Endocrine, Metabolic & Immune Disorders-Drug Targets (Formerly Current Drug Targets - Immune, Endocrine & Metabolic Disorders) - Volume 22, Issue 3, 2022

Background: Breast cancer is the most commonly occurring cancer in women worldwide. Early breast cancer is a kind of invasive neoplasm that has not proliferated beyond the breast or the axillary lymph nodes. Current therapeutic strategies for breast cancer mainly include local therapies such as surgery or radiotherapy and systemic therapies like chemotherapy, endocrine, and targeted therapy. Nowadays, the adjuvant treatment for hormone receptor-positive early breast cancer in postmenopausal women remains the main effective systemic therapy which can improve disease- free survival and overall survival; it involves several endocrine treatment regimens, including Selective Estrogen Receptor Modulators (SERMs), Aromatase Inhibitors (AIs), or a combination of them. AIs have been shown to be more effective in preventing recurrence in postmenopausal women with early breast cancer when compared with tamoxifen, thus representing the standard of care for adjuvant endocrine therapy. Although AIs are usually well-tolerated, they can have some side effects. Apart from the appearance of arthralgias or myalgias and cardiovascular events, AI therapies, reducing already low endogenous postmenopausal estradiol levels, cause increased bone loss and increase fracture risk in postmenopausal women. Objectives: The objective of this review is to evaluate the therapeutic options in the management of Aromatase Inhibitor-Associated Bone Loss (AIBL). Methods: We reviewed the current literature dealing with different therapeutic options in the treatment of AIBL. Results: Clinical practice guidelines recommend a careful evaluation of skeletal health in all women with breast cancer before AI therapy initiation. Adequate calcium and vitamin D intake have also been suggested. Pharmacological attempts to minimize AI-related bone loss have focused on the use of antiresorptive agents, such as bisphosphonates and denosumab to protect bone integrity and reduce the risk of fractures. Furthermore, clinical trials have shown that by making the bone microenvironment less susceptible to breast cancer metastasis, these drugs are able to increase disease- free survival. Conclusions: AI, that are the pillar of the systemic treatment for patients with hormone receptorpositive breast cancer, are associated with different side effects, and in particular, osteoporosis and fractures. Both bisphosphonates and denosumab are able to prevent this negative effect.

Background: Diabetic nephropathy-related osteoporosis (DNOP) is the most common comorbid bone metabolic disorder associated with diabetes mellitus (DM). The Liuwei Dihuang Pill (LWD) is a traditional Chinese herbal medicine widely used to treat diabetic complications, including diabetic nephropathy (DN). This study aimed to identify the biomarkers of the mechanisms of DNOP in LWD with systems biology approaches. Methods: Herein, we performed an integrated analysis of the GSE51674 and GSE63446 datasets from the GEO database via weighted gene co-expression network and network pharmacology (WGCNA) analysis. In addition, a network pharmacology approach, including bioactive compounds, was used with oral bioavailability (OB) and drug-likeness (DL) evaluation. Next, target prediction, functional enrichment analysis, network analysis, and virtual docking were used to investigate the mechanisms of LWD in DNOP. Results: WGCNA successfully identified 63 DNOP-related miRNAs. Among them, miR-574 was significantly upregulated in DN and OP samples. A total of 117 targets of 22 components associated with LWD in DNOP were obtained. The cellular response to nitrogen compounds, the AGERAGE signaling pathway in diabetic complications, and the MAPK signaling pathway were related to the main targets. Network analysis showed that kaempferol and quercetin were the most significant components. MAPK1 was identified as a potential target of miR-574 and the hub genes in the protein-protein interaction (PPI) network. The docking models demonstrated that kaempferol and quercetin had a strong binding affinity for Asp 167 of MAPK1. Conclusion: This study demonstrated that miR-574 may play important roles in DNOP, and the therapeutic effects of kaempferol and quercetin on LWD in DNOP might be mediated by miR-574 by targeting MAPK1. Our results provide new perspectives for further studies on the anti-DNOP mechanism of LWD.

Background & Aims: Patients with thalassemia have a lifelong need for blood transfusion, which makes them more risky to hepatitis C virus (HCV). Iron overload and chronic HCV are considered risk factors for patients with thalassemia to develop liver insults. The aim of the present study is to investigate the safety and efficacy of sofosbuvir/ledipasvir in the treatment of chronic HCV infection in Egyptian adult patients with β- thalassemia major. Methods: A retrospective study included 53 patients with β-thalassemia major with chronic HCV treated with sofosbuvir (400 mg) and ledipasvir (90 mg) as a single pill fixed-dose combination once daily for 12 weeks. The effectiveness of the treatment was assessed by the sustained virologic response (SVR) at 12 weeks after the end of the treatment. Results: SVR was achieved in 96.23% of patients. 47.17% of patients had minor side effects. There was a significant reduction in ALT, AST, and serum ferritin 12 weeks post-therapy. There was an insignificant change in hemoglobin level or blood transfusion requirement 12 weeks posttherapy. There was no change in iron chelators doses throughout the study period. Conclusion: Sofosbuvir/ledipasvir regimen seems to be safe and highly effective in the treatment of chronic HCV in patients with β-thalassemia major.

Background: There are anecdotal claims on the use of Cannabis sativa L. in the treatment of Alzheimer’s disease, but there is a lack of scientific data to support the efficacy and safety of Cannabis sativa L. for Alzheimer’s disease. Aim: The aim of the study was to evaluate the effect of aerial parts of Cannabis sativa L. on the cholinesterases and β-secretase enzymes activities as one of the possible mechanisms of Alzheimer’s disease. Methods: The phytochemical and heavy metal contents were analysed. The extracts were screened for acetylcholinesterase, butyrylcholinesterase and β-secretase activity. Cytotoxicity of extracts was performed in normal vero and pre-adipocytes cell lines. The extracts were characterized using high-performance thin layer chromatography and high-performance liquid chromatography for their chemical fingerprints. Alkaloids, flavonoids and glycosides were present amongst the tested phytochemicals. Cannabidiol concentrations were comparatively high in the hexane and dichloromethane than in dichloromethane: methanol (1:1) and methanol extracts. Results: Hexane and dichloromethane extracts showed a better inhibitory potential towards cholinesterase activity, while water, hexane, dichloromethane: methanol (1:1) and methanol showed an inhibitory potential towards β-secretase enzyme activity. All extracts showed no cytotoxic effect on pre-adipocytes and vero cells after 24- and 48-hours of exposure. Conclusion: Therefore, this may explain the mechanism through which AD symptoms may be treated and managed by Cannabis sativa L. extracts.

Background & Objective: Erectile dysfunction (ED) is one of the extrahepatic manifestations of hepatitis C virus infection that greatly affects patients’ quality of life. Unfortunately, some of the drugs used for HCV treatment may have a negative impact on the patient’s erectile function, such as the pegylated interferon. Currently, with the introduction of direct-acting antiviral drugs, there is scarce data in the literature about its potential impact on erectile function. In these settings, we aimed to assess the impact of sofosbuvir-based therapy on male erectile function. Methods: This prospective interventional study was carried out in Benha University hospitals between January 2019 and May 2020. The study included all consecutive HCV patients with simultaneous ED coming to the hepatology outpatient clinic. Patients were divided into a study group who received sofosbuvir-based therapy (group A) or a control group who received silymarin therapy (group B). The International Index of Erectile Function-5 (IIEF-5) was used for the assessment of erectile function at different time points (pretreatment, 6 months, and 12 months after treatment). Different variables in both groups have been statistically analyzed. Results: Overall, 75 patients who received sofosbuvir-based therapy and a control group (n = 35) matched for age and pretreatment variables (Child–Turcotte–Pugh score and Fibrosis128;4 score). There was no significant difference between both groups in the pretreatment data. On the other hand, the posttreatment IIEF-5 was significantly higher in the sofosbuvir arm compared to the silymarin arm both at six months (p<0.001) and at 12 months (p<0.001). Furthermore, the age and the stage of liver fibrosis were negatively correlated with IIEF-5 at all-time points. Conclusion: The age and the stage of liver fibrosis are significantly correlated with the degree of ED. Furthermore, sofosbuvir-based therapy may be associated with significant improvement in patients with erectile function.

Background: Premature ovarian failure (POF) refers to pathological amenorrhea before 40 years. Objective: To explore the regulatory effect of Rg1 on POF and clarify associated mechanisms. Materials and Methods: POF mice were induced by injecting with D-galactose (D-gal, 200 mg/kg/- day). Mice were divided into phosphate buffered saline (PBS), D-gal (POF mice), D-gal/Rg1 group (POF mice administrating D-gal/Rg1). Weight growth rate and ovarian weight coefficient were measured. Serum estradiol (E2), follicle stimulating hormone (FSH), luteinizing hormone (LH), superoxide dismutase (SOD), catalase (CAT) levels were examined using ELISA. The status of follicle and corpus luteum was determined using hematoxylin-eosin (HE) staining. P16INK4a and silent- mating type information regulation-2 homolog-1 (SIRT1) were determined using western blotting and RT-PCR. Results: Weight growth rate and ovarian weight coefficient of mice in D-gal group were significantly decreased than PBS group (p<0.05). Serum E2, LH, SOD, CAT levels were significantly decreased, FSH levels were remarkably increased in D-gal group than PBS group (p<0.05). Rg1 (D-- gal/Rg1 group) significantly increased weight growth rate and ovarian weight coefficient, enhanced E2, LH, SOD, CAT levels and decreased FSH levels than D-gal group (p<0.05). HE staining demonstrated normal follicle morphology/structure of mice in PBS group and decreased the number of follicles, obvious vacuolation of corpus luteum and increased atretic follicles of mice in D-gal group. Compared with D-gal group, the number of follicles was increased, luteal follicles were decreased in mice in D-gal/Rg1 group (p<0.05). Rg1 significantly (D-gal/Rg1) downregulated p16INK4a and upregulated SIRT1 expression in ovarian tissues of mice compared to the D-gal group (p<0.05). Conclusion: Rg1 could delay premature ovarian failure in D-gal induced POF mouse model through downregulating p16INK4a and upregulating SIRT1 expression.

Background: Primary Sjögren Syndrome (pSS) is a chronic autoimmune disease characterized by epithelial atrophy, mononuclear infiltration in exocrine glands resulting in the defective function of these glands. In pSS, atrophy of the epithelium is caused by an increased amount of apoptosis. Objective: The main aim of this study is to investigate the role of the apoptosis-related factors by studying Bcl-2, Fas and FasL expression in relation to the extent of inflammation as well as the effect of therapy on the expression of these mediators. Methods: In pSS patients (n=62) documented for their serological and clinical features, Fas, FasL and Bcl-2 plasma levels were assessed using enzyme-linked immunosorbent assays. In the same context, we investigated their expression by immunohistochemistry analysis in the labial salivary glands samples in association with the extent of inflammation. Results: Interestingly, our results indicated that in pSS patients, the plasmatic Bcl-2, Fas and FasL levels, which appeared to be associated with the severity of inflammation and were significantly elevated in comparison to the healthy controls. Moreover, a significant decrease in all these factors was observed in patients after combined corticosteroids-hydroxychloroquine therapy. Importantly, we report a strong positive correlation between Bcl-2 and NO levels. The immunohistochemical staining reveals a strong Bcl-2 expression in infiltrating mononuclear cells and a total absence in the acinar cells. The Bcl-2 level varies according to the severity of pathology. However, the expression of Fas and FasL was less important and predominantly localized in infiltrating mononuclear cells. Conclusion: Our current study highlights the involvement of Bcl-2, Fas and FasL in pSS glands injury. These factors may act as useful predictor markers of a clinical course in pSS, suggesting a novel approach in the pSS patients monitoring.

Background: Multiple endocrine neoplasia type 2A (MEN 2A) is mainly caused by germline RET codon C634 mutation and is characterized by Medullary Thyroid Carcinoma (MTC), pheochromocytoma (PHEO), and hyperparathyroidism (HPTH). The early diagnosis and initial normative treatment are helpful for the long-term outcome of MEN2A. Methods: Three index cases and their 29 relatives from three families with MEN2A were included in this study. Genetic screening was performed on all participants. Demographic, clinical profiles, tumor histopathologic features, and follow-up records were systematically analyzed. Results: In total, RET C634Y mutation was identified in 10 individuals (10/32, 31.3%). Among them, 5 presented with MTC symptoms, whereas the other 5 did not show apparent clinical manifestation, and all were subjected to thyroidectomy with varying neck dissection. Compared to individuals in the former, the latter benefited greatly from RET screening with significantly younger age at diagnosis of MTC and surgery (18.1 ± 13.8 years vs. 39.0 ± 14.1 years, P =0.045), and lessaggressive MTC behavior (size: 0.74 vs. 2.82 cm, P =0.026; LN+/resected: 20.0% vs. 100.0%, P =0.048) and also lower recurrence rate of MTC (20.0% vs. 100.0%, P =0.048). The PHEO was identified in 6 of the 10 carriers (60.0%), and all had undergone adrenal-sparing surgery. During the 10 years of follow-up, one (16.7%) developed recurrence of PHEO. Conclusion: Integrated RET screening, serum calcitonin, and plasma metanephrine/ normetanephrine levels can facilitate the early diagnosis and standardized MTC/PHEO surgery to improve the prognosis of MEN2A. Laparoscopic adrenal-sparing surgery prior to the bilateral total thyroidectomy is a preferred surgical approach for PHEO.

Background: Polycystic ovary syndrome (PCOS) is the most common endocrine abnormality among women of reproductive age. Insulin resistance is known as the hallmark of PCOS that leads to hyperinsulinemia and type 2 diabetes in PCOS patients. Objective: This study aimed to evaluate the expression pattern of IRS1 as a candidate gene in insulin resistance development in the PCOS rat models. Methods: In this study, estradiol valerate was used for PCOS induction. Then, all of the rats were divided into five experimental groups and treated with Astragalus hamosus extract. Ethanol was used for extraction by Soxhlet, and extracts were analyzed by GC-MS. Ovarian morphology was analyzed using histological experiments. Finally, the expression of IRS1 and hormonal titration of testosterone and insulin were evaluated using qRT-PCR and ELISA assays, respectively. Results: Induction of PCOS led to an increase in body weight, which decreased after treatment with the extract. Histological assessment declared an increased number of corpora lutea in treated groups and reduced cystic follicles compared to the PCOS group. Astragalus hamosus extract-treated groups exhibited decreased levels of insulin and testosterone compared to the PCOS group. qRT-PCR results showed an increase in the expression levels of IRS1 in the treated groups compared to the PCOS group. Conclusion: This study indicated the impact of Astragalus hamosus extract on PCOS by clarifying the increased levels of IRS1 expression in the treated groups compared to the PCOS group.

Background: Direct locoregional treatments were recently proposed for the local control of cervical and distant metastasis of thyroid cancer, but data on their use as part of a multimodality approach for primary thyroid tumors are poor. In this feasibility study, laser ablation (LTA) was successfully used for the initial debulking of unresectable radioiodine-refractory thyroid cancer in sequential therapy with Tyrosine-Kinase Inhibitors (TKI). Case Presentation: A 69-year-old woman underwent partial resection of papillary thyroid cancer with extensive tracheal infiltration. Post-treatment whole-body scan (¹³¹I, 8140 MBq) showed the absence of cervical thyroid uptake. The patient experienced a rapid increase in her cervical mass associated with dysphonia, dyspnea, and dysphagia. Due to a concomitant severe hypertensive state and cardiac failure, the patient was treated with LTA after a multidisciplinary consultation. After local anesthesia, two 300 nm optic fibers were inserted into the lesion through 21G spinal needles. Two illuminations with 4-watt output power and 3600 Joules energy delivery were performed with a diode-laser source. LTA resulted in rapid cancer debulking, and mass volume decreased from 23.9 to 7.5 mL resulting in significant improvement of pressure symptoms. Three months later, the patient was started on lenvatinib due to the initial regrowth of the tumor mass. The cervical tumor burden was controlled by TKI for 20 months when a rapid disease progression occurred, and the patient died. Discussion: Locally advanced, unresectable, and radioiodine-refractory thyroid tumors can be managed with a novel multimodality approach. The initial debulking with LTA of the locally aggressive disease results in rapid control of the tumor burden threatening patients’ life and is effectively followed by long-term control with TKI treatment. Conclusion: Based on this experience, sequential multimodality treatment with an initial locally directed laser ablation procedure followed by TKI therapy may be considered as a salvage option in patients with unresectable and rapidly progressive RR thyroid tumors.

Background: Immunotherapy with immune checkpoint inhibitors is a new frontier for cancer treatment. On the safety profile, this drugs class is associated with a new spectrum of side effects, the so-called immune-related adverse events that can potentially affect any organs, mainly endocrine glands. Scant data are available to inform the appropriate strategy of their management and treatment. Case Presentation: A 74-years old man with a squamous non-small cell lung cancer on nivolumab was hospitalized for fatigue, nausea, vomiting and severe hyponatremia. Biochemical tests were significant for hypotonic hyponatremia with a high urine sodium concentration. Endocrine tests showed overt primary hypothyroidism and low serum cortisol and aldosterone levels associated with an elevated circulating level of adrenocorticotrophic hormone. Adrenal antibody screening and the search of adrenal lesion on CT abdomen were negative. Thus, a nivolumab-induced primary adrenal insufficiency was diagnosed. Nivolumab withdrawal and replacement treatment with glucocorticoid and mineralocorticoid allowed clinical and biochemical recovery. Conclusion: Physicians need to be aware of potential immune-related adverse events in all patients treated with an immune checkpoint inhibitor. Their timely recognition is essential to carry out the proper treatment.