Endocrine, Metabolic & Immune Disorders-Drug Targets (Formerly Current Drug Targets - Immune, Endocrine & Metabolic Disorders) - Volume 21, Issue 10, 2021

Prolonged treatment with Gonadotropin-Releasing Hormone (GnRH) agonists is known to induce bone loss among prostate cancer patients. However, evidence on the skeletal effects of GnRH antagonists is relatively less well-known. This review aims to examine the effects of GnRH antagonists on bone health. GnRH antagonists are an effective treatment for hormone-dependent conditions, such as advanced prostate cancer and endometriosis. They induce a competitive and reversible GnRH-receptor blockage, thereby suppressing the release of gonadotropins and sex hormones. The sex hormone ablation results in undesirable side effects, including accelerated bone loss. In animal studies, treatment with GnRH antagonists is reported to cause deterioration of bone microstructure. Human clinical trials revealed significant bone loss at the spine, hip and femur in patients treated with GnRH antagonists. Thus, osteoporosis and the resultant fragility fractures pose a significant impact on health and quality of life of GnRH antagonist users. Thus, early preventive measures of bone loss are critical in preventing fractures and its associated morbidity in these patients.

Background: Regardless of the enormous success of vaccines over decades, the formulation of biocompatible and highly effective vaccines is still insufficient for combating new pathogens. Discussion: The degree of effectiveness of any vaccine largely depends on the choice of appropriate adjuvant. Along with the optimum biocompatibility, an ideal adjuvant must be biodegradable, economical and easy to manufacture. To date, various organic and inorganic substances have been used as an adjuvant to augment the effectiveness of the vaccine. Immunological adjuvants are essential for strong and long-term effects against various pathogens. However, a very limited number of licensed adjuvants are available for the formulation of a successful vaccine. This leads to a challenging situation in medical science. Conclusion: The present review concisely summarizes the mechanism of action of various bioactive organic and inorganic immunological adjuvants, their limitations and future perspectives for their appropriate modification. Current trends of anticancer therapies using immunological adjuvants have also been highlighted in this review.

The classification of adeno-pituitary tumor was deeply revised over the last 20 years, in order to better describe the variable and complex biological and clinical behavior of these neoplasia and to identify prognostic markers of aggressiveness and poor prognosis. Recently, the International Pituitary Pathology Club proposed to replace the term “pituitary adenoma” with “pituitary neuroendocrine tumour” (PitNET), to reflect similarities of adeno-pituitary tumours with neuroendocrine neoplasia of other organs, underling better the variable behaviour of adeno-pituitary neoplasia. A definitive consensus was not reached on this issue. In this review, we will describe how molecular and biological marker can predict aggressiveness of PitNETs and impact on therapeutic management of PitNETs.

Within the pathophysiology of epilepsy, as a chronic brain disorder, the involvement of neuroinflammation has been extensively implied. Recurrent seizures of epilepsy have been associated with elevated levels of immune mediators that seem to play a pivotal role in triggering them. Neurons, glia, and endothelial cells of the blood-brain barrier (BBB) take part in such inflammatory processes by expressing receptors of associated mediators through autocrine and paracrine stimulation of intracellular signaling pathways. In this milieu, elevated cytokine levels in serum and brain tissue have been reported in patients with an epileptic profile. Noteworthy, interleukin (IL)-1β, IL-6, and tumor necrosis factor-alpha (TNF-α) are the proinflammatory cytokines mostly associated, in literature, with the pathogenesis of epilepsies. In this review, we examine the function of these cytokines in connection with transforming growth factor-beta (TGF-β), IL-8, IL-12, IL-18, and macrophage inflammatory protein (MIP) as potential proinflammatory mediators in the neuropathology of epilepsy.

In late 2019, SARS-COV-2 disease was firstly discovered in Wuhan, China and then it infected millions of people worldwide. Later, the World Health Organization (WHO) described COVID-19 as the first pandemic invading the world in the 21st century. The WHO has declared that the emerging infection will last long enough to force adjustments not only in people's lifestyles but also in the health care system. This amendment is expected to spread through many medical practices and specialties. A lot of diagnostic and therapeutic modalities have been proposed for COVID-19 management. The best strategy for the management of patients requires a multi-disciplinary team approach with correct decisions regarding the right timing of each modality of treatment. The participating multidisciplinary team for COVID-19 management includes six infectious diseases experts in Tanta University; one critical care management expert, an emergency medicine expert and two pharmacists in Tanta University. In this review, we reported our multi-disciplinary team experience with up to date literature guidance to propose a valid protocol for the management of COVID-19 patients in a limited resources setting.

The existence of a causal relationship between the rise of the death rate in COVID-19 infected patients and their sufferance from non-communicable pathophysiological conditions, particularly chronic diseases, was recently evidenced. In fact, in addition to the immunodeficiency generated by chronic disease conditions, COVID-19 also led to affect the immune system. Furthermore, the novel coronavirus attacks the lungs and other vital organs such as heart, kidneys, and brain. All these outcomes are accused of being involved in the increasing vulnerability and comorbidity in COVID-19- infected people with chronic diseases. Pharmacological, dietetic and natural approaches were suggested after deep bibliographic research for presenting preventive recommendations for this category of patients in order to avoid the fatal complications of this infection, and consequently limiting the risk of comorbidity. In this regard, some medications could enter into interaction with COVID-19 infection in patients with diabetes or hypertension and thereafter lead to fatal complications. Furthermore, regarding their nutritional values, some foods are more useful than others during this pandemic period because they are rich in vitamins, minerals, antioxidants and perhaps some bioactive phytochemicals, which are known to be effective in improving immune response, managing chronic diseases and/or having antiviral activities. In addition, vitamins, minerals, antioxidants, prebiotics and probiotics could be helpful in these conditions. Interestingly, in order to understand the mechanism of this causality and suggesting efficacious solutions, this review deserves considerable epidemiologic, clinical and experimental investigations.

Vitamins are essential substances for normal cell functions, growth, and development. However, they cannot be produced by the human organism, so intake must be through the diet. Vitamin deficiency causes the onset of different diseases, ranging from pellagra to pernicious anemia, which can be corrected by reintroducing the missing vitamin form. To supply the right amount of vitamins to the body, every vitamin naturally occurring in foodstuff has been identified, extracted and synthetically produced, thus allowing either food fortification with these compounds or their pharmaceutical production. Furthermore, the increased importance attributed nowadays to body wellness and the pursuit of a permanent status of health at all costs has greatly encouraged a high consumption of vitamin supplements in modern society, since vitamin megadoses may be responsible for adverse or toxic effects. However, excessive vitamins can induce hypervitaminosis. In the USA, a national survey confirmed that 52% of adult Americans take at least one or more supplement products, vitamins and minerals being the most popular supplements in that country. Although vitamins are widespread natural substances, they may induce immediate or delayed type hypersensitivity reactions. Such adverse events are still underestimated and poorly recognized because only single cases have been reported in the literature, and no general review has yet investigated the mechanisms underlying sensitization to each vitamin, the diagnosis, and the management strategies adopted for vitamin hypersensitivity. Although delayed-type reactions to different vitamins are described in the literature, in our review, attention has been focused mainly on immediate- type reactions. Due to the importance of vitamins, further information regarding the above aspects (pathomechanisms, diagnosis and management) would be highly desirable to focus the state of the art on this particular, underestimated form of allergy, thus increasing allergists' awareness on these elusive hypersensitivity reactions.

Breast milk has been considered the best source of nutrition for newborns. Several epidemiological and basic experimental studies have been conducted to understand the nutritional advantages of breast milk. Previous findings have emphasized the importance of good maternal nutrition. Maternal milk provides macromolecules, minerals, immune cells, antibodies, hormones, and regular flora to strengthen their offspring preventing various diseases. Maternal milk helps to facilitate physiological, and molecular maturation of several systems, which are important for the final maturation of organs and newborn body development. Currently, breastfeeding is being abandoned for various reasons, such as lower milk production, lack of time, abandonment of the family, social or emotional problems and adverse environmental conditions. These permanent alterations during a critical developmental window have negative consequences in regard to the development of the offspring and organ maturation leading to metabolic, reproductive, hormonal and physiological problems from early life to adulthood. This review describes the advantages of breast milk and the importance for the mother to maintain an adequate diet during pregnancy and lactation, in addition to maintaining a healthy lifestyle and harmonious family relationships. Such an environment will contribute to the complete maturation and development of the offspring.

Introduction: Angiotensin II (ANG II) and vasopressin (VP) interact in several physiological mechanisms, playing a role in arterial hypertension and congestive heart failure. Aim and Methods of Search: To overview the primary mechanism involved in the regulation of cardiovascular function, PubMed/Medline was searched, and authors selected original articles and reviews written in English. Results: Angiotensin II (ANG II) and vasopressin (VP) are involved in several physiological mechanisms. ANG II stimulates VP release via angiotensin receptor 1. ANG II and VP stimulate aldosterone synthesis and secretion and enhance its action at the renal collecting duct level. VP is also involved in the cardiovascular reflex control of the sympathetic nervous system (SNS). Also, VP potentiates vasoconstriction and cardiac contractility, enhancing the effect of ANG II on sympathetic tone and arterial pressure. On the other hand, ANG II and VP act antagonistically in regulating baroreflex control of the SNS. There is evidence that high VP plasma levels increase baroreflex sympatho-inhibitory responses, and the arterial baroreflex response is shifted to lower pressure. This cardiovascular reflex control is mediated mainly in the brain, specifically in the circumventricular organ area postrema (AP). The modulation of cardiovascular reflex control induced by VP is abolished after lesions of the AP. VP modulation of baroreflex function is also under the control of α2-adrenergic pathway arising from the nucleus of the solitary tract (NTS) and synapsing on VP-ergic neurons of supraoptic and paraventricular nuclei. Presynaptic α2-adrenergic stimulation within the NTS inhibits VP release induced by hypovolemia and the effects of VP and AP on baroreflex control of SNS, thus showing baroreceptor afferent inputs are processed within the NTS and contribute to the increased baroreflex sympatho-inhibitory responses. Discussion: In patients with congestive heart failure (CHF), plasma VP levels are elevated, inducing an up-regulation of aquaporin 2 water channel expression in renal collecting duct (CD) cells provoking exaggerated water retention and dilutional hyponatremia. Antagonists of VP and ANG II receptors reduce edema, body weight, and dyspnea in CHF patients. Conclusion: Hormonal imbalance between ANG II, VP, and SNS may induce hypertension and impaired water-electrolyte balance in cardiovascular diseases.

Immune dysregulation, neuronal inflammation, and oligodendrocyte degradation are key causes for autoimmune disorders like multiple sclerosis (MS) and various other immune dysregulated neurodegenerative complications responsible for CNS-mediated immune responses. Sirtuin (SIRT-1) is a nicotinamide adenosine dinucleotide (NAD)-dependent transcriptional protein that deacetylases and removes acetyl groups from its transcription factors like P53, FOXO, NF-b, PGC-1α. SIRT-1 mediates a wide range of physiological functions, including gene transcription, metabolism, neuronal apoptosis, and glucose production. SIRT-1 dysregulation targets transcription factors, and other molecular alterations such as gene expression modification influence neuronal plasticity, inhibit Th17 cells, and interleukin-1β can aggravate brain diseases. Preclinical and clinical findings show that the upregulation of SIRT-1 reduces autoimmunity, neurodegeneration, and neuroexcitation. Even though drugs are being developed for symptomatic therapies in clinical trials, there are particular pharmacological implications for improving post-operative conditions in neurodegenerative patients where intensive care is required. Understanding the SIRT-1 signaling and identifying immune-mediated neuron deterioration can detect major therapeutic interventions that could prevent neuro complications. Thus, in the current review, we have addressed the manifestations of disease by the downregulation of SIRT-1 that could potentially cause MS and other neurodegenerative disorders and provided data on existing available and effective drug therapies and disease management strategies.

Background: Melatonin is a biomarker of the central circadian clock and its chronobiotic actions entraining circadian rhythms to the light-dark cycle are well known. Reduction in melatonin levels and altered circadian rhythms have been associated with a high risk of breast cancer. Melatonin has also been shown to display anti-proliferative effects on breast cancer growth and proliferation. Evaluation of melatonin circadian rhythm alterations in patients bearing breast cancer may have interesting prognostic and therapeutic applications. Objective: To review studies evaluating the circadian rhythm of melatonin in breast cancer patients. The effects of surgery and chemotherapy on melatonin secretion were also reviewed. Methods: Electronic databases, including PubMed/MEDLINE and Scopus, were searched from their inception to May 2020, using the keywords "Melatonin", "Circadian rhythm" and "Breast cancer". Results: Patients with breast cancer maintain a circadian rhythm of melatonin secretion with relatively high levels during the night and low levels during the day, however, a reduction in nocturnal melatonin peak and decreased amplitude of melatonin circadian rhythms in these patients have also been reported. Melatonin levels can influence estrogen receptor concentrations in hormone-dependent estrogen- positive breast cancer. Chemotherapy alters melatonin levels and breast surgery tends to alter melatonin secretion at first-day post-operation. Melatonin levels correlate with clinical and psychological symptoms of breast cancer, such as sleep quality and depression severity. Conclusion: Circadian rhythm and the concentration of melatonin in the blood are altered in patients with breast cancers, and it can modify not only the sleep-wake cycle and, thus, patients’ quality of life but due to melatonin’s antioxidant effects, the effect of therapies can be modulated. Due to the heterogonous protocols used to assess melatonin and variable environmental factors during sampling, further studies need to control, such variables in order to tailor clinical trials based on melatonin rhythm adjustment and/or supplementation in breast cancer patients.

Colorectal cancer is known to be the paramount reason for cancer deaths around the globe. It occurs due to the aggregation of epigenetic and genetic alterations in colon epithelial cells that transmute them into adenocarcinomas. Epigenetic mechanisms are interpreted as the changes in expression of the gene which is not associated with the alterations in the principal DNA sequence, while genetic changes involve modifications in oncogenes and tumor suppressor genes. The changes in the epigenetic in colon cancer that transmute colonic epithelial cells include chromatin modifications, microRNA expression, telomere length, and DNA methylation. DNA hypermethylation causes down-regulation and unsuitable expression of specific microRNA which can behave like tumor suppressor genes. Histone modifications can also influence the chromatin remodeling and gene expression, hence performs an eminent function in the silencing of the gene in colon cancer. Moreover, the telomere/telomerase interaction is a prime mechanism to embrace both cellular replicative potential and genomic instability and its malfunction plays a primary role in colon cancer. Deducing the genesis and the function of epigenetic abnormality in colon cancer pathogenesis will lead to potent prevention and therapeutic approach for colon cancer patients. Epigenetic drugs which emphasize the convertible essence of the epigenetic occurrences have accompanied the probability of epigenetic approach as a treatment alternative in colon cancer. Hence, this review is undertaken to critically envelop the recently advanced events in colorectal cancer therapies with a special emphasis on remedies targeting epigenetic modulators and future challenges towards therapeutic interventions.

Background: Type one diabetes mellitus (T1DM) is an autoimmune disease characterized by gradual destruction of beta cells in islets of Langerhans. Teplizumab is a humanized anti- CD3 monoclonal antibody, which may have beneficial effects for T1DM patients. Objective: The aim of the study was to assess the safety and efficacy of teplizumab in T1DM patients. Methods: We searched electronic databases using related keywords for randomized clinical trials assessing the safety and efficacy of teplizumab. We evaluated the retrieved citations for eligibility, and we extracted the data and then analyzed it using Review Manager Software. Results: We included eight randomized clinical trials with 866 patients. Teplizumab was associated with lower insulin use than placebo at 6 months (MD = -0.17, 95% CI [-0.24, -0.09], P < 0.001), 12 months (MD = -0.12, 95% CI [-0.18, -0.06], P < 0.001), 18 months (MD = -0.22, 95% CI [-0.32, -0.11], P < 0.001) and 24 months (MD = -0.17, 95% CI [-0.28, -0.06], P = 0.003). The area under the curve of C-peptide was significantly increased in teplizumab group at 12 months (MD = 0.08, 95% CI [0.01, 0.15], P = 0.03), 18 months (MD = 0.13, 95% CI [0.01, 0.25], P = 0.03) and 24 months (MD = 0.13, 95% CI [0.01, 0.24], P = 0.03). No significant effect of teplizumab on HbA1c levels was observed at any time point. Teplizumab was found to be associated with some side effects such as lymphopenia, skin and subcutaneous tissue disorders. Conclusion: Teplizumab is associated with lower insulin use and higher AUC of C-peptide in type 1 diabetic patients with no significant effect on Hb1c levels. Besides, teplizumab has shown some adverse effects.

Objective: To investigate the therapeutic effect and mechanism of Triptolide on renal injury in diabetic nephropathy rats. Methods: A total of 15 male SD rats aged 8 weeks were randomly divided into five groups (3 rats in each group): control group, model group, Triptolide low-dose (Triptolide-L) group, Triptolide medium- dose (Triptolide-M) group, Triptolide high-dose (Triptolide-H) group. The rat models of diabetic nephropathy (DN) were established by a single intraperitoneal injection of STZ after being fed with high-fat and high-sugar diet for 4 weeks, and the fasting blood glucose (FBG) concentration of rats was detected. After 4 weeks, HE-staining was used to evaluate the renal pathological damage in rats; biochemical analysis was used to determine the blood urea nitrogen (BUN), serum creatinine (SCr), total cholesterol (TC), triglyceride (TG); ELISA was used to measure the serum inflammatory factor levels; Western blot (WB) was used to detect the expression of TGF-β1/Smads pathway proteins. Results: In the four FBG tests (once a week), the FBG concentration in the model group was significantly higher than that in the control group, while Triptolide-treated rats were significantly lower than that in the model group. Rats in Model group showed obvious renal injury, and Triptolide significantly improved the renal injury in DN rats. Compared with the control group, the expression of BUN, SCr, TC, TG, inflammatory factors TNF-α, IL-6 and IL-1β in the model group increased significantly. WB results showed that the expressions of TGF-β1, Smad3, α -SMA and vimentin in the kidney significantly increased, while the Smad7 expression significantly decreased. Triptolide significantly reduced the levels of BUN, SCr, TC, TG and TNF-α, IL-6, IL-1β in diabetic rats, decreased the expression of TGF-β1, Smad3, α-SMA, vimentin, and increased the Smad7 expression. In different doses of Triptolide treatment group, its effect showed a significant concentration dependence. Conclusion: Triptolide alleviates renal injury in diabetic rats by inhibiting the TGF-β1/Smads signaling pathway.

Background: In this study, we explored the impacts of moderate-to-high intensity resistance circuit training (MHRCT) and Ursolic acid (UA) supplementation to improve these pathological changes in young older obese women (women between the ages of 50 and 70). Methods: The study included twenty-five young older women (age > 50 years and ≤70 years) with stage I-II obesity (BMI ≥ 30 and <40 kg/m2), who received eight weeks placebo with MHRCT, and MHRCT with UA supplementation. UA or placebo orally was ingested as a capsule three times per day for eight weeks. The following parameters were evaluated post- and pre-intervention. Data were analyzed using ANOVA with repeated measures. Results: Interleukin-15 (IL-15), Interleukin-6 (IL-6), Insulin, and HOMA-IR decreased significantly in the placebo and UA groups versus control, but the UA group significantly decreased compared with the placebo (p<0.05). In turn, the Brain-Derived Neurotrophic Factor (BDNF) and Irisin levels showed a significant increase in the placebo and UA groups versus control. However, the BDNF in the UA group significantly increased compared with the placebo (p < 0.05). Conclusion: We demonstrated that applying resistance training can reverse the pathological changes that may occur with aging and a sedentary lifestyle. Our results showed that UA could enhance the effects of this type of exercise. Therefore, a combination of the resistance training program and UA supplementation may be considered as a novel and influential intervention to metabolic derangements and may also decrease the burden associated with this condition.

Background: Fibromyalgia syndrome (FMS) is a chronic disease characterized by widespread body pain, weakness in certain parts of the body (critical points), low pain tolerance, sleep disturbances, and fatigue. This syndrome is considered rare in Jordan. Objectives: The research aimed to find out the association of the angiotensin converting enzyme, methylenetetrahydrofolate reductase, and vitamin D receptor (ACE, MHFTR, and VDR, respectively) genotypes with FMS among Jordanian patients. Methods: This work included 22 FM patients and 22 healthy individuals of Jordanian Arabic origin. The ACE rs4646994, MTHFR rs1801133, and VDR rs2228570 genotypes were determined using polymerase chain reaction (PCR) followed by restriction fragment length polymorphism. Results: No associations between ACE rs4646994, MTHFR rs1801133, and VDR rs2228570 with the vulnerability of a person for the development of FMS were found. However, we found an association between the ACE rs4646994 genotype and restless leg among FM patients. Conclusion: Based on the result from this study, it appears that the ACE rs4646994 genotype is associated with restless leg among FMS patients of Jordanian origin. Further clinical investigations with larger sample sizes are required to confirm these findings and understand the molecular mechanism of ACE rs4646994 genetic variant in the restless leg syndrome among FM patients.

Background: Neonatal jaundice is a common neonatal disease that has adverse effects on neonates, especially preterm neonates, when indirect bilirubin level is adequately high to pass the blood-brain barrier, causing bilirubin encephalopathy or kernicterus. Aim: This study aimed to investigate the value of zinc (Zn) supplementation in preterm neonates with jaundice and whether it will be beneficial. Patients and Methods: A prospective randomized clinical trial, with the identification number TCTR20200504007, was conducted at Tanta University Hospital from July 2016 to March 2018 on 200 preterm neonates with jaundice. The studied neonates were divided into two groups: group 1, which received Zn and phototherapy, and group 2, which received phototherapy only and did not receive Zn. In group 1, 100 preterm neonates with jaundice received Zn as 0.6 mL (cm³) of zinc origin/kg/day orally through the oro-nasogastric tube divided into two doses (every 12 h), which was equal to 1.2 mg elemental zinc/kg/day orally for 10 days. Results: There was no significant difference in serum bilirubin level between the two groups on the 2nd, 4th, and 6th days of admission, while the serum bilirubin level was significantly decreased in group 1 compared with that in group 2 only on the 8th, 9th, and 10th days of admission. The p-- values were 0.045*, 0.027*, and 0.004*, respectively. Conclusion: Zn administration to preterm neonates with jaundice was found to be beneficial in decreasing serum bilirubin level. Recommendation: Zn supplementation should be provided to preterm neonates with jaundice.

Background: Hypothyroidism is a frequently observed comorbidity in patients with chronic heart failure (CHF), possibly giving rise to unfavorable outcomes. Aim: The aim of the study was to evaluate the impact of TSH changes over time on cardiac function and prognosis of outpatients with CHF. Methods: Patients underwent clinical, electrocardiographic, and echocardiographic evaluations at baseline and after 12 months. Moreover, blood chemistry tests were performed to evaluate renal function, cardiac biomarkers, fT3, fT4, and TSH levels. Based on TSH serum levels, patients were retrospectively classified into four categories: Group 1, patients with improved thyroid function at one-year follow up vs. baseline; Group 2, patients with stable and mildly high TSH values (3.74 – 10 mUI/L); Group 3, patients with worsening thyroid function; Euthyroid patients Group, TSH levels within the normal range of reference at baseline as well as at 12 months follow-up. We considered as end-points: one-year changes of laboratory and echocardiographic parameters; hospitalizations due to worsening of HF (acute decompensated heart failure - ADHF); death for all causes. Results: Among 257 patients, 174 (67.7%) were euthyroid at baseline and after 12 months. Group 1 patients (n. 22, 8.6%) showed a significant improvement in systolic and diastolic function, filling pressures, NT-proBNP and Galectin-3. Group 2 patients (n. 34, 13.2%) did not exhibit significant modifications in studied parameters. Group 3 patients (n. 27, 10.5%) showed worsening of diastolic function and NT-proBNP and a greater risk of ADHF (HR: 2.12; 95%CI: 1.20-3.74; p: 0.009) and death (HR: 4.05; 95%CI: 2.01-8.15; p<0.001). Conclusion: In patients with CHF, changes in thyroid function over time influenced echocardiographic parameters and biomarkers reflecting modifications of cardiac function and prognosis, thus suggesting the clinical relevance of thyroid deficiency screening and correction.