American Journal of Physiology. Cell Physiology

Diabetes alters the function of ion channels responsible for regulating arterial smooth muscle membrane potential, resulting in vasoconstriction. Our prior research demonstrated an elevation of TMEM16A in diabetic arteries. Here, we explored the mechanisms involved in Transmembrane protein 16A ( TMEM16A) gene expression. Our data indicate that a Snail-mediated repressor complex regulates arterial TMEM16A gene transcription. Snail expression was reduced in diabetic arteries while TMEM16A expression was upregulated...

Adipose-derived stem cells (ADSCs) play an important role in the differential capacity for excess energy storage between upper body abdominal (ABD) adipose tissue (AT) and lower body gluteofemoral (GF) AT. We cultured ADSCs from subcutaneous ABD AT and GF AT isolated from eight women with differential body fat distribution and performed single-cell RNA sequencing. Six populations of ADSCs were identified and segregated according to their anatomical origin. The three ADSC subpopulations in GF AT were characterized by strong cholesterol/fatty acid (FA) storage and proliferation signatures...

Cardiometabolic diseases are often associated with heightened levels of angiotensin II (Ang II), which accounts for the observed oxidative stress, inflammation, and fibrosis. Accumulating evidence indicates a parallel upregulation of dipeptidyl dipeptidase 4 (DPP4) activity in cardiometabolic diseases, with its inhibition shown to mitigate oxidative stress, inflammation, and fibrosis. These findings highlight an overlap between the pathophysiological mechanisms used by Ang II and DPP4. Recent evidence demonstrates that targeted inhibition of DPP4 prevents the rise in Ang II and its associated molecules in experimental models of cardiometabolic diseases...

Ketone bodies are short-chain fatty acids produced by the liver during periods of limited glucose availability, such as during fasting or low carbohydrate feeding. Recent studies have highlighted important nonmetabolic functions of the most abundant ketone body, β-hydroxybutyrate (BHB). Notably, many of these functions, including limiting specific sources of inflammation, histone deacetylase inhibition, NFκB inhibition, and GPCR stimulation, are particularly important to consider in immune cells...

Ketogenic diets (KDs), fasting, or prolonged physical activity elevate serum ketone bodies (KBs) levels, providing an alternative fuel source for the brain and other organs. However, KBs play pleiotropic roles that go beyond their role in energy production. KBs can act as signaling metabolites, influence gene expression, proteins' posttranslational modifications (PTMs), inflammation, and oxidative stress. Here, we explore the impact of KBs on mammalian cell physiology, including aging and tissue regeneration...

Incretin-based therapy is an antidiabetic and antiobesity approach mimicking glucagon-like peptide-1 (GLP-1) with additional end-organ protection. This review solely focuses on randomized, controlled mechanistic human studies, investigating the renal effects of GLP-1. There is no consensus about the localization of GLP-1 receptors (GLP-1Rs) in human kidneys. Rodent and primate data suggest GLP-1R distribution in smooth muscle cells in the preglomerular vasculature. Native GLP-1 and GLP-1R agonists elicit renal effects...

No abstract text is available yet for this article.

No abstract text is available yet for this article.

Fibrosis, morphologic end-result of plethora of chronic conditions and the scorch for organ function, has been thoroughly investigated. One aspect of its development and progression, namely the permissive role of vascular endothelium, has been overshadowed by studies into (myo)fibroblasts and TGFβ; thus, it is the subject of the present review. It has been established that tensile forces of the extracellular matrix acting on cells are a prerequisite for mechanochemical coupling leading to liberation of TGFβ and formation of myofibroblasts...

This review examined how Hippo cell signaling and HS-proteoglycans (HSPGs) regulate tissue form and function. Despite being a non-weight bearing tissue the brain is regulated by Hippo mechanoresponsive cell signalling pathways during embryonic development. HS-proteoglycans interact with growth factors, morphogens and extracellular matrix components to regulate development and pathology. Pikachurin and Eyes Shut interact with dystroglycan to stabilize the photoreceptor axoneme primary cilium and ribbon synapse facilitating phototransduction and neurotransduction with bipolar retinal neuronal networks in ocular vision, the primary human sense...

We studied urea, thiourea, and methylurea transport and interaction in human red blood cells (RBC) under conditions of self-exchange (SE), net efflux (NE), and net influx (NI) at pH 7.2. We combined four methods, a four-centrifuge technique, the Millipore-Swinnex filtering technique, the continuous flow tube method, and a continuous pump method to measure the transport of the 14 C-labeled compounds. Under SE conditions both urea and thiourea show perfect Michaelis-Menten kinetics with half saturation constants, K1/2,SE (mM), of ≈300 (urea) and ≈20 (thiourea)...

The phosphodiesterase enzymes mediate calcium-phosphate deposition in various tissues, although which enzymes are active in bone mineralization is unclear. Using gene array analysis, we found that a member of ecto-nucleotide pyrophosphatase/phosphodiesterase family, ENPP2, was strongly down-regulated with age in stromal stem cells that produce osteoblasts and make bone. This is in keeping with reduced bone formation in older animals. Thus, we hypothesized that ENPP2 is, at least in part, an early mediator of bone formation and thus may reflect reduced bone formation with age...

Loss of function mutations in the SLC26A3 gene cause chloride-losing diarrhea in mice and humans. While systemic adaptive changes in patients and mice have been documented, it is unclear how the colonic enterocyte adapts to the loss of its highly expressed anion exchanger in the luminal membrane. To address this question, SLC26A3 was deleted in the self-differentiating Caco2BBe colonic cell line by the CRISPR/Cas9 technique. We selected a clone with loss of SLC26A3 protein expression and morphological features indistinguishable from those of the native cell line...

Diabetic cardiomyopathy (DCM) is closely related to ferroptosis, a new type of cell death that mainly manifests as intracellular iron accumulation and lipid peroxidation. Paeoniflorin (PA) helps improve impaired glucose tolerance and affects intestinal flora distributiona and induce significant resistance to ferroptosis in various models . In this study,we found PA improved cardiac dysfunction in mice with DCM by alleviating myocardial damage, resisting oxidative stress and ferroptosis, and changing the community composition and structure of the intestinal microbiota...

Cardiotonic steroids (CTS), used by certain insects, toads, and rats for protection from predators, became, thanks to Withering's trailblazing 1785 monograph, the mainstay of heart failure (HF) therapy. In the 1950's and 60's we learned that the CTS receptor was part of the sodium pump (NKA) and that the Na+ /Ca2+ exchanger was critical for the acute cardiotonic effect of digoxin- and ouabain-related CTS. This "settled" view was upended by seven revolutionary observations. First, sub-nanomolar ouabain sometimes stimulates NKA whilst higher concentrations are invariably inhibitory...

Mitsugumin 23 (MG23) has been identified as a ball-shaped cation channel in the sarcoplasmic reticulum (SR) but its physiological role remains unclear. This study aimed to examine the contribution of MG23 to Ca2+ storage function in skeletal muscle by using Mg23 -knockout ( Mg23 -/- ) mice. There was no difference in the isometric specific force of the extensor digitorum longus (EDL) and soleus (SOL) muscles between Mg23 -/- and wild-type (Wt) mice. In Mg23 -/- mice, the calsequestrin 2 content in the EDL muscle and SR Ca2+ -ATPase 2 content in the SOL were increased...

17-beta-hydroxysteroid dehydrogenase 13 (HSD17B13), a lipid droplet-associated enzyme, is primarily expressed in the liver and plays an important role in lipid metabolism. Targeted inhibition of enzymatic function is a potential therapeutic strategy for treating steatotic liver disease (SLD). The present study is aimed at investigating the effects of the first selective HSD17B13 inhibitor, BI-3231, in a model of hepatocellular lipotoxicity using human cell lines and primary mouse hepatocytes, in vitro . Lipotoxicity was induced with palmitic acid in HepG2 cells and freshly isolated mouse hepatocytes and the cells were co-incubated with BI-3231 to assess the protective effects...

β-hydroxybutyrate (βOHB) is the major ketone in the body and it is recognized as a metabolic energy source and an important signaling molecule. While ketone oxidation is essential in the brain during prolonged fasting/starvation, other organs such as skeletal muscle and the heart also use ketones as metabolic substrates. Additionally, βOHB-mediated molecular signaling events occur in heart and skeletal muscle cells, and via metabolism and/or signaling, ketones may contribute to optimal skeletal muscle health and cardiac function...

No abstract text is available yet for this article.

Mast-Cell Expressed Membrane Protein-1 (MCEMP1) is higher in Idiopathic Pulmonary Fibrosis (IPF) patients with increased risk of death. Here we aimed to establish the mechanistic role of MCEMP1 in pulmonary fibrosis. We identified increased MCEMP1 expression in classical monocytes and alveolar macrophages in IPF compared to controls. MCEMP1 was upregulated by TGFβ at the mRNA and protein levels in THP-1. TGFβ-mediated MCEMP1 upregulation results from the cooperation of SMAD3 and SP1 via concomitant binding to SMAD3/SP1 cis-regulatory elements within the MCEMP1 promoter...