Endocrine, Metabolic & Immune Disorders-Drug Targets (Formerly Current Drug Targets - Immune, Endocrine & Metabolic Disorders) - Volume 24, Issue 2, 2024

Obesity and cancer have been found to have a direct link in epidemiological studies. Obesity raises the risk of cancer and associated chronic disorders. Furthermore, an imbalance of adipokines, like leptins, plays a crucial role in neoplasm pathogenesis, cell migration, and thereby, cancer metastasis. Also, leptin increases human epidermal growth factor receptor 2 (HER2) protein levels through the STAT3-mediated (signal transducer and activator of transcription) upregulation of heat shock protein (Hsp90) in breast cancer cells. It has been noticed that insulin and insulin-like growth factors (IGFs) act as mitosis activators in the host and cancerous breast epithelial cells. The condition of hyperinsulinemia explains the positive association between colorectal cancer and obesity. Furthermore, in prostate cancer, an alteration in sex hormone levels, testosterone and dihydrotestosterone, has been reported to occur, along with increased oxidative stress, which is the actual cause of the tumors. Whereas, there have been two interconnected factors that play a crucial role in the psychological cycle concerned with lung cancer. The review article focuses on all the prospects of etiological mechanisms that have found linkage with obesity and breast, colon, lung, and prostate cancers. Furthermore, the article has also highlighted how these new insights into the processes occur and, due to which reasons, obesity contributes to tumorigenesis. This review provides a detailed discussion on the progression, which can assist in the development of new and innovative techniques to interfere in this process, and it has been supported with insights based on evidence literature on approved clinical treatments for obesity and cancer.

Inborn errors of metabolism (IEMs) are a vast array of inherited/congenital disorders, affecting a wide variety of metabolic pathways and/or biochemical processes inside the cells. Although IEMs are usually rare, they can be represented as serious health problems. During the neonatal period, these inherited defects can give rise to almost all key signs of liver malfunction, including jaundice, coagulopathy, hepato- and splenomegaly, ascites, etc. Since the liver is a vital organ with multiple synthetic, metabolic, and excretory functions, IEM-related hepatic dysfunction could seriously be considered life-threatening. In this context, the identification of those hepatic manifestations and their associated characteristics may promote the differential diagnosis of IEMs immediately after birth, making therapeutic strategies more successful in preventing the occurrence of subsequent events. Among all possible liver defects caused by IEMs, cholestatic jaundice, hepatosplenomegaly, and liver failure have been shown to be manifested more frequently. Therefore, the current study aims to review substantial IEMs that mostly result in the aforementioned hepatic disorders, relying on clinical principles, especially through the first years of life. In this article, a group of uncommon hepatic manifestations linked to IEMs is also discussed in brief.

Background: Several studies have identified CD163 as a potential mediator of diabetes mellitus through an immune-inflammation. Further study is necessary to identify its specific mechanism. Objectives: In this study, we aimed to investigate CD163 as a potential biomarker associated with immune inflammation in diabetes mellitus through a systematic review and bioinformatics analysis. Methods: We searched PubMed, Web of Science, the Cochrane Library, and Embase databases with a time limit of September 2, 2022. Furthermore, we conducted a systematic search and review based on PRISMA guidelines. Additionally, diabetic gene expression microarray datasets GSE29221, GSE30528, GSE30529, and GSE20966 were downloaded from the GEO database (http://www.ncbi.nlm.nih.gov/geo) for bioinformatics analysis. The PROSPERO number for this study is CRD420222347160. Results: Following the inclusion and exclusion criteria, seven articles included 1607 patients, comprising 912 diabetic patients and 695 non-diabetic patients. This systematic review found significantly higher levels of CD163 in diabetic patients compared to non-diabetic patients. People with diabetes had higher levels of CRP expression compared to the control group. Similarly, two of the three papers that used TNF- α as an outcome indicator showed higher expression levels in diabetic patients. Furthermore, IL-6 expression levels were higher in diabetic patients than in the control group. A total of 62 samples were analyzed by bioinformatics (33 case controls and 29 experimental groups), and 85 differential genes were identified containing CD163. According to the immune cell correlation analysis, CD163 was associated with macrophage M2, γδ T lymphocytes, macrophage M1, and other immune cells. Furthermore, to evaluate the diagnostic performance of CD163, we validated it using the GSE20966 dataset. In the validation set, CD163 showed high diagnostic accuracy. Conclusion: This study suggests CD163 participates in the inflammatory immune response associated with diabetes mellitus and its complications by involving several immune cells. Furthermore, the results suggest CD163 may be a potential biomarker reflecting immune inflammation in diabetic mellitus.

Background: The medicinal plants of the Cucurbitaceae family, such as Solena heterophylla Lour. fruits, have significant ethnobotanical value and are readily accessible in North East India. Aims: We conducted a study on Solena heterophylla Lour. fruits to evaluate their anti-diabetic activity in vivo, standardize their HPTLC, and profile their metabolites using LC-QTOF-MS. We aimed to explore the molecular mechanism behind their effects on oxidative stress and glycosylated hemoglobin (HbA1c). Methods: Firstly, the ethyl acetate fraction of Solena heterophylla Lour. fruits was standardized using Cucurbitacin B as a standard marker by conducting HPTLC evaluation. Next, we delved into analyzing metabolite profiling. In addition, the standardized fraction was utilized in an experimental study to investigate the molecular mechanism of action in an in vivo high-fat diet and a low dose of streptozotocin-induced diabetic model. Results: We have reportedly identified 52 metabolites in the ethyl acetate fraction of Solena heterophylla (EASH). In the in vitro tests, it has been observed that this extract from plants possesses notable inhibitory properties against α-amylase and α-glucosidase. Solena heterophylla fruits with high levels of Cucurbitacin B (2.29% w/w) helped lower FBG levels in animals with EASH treatment. EASH treatment reduced HbA1c levels and normalized liver lipid peroxidation and antioxidant enzyme levels. SGOT, SGPT, and SALP serum enzyme levels also returned to normal. Conclusion: Based on the current evaluation, it was found that EASH exhibited encouraging hypoglycemic effects in diabetic rats induced by a low dose of STZ and high-fat diet, which warrants further investigation.

Background and Aim: Uremic pruritus (UP) is one of the most distressing symptoms in hemodialysis (HD) patients. Subclinical hypothyroidism (SCH) is a biochemical condition with high prevalence in HD patients. The present multicentric study aimed to assess the relationship between UP and SCH in HD patients. Methods: The present cross-sectional study included 328 HD patients. All patients were submitted to careful history through clinical examination and standard laboratory assessment. Pruritis was evaluated using the pruritis visual analog scale (VAS). Patients were diagnosed with SCH if they had TSH levels above the upper limit of the normal reference range in association with normal free thyroxine (FT4) levels. Results: Among the studied patients, there were 196 patients (59.8 %) with UP. Comparison between patients with UP and patients without revealed that patients in the former group had significantly longer HD duration (median (IQR): 47.5 (27.0-72.5) versus 36.0 (23.0-50.5) months, p < 0.001) and lower Kt/v (median (IQR): 1.4 (1.09-1.7) versus 1.54 (1.12-1.91), p = 0.009). Moreover, they had significantly higher ferritin (median (IQR): 653.0 (526.0-800.0) versus 628.0 (470.8- 716.0) ng/mL), hsCRP (median (IQR): 12.0 (8.0-14.0) versus 8.0 (6.0-9.0) mg/dL, p < 0.001) and TSH levels (median (IQR): 4.34 (1.98-5.2) versus 3.34 (1.9-4.85) μIU/ml) with a significantly higher frequency of SCH (45.9 % versus 28.8 %, p = 0.002). Logistic regression analysis identified hemodialysis duration (OR (95%) CI): 1.02 (1.009-1.028), p < 0.001), ferritin levels (OR (95% CI): 1.002 (1.001-1.003), p < 0.001), and SCH (OR (95% CI): 0.54 (0.32-0.89), p = 0.016) as significant predictors of UP. Conclusion: The present study suggested a possible link between SCH and the development of UP in HD patients.

Background: Common variable immunodeficiency (CVID) is a primary immunodeficiency characterized by chronic/recurrent respiratory infections, bronchiectasis, autoimmunity, inflammatory, gastrointestinal diseases and malignancies associated with a chronic inflammatory state and increased risk of osteoporosis and muscle loss. Aim: The aim of this study was to evaluate bone mineral density (BMD), body composition and their relationship with lymphocyte subpopulations in CVID patients. Methods: Dual-energy X-ray absorptiometry was performed to assess BMD, lean mass, and fat mass in CVID patients. Peripheral blood CD4⁺, CD8⁺, and CD19⁺ cells were measured using flow cytometry. Results: Thirty-three patients (37.3 ± 10.8 years old) were examined. Although only 11.8% of the individuals were malnourished (BMI <18.5 kg/m2), 27.7% of them had low skeletal muscle mass index (SMI), and 57.6% of them had low BMD. Patients with osteopenia/osteoporosis presented lower weight (p = 0.007), lean mass (p = 0.011), appendicular lean mass (p = 0.011), SMI (p = 0.017), and CD4+ count (p = 0.030). Regression models showed a positive association between CD4+ count and bone/muscle parameters, whereas CD19+ B cell count was only associated with muscle variables. Analysis of ROC curves indicated a cutoff value of CD4+ count (657 cells/mm3; AUC: 0.71, 95% CI 0.52-0.90) which was related to low BMD. Weight (p = 0.004), lean mass (p = 0.027), appendicular lean mass (p = 0.022), SMI (p = 0.029), total bone mineral content (p = 0.005), lumbar (p = 0.005), femoral neck (p = 0.035), and total hip BMD (p<0.001) were found to be lower in patients with CD4+ count below the cutoff. Conclusion: CVID patients presented with low BMD, which was associated with CD4+ count. Moreover, low muscle parameters were correlated with B cell count.

Aims: This cross-sectional study aimed to analyze the relationship between live birth and the prevalence of obesity in Chinese women over 40 years of age. Methods: From April to November 2011, the Endocrinology Branch of the Chinese Medical Association conducted the REACTION project, a national, multicenter, cross-sectional study of Chinese adults aged 40 years and older. Demographic and medical data were collected through validated questionnaires and equipment. Anthropometric indicators, blood pressure, and biochemical data were measured by professional medical personnel. Data were analyzed using descriptive statistics and logistic analysis. Multivariate regression models were used to analyze obesity-related risk factors. Results: The prevalence of obesity among women increased gradually from 3.8% to 6.0% with an increasing number of live births. Women with two live births had the highest prevalence of overweight at 34.3%. Overall, the obesity and overweight rates were slightly higher in premenopausal women than in postmenopausal women. Univariate regression analysis showed that the risk of obesity in women increased with an increasing number of live births. In addition, multivariate regression analysis showed that the risk of obesity increased with an increasing number of live births in women with systolic blood pressure (SBP) < 121 mmHg or current smoking (P < 0.05). Conclusion: The risk of obesity increases with the number of live births in Chinese women over 40 years of age with SBP < 121 mmHg or current smoking. Our findings may facilitate the development of interventions to prevent obesity in this population.

Background: Congenital amegakaryocytic thrombocytopenia (CAMT) is a bone marrow failure syndrome with autosomal recessive inheritance characterized by the lack of megakaryocytes and thrombocytopenia. The cause of the disease is a mutation in the c-Mpl gene, which encodes the thrombopoietin (TPO) receptor. The main treatment for this genetic disorder is an allogeneic hematopoietic stem cell transplant (allo-HSCT). However, transplant-related mortality, development of acute and chronic graft-versushost disease (GvHD), and susceptibility to opportunistic infections are major barriers to transplantation. Delay in the reconstitution of T cells and imbalance in the regeneration of distinct functional CD4 and CD8 T-cell subsets mainly affect post-transplant complications. We report a case of CAMT, who developed acute GvHD but had no signs and symptoms of chronic GvHD following allo-HSCT. Case Presentation: At the age of four, she presented with petechiae and purpura. In laboratory investigations, pancytopenia without organomegaly, and cellularity less than 5% in bone marrow biopsy, were observed. A primary diagnosis of idiopathic aplastic anemia was made, and she was treated with prednisolone, cyclosporine, and anti-thymocyte globulin (ATG), which did not respond. Genetic analysis revealed the mutation c.1481T>G (p. L494W) in exon 10 of the c-Mpl gene, and the diagnosis of CAMT was confirmed. The patient underwent allo-HSCT from a healthy sibling donor. Alloimmunization reactions and immune disorders were present due to long-term treatment with immunosuppressive medications and repeated blood and platelet transfusions. Hence, the regeneration of T-lymphocytes after allo-HSCT was evaluated. Conclusion: Successful treatment of acute GvHD prevented advancing the condition to chronic GvHD, and this was accompanied by delayed T-cell reconstitution through an increase in Treg:Tcons ratio.

Background: Resistance to TSH is defined as reduced sensitivity to normal, biologicallyactive TSH, and abnormally high levels of TSH are needed to achieve normal levels of thyroid hormones. Case Presentation: A 15-year-old female patient, having been treated since childhood with levothyroxine for hyperthyrotropinemia was referred to our institution complaining of tachycardia after the levothyroxine therapy had been increased. Thyroid ultrasound features were normal, and thyroid antibodies were negative. The therapy was gradually tapered in light of the symptoms, although subclinical hypothyroidism was evident at thyroid function tests. First-degree relatives were tested for thyroid function, and the father was also found to have a previously-unknown subclinical hypothyroidism. The patient underwent genetic testing for TSH receptor (TSHR) gene mutations, which revealed a gene variant hitherto not described: p.C598R (c.1792T>C). The father was also tested and was found to carry the same mutation, while other first-degree relatives were wild-type for the TSHR gene. An in-silico analysis was performed, which revealed a loss-of-function phenotype corresponding to the described variant, suggesting a novel loss-of-function TSH receptor gene mutation. Conclusion: In this case report, we present a novel loss-of-function gene mutation in the TSH receptor gene associated with a TSH resistance phenotype.