Endocrine, Metabolic & Immune Disorders-Drug Targets (Formerly Current Drug Targets - Immune, Endocrine & Metabolic Disorders) - Volume 22, Issue 5, 2022

Diabetic Nephropathy (DN) is known as one of the driving sources of End-Stage Renal Disease (ESRD). DN prevalence continues to increase in every corner of the world andthat has been a major concern to healthcare professionals as DN is the key driver of Diabetes Mellitus (DM) morbidity and mortality. Hyperglycaemia is closely connected with the production of Reactive Oxygen Species (ROS) that cause oxidative stress response as well as numerous cellular and molecular modifications. Oxidative stress is a significant causative factor to renal damage, as it can activate other immunological pathways, such as inflammatory, fibrosis, and apoptosis pathways. These pathways can lead to cellular impairment and death as well as cellular senescence. Natural substances containing bioactive compounds, such as polyphenols, have been reported to exert valuable effects on various pathological conditions, including DM. The role of polyphenols in alleviating DN conditions has been documented in many studies. In this review, the potential of polyphenols in ameliorating the progression of DN via modulation of oxidative stress, inflammation, fibrosis, and apoptosis, as well as cellular senescence, has been addressed. This information may be used as the strategies for the management of DN and development as nutraceutical products to overcome DN development.

Eating Disorders (ED) are associated with multiple physical complications that strongly affect the physical health of these young and fragile patients and can also cause significant mortality, the highest among psychiatric pathologies. Among the various organic complications, albeit still little known, the gynecological implications, up to infertility, are very widespread. Both among adolescent and adult patients, gynecological symptoms can be very widespread and range from menstrual irregularities to amenorrhea, from vaginitis to ovarian polycystosis, up to complications during the gestational phase and in postpartum, in addition to the possible consequences on the unborn child. Among the most frequent and significant gynecological disorders in women with ED, there are menstrual irregularities that may occur with oligomenorrhea or even amenorrhea. This symptom, although no longer part of the DSM-5 diagnostic criteria for defining Anorexia Nervosa (AN), must be considered a very relevant event in the overall evaluation of young women and adolescents with eating disorders. Functional Hypothalamic Amenorrhea in ED patients is related to psychological distress, excessive exercise, disordered eating, or a combination of these factors which results in suppression of the hypothalamic- pituitary-ovarian axis, resulting in hypoestrogenism. The objective of this paper is to summarize the causes and the mechanism underlying the menstrual disorders and to provide a better understanding of the correlation between the reproductive system and the mechanisms that regulate food intake and eating habits. In addition, early recognition of risk factors for eating disorders for gynecological implications can help put more accurate assessments of patients to prevent potentially fatal complications. The importance of the involvement of specialist gynecologists in the multidisciplinary team that has to follow patients with eating disorders is also discussed.

Background: Currently, the relationship between insulin therapy and COVID-19 outcome is not yet established. Our study aims to evaluate the possible association between insulin and the composite poor outcome of COVID-19. Methods: We systematically searched the PubMed and Europe PMC database using specific keywords related to our aims until December 12th, 2020. All articles published on COVID-19 and insulin were retrieved. Statistical analysis was done using Review Manager 5.4 and Comprehensive Meta-Analysis version 3 software. Results: Our pooled analysis showed that insulin use was associated with composite poor outcomes of COVID-19 [OR 2.06 (95% CI 1.70 – 2.48), p < 0.00001, I2 = 83%, random-effect modelling], and its subgroup which comprised of risk of COVID-19 [OR 1.70 (95% CI 1.40 – 2.08), p < 0.00001, I2 = 34%, random-effect modelling], severe COVID-19 [OR 2.30 (95% CI 1.60 – 3.30), p < 0.00001, I2 = 88%, random-effect modelling], and mortality [OR 2.14 (95% CI 1.47 – 3.10), p < 0.0001, I2 = 85%, random-effect modelling]. Meta-regression showed that the association was influenced by age (p = 0.008), but not by diabetes p = 0.423) and cardiovascular disease (p = 0.086). Conclusion: Physicians should be more aware and take extra precautions with diabetes patients who use insulin therapy.

Aim: To evaluate differences between insomnia condition and the flexibility attitude to eat in Italian nurses directly involved in the care of patients affected by Covid-19 according to sex, Body Mass Index, shift working condition and incidence of new Covid-19 cases in the region of participants. Moreover, any correlations between the insomnia condition and the flexibile attitude to eat have been investigated. Methods: An online questionnaire was administered in October 2020, which included: the socio-demographic section, the insomnia condition assessment and the behavioral flexibility evaluation to develop in connection with developing an eating disorder. Results: 341 Italian nurses answered the questionnaire. Regarding the insomnia condition levels, nurses belonging to regions with a higher incidence rate of the Covid-19 pandemic recorded higher levels of insomnia than others (p=.004). Females and nurses belonging to regions with lower Covid-19 incidence rate recorded a significant higher total eating flexibility attitude (p=.003; p<.001), also, in the Food and Exercise flexibility (p=.007; p<.001). As regards the flexibility attitude for weight and shape, significant differences were recorded among nurses according to their BMI values (p<.001) and to their incidence rate of the belonging region (p<.001). The insomnia condition levels significantly correlated with the flexibility attitude to eat both in its total score (p=.010), in the general score (p=.010) and in the weight and shape score (p<.001). All correlations between the insomnia conditions and the flexibility to eat were significantly inverse with the exception for of the food and exercise dimension. All the flexibility attitudes to eat sub dimensions significantly correlated among them (p<.001). Conclusion: There was a direct correlation among socio-demographic factors, BMI values, insomnia and behavioral flexibility scores in Italian nurses so, it could be assumed that the nursing profession is at risk of developing a metabolic syndrome condition and, therefore, it could be considered as a psychoendocrinological employment disease during the Covid-19 outbreak.

Background: This study was conducted by considering the vital role of Vascular Endothelial Growth Factor (VEGF) in the development of Diabetic Retinopathy (DR) on the one hand and the frequent association between Subclinical Hypothyroidism (SCH) and DR on the other hand. Objective: The present study was proposed to explore the possible role of VEGF in the relation between SCH and DR; thus, we investigated the relationship between SCH and VEGF levels in patients with DR. Methods: Two hundred patients with DR were recruited in this study [100 patients with Proliferative Diabetic Retinopathy (PDR) and 100 patients with Non-Proliferative Diabetic Retinopathy (NPDR)]. Patients with DR were divided into 2 groups according to thyroid function, patients with SCH or those with euthyroidism. Patients were subjected to careful history taking and underwent clinical and ophthalmological examination. Fasting blood glucose, glycosylated hemoglobin, fasting insulin, Homeostasis Model Assessment of Insulin Resistance (HOMA-IR), TSH, FT4, FT3, VEGF, and thyroid volume were assessed. Results: Among all the studied patients, 21.5% (43/200) had SCH. DR patients with SCH had older age, longer diabetes duration, and higher HbA1c, HOMA-IR, and VEGF than those with euthyroidism. The frequency of PDR in patients with SCH was 72.1% (31/43) and 43.9% (69/157) in those with euthyroidism, whereas the frequency of NPDR in patients with SCH was 27.9 (12/43) and 56.1% (88/157) in those with euthyroidism (P 0.003). In multivariate analysis, PDR, HOMA- IR, and VEGF levels were the significant predictor variables of SCH. Conclusion: Increased VEGF levels may be implicated in the relationship between SCH and DR.

Aims: The aim of the study was to assess the effect of blocking TLR9 signaling on the proliferation of cervical cancer cells and its angiogenic property. Background: Toll-Like Receptors (TLRs) have been implicated for their crucial role in not only cervical cancer but also in other malignancies. TLR9 is expressed on an array of cells such as macrophages, dendritic cells, melanocytes, and keratinocytes and is reported to modulate oncogenesis along with tumorigenesis by augmenting NF-ΚB mediated inflammation within the tumor environment. TLR9 has also been reported to positively regulate oncogenesis within the cervix and as a marker to evaluate malignant remodeling of cervical squamous cells. Therefore, this study was designed to explore the functional relevance of blocking the TLR9signaling pathway in cervical cancer cells. Objective: The objective of the current study was to investigate the effect of human TLR9 antagonist, ODN INH-18, on apoptosis and cell cycle regulation, and angiogenic property of human cervical cancer Caski cells. Methods: MTT assay was performed to measure cell viability and flow cytometry analysis was performed to assess cell cycle arrest. Quantitative Real-Time PCR (qRT-PCR) analysis was performed to measure fold change in the gene expression of various markers of apoptosis, cell cycle regulation, and angiogenesis. Results: The qRT-PCR results showed a higher expression level of TLR9 mRNA in Caski cervical cancer cells as compared to normal cervical keratinocytes. The apoptotic, angiogenic, and cell cycle regulatory factors were also deregulated in Caski cells in comparison to normal keratinocytes. The MTT assay demonstrated that treatment of TLR9 antagonist, ODN INH18, significantly reduced the proliferation of Caski cells in a dose-dependent manner. Treatment of ODN INH18 led to substantial cell cycle arrest in Caski cells at G0/G1 phase. Moreover, the qRT-PCR results demonstrated that ODN INH18 treatment led to suppressed mRNA expression of Bcl-2 and enhanced expression of Bax, signifying the induction of apoptosis in Caski cells. Moreover, the expression of cyclin D1, Cdk4, and Cdc25A was found to be reduced whereas expression of p27 was increased in ODN INH18-treated Caski cells; indicating G0/G1 phase arrest. Interestingly, expression of VEGF and VCAM-1 was found to be significantly inhibited in ODN INH18-treated Caski cells, substantiating alleviation of angiogenic property of cervical cancer cells. Conclusion: The results of our study suggest that inhibiting TLR9 signaling might be an interesting therapeutic intervention for the treatment of cervical cancer.

Introduction: The pre-supplementary motor area (Pre-SMA) plays a pivotal role in the control of voluntary motor control and freezing of gait (FOG) pathophysiological mechanism. Here, we aimed to modulate if the pre-SMA would have beneficial effects on motor and behavioural outcomes in freezing of gait. To test this hypothesis, we examined the left pre-SMA stimulating effect of repetitive Transcranial Magnetic Stimulation (rTMS) on motor, cognitive and behavioural parameters in Parkinson’s patients with FOG. Methods: The study included 20 Parkinson’s patients with FOG (3 females, 17 males) who received the left Pre-SMA rTMS procedure. The clinical assessments were performed on all patients at the baseline and the patients were re-evaluated under the same clinical conditions one week after the end of the sessions. Results & Discussion: We found significant improvements in motor, cognitive and behavioural symptoms (p<0.05). The main finding of our study is that Pre-SMA is an attractive stimulation area leading to critical improvement of symptoms of Parkinson’s patients with FOG. Conclusion: The high-frequency rTMS stimulation over the left preSMA has a restorative effect on the motor, cognitive and behavioural symptoms of Parkinson’s patients with FOG.

Background: Probiotics are a group of bacteria that play a critical role in intestinal microbiota homeostasis and may help adjunctively treat certain diseases like metabolic and immune disorders. Objective: We recently generated a space-flight mutated Lactobacillus plantarum SS18-50 with good in vitro probiotic characteristics. In the current research, we designed two in vivo experiments to evaluate whether L. plantarum SS18-50 had the ability to increase beneficial gut bacteria, regulate oxidative status and ameliorate inflammation in mice. Methods: Experiments I: the ICR mice were gavaged with L. plantarum SS18-50 or its wild type L. plantarum GS18 at 10⁷ or 10⁹ CFU/kg BW daily for one month, during which the body weight was recorded weekly. The feces were collected to determine the abundance of two main beneficial bacterial groups including Lactobacillus and Bifidobacterium by selective culturing, while the total triglycerides and cholesterols in sera were determined using commercial kits. Experiment II: the mice were gavaged with loperamide hydrochloride (Lop) to develop oxidative stress and inflammation phenotypes. At the same time, the experimental mice were gavaged with L. plantarum SS18-50 or wild type L. plantarum GS18 at 10⁷ or 10⁹ CFU/kg BW daily for one month. At the end of the experiment, oxidative indicators (SOD and MDA) and inflammatory cytokines (IL-17A and IL-10) were measured by commercial kits. Results: Results showed that L. plantarum SS18-50 increased the abundance of Lactobacillus and Bifidobacterium in mice after one month’s administration. L. plantarum SS18-50 also showed the anti-oxidant activity by increasing SOD and decreasing MDA and exerted the anti-inflammatory effect by increasing IL-10 and decreasing IL-17A in Lop treated mice. Both the wild type stain and the space mutant had such biomedical effects, but L. plantarum SS18-50 was better in increasing gut beneficial bacteria and oxidative regulation than the wild type (P<0.05). Conclusion: We conclude that L. plantarum SS18-50 has a great potential to serve as a dietary functional probiotic supplement and/or adjunctive treatment strategy.

Background and Aim: Subclinical hypothyroidism (SCH) is frequently seen in diabetic patients. Elevated levels of uric acid (UA) were also reported in diabetic patients. No study assessed the relation between SCH and UA levels in diabetic patients. We aimed to evaluate this relation and the association of both conditions with other clinical and laboratory parameters in diabetic patients. Subjects and Methods: This cross-sectional study included 100 T2DM patients in addition to 50 age and sex matched healthy controls. Diabetic patients comprised 50 patients with SCH and 50 euthyroid patients. All participants were subjected to careful history taking, thorough clinical examination and standard laboratory work up. The performed investigations included fasting and postprandial blood sugar, fasting insulin levels, HbA1c levels, thyroid hormones (FT3, FT4 and TSH), renal profile and serum UA. Results: Comparison between the studied groups regarding serum UA levels revealed significantly higher levels in the diabetic group (5.4 ± 1.9 versus 4.2 ± 1.0 mg/dl, p<0.001). SCH + DM patients had significantly higher UA levels in comparison to DM group (6.1 ± 1.8 versus 4.8 ± 1.7 mg/dl, p<0.001) and control group (6.1 ± 1.8 versus 4.2 ± 1.0 mg/dl, p<0.001). SCH + DM patients had significantly higher HbA1c levels (8.9 ± 1.1 versus 7.6 ± 1.3%, p<0.001), HOMA-IR (3.9 ± 0.8 versus 2.8 ± 1.0, p<0.001) and UA levels (6.1 ± 1.8 versus 4.8 ± 1.7, p<0.001). Correlation analysis identified a significant direct correlation between serum UA and HOMA-IR in DM + SCH patients (r=0.4,p=0.004). In univariate analysis, presence of SCH [OR (95% CI): 2.57 (1.07-6.15), p=0.034] and nephropathy [OR (95% CI): 4.57 (1.77-11.8), p=0.002] was significant predictors of higher (upper tertile) UA in the studied patients. However, in multivariate analysis, only nephropathy [OR (95% CI): 4.25 (1.62-11.17), p=0.003] continued to be significant while SCH showed a marginal trend [OR (95% CI): 0.43 (0.17-1.08), p=0.073]. Conclusion : The present study suggests an association between SCH and increased UA levels in diabetic patients.

Background: Common variable immunodeficiency (CVID) is the most prevalent symptomatic primary immunodeficiencies. LPS-responsive beige-like anchor protein (LRBA) deficiency is a combined immunodeficiency characterized by a CVID-like phenotype. Affected patients by LRBA and CVID present a wide range of clinical manifestations, including hypogammaglobulinemia, recurrent infections, autoimmunity, as well as T cell abnormality. Methods: The study population comprised of patients with CVID (n=10), LRBA deficiency (n=11), and healthy controls (n=12). CD4+ T cell frequency and CD4 MFI (mean fluorescence intensity) were evaluated using flow cytometry before and after stimulation with PMA/ION. Results: The frequencies of CD4+ T cells were significantly lower in patients with LRBA deficiency than in HCs before and after treatment. In the unstimulated state, the CD4+ T cells frequency in CVID patients was significantly lower than in HCs. There were no statistically significant differences between patients and healthy individuals in CD4+ T cell proliferation. Compared to HCs, LRBA and CVID patients showed a lower CD4 MFI in unstimulated conditions. Furthermore, CD4 MFI decreased in both patients and the control group following activation. Conclusion: Despite the reported decrease in CD4+ T cell frequency in patients with CVID and LRBA deficiency, our findings demonstrated that their CD4+ T cells have a normal proliferative response to stimuli similar to healthy individuals.