomized, open-label, cross-over clinical study enrolling 20 Caucasian outpatients aged 18–75 years with serum LDL-C between 130 and 180 mg/dL. Patients assumed two different dietary supplements (A and N) both containing monacolin K 10 mg for 8 weeks each, separated by a 4-week wash-out period. Evaluated parameters were: Total cholesterol (Tot-C), low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), triglycerides (TG), fasting blood glucose, aspartate aminotransferase, alanine aminotransferase, creatinekinase, gamma-glutamyl-transpeptidase, brachial arterial pressure and heart rate, measured at the start and at the end of each treatment period. Safety was monitored through the study. Results LDL-C decreased by 23.3% during treatment with N (p

The sensitivity of immunoassays was reported to be increased by the orientation of antibodies. We investigated how the size and valence of antigens and orientation and valence of antibodies contribute to the analytical sensitivity of ELISA. Antigens differing in size and number of epitopes were compared using oriented and non-oriented ELISAs: the orientation of antibodies was obtained coating half-fragment antibodies on maleimide microplates, while, in non-oriented ELISA, whole antibodies were randomly physisorbed. The oriented assay performed better than the non-oriented one at each concentration (0.4–3.3 ng/mL) of a small monomeric antigen (cardiac Troponin I, 24 kDa, Rh 3 nm). No significant differences were observed with a large monovalent antigen (prostate-specific antigen-alpha(1) antichymotrypsin, 90 kDa, Rh > 3 nm), since its steric hindrance overcame the increased availability of antigen binding sites given by orientation. Large multivalent antigens (ferritin, 280 kDa, Rh 6 nm; α-fetoprotein, >70 kDa, Rh > 3.3 nm) performed better in non-oriented assays. In this case, the repeated epitopes on the surface of the antigens favored the engagement of both antigen binding sites of the whole IgG, thus suggesting that avidity represented the leading force in this experimental setting. In conclusion, the design of high-sensitivity ELISAs should consider the dimension and valency of antigens in addition to the affinity and avidity of antibodies.

Autoimmune polyglandular syndromes (APS) are classified into four main categories, APS1–APS4. APS1 is caused by AIRE gene loss of function mutations, while the genetic background of the other APS remains to be clarified. Here, we investigated the potential association between AIRE gene promoter Single Nucleotide Polymorphisms (SNPs) and susceptibility to APS. We sequenced the AIRE gene promoter of 74 APS patients, also analyzing their clinical and autoantibody profile, and we further conducted molecular modeling studies on the identified SNPs. Overall, we found 6 SNPs (-230Y, -655R, -261M, -380S, -191M, -402S) of the AIRE promoter in patients' DNA. Interestingly, folding free energy calculations highlighted that all identified SNPs, except for -261M, modify the stability of the nucleic acid structure. A rather similar percentage of APS3 and APS4 patients had polymorphisms in the AIRE promoter. Conversely, there was no association between APS2 and AIRE promoter polymorphisms. Further AIRE promoter SNPs were found in 4 out of 5 patients with APS1 clinical diagnosis that did not harbor AIRE loss of function mutations. We hypothesize that AIRE promoter polymorphisms could contribute to APS predisposition, although this should be validated through genetic screening in larger patient cohorts and in vitro and in vivo functional studies. [ABSTRACT FROM AUTHOR]

Various immunotherapies for the treatment of type 1 diabetes are currently under investigation. Some of these aim to rescue the remaining beta cells from autoimmune attack caused by the disease. Among the strategies employed, p53 has been envisaged as a possible target for immunomodulation. We studied the possible effect of p53 activation on Treg subsets and Treg/Teff balance in type 1 diabetes patients' PBMC. Upon p53 activation, we observed an increase in CD8+ Treg and activated CD8+ Teff whilst CD8+ Teff cells significantly decreased in healthy PBMC when stimulated with anti-CD3/CD28. No effect was detected on percentages of CD4+ Treg, while a reduction was seen in CD4+ Teff cells and an increase in activated CD4+ Teff cells. In patients' PBMC, upon p53 activation followed by 6 days of anti-CD3/CD28 stimulation, CD8+ Treg and activated CD8+ Teff were increased while CD8+ Teff were decreased. No differences were detected in the CD4+ counterparts. CD8+ Teff PD1+, CD8+ Teff PD1low were increased upon p53 activation in type 1 diabetics compared to controls while CD8+ Teff PD1high were increased in both groups. The same increased percentages were detected for CD4+ counterparts. CD4+ Treg PD1high cells were decreased in diabetics upon p53 activation at day 6 of anti-CD3/CD28 stimulation. In conclusion, a Teff dysregulation is observed upon p53 activation suggesting that molecules promoting p53 cannot be used for therapy in type 1 diabetics.

Artocarpus tonkinensis (Moraceae) is a tree that grows in north Vietnam whose leaf decoction is used as a traditional remedy by the Hmong ethnic group to treat arthritis and backache. Our study evaluated the decoction’s efficacy and mechanism of action in DBA/1J mice with collagen-induced arthritis (CIA). Mice treated with the decoction (At) either from the first collagen immunization or after CIA development experienced significantly less joint edema and inflammatory infiltration, whereas CIA-induced cartilage damage could only be prevented by early At treatment. Autoimmune gene expression profiles showed that Th17 cell-associated chemokine CCL20 and cytokines IL-6, IL-17, and IL-22 were strongly downregulated by At. Reduced expression of IL-2, IL-17, IL-22, and FasL in lymph node cells from At-treated mice was further confirmed by real-time PCR. The decoction also inhibited polarization of Th17 cells from CD4+ splenic T cells according to levels of IL-17 and RORC, a Th17 cell-specific transcription factor. Chromatographic analysis identified At’s major component as maesopsin-β-D-glucoside, which could inhibit in vitro differentiation of Th17 cells. The decoction significantly alleviated the signs and symptoms of CIA and inhibited the development and function of Th17 cells, highlighting its potent anti-inflammatory activity.

Context: Glomerular hyperfiltration may represent a direct pathogenetic link between obesity and kidney disease. The most widely used methods to estimate creatine clearance such as Cockroft-Gault (CG), Modification of Diet in Renal Disease (MDRD), and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) have not been validated in subjects with obesity. Objective: The performance of prediction formulas was compared with measured creatinine clearance (mCrCl) in subjects with obesity. Methods: The study population included 342 patients with obesity (mean BMI 47.6 kg/m²) without primary kidney disease. A urine collection was performed over 24 hours for measurement of CrCl. Results: mCrCl increased with body weight. The CG formula showed an overestimation at high CrCl, whereas an underestimation resulted from CKD-EPI and MDRD. To improve the accuracy of estimated CrCl (eCrCl), a new CG-based formula was developed: 53 + 0.7 X (140 - Age) x Weight/(96xSCr) x (0.85 if female) A cut-off point for BMI of 32 kg/m² was identified, at which the new formula may be applied to improve eCrCl. Conclusion: In patients with obesity the glomerular filtration rate increases with body weight, and it is associated with the presence of albuminuria, suggesting an early kidney injury. We propose a novel formula that improves the accuracy of eCrCl to avoid missed diagnoses of hyperfiltration in patients with obesity. [ABSTRACT FROM AUTHOR]

Context: Bergamot, mainly produced in the Ionian coastal areas of Southern Italy (Calabria), has been used since 1700 for its balsamic and medicinal properties. Phytochemical profiling has confirmed that bergamot juices are rich in flavonoids, including flavone and flavanone glycosides which are responsible for its beneficial effects. Objective: Recently, it was shown that the combination of natural compounds with conventional treatments improves the efficacy of anticancer therapies. Natural compounds with anticancer properties attack cancerous cells without being toxic to healthy cells. Bergamot can induce cytotoxic and apoptotic effects and prevent cell proliferation in various cancer cells. Methods: In this review, the antiproliferative, pro-apoptotic, anti-inflammatory, and antioxidant effects of bergamot are described. Information was compiled from databases such as PubMed, Web of Science, and Google Scholar using the key words 'bergamot' accompanied by 'inflammation' and, 'cancer' for data published from 2015–2021. Results:In vitro and in vivo studies provided evidence that different forms of bergamot (extract, juice, essential oil, and polyphenolic fraction) can affect several mechanisms that lead to anti-proliferative and pro-apoptotic effects that decrease cell growth, as well as anti-inflammatory and antioxidant effects. Conclusions: Considering the effects of bergamot and its new formulations, we affirm the importance of its rational use in humans and illustrate how bergamot can be utilized in clinical applications. Numerous studies evaluated the effect of new bergamot formulations that can affect the absorption and, therefore, the final effects by altering the therapeutic profile of bergamot and enhancing the scientific knowledge of bergamot. [ABSTRACT FROM AUTHOR]

Type 1 diabetes is an autoimmune disease where autoreactive T lymphocytes destroy pancreatic beta cells. We previously reported a defect in CD4+ Tregs cell proliferation and reduced CD4+ Tregs PD-1 expression in patients. Another 'memory-like' regulatory subset, CD8+ Tregs, evaluated as CD8+CD25+FOXP3+, has recently raised interest for their effective suppressive activity. Different CD8+ T cell populations, their proliferation capacity and expression of PD-1 molecule were evaluated by flow-cytometer analysis in newly diagnosed, long-term Type 1 diabetes patients compared to healthy normal donors. Under basal conditions, CD8+ Tregs and CD8+ Teffs were seemingly represented among study groups while there was evidence of diminished expression of PD-1 in Teff subsets of long-term patients. After 3 days of PMA/ionomycin stimulation, patients CD8+ Tregs showed decreased percentage in respect to control group. CD8+ Teffs were instead increased in long-term diabetics versus controls. PD-1+CD8+ Tregs were represented at a much lower percentage in long-term diabetic patients, in respect to controls. Importantly, patients CD8+ Tregs and CD8+ Teffs presented a significant proliferation defect in respect to the control group. In conclusion, our study indicates that a defect of CD8+ Tregs is observed in diabetics. This subset could thus represent a novel target of immunotherapy in patients.