Image-based quantification of mitochondrial iron uptake via Mitoferrin-2.

Iron is a trace element that is critical for most living organisms and plays a key role in a wide variety of metabolic processes. In the mitochondrion, iron is involved in producing iron-sulfur clusters and synthesis of heme and kept within physiological ranges by concerted activity of multiple molecules. Mitochondrial iron uptake is mediated by the solute carrier transporters Mitoferrin-1 (SLC25A37) and Mitoferrin-2 (SLC25A28).

Functional characterization of SLC39 family members ZIP5 and ZIP10 in overexpressing HEK293 cells reveals selective copper transport activity.

Zinc is the second most prevalent metal element present in living organisms, and control of its concentration is pivotal to physiology. The amount of zinc available to the cell cytoplasm is regulated by the activity of members of the SLC39 family, the ZIP proteins. Selectivity of ZIP transporters has been the focus of earlier studies which provided a biochemical and structural basis for the selectivity for zinc over other metals such as copper, iron, and manganese.

Spatiotemporal organisation of protein processing in the kidney.

The kidney regulates plasma protein levels by eliminating them from the circulation. Proteins filtered by glomeruli are endocytosed and degraded in the proximal tubule and defects in this process result in tubular proteinuria, an important clinical biomarker. However, the spatiotemporal organization of renal protein metabolism in vivo was previously unclear.

Intravital kidney microscopy: entering a new era.

The development of intravital imaging with multiphoton microscopy has had a major impact on kidney research. It provides the unique opportunity to visualize dynamic behavior of cells and organelles in their native environment and to relate this to the complex 3-dimensional structure of the organ. Moreover, changes in cell/organelle function can be followed in real time in response to physiological interventions or disease-causing insults.

The proximal tubule, protein uptake, and the riddle of the segments.

The proximal tubule is divided anatomically into 3 distinct segments-S1 to S3-on the basis of differences in cellular ultrastructure, but the functional processes that define and shape these remain elusive. In a new study, Christensen used 3-dimensional nephron reconstruction, electron microscopy, and antibody staining to precisely map protein uptake to the structure of the proximal tubule. They reported striking axial patterns in endocytosis along the segments, which showed substantial plasticity in disease states.

Changes in NAD and Lipid Metabolism Drive Acidosis-Induced Acute Kidney Injury.

Background: The kidney plays an important role in maintaining normal blood pH. Metabolic acidosis (MA) upregulates the pathway that mitochondria in the proximal tubule (PT) use to produce ammonia and bicarbonate from glutamine, and is associated with AKI. However, the extent to which MA causes AKI, and thus whether treating MA would be beneficial, is unclear.

The iron chelator Deferasirox causes severe mitochondrial swelling without depolarization due to a specific effect on inner membrane permeability.

The iron chelator Deferasirox (DFX) causes severe toxicity in patients for reasons that were previously unexplained. Here, using the kidney as a clinically relevant in vivo model for toxicity together with a broad range of experimental techniques, including live cell imaging and in vitro biophysical models, we show that DFX causes partial uncoupling and dramatic swelling of mitochondria, but without depolarization or opening of the mitochondrial permeability transition pore. This effect is explained by an increase in inner mitochondrial membrane (IMM) permeability to protons, but not small molecules.

Targeting glycolysis in proliferative kidney diseases.

Glycolytic activity is increased in proliferating cells, leading to the concept that glycolysis could be a therapeutic target in cystic diseases and kidney cancer. Preclinical studies using the glucose analog 2-deoxy-d-glucose have shown promise; however, inhibiting glycolysis in humans is unlikely to be without risks. While proximal tubules are predominantly aerobic, later segments are more glycolytic.

Improved glycaemic variability and time in range with dapagliflozin versus gliclazide modified release among adults with type 2 diabetes, evaluated by continuous glucose monitoring: A 12-week randomized controlled trial.

Aims: To evaluate whether there is a difference between the effects of dapagliflozin and gliclazide modified release (MR) on glycaemic variability (GV) and glycaemic control, as assessed by continuous glucose monitoring (CGM), in individuals with uncontrolled type 2 diabetes.

Materials And Methods: This randomized, open-label, active-controlled study was conducted in individuals with uncontrolled type 2 diabetes who were drug-naïve or on steady-dose metformin monotherapy. Participants were treated once daily with 10 mg dapagliflozin or 120 mg gliclazide MR.

Axial differences in endocytosis along the kidney proximal tubule.

The proximal tubule (PT) reabsorbs filtered proteins via receptor-mediated endocytosis to prevent energetically inefficient wasting in the urine. Recent intravital imaging studies have suggested that protein reabsorption occurs in early (S1) segments, which have a very high capacity. In contrast, uptake of fluid phase substrates also occurs in distal (S2) segments.

Increased levels of midbrain immune-related transcripts in schizophrenia and in murine offspring after maternal immune activation.

The pathophysiology of dopamine dysregulation in schizophrenia involves alterations at the ventral midbrain level. Given that inflammatory mediators such as cytokines influence the functional properties of midbrain dopamine neurons, midbrain inflammation may play a role in schizophrenia by contributing to presynaptic dopamine abnormalities. Thus, we quantified inflammatory markers in dopaminergic areas of the midbrain of people with schizophrenia and matched controls.

Combined Structural and Functional Imaging of the Kidney Reveals Major Axial Differences in Proximal Tubule Endocytosis.

Background: The kidney proximal convoluted tubule (PCT) reabsorbs filtered macromolecules receptor-mediated endocytosis (RME) or nonspecific fluid phase endocytosis (FPE); endocytosis is also an entry route for disease-causing toxins. PCT cells express the protein ligand receptor megalin and have a highly developed endolysosomal system (ELS). Two PCT segments (S1 and S2) display subtle differences in cellular ultrastructure; whether these translate into differences in endocytotic function has been unknown.

Mouse models of maternal immune activation: Mind your caging system!

Rodent models of maternal immune activation (MIA) are increasingly used as experimental tools to study neuronal and behavioral dysfunctions in relation to infection-mediated neurodevelopmental disorders. One of the most widely used MIA models is based on gestational administration of poly(I:C) (= polyriboinosinic-polyribocytdilic acid), a synthetic analog of double-stranded RNA that induces a cytokine-associated viral-like acute phase response. The effects of poly(I:C)-induced MIA on phenotypic changes in the offspring are known to be influenced by various factors, including the precise prenatal timing, genetic background, and immune stimulus intensity.

MicroRNA Expression Profiling in the Prefrontal Cortex: Putative Mechanisms for the Cognitive Effects of Adolescent High Fat Feeding.

The medial prefrontal cortex (mPFC), master regulator of higher-order cognitive functions, is the only brain region that matures until late adolescence. During this period, the mPFC is sensitive to stressful events or suboptimal nutrition. For instance, high-fat diet (HFD) feeding during adolescence markedly impairs prefrontal-dependent cognition.

Effects of light and dark phase testing on the investigation of behavioural paradigms in mice: Relevance for behavioural neuroscience.

Different timing and light phases are critical factors in behavioural neuroscience, which can greatly affect the experimental outcomes of the performed tests. Despite the fact that time of testing is one of the most common factors that varies across behavioural laboratories, knowledge about the consequences of testing time on behavioural readouts is limited. Thus, in this study we systematically assessed the effect of this factor on the readout of a variety of elementary and recurrent behavioural paradigms in C57Bl/6 mice.

A randomized controlled trial to compare the effects of sulphonylurea gliclazide MR (modified release) and the DPP-4 inhibitor vildagliptin on glycemic variability and control measured by continuous glucose monitoring (CGM) in Brazilian women with type 2 diabetes.

Aims: This study aims to evaluate whether there is a difference between the effects of vildagliptin and gliclazide MR (modified release) on glycemic variability (GV) in women with type 2 diabetes (T2DM) as evaluated by continuous glucose monitoring (CGM).

Methods: An open-label, randomized study was conducted in T2DM women on steady-dose metformin monotherapy which were treated with 50 mg vildagliptin twice daily or 60-120 mg of gliclazide MR once daily. CGM and GV indices calculation were performed at baseline and after 24 weeks.

Vildagliptin has the same safety profile as a sulfonylurea on bone metabolism and bone mineral density in post-menopausal women with type 2 diabetes: a randomized controlled trial.

Background: Several antidiabetic therapies affect bone metabolism. Sulfonylureas have the lowest impact on bone among oral antidiabetics. The objective of this study is to compare the effects of vildagliptin and gliclazide modified release (MR) on bone turnover markers (BTMs) and bone mineral density (BMD) in postmenopausal women with uncontrolled type 2 diabetes (T2D).