Ferroptosis inhibitors reduce celastrol toxicity and preserve its insulin sensitizing effects in insulin resistant HepG2 cells.

OBJECTIVE: Research has shown that celastrol can effectively treat a variety of diseases, yet when passing a certain dosage threshold, celastrol becomes toxic, causing complications such as liver and kidney damage and erythrocytopenia, among others. With this dichotomy in mind, it is extremely important to find ways to preserve celastrol's efficacy while reducing or preventing its toxicity. METHODS: In this study, insulin-resistant HepG2 (IR-HepG2) cells were prepared using palmitic acid and used for in vitro experiments. IR-HepG2 cells were treated with celastrol alone or in combination with N-acetylcysteine (NAC) or ferrostatin-1 (Fer-1) for 12, 24 or 48 h, at a range of doses. Cell counting kit-8 assay, Western blotting, quantitative reverse transcription-polymerase chain reaction, glucose consumption assessment, and flow cytometry were performed to measure celastrol's cytotoxicity and whether the cell death was linked to ferroptosis. RESULTS: Celastrol treatment increased lipid oxidation and decreased expression of anti-ferroptosis proteins in IR-HepG2 cells. Celastrol downregulated glutathione peroxidase 4 (GPX4) mRNA. Molecular docking models predicted that solute carrier family 7 member 11 (SLC7A11) and GPX4 were covalently bound by celastrol. Importantly, we found for the first time that the application of ferroptosis inhibitors (especially NAC) was able to reduce celastrol's toxicity while preserving its ability to improve insulin sensitivity in IR-HepG2 cells. CONCLUSION: One potential mechanism of celastrol's cytotoxicity is the induction of ferroptosis, which can be alleviated by treatment with ferroptosis inhibitors. These findings provide a new strategy to block celastrol's toxicity while preserving its therapeutic effects. Please cite this article as: Liu JJ, Zhang X, Qi MM, Chi YB, Cai BL, Peng B, Zhang DH. Ferroptosis inhibitors reduce celastrol toxicity and preserve its insulin sensitizing effects in insulin resistant HepG2 cells. J Integr Med. 2024; 22(3): 286-294.

Effects of vitamin family members on insulin resistance and diabetes complications.

The following letter to the editor highlights the article "Effects of vitamin D supplementation on glucose and lipid metabolism in patients with type 2 diabetes mellitus and risk factors for insulin resistance" in World J Diabetes 2023 Oct 15; 14 (10): 1514-1523. It is necessary to explore the role of vitamin family members in insulin resistance and diabetes complications.

Alpha lipoic acid administration improved both peripheral sensitivity to insulin and liver clearance of insulin reducing potential risk of diabetes and nonalcoholic fatty liver disease in overweight/obese PCOS patients.

OBJECTIVE: To evaluate the effects of alpha lipoic acid (ALA) on hormonal and metabolic parameters in a group of overweight/obese Polycystic Ovary Syndrome (PCOS) patients. METHODS: This was a retrospective study in which thirty-two overweight/obese patients with PCOS (n = 32) not requiring hormonal treatment were selected from the database of the ambulatory clinic of the Gynecological Endocrinology Center at the University of Modena and Reggio Emilia, Italy. The hormonal profile, routine exams and insulin and C-peptide response to oral glucose tolerance test (OGTT) were evaluated before and after 12 weeks of complementary treatment with ALA (400 mg/day). Hepatic Insulin Extraction (HIE) index was also calculated. RESULTS: ALA administration significantly improved insulin sensitivity and decreased ALT and AST plasma levels in all subjects, though no changes were observed on reproductive hormones. When PCOS patients were subdivided according to the presence or absence of familial diabetes background, the higher effects of ALA were observed in the former group that showed AST and ALT reduction and greater HIE index decrease. CONCLUSION: ALA administration improved insulin sensitivity in overweight/obese PCOS patients, especially in those with familial predisposition to diabetes. ALA administration improved both peripheral sensitivity to insulin and liver clearance of insulin. Such effects potentially decrease the risk of nonalcoholic fat liver disease and diabetes in PCOS patients.

Selenium, diabetes, and their intricate sex-specific relationship.

Selenium (Se) is an essential trace element, which is inserted as selenocysteine (Sec) into selenoproteins during biosynthesis, orchestrating their expression and activity. Se is associated with both beneficial and detrimental health effects; deficient supply or uncontrolled supplementation raises concerns. In particular, Se was associated with an increased incidence of type 2 diabetes (T2D) in a secondary analysis of a randomized controlled trial (RCT). In this review, we discuss the intricate relationship between Se and diabetes and the limitations of the available clinical and experimental studies. Recent evidence points to sexual dimorphism and an association of Se deficiency with gestational diabetes mellitus (GDM). We highlight the emerging evidence linking high Se status with improved prognosis in patients with T2D and lower risk of macrovascular complications.

The Lipophilic Extract from Ginkgo biloba L. Leaves Promotes Glucose Uptake and Alleviates Palmitate-Induced Insulin Resistance in C2C12 Myotubes.

Ginkgo biloba L. (ginkgo) is a widely used medicinal plant around the world. Its leaves, which have been used as a traditional Chinese medicine, are rich in various bioactive components. However, most of the research and applications of ginkgo leaves have focused on terpene trilactones and flavonol glycosides, thereby overlooking the other active components. In this study, a lipophilic extract (GL) was isolated from ginkgo leaves. This extract is abundant in lipids and lipid-like molecules. Then, its effect and potential mechanism on glucose uptake and insulin resistance in C2C12 myotubes were investigated. The results showed that GL significantly enhanced the translocation of GLUT4 to the plasma membrane, which subsequently promoted glucose uptake. Meanwhile, it increased the phosphorylation of AMP-activated protein kinase (AMPK) and its downstream targets. Both knockdown of AMPK with siRNA and inhibition with AMPK inhibitor compound C reversed these effects. Additionally, GL ameliorated palmitate-induced insulin resistance by enhancing insulin-stimulated glucose uptake, increasing the phosphorylation of protein kinase B (PKB/AKT), and restoring the translocation of GLUT4 from the cytoplasm to the membrane. However, pretreatment with compound C abolished these beneficial effects of GL. In conclusion, GL enhances basal glucose uptake in C2C12 myotubes and improves insulin sensitivity in palmitate-induced insulin resistant myotubes through the AMPK pathway.

Is chromium(III) pharmacologically relevant? An update focused on studies with diabetic rodent models.

A decade ago, the author assessed the status of chromium as the trivalent ion as an essential element and as a therapeutic agent based on rodent studies for this journal. The current review was undertaken to update considerations regarding the status of chromium, focusing on studies of Cr supplementation of diabetic rodent models over the last decade. Cr can no longer be considered an essential trace element for humans. Observed effects of Cr on rodent models of insulin resistance and diabetes are best interpreted in terms of a pharmacological role for Cr. The review of studies on the effects of Cr on rat models of diabetes is updated, and the results continue to suggest Cr increases insulin sensitivity in peripheral tissues of the rodent models. The lack of effects in human studies may stem from humans receiving a comparably smaller dose than the rodent models. However, given the different responses to Cr in the rodent models, humans could potentially have different responses to Cr. Recent studies primary utilizing rodents suggest two potential complementary but also contradictory modes of action for Cr(III) at a molecular level.

Centella asiatica mitigates the detrimental effects of Bisphenol-A (BPA) on pancreatic islets.

Bisphenol-A (BPA) is widely used in food packaging and household products, leading to daily human exposure and potential health risks including metabolic diseases like type 2 diabetes mellitus (T2DM). Understanding BPA's mechanisms and developing intervention strategies is urgent. Centella asiatica, a traditional herbal medicine containing pentacyclic triterpenoids, shows promise due to its antioxidant and anti-inflammatory properties, utilized for centuries in Ayurvedic therapy. We investigated the effect of Centella asiatica (CA) ethanol extract on BPA-induced pancreatic islet toxicity in male Swiss albino mice. BPA administration (10 and 100 µg/kg body weight, twice daily) for 21 days caused glucose homeostasis disturbances, insulin resistance, and islet dysfunction, which were partially mitigated by CA supplementation (200 and 400 mg/kg body weight). Additionally, heightened oxidative stress, elevated levels of proinflammatory cytokines, loss of mitochondrial membrane potential (MMP), abnormal cell cycle, and increased apoptosis were implicated in the detrimental impact of BPA on the endocrine pancreas which were effectively counteracted by CA supplementation. In summary, CA demonstrated a significant ability to mitigate BPA-induced apoptosis, modulate redox homeostasis, alleviate inflammation, preserve MMP, and regulate the cell cycle. As a result, CA emerged as a potent agent in neutralizing the diabetogenic effects of BPA to a considerable extent.

Lycium Barbarum Polysaccharides Improves Cognitive Functions in ICV-STZ-Induced Alzheimer's Disease Mice Model by Improving the Synaptic Structural Plasticity and Regulating IRS1/PI3K/AKT Signaling Pathway.

Lycium barbarum polysaccharide (LBP) have a certain curative effect on hypoglycemic and neuroprotective effects, but the specific mechanism is unclear and needs to be further explored. This study aimed to clarify the mechanisms of LBP in the treatment of ICV-STZ mice model of AD from the perspectives of insulin resistance, IRS1/PI3K/AKT signaling pathway, and synaptic protein expression. We used male C57BL/6J mice injected with STZ (3 mg/kg) in the lateral ventricle as an AD model. After treatment with LBP, the learning and memory abilities of ICV-STZ mice were enhanced, and the pathological changes in brain tissue were alleviated. LBP can regulate the expression of proteins related to the IRS1/PI3K/AKT signaling pathway and thereby reducing Aß deposition and tau protein phosphorylation in the brain of ICV-STZ mice. In addition, LBP also can up-regulate the expression of synaptic proteins. The results indicated that LBP played a neuroprotective role by regulating the IRS1/PI3K/AKT pathway, inhibiting tau protein hyperphosphorylation and improving the expression levels of synapse-related proteins.

Vitamins C, E, and ß-Carotene and Risk of Type 2 Diabetes: A Systematic Review and Meta-Analysis.

A systematic review and meta-analysis was conducted to assess the relationship between the common dietary antioxidants vitamin C, vitamin E, and ß-carotene and type 2 diabetes (T2D) and related traits. MEDLINE, Embase, and the Cochrane Library were searched for relevant publications up until May 2023. Studies were eligible if they had a cohort, case-control, or randomized controlled trial (RCT) design and examined dietary intake, supplementation, or circulating levels of these antioxidants as exposure, and insulin resistance, ß-cell function, or T2D incidence as outcomes. Summary relative risks (RR) or mean differences (MD) with 95% confidence intervals (CI) were estimated using random-effects models. The certainty of the evidence was assessed with the Grading of Recommendations, Assessment, Development and Evaluations framework. Among 6190 screened records, 25 prospective observational studies and 15 RCTs were eligible. Inverse associations were found between dietary and circulating antioxidants and T2D (observational studies). The lowest risk was seen at intakes of 70 mg/d of vitamin C (RR: 0.76; CI: 0.61, 0.95), 12 mg/d of vitamin E (RR: 0.72; CI: 0.61, 0.86), and 4 mg/d of ß-carotene (RR: 0.78; CI: 0.65, 0.94). Supplementation with vitamin E (RR: 1.01; CI: 0.93, 1.10) or ß-carotene (RR: 0.98; CI: 0.90, 1.07) did not have a protective effect on T2D (RCTs), and data on vitamin C supplementation was limited. Regarding insulin resistance, higher dietary vitamin C (RR: 0.85; CI: 0.74, 0.98) and vitamin E supplementation (MD: -0.35; CI: -0.65, -0.06) were associated with a reduced risk. The certainty of evidence was high for the associations between T2D and dietary vitamin E and ß-carotene, and low to moderate for other associations. In conclusion, moderate intakes of vitamins C, E, and ß-carotene may lower risk of T2D by reducing insulin resistance. Lack of protection with supplementation in RCTs suggests that adequate rather than high intakes may play a role in T2D prevention. This systematic review and meta-analysis was registered in PROSPERO with registration number CRD42022343482.

The Effect of Micronutrients on Obese Phenotype of Adult Mice Is Dependent on the Experimental Environment.

The environment of the test laboratory affects the reproducibility of treatment effects on physiological phenotypes of rodents and may be attributed to the plasticity of the epigenome due to nutrient-gene-environment interactions. Here, we explored the reproducibility of adding a multi-vitamin-mineral (MVM) mix to a nutrient-balanced high-fat (HF) diet on obesity, insulin resistance (IR), and gene expression in the tissues of adult male mice. Experiments of the same design were conducted in three independent animal facilities. Adult C57BL/6J male mice were fed an HF diet for 6 weeks (diet induced-obesity model) and then continued for 9-12 weeks on the HF diet with or without 5-fold additions of vitamins A, B1, B6, B12, Zn, and 2-fold Se. The addition of the MVM affected body weight, fat mass, gene expression, and markers of IR in all three locations (p < 0.05). However, the direction of the main effects was influenced by the interaction with the experimental location and its associated environmental conditions known to affect the epigenome. In conclusion, MVM supplementation influenced phenotypes and expression of genes related to adipose function in obese adult male mice, but the experimental location and its associated conditions were significant interacting factors. Preclinical studies investigating the relationship between diet and metabolic outcomes should acknowledge the plasticity of the epigenome and implement measures to reproduce studies in different locations.

Characteristics of Polycystic Ovary Syndrome: A Case Report Investigating the Role of Kapha and Pitta Doshas.

Polycystic ovary syndrome (PCOS) presents complex challenges in diagnosis and treatment due to its multifactorial nature. This case study focuses on a 31-year-old woman exhibiting symptoms of weight gain, irregular menstruation cycles, and hirsutism, leading to a diagnosis of PCOS. Conventional diagnostic criteria and ultrasound confirmation of multiple ovarian cysts supported the diagnosis. By integrating Ayurvedic principles alongside Western medical techniques, this study sought to address imbalances in the Kapha and Pitta doshas, fundamental energies according to Ayurveda, believed to contribute to PCOS symptoms. Clinical findings emphasized the role of Pitta dosha imbalance in inflammation, hormonal irregularities, and excessive body heat, while Kapha dosha imbalance manifested in fluid retention, weight gain, and increased mucus production. A holistic treatment approach was devised, aiming to restore doshic balance while addressing hormonal and metabolic dysregulation. The treatment protocol comprised lifestyle modifications, advocating for a regular exercise regimen focusing on activities enhancing insulin sensitivity and promoting weight loss. Swimming, yoga, and brisk walking were recommended to achieve these goals. Dietary interventions tailored to balance Kapha and Pitta doshas were prescribed, emphasizing nourishing, warming foods low in carbohydrates to prevent weight gain and boost metabolism. Anti-inflammatory foods, such as turmeric and ginger, were incorporated to mitigate inflammation. The integration of Ayurvedic principles alongside Western medicine offered a comprehensive approach to PCOS management, addressing both the root causes and symptoms of the condition. This personalized treatment strategy aimed not only to alleviate immediate symptoms but also to promote long-term health and well-being by restoring doshic equilibrium and optimizing hormonal and metabolic functions. In conclusion, this case study highlights the potential efficacy of combining Ayurvedic and Western medical approaches in the management of PCOS, offering a tailored and holistic treatment paradigm for patients seeking comprehensive care.

Comparison of the effects of monounsaturated fatty acids and polyunsaturated fatty acids on the lipotoxicity of islets.

Background: Monounsaturated fatty acids (MUFAs) and polyunsaturated fatty acids (PUFAs) have been reported to combat saturated fatty acid (SFA)-induced cellular damage, however, their clinical effects on patients with metabolic diseases such as diabetes and hyperlipidemia are still controversial. Since comparative studies of the effects of these two types of unsaturated fatty acids (UFAs) are still limited. In this study, we aimed to compare the protective effects of various UFAs on pancreatic islets under the stress of SFA-induced metabolic disorder and lipotoxicity. Methods: Rat insulinoma cell line INS-1E were treated with palmitic acid (PA) with or without UFAs including eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), arachidonic acid (AA), and oleic acid (OA) to determine cell viability, apoptosis, endoplasmic reticulum (ER) stress, and inflammatory. In vivo, male C57BL/6 mice were fed a 60% high-fat diet (HFD) for 12 w. Then the lard in HFD was partially replaced with fish oil (FO) and olive oil (OO) at low or high proportions of energy (5% or 20%) to observe the ameliorative effects of the UFA supplement. Results: All UFAs significantly improved PA-induced cell viability impairment in INS-1E cells, and their alleviation on PA induced apoptosis, ER stress and inflammation were confirmed. Particularly, OA had better effects than EPA, DHA, and AA on attenuating cellular ER stress. In vivo, the diets with a low proportion of UFAs (5% of energy) had limited effects on HFD induced metabolic disorder, except for a slight improved intraperitoneal glucose tolerance in obese mice. However, when fed diets containing a high proportion of UFAs (20% of energy), both the FO and OO groups exhibited substantially improved glucose and lipid metabolism, such as decrease in total cholesterol (TC), low-density lipoprotein (LDL), fasting blood glucose (FBG), and fasting blood insulin (FBI)) and improvement of insulin sensitivity evidenced by intraperitoneal glucose tolerance test (IPGTT) and intraperitoneal insulin tolerance test (IPITT). Unexpectedly, FO resulted in abnormal elevation of the liver function index aspartate aminotransferase (AST) in serum. Pathologically, OO attenuated HFD-induced compensatory hyperplasia of pancreatic islets, while this effect was not obvious in the FO group. Conclusions: Both MUFAs and PUFAs can effectively protect islet ß cells from SFA-induced cellular lipotoxicity. In particular, both OA in vitro and OO in vivo showed superior activities on protecting islets function and enhance insulin sensitivity, suggesting that MUFAs might have greater potential for nutritional intervention on diabetes.

A combination of silymarin and garlic extract enhances thyroid hormone activation and body metabolism in orally intoxicated male rats with atrazine: Impact on hepatic iodothyronine deiodinase type 1.

Atrazine is a widely applied herbicide to improve crop yield and maintain general health. It has been reported to impair thyroid function and architecture in experimental animals. Alterations in thyroid hormones disrupt normal body function and metabolism. Silymarin, a hepatoprotective flavonolignan, was found to improve thyroid function and body metabolism. Additionally, garlic displays several protective effects on body organs. Therefore, this study explored the prophylactic impact of natural compounds comprising silymarin and garlic extract on disrupted thyroid function, hepatic iodothyronine deiodinase type 1, and metabolic parameters in atrazine-intoxicated male rats. We found that daily pre- and co-treatment of atrazine-intoxicated male rats with silymarin (100 mg/kg, p.o) and/or garlic extract (10 mg/kg, p.o) significantly improved thyroid activation and hepatic functionality as evidenced by the re-establishment of T3, T3/T4, and TSH values as well as ALT and AST activities. Interestingly, individual or concurrent supplementation of the atrazine group with silymarin and garlic extract prevented the down-regulation in hepatic iodothyronine deiodinase type 1. These effects were coupled with the repletion of serum and hepatic antioxidants and the amelioration of lipid peroxidation. In addition, current natural products markedly alleviated weight gain, dyslipidemia, hyperglycemia, glucose intolerance, and insulin resistance. Notably, a cocktail of silymarin and garlic extract exerted superior protection against atrazine-triggered deterioration of thyroid, hepatic, and metabolic functioning to individual treatments. Present findings pinpoint the prophylactic and synergistic influence of silymarin and garlic extract combinatorial regimen on thyroid activation and body metabolism via enhancing antioxidant potential, maintaining hepatic function, and iodothyronine deiodinase type 1.

Hypothalamic POMC neuron-specific knockout of MC4R affects insulin sensitivity by regulating Kir2.1.

BACKGROUND: Imbalance in energy regulation is a major cause of insulin resistance and diabetes. Melanocortin-4 receptor (MC4R) signaling at specific sites in the central nervous system has synergistic but non-overlapping functions. However, the mechanism by which MC4R in the arcuate nucleus (ARC) region regulates energy balance and insulin resistance remains unclear. METHODS: The MC4Rflox/flox mice with proopiomelanocortin (POMC) -Cre mice were crossed to generate the POMC-MC4Rflox/+ mice. Then POMC-MC4Rflox/+ mice were further mated with MC4Rflox/flox mice to generate the POMC-MC4Rflox/flox mice in which MC4R is selectively deleted in POMC neurons. Bilateral injections of 200 nl of AAV-sh-Kir2.1 (AAV-sh-NC was used as control) were made into the ARC of the hypothalamus. Oxygen consumption, carbon dioxide production, respiratory exchange ratio and energy expenditure were measured by using the CLAMS; Total, visceral and subcutaneous fat was analyzed using micro-CT. Co-immunoprecipitation assays (Co-IP) were used to analyze the interaction between MC4R and Kir2.1 in GT1-7 cells. RESULTS: POMC neuron-specific ablation of MC4R in the ARC region promoted food intake, impaired energy expenditure, leading to increased weight gain and impaired systemic glucose homeostasis. Additionally, MC4R ablation reduced the activation of POMC neuron, and is not tissue-specific for peripheral regulation, suggesting the importance of its central regulation. Mechanistically, sequencing analysis and Co-IP assay demonstrated a direct interaction of MC4R with Kir2.1. Knockdown of Kir2.1 in POMC neuron-specific ablation of MC4R restored the effect of MC4R ablation on energy expenditure and systemic glucose homeostasis, indicating by reduced body weight and ameliorated insulin resistance. CONCLUSION: Hypothalamic POMC neuron-specific knockout of MC4R affects energy balance and insulin sensitivity by regulating Kir2.1. Kir2.1 represents a new target and pathway that could be targeted in obesity.

Anti-Inflammatory and Anti-Adipocyte Dysfunction Effects of Ficus lindsayana Latex and Root Extracts.

Low-grade chronic inflammation and adipocyte dysfunction are prominent risk factors of insulin resistance and type 2 diabetes mellitus (T2DM) in obesity. Thus, prevention of inflammation and adipocyte dysfunction could be one possible approach to mitigate T2DM development. Several Ficus species have been used in traditional medicine for ameliorating inflammation and T2DM. Our previous studies reported biological effects of Ficus lindsayana including antioxidant, anti-cancer, and anti-α-glucosidase activities. Further, this study therefore investigated whether F. lindsayana latex (FLLE) and root (FLRE) extracts inhibit inflammation-stimulated insulin resistance in adipocytes and inflammation in macrophages. FLLE and FLRE (200 µg/mL) had no significant cytotoxicity for macrophages, adipocytes, and blood cells (PBMCs and RBCs). FLRE had a total flavonoid content about three times higher than FLLE, while both had similar levels of total phenolic content. FLRE showed higher abilities than FLLE in suppressing inflammation in both macrophages and adipocytes and reversing the inflammation-induced insulin resistance in adipocytes. In TNF-α-induced adipocytes, FLRE significantly improved insulin-induced glucose uptake and insulin-suppressed lipolysis, while FLLE only significantly improved glucose uptake. Moreover, FLRE and FLLE remarkably reduced chemoattractant (MCP-1) but improved adipogenic (PPARγ and CEBPα) gene expression, leading to the promotion of adipogenesis and the suppression of insulin resistance. In LPS-induced macrophages, FLRE, but not FLLE, significantly inhibited LPS-induced NO production. Moreover, FLRE significantly reduced LPS-stimulated iNOS, COX-2, IL-1ß, IL-6, and TNF-α gene expression. These results may provide the potential data for the development of this plant, especially the root part, as an alternative medicine, functional ingredient, or food supplement for the prevention of inflammation and obesity-associated insulin resistance, as well as T2DM.

Compound Danshen Dripping Pill effectively alleviates cGAS-STING-triggered diseases by disrupting STING-TBK1 interaction.

BACKGROUND: The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon (IFN) genes (STING) pathway is critical in the innate immune system and can be mobilized by cytosolic DNA. The various inflammatory and autoimmune diseases progression is highly correlated with aberrant cGAS-STING pathway activation. While some cGAS-STING pathway inhibitor were identified, there are no drugs that can be applied to the clinic. Compound Danshen Dripping Pill (CDDP) has been successfully used in clinic around the world, but the most common application is limited to cardiovascular disease. Therefore, the purpose of the present investigation was to examine whether CDDP inhibits the cGAS-STING pathway and could be used as a therapeutic agent for multiple cGAS-STING-triggered diseases. METHODS: BMDMs, THP1 cells or Trex1-/- BMDMs were stimulated with various cGAS-STING-agonists after pretreatment with CDDP to detect the function of CDDP on IFN-ß and ISGs productionn. Next, we detect the influence on IRF3 and P65 nuclear translocation, STING oligomerization and STING-TBK1-IRF3 complex formation of CDDP. Additionally, the DMXAA-mediated activation mice model of cGAS-STING pathway was used to study the effects of CDDP. Trex1-/- mice model and HFD-mediated obesity model were established to clarify the efficacy of CDDP on inflammatory and autoimmune diseases. RESULTS: CDDP efficacy suppressed the IRF3 phosphorylation or the generation of IFN-ß, ISGs, IL-6 and TNF-α. Mechanistically, CDDP did not influence the STING oligomerization and IRF3-TBK1 and STING-IRF3 interaction, but remarkably eliminated the STING-TBK1 interaction, ultimately blocking the downstream responses. In addition, we also clarified that CDDP could suppress cGAS-STING pathway activation triggered by DMXAA, in vivo. Consistently, CDDP could alleviate multi-organ inflammatory responses in Trex1-/- mice model and attenuate the inflammatory disorders, incleding obesity-induced insulin resistance. CONCLUSION: CDDP is a specifically cGAS-STING pathway inhibitor. Furthermore, we provide novel mechanism for CDDP and discovered a clinical agent for the therapy of cGAS-STING-triggered inflammatory and autoimmune diseases.

Fatty liver index (FLI): more than a marker of hepatic steatosis

Fatty liver index (FLI) was developed as a simple and accurate marker of hepatic steatosis. FLI is derived from an algorithm based on body mass index, waist circumference, and levels of triglycerides and gamma-glutamyltransferase, and it is widely used in clinical and epidemiological studies as a screening tool for discriminating between healthy and nonalcoholic fatty liver disease (NAFLD) subjects. However, a systematic review of the literature regarding FLI revealed that this index has more extensive relationships with biochemical and physiological parameters. FLI is associated with key parameters of lipid, protein and carbohydrate metabolism, hormones, vitamins and markers of inflammation, or oxidative stress. FLI can be a predictor or risk factor for a number of metabolic and nonmetabolic diseases and mortality. FLI is also used as an indicator for determining the effects of health-related prevention interventions, medications, and toxic substances on humans. Although in most cases, the exact mechanisms underlying these associations have not been fully elucidated, they are most often assumed to be mediated by insulin resistance, inflammation, and oxidative stress. Thus, FLI may be a promising marker of metabolic health due to its multiple associations with parameters of physiological and pathological processes. In this context, the present review summarizes the data from currently available literature on the associations between FLI and biochemical variables and physiological functions. We believe that this review will be of interest to researchers working in this area and can provide new perspectives and directions for future studies on FLI. (AU)

Effects of Ecklonia stolonifera Extract on Metabolic Dysregulation in High-Fat Diet-Induced Obese Mice.

This study aimed to test the hypothesis that long-term and low-dose supplementation with an ethanol extract of Ecklonia stolonifera may confer protection against high-fat diet (HFD)-induced obesity in mice. Male C57BL/6J mice were divided into two groups, one of which was fed an HFD (40 kcal% fat) and the other an HFD+E. stolonifera (0.006%, w/w, ∼5 mg/kg body weight/day) for 16 weeks. E. stolonifera supplementation significantly reduced body weight from week 3 and until the end of the experiment. E. stolonifera-supplemented mice also exhibited lower fat mass (epididymal, perirenal, and mesenteric fat) and smaller adipocyte size than HFD control mice. The two groups displayed similar food intakes, but E. stolonifera markedly decreased lipogenesis and increased lipolysis and fatty acid oxidation in adipose tissue. Moreover, E. stolonifera significantly decreased plasma and hepatic lipid levels, hepatic lipid droplet accumulation, plasma aminotransferase levels, and liver weight by decreasing lipogenesis and increasing fatty acid oxidation. As E. stolonifera-supplemented mice showed improvements in hyperglycemia, insulin resistance, and inflammation, compared to control mice, it is possible that the beneficial effects of E. stolonifera on obesity might be associated with decreased inflammation and insulin resistance. Collectively, these results indicate that E. stolonifera could be used as a novel means of preventing and treating obesity and obesity-related metabolic disorders.

Pathophysiological-Based Nutritional Interventions in Cirrhotic Patients with Sarcopenic Obesity: A State-of-the-Art Narrative Review.

In recent decades, following the spread of obesity, metabolic dysfunction has come to represent the leading cause of liver disease. The classical clinical presentation of the cirrhotic patient has, therefore, greatly changed, with a dramatic increase in subjects who appear overweight or obese. Due to an obesogenic lifestyle (lack of physical activity and overall malnutrition, with an excess of caloric intake together with a deficit of proteins and micronutrients), these patients frequently develop a complex clinical condition defined as sarcopenic obesity (SO). The interplay between cirrhosis and SO lies in the sharing of multiple pathogenetic mechanisms, including malnutrition/malabsorption, chronic inflammation, hyperammonemia and insulin resistance. The presence of SO worsens the outcome of cirrhotic patients, affecting overall morbidity and mortality. International nutrition and liver diseases societies strongly agree on recommending the use of food as an integral part of the healing process in the comprehensive management of these patients, including a reduction in caloric intake, protein and micronutrient supplementation and sodium restriction. Based on the pathophysiological paths shared by cirrhosis and SO, this narrative review aims to highlight the nutritional interventions currently advocated by international guidelines, as well as to provide hints on the possible role of micronutrients and nutraceuticals in the treatment of this multifaceted clinical condition.

Glycolysis-Mediated Activation of v-ATPase by Nicotinamide Mononucleotide Ameliorates Lipid-Induced Cardiomyopathy by Repressing the CD36-TLR4 Axis.

BACKGROUND: Chronic overconsumption of lipids followed by their excessive accumulation in the heart leads to cardiomyopathy. The cause of lipid-induced cardiomyopathy involves a pivotal role for the proton-pump vacuolar-type H+-ATPase (v-ATPase), which acidifies endosomes, and for lipid-transporter CD36, which is stored in acidified endosomes. During lipid overexposure, an increased influx of lipids into cardiomyocytes is sensed by v-ATPase, which then disassembles, causing endosomal de-acidification and expulsion of stored CD36 from the endosomes toward the sarcolemma. Once at the sarcolemma, CD36 not only increases lipid uptake but also interacts with inflammatory receptor TLR4 (Toll-like receptor 4), together resulting in lipid-induced insulin resistance, inflammation, fibrosis, and cardiac dysfunction. Strategies inducing v-ATPase reassembly, that is, to achieve CD36 reinternalization, may correct these maladaptive alterations. For this, we used NAD+ (nicotinamide adenine dinucleotide)-precursor nicotinamide mononucleotide (NMN), inducing v-ATPase reassembly by stimulating glycolytic enzymes to bind to v-ATPase. METHODS: Rats/mice on cardiomyopathy-inducing high-fat diets were supplemented with NMN and for comparison with a cocktail of lysine/leucine/arginine (mTORC1 [mechanistic target of rapamycin complex 1]-mediated v-ATPase reassembly). We used the following methods: RNA sequencing, mRNA/protein expression analysis, immunofluorescence microscopy, (co)immunoprecipitation/proximity ligation assay (v-ATPase assembly), myocellular uptake of [3H]chloroquine (endosomal pH), and [14C]palmitate, targeted lipidomics, and echocardiography. To confirm the involvement of v-ATPase in the beneficial effects of both supplementations, mTORC1/v-ATPase inhibitors (rapamycin/bafilomycin A1) were administered. Additionally, 2 heart-specific v-ATPase-knockout mouse models (subunits V1G1/V0d2) were subjected to these measurements. Mechanisms were confirmed in pharmacologically/genetically manipulated cardiomyocyte models of lipid overload. RESULTS: NMN successfully preserved endosomal acidification during myocardial lipid overload by maintaining v-ATPase activity and subsequently prevented CD36-mediated lipid accumulation, CD36-TLR4 interaction toward inflammation, fibrosis, cardiac dysfunction, and whole-body insulin resistance. Lipidomics revealed C18:1-enriched diacylglycerols as lipid class prominently increased by high-fat diet and subsequently reversed/preserved by lysine/leucine/arginine/NMN treatment. Studies with mTORC1/v-ATPase inhibitors and heart-specific v-ATPase-knockout mice further confirmed the pivotal roles of v-ATPase in these beneficial actions. CONCLUSION: NMN preserves heart function during lipid overload by preventing v-ATPase disassembly.