Endocrine, Metabolic & Immune Disorders-Drug Targets (Formerly Current Drug Targets - Immune, Endocrine & Metabolic Disorders) - Volume 23, Issue 5, 2023

Background: Various nutraceuticals from different sources have various beneficial actions and have been reported for many years. The important findings from the research conducted using various nutraceuticals exhibiting significant physiological and pharmacological activities have been summarized. Methods: An extensive investigation of literature was done using several worldwide electronic scientific databases like PUBMED, SCOPUS, Science Direct, Google Scholar, etc. The entire manuscript is available in the English language that is used for our various compounds of interest. These databases were thoroughly reviewed and summarized. Results: Nutraceuticals obtained from various sources play a vital role in the management of peripheral neuropathy associated with diabetes. Treatment with nutraceuticals has been beneficial as an alternative in preventing the progression. In particular, in vitro and in vivo studies have revealed that a variety of nutraceuticals have significant antioxidant and anti-inflammatory properties that may inhibit the early diabetes-driven molecular mechanisms that induce DPN. Conclusion: Nutraceuticals obtained from different sources like a plant, an animal, and marine have been properly utilized for the safety of health. In our opinion, this review could be of great interest to clinicians, as it offers a complementary perspective on the management of DPN. Trials with a well-defined patient and symptom selection have shown robust pharmacological design as pivotal points to let these promising compounds become better accepted by the medical community.

Background: Osseo-integrated implants provide effective treatment results for edentulous patients. However, despite the high success and survival rates of dental implants, several factors, such as poor oral hygiene and a history of periodontal disease, and systemic diseases, such as diabetes mellitus, could influence the outcome of the treatment. In fact, poor glycemic control can affect the healing process. Diabetes mellitus is considered a relative contraindication for dental implant therapy due to the fact that the success rates of the implants seem to be lower in diabetic patients, even if there is no total agreement among the results reported in the literature. The analysis of peri-implant inflammation indices, bone loss around the implant and glycemic index can provide us with useful information on the relationship between glycaemia in diabetic patients and the course of peri-implantitis, as well as implant success in the short term. Objective: The purpose of this review is to establish how peri-implant inflammation parameters vary in diabetic versus non-diabetic patients. Methods: This review was conducted on the basis of PRISMA. The search was conducted by three independent reviewers searching for keywords in three databases: PubMed, Scopus, Web Of Sciences (WOS), and the Cochrane Central Register of Controlled Trial. Results: A total of 1159 records were identified, and 11 articles were included in the qualitative analysis. Conclusion: The analysis of the extracted data from the included studies suggests that some periimplant inflammation indices, such as bleeding on probing and bone loss around the implant, appear to be increased in diabetic patients with glycometabolic decompensation, compared with control not affected by diabetes mellitus.

Background: Diabetes is a highly prevalent disease in the world. Type 2 diabetes mellitus (T2DM) is growing at an alarming rate due to rapid urbanization, migration, aging population, and lifestyle changes. Introduction: We have summarized the global T2DM distribution in specific International Diabetes Federation (IDF)-defined regions and various countries and highlighted the high risk of T2DM prevalence in Asian Indians living in India and worldwide. Methods: A systematic review was conducted using combinations of the following key concepts ‘T2DM’; ‘global distribution’; ‘Asian Indians’; ‘high risk’ and ‘prevalence’ by searching PubMed and EMBASE databases for articles describing the global distribution of T2DM. From 430 searched articles, 54 full-text articles were reviewed to study the distribution, risk, and prevalence of diabetes in various countries. Results: As per IDF Atlas, 463 million people in 2019 have diabetes worldwide, and it is expected to rise to 700 million by 2045. The global distribution of T2DM differs from various countries to various regions. Asia is the epicenter of diabetes, where 60% of people with diabetes live, mainly in China (139.9 million) and India (65 million). South Asians are more susceptible to developing T2DM as compared to ethnic Europeans. Asian Indians living worldwide are at a high risk of developing T2DM. Those who have migrated to various countries (USA, UK, Australia, Singapore, Mauritius, New Zealand, Fiji, etc.) have a higher prevalence of T2DM than the native population and even more significant than those Indians living in India due to being more insulin resistant. Indians develop T2DM at a younger age and at a lower BMI due to genetic makeup and behavioral and environmental determinants, including diet and sedentary lifestyle and westernization. Conclusion: In conclusion, insulin levels were found to be higher not only in adults but also in adolescents and young adults. In addition, rapid urbanization, migration, industrial modernization, and lifestyle changes are other factors responsible for the development of T2DM.

Background: Trimethylamine N-Oxide (TMAO), as a gut microbiota-derived metabolite, has been associated with a number of chronic diseases like cardiovascular diseases. Objective: Considering the increasing prevalence of non-communicable diseases (NCDs), we conducted a systematic review to discuss the TMAO association with NCDs. Methods: A comprehensive search has been conducted on PubMed, Web of Science, and Scopus databases up to December, 2020. The inclusion criteria were all related observational studies that surveyed the association between TMAO levels and non-communicable diseases. Interventional studies, animal experiments, reviews, case reports, letters, congress abstracts, and studies that were not published in English were excluded. Moreover, related review studies were separately discussed. Results: Within 2191 recorded studies, 99 cross-sectional, case-control and cohort studies met the inclusion criteria. The most common diseases associated with TMAO levels are cardiovascular diseases, diabetes, kidney disease, stroke, inflammatory diseases, neurological disorders, and cancer. Elevated TMAO levels as a consequence of alteration in gut microbiota composition and dietary intake can lead to the incidence of NCDs. The high levels of TMAO can disrupt the homeostasis of glucose and lipids and induce inflammation that leads to serious NCDs. Conclusion: There is a dose-response relationship between TMAO levels and NCDs progression. Therefore, it can be studied as a therapeutic target or prognostic biomarker for dealing with NCDs.

Aim: The aim of the study was to determine the effect of tert-butylhydroquinone (tBHQ) supplementation on some biochemical parameters in pregnant diabetic rats and the foetus. Background: The global incidence of gestational diabetes mellitus (GDM) has been on the increase despite current interventional therapies, underscoring the need for alternative or complementary therapeutic approaches. Objective: The objective is to determine the effect of tBHQ on blood glucose, insulin resistance, body weight, relative liver and kidney weights, serum lipid profile (total cholesterol, triacylglycerol, high-density lipoprotein cholesterol and very low-density lipoprotein cholesterol), liver function (albumin, aspartate and alanine amino transaminases) and kidney function markers (urea, creatinine and uric acid) in the sera, and study maternal and foetal renal levels of oxidative stress and inflammatory markers, foetal weights and histology of the kidney of streptozotocin (STZ)-induced GDM in rats. Methods: Twenty female pregnant rats were used, and they were divided into four groups of control (normal pregnancy), disease (diabetic untreated), metformin (received 200 mg/kg metformin dissolved in distilled water) and tBHQ groups (received 25 mg/kg tBHQ in 1% corn oil), respectively, with five rats in each group. GDM was induced in the disease and treated groups by intraperitoneal injection of STZ (45 mg/kg in sodium citrate buffer, pH 4.5). Results: STZ induction in the disease group significantly increased their blood glucose levels (P<0.05), altered their body and foetal weights, relative liver and kidney weights, serum lipid profile, liver and kidney function markers in the sera (relative to the control), inducing oxidative stress and inflammation to the maternal and foetal kidneys and altering the maternal kidney histology, which was found to be improved following supplementation with tBHQ in a manner akin to or even better than metformin. Conclusion: tBHQ was found beneficial in protecting the foetal kidneys against oxidative stress and the foetus against mortality arising from maternal hyperglycaemia. Finally, the study showed the potential of tBHQ in mitigating histological changes in the maternal kidney arising from STZinduced hyperglycemia in rats.

Background: Most commonly reported clinical manifestations are fever, fatigue and dry cough. Interestingly, a small percentage of patients experience GI symptoms, with the most common being anorexia, diarrhea, nausea and vomiting. We aimed to conduct a comparative study on COVID-19 patients with or without gastrointestinal patients (GI). Aims: The pandemic of coronavirus disease 2019 (COVID-19) has emerged as a dire health problem, causing a massive crisis for global health. Methods: Collective data of clinical manifestations and laboratory reports of patients admitted to Razi Hospital, Ahvaz, Khuzestan, Iran, for two weeks were analyzed. Results: Our results showed that GI symptoms are not statistically significant criteria to be predictive or prognostic factors in COVID-19 patients, although they are probably related to the acute or non-acute phase of the disease. Moreover, non-specific GI symptoms seem to result from cytokine storm that occurred during the disease. Conclusion: Therefore, our results did not support GI tract involvement as a common route of COVID- 19 infection. Maybe future research will shed light on why and how the gastrointestinal system becomes infected by COVID-19.

Background: Congenital hypothyroidism (CH) is the most common neonatal endocrine disorder. This study aimed to investigate whether disturbances in amino acid metabolism and fatty acid oxidation existed in neonates with CH compared to healthy neonates. Methods: In this case-control study, we evaluated the metabolomics of neonates with newly diagnosed CH and healthy neonates. Forty-three metabolites, including 13 amino acids and 30 acylcarnitines, were investigated. Results: Two hundred neonates with CH and 209 healthy children were enrolled. The mean age of males and females was 4.8 ± 2.4 and 5.52 ± 3.2 days in the case group and 5.1 ± 2.6 and 4.7 ± 3.6 days in the control group, respectively. Of the metabolites, 34 were significantly different between the two groups. Five amino acids and four acylcarnitines did not differ significantly between groups. Conclusion: These findings pave the way for a better understanding of the relationship between alterations and the clinical manifestation of CH, which has the potential for identifying novel therapeutics.

Background: Diabetes mellitus is a long-term disorder with high prevalence globally. It can be classified into two types: Type 1 diabetes and Type 2 diabetes mellitus. Diabetes mellitus is considered a multifactorial disorder in which genetic factors such as cytokines play a major role. Cytokines play a role in immune modulation and are associated with the development of diabetes mellitus. Single nucleotide polymorphisms in cytokines were studied extensively in different populations to determine their association with a predisposition to diabetes mellitus. Objective: The aim of this study was to estimate the frequency of single nucleotide polymorphisms in the cytokine genes TNF-α, TGF-β, IL-6, IL-10, and IFN-γ in 102 Jordanian diabetes mellitus patients in comparison to 50 controls and their association to diabetes mellitus susceptibility. Methods: Analysis was performed using the highly specific polymerase chain reaction-sequence specific primers methodology. Results: Our findings showed that the IL-10-1082 G/G genotype (P = 0.02) and the TGF-β1 codon 25*G allele (P < 0.01) may be considered risk factors for type 2 diabetes mellitus. In addition, the IFN-γ-874*A allele (P = 0.04) seems to increase the predisposition to type 1 diabetes. Conclusion: Our study showed that the IL-10-1082 G/G genotype and TGF-β1 codon 25*G allele are associated with type 2 diabetes mellitus while the IFN- γ -874*A allele is associated with type 1 diabetes. Our findings may help in the early detection of diabetes mellitus, which would in turn help in undergoing the needed preventative measures to delay the onset of diabetes mellitus.

Background: Quercetin is a kind of flavonoid with important bioactivities, such as hypoglycemic, antioxidant, anti-inflammatory, and anti-allergic properties. Although it is unstable, it is worth exploring how to better exert its anti-allergic effect. Objective: The current study aimed to elucidate the anti-allergic effect of quercetin liposomes on RBL-2H3 cells in vitro. Methods: Quercetin liposomes were prepared to improve the anti-allergic activity of quercetin through a green thin-film dispersion method. We compared the anti-allergic effects of quercetin and quercetin liposomes in RBL-2H3 cells. The anti-allergic activity of the quercetin liposomes was evaluated by the level of β-hexosaminidase, histamine, Ca²⁺, IL-4, IL-8, and MCP-1. Results: The results showed that quercetin liposomes could significantly restrain the release of β-hexosaminidase and histamine, calcium influx, and the expression of inflammatory factors, whose effect is stronger than quercetin. Conclusion: Collectively, our research suggests that the quercetin liposome can be used as a potential allergy antagonist.

Aims: To explore the ATF2 expression of preeclampsia patients and investigate whether the level of ATF2 expression impacted the low-dose aspirin treatment of preeclampsia patients. Background: Preeclampsia is a severe pregnancy-related hypertension disorder and refers to hypertension. Objective: This study was designed to explore the activating transcription factor 2 (ATF2) expression of preeclampsia patients and investigate whether the level of ATF2 expression impacted the low-dose aspirin treatment of preeclampsia patients. Methods: Firstly, we collected the plasma of normal and preeclampsia pregnancies and quantified the expressions of ATF2 by ELISA. Then we quantified the expression of the three downstream target genes of ATF2 (IL-8, IL-6 and MMP-2). Finally, we collected and quantified the interventional and observational group plasma. All data were compared by t-test (p<0.05). Results: ATF2 and its target genes (IL-6, IL-8 and MMP-2) were upregulated in preeclampsia patients. In addition, ATF2 and its target genes were downregulated in the interventional group (LDA-treated group). Conclusion: Our results indicated that LDA could inhibit ATF2 expression in preeclampsia. It suggests that ATF2 may be a potential target of LDA in the prevention of preeclampsia.

Background: Migraine is a disabling neurogenic disorder characterized by recurrent headache attacks. Adipokines act as inflammatory and pain mediators that contribute to migraine pathogenesis. Leptin and adiponectin levels change in migraine patients and are associated with headache attacks. Curcumin can exert modulatory and analgesic effects on adipokines through several mechanisms, from gene expression to suppressing pain. The aim of the present study was to evaluate the effects of nano-curcumin supplementation on leptin and adiponectin gene expression, their serum levels and migraine symptoms in patients with migraine. Methods: Forty-four episodic migraine patients enrolled in this trial were divided into two groups as nano-curcumin (80 mg/day) and placebo group, over a two-month period. At the beginning and the end of the study, the mRNA expression of leptin and adiponectin from isolated PBMCs and their serum levels were measured using real-time PCR and ELISA method, respectively. The headache frequencies, severity and duration of pain were also recorded. Results: The results of the present research showed that nano-curcumin can up-regulate adiponectin mRNA and increase its serum level significantly (P < 0.05). In the case of leptin, a reduction in gene expression and concentration was found in the nano-curcumin group but it was not statistically significant (P > 0.05). Nano-curcumin also significantly reduced the frequency, severity and duration of headaches (P < 0.05). Conclusion: These findings indicate that nano-curcumin supplement can be considered as a promising approach to migraine management and clinical symptoms improvement.

Background: 11β hydroxylase deficiency (11βOHD) ranks as the second most common enzyme deficiency that causes congenital adrenal hyperplasia. Depending on the severity of the enzyme deficiency, it can lead to cortisol deficiency, androgen excess and hypertension due to increased mineralocorticoid precursor levels. Many different types of mutations in the CYP11B1 gene located on chromosome 8q24.3 have been shown to cause 11βOHD. Here, we report a novel missense mutation that leads to 11βOHD in a female patient. Case Presentation: A 35-year-old female patient was admitted to the Endocrinology Department with a complaint of abdominal pain. The patient had a history of genital reconstruction surgery twice in childhood. On physical examination, an abdominal mass was detected. Laboratory examination of the patient revealed low levels of cortisol, potassium and high levels of ACTH, 11-deoxycortisol and androstenedione, suggesting 11βOHD. Genotyping showed a novel homozygous missense mutation (c.1385T>C L462P variant) detected on the 8th chromosome where the CYP11B1 gene is located. Glucocorticoid therapy was commenced for the patient whose diagnosis of 11βOHD was confirmed by both hormonal and genetic tests. A mass originating from the left adrenal gland with the largest diameter of 7 cm was compatible with myelolipoma. Conclusion: In this case report, we aimed to contribute to the literature by reporting a new missense mutation in the CYP11B1 gene, leading to classic type 11βOHD that has not been described before.

Background: H syndrome is a rare genodermatosis deriving from a mutation in the SLC29A3 gene and affecting numerous systems, particularly the skin. The syndrome exhibits different clinical characteristics involving several systems, most beginning with the letter "H." The most common clinical findings are cutaneous hyperpigmentation, flexion contracture in the fingers, hearing loss, short stature, insulin-dependent diabetes mellitus, heart anomalies, hepatosplenomegaly, and hypogonadism. Fewer than 150 cases have been reported so far and vast majority of them consisted with patients with Arab ethnicity. Case Presentation: We describe a patient presenting with short stature, developing diabetes mellitus at follow-ups, with homozygous deletion determined in exon 3 of the SLC29A3 gene, and diagnosed with H syndrome, reported due to the presence and rarity of renal involvement (hematuria and proteinuria). Conclusion: In conclusion, despite its rarity, endocrinologists, rheumatologists/nephrologists, and dermatologists need to be aware of H syndrome as a pleiotropic syndrome. H syndrome should be considered in the differential diagnosis of patients with cutaneous hyperpigmentation (particularly in the bilateral thigh and calf region) together with proteinuria/hematuria. In addition, periodic urine analysis should be performed in patients with H syndrome.

Background: Hypothalamic-pituitary region lymphoma is rare and diabetes insipidus (DI) represents one of the most common endocrine manifestations. We report the first case of hypothalamic lymphoma associated with both the syndrome of inappropriate antidiuresis (SIAD) and DI. Case Presentation: A 64-year-old woman with a history of stage IV large B-cell non-Hodgkin lymphoma, underwent atypical right lung resection for pulmonary nodules. A few days after surgery, the patient presented severe normovolemic hyponatremia and serum hypo-osmolarity, therefore, we suspected a paraneoplastic syndrome (SIAD) related to the lung neoplasm, histologically diagnosed as typical carcinoid. The brain magnetic resonance imaging (MRI) showed a 9 mm lesion in the hypothalamic region that significantly increased one month later with the onset of neurological symptoms. A trans-sphenoidal biopsy showed localization of the large B-cell lymphoma. After surgery, the patient presented with polyuria and polydipsia, so desmopressin therapy was started. In the following days, serum osmolarity and sodium fluctuated between normal and low values, then DI was excluded, and SIAD became more likely. Desmopressin therapy was discontinued and hyponatremia was treated with sodium infusion. Hypothalamic lymphoma was treated with chemotherapy and radiotherapy with substantial shrinkage. The hyponatremia persisted during anticancer treatments and improved only after radiotherapy, confirming paraneoplastic SIAD. Conclusion: Lymphomas of the hypothalamic region can cause electrolyte imbalance for various causes. The differential diagnosis between SIAD, DI and impaired thirst centers may not be straightforward and the electrolyte disorders must be evaluated step by step in all different stages of the disease.