TRIM32 regulates insulin sensitivity by controlling insulin receptor degradation in the liver.

Impaired insulin receptor signaling is strongly linked to obesity-related metabolic conditions like non-alcoholic fatty liver disease (NAFLD) and Type 2 diabetes (T2DM). However, the exact mechanisms behind impaired insulin receptor (INSR) signaling in obesity induced by a high-fat diet remain elusive. In this study, we identify an E3 ubiquitin ligase, tripartite motif-containing protein 32 (TRIM32), as a key regulator of hepatic insulin signaling that targets the insulin receptor (INSR) for ubiquitination and proteasomal degradation in high-fat diet (HFD) mice.

Julolidine-based small molecular probes for fluorescence imaging of RNA in live cells.

Intracellular RNA imaging with organic small molecular probes has been an intense topic, although the number of such reported dyes, particularly dyes with high quantum yields and long wavelength excitation/emission, is quite limited. The present work reports the design and synthesis of three cationic julolidine-azolium conjugates (OX-JLD, BTZ-JLD and SEZ-JLD) as turn-on fluorescent probes with appreciably high quantum yields and brightness upon interaction with RNA. A structure-efficiency relationship has been established for their potential for the interaction and imaging of intracellular RNA.

The emergence and advancement of Tsuji-Trost reaction triggered carbon monoxide recognition and bioimaging.

Considering that carbon monoxide is both a vital gasotransmitter and an obnoxious gas, tremendous efforts have been dedicated toward its recognition through various methods. However, the fluorescent light-up approach through the exploration of optical markers remains one of the most convenient methods owing to its several advantages. Amongst the different approaches towards the development of CO responsive optically active molecular markers, the Tsuji-Trost reaction-based CO recognition strategy has remained one of the most significant areas of interest across researchers working in this field.

Liver-Derived S100A6 Propels β-Cell Dysfunction in NAFLD.

Nonalcoholic fatty liver disease (NAFLD) is an independent predictor of systemic insulin resistance and type 2 diabetes mellitus (T2DM). However, converse correlates between excess liver fat content and β-cell function remain equivocal. Specifically, how the accumulation of liver fat consequent to the enhanced de novo lipogenesis (DNL) leads to pancreatic β-cell failure and eventually to T2DM is elusive.

Near-infrared emissive cyanine probes for selective visualization of the physiological and pathophysiological modulation of albumin levels.

With the promising advantages of the near-infrared region (NIR) emissive markers for serum albumin becoming very prominent recently, we devised CyG-NHS as the cyanine derived longest NIR-I emissive optical marker possessing albumin selective recognition ability in diverse biological milieu. Multiscale modeling involving molecular docking, molecular dynamics, and implicit solvent binding free energy calculations have been employed to gain insights into the unique binding ability of the developed probe at domain-I of albumin, in contrast to the good number of domain IIA or IIIA binding probes available in the literature reports. The binding free energy was found to be -31.

Design, synthesis, and biological evaluation of a small molecule oral agonist of the glucagon-like-peptide-1 receptor.

An absolute or relative deficiency of pancreatic β-cells mass and functionality is a crucial pathological feature common to type 1 diabetes mellitus and type 2 diabetes mellitus. Glucagon-like-peptide-1 receptor (GLP1R) agonists have been the focus of considerable research attention for their ability to protect β-cell mass and augment insulin secretion with no risk of hypoglycemia. Presently commercially available GLP1R agonists are peptides that limit their use due to cost, stability, and mode of administration.

Molecular pathways dysregulated by Pb exposure prompts pancreatic beta-cell dysfunction.

Type 2 diabetes mellitus (T2DM) is a metabolic disease characterized by reduced insulin sensitivity and dysfunction of β-cells. Although the increasing prevalence of diabetes worldwide is largely attributed to genetic predisposition or lifestyle factors (insufficient physical activity), and caloric intake. Environmental factors, exposure to xenobiotics and heavy metals have also been reported to be causative factors of T2DM.

Organosulfur/Selenium-Based Highly Fluorogenic Molecular Probes for Live-Cell Nucleolus Imaging.

We present fluorogenic cationic organo chalcogens that are highly selective to RNA. We have demonstrated that the conformational dynamics and subsequently the optical properties of these dyes can be controlled to facilitate efficient bioimaging. We report the application of organoselenium and organosulfur-based cell-permeable red-emissive probes bearing a favorable cyclic sidearm for selective and high contrast imaging of cell nucleoli.

LDN Protects Bone Property Deterioration at Different Hierarchical Levels in T2DM Mice Bone.

Type 2 diabetes mellitus (T2DM) commonly affects bone quality at different hierarchical levels and leads to an increase in the risk of bone fracture. Earlier, some anti-diabetic drugs showed positive effects on bone mechanical properties. Recently, we have investigated that low-dose naltrexone (LDN), a TLR4 antagonist treatment, improves glucose tolerance in high-fat diet (HFD)-induced T2DM mice and also gives protection against HFD-induced weight gain.

NF-κB p65 regulates hepatic lipogenesis by promoting nuclear entry of ChREBP in response to a high carbohydrate diet.

Overconsumption of sucrose and other sugars has been associated with nonalcoholic fatty liver disease (NAFLD). Reports suggest hepatic de novo lipogenesis (DNL) as an important contributor to and regulator of carbohydrate-induced hepatic lipid accumulation in NAFLD. The mechanisms responsible for the increase in hepatic DNL due to overconsumption of carbohydrate diet are less than clear; however, literatures suggest high carbohydrate diet to activate the lipogenic transcription factor carbohydrate response element-binding protein (ChREBP), which further transcribes genes involved in DNL.

Influence of low dose naltrexone on Raman assisted bone quality, skeletal advanced glycation end-products and nano-mechanical properties in type 2 diabetic mice bone.

Type 2 diabetes mellitus (T2DM) commonly affects the bone mineral phase and advanced glycation end-products (AGEs) which eventually led to changes in bone material properties on the nano and macro-scale. Several anti-diabetic compounds are widely used to control high blood sugar or glucose caused by T2DM. Low Dose Naltrexone (LDN), an opiate receptor antagonist, and a known TLR4 antagonist, treatment can improve glucose tolerance and insulin sensitivity in high-fat-diet (HFD) induced T2DM mice.

Causative and Sanative dynamicity of ChREBP in Hepato-Metabolic disorders.

ChREBP is the master regulator of carbohydrate dependent glycolytic and lipogenic flux within metabolic tissues. It plays a vital role in hyper-calorific milieu by activating glycolysis, lipogenesis along with pentose phosphate shunt and glycogen synthesis, fostering immediate reduction in the systemic glycemic levels. Liver being the primary organ to sense disproportionate dietary intake and linked physiological stress, stimulates ChREBP to perform the aforementioned processes.

A Novel Near Infrared Spectroscopy Based Device for Albumin Estimation.

In this paper we have proposed a fluorescence based spectroscopy device which can be used to quantitatively estimate the amount of albumin that gets excreted out of our body. Albumin is a significant protein in bio-fluids and performs a wide range of metabolic functions. The dye that has been used as a fluorescent indicator for the presence of albumin in this study has been earlier tested with bovine serum albumin (BSA) and human serum albumin (HSA) with satisfactory results.

Low-dose naltrexone rescues inflammation and insulin resistance associated with hyperinsulinemia.

The incidence of diabetes, obesity, and metabolic diseases has reached an epidemic status worldwide. Insulin resistance is a common link in the development of these conditions, and hyperinsulinemia is a central hallmark of peripheral insulin resistance. However, how hyperinsulinemia leads to systemic insulin resistance is less clear.

Naltrexone a potential therapeutic candidate for COVID-19.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is the cause of Coronavirus Disease (COVID-19) that has resulted in a global pandemic. At the time of writing, approximately 16.06 million cases have been reported worldwide.

An alternatively spliced, non-signaling insulin receptor modulates insulin sensitivity via insulin peptide sequestration in .

In the nematode , insulin signaling regulates development and aging in response to the secretion of numerous insulin peptides. Here, we describe a novel, non-signaling isoform of the nematode insulin receptor (IR), DAF-2B, that modulates insulin signaling by sequestration of insulin peptides. DAF-2B arises via alternative splicing and retains the extracellular ligand binding domain but lacks the intracellular signaling domain.

Long Range Emissive Water-Soluble Fluorogenic Molecular Platform for Imaging Carbon Monoxide in Live Cells.

Despite its murderous act, carbon monoxide (CO) is found to be a very crucial small gaseous messenger molecule in dictating prime biological and physiological processes. Determination of endogenous or exhaled CO levels can throw significant light on smoking status and can be used as a breath biomarker of inflammatory diseases. Therefore, fluorescence imaging of CO in biofluids will empower one with the minute details of various disease states that involve CO.

Molecular Scale Optimum Hydrophobicity To Establish an Enhanced Probe-Protein Interaction: Near-Infrared Imaging of Albumin Biosynthesis Modulation.

Albumin is the most abundant serum protein and shows variation in its synthesis rate in different physiological and pathophysiological conditions. Thus, there might be an association expected between serum albumin concentration and body health. A library of NIR probes engineered with the optimum hydrophobicity has been developed and characterized using spectroscopy techniques and was employed to understand the variation of hepatic albumin synthesis rates on physiological and pathophysiological states.

Chronic exposure to Pb perturbs ChREBP transactivation and coerces hepatic dyslipidemia.

Dysregulated hepatic de novo lipogenesis contributes to the pathogenesis of nonalcoholic fatty liver disease in both humans and rodents. Clinical evidence suggests fatty liver to have a positive correlation with serum lead (Pb ) levels. However, an exact mechanism of Pb -induced fatty liver progression is still unknown.

Zinc oxide nanoparticles attenuate hepatic steatosis development in high-fat-diet fed mice through activated AMPK signaling axis.

Insulin resistance is thought to be a common link between obesity and Non-Alcoholic Fatty Liver Disease (NAFLD). NAFLD has now reached epidemic status worldwide and identification of molecules or pathways as newer therapeutic strategies either to prevent or overcome insulin resistance seems critical. Dysregulated hepatic lipogenesis (DNL) is a hallmark of NAFLD in humans and rodents.

Novel insights into the dynamics behavior of glucagon-like peptide-1 receptor with its small molecule agonists.

The glucagon-like peptide-1 receptor (GLP-1R) is a well-known target of therapeutics industries for the treatment of various metabolic diseases like type 2 diabetes and obesity. The structural-functional relationships of small molecule agonists and GLP-1R are yet to be understood. Therefore, an attempt was made on structurally known GLP-1R agonists (Compound 1, Compound 2, Compound A, Compound B, and (S)-8) to study their interaction with the extracellular domain of GLP-1R.

A long-range emissive mega-Stokes inorganic-organic hybrid material with peripheral carboxyl functionality for As(v) recognition and its application in bioimaging.

We demonstrate a strategy for the recognition of As in aqueous solution using a red-emissive probe based on a perylene-Cu ensemble decorated with peripheral free carboxyl functionality. Single crystal analysis helped us to understand the chemical structure of the probe. To the best of our knowledge, this is the first probe for arsenic detection which emits in the red region (λ = 600 nm).

Interventions to improve β-cell mass and function.

Diabetes mellitus (T2DM) has become an epidemiologically important disease worldwide and is also becoming a great matter of concern due to the effects associated with it like: high morbidity, elevated health care cost and shortened life span. T2DM is a chronic metabolic disease characterized by insulin resistance as well as β-cell dysfunction. It is widely accepted that in the face of insulin resistance, euglycemia can be maintained by increase in pancreatic β-cell mass and insulin secretion.