Endocrine, Metabolic & Immune Disorders-Drug Targets (Formerly Current Drug Targets - Immune, Endocrine & Metabolic Disorders) - Volume 24, Issue 8, 2024

Peptic ulcers (PU) are one of the commonest yet problematic diseases found to be existing in the majority of the population. Today, drugs from a wide range of therapeutic classes are available for the management of the disease. Still, the complications of the condition are difficult to tackle and the side effect profile is quite a concern. The literature indicates that Toll-like receptors (TLRs) and Semaphorins (SEMAs) have been under study for their various pharmacological actions over the past few decades. Both these signalling pathways are found to regulate immunological and inflammatory responses. Moreover, receptors and signalling molecules from the family of TLRs and SEMAs are found to have bacterial recognition and antibacterial properties which are essential in eradicating Helicobacter pylori (H. pylori), one of the major causative agents of PU. Our understanding of SEMAs, a class of proteins involved in cell signalling, is relatively less developed compared to TLRs, another class of proteins involved in the immune response. SEMAs and TLRs play different roles in biological processes, with SEMAs primarily involved in guiding cell migration and axon guidance during development, while TLRs are responsible for recognizing pathogens and initiating an immune response. Here, in this review, we will discuss in detail the signalling cascade of TLRs and SEMAs and thereby understand its association with PU for future therapeutic targeting. The review also aims at providing an overview of the study that has been into exploring the role of these signalling pathways in the management of PU.

Introduction: The prevalence of hypothyroidism increases along with aging, resulting in one of the most common comorbidities among patients over 75 years. The leading causes of hypothyroidism in older adults are iatrogenic, Hashimoto's thyroiditis, and medications. The narrative review aimed to discuss the clinical characteristics of hypothyroidism in older adults and the impact of hormonal replacement therapy on survival rates. Thyroid function declines over time due to physiological changes in the thyroid stimulating hormone signaling, iodine absorption and metabolism, thyroid hormone metabolism, and activity at peripheral sites. A serum TSH value over the upper limit of the normal reference range is not necessarily attributable to hypothyroidism. However, an appropriate diagnostic work-up is required to rule out true hypothyroidism and discriminate the etiology (i.e., thyroid autoimmune diseases, iodine deficiency, drug-induced hypothyroidism). Levothyroxine treatment should be considered in cases of overt hypothyroidism. A complete risk-to-benefit assessment, particularly considering the overall health status, life expectancy, cognitive function, mood, and cardiovascular and neurological background, should be considered before treating subclinical hypothyroidism with more potential benefits in patients under 75 years old. Levothyroxine formulations facilitating hormone absorption and increasing compliance to long-term treatment should be preferred. TSH target should usually be set over 3 mIU/ml. Defining optimal diagnostic approaches and targeted therapeutic strategies should be considered in the personalized management of aged patients with hypothyroidism.

Background: Hypersensitivity reactions to non-steroidal anti-inflammatory drugs (HR-NSAIDs) are common adverse events related to the widespread use of over-the-counter NSAIDs for the treatment of a variety of inflammatory conditions. Urticaria is the most commonly reported immediate cutaneous clinical sign of HR-NSAIDs, but it can be a manifestation of pathophysiologically different clinical entities that require different therapeutic strategies. The aim of this study is to ease the identification of the correct phenotype of HR-NSAIDs in patients reporting urticaria associated with the intake of NSAIDs and provide updated information about their diagnosis and management. Methods: The study is a narrative review conducted by collecting the most relevant and up-todate data related to the classification, pathophysiology, severity, and prognosis of NSAID hypersensitivity reactions. PubMed and Embase scientific databases were used as search engines to select relevant articles. Results: Patients developing HR-NSAIDs can be divided into two categories: selective responders (SR), who develop reactions after the administration of a single specific NSAID due to an underlying IgE or T-cell mediated hypersensitivity mechanism, or cross-intolerant (CI), who develop reactions to more than one chemically unrelated NSAIDs due to abnormalities in the biochemical pathways related with prostaglandin metabolism, independently from an underlying immunological mechanism. Five major different categories of HR-NSAIDs have been identified: NSAIDs-exacerbated cutaneous disease (NECD), NSAIDs-induced urticaria/angioedema with/without respiratory and systemic symptoms of anaphylaxis (NIUAA), and NSAIDsexacerbated respiratory disease (NERD), which are developed by CI patients, and single NSAIDs-induced urticaria, angioedema and/ or anaphylaxis (SNIUAA) and single NSAIDsinduced delayed hypersensitivity reactions (SNIDHR), which are developed by CI patients. In vivo and in vitro diagnostic tests have rarely been shown to be reliable in all these entities and therefore are not routinely used in clinical practice. The management in SR patients consists of strict avoidance of the culprit drug, while for cross-intolerance reactions oral tolerance tests with safe alternative drugs (e.g. weak COX-1 inhibitors or selective COX-2 inhibitors) can be performed. Conclusion: HR-NSAIDs are being observed with increasing frequency, however, the pathogenesis behind some NSAIDS-associated clinical entities is still unclear. Diagnosis is mostly based on a thorough clinical history and confirmed by a drug challenge test. Clinical management is based on strict avoidance and use of alternative tolerated medications. Overall, all therapeutic decisions depend on the correct identification of the type of reaction the patient experienced.

Chronic obstructive pulmonary disease (COPD) is a serious respiratory disease with high morbidity, disability and mortality worldwide. Every year, many people die from the disease or its comorbidities. Osteoporosis is a common complication of COPD, which can lead to increased fractures in COPD patients, aggravate the disease, and then bring great pain and burden to patients. The possible factors leading to osteoporosis in COPD patients include systemic inflammation, corticosteroid use, vitamin D deficiency, physical inactivity, tobacco exposure, lower bone mineral density, hypogonadism, hypoxia, and anemia. In clinical practice, the rate of diagnosis and treatment of osteoporosis in patients with COPD is low. Several studies demonstrated that treating osteoporosis with bisphosphonates could improve bone density, make breathing easier, and improve the quality of life of COPD patients. However, no studies have examined the effect of anti-osteoporosis therapy on fracture prevention in COPD patients. More research is needed to clarify how to implement holistic medical interventions in COPD patients with osteoporosis. We recommend that every COPD patient be screened for osteoporosis and treated with standard medications for primary osteoporosis.

Background: Timely identification and intervention of psychological disorders bear significant import in ameliorating the ensuing therapeutic trajectories in primary bone tumor patients. Moreover, perturbations in thyroxine and thyroid-stimulating hormone (TSH) levels have been linked to manifestations of depressive and anxiety-related symptoms. However, the precise interplay governing the nexus of anxiety, depression, and the levels of thyroxine and TSH within the context of primary bone tumor patients remains presently unexplored. Objective: The objective of this study is to investigate the potential correlation between the hypothalamus- pituitary-thyroxine (HPT) axis and the depressive as well as anxious states observed in patients afflicted with bone tumors. Methods: Patients with primary bone tumors were required to accept the assessments of anxiety and depressive symptoms as well as thyroid axis hormone concentrations. The depressive and anxiety symptoms were assessed using the Hamilton Depression Rating Scale (HAMD) and the Hamilton Anxiety Scale (HAMA) score. During each follow-up, peripheral venous blood samples were collected for subsequent analysis using radioimmunoassay methods to measure serum- free T3, free T4, and TSH levels, with the calculated free T3 to free T4 ratio indicating peripheral free T4 to free T3 conversion. Tests for trend were conducted to assess thyroid axis hormone concentrations, HAMA scores, and HAMD scores, while the correlation between HAMA or HAMD scores and thyroid axis hormone concentrations was examined through univariate regression analyses. Results: The study included 30 primary bone tumor patients. Initial high HAMA and HAMD scores decreased over a year after surgery (P < 0.05), reflecting diminishing anxiety and depression. TSH levels reduced postoperatively, contrasting with increased free-T3 and free-T4 levels (p < 0.01). Multivariate analysis affirmed that positive correlations were noted between TSH and anxiety/depression scores, while free-T3 correlated negatively, adjusted for demographic factors (p < 0.05). No significant associations emerged between HAMA/HAMD scores and free-T4 or free-T3 to free-T4 ratio (p > 0.05). Conclusion: The early identification of the low T3 syndrome could prove instrumental in both intervening and preventing adverse emotional states associated with primary bone tumors.

Background: Multiple sclerosis (MS) is a chronic autoimmune disease of the Central Nervous System (CNS) that affects individuals between the ages of 20 and 40 years, with a higher prevalence among women. Prevalence of this disease has increased significantly in re-cent decades in different geographical areas. There is evidence to suggest that both genetic and environmental factors play a role in the development of MS. Objective: This study aims to investigate the potential relationship between diet and MS in the Azeri population of the East Azerbaijan province of Iran. Methods: 467 MS patients and 260 non-related healthy individuals under the age of 15 com-pleted a dietary demographic questionnaire. The relationship between food consumption and MS was evaluated using the obtained data. Results: MS patients had a significantly higher consumption of fat, high-fat dairy, fast food, soybean, sausages and kielbasa, pickles, and leftover food (p-value=0.0001), while healthy in-dividuals had a higher consumption of fruit (p-value=0.0001). Consumption of Meat, sweets, and fizzy drinks was also found to be higher in MS patients (p-value<0.05). There was no sig-nificant difference in the consumption of vegetables, cakes biscuits, and spices between the two groups (p-value>0.05). Conclusion: The results suggest that fruit consumption under the age of 15 may be a protective factor against MS, while the consumption of fat, high-fat dairy, fast food, soybean, sausages and kielbasa, pickles, leftover food, meat, sweets, sauce, and fizzy drinks under the age of 15, may-be risk factors for MS.

Background: Macrovascular lesions are the main cause of death and disability in diabetes mellitus, and excessive accumulation of cholesterol and lipids can lead to long-term and repeated damage of vascular endothelial cells. Umbilical cord mesenchymal stem cells (UCMSCs) can attenuate vascular endothelial damage in type 1 diabetic mice, while Fufang Xueshuantong capsule (FXC) has a protective effect on endothelial function; however, whether FXC in combination with UCMSCs can improve T2DM macrovascular lesions as well as its mechanism of action are not clear. Therefore, the aim of this study was to reveal the role of FXC + UCMSCs in T2DM vasculopathy and their potential mechanism in the treatment of T2DM. Methods: The control and T2DM groups were intragastrically administered with equal amounts of saline, the UCMSCs group was injected with UCMSCs (1×10⁶, resuspended cells with 0.5 mL PBS) in the tail vein, the FXC group was intragastrically administered with 0.58 g/kg FXC, and the UCMSCs + FXC group was injected with UCMSCs (1×10⁶) in the tail vein, followed by FXC (0.58 g/kg), for 8 weeks. Results: We found that FXC+UCMSCs effectively reduced lipid levels (TG, TC, and LDL-C) and ameliorated aortic lesions in T2DM rats. Meanwhile, Nrf2 and HO-1 expression were upregulated. We demonstrated that inhibition of Nrf-2 expression blocked the inhibitory effect of FXC+UCMSCs-CM on apoptosis and oxidative stress injury. Conclusion: Our data suggest that FXC+UCMSCs may attenuate oxidative stress injury and macroangiopathy in T2DM by activating the Nrf-2/HO-1 pathway.

Background and Aims: Pathogenic bacteria and host cells counteract or neutralize each other's effect in two fundamental ways: Direct invasion and secretion of various substances. Among these, lipases secreted by pathogenic bacteria and host cell lysozyme are key actors. Secreted lipases from pathogenic bacterial are suggested as a key player in the pathogen-host interaction. Among the gut microbial energy sources, glucose and fats have been referred to as one of the best inducers and substrates for bacterial lipases. Enrichment of bacterial growth medium with extra glucose or oil has been shown to induce lipase production in pathogenic bacteria. More recently, research has focused on the role of human gut phage alterations in the onset of dysbiosis because the bacteria-phage interactions can be dramatically affected by the nutrient milieu of the gut. However, the reciprocal role of bacterial lipases and phages in this context has not been well studied and there is no data available about how high glucose or fat availability might modulate the cellular milieu of the pathogenic bacteria-phage-eukaryotic host cell interface. The purpose of this study was to evaluate the immunologic outcome of pathogenic bacteria- phage interaction under normal, high glucose, and high butter oil conditions to understand how nutrient availability affects lipase activity in pathogenic bacteria and, ultimately, the eukaryotic host cell responses to pathogenic bacteria-phage interaction. Materials and Methods: 10 groups of co-cultured T84 and HepG2 cells were treated with Pseudomonas aeruginosa strain PAO1 (P.a PAO1) in the presence and absence of its KPP22 phage and incubated in three different growth media (DMEM, DMEM + glucose and DMEM + butter oil). Structural and physiological (barrier function and cell viability), inflammatory (IL-6 and IL-8), metabolic (glucose and triglycerides), and enzymatic (lipases and lysozyme) parameters were determined. Results: Excess glucose or butter oil enhanced additively extracellular lipase activity of P.a PAO1. Excess glucose or butter oil treatments also magnified P. a PAO1- induced secretion of inflammatory signal molecules (IL-1β, IL-6) from co-cultured cells, concomitant with the enhancement of intracellular triglycerides in co-cultured HepG2 cells, these effects being abolished by phage KPP22. Conclusion: The results of the present study imply that KPP22 phage influences the interplay between food substances, gut bacterial lipases, and the gut cellular milieu. This can be applied in two-way interaction: by affecting the microbial uptake of excess free simple sugars and fats from the gut milieu leading to decreased bacterial lipases and by modulating the immune system of the intestinal -liver axis cells. Further studies are needed to see if the biological consequences of these effects also occur in vivo.

Objective: To investigate and validate ferroptosis genes (FRGs) in ulcerative colitis (UC) for diagnostic, subtype, and biological agent reactivity, with the goal of providing a foundation for the identification of novel therapeutic targets and the rational use of infliximab in clinical practice. Methods: UC datasets and FRGs were selected from the Gene Expression Omnibus (GEO) and FerrDb databases. WGCNA was used to identify characteristic genes of UC. LASSO and SVM models were used to discover key FRGs in UC. A nomogram was constructed for diagnosing UC using logistic regression (LR), We performed internal and external validation for the model. Furthermore, we constructed a hub-gene-signature prediction model for the effectiveness of infliximab in treating UC and deployed it on the website. Finally, the hub gene-drug interaction networks were constructed. Results: Nineteen ferroptosis-related genes associated with UC were identified through bioinformatics analysis. FTH1 and GPX4 were two of the down-regulated genes.The seventeen upregulated genes consisted of DUOX1, DUOX2, SOCS1, LPIN1, QSOX1, TRIM21, IDO1, SLC7A11, MUC1, HSPA5, SCD, ACSL3, NOS2, PARP9, PARP14, LCN2, and TRIB2. Five hub genes, including LCN2, QSOX1, MUC1, IDO1, and TRIB2, were acquried via machine learning. The mean auc of internal validation was 0.964 and 0.965 respectively, after using cross-validation and bootstrap in the training set based on the 5 hub-gene diagnostic models. In the external validation set, the AUC reached 0.976 and 0.858. RF model performs best in predicting infliximab effectiveness. In addition, we identified two ferroptosis subtypes. Cluster A mostly overlaps with the high-risk score group, with a hyperinflammatory phenotype. Conclusions: This research indicated that five hub genes related to ferroptosis might be potential markers in diagnosing and predicting infliximab sensitivity for UC.

Objective: To study the etiological characteristics of community-acquired pneumonia (CAP) combined with type 2 diabetes (T2D), providing a reference for early clinical diagnosis and treatment of the disease. Methods: We selected a total of 93 patients with CAP and analyzed their metagenomics nextgeneration sequencing (mNGS) data. The case group comprised 46 patients with combined CAP/T2D, and the control group comprised 47 patients without diabetes. We analyzed the pathogenic findings of the two groups. Results: There were statistically significant differences in age between the two groups (P = 0.001). Leukocytes (P = 0.012), blood platelets (P = 0.034), fibrinogen (P = 0.037), D-dimer (P = 0.000), calcitonin ogen (P = 0.015), ultrasensitive C-reactive protein or C-reactive protein (CRP) (P = 0.000), serum amyloid A (P = 0.000), and erythrocyte sedimentation rate (P = 0.003) were higher in the case group than in the control group. Albumin was lower in the case group than in the control group. All differences were statistically significant. The infection rates of Klebsiella pneumoniae (P = 0.030), Pseudomonas aeruginosa (P = 0.043), and Candida albicans (P = 0.032) were significantly different between the two groups. Conclusion: Compared with those without diabetes, the infection rates of Klebsiella pneumoniae, Pseudomonas aeruginosa, and Candida albicans were higher in patients with combined CAP/T2D.

Background: Research suggests that lowering maternal morbidities associated with gestational diabetes mellitus (GDM) can be achieved with earlier risk group identification. Aims: Therefore, the purpose of this study was to examine potential markers for identifying first-trimester pregnant women who are at high risk for developing GDM. Methods: This was a retrospective cohort study. The pertinent maternal clinical data were retrieved prior to 13+6 weeks of gestation, and a binary logistic regression analysis was used to identify potential GDM predictors. The predictive accuracy was evaluated using the area below the receiver operating characteristics curves. Results: In comparison to the control group, the GDM group had significantly higher mean values for age, body mass index (BMI), mean fasting blood glucose (FBG), and hemoglobin (p < 0.05). The Pearson’s correlation coefficients indicated that the first-trimester FBG was significantly positively correlated with the second-trimester FBG. Higher FBG and BMI values were associated with an increased risk of developing GDM (odds ratio (OR) = 3.04, 95% confidence interval [CI] = 2.03-4.55 and OR = 1.18, 95% CI = 1.12–1.25). In terms of predicting GDM, the FBG parameter demonstrated the greatest area under the curve values (0.66), followed by the BMI parameter (0.69). For GDM prediction, the cut-off value for FBG was 4.32 mM, whereas that for BMI was 23.7 kg/m2. Conclusions: The first-trimester FBG and BMI could be utilized to predict gestational diabetes.

Background: Obesity often co-exists with metabolic abnormalities, but the results of studies on the relationship between obesity, metabolic abnormalities and the risk of gout are inconsistent. Objectives: We aimed to study whether there was a mutual regulation between obesity, metabolic abnormalities and the risk of gout. Methods: We conducted a cross-sectional study to expound the association between obesity based on different metabolic statuses and the risk of gout. Patients were derived from Nationwide Readmission Database (2018 sample). Results: A total of 9,668,330 records were recruited for analysis from January to December. The risk of gout in the obesity group, metabolic abnormalities group and obesity combined with metabolic abnormalities group was 1.67 times (OR = 1.67, 95%CI 1.64-1.70), 3.12 times (OR = 3.12, 95%CI 3.09-3.15) and 4.27 times (OR = 4.27, 95%CI 4.22-4.32) higher than that in the normal control group. For different metabolic components, OR value was highest in hypertension group (OR = 2.65, 95%CI 2.60-2.70 and OR = 4.85, 95%CI 4.73-4.97), followed by dyslipidemia group (OR = 2.23, 95%CI 2.16-2.30 and OR = 3.74, 95%CI 3.55-3.95) and in hyperglycemia group (OR = 1.73, 95%CI 1.66-1.80 and OR = 2.94, 95%CI 2.78-3.11). Fewer components of metabolic syndrome were associated with a lower risk of gout in both nonobese and obese patients. Conclusion: When metabolic abnormalities were present, obesity induced a higher risk of gout. Different components of metabolic abnormalities had different effects on the risk of gout occurrence, and the number of metabolic abnormalities was closely related to the risk of gout occurrence. Follow-up and intervention methods targeting obesity and metabolic abnormalities should be considered for patients with gout.

Background: Podocyte injury and inflammatory response are the core contributors to the pathogenesis of diabetic nephropathy. This study aims to identify novel regulatory miRNAs and elucidate their underlying mechanisms, which will help us understand the pathogenesis of diabetic nephropathy more comprehensively. Materials and Methods: Different glucose concentrations were used to treat podocytes to mimic the pathology of diabetic nephropathy in vitro. Flow cytometry was used to determine cell apoptosis. Inflammatory cytokines released by podocytes were measured by using an enzymelinked immunosorbent assay (ELISA). Western Blot was used to detect the expression of PRKAB2 protein in podocytes. Results: Genecard and g: profiler results revealed that miR-29b might be involved in regulating HG-induced cell injury. QRT-PCR indicated that HG-induced downregulation of miR-29b in podocytes. MiR-29b knockdown promoted cell apoptosis and inflammatory response in podocytes. MiR-29b overexpression repressed cell apoptosis and inflammatory response induced by high glucose treatment in podocytes. Luciferase reporter assay and Western Blot showed that miR-29b targeted PRKAB2 to negatively regulate PRKAB2 expression directly. Knockdown of PRKAB2 reversed the increased cell apoptosis and inflammation induced by miR-29b inhibitors. Conclusion: MiR-29b plays a role in inhibiting inflammation and apoptosis in high glucose (HG) treated podocytes by negatively regulating PRKAB2 expression. This study provides new potential targets and ideas for the treatment of diabetic nephropathy.

Aim: This guideline (GL) is aimed at providing a clinical practice reference for the management of sporadic primary hyperparathyroidism (PHPT) in adults. PHPT management in pregnancy was not considered. Methods: This GL has been developed following the methods described in the Manual of the Italian National Guideline System. For each question, the panel appointed by Associazione Medici Endocrinology (AME) and Società Italiana dell’Osteoporosi, del Metabolismo Minerale e delle Malattie dello Scheletro (SIOMMMS) identified potentially relevant outcomes, which were then rated for their impact on therapeutic choices. Only outcomes classified as “critical” and “important” were considered in the systematic review of evidence. Those classified as “critical” were considered for the clinical practice recommendations. Results: The present GL provides recommendations about the roles of pharmacological and surgical treatment for the clinical management of sporadic PHPT. Parathyroidectomy is recommended in comparison to surveillance or pharmacologic treatment in any adult (outside of pregnancy) or elderly subject diagnosed with sporadic PHPT who is symptomatic or meets any of the following criteria: • Serum calcium levels >1 mg/dL above the upper limit of normal range. • Urinary calcium levels >4 mg/kg/day. • Osteoporosis disclosed by DXA examination and/or any fragility fracture. • Renal function impairment (eGFR <60 mL/min). • Clinic or silent nephrolithiasis. • Age ≤50 years. Monitoring and treatment of any comorbidity or complication of PHPT at bone, kidney, or cardiovascular level are suggested for patients who do not meet the criteria for surgery or are not operated on for any reason. Sixteen indications for good clinical practice are provided in addition to the recommendations. Conclusion: The present GL is directed to endocrinologists and surgeons - working in hospitals, territorial services or private practice - and to general practitioners and patients. The recommendations should also consider the patient’s preferences and the available resources and expertise.