Endocrine, Metabolic & Immune Disorders-Drug Targets (Formerly Current Drug Targets - Immune, Endocrine & Metabolic Disorders) - Volume 23, Issue 8, 2023

Introduction: The coronavirus pandemic has disproportionately affected older adults and has provided an incentive to find alternatives to emergency department attendance to avoid unnecessary exposure to the SARS-CoV-2 virus. To address this issue, a specialist geriatric multidisciplinary team at Queen Elizabeth Hospital set up a novel telemedicine approach to the ambulance service with the aim of reducing unnecessary emergency department attendance for older adults. This study provides a service evaluation in its first year of use. Methods: Service evaluation in the first year of the ‘Ask OPAL’ (older person Assessment and liaison) hotline for ambulance paramedics, run by a multidisciplinary acute geriatrics team at the Queen Elizabeth Hospital, Birmingham. Data on the number, patient demographics, intervention, and outcome of the calls, were recorded. Results: During the study period, 2552 ‘Ask OPAL’ calls were conducted. Of the 2552 calls carried out, 1755 patients (69%) remained at home. Of the patients who remained at home, 76% received verbal advice only, while 24% were referred to community services in addition to receiving verbal advice. Conclusion: In conclusion, the use of an integrated multidisciplinary team communicating with paramedics via telemedicine appears to be successful in preventing avoidable hospital admissions in complex patients.

Background: Epidemiological studies have shown that food is a compelling means of maintaining a state of well-being and preventing diseases. Many malignant diseases are related to nutrition, and the nutrient-organism interaction could define the balance between health and disease. Nutrients and dietary components influence epigenetic phenomena and modify drug response so that food-organism interactions may influence individual predisposition to disease and its potential therapeutic response. Aims: In this review, we highlighted emerging opinions and data on a large cluster of nutraceuticals, as well as functional foods and specific dietary patterns, with respect to cancer, including breast, pancreas, prostate, and colorectal. Only those nutraceuticals and nutritional supplements yielding sufficient and convincing data have been reported in this review; molecules with inconclusive clinical evidence will not be discussed. Conclusion: Growing and accumulating evidence is validating the use of nutraceuticals in cancer settings. However, a knowledge gap remains in terms of causal evidence for several compounds where a window for further clinical studies is left.

Thyroid diseases, including congenital hypothyroidism, thyroiditis, and childhood thyrotoxicosis, are progressively increasing. The incidence of thyroid cancer in children and adolescents has also increased in recent decades, mirroring the trends observed in adults. These epidemiologic trends develop in parallel with the rising costs associated with diagnosis and treatment of thyroid diseases. Both genetic and environmental factors are involved in these diseases, and a number of widely diffused toxic chemicals of anthropogenic origin can impair thyroid function and make thyroid cancer worse. Synthetic substances persistently contaminate environmental matrices (i.e., air, soil, water) and the food chain and bio-accumulate in humans, starting from in utero life. Environmental toxins such as air pollutants, endocrine disruptors, and high-frequency electromagnetic fields can act on common targets through common pathways, combined mechanisms, and with trans-generational effects, all of which contribute to thyroid damage. Both experimental and epidemiologic observations show that mechanisms of damage include: modulation of synthesis; transportation and metabolism of thyroid hormones; direct interference with hormone receptors: modulation of gene expression; and autoimmunity. We should not underestimate the available evidence linking environmental pollutants with thyroid disease, cancer included, since toxic substances increasingly diffuse and thyroid hormones play a key role in maintaining systemic metabolic homeostasis during body development. Thus, primary prevention measures are urgently needed in particular to protect children, the most exposed and vulnerable subjects.

Background: The Italian population’s habits changed dramatically during the “COVID- 19 lockdown” due to physical distancing and self-isolation. Moreover, medical consultations of patients with chronic diseases, such as type 2 diabetes (T2D), were suspended or postponed, unless urgent or semi-urgent, for several consecutive months. Thus, it is expected that the lockdown could have affected glucometabolic control in T2D. Purpose: The aim of the study was to assess changes in glucometabolic control in a cohort of T2D patients before (T1) and after (T2) the COVID-19 lockdown (March-May 2020). Methods: The study was approved by the Ethics Committee of the University of Bari, and all patients provided informed written consent to participate. Medical history, complete physical examination, and laboratory assessment were conducted as real-life clinical practice. Changes in clinical and laboratory variables between T1 and T2 were calculated. Results: In detail, 13 patients were on metformin as monotherapy, 36 on GLP-1RA, 12 on sodiumglucose transporter 2 inhibitors (SGLT-2i), and 2 on dipeptidyl-peptidase 4 inhibitors (DPP4i). The mean age was 65.3 years (43-83). Study participants were mainly men (73%). The body weight (BW) ranged from 56 to 145 kg, and the waist circumference ranged from 88 to 146 cm. The mean HbA1c was 51.0 mmol/mol. At T2, no statistically significant changes were observed frombaseline except for BW [-1.6 (-2.60 to -0.62)] and HbA1c [-2.90 (-4.69; -1.12)]. Conclusion: We evaluated the effects of the COVID-19 lockdown on glucometabolic control in patients with background well-controlled T2D. We found that the lockdown had no adverse effects on metabolic profile regardless of background clinical characteristics and antihyperglycemic management. Despite limitations due to the nature of this study (sample size, retrospective observation, lack of data on lifestyle changes in our patients' everyday lives), T2D patients managed in our Diabetes Centers faced the lockdown-related restrictions without any detrimental consequence.

Tirzepatide (mounjaro&^®) is a derivative of the human glucose-dependent insulinotropic polypeptide (GIP) hormone with a position-20 being modified with 1,20-eicosanedioic acid via a chemical linker. It acts as a glucagon-like peptide-1 (GLP-1) receptor and GIP receptor agonist. It has recently been approved by FDA as an adjunct therapy to exercise and diet to improve glycemic control in patients with type II diabetes mellitus (T2DM). It represents a new transforming paradigm in the management of T2DM. This mini-review will shed light on its different pharmacokinetic and pharmacodynamic aspects.

Background: Diabetes mellitus (DM) is a metabolic disorder characterized by progressive β cell dysfunction. Sheng-Mai Injection (SMI), a Traditional Chinese medicine preparation, is widely used for DM and its related complications. Objective: This meta-analysis aimed to summarize the applications of SMI in DM and related complications. Methods: Eight databases were searched, and meta-analyses were performed. Results: Fifteen studies, including 1273 participants, were included. All studies and participants included were from China. Pooled effects showed that SMI might reduce glycated hemoglobin (MD -0.46%; 95% CI -0.89 to -0.03; P < 0.01), fasting blood glucose (MD -0.83 mmol/L; 95% CI -1.30 to -0.36; P < 0.01), two-hour postprandial glucose (MD -1.27 mmol/L; 95% CI -1.96 to -0.58; P < 0.01), 24-hour urinary protein (MD -0.28 mg; 95% CI -0.51 to -0.06; P = 0.01), blood urea nitrogen (MD -1.31 mg; 95% CI -2.08 to -0.54; P < 0.05), Scr (MD -2.60; 95% CI -3.43 to -1.77; P < 0.05), ulnar nerve motor nerve conduction velocity (MNCV) (MD 1.45; 95% CI 0.03 to 2.87; P < 0.05), and tibial nerve sensory nerve conduction velocity (SNCV) (MD 1.84; 95% CI 0.1 to 3.58; P < 0.05). There was no evidence of an effect on common peroneal nervous MNCV and SNCV, tibial nerve MNCV, median nerve MNCV, and SNCV. Adverse effects included less frequent gastrointestinal reactions, elevated transaminase, leucopenia, fever, and rash. Conclusion: Combination use of SMI based on conventional hypoglycemic treatment can significantly improve HbA1c, FBG, and 2hPG in DM and reduce 24-hour urinary protein, Scr, and BUN in DM patients. SMI was found to have no effect on the neurological function of diabetic peripheral neuropathy.

Background: The diagnosis of Type 2 Diabetes Mellitus (T2DM) is made by demonstrating the hypoglycemic condition, which involves the determination of plasma glucose, and the follow-up of hypoglycemic treatment is performed by assessing the glycated hemoglobin (HbA1c) concentration. Aim: The aim of this study was to evaluate the saliva as an alternative sample in assessing the adherence to treatment with oral hypoglycemic agents in patients with Type 2 Diabetes. Methods: We selected 68 patients with T2DM, who were subjected to venous blood and saliva collection, in addition to answering a standardized questionnaire on adherence to hypoglycemic treatment. Laboratory tests performed on saliva, whole blood, serum or plasma included assessment of glycemia, urea, creatinine, uric acid, total cholesterol, HDL-cholesterol, LDL-cholesterol, VLDL-cholesterol, and glycated hemoglobin. Results: It was concluded that 82% of the patients adhered to hypoglycemic treatment based on glycated hemoglobin concentration (cut-off value of 7.0%). Comparing the groups that adhered to hypoglycemic treatment and those that did not adhere, statistical differences (P<0.05) were observed in the glucose, HDL-cholesterol, triglycerides, and insulin use (insulin therapy) parameters. Plasma glucose and urea serum concentration showed positive correlations when compared to saliva samples. Regarding the questionnaire, it was found that 35% of the patients presented positive screening for belief barriers and 83% positive score for recall barriers, and the positive screening correlated with glycated hemoglobin. Conclusion: Data have shown that it is possible to use saliva as an alternative sample to the laboratory assessment of hypoglycemic treatment adherence in T2DM patients.

Background: Patients with type 2 diabetes mellitus (T2DM) are at high risk for osteoporosis. SIRT1 plays an important regulatory role in the occurrence and development of diabetes mellitus; however, it is still not clear whether SIRT1 is directly related to the osteogenic ability of bone marrow mesenchymal stem cells (BMSCs) in T2DM patients. Methods: We obtained BMSCs from patients with T2DM and healthy volunteers to determine the effect of SIRT1 expression on the osteogenic capacity of BMSCs. As a result, SIRT1 expression in BMSCs in T2DM was significantly lower compared to healthy volunteers, but the proliferative capacity of BMSCs in the T2DM group was not significantly different from that of healthy volunteers. Results: During osteogenic differentiation, the expression of SIRT1 in MSCs from T2DM patients was significantly decreased, and the osteogenic differentiation ability of MSCs from T2DM patients was significantly lower than healthy volunteers. After intervention with resveratrol, the expression of SIRT1 increased significantly, and the apoptotic rate of MSCs in T2DM patients decreased significantly. Moreover, resveratrol promoted osteoblast differentiation of MSCs. Conclusion: Our study confirmed that the expression of SIRT1 is directly related to the osteogenic potential of BMSCs in patients with T2DM. Resveratrol promoted the osteogenic differentiation of BMSCs by increasing the expression of SIRT1. The increased expression of SIRT1 significantly reduced BMSC apoptosis during osteogenic differentiation, which is one of the important mechanisms by which SIRT1 regulates the osteogenic ability of BMSCs. Our data also provide strong evidence that resveratrol may be used in the treatment of osteoporosis in patients with T2DM.

Background and Objectives: Sjogren’s syndrome (SS) is a chronic autoimmune disease, particularly involving the lacrimal and salivary glands, with dryness as the main symptom. To date, the pathogenesis of SS is not fully understood. Recently, numerous miRNAs were implicated in SS etiology and pathogenesis. Methods: Ocular wash was collected from SS patients and healthy controls. INF-γ-treated salivary gland epithelial cells (SGECs) were utilized as SS in vitro models. Expressions of miR-223-3p and inositol 1,4,5-trisphosphate receptor type 3 (ITPR3) in ocular wash specimens and cells were measured by RT-qPCR assay and western blot analysis, respectively. ELISA assay was exploited to detect IL-6, IL-12, and TNF-γ levels. CCK-8, flow cytometry, and western blot assay were exploited to determine cell viability, apoptosis, and apoptosis-related protein levels. Results: ITPR3 was a direct downstream gene of miR-223-3p and negatively modulated by miR-223- 3p. MiR-223-3p increased while ITPR3 decreased in samples from SS patients and INF-γ-induced SGECs. miR-223-3p knockdown facilitated INF-γ-induced SGECs cell viability and restrained apoptosis and inflammation response through the NF-ΚB pathway. Conclusion: MiRNA-223-3p is implicated in the process of SS initiation and development. It may become one of the targets for the treatment of SS in the future, as well as a possible indicator for clinical monitoring of disease activity.

Background: Allergic asthma is a chronic inflammatory illness of the respiratory system characterized by an increase in the number of inflammatory cells in the airways and trouble breathing. Mesenchymal stem cells (MSCs) have the potential to be used in inflammatory diseases as a cellular immunosuppressive treatment. They express calcitriol receptors and communicate with other immunocytes, which increases their anti-inflammatory activity. This study aimed to determine the effects of calcitriol-treated MSC treatment on allergic asthma pathways in a mouse model. Methods: To generate a mouse model of asthma, the mice were sensitized intraperitoneally with ovalbumin (OVA) and aluminum hydroxide emulsion and then challenged intra-nasally with OVA. On day 14, experimental mice received tail vein injections of calcitriol-treated MSCs in PBS prior to allergen exposure. The cytokines assays including IL-4, 10, 12, 17, TGF-β and IFN-γ, splenocytes proliferation, and histological examination of lungs samples were performed. The mice were sensitized with OVA and the response to dexamethasone treatment was compared. Results: Calcitriol-treated MSCs significantly increased the levels of IL-12, TGF-β, and IFN-γ compared to non-treated MSCs groups. Moreover, calcitriol-treated and non-treated MSCs significantly decreased IL-4 and IL-17 compared to asthmatic groups. The results of the histopathological examination showed that calcitriol-treated MSCs reduced the accumulation of inflammatory cells and bronchial wall thickening in comparison with the asthma group. Conclusion: Using the allergic asthma model, we were able to show that calcitriol-treated MSCs had an inhibitory impact on airway inflammation. Our findings suggest that the injection of calcitrioltreated MSCs may be a viable treatment option for allergic asthma.

Aim: The study aims to show that sodium selenite (Ss) would have an immunomodulatory effect on the functional activity of proinflammatory macrophages (Mφs) during their extended extracellular activation at the onset of human type 1 diabetes (T1D). Background: Exacerbated activation of proinflammatory “M1” macrophages (Mφs) can promote chronic local pancreatic islet inflammation and T1D development. Objective: We investigated the ex vivo effects of Ss on the immune modulation of global/extended activation of human proinflammatory M1-like Mφs. Methods: Experiments were carried out on primary monocytes-derived Mφs (MDMs). Results: The levels of IL-1β, TNF-α, H2O2 and intracellular free calcium ions (ifCa²⁺), and the ratios of IL-1β-to-IL-10 and TNF-α-to-IL-10 were markedly increased in T1D Mφs than in healthy control Mφs. Conversely, both IL-10 production and arginase 1 (ARG1) activity were downregulated in T1D Mφs. Additionally, Ss treatment induced a marked downregulation of respiratory burst, ifCa²⁺ levels, M1-like Mφ-associated inducible nitric oxide (NO) synthase (iNOS) activity, cell necrosis and related necroinflammation biomarkers, including IL-1β and TNF-α, CD14 expression, and the ratios of iNOS-to-ARG1, IL-1β-to-IL-10, and TNF-α-to-IL-10. Moreover, Ss upregulated anti-inflammatory “M2-like” Mφ activity as demonstrated by ARG1 activity and IL-10 production, as well as phagocytosis capacity. Conclusion: Ss exerts a potent immunomodulatory role on functional activities of human proinflammatory T1D M1-like Mφs subjected to extended activation, as well as on the M1-like/M2-like dichotomy. Additionally, the current study provides a novel therapeutic approach using Ss to promote the anti-inflammatory function of Mφs at the onset of T1D.

Diaminopyrimidine compounds having the following general structure (I), compositions comprising an effective amount of a diaminopyrimidine compound, and methods for treating or preventing fibrotic liver disorders or other diseases associated with the JNK pathway are discussed in this patent study.