The role of miR-143/miR-145 in the development, diagnosis, and treatment of diabetes.

Objectives: Diabetes mellitus [DM], is a multifaceted metabolic disease, which has become a worldwide threat to human wellness. Over the past decades, an enormous amount of attention has been devoted to understanding how microRNAs [miRNAs], a class of small non-coding RNA regulators of gene expression at the post-transcriptional level, are tied to DM pathology. It has been demonstrated that miRNAs control insulin synthesis, secretion, and activity. This review aims to provide an evaluation of the use of miR-143 and miR-145 as biomarkers for the diagnosis and prognosis of diabetes. Methods: The use of miR-143 and miR-145 as biomarkers for the diagnosis and prognosis of diabetes has been studied, and research that examined this link was sought after in the literature. In addition, we will discuss the cellular and molecular pathways of insulin secretion regulation by miR-143/145 expression and finally their role in diabetes. Results: In the current review, we emphasize recent findings on the miR-143/145 expression profiles as novel DM biomarkers in clinical studies and animal models and highlight recent discoveries on the complex regulatory effect and functional role of miR-143/145 expression in DM. Conclusion: A novel clinical treatment that alters the expression and activity of miR-143/miR-145 may be able to return cells to their natural state of glucose homeostasis, demonstrating the value of using comprehensive miRNA profiles to predict the beginning of diabetes. Supplementary Information: The online version contains supplementary material available at 10.1007/s40200-023-01317-y.

Diagnoses of muscular dystrophy in a veterans health system.

INTRODUCTION/AIMS: Early diagnosis of a chronic neuromuscular disease such as muscular dystrophy (MD) generally excludes an individual from active-duty military service. However, it is not known whether veterans are sometimes diagnosed with milder forms of MD at a later timepoint. We aimed to determine the prevalence of MD in a veterans health system. METHODS: We abstracted clinical and genetic test data on patients who received care for a diagnosis of MD at the North Florida/South Georgia Veterans Health System between 2008 and 2021. We then determined which of these individuals would meet criteria for a definite diagnosis of MD, based on electrodiagnostic testing, muscle biopsy, and genetic testing of the individual or an affected first degree relative. RESULTS: We identified 12 patients with definite MD and 36 with possible or probable MD. The definite cases included myotonic dystrophy type 1 (4), myotonic dystrophy type 2 (3), oculopharyngeal MD (2), Becker MD (1), distal MD (1), and facioscapulohumeral MD (1). At least five of the cases classified as definite developed symptoms after discharge from active duty. DISCUSSION: Clinicians who care for veterans should be knowledgeable about, and have access to, diagnostic testing and treatment options for MD. When conducting MD surveillance, it is important to include veterans health systems as a data source. Mild cases of MD and those of later onset appear to be compatible in some cases with successful completion of military service.

Genetic Patterns of Selected Muscular Dystrophies in the Muscular Dystrophy Surveillance, Tracking, and Research Network.

Background and Objectives: To report the genetic etiologies of Emery-Dreifuss muscular dystrophy (EDMD), limb-girdle muscular dystrophy (LGMD), congenital muscular dystrophy (CMD), and distal muscular dystrophy (DD) in 6 geographically defined areas of the United States. Methods: This was a cross-sectional, population-based study in which we studied the genes and variants associated with muscular dystrophy in individuals who were diagnosed with and received care for EDMD, LGMD, CMD, and DD from January 1, 2008, through December 31, 2016, in the 6 areas of the United States covered by the Muscular Dystrophy Surveillance, Tracking, and Research Network (MD STARnet). Variants of unknown significance (VUSs) from the original genetic test reports were reanalyzed for changes in interpretation. Results: Among 243 individuals with definite or probable muscular dystrophy, LGMD was the most common diagnosis (138 cases), followed by CMD (62 cases), DD (22 cases), and EDMD (21 cases). There was a higher proportion of male individuals compared with female individuals, which persisted after excluding X-linked genes (EMD) and autosomal genes reported to have skewed gender ratios (ANO5, CAV3, and LMNA). The most common associated genes were FKRP, CAPN3, ANO5, and DYSF. Reanalysis yielded more definitive variant interpretations for 60 of 144 VUSs, with a mean interval between the original clinical genetic test of 8.11 years for all 144 VUSs and 8.62 years for the 60 reclassified variants. Ten individuals were found to have monoallelic pathogenic variants in genes known to be primarily recessive. Discussion: This study is distinct for being an examination of 4 types of muscular dystrophies in selected geographic areas of the United States. The striking proportion of resolved VUSs demonstrates the value of periodic re-examinations of these variants. Such re-examinations will resolve some genetic diagnostic ambiguities before initiating repeat testing or more invasive diagnostic procedures such as muscle biopsy. The presence of monoallelic pathogenic variants in recessive genes in our cohort indicates that some individuals with muscular dystrophy continue to face incomplete genetic diagnoses; further refinements in genetic knowledge and diagnostic approaches will optimize diagnostic information for these individuals.

Neuroprotective effect of secukinumab against rotenone induced Parkinson's disease in rat model: Involvement of IL-17, HMGB-1/TLR4 axis and BDNF/TrKB cascade.

Neuroinflammatory status produced via activation of toll like receptor-4 (TLR-4) and interleukin-17 receptor (IL-17R) is one of the principal mechanisms involved in dopaminergic neuronal loss in Parkinson's disease (PD). Activation of TLR-4 and IL-17R stimulates reactive oxygen species (ROS) and proinflammatory cytokines (IL-17, IL-1ß, TNFα, IL-6) production that augments neurodegeneration and reduces neuro-survival axis (TrKB/Akt/CREB/BDNF). So, reducing IL-17-driven neuroinflammation via secukinumab, monoclonal antibody against IL-17A, may be one of therapeutic approach for PD. Moreover, the aim was extended to delineate the possible neuroprotective mechanism involved against neuronal loss in rotenone induced PD in rats. Rats received 11 subcutaneous injection of rotenone (1.5 mg/kg) every other day for 21 consecutive days and treated with 2 subcutaneous injections of secukinumab (15 mg/kg) on day 9 and 15, one hour after rotenone administration. Treatment with secukinumab improved motor impairment and muscle incoordination induced by rotenone, as verified by open field and rotarod tests. Moreover, secukinumab attenuated neuronal loss and improve histopathological profile. Noteworthy, secukinumab reduces neuro-inflammatory status by hindering the interaction between IL and 17A and IL-17RA together with inhibiting the activation of TLR-4 and its downstream cascade including pS536-NFκB p65, IL-1ß and HMGB-1. Additionally, secukinumab stimulated neuro-survival signalling cascade via activation pY515-TrKB receptor and triggered upsurge in its downstream targets (pS473-Akt/pS133-CREB/BDNF). Furthermore, secukinumab increased striatal tyrosine hydroxylase immunoexpression, the rate limiting step in dopamine biosynthesis, to guard against dopaminergic neuronal loss. In conclusion, secukinumab exerts a neuroprotective effect against rotenone induced neuronal loss via inhibition IL17A/IL17RA interaction and HMGB-1/TLR-4/NF-κBp65/IL1ß signalling cascade, together with activation of TrKB/ Akt/CREB/BDNF axis.

Study of DYRK1B gene expression and its association with metabolic syndrome in a small cohort of Egyptians.

BACKGROUND: A cluster of many risk factors for type 2 diabetes and cardiovascular disease is used to describe the metabolic syndrome (MetS). Moreover, genetic differences associated with metabolic syndrome play a key role in its prevalence and side effects. This study aims to investigate the expression of DYRK1B and its association with metabolic syndrome in a small cohort of Egyptian. MATERIALS AND METHODS: A total of 100 adult Egyptians (50 with MetS and 50 healthy control subjects) were included to this study. Clinical, biochemical and anthropometric analysis were assessed. Relative gene expressions of DYRK1B were compared between two groups of subjects using real time PCR. RESULTS: We observed marked overexpression in DYRK1B (p < 0.05) in MetS subjects when compared with the healthy control subjects. CONCLUSION: This is the first study to provide evidence that DYRK1B is highly expressed among the MetS subjects.

Efficacy and resistance of different artemisinin-based combination therapies: a systematic review and network meta-analysis.

BACKGROUND: Malaria parasites have developed resistance to most of the known antimalarial drugs in clinical practice, with reports of artemisinin resistance emerging in South East Asia (SEA). We sort to find the status of artemisinin resistance and efficacy of different modalities of the current artemisinin-based combination therapies (ACTs). METHODS: We carried out a systematic search in 11 electronic databases to identify in vivo studies published between 2001 and 2017 that reported artemisinin resistance. This was then followed by A network meta-analysis to compare the efficacy of different ACTs. Quality assessment was performed using the Cochrane Risk of Bias (ROB) tool for randomized controlled trials and National Institute of Health (NIH) tool for cross-sectional studies. The study protocol was registered in PROSPERO under number CRD42018087574. RESULTS: With 8400 studies initially identified, 82 were eligible for qualitative and quantitative analysis. Artemisinin resistance was only reported in South East Asia. K13 mutation C580Y was the most abundant mutation associated with resistance having an abundance of 63.1% among all K13 mutations reported. Although the overall network meta-analysis had shown good performance of dihydroartemisinin piperaquine in the early years, a subgroup analysis of the recent years revealed a poor performance of the drug in relation to recrudescence, clinical failure and parasitological failure especially in the artemisinin resistant regions. CONCLUSION: With report of high resistance and treatment failure against the leading artemisinin combination therapy in South East Asia, it is imperative that a new drug or a formulation is developed before further spread of resistance.