A light-responsive neural circuit suppresses feeding.

Light plays an essential role in a variety of physiological processes, including vision, mood, and glucose homeostasis. However, the intricate relationship between light and an animal's feeding behavior has remained elusive. Here, we found that light exposure suppresses food intake, whereas darkness amplifies it in male mice. Interestingly, this phenomenon extends its reach to diurnal male Nile grass rats and healthy humans. We further show that lateral habenula (LHb) neurons in mice respond to light exposure, which in turn activates 5-HT neurons in the dorsal Raphe nucleus (DRN). Activation of the LHb → 5-HTDRN circuit in mice blunts darkness-induced hyperphagia, while inhibition of the circuit prevents light-induced anorexia. Together, we discovered a light responsive neural circuit that relays the environmental light signals to regulate feeding behavior in mice.Significance statement Feeding behavior is influenced by a myriad of sensory inputs, but the impact of light exposure on feeding regulation has remained enigmatic. Here, we showed that light exposure diminishes food intake across both nocturnal and diurnal species. Delving deeper, our findings revealed that the LHb → 5-HTDRN neural circuit plays a pivotal role in mediating light-induced anorexia in mice. These discoveries not only enhance our comprehension of the intricate neuronal mechanisms governing feeding in response to light but also offer insights for developing innovative strategies to address obesity and eating disorders.

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.

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.

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.

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.

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.

Retrospective review analysis of COVID-19 patients co-infected with Mycoplasma pneumoniae.

INTRODUCTION: Coronavirus disease 2019 (COVID-19) is an extremely infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The outbreak of this virus has resulted in significant morbidity and mortality throughout the world. We have seen an unprecedented spread of this virus, leading to extreme pressure on health-care services. Mycoplasma pneumoniae causes atypical bacterial pneumonia and is known to co-infect patients with viral pneumonias. METHODS: In this retrospective study, patients' data of 580 inpatients with confirmed SARS-CoV-2 infection were reviewed retrospectively over a 3-month period which included the the first peak of COVID-19 infections in the UK. RESULTS: Eight patients with COVID-19 and M. pneumoniae coinfection were identified - four males and four females. All patients were Caucasian, with an age range of 44-89 years. 37.5% of patients were hypertensive, whereas 25% had Type 2 diabetes mellitus. Dyspnea, cough, and pyrexia were found to be very common in these patients. Majority of the patients had abnormal C-reactive protein, lymphopenia, neutrophilia along with bilateral consolidation, and ground-glass opacities. Two patients required admission to intensive care, both of whom unfortunately died along with one patient receiving ward based care. CONCLUSION: Our confirmed the presence of co-infection with M. pneumoniae and describes the clinical features, investigation results, clinical course, and outcomes for these patients. Further research is needed to review the role of procalcitonin in excluding bacterial co-infection and to assess the impact of co-infection of patients with COVID-19 on morbidity and mortality.

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.

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. In this study, we explored the dynamics, intrinsic stability, and binding mechanisms of these molecules through computational modeling, docking, molecular dynamics (MD) simulations and molecular mechanics Poisson-Boltzmann surface area (MM/PBSA) binding free energy estimation. Molecular docking study depicted that hydrophobic interaction (pi-pi stacking) plays a crucial role in maintaining the stability of the complex, which was also supported by intermolecular analysis from MD simulation study. Principal component analysis suggested that the terminal ends along with the turns/loops connecting adjacent helix and strands exhibit a comparatively higher movement of main chain atoms in most of the complexes. MM/PBSA binding free energy study revealed that non-polar solvation (van der Waals and electrostatic) energy subsidizes significantly to the total binding energy, and the polar solvation energy opposes the binding agonists to GLP-1R. Overall, we provide structural features information about GLP-1R complexes that would be conducive for the discovery of new GLP-1R agonists in the future for the treatment of various metabolic diseases. Communicated by Ramaswamy H. Sarma.

Small Molecule Inhibiting Nuclear Factor-kB Ameliorates Oxidative Stress and Suppresses Renal Inflammation in Early Stage of Alloxan-Induced Diabetic Nephropathy in Rat.

Diabetic nephropathy is one of the major microvascular complications of diabetes mellitus which ultimately gives rise to cardiovascular diseases. Prolonged hyperglycaemia and chronic renal inflammation are the two key players in the development and progression of diabetic nephropathy. Nuclear factor kB (NF-kB)-mediated inflammatory cascade is a strong contributor to the renovascular inflammation in diabetic nephropathy. Here, we studied the effects of piceatannol, a potent NF-kB inhibitor, on various oxidative stress markers and NF-kB dependent diabetic renoinflammatory cascades in rat induced by alloxan (ALX). Experimental diabetes was induced in male Wistar rats by a single intraperitoneal dose, 150 mg/kg body-weight (b.w.) of ALX. Diabetic rats were treated with Piceatannol (PCTNL) at a dose of 30 and 50 mg/kg b.w. After 14 days of oral treatment, PCTNL significantly restored blood sugar level, glomerular filtration rate, serum markers and plasma lipids. PCTNL administration also reversed the declined activity of cellular antioxidant machineries namely superoxide dismutase and glutathione and the elevated levels of malondialdehyde and nitric oxide. Moreover, piceatannol-treated groups showed marked inhibition of renal pro-inflammatory cytokines and NF-kB p65/p50 binding to DNA. Renal histopathological investigations also supported its ameliorative effects against diabetic kidney damage. Importantly, effects were more prominent at a dose of 50 mg/kg, and in terms of body-weight gain, PCTNL failed to effect significantly. However, overall findings clearly demonstrated that PCTNL provides remarkable renoprotection in diabetes by abrogating oxidative stress and NF-kB activation - and might be helpful in early stage of diabetic nephropathy.