Endocrine, Metabolic & Immune Disorders-Drug Targets (Formerly Current Drug Targets - Immune, Endocrine & Metabolic Disorders) - Volume 21, Issue 1, 2021

Mammalian physiology is regulated by circadian clock through oscillating feedback loops controlling cellular processes and behaviors. Recent findings have led to an interesting connection between circadian disruption and colorectal cancer progression and incidence through controlling the hallmarks of cancer, namely cell cycle, cell metabolism and cell death. Deeper understanding of the circadian mechanisms that define the colorectal cancer pathophysiology is the need of the hour to define a chronotherapy for improving colorectal cancer patient survival. This review identifies the key areas in which circadian genes interact with cellular pathways to modify the outcome with respect to colorectal cancer incidence and progression.

Background: Colorectal cancer (CRC) is one of the leading causes of death across the globe. Early diagnosis with high sensitivity can prevent CRC progression, thereby reducing the condition of metastasis. Objective: The purpose of this review is (i) to discuss miRNA based biomarkers responsible for CRC, (ii) to brief on the different methods used for the detection of miRNA in CRC, (iii) to discuss different nanobiosensors so far found for the accurate detection of miRNAs in CRC using spectrophotometric detection, piezoelectric detection. Methods: The keywords for the review like micro RNA detection in inflammation, colorectal cancer, nanotechnology, were searched in PubMed and the relevant papers on the topics of miRNA related to CRC, nanotechnology-based biosensors for miRNA detection were then sorted and used appropriately for writing the review. Results: The review comprises a general introduction explaining the current scenario of CRC, the biomarkers used for the detection of different cancers, especially CRC and the importance of nanotechnology and a general scheme of a biosensor. The further subsections discuss the mechanism of CRC progression, the role of miRNA in CRC progression and different nanotechnology-based biosensors so far investigated for miRNA detection in other diseases, cancer and CRC. A scheme depicting miRNA detection using gold nanoparticles (AuNPs) is also illustrated. Conclusion: This review may give insight into the different nanostructures, like AuNPs, quantum dots, silver nanoparticles, MoS2derived nanoparticles, etc., based approaches for miRNA detection using biosensors.

MicroRNAs are a class of small non-coding RNAs that perform a crucial function in posttranscriptional gene regulation. Dysregulation of these microRNAs is associated with many types of cancer progression. In tumorigenesis, downregulated microRNAs might function as a tumour suppressor by repressing oncogenes, whereas overexpressed miRs might function as oncogenes by suppressing tumour suppressor. Similarly, Metadherin (also known as AEG-1/ LYRIC), is an oncogene, the levels of which are found to be very high in various cancers and play a crucial role in the proliferation of cells and invasion. Our review focuses on the study, which shows the alteration of microRNA expression profile and suppression of carcinogenesis when MTDH/AEG-1 is targeted. It summarises the studies where downregulation and upregulation of AEG-1 and microRNAs, respectively, alter the biological functions of the cell, such as proliferation and apoptosis. Studies have reported that AEG-1 can be direct or indirect target of microRNA, which could provide a new-insight to know the underlying molecular mechanism and might contribute to the progress of new therapeutic strategies for the disease.

MicroRNAs regulate gene expression at the posttranscriptional level by binding to the mRNA of their target genes. The dysfunction of miRNAs is strongly associated with the inflammation of the colon. Besides, some microRNAs are shown to suppress tumours, while others promote tumour progression and metastasis. Inflammatory bowel diseases include Crohn’s disease and Ulcerative colitis, which increase the risk factor for inflammation-associated colon cancer. MicroRNAs are shown to be involved in gastrointestinal pathologies by targeting the transcripts encoding proteins of the intestinal barrier and their regulators that are associated with inflammation and colon cancer. Detection of these microRNAs in the blood, serum, tissues, faecal matter, etc, will enable us to use these microRNAs as biomarkers for early detection of the associated malignancies and design novel therapeutic strategies to overcome the same. Information on MicroRNAs can be applied for the development of targeted therapies against inflammation-mediated colon cancer.

Colorectal cancer (CRC) is the third most common cancer worldwide, with high morbidity and mortality rates. The diagnosis and treatment of CRC have the most significant value for disease- free survival. Early diagnosis and early surgical resection are generally considered to be the most effective ways to reduce CRC mortality. In the past few years, many researchers have focused on the role of microRNAs in different tumors, making the functions of microRNAs gradually clear. The present study reviews the role of microRNAs in the diagnosis and treatment of colorectal cancer. Compared with the usual diagnosis methods and biomarker, circulating microRNAs can be promising new effective biomarkers for CRC diagnosis and treatment.

Autophagy is an evolutionarily conserved pathway that eliminates unwanted proteins out of the cell and increases cell survival. However, dysfunctional autophagy is associated with cancer progression, cellular adaptation, cancer metastasis and makes it an attractive therapeutic target. MicroRNAs (miRNAs) are small single-stranded non-coding RNA molecules that usually bind to 3’UTR of mRNAs. This interaction eventually inhibits protein synthesis by repressing translation and/or by degrading mRNAs. miRNAs play a crucial role in the regulation of autophagy and also behave as both tumor suppressors and promoters in colorectal cancer. This paper defines an overall molecular view of how miRNAs regulate the dual role of autophagy in colorectal cancer. It also highlights how long noncoding RNAs modulate miRNAs expression to regulate autophagy in colorectal cancer. Thus, targeting autophagy by miRNAs seems to be a potential therapeutic strategy for colorectal cancer.

The development of colorectal cancer (CRC) is a multistage process. The inflammation of the colon as in inflammatory bowel disease (IBD) such as ulcerative colitis (UC) or Crohn’s disease (CD) is often regarded as the initial trigger for the development of inflammation-associated CRC. Many cytokines such as tumor necrosis factor alpha (TNF-α) and interleukins (ILs) are known to exert proinflammatory actions, and inflammation initiates or promotes tumorigenesis of various cancers, including CRC, through differential regulation of microRNAs (miRNAs/miRs). miRNAs can be oncogenic miRNAs (oncomiRs) or anti-oncomiRs/tumor suppressor miRNAs, and they play key roles during colorectal carcinogenesis. However, the functions and molecular mechanisms of regulation of miRNAs involved in inflammation-associated CRC are still anecdotal and largely unknown. Consolidating the published results and offering perspective solutions to circumvent CRC, the current review is focused on the role of miRNAs and their regulation in the development of CRC. We have also discussed the model systems adapted by researchers to delineate the role of miRNAs in inflammation-associated CRC.

Chronic inflammation can lead to the development of many diseases, including cancer. Inflammatory bowel disease (IBD) that includes both ulcerative colitis (UC) and Crohn's disease (CD) are risk factors for the development of colorectal cancer (CRC). Many cytokines produced primarily by the gut immune cells either during or in response to localized inflammation in the colon and rectum are known to stimulate the complex interactions between the different cell types in the gut environment resulting in acute inflammation. Subsequently, chronic inflammation, together with genetic and epigenetic changes, have been shown to lead to the development and progression of CRC. Various cell types present in the colon, such as enterocytes, Paneth cells, goblet cells, and macrophages, express receptors for inflammatory cytokines and respond to tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), IL-6, and other cytokines. Among the several cytokines produced, TNF-α and IL-1β are the key pro-inflammatory molecules that play critical roles in the development of CRC. The current review is intended to consolidate the published findings to focus on the role of pro-inflammatory cytokines, namely TNF-α and IL-1β, on inflammation (and the altered immune response) in the gut, to better understand the development of CRC in IBD, using various experimental model systems, preclinical and clinical studies. Moreover, this review also highlights the current therapeutic strategies available (monotherapy and combination therapy) to alleviate the symptoms or treat inflammation-associated CRC by using monoclonal antibodies or aptamers to block pro-inflammatory molecules, inhibitors of tyrosine kinases in the inflammatory signaling cascade, competitive inhibitors of pro-inflammatory molecules, and the nucleic acid drugs like small activating RNAs (saRNAs) or microRNA (miRNA) mimics to activate tumor suppressor or repress oncogene/pro-inflammatory cytokine gene expression.

Background: In addition to the well-known role played in lactation and parturition, Oxytocin (OT) and OT receptor (OTR) are involved in many other aspects such as the control of maternal and social behavior, the regulation of the growth of the neocortex, the maintenance of blood supply to the cortex, the stimulation of limbic olfactory area to mother-infant recognition bond, and the modulation of the autonomic nervous system via the vagal pathway. Moreover, OT and OTR show antiinflammatory, anti-oxidant, anti-pain, anti-diabetic, anti-dyslipidemic and anti-atherogenic effects. Objective: The aim of this narrative review is to summarize the main data coming from the literature dealing with the role of OT and OTR in physiology and pathologic conditions focusing on the most relevant aspects. Methods: Appropriate keywords and MeSH terms were identified and searched in Pubmed. Finally, references of original articles and reviews were examined. Results: We report the most significant and updated data on the role played by OT and OTR in physiology and different clinical contexts. Conclusion: Emerging evidence indicates the involvement of OT system in several pathophysiological mechanisms influencing brain anatomy, cognition, language, sense of safety and trust and maternal behavior, with the possible use of exogenous administered OT in the treatment of specific neuropsychiatric conditions. Furthermore, it modulates pancreatic β-cell responsiveness and lipid metabolism leading to possible therapeutic use in diabetic and dyslipidemic patients and for limiting and even reversing atherosclerotic lesions.

Background: The use of herbal therapies for treatment and management of diabetes mellitus and complications associated with this chronic condition is increasing. Plants contain a bounty of phytochemicals that have been proven to be protective by reducing the risk of various ailments and diseases, including alkaloids. Moreover, alkaloids are known to be among the oldest natural products used by humans for highlighting drugs that play crucial roles as therapeutic agents. The reason for this expanding interest and uses of alkaloids as a part of plant natural compounds-based treatments is that a significant proportion of diabetic patients do not respond very well to conventional therapeutic medication. Furthermore, other explanations to this fact are the cost of medication, side-effects, accessibility, and availability of health facilities and drugs and the inefficiency of these medicines in certain cases. Objective: In this study we aimed to review the literature on the valuable effects of herbs and plants and their isolated alkaloids compounds as medication for management of diabetes, a prevalent risk factor for several other disorders and illnesses. Methods: In the current review, PubMed, ScienceDirect, Springer and google scholar databases were used and the criterion for inclusion was based on the following keywords and phrases: diabetes, hyperglycemia, complications of diabetes, alkaloids, antidiabetic alkaloids, hypoglycemic alkaloids, alkaloids and complications of diabetes mellitus, mechanisms of action and alkaloids. Results: In the current review, we demonstrate that alkaloids in the form of extracts and isolated molecules obtained from a large variety of species demonstrated their efficiency for improving raises in blood glucose either in animal models via experimental studies or in human subjects via clinical trials. Medicinal species as chillies (Capsicum annuum), turmeric (Curcuma longa), barberry (Berberis vulgaris) and cress (Lepidium sativum) are among the most common and therapeutic plants used for controlling diabetes that were the subject of several experimental and clinical investigations. Whereas, isolated alkaloids such as berberine, capsaicin and trigonelline have received more interest in this field. Interestingly, the therapeutic impact of alkaloids against blood glucose pathogenesis is mediated through a variety of signaling cascades and pathways, via inhibiting or stimulating diversity of systems such as inhibition of α-glucosidase enzyme, blockade of PTP- 1B, deactivation of DPP-IV, increasing insulin sensitivity and modulating the oxidative stress. Conclusion: Based on the findings of the present review, alkaloids could be used as preventive and curative agents in the case of endocrine disorders, particularly diabetes and could play a promoting function for the discovery of new antidiabetic agents.

Background: Corn silk is the elongated stigma of the female flower of Zea mays and traditionally used to treat diabetes mellitus (DM). Objective: To investigate the beneficial effects of corn silk extract (CSE) on HFD/STZ-induced diabetic C56BL/6J mice. Methods: Establishment of a T2DM model through feeding HFD combined with STZ. T2DM was randomly divided into 5 groups: diabetic control mice treated with vehicle (model group, n=10), metformin- treated group (metformin: 150 mg/kg.d, n=10), three CS-treated groups (CS: 300, 600 and 1200 mg/kg.d, n=10). After four weeks of CS treatment, the body weight, FBG, IR, TC, TG, LDL-C, MDA and SOD levels of mice were measured. In addition, the liver tissue was histomorphologically analyzed by HE stain followed a light microscopy observation. Results: 4-week CSE treatment significantly reduced FBG and enhanced the glucose tolerance; improved IR indicated by decreased HOMA-IR and elevated ISI; alleviated hyperlipidemia indicated by decreased TC, TG, LDL-C, and increased HDL-C; reduced oxidative stress by decreased MDA and elevated SOD activity; decreased hepatic lipid accumulation and prevented liver tissue morphological change in T2DM. In addition, CSE treatments effectively prevent the weight gain loss of diabetic mice. Conclusion: These results confirmed the traditionally claimed benefits of corn silk on DM, which suggested that the corn silk possessed the anti-diabetic potential and could be further developed as a cheap and plant-derived agent for the treatment of type 2 diabetes mellitus.

Background/Aims: Recurrent aphthous stomatitis (RAS) is one of the common oral inflammatory diseases. As immunological and genetic factors have been held responsible for the pathogenesis of RAS, the objective of this study was to determine whether the interleukin-1 receptor antagonist (IL-1Ra) gene variable number tandem repeat (VNTR) variant is a risk factor for the development of RAS in Turkish patients and to define its contribution to the increased risk. Methods: The IL-1Ra VNTR variant was evaluated in 169 RAS patients and 171 healthy controls by the polymerase chain reaction (PCR) method. Results: No statistically significant difference was found in the genotype distributions and allele frequencies of IL-1Ra VNTR variant between RAS patients and healthy controls. Conclusion: Lack of association between IL-1Ra VNTR variant and RAS could indicate that IL-1Ra has no significant role in the pathophysiology of RAS. However, it still appears to be very worthwhile to continue to search for cytokine gene variants in order to predict the development of such disease.

Objective: Asthma is an inflammatory airway disease affecting most of the population in the world. The current medication for asthma relieves airway inflammation but it has serious adverse effects. Biochanin A (BCA), a phytoestrogen, is an active component present in red clover, alfalfa, soy having anti-oxidant and anti-inflammatory properties. BCA was identified as a natural activator of peroxisome proliferator-activated receptor-gamma (PPARγ). Methods: The study aims to evaluate the effects of BCA in ovalbumin (OVA)-induced murine model of asthma and to study the role of PPARγ. Results: We found that BCA administration reduced the severity of murine allergic asthma as evidenced histologically, and measurement of allergen-specific IgE levels in serum as well as in BAL fluid. BCA also reversed the elevated levels of inflammatory cytokines, cell infiltration, protein leakage into the airways and expression of hemoxygenase-1 in OVA-induced lungs. Further, we confirmed that BCA mediated inhibitory effects are mediated through PPARγ as assessed by treatment with PPARγ antagonist GW9662. Conclusion: Our results suggest that BCA is efficacious in a preclinical model of asthma and may have the potential for the treatment of asthma in humans.

Objective: To observe the effects of angiotensin-(1-7) (Ang-(1-7)) on glucose metabolism, islet function and insulin resistance in a rat model of streptozotocin-induced diabetes mellitus (DM) and investigate its mechanism. Methods: Thirty-four male Wistar rats were randomly divided into 3 groups: control group, which was fed a standard diet, DM group, high-fat diet and injected with streptozotocin, and Ang-(1-7) group receiving an injection of streptozotocin followed by Ang-(1-7) treatment. Blood glucose level, fasting serum Ang II and insulin levels, and homeostasis model assessment of insulin resistance (HOMA-IR) were measured. The pancreases were collected for histological examination, protein and gene expression analysis. Results: Compared with the control group, fasting blood glucose, serum angiotensin II level, and HOMA-IR value increased, while serum insulin level decreased in the DM group. Moreover, islet structure was damaged, β cells were irregularly arranged, the cytoplasm was loose in the DM group. Expressions of Pancreatic duodenal homeobox-1 (Pdx1), glucose transporter-2 (Glut2) and glucokinase (Gk) were significantly decreased in the DM group compared with the control group. However, the DM-associated changes were dramatically reversed following Ang-(1-7) treatment. Conclusion: Ang-(1-7) protects against streptozotocin-induced DM through the improvement of insulin secretion, insulin resistance and islet fibrosis, which is associated with the upregulation of Pdx1, Glut2 and Gk expressions.

Background: Adverse effects associated with current therapy for Ulcerative colitis (UC) over prolonged treatment periods and the high relapse rate limit their use. Incorporating fruits as regular diet has beneficial role in the management of UC. Phloretin, a dihydrochalcone of apple is reported for its anti-oxidant and anti-inflammatory effects. Our study aims to evaluate the effectiveness of phloretin on experimentally induced ulcerative colitis in rats. Methods: In vitro study was performed using Raw 264.7 cells stimulated with LPS (1μg/mL) and in in-vivo study, colitis was induced by intra rectal administration of 4% Acetic acid. Phloretin (50 mg/kg) was given orally for 3 days to Wistar rats after induction for the post-treatment group and 1 day before induction to the pre-treatment group. Macroscopical, biochemical and histopathological evaluations were performed to assess the effectiveness. Results: A concentration dependent inhibition of MPO and iNOS activity was obtained in LPS stimulated neutrophil cells. Phloretin exerted ameliorative effect in both pre and post-treatment groups by restoring plasma ALP and LDH level and reduce inflammatory markers like myeloperoxidase, nitric oxide and eosinophil peroxidase level as well as downregulates colon ICAM-1 gene in acetic acid induced ulcerative colitis in rats. Antioxidative potency was confirmed by restoring tissue GSH level. Phloretin prevents mucosal damage and it was confirmed by histopathological analysis. Conclusion: Collectively, our findings provide evidence that phloretin might be useful as a natural therapeutic agent in the management of UC as well as may pose a promising outcome for future clinical usage.

Background: Diabetes is a metabolic disorder affecting a large percentage of the population worldwide. The chronic hyperglycemic condition leads to the generation of advanced glycation end products, reactive oxygen species and inflammatory cytokines, which worsen the functioning of the kidney. Clinical management of diabetic nephropathy is difficult as it requires a multi-focused approach. Hence, a combination of lisinopril a drug used in clinical practice for nephropathy, and naringenin, a flavonoid reported to have a significant effect in nephropathy, may show additive or synergistic effect with less side effects. Objective: The objective of the present study was to evaluate the effect of a combination of lisinopril with naringenin in diabetic nephropathy. Methods: Diabetes was induced in male Sprague Dawley rats by streptozotocin (55 mg/kg, i.p.). After four weeks of diabetes induction animals were treated with naringenin alone and a combination of Lisinopril and naringenin for the next four weeks. At the end of the study, various urine and biochemical parameters were evaluated. Oxidative stress parameters like malondialdehyde, reduced glutathione; catalase and superoxide dismutase for kidney tissues were estimated and histopathology studies of kidneys were carried out. Results: The combination of lisinopril (10 mg/kg) and naringenin (25 and 50 mg/kg) treatment showed significant improvement in the biochemical and urine parameters. Combination treatment also attenuated renal oxidative stress and renal damage as observed in histopathological studies. Conclusion: Treatment with a combination of lisinopril and naringenin showed a promising effect on diabetic nephropathy in rats.

Background: We aimed prospectively to investigate the laboratory and electrocardiographic parameters (heart rate, QRS, QT, QTc, Tpe, Tpe/QTc, and arrhythmia prevalence) in patients with Graves’ disease before and after antithyroid therapy. Methods: Seventy-one patients (48 female, and 23 male), of age between 18-50 years (mean±SD: 36.48±12.20) with GD were included in the study. Patients were treated with antithyroid therapy (thioamides and/or surgical therapy) to maintain euthyroid status. Patients were examined in terms of electrocardiographic parameters before and after the treatment. Results: Mean TSH, free thyroxin (fT4), and tri-iodothyrionine (fT3) levels of all patients were 0.005±0.21, 3.27± 1.81, 11.42±7.44, respectively. While 9 patients (group 2) underwent surgical therapy, had suspicious malignant nodule or large goiter, and unresponsiveness to medical treatment; the other patients (n=62, group 1) were treated with medical therapy. Patients with surgical therapy had more increased serum fT4 (p=0.045), anti-thyroglobulin value (p=0.018) and more severe graves orbitopathy (n=0.051) before treatment when compared to a medical therapy group. Baseline Tpe duration and baseline Tpe/QTc ratio and frequency of supraventricular ectopic beats were found to be significantly higher in group 2 when compared to group 1 (p=0.00, p=0.005). Otherwise, the baseline mean heart rate, QRS duration, QTc values of both groups were similar. Although the patients came at their euthyroid status, group 2 patients still suffered from more sustained supraventricular ectopics beats than group 1. Conclusion: Distinct from the medical treatment group, surgical treatment group with euthyroidism for at least 3 months still suffered from an arrhythmia (Tpe, Tpe/QTc, supraventricular and ventricular ectopic beats).