Diet-induced induction of hepatic serine/threonine kinase STK38 triggers proinflammation and hepatic lipid accumulation.

Nonalcoholic fatty liver disease (NAFLD) is one of the most common liver diseases worldwide. Although the involvement of chronic overnutrition, systemic inflammation, and insulin resistance in the development of NAFLD is well-established, however, the associations among these remain to be elucidated. Several studies have reported that chronic overnutrition, such as excessive consumption of fats (high-fat diet, HFD), can cause insulin resistance and inflammation. However, the mechanisms by which HFD exerts inflammation and thereby promotes insulin resistance and intrahepatic fat accumulation remain poorly understood. Here, we show that HFD induces the expression of hepatic serine/threonine kinase 38 (STK38), which further induces systemic inflammation leading to insulin resistance. Notably, ectopic expression of STK38 in mouse liver leads to lean NAFLD phenotype with hepatic inflammation, insulin resistance, intrahepatic lipid accumulation, and hypertriglyceridemia in mice fed on a regular chow diet. Further, depletion of hepatic STK38 in HFD-fed mice remarkably reduces proinflammation, improves hepatic insulin sensitivity, and decreases hepatic fat accumulation. Mechanistically, two critical stimuli are elicited by STK38 action. For one stimulus, STK38 binds to Tank-Binding protein Kinase 1 and induces Tank-Binding protein Kinase 1 phosphorylation to promote NF-κß nuclear translocation that mobilizes the release of proinflammatory cytokines and eventually leads to insulin resistance. The second, stimulus involves intrahepatic lipid accumulation by enhanced de novo lipogenesis via reducing the AMPK-ACC signaling axis. These findings identify STK38 as a novel nutrient-sensitive proinflammatory and lipogenic factor in maintaining hepatic energy homeostasis, and it provides a promising target for hepatic and immune health.

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 ß-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 ß-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. To address this drawback, strategically designed distinct sets of small molecules were docked on GLP1R ectodomain and compared with previously known small molecule GLP1R agonists. One of the small molecule PK2 (6-((1-(4-nitrobenzyl)-1H-1,2,3-triazol-4-yl)methyl)-6H-indolo[2,3-b]quinoxaline) displays stable binding with GLP1R ectodomain and induces GLP1R internalization and increasing cAMP levels. PK2 also increases insulin secretion in the INS-1 cells. The oral administration of PK2 protects against diabetes induced by multiple low-dose streptozotocin administration by lowering high blood glucose levels. Similar to GLP1R peptidic agonists, treatment of PK2 induces ß-cell replication and attenuate ß-cell apoptosis in STZ-treated mice. Mechanistically, this protection was associated with decreased thioredoxin-interacting protein expression, a potent inducer of diabetic ß-cell apoptosis and dysfunction. Together, this report describes a small molecule, PK2, as an orally active nonpeptidic GLP1R agonist that has efficacy to preserve or restore functional ß-cell mass.

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. However, there have been no attempts to exclusively summarize the commendable work done in this area yet. The current review, therefore, attempts to summarize the developments of various optical probes following this reaction strategy until the year 2022. This review provides detailed mechanistic insights into the Tsuji-Trost mediated CO detection strategy. Besides, discussions on the strategic development and employment of probes based on various allyl derivatives - allyl carbamate/carbonate/ethers - will provide a thorough understanding of the detection method. The significant advancements of the Tsuji-Trost reaction as an interesting strategy that is accepted and extensively explored for monitoring CO in various media including air, aqueous solutions and living systems have been elaborately discussed. Various potential applications and utilization of these developed fluorogenic probes for tracing CO in different living systems have been examined systematically. Moreover, monitoring of exogenous/endogenous CO levels, modulation of intracellular CO concentration under various induced conditions and bioimaging of CO in in vivo models have also been detailed here. Briefly, this review summarizes the current prospects of this detection method and the future directions in related fields.

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. Given their chemical structure, the free rotation between the donor and the acceptor gets restricted when the probes bind with RNA resulting in strong fluorescence emission towards a higher wavelength upon photoexcitation. A detailed investigation revealed that the photophysical properties and the optical responses of two probes, viz. BTZ-JLD and SEZ-JLD, towards RNA are very promising and qualify them to be suitable candidates for biological studies, particularly for cellular imaging applications. The probes allow imaging of intracellular RNA with prominent staining of nucleoli in live cells under a range of physiological conditions. The results of the cellular digest test established the appreciable RNA selectivity of BTZ-JLD and SEZ-JLD inside the cellular environment. Moreover, a comparison between the relative intensity profile of SEZ-JLD before and after the RNA-digestion test inside the cellular environment indicated that the interference of cellular viscosity in fluorescence enhancement is insignificant, and hence, SEZ-JLD can be used as a cell membrane permeable cationic molecular probe for deep-red imaging of intracellular RNA with a good degree of selectivity.

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. Here, we provide an evidence of an unknown link between nuclear factor kappa-light chain enhancer of activated B cells (NF-κB) activation and increased DNL. Our data indicates high carbohydrate diet to enforce nuclear shuttling of hepatic NF-κB p65 and repress transcript levels of sorcin, a cytosolic interacting partner of ChREBP. Reduced sorcin levels, further prompted ChREBP nuclear translocation, leading to enhanced DNL and intrahepatic lipid accumulation both in vivo and in vitro. We further report that pharmacological inhibition of NF-κB abrogated high carbohydrate diet-mediated sorcin repression and thereby prevented ChREBP nuclear translocation and this, in turn, attenuated hepatic lipid accumulation both in in vitro and in vivo. Additionally, sorcin knockdown blunted the lipid-lowering ability of the NF-κB inhibitor in vitro. Together, these data suggest a heretofore unknown role for NF-κB in regulating ChREBP nuclear localization and activation, in response to high carbohydrate diet, for further explorations in lines of NAFLD therapeutics.

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. We now provide evidence that hyperinsulinemia promotes the release of soluble pro-inflammatory mediators from macrophages that lead to systemic insulin resistance. Our observations suggest that hyperinsulinemia induces sirtuin1 (SIRT1) repression and stimulates NF-κB p65 nuclear translocation and transactivation of NF-κB to promote the extracellular release of pro-inflammatory mediators. We further showed that low-dose naltrexone (LDN) abrogates hyperinsulinemia-mediated SIRT1 repression and prevents NF-κB p65 nuclear translocation. This, in turn, attenuates the hyperinsulinemia-induced release of pro-inflammatory cytokines and reinstates insulin sensitivity both in in vitro and in vivo diet-induced hyperinsulinemic mouse model. Notably, our data indicate that Sirt1 knockdown or inhibition blunts the anti-inflammatory properties of LDN in vitro Using numerous complementary in silico and in vitro experimental approaches, we demonstrated that LDN can bind to SIRT1 and increase its deacetylase activity. Together, these data support a critical role of SIRT1 in inflammation and insulin resistance in hyperinsulinemia. LDN improves hyperinsulinemia-induced insulin resistance by reorienting macrophages toward anti-inflammation. Thus, LDN treatment may provide a novel therapeutic approach against hyperinsulinemia-associated insulin resistance.

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. Therefore, reducing DNL accretion may be critical in the development of therapeutics of NAFLD. In our in vivo model (high-fat-diet fed [HFD] obese mice) we found Zinc oxide nanoparticles (ZnO NPs) significantly decreased HFD-induced hepatic steatosis and peripheral insulin resistance. This protective mechanism of ZnO NPs was signaled through hepatic SIRT1-LKB1-AMPK which restricted SREBP-1c within the cytosol limiting its transcriptional ability and thereby ameliorating HFD mediated DNL. These observations indicate that ZnO NP can serve as a therapeutic strategy to improve the physiological homeostasis during obesity and its associated metabolic abnormalities.

Renal Clearable New NIR Probe: Precise Quantification of Albumin in Biofluids and Fatty Liver Disease State Identification through Tissue Specific High Contrast Imaging in Vivo.

Development of a highly photostable, renal clearable, and nontoxic new NIR probe (CyG) for precise quantification of albumin in different biofluids and liver targeted in vivo albumin visualization is demonstrated. CyG's inherent property to interact selectively with albumin among different biomolecules in intracellular environment with high degree of sensitivity helps CyG in targeted liver imaging. In addition to its long excitation/emission wavelengths (λex = 740 nm, λem = 804 nm), which are much above the biological tissue opaque window (400-700 nm) ensuring better photon penetration, diminished tissue autofluorescence and high contrasts, its molecular mass and size are far below the renal cutoff and hence, CyG qualifies as imaging material for clinical studies. We anticipate that CyG will provide new strategies to overcome the pitfall of present day albumin detection methods as well as accelerate the detection process at relatively lower costs without compromising the accuracy of detection. Moreover, the renal excretion kinetic and intrahepatic albumin binding affinity of CyG can further be used to differentiate between fatty liver from healthy liver in an experimentally arrived mouse model using noninvasive technique.

NIR-I emissive cyanine derived molecular probe for selective monitoring of hepatic albumin levels during hyperglycemia.

In this study, we report a small molecule optical marker BI-CyG derived from the structural engineering of a cyanine scaffold. The developed probe offers suitable advantages over existing cyanine-based albumin specific probes in terms of its excitation and emission wavelengths, which are 760 and 830-832 nm, respectively. Structural tuning of the cyanine architecture leading to extended π-conjugation and resulting in a suitable bathochromic shift in the emission wavelength of the probe is represented in this study. The probe besides emitting in the NIR region, also possesses the desirable characteristics of being a potential target selective optical marker, as established from various biophysical studies. Molecular modelling and simulation studies provided critical insights into the binding of the probe in the protein microenvironment, which was further supported by experimental studies. The probe displayed intracellular albumin selectivity and was utilized for demonstrating alteration in albumin levels in pathological states such as hyperglycemia in hepatic cells. The present study also sheds some light on using BI-CyG as an imaging probe and on the role of metformin as a suitable drug for balancing hyperglycemia-induced reduced intra-hepatic albumin levels. The study, thus, attempts to highlight the structural derivatization of cyanine to afford a potential probe for serum albumin and its deployment to image altering albumin levels in an induced pathological condition, hyperglycemia.

Molecular pathways dysregulated by Pb2+ exposure prompts pancreatic beta-cell dysfunction.

Type 2 diabetes mellitus (T2DM) is a metabolic disease characterized by reduced insulin sensitivity and dysfunction of ß-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. At this juncture, we, through our work unveil a plausible link between Pb2+ exposure and diabetes mellitus, and delineated a comprehensive understanding of the potential mechanisms of Pb2+-induced ß-cells dysfunction. In our in vivo observations, we found that Pb2+ exposure strongly reduced glucose-stimulated insulin secretion and diminished functional pancreatic ß-cell mass. Mechanistically, we found that Pb2+ downregulates intracellular cAMP level via hyper-activating Ca2+/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1C and thereby reduces glucose-stimulated insulin secretion. Further, we report that Pb2+ inhibited mitochondrial adenosine triphosphate production and also identified Pb2+ as a negative regulator of ß-cell proliferation via Ca2+/calmodulin-dependent protein kinase kinases-pAMPK-pRaptor axis. Together, our findings strongly reinforce Pb2+ to hijack the physiological role of calcium ions, by mimicking Ca2+ within pancreatic ß-cell and thereby stands as a diabetogenic xenobiotic.

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. Like other coronaviruses, SARS-CoV-2 relies on the surface Spike glycoprotein to access the host cells, mainly through the interaction of its Receptor Binding Domain (RBD) with the host receptor Angiotensin-Converting Enzyme2 (ACE2). SARS-CoV-2 infection induces a profound downstream pro-inflammatory cytokine storm. This release of the pro-inflammatory cytokines is underpinning lung tissue damage, respiratory failure, and eventually multiple organ failure in COVID-19 patients. The phosphorylation status of ERK1/2 is positively correlated with virus load and ERK1/2 inhibition suppressed viral replication and viral infectivity. Therefore, molecular entities able to interfere with binding of the SARS-CoV-2 Spike protein to ACE2, or damping hyperinflammatory cytokines storm, blocking ERK1/2 phosphorylation have a great potential to inhibit viral entry along with viral infectivity. Herein, we report that the FDA-approved non-peptide opioid antagonist drug, naltrexone suppresses high fat/LPS induced pro-inflammatory cytokine release both from macrophage cells and Adipose Tissue Macrophage. Moreover, Low Dose Naltrexone (LDN) also showed its activity as an ERK1/2 inhibitor. Notably, virtual docking and simulation data also suggest LDN may disrupt the interaction of ACE2 with RBD. LDN may be considered as a target as the treatment and (or) adjuvant therapy for coronavirus infection. Clinical toxicity measurements may not be required for LDN since naltrexone was previously tested and is an approved drug by the FDA.Communicated by Ramaswamy H. Sarma.

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 -31.8 kcal mol-1 majorly predominated by hydrophobic interactions. Besides, the conformational dynamics of CyG-NHS in an aqueous medium and the albumin microenvironment have been comprehensively studied and discussed. The potentiality of this optical platform to monitor the intracellular albumin levels in human hepatoma (HepG2) cells in different pathophysiological states has been demonstrated here. Also, the competency of the phenformin drug in restoring the albumin levels in chronic hyperinsulinemic and hypercholesterolemic in vitro models has been established through the visualization approach. Altogether, the findings of this study throw light on the significance of the development of a suitable optical marker for the visualization of critical bioevents related to albumin.

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. The probes exhibit high quantum yield upon interacting with RNA in an aqueous solution. An in-depth multiscale simulation study reveals that the prominent rotational freezing of the electron-donating sidearm of the probes in the microenvironment of RNA helps in attaining more planar conformation when compared to DNA. It exerts a greater extent of intramolecular charge transfer and hence leads to enhanced fluorescence emission. A systematic structure-interaction relationship study highlighted the impact of heavy-chalcogens toward the improved emissive properties of the probes.

Liver-Derived S100A6 Propels ß-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 ß-cell function remain equivocal. Specifically, how the accumulation of liver fat consequent to the enhanced de novo lipogenesis (DNL) leads to pancreatic ß-cell failure and eventually to T2DM is elusive. Here, we have identified that low-molecular-weight calcium-binding protein S100A6, or calcyclin, inhibits glucose-stimulated insulin secretion (GSIS) from ß cells through activation of the receptor for the advanced glycation end products and diminution of mitochondrial respiration. Serum S100A6 level is elevated both in human patients with NAFLD and in a high-fat diet-induced mouse model of NAFLD. Although serum S100A6 levels are negatively associated with ß-cell insulin secretory capacity in human patients, depletion of hepatic S100A6 improves GSIS and glycemia in mice, suggesting that S100A6 contributes to the pathophysiology of diabetes in NAFLD. Moreover, transcriptional induction of hepatic S100A6 is driven by the potent regulator of DNL, carbohydrate response element-binding protein (ChREBP), and ectopic expression of ChREBP in the liver suppresses GSIS in a S100A6-sensitive manner. Together, these data suggest elevated serum levels of S100A6 may serve as a biomarker in identifying patients with NAFLD with a heightened risk of developing ß-cell dysfunction. Overall, our data implicate S100A6 as, to our knowledge, a hitherto unknown hepatokine to be activated by ChREBP and that participates in the hepato-pancreatic communication to impair insulin secretion and drive the development of T2DM in NAFLD.

Identification of the aryl hydrocarbon receptor target gene TiPARP as a mediator of suppression of hepatic gluconeogenesis by 2,3,7,8-tetrachlorodibenzo-p-dioxin and of nicotinamide as a corrective agent for this effect.

The environmental toxin TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin, dioxin) produces diverse toxic effects including a lethal wasting syndrome whose hallmark is suppressed hepatic gluconeogenesis. All TCDD toxicities require activation of the aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor. Whereas the mechanism for AHR induction of target genes is well understood, it is not known how AHR activation produces any TCDD toxicity. This report identifies for the first time an AHR target gene, TiPARP (TCDD-inducible poly(ADP-ribose) polymerase, PARP7) that can mediate a TCDD toxicity, i.e. suppression of hepatic gluconeogenesis. TCDD suppressed hepatic glucose production, expression of key gluconeogenic genes, phosphoenolpyruvate carboxykinase (PEPCK), and glucose-6-phosphatase (G6Pase), and NAD(+) levels, and increased PARP activity and TiPARP expression. TCDD also increased acetylation and ubiquitin-dependent proteosomal degradation of the peroxisome proliferator-activated receptor γ coactivator 1 α (PGC1α), a coactivator of PEPCK and G6Pase transcription. TiPARP overexpression reproduced TCDD effects on glucose output and NAD(+) levels whereas TiPARP silencing diminished them. TiPARP overexpression also increased PGC1α acetylation and decreased PGC1α levels. In contrast, silencing of cytochromes P450 (CYP) 1A, main AHR-induced genes, did not alter TCDD suppression of gluconeogenesis. The vitamin B3 constituent, nicotinamide (NAM), prevented TCDD suppression of glucose output, NAD(+), and gluconeogenic genes and stabilized PGC1α. The corrective effects of NAM could be attributed to increased NAD(+) levels and suppression of AHR target gene induction. The results reveal that TiPARP can mediate a TCDD effect, that the AHR is linked to PGC1α function and stability and that NAM has novel AHR antagonist activity.

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. However, the influences of LDN on the local bone quality, mineralization of the bone, and the skeletal AGEs levels have not been fully elucidated. The objective of this study is to understand the effect of LDN on Raman assisted bone quality, skeletal AGEs (determined by Raman spectroscopy), and nano-mechanical properties in HFD induced T2DM mice bone. In order to investigate these, mice and corresponding bones were divided into four groups (divided based on diet and treatment), (a) normal control diet treated with saline water, (b) normal control diet treated with LDN, (c) HFD treated with saline water, and (d) HFD treated with LDN. In T2DM condition (HFD treated with saline water), alteration of Raman-based compositional measures in bone quality including mineral-to-matrix ratios, carbonate substitution, mineral crystallinity, and collagen quality was observed. Our data also indicated that T2DM enhances the skeletal AGEs, and impairs the nano-mechanical properties. Interestingly, present results indicated that LDN controls the Raman-based compositional measures in bone quality in HFD induced T2DM mice bone. Additionally, LDN also protects the alteration of the skeletal AGEs levels and nano-mechanical properties in T2DM mice bone. This study concluded that LDN can control the HFD induced T2DM affected bone abnormalities at multiple hierarchical levels.

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. However, effects on bone are still unknown. In this study, the effects of LDN on the bone properties at different hierarchical levels in T2DM mice bone were investigated. In order to investigate these, four different groups of bone (divided based on diet and treatment) were considered in this present study. These are (a) normal control diet treated with saline water, (b) normal control diet treated with LDN, (c) HFD treated with saline water, and (d) HFD treated with LDN. Bone properties were measured in terms of fracture toughness, nano-Young's modulus, hardness, mineral crystal size, bone composition, and bulk mineral to matrix ratio. Results indicated that fracture toughness, nano-Young's modulus, and hardness were decreased in T2DM bone as compared to normal bone, and interestingly, treatment with the LDN increases these material properties in T2DM mice bone. Similarly, as compared to the normal bone, decrease in the mineral crystal size and bulk mineral-to-matrix ratio was observed in the T2DM bone, whereas LDN treatment protects these alterations in the T2DM mice bone. The bone size (bone geometry) was increased in the case of HFD-induced T2DM bone; however, LDN cannot protect to increase the bone size in the T2DM mice bone. In conclusion, LDN can be used to control the T2DM-affected bone properties at different hierarchical levels.

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. Activated ChREBP also inhibits lipolysis and encourages proper disposal of excessive triglycerides into adipocytes from the liver ablating hepatic intracellular lipid trafficking. Chronic overeating or onset of positive energy balance, hyper-activates ChREBP and signals development, intensification of hepato-metabolic disorders, and allied discrepancies in the whole-body metabolic functioning. ChREBP thus gets negatively connotated as the primary regulator of hepatic disorders, owing to its inherent features as the primary glycemic sensor and the only transcription factor that can transduce glucose-dependent glycolytic and lipogenic signals. Through this review, we - try to recapitulate and emphasize on the sanative events coordinated by ChREBP in several pathophysiological states. In totality, we aim to uncouple the disease-causing aspects of ChREBP from its positive attributes evoked during a metabolic crisis, in hepato-metabolic diseases.

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. The method is based on principle of fluorescence in near infrared range (NIR) of 700 to 850 nm by using a novel dye with the test mixture. The chosen near infrared range has a benefit of absence of the auto fluorescence of the bio-molecules present in urine other than the albumin molecules. The system consists of: light source, spectroscopic chamber, sensing and computational unit. The study shows the stability and reproducibility of device so as to avoid fluctuations of voltage and other undesirables. The optimization with bovine serum albumin and human serum albumin has been done and the device can sense as low as 100 nM concentration precisely and accurately.Clinical Relevance-The system being presented is intended for developing a low cost point of care testing device for determining albumin concentration in urine.

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

In the nematode C. elegans, 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. A daf-2b splicing reporter revealed active regulation of this transcript through development, particularly in the dauer larva, a diapause stage associated with longevity. CRISPR knock-in of mScarlet into the daf-2b genomic locus confirmed that DAF-2B is expressed in vivo and is likely secreted. Genetic studies indicate that DAF-2B influences dauer entry, dauer recovery and adult lifespan by altering insulin sensitivity according to the prevailing insulin milieu. Thus, in C. elegans alternative splicing at the daf-2 locus generates a truncated IR that fine-tunes insulin signaling in response to the environment.