Endocrine, Metabolic & Immune Disorders-Drug Targets (Formerly Current Drug Targets - Immune, Endocrine & Metabolic Disorders) - Volume 23, Issue 11, 2023

Pancreatic neuroendocrine neoplasms (PNETs) are rare but can be associated with significant morbidity and mortality. PNETs can be difficult to diagnose and have a propensity for metastasis before their diagnosis is established. To this end, many PNETs do not become apparent until late in their clinical course. Endoscopic ultrasound (EUS) has become the modality of choice for detecting these lesions due to its high tumor detection rate. Additionally, therapeutic techniques have arisen from EUS which allow for the treatment of PNETs. Overall, EUS has become a powerful diagnostic and therapeutic modality for addressing pancreatic lesions such as PNETs. In this perspective article, we provide an overview of the therapeutic potentials of EUS in the management of PNETs.

Introduction: Atherosclerotic Cardiovascular Diseases (CVD) are among the most relevant causes of morbidity and mortality worldwide, especially in aged people. Statins are one of the leading pharmacological interventions against atherosclerosis and are widely used to reduce the risk of occurring coronary artery diseases and related outcomes in both primary and secondary prevention. The management of chronic diseases is improved considerably over time, leading to an increase in life expectancy despite heavier comorbidity-related burdens in the elderly. Aims: The paper focused on the role of statins in the management of atherosclerosis and related burdens in elderly patients. Results: Statins are essential in reducing the risk of CVD in secondary and primary prevention, particularly in high-risk individuals. Guidelines encourage using specific algorithms with age-specific cutoffs to assess individual cardiovascular risk irrespective of baseline age, as the expansion of life expectancy produces favorable effects of statin treatment in those over 70. Discussion: Besides the estimation of baseline CV risk, a specific age-related assessment is also necessary before prescribing statin treatment in aged people focusing on frailty, potential pharmacological interactions due to polypharmacotherapy, cognitive impairment, and background chronic comorbidities, such as diabetes mellitus. Before starting statin therapy, an accurate choice of type and dose of statins is needed as potential adverse events are more prevalent with high-dose than low-to-moderatedose regimens and with lipophile than hydrophile statins (e.g., potential implication on intra-cerebral cholesterol metabolism). Conclusion: Despite possible adverse events, elderly patients should receive statins, when appropriate, to avoid the first occurrence of recurrent cardiovascular events and related burdens.

Lifestyle modifications (i.e., nutrition and physical activity) remain the main tools in the context of childhood obesity’s treatment and prevention of short and long-term consequences. At the same time, parental perception of child weight represents an even more important tool. It is known that more than half of parents of overweight/obese children underestimate their child’s weight status or are not worried about the risks associated with childhood overweight/obesity. Consequently, parental perception of childhood obesity can often be erroneous, and, even when accurate, subsequent parental behaviors can inadvertently contribute to the onset or persistence of childhood and adult obesity. Starting from the evidence that targeting a parent to induce a behavioral change is more effective than targeting the child only without parental participation, parental perceptions of childhood obesity can therefore represent a very important tool to take into consideration to achieve improvements in the context of childhood obesity. Therefore, knowledge of parental perception of children's weight status is needed to help pediatricians to organize and adapt activities and programs that promote healthy weight management among children. Specifically, early assessments of parents' perceptions of a child's weight, followed by regular follow-up visits, appropriate feedback, continuing education efforts, and efforts to follow the child’s weight status over time, can be potentially very helpful.

Diabetes Mellitus (DM) is a metabolic disorder characterized by hyperglycemia. Over the years, scientists have identified many factors that may have causal relationships with DM development. Identified factors are either genetic or environmental, and they may promote or prevent DM development. This review discusses various factors that are involved in the molecular pathogenesis, development, and therapeutic strategies of type 2 diabetes. DM is caused by interactions between multiple factors and triggers. Altered metabolic pathways and cellular functions, primarily in organs involved in glucose metabolisms, such as the pancreas and liver, often result in metabolic dysfunction, leading to DM. Additionally, abnormal levels of some factors, the presence of some pathogens, or the use of some types of medicine, such as immuno-inflammatory mediators, glucagon, apolipoprotein E4, chromogranin-A, exosomes, vitamin D, viruses, glucocorticoid medication, and antipsychotic drugs, may play roles in the development of DM. Some of these factors and mechanisms are well-studied, while others are more controversial and have contradicting experimental results. Further research is needed to confirm the roles of these factors in DM and fully understand how they contribute to DM development. Numerous medications for diabetics have been developed to help alleviate the symptoms of hyperglycemia and its complications. Several types of small compounds or peptide drugs with anti-diabetic effects can decrease blood glucose levels, improve insulin resistance, and inhibit key enzymes involved in the development and progression of diabetes. Here, we review the commonly used effective antidiabetic drugs, including the most recent innovative ones, such as GLP- 1R/GIPR and GLP-1R/GCGR agonists, and Chinese medicine.

Objective: This study was to investigate the clinical significance of miR-551b-5p and SETD2 in thyroid cancers (TC) and their effects on the biological function of TC cells. Methods: The expression level of miR-551b-5p and SETD2 in tumor/nontumor tissues and TC cell lines was measured by quantitative real-time polymerase chain reaction (RT-qPCR). Subsequently, the relationship between miR-551b-5p or SETD2 expression and the clinicopathological feature was detected by Chi-square analysis. Kaplan-Meier and multivariate Cox regression analyses were used to assess their prognostic values. Finally, the regulatory effects of miR-551b-5p and SETD2 on the proliferation, migration and invasion ability of TC cells were detected by CCK-8 and Transwell assays. Results: Compared with non-tumor groups, the expression of miR-551b-5p was significantly increased in patients' tissues and TC cell lines, while SETD2 mRNA expression was decreased. Patients with up-regulated miR-551b-5p or downregulated SETD2 mRNA in TC showed more positive lymph node metastasis and advanced TNM stage. High miR-551b-5p expression level and low SETD2 mRNA level were related to poor survival rate. miR-551b-5p and SETD2 might be potential prognostic biomarkers for TC. miR-551b-5p knockdown can inhibit cell proliferation, migration and invasion by targeting SETD2. Conclusion: miR-551b-5p and SETD2 may be valuable prognostic biomarkers and new therapeutic targets for TC.

Objective: Bladder cancer (BCa) is a malignant urological tumor with a high prevalence and poor prognosis. Extracellular vesicles (EVs) are increasingly becoming current hotspots owing to their involvement in cancer progression. This paper probed into the action of cancer-associated fibroblast-derived EVs (CAF-EVs) in the immune escape of BCa. Methods: CAFs were identified by immunofluorescence. EVs were extracted from CAFs via ultracentrifugation and later characterized. BCa cells (T24 cell line) were co-cultured with CD8+ T cells and then treated with CAF-EVs. The uptake of EVs by T24 cells was examined by confocal laser microscopy. T24 cell apoptosis and invasion were assessed using flow cytometry and invasion assay. CD8+ T cell proliferation was evaluated using CFSE staining. The levels of cytokines (IFN-γ, IL-2, and TNF-α) were measured by ELISA. PD-L1 and PD-1 levels were determined utilizing RT-qPCR and flow cytometry. BCa mouse models were established to identify the effect of CAF-EVs on BCa progression in vivo. Results: CAF-EVs decreased apoptosis and enhanced invasion of T24 cells, reduced proliferation of CD8+ T cells, and diminished levels of IFN-γ, IL-2, and TNF-α secreted by CD8+ T cells. CAF-EVs promoted the immune escape of T24 cells by carrying PD-L1. Downregulation of PDL1 expression in T24 cells or EVs partially counteracted the promotion of CAF-EVs on immune escape by reducing the binding of PD-L1 and PD-1. Additionally, CAF-EVs raised tumor volume and weight, upregulated PD-L1 expression, and weakened CD8+ T cell infiltration in BCa mice. Conclusion: CAF-EVs facilitate the immune escape of BCa by upregulating PD-L1/PD-1.

Aim: To investigate which risk factors are strictly connected to nomophobia in Italian nurses, according to socio-demographic characteristics, Body Mass Index scores, physical activity habits, anxiety, and depression. Methods: An “ad hoc” online questionnaire has been created and then administered to Italian nurses. Data include sex, age, years of work experience, shift work per day, nursing educational level, Body Mass Index, physical activity, anxiety, depression, and nomophobia conditions. Univariate logistic regression has been performed to explore what potential factors may contribute to the nomophobia condition. Results: A total of 430 nurses agree to participate. No respondents record severe nomophobia levels, as 308 (71.6%) register mild and 58 (13.5%) register moderate levels and 64 (14.9%) report no abnormal condition. Females seem to be more exposed than males to nomophobia (p < 0.001); nurses aged from 31 to 40 years and also with less than 10 years of work experience are more affected comparnig to the other sub groups (p < 0.001). Nurses who practice low physical activity report significant high levels in nomophobia (p < 0.001) and nurses reporting high anxiety levels also suffer from nomophobia (p < 0.001). The trend is inverse by considering depression condition since most of the nurses suffering from mild or moderate nomophobia levels report the absence of depression condition (p < 0.001). No statistical differences have been reported between nomophobia levels and shift work (p = 0.269), nursing educational level (p = 0.242), and BMI levels (p = 0.183). Anxiety and physical activity report strong relationships with nomophobia condition (p < 0.001). Conclusion: Nomophobia may affect all individuals, especially young individuals. Although further studies on nurses will be implemented, including the workplace and training environments of nurses by allowing a clearer picture of the levels of “nomophobia” in general, as nomophobic behavior may have negative repercussions both in social and professional spheres.

Background and Aims: The host micronutrient milieu is a compilation of factors of both endogenous and exogenous origin. This milieu shapes the host's immune responses and can control the inflammatory response of the host when infected. Among vitamins, B12 plays a key role in the defense process because there is intense competition for it between pathogenic invaders and infected host cells. Alcoholic beverages and antibiotics can cause biological (in vivo) interferences that affect pathogenhost crosstalk. Ethanol is known to interfere with the absorption, distribution, and excretion of vitamin B12 in men and animals. However, the molecular mechanisms underlying this backdrop are not fully understood. Here, we explored how Gram-positive ethanol-producing and Gram-negative vitamin B12- producing microbes of the infected milieu interact to influence biomarkers of host cell defense responses in absorbing, digesting, and defensive cells. Material and Methods: We investigated two different cell types of colon and liver origin, hepatic-like Huh7 cells and HT- 29/B6 colon cells. To assess the ability of secreted factors from bacteria to exert influence on co-cultured cell's secretion of host-defense markers in response to invading pathogens, cocultured human colonic HT-29/B6 and human hepatic Huh-7 (hereafter Huh7) cells were stimulated or not with Klebsiella pneumoniae 52145 for 24 h in the presence or absence of either Weissella confusa strain NRRL-B-14171 (as a Gram-positive producer of ethanol), Limosilactobacillus reuteri 20016 (as a Gram-positive producer of vitamin B12), or Pseudomonas nitroreducens 1650 (as a Gram-negative producer of vitamin B12). After stimulation, molecular functional biomarkers of host cell defense responses including total MMP-1, lysozyme activity, ALP, and IL-25 were measured. Results: While simultaneously reducing IL-25 secretion, Kp52145 alone significantly elicited MMP-1, lysozyme, and ALP secretion from co-cultured cells, as compared to no treatment. When compared with Kp 52145 stimulation alone, Pn1650 significantly potentiated MMP-1 and lysozyme secretions from Kp 52145-stimulated co-cultured cells by 29.7% and 67.4%, respectively. Simultaneously, a potentiated suppression (an overall decrease of 77.3%) in IL-25 secretion occurred 24 hours after Kn52145 plus Pn1650 administration. Compared to Kp52145-stimulation alone, treatment with W. confusa NRRL-B-14171 and Kp52145-stimulated co-cultured cells was associated with significant additive induction of MMP-1 and lysozyme secretions. However, compared to Kp52145-stimulation alone, W. confusa NRRL-B-14171 treatment significantly potentiated Kp52145-induced suppression of IL-25. Using the same condition as mentioned above and compared to Kp52145-stimulation alone, L. reuteri 20016 treatment altered the secretion pattern in response to Kp52145: L. reuteri 20016-treated cells displayed less aversive responses towards Kp52145, suggesting that L. reuteri 20016 modulation may act differently on Kp52145 - induced signaling. Conclusion: Gram-negative and Gram-positive vitamin B12- producing bacteria differently affect the secretion of key immune biomarkers in co-cultured HT-29/B6 and Huh7 cells following exposure to Kp52145. Ethanol-producing bacteria additively potentiate pathogenicity and inflammatory responses upon infection. To confirm the biological consequences of these effects on human gut microbiota and health, further studies are warranted, incorporating ex vivo studies of human colon samples and host biomarkers such as cytohistological, molecular, or biochemical measurements.

Aims: This study aims to examine the associations between various non-insulin-based insulin resistance (nIIR) indices and subclinical atherosclerosis assessed by carotid intima-media thickness (cIMT) in young adults. Background: nIIR indices, e.g., serum triglycerides (TG) have been reported with an association with cIMT in middle- and old-aged adults. Objective: We examined the associations of various well-known nIIR indices reported before with cIMT in young adults. Methods: A total of 1,822 young adults free of diabetes in Taiwan were included in 2018-2020. nIIR indices were assessed by TG concentrations, the TyG index, defined as Ln (TG *fasting glucose/2), the TG/high-density lipoprotein cholesterol (HDL-C) ratio, defined as TG divided by HDL-C, and the metabolic score for IR (METS-IR), defined as Ln[(2*fasting glucose)+TG) * body mass index (BMI)/(Ln(HDL-C))]. Multivariable linear regression analyses with adjustments for age, sex, anthropometrics, smoking, alcohol consumption, blood pressure, and total cholesterol were used to determine the associations. For TG only, HDL-C and fasting glucose were additionally adjusted. Results: In the overall participants, there was an association between cIMT and TG (β: 0.057, p = 0.04). In subgroup analyses, cIMT was associated with TG (β: 0.127, p = 0.004), the TyG index (β: 0.119, p = 0.01), and TG/HDL-C (β: 0.081, p = 0.03) in the overweight / obese (BMI ≥25 kg/m2), while not in the normal weight individuals. However, cIMT was correlated with TG (β: 0.086, p = 0.01) and TG/HDL-C (β: 0.077, p = 0.01) in those without hyperuricemia, while not in those with hyperuricemia. No association between the METS-IR and cIMT in any young adult subgroups was observed. Conclusion: This study highlights that some nIIR indices could be used to assess cIMT in young adults, particularly for those with obesity and those without hyperuricemia. The TG-based indices instead of the novel marker, METS-IR, are suggestive as stronger predictors of greater cIMT in young adults.

Aim: Lack of CYP17A1 prevents sex steroid biosynthesis, yielding a female phenotype in 46, XY males and sexual infantilism in both sexes; overproduction of 11-deoxycorticosterone (DOC) in the zona fasciculata typically causes mineralocorticoid hypertension. In this study, we report two cases of severe hypokalemia, hyperaldosteronism, and sexual infantilism. Case Presentation: Case 1 admitted severe hypertension and hypokalemia with female external genitalia with 46, XY. The patient also had right adrenal masses of 35*30 mm diameters. Case 2 was presented with delayed pubertal development with 46, XX genotype. In addition, she had severe hypertension and hypokalemia with nodular surrenal hyperplasia in her abdomen imaging. Methods: Further hormonal and biochemical results were followed as elevated adrenocorticotropic hormone (ACTH) levels, low serum cortisol, 17 hydroxy progesterone (17 OHP) and dehydroepiandrosterone sulphate (DHESO4) and estradiol (E2) levels in both cases. Results: Genetical analyses confirmed 17 OHP deficiency in both cases. Conclusion: The condition of patients with 17 alpha-hydroxylase deficiency may substantially resemble primary hyperaldosteronism and must be considered in patients as primary hypogonadism (and) associated with mineralocorticoid hypertension.

Background: After COVID-19 infection, various mechanisms may initiate an increased risk of developing DM. This study presented a newly developed autoimmune Type 1 DM (T1DM) case in an adult patient after a SARS-CoV-2 infection. Case Presentation: A 48-year-old male patient presented with complaints of weight loss and blurred vision. His blood sugar and HbA1c were measured as 557 mg/dl and 12.6%, respectively. His medical records showed no known diagnosis of DM. He had a SARS-CoV-2 infection 4 weeks ago. Then, we diagnosed DM and started basal-bolus insulin therapy. C-peptides and autoantibodies were requested from the patient to explore the etiology of diabetes. Glutamic acid decarboxylase (GAD) antibody was > 2000 U/mL (ref: 0-10); therefore, the patient was accepted as having autoimmune T1DM. New-onset DM cases triggered by COVID-19 have increasingly been reported recently. SARS-CoV-2 virus, using the ACE2 receptor in the pancreas, can enter beta cells and causes damage to these islets and impaired insulin secretion, leading to acute diabetes mellitus. In addition, the abnormal immunity elicited by SARS-CoV-2 can also induce autoimmune destruction of pancreatic islet cells. Conclusion: T1DM may be an uncommon but possible complication due to the COVID-19 virus among genetically predisposed individuals. Overall, the case highlights the importance of preventive measures, such as vaccination, to protect against COVID-19 and its complications.