An Update on the Molecular and Cellular Basis of Pharmacotherapy in Type 2 Diabetes Mellitus.

Diabetes mellitus (DM) is a chronic illness with an increasing global prevalence. More than 537 million cases of diabetes were reported worldwide in 2021, and the number is steadily increasing. The worldwide number of people suffering from DM is projected to reach 783 million in 2045. In 2021 alone, more than USD 966 billion was spent on the management of DM. Reduced physical activity due to urbanization is believed to be the major cause of the increase in the incidence of the disease, as it is associated with higher rates of obesity. Diabetes poses a risk for chronic complications such as nephropathy, angiopathy, neuropathy and retinopathy. Hence, the successful management of blood glucose is the cornerstone of DM therapy. The effective management of the hyperglycemia associated with type 2 diabetes includes physical exercise, diet and therapeutic interventions (insulin, biguanides, second generation sulfonylureas, glucagon-like peptide 1 agonists, dipeptidyl-peptidase 4 inhibitors, thiazolidinediones, amylin mimetics, meglitinides, α-glucosidase inhibitors, sodium-glucose cotransporter-2 inhibitors and bile acid sequestrants). The optimal and timely treatment of DM improves the quality of life and reduces the severe burden of the disease for patients. Genetic testing, examining the roles of different genes involved in the pathogenesis of DM, may also help to achieve optimal DM management in the future by reducing the incidence of DM and by enhancing the use of individualized treatment regimens.

Adropin's Role in Energy Homeostasis and Metabolic Disorders.

Adropin is a novel 76-amino acid-peptide that is expressed in different tissues and cells including the liver, pancreas, heart and vascular tissues, kidney, milk, serum, plasma and many parts of the brain. Adropin, encoded by the Enho gene, plays a crucial role in energy homeostasis. The literature review indicates that adropin alleviates the degree of insulin resistance by reducing endogenous hepatic glucose production. Adropin improves glucose metabolism by enhancing glucose utilization in mice, including the sensitization of insulin signaling pathways such as Akt phosphorylation and the activation of the glucose transporter 4 receptor. Several studies have also demonstrated that adropin improves cardiac function, cardiac efficiency and coronary blood flow in mice. Adropin can also reduce the levels of serum triglycerides, total cholesterol and low-density lipoprotein cholesterol. In contrast, it increases the level of high-density lipoprotein cholesterol, often referred to as the beneficial cholesterol. Adropin inhibits inflammation by reducing the tissue level of pro-inflammatory cytokines such as tumor necrosis factor alpha and interleukin-6. The protective effect of adropin on the vascular endothelium is through an increase in the expression of endothelial nitric oxide synthase. This article provides an overview of the existing literature about the role of adropin in different pathological conditions.

The Effect of Oxytocin on Intracellular Ca2+ Release in Cardiac Cells.

Ca2+ signaling is vital for the proper functioning of all cells, including cells of the cardiovascular system. Membrane receptors for many hormones trigger intracellular Ca2+ signaling via the activation of phospholipase C and production of inositol-1,4,5-trisphosphate (InsP3). Several research groups have demonstrated the expression of oxytocin (OXT) and oxytocin receptors (OXTR) in the heart and suggested a cardioprotective role of OXT against several pathological conditions. Here we describe the protocol for measuring the effects of oxytocin on intracellular Ca2+ dynamics in newborn rat cardiac myocytes and cardiac fibroblasts maintained in short-term culture.

Vitamin D Is Necessary for Murine Gastric Epithelial Homeostasis.

Unlike other organs, the importance of VD in a normal stomach is unknown. This study focuses on understanding the physiological role of vitamin D in gastric epithelial homeostasis. C57BL/6J mice were divided into three groups that were either fed a standard diet and kept in normal light/dark cycles (SDL), fed a standard diet but kept in the dark (SDD) or fed a vitamin D-deficient diet and kept in the dark (VDD). After 3 months, sera were collected to measure vitamin D levels by LC-MS/MS, gastric tissues were collected for immunohistochemical and gene expression analyses and gastric contents were collected to measure acid levels. The VDD group showed a significant decrease in the acid-secreting parietal cell-specific genes Atp4a and Atp4b when compared with the controls. This reduction was associated with an increased expression of an antral gastrin hormone. VDD gastric tissues also showed a high proliferation rate compared with SDL and SDD using an anti-BrdU antibody. This study indicates the requirement for normal vitamin D levels for proper parietal cell functions.

Oxytocin induces intracellular Ca2+ release in cardiac fibroblasts from neonatal rats.

Pituitary neuropeptide oxytocin is increasingly recognised as a cardiovascular hormone, in addition to its many regulatory roles in other organ systems. Studies in atrial and ventricular myocytes from the neonatal and adult rats have identified synthesis of oxytocin and the expression of oxytocin receptors in these cells. In cardiac fibroblasts, the most populous non-myocyte cell type in mammalian heart, the oxytocin receptors have not been described before. In the present study, we have investigated the direct effects of oxytocin on intracellular Ca2+ dynamics in ventricular myocytes and fibroblasts from new born rats. In myocytes, oxytocin increased the frequency of spontaneous Ca2+ transients and decreased their amplitude. Our data suggest that oxytocin receptors are also present and functional in the majority of cardiac fibroblasts. We used selective oxytocin receptor inhibitor L-371,257 and a number of intracellular Ca 2+ release blockers to investigate the mechanism of oxytocin induced Ca2+ signalling in cardiac fibroblasts. Our findings suggest that oxytocin induces Ca2+ signals in cardiac fibroblasts by triggering endoplasmic reticulum Ca2+ release via inositol trisphosphate activated receptors. The functional significance of the oxytocin induced Ca2+ signalling in cardiac fibroblasts, especially for their activation into secretory active myofibroblasts, remains to be investigated.

Asthma-Targeted MURs: How Confident are Community Pharmacists in Delivering Different Interventions?

This study aimed to identify and determine the confidence level of community pharmacists in providing different interventions during asthma-targeted medicine use reviews (MURs). A self-administered questionnaire was posted to 487 pharmacies accredited to provide the service, across Greater London, Southampton, Cornwall, Sheffield and Norwich. A total of 122 responses were obtained, giving a response rate of 25% (122/487). Around half of the community pharmacists (51.6%) were providing more than 60 asthma-targeted MURs annually with inhaler technique being the most offered intervention and stepping up/down therapy being the least. The majority of community pharmacists (94.3%) were confident in providing inhaler technique advice, followed by smoking cessation (91%). However, confidence was less with relevant vaccination (61.5%) and stepping up/down patients' therapy (56.6%). Confidence level can vary between community pharmacists regarding different interventions provided during respiratory MURs. The results stress the need to promote community pharmacists' confidence in providing interventions such as stepping up/down therapy during asthma-targeted MURs. Additional research in this field is highly recommended in order to evaluate community pharmacists' confidence level on a national scale and to determine the factors influencing it. The study also suggests that provision of different interventions during respiratory MURs can be related to how community pharmacists perceive their role.

Prognostic variables and scores identifying the end of life in COPD: a systematic review.

INTRODUCTION: COPD is a major cause of mortality, and the unpredictable trajectory of the disease can bring challenges to end-of-life care. We aimed to investigate known prognostic variables and scores that predict prognosis in COPD in a systematic literature review, specifically including variables that contribute to risk assessment of patients for death within 12 months. METHODS: We conducted a systematic review on prognostic variables, multivariate score or models for COPD. Ovid MEDLINE, EMBASE, the Cochrane database, Cochrane CENTRAL, DARE and CINAHL were searched up to May 1, 2016. RESULTS: A total of 5,276 abstracts were screened, leading to 516 full-text reviews, and 10 met the inclusion criteria. No multivariable indices were developed with the specific aim of predicting all-cause mortality in stable COPD within 12 months. Only nine indices were identified from four studies, which had been validated for this time period. Tools developed using expert knowledge were also identified, including the Gold Standards Framework Prognostic Indicator Guidance, the RADboud Indicators of Palliative Care Needs, the Supportive and Palliative Care Indicators Tool and the Necesidades Paliativas program tool. CONCLUSION: A number of variables contributing to the prediction of all-cause mortality in COPD were identified. However, there are very few studies that are designed to assess, or report, the prediction of mortality at or less than 12 months. The quality of evidence remains low, such that no single variable or multivariable score can currently be recommended.

International inter-rater agreement in scoring acne severity utilizing cloud-based image sharing of mobile phone photographs.

BACKGROUND: Cloud-based image sharing technology allows facilitated sharing of images. Cloud-based image sharing technology has not been well-studied for acne assessments or treatment preferences, among international evaluators. We evaluated inter-rater variability of acne grading and treatment recommendations among an international group of dermatologists that assessed photographs. METHODS: This is a prospective, single visit photographic study to assess inter-rater agreement of acne photographs shared through an integrated mobile device, cloud-based, and HIPAA-compliant platform. Inter-rater agreements for global acne assessment and acne lesion counts were evaluated by the Kendall's coefficient of concordance while correlations between treatment recommendations and acne severity were calculated by Spearman's rank correlation coefficient. RESULTS: There was good agreement for the evaluation of inflammatory lesions (KCC = 0.62, P < 0.0001), noninflammatory lesions (KCC = 0.62, P < 0.0001), and the global acne grading system score (KCC = 0.69, P < 0.0001). Topical retinoid, oral antibiotic, and isotretinoin treatment preferences correlated with photographic based acne severity. CONCLUSIONS: Our study supports the use of mobile phone based photography and cloud-based image sharing for acne assessment. Cloud-based sharing may facilitate acne care and research among international collaborators.

Prognostic variables and scores identifying the last year of life in COPD: a systematic review protocol.

INTRODUCTION: People living with advanced chronic obstructive pulmonary disease (COPD) suffer from significant morbidity, reduced quality of life and high mortality, and are likely to benefit from many aspects of a palliative care approach. Prognostic estimates are a meaningful part of decision-making and better evidence for such estimates would facilitate advance care planning. We aim to provide quality evidence on known prognostic variables and scores which predict a prognosis in COPD of <12 months for use in the community. METHODS AND ANALYSIS: We will conduct a systematic review of randomised or quasi-randomised controlled trials, prospective and retrospective longitudinal cohort and case-control studies on prognostic variables, multivariate scores or models for COPD. The search will cover the period up to April 2016. Study selection will follow the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, with data extraction using fields from the Critical Appraisal and Data Extraction for Systematic Reviews of Prediction Modelling Studies (CHARMS) checklist for multivariate models, and study quality will be assessed using a modified version of the Quality In Prognosis Studies (QUIPS) tool. ETHICS AND DISSEMINATION: The results will be disseminated through peer-reviewed publications and national and international conference presentations. SYSTEMATIC REVIEW REGISTRATION NUMBER: CRD42016033866.

Potentiation of the effect of erlotinib by genistein in pancreatic cancer: the role of Akt and nuclear factor-kappaB.

The epidermal growth factor receptor (EGFR) is a target of new therapies in most nonhematologic cancers. EGFR blockade alone may not be sufficient for the control of growth and invasion of human pancreas cancer because of the independent activation of Akt and nuclear factor-kappaB (NF-kappaB). The expression of EGFR, Akt, and NF-kappaB was determined in six human pancreatic cancer cell lines. Selected cells for specific expression were treated with erlotinib, genistein, gemcitabine, or the combination. Growth inhibition was evaluated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, and apoptosis was assayed by ELISA. EGFR, phosphorylated EGFR, phosphorylated Akt, and survivin expressions were determined by immunoblotting. Electrophoretic mobility shift assay was used to evaluate the DNA binding activity of NF-kappaB. Genistein significantly increased (P < 0.05) erlotinib-induced growth inhibition and apoptosis in BxPC-3, CAPAN-2, and AsPC-1 cells. In the BxPC-3 cell line, significant down-regulation of EGFR, phosphorylated Akt, NF-kappaB activation, and survivin was observed in the cells treated with the combination compared with the erlotinib-treated cells. In the HPAC and MIAPaCa cell line, no potentiation of the effects of erlotinib by genistein on cell growth or inhibition of the EGFR/Akt/NF-kappaB was observed. Genistein potentiated growth inhibition and apoptosis of the gemcitabine and erlotinib combination in COLO-357 cell line. Genistein potentiates the growth inhibition and apoptosis induced by erlotinib and gemcitabine in certain pancreatic cancer cells. Akt and NF-kappaB inhibition represents one of the mechanisms for the potentiation of erlotinib- and gemcitabine-induced cell death by genistein.