The protein corona determines the cytotoxicity of nanodiamonds: implications of corona formation and its remodelling on nanodiamond applications in biomedical imaging and drug delivery

The use of nanodiamonds for biomedical and consumer applications is growing rapidly. As their use becomes more widespread, so too do concerns around their cytotoxicity. The cytotoxicity of nanodiamonds correlates with their cellular internalisation and circulation time in the body. Both internalisation and circulation time are influenced by the formation of a protein corona on the nanodiamond surface. However, a precise understanding of both how the corona forms and evolves and its influence on cytotoxicity is lacking. Here, we investigated protein corona formation and evolution in response to two classes of nanodiamonds, pristine and aminated, and two types of proteins, bovine serum albumin and fibronectin. Specifically, we found that a corona made of bovine serum albumin (BSA), which represents the most abundant protein in blood plasma, reduced nanodiamond agglomeration. Fibronectin (FN9-10), the second most abundant protein found in the plasma, exhibited a significantly higher nanodiamond binding affinity than BSA, irrespective of the nanodiamond surface charge. Finally, nanodiamonds with a BSA corona displayed less cytotoxicity towards nonphagocytic liver cells. However, regardless of the type of corona (FN9-10 or BSA), both classes of nanodiamonds induced substantial phagocytic cell death. Our results emphasise that a precise understanding of the corona composition is fundamental to determining the fate of nanoparticles in the body

Lymphocyte-Derived Exosomal MicroRNAs Promote Pancreatic β Cell Death and May Contribute to Type 1 Diabetes Development.

Type 1 diabetes is an autoimmune disease initiated by the invasion of pancreatic islets by immune cells that selectively kill the β cells. We found that rodent and human T lymphocytes release exosomes containing the microRNAs (miRNAs) miR-142-3p, miR-142-5p, and miR-155, which can be transferred in active form to β cells favoring apoptosis. Inactivation of these miRNAs in recipient β cells prevents exosome-mediated apoptosis and protects non-obese diabetic (NOD) mice from diabetes development. Islets from protected NOD mice display higher insulin levels, lower insulitis scores, and reduced inflammation. Looking at the mechanisms underlying exosome action, we found that T lymphocyte exosomes trigger apoptosis and the expression of genes involved in chemokine signaling, including Ccl2, Ccl7, and Cxcl10, exclusively in β cells. The induction of these genes may promote the recruitment of immune cells and exacerbate β cell death during the autoimmune attack. Our data point to exosomal-miRNA transfer as a communication mode between immune and insulin-secreting cells

A circular RNA generated from an intron of the insulin gene controls insulin secretion.

Fine-tuning of insulin release from pancreatic β-cells is essential to maintain blood glucose homeostasis. Here, we report that insulin secretion is regulated by a circular RNA containing the lariat sequence of the second intron of the insulin gene. Silencing of this intronic circular RNA in pancreatic islets leads to a decrease in the expression of key components of the secretory machinery of β-cells, resulting in impaired glucose- or KCl-induced insulin release and calcium signaling. The effect of the circular RNA is exerted at the transcriptional level and involves an interaction with the RNA-binding protein TAR DNA-binding protein 43 kDa (TDP-43). The level of this circularized intron is reduced in the islets of rodent diabetes models and of type 2 diabetic patients, possibly explaining their impaired secretory capacity. The study of this and other circular RNAs helps understanding β-cell dysfunction under diabetes conditions, and the etiology of this common metabolic disorder

A circular RNA generated from an intron of the insulin gene controls insulin secretion

Fine-tuning of insulin release from pancreatic β-cells is essential to maintain blood glucose homeostasis. Here, we report that insulin secretion is regulated by a circular RNA containing the lariat sequence of the second intron of the insulin gene. Silencing of this intronic circular RNA in pancreatic islets leads to a decrease in the expression of key components of the secretory machinery of β-cells, resulting in impaired glucose- or KCl-induced insulin release and calcium signaling. The effect of the circular RNA is exerted at the transcriptional level and involves an interaction with the RNA-binding protein TAR DNA-binding protein 43 kDa (TDP-43). The level of this circularized intron is reduced in the islets of rodent diabetes models and of type 2 diabetic patients, possibly explaining their impaired secretory capacity. The study of this and other circular RNAs helps understanding β-cell dysfunction under diabetes conditions, and the etiology of this common metabolic disorder

Can medical therapy mimic the clinical efficacy or physiological effects of bariatric surgery?

The number of bariatric surgical procedures performed has increased dramatically. This review discusses the clinical and physiological changes, and in particular, the mechanisms behind weight loss and glycaemic improvements, observed following the gastric bypass, sleeve gastrectomy and gastric banding bariatric procedures. The review then examines how close we are to mimicking the clinical or physiological effects of surgery through less invasive and safer modern interventions that are currently available for clinical use. These include dietary interventions, orlistat, lorcaserin, phentermine/topiramate, glucagon-like peptide-1 receptor agonists, dipeptidyl peptidase-4 inhibitors, pramlintide, dapagliflozin, the duodenal–jejunal bypass liner, gastric pacemakers and gastric balloons. We conclude that, based on the most recent trials, we cannot fully mimic the clinical or physiological effects of surgery; however, we are getting closer. A ‘medical bypass' may not be as far in the future as we previously thought, as the physician's armamentarium against obesity and type 2 diabetes has recently got stronger through the use of specific dietary modifications, novel medical devices and pharmacotherapy. Novel therapeutic targets include not only appetite but also taste/food preferences, energy expenditure, gut microbiota, bile acid signalling, inflammation, preservation of β-cell function and hepatic glucose output, among others. Although there are no magic bullets, an integrated multimodal approach may yield success. Non-surgical interventions that mimic the metabolic benefits of bariatric surgery, with a reduced morbidity and mortality burden, remain tenable alternatives for patients and health-care professionals

Pharmacology and therapeutic implications of current drugs for type 2 diabetes mellitus

Type 2 diabetes mellitus (T2DM) is a global epidemic that poses a major challenge to health-care systems. Improving metabolic control to approach normal glycaemia (where practical) greatly benefits long-term prognoses and justifies early, effective, sustained and safety-conscious intervention. Improvements in the understanding of the complex pathogenesis of T2DM have underpinned the development of glucose-lowering therapies with complementary mechanisms of action, which have expanded treatment options and facilitated individualized management strategies. Over the past decade, several new classes of glucose-lowering agents have been licensed, including glucagon-like peptide 1 receptor (GLP-1R) agonists, dipeptidyl peptidase 4 (DPP-4) inhibitors and sodium/glucose cotransporter 2 (SGLT2) inhibitors. These agents can be used individually or in combination with well-established treatments such as biguanides, sulfonylureas and thiazolidinediones. Although novel agents have potential advantages including low risk of hypoglycaemia and help with weight control, long-term safety has yet to be established. In this Review, we assess the pharmacokinetics, pharmacodynamics and safety profiles, including cardiovascular safety, of currently available therapies for management of hyperglycaemia in patients with T2DM within the context of disease pathogenesis and natural history. In addition, we briefly describe treatment algorithms for patients with T2DM and lessons from present therapies to inform the development of future therapies