Bibliometrics and visualization analysis of literature on male hypogonadism from 2000 to 2023: research focus and frontiers.

Male hypogonadism can seriously affect male health and fertility, yet comprehensive bibliometric and visualization analyses of research in this area have been lacking. This study aimed to examine the distribution of literature, identify research hotspots, and discern development trends in male hypogonadism by analyzing 4026 English documents published between 2000 and 2023 using bibliometric and visual analyses. The results indicated a significant increase in publications and citations related to male hypogonadism over the past two decades, with the United States, the University of Florence, Maggi M, and the Journal of Clinical Endocrinology & Metabolism recognized as the most productive and highly cited country, institution, author, and journal, respectively. The article titled "The GPR54 gene as a regulator of puberty" received the highest number of citations. The keywords were categorized into four distinct clusters, including the etiology and pathogenesis of male hypogonadism, symptoms of late-onset hypogonadism, testosterone replacement therapy and its contraindications, the correlation between male hypogonadism and metabolic syndrome (MetS), obesity, and the epidemiology of male hypogonadism. The most frequently co-occurring keywords were "hypogonadism", "testosterone", and "men", while "oxidative stress" was the most prominent burst keyword. The analysis also identified "male infertility" and "oxidative stress" as the primary burst keywords in the last five years, indicating their emerging high-interest topics. Overall, this study provides a comprehensive overview of male hypogonadism research, offering valuable insights for researchers interested in this area, including potential collaborators, current research hotspots, and future research directions.

Montelukast prevents mice against carbon tetrachloride- and methionine-choline deficient diet-induced liver fibrosis: Reducing hepatic stellate cell activation and inflammation.

AIMS: Montelukast is an antagonist of cysteinyl leukotriene receptor 1 (CysLTR1) that protects against inflammation and oxidative stress. However, the function of montelukast in liver fibrosis remains unknown. In this study, we examined whether the pharmacological inhibition of CysLTR1 could protect mice against hepatic fibrosis. MATERIALS AND METHODS: Carbon tetrachloride (CCl4) and methionine-choline deficient (MCD) diet models were used in this study. The expression of CysLTR1 in liver were detected by RT-qPCR and Western blot analysis. Liver hydroxyproline levels, fibrotic genes expression, serum biochemical indexes and inflammatory factors were used to evaluate the effect of montelukast on liver fibrosis, injury, and inflammation. In vitro, we used the RT-qPCR and Western blot analysis to assess CysLTR1 in mouse primary hepatic stellate cell (HSC) and human LX-2 cell line. The role of montelukast on HSC activation and the underlying mechaisms were determined using RT-qPCR analysis, Western blot and immunostaining assays. KEY FINDINGS: Chronic stimulation from CCl4 and MCD diet upregulated the mRNA and protein levels of CysLTR1 in the liver. Pharmacological inhibition of CysLTR1 by montelukast ameliorated liver inflammation and fibrosis in both models. Mechanistically, montelukast suppressed HSC activation by targeting the TGFß/Smad pathway in vitro. The hepatoprotective effect of montelukast was also associated with reduced liver injury and inflammation. SIGNIFICANCE: Montelukast suppressed CCl4- and MCD-induced chronic hepatic inflammation and liver fibrosis. CysLTR1 might be a therapeutic target for treating liver fibrosis.

Klotho as Potential Autophagy Regulator and Therapeutic Target.

The protein Klotho can significantly delay aging, so it has attracted widespread attention. Abnormal downregulation of Klotho has been detected in several aging-related diseases, such as Alzheimer's disease, kidney injury, cancer, chronic obstructive pulmonary disease (COPD), vascular disease, muscular dystrophy and diabetes. Conversely, many exogenous and endogenous factors, several drugs, lifestyle changes and genetic manipulations were reported to exert therapeutic effects through increasing Klotho expression. In recent years, Klotho has been identified as a potential autophagy regulator. How Klotho may contribute to reversing the effects of aging and disease became clearer when it was linked to autophagy, the process in which eukaryotic cells clear away dysfunctional proteins and damaged organelles: the abovementioned diseases involve abnormal autophagy. Interestingly, growing evidence indicates that Klotho plays a dual role as inducer or inhibitor of autophagy in different physiological or pathological conditions through its influence on IGF-1/PI3K/Akt/mTOR signaling pathway, Beclin 1 expression and activity, as well as aldosterone level, which can help restore autophagy to beneficial levels. The present review examines the role of Klotho in regulating autophagy in Alzheimer's disease, kidney injury, cancer, COPD, vascular disease, muscular dystrophy and diabetes. Targeting Klotho may provide a new perspective for preventing and treating aging-related diseases.

Roles of nuclear receptors in hepatic stellate cells.

Introduction: Hepatic stellate cells (HSCs) are essential for physiological homeostasis of the liver extracellular matrix (ECM). Excessive transdifferentiation of HSC from a quiescent to an activated phenotype contributes to disrupt this balance and can lead to liver fibrosis. Accumulating evidence has suggested that nuclear receptors (NRs) are involved in the regulation of HSC activation, proliferation, and function. Therefore, these NRs may be therapeutic targets to balance ECM homeostasis and inhibit HSC activation in liver fibrosis.Areas covered: In this review, the authors summarized the recent progress in the understanding of the regulatory role of NRs in HSCs and their potential as drug targets in liver fibrosis.Expert opinion: NRs are still potential therapy targets for inhibiting HSCs activation and liver fibrosis. However, the development of NRs agonists or antagonists to inhibit HSCs requires fully consideration of systemic effects.

Feeding-induced hepatokine, Manf, ameliorates diet-induced obesity by promoting adipose browning via p38 MAPK pathway.

Activating beige adipocytes in white adipose tissue (WAT) to increase energy expenditure is a promising strategy to combat obesity. We identified that mesencephalic astrocyte-derived neurotrophic factor (Manf) is a feeding-induced hepatokine. Liver-specific Manf overexpression protected mice against high-fat diet-induced obesity and promoted browning of inguinal subcutaneous WAT (iWAT). Manf overexpression in liver was also associated with decreased adipose inflammation and improved insulin sensitivity and hepatic steatosis. Mechanistically, Manf could directly promote browning of white adipocytes via the p38 MAPK pathway. Blockade of p38 MAPK abolished Manf-induced browning. Consistently, liver-specific Manf knockout mice showed impaired iWAT browning and exacerbated diet-induced obesity, insulin resistance, and hepatic steatosis. Recombinant Manf reduced obesity and improved insulin resistance in both diet-induced and genetic obese mouse models. Finally, we showed that circulating Manf level was positively correlated with BMI in humans. This study reveals the crucial role of Manf in regulating thermogenesis in adipose tissue, representing a potential therapeutic target for obesity and related metabolic disorders.

Inhibition of 5-Lipoxygenase in Hepatic Stellate Cells Alleviates Liver Fibrosis.

Background and Purpose: Activation of hepatic stellate cells (HSC) is a central driver of liver fibrosis. 5-lipoxygenase (5-LO) is the key enzyme that catalyzes arachidonic acid into leukotrienes. In this study, we examined the role of 5-LO in HSC activation and liver fibrosis. Main Methods: Culture medium was collected from quiescent and activated HSC for target metabolomics analysis. Exogenous leukotrienes were added to culture medium to explore their effect in activating HSC. Genetic ablation of 5-LO in mice was used to study its role in liver fibrosis induced by CCl4 and a methionine-choline-deficient (MCD) diet. Pharmacological inhibition of 5-LO in HSC was used to explore the effect of this enzyme in HSC activation and liver fibrosis. Key Results: The secretion of LTB4 and LTC4 was increased in activated vs. quiescent HSC. LTB4 and LTC4 contributed to HSC activation by activating the extracellular signal-regulated protein kinase pathway. The expression of 5-LO was increased in activated HSC and fibrotic livers of mice. Ablation of 5-LO in primary HSC inhibited both mRNA and protein expression of fibrotic genes. In vivo, ablation of 5-LO markedly ameliorated the CCl4- and MCD diet-induced liver fibrosis and liver injury. Pharmacological inhibition of 5-LO in HSC by targeted delivery of the 5-LO inhibitor zileuton suppressed HSC activation and improved CCl4- and MCD diet-induced hepatic fibrosis and liver injury. Finally, we found increased 5-LO expression in patients with non-alcoholic steatohepatitis and liver fibrosis. Conclusion: 5-LO may play a critical role in activating HSC; genetic ablation or pharmacological inhibition of 5-LO improved CCl4-and MCD diet-induced liver fibrosis.

Inhibition of the sodium-glucose co-transporter SGLT2 by canagliflozin ameliorates diet-induced obesity by increasing intra-adipose sympathetic innervation.

BACKGROUND AND PURPOSE: Inhibition of the sodium-glucose cotransporter 2 (SGLT2) induces hypoglycaemia by increasing urinary glucose excretion and increasing the use of fat. However, the underlying mechanism is poorly understood. This study was aimed to determine the effects of canagliflozin, a selective SGLT2 inhibitor, on diet-induced obesity and the underlying mechanism(s). EXPERIMENTAL APPROACH: Adult C57BL/6J male mice were fed with a standard chow diet or high-fat diet supplemented with vehicle or canagliflozin. Whole body energy expenditure was monitored by metabolic cages, noradrenaline levels were measured by HPLC, glucose uptake was measured by PET/CT, and mRNA and protein expression were measured by RT-PCR and western blotting analysis. KEY RESULTS: Mice treated with canagliflozin were resistant to high-fat diet-induced obesity and its metabolic consequences. Canagliflozin treatment decreased fat mass and increased energy expenditure via increasing thermogenesis and lipolysis in adipose tissue. Mechanistically, SGLT2 inhibition by canagliflozin elevated adipose sympathetic innervation and fat mobilization via a ß3 -adrenoceptor-cAMP-PKA signalling pathway. Finally, we showed that canagliflozin improved insulin resistance and hepatic steatosis in mice fed with a high-fat diet. CONCLUSIONS AND IMPLICATIONS: Chronic inhibition of SGLT2 increased energy consumption by increasing intra-adipose sympathetic innervation to counteract diet-induced obesity. The present study reveals a new therapeutic function for SGLT2 inhibitors in regulating energy homeostasis.

Fingolimod suppressed the chronic unpredictable mild stress-induced depressive-like behaviors via affecting microglial and NLRP3 inflammasome activation.

Depression is a common aspect of the modern lifestyle, and most patients are recalcitrant to the current antidepressants. Fingolimod (FTY720), a sphingosine analogue approved for the treatment of multiple sclerosis, has a significant neuroprotective effect on the central nervous system. The aim of this study was to determine the potential therapeutic effect of FTY720 on the behavior and cognitive function of rats exposed daily to chronic unpredictable mild stress (CUMS), and elucidate the underlying mechanisms. The 42-day CUMS modeling induced depression-like behavior as indicated by the scores of sugar water preference, forced swimming, open field and Morris water maze tests. Mechanistically, CUMS caused significant damage to the hippocampal neurons, increased inflammation and oxidative stress, activated the NF-κB/NLRP3 axis, and skewed microglial polarization to the M1 phenotype. FTY720 not only alleviated neuronal damage and oxidative stress, but also improved the depression-like behavior and cognitive function of the rats. It also inhibited NF-κB activation and blocked NLRP3 inflammasome assembly by down-regulating NLRP3, ACS and caspase-1. Furthermore, FTY720 inhibited the microglial M1 polarization markers iNOS and CD16, and promoted the M2 markers Arg-1 and CD206. This in turn reduced the levels of TNF-α, IL-6 and IL-1ß, and increased that of IL-10 in the hippocampus. In conclusion, FTY720 protects hippocampal neurons from stress-induced damage and alleviates depressive symptoms by inhibiting neuroinflammation. Our study provides a theoretical basis for S1P receptor modulation in treating depression.

The diabetes medication canagliflozin promotes mitochondrial remodelling of adipocyte via the AMPK-Sirt1-Pgc-1α signalling pathway.

The diabetes medication canagliflozin (Cana) is a sodium glucose cotransporter 2 (SGLT2) inhibitor acting by increasing urinary glucose excretion and thus reducing hyperglycaemia. Cana treatment also reduces body weight. However, it remains unclear whether Cana could directly work on adipose tissue. In the present study, the pharmacological effects of Cana and the associated mechanism were investigated in adipocytes and mice. Stromal-vascular fractions (SVFs) were isolated from subcutaneous adipose tissue and differentiated into mature adipocytes. Our results show that Cana treatment directly increased cellular energy expenditure of adipocytes by inducing mitochondrial biogenesis independently of SGLT2 inhibition. Along with mitochondrial biogenesis, Cana also increased mitochondrial oxidative phosphorylation, fatty acid oxidation and thermogenesis. Mechanistically, Cana promoted mitochondrial biogenesis and function via an Adenosine monophosphate-activated protein kinase (AMPK) - silent information regulator 1 (Sirt1) - peroxisome proliferator-activated receptor γ coactivator-1α (Pgc-1α) signalling pathway. Consistently, in vivo study demonstrated that Cana increased AMPK phosphorylation and the expression of Sirt1 and Pgc-1α. The present study reveals a new therapeutic function for Cana in regulating energy homoeostasis. ABBREVIATIONS: Ucp-1, uncoupling protein 1; cAMP, cyclic adenosine monophosphate; PKA, cAMP-dependent protein kinase A; SGLT, sodium glucose cotransporter; Cana, canagliflozin; T2DM: type 2 diabetes; Veh, vehicle; Pgc-1α, peroxisome proliferator-activated receptor γ coactivator-1α; SVFs, stromal-vascular fractions; FBS, bovine serum; Ad, adenovirus; mtDNA, mitochondrial DNA; COX2, cytochrome oxidase subunit 2; RT-PCR, real-time PCR; SDS-PAGE, sodium dodecyl sulphate-polyacrylamide gel electrophoresis; Prdm16, PR domain zinc finger protein 16; Cidea, cell death inducing DFFA-like effector A; Pgc-1ß, peroxisome proliferator-activated receptor γ coactivator-1ß; NRF1, nuclear respiratory factor 1; Tfam, mitochondrial transcription factor A; OXPHOS, oxidative phosphorylation; FAO, fatty acid oxidation; AMPK, Adenosine monophosphate-activated protein kinase; p-AMPK, phosphorylated AMPK; Sirt1, silent information regulator 1; mTOR, mammalian target of rapamycin; WAT, white adipose tissue; Fabp4, fatty acid binding protein 4; Lpl, lipoprotein lipase; Slc5a2, solute carrier family 5 member 2; ERRα, oestrogen related receptor α; Uqcrc2, ubiquinol-cytochrome c reductase core protein 2; Uqcrfs1, ubiquinol-cytochrome c reductase, Rieske iron-sulphur polypeptide 1; Cox4, cytochrome c oxidase subunit 4; Pparα, peroxisome proliferator activated receptor α; NAD+, nicotinamide adenine dinucleotide; Dio2, iodothyronine deiodinase 2; Tmem26, transmembrane protein 26; Hoxa9, homeobox A9; FCCP, carbonyl cyanide 4-(trifluoromethoxy) phenylhydrazone; Rot/AA, rotenone/antimycin A; OCR, oxygen consumption rate; Pparγ, peroxisome proliferator activated receptor γ; C/ebp, CCAAT/enhancer binding protein; LKB1, liver kinase B1; AUC, area under the cure; Vd, apparent volume of distribution.

Sirt6 in pro-opiomelanocortin neurons controls energy metabolism by modulating leptin signaling.

OBJECTIVE: Sirt6 is an essential regulator of energy metabolism in multiple peripheral tissues. However, the direct role of Sirt6 in the hypothalamus, specifically pro-opiomelanocortin (POMC) neurons, controlling energy balance has not been established. Here, we aimed to determine the role of Sirt6 in hypothalamic POMC neurons in the regulation of energy balance and the underlying mechanisms. METHODS: For overexpression studies, the hypothalamic arcuate nucleus (ARC) of diet-induced obese mice was targeted bilaterally and adenovirus was delivered by using stereotaxic apparatus. For knockout studies, the POMC neuron-specific Sirt6 knockout mice (PKO mice) were generated. Mice were fed with chow diet or high-fat diet, and body weight and food intake were monitored. Whole-body energy expenditure was determined by metabolic cages. Parameters of body composition and glucose/lipid metabolism were evaluated. RESULTS: Sirt6 overexpression in the ARC ameliorated diet-induced obesity. Conversely, selective Sirt6 ablation in POMC neurons predisposed mice to obesity and metabolic disturbances. PKO mice showed an increased fat mass and food intake, while the energy expenditure was decreased. Mechanistically, Sirt6 could modulate leptin signaling in hypothalamic POMC neurons, with Sirt6 deficiency impairing leptin-induced phosphorylation of signal transducer and activator of transcription 3. The effects of leptin on reducing food intake and body weight and leptin-stimulated lipolysis were also impaired. Moreover, Sirt6 inhibition diminished the leptin-induced depolarization of POMC neurons. CONCLUSIONS: Our results reveal a key role of Sirt6 in POMC neurons against energy imbalance, suggesting that Sirt6 is an important molecular regulator for POMC neurons to promote negative energy balance.

Montelukast Prevents Mice Against Acetaminophen-Induced Liver Injury.

Acetaminophen (APAP) is a widely used over-the-counter antipyretic and analgesic drug. Overdose of APAP is the leading cause of hospital admission for acute liver failure. Montelukast is an antagonist of cysteinyl leukotriene receptor 1 (Cysltr1), which protects from inflammation and oxidative stress. However, the function of montelukast in APAP-induced hepatotoxicity remains unknown. In this study, we examined whether pharmacological inhibition of Cystlr1 could protect mice against APAP-induced hepatic damage. We found that APAP treatment upregulated messenger RNA and protein levels of Cysltr1 both in vitro and in vivo. Pharmacological inhibition of Cysltr1 by montelukast ameliorated APAP-induced acute liver failure. The hepatoprotective effect of montelukast was associated with upregulation of hepatic glutathione/glutathione disulfide level, reduction in c-Jun-NH2-terminal kinase activation and oxidative stress. In mouse primary hepatocytes, inhibition of Cysltr1 by montelukast ameliorated the expression of inflammatory-related genes and APAP-induced cytotoxicity. We conclude that montelukast may be used to treat APAP-induced acute hepatic injury.

Mixed micelles loaded with the 5-benzylidenethiazolidine-2,4-dione derivative SKLB023 for efficient treatment of non-alcoholic steatohepatitis.

Background: SKLB023, a novel 5-benzylidenethiazolidine-2,4-dione based-derivative, specifically inhibits inducible nitric oxide synthase and shows promise for treating non-alcoholic steatohepatitis (NASH). However, its poor water solubility and low bioavailability limits its clinical use. Here the drug was loaded into phosphatidylcholine-bile salt-mixed micelles (PBMM/SKLB023) to overcome these limitations. Methods: PBMM/SKLB023 was developed using a simple co-precipitation method, and formulation parameters were optimized. The pharmacokinetics of PBMM/SKLB023 were investigated in Wistar rats, and therapeutic efficacy was assessed in a mouse model of NASH induced by a diet deficient in methionine- and choline. Results: PBMM/SKLB023 particles were 11.36±2.08 nm based on dynamic light scattering, and loading the drug into micelles improved its water solubility 300-fold. PBMM/SKLB023 inhibited proliferation and activation of HSC-T6 cells more strongly than free SKLB023. PBMM/SKLB023 showed longer mean retention time and higher bioavailability than the free drug after intravenous injection in Wistar rats. In the mouse model of NASH, PBMM/SKLB023 alleviated hepatic lipid accumulation, inflammation, and fibrosis to a significantly greater extent than free SKLB023. Conclusion: PBMM/SKLB023 shows therapeutic potential for treating NASH and liver fibrosis.

Irisin Is Controlled by Farnesoid X Receptor and Regulates Cholesterol Homeostasis.

OBJECTIVE: The aim of this study was to investigate whether the nuclear receptor farnesoid X receptor (FXR) could regulate FNDC5/Irisin expression and the role of Irisin in hyperlipidemia and atherosclerosis in ApoE-/- mice. METHODS AND RESULTS: We treated primary human hepatocytes, HepG2 cells, and Rhesus macaques with FXR agonist (CDCA, GW4064, and ivermectin). FNDC5 expression was highly induced by CDCA and GW4064 in hepatocytes, HepG2 cells, and the circulating level of Irisin increased in Rhesus macaques. Luciferase reporter and CHIP assays were used to determine whether FXR could regulate FNDC5 promoter activity. Irisin-ApoE-/- and ApoE-/- mice were used to study the metabolic function of Irisin in dyslipidemia and atherosclerosis. Irisin-ApoE-/- mice showed improved hyperlipidemia and alleviated atherosclerosis as compared with ApoE-/- mice. Irisin upregulated the expression of Abcg5/Abcg8 in liver and intestine, which increased the transport of biliary cholesterol and fecal cholesterol output. CONCLUSION: Activation of FXR induces FNDC5 mRNA expression in human and increased the circulating level of Irisin in Rhesus macaques. FNDC5/Irisin is a direct transcriptional target of FXR. Irisin may be a novel therapeutic strategy for dyslipidemia and atherosclerosis.

An integrin-based nanoparticle that targets activated hepatic stellate cells and alleviates liver fibrosis.

Activation of hepatic stellate cells (HSCs) contributes to the development of liver fibrosis. Because of a relatively small population of HSCs in the liver and the lack of specific membrane targeting proteins, HSC-targeted therapy remains a major clinical challenge. Here we first showed that a hallmark of activated HSC (aHSC) is their increased expression of integrin αvß3. Thus we established sterically stable liposomes that contain the cyclic peptides (cRGDyK) with a high affinity to αvß3 to achieve aHSC-specific delivery. Our results showed that the cRGDyK-guided liposomes were preferentially internalized by activated HSCs in vitro and in vivo, and the internalization was abolished by excess free cRGDyK or knockdown of αvß3. In contrast, quiescent HSCs, hepatocytes, Kupffer cells, sinusoidal endothelial cells, or biliary cells showed minimal uptake of the cRGDyK-guided liposomes. When loaded with the hedgehog inhibitor vismodegib, the cRGDyK-guided liposomes inhibited hedgehog pathway signaling specifically in activated HSCs. Moreover, treatment of mice with vismodegib-loaded cRGDyK-liposomes markedly inhibited the fibrogenic phenotype in bile duct ligation- or thioacetamide-treated mice. We conclude that the cRGDyK-guided liposomes can specifically target the activated HSCs, but not quiescent HSCs. This nanoparticle system showed great promise to deliver therapeutic agents to aHSC to treat liver fibrosis.

Liver-specific Sirtuin6 ablation impairs liver regeneration after 2/3 partial hepatectomy.

Sirtuin 6 (Sirt6) is an NAD+-dependent deacetylase that regulates central metabolic functions such as glucose homeostasis, fat metabolism, and cell apoptosis. However, the tissue-specific function of Sirt6 in liver regeneration remains unknown. Here, we show that liver-specific Sirt6 knockout (Sirt6LKO) impaired liver reconstitution after 2/3 partial hepatectomy, which was attributed to an alteration of cell cycle progression. Sirt6 LKO delayed hepatocyte transition into S phase during liver regeneration, as shown by the analysis of cell cycle-related proteins and the immuno staining of Ki-67 and 5-bromo-2-deoxyuridine (BrdU). The delayed cell cycle in Sirt6 LKO mice was attributed to the disruption of m-TOR and Akt activity, which is an important pro-proliferation pathway in liver regeneration. Sirt6 LKO also reduced carbon tetrachloride (CCl4 )-induced liver damage. Our results suggest that Sirt6 LKO impaired liver regeneration via delayed cell cycle and impaired m-TOR and Akt activity.

Hepatocyte-specific Sirt6 deficiency impairs ketogenesis.

Sirt6 is an NADH (NAD+)-dependent deacetylase with a critical role in hepatic lipid metabolism. Ketogenesis is controlled by a signaling network of hepatic lipid metabolism. However, how Sirt6 functions in ketogenesis remains unclear. Here, we demonstrated that Sirt6 functions as a mediator of ketogenesis in response to a fasting and ketogenic diet (KD). The KD-fed hepatocyte-specific Sirt6 deficiency (HKO) mice exhibited impaired ketogenesis, which was due to enhanced Fsp27 (fat-specific induction of protein 27), a protein known to regulate lipid metabolism. In contrast, overexpression of Sirt6 in mouse primary hepatocytes promoted ketogenesis. Mechanistically, Sirt6 repressed Fsp27ß expression by interacting with Crebh (cAMP response element-binding protein H) and preventing its recruitment to the Fsp27ß gene promoter. The KD-fed HKO mice also showed exacerbated hepatic steatosis and inflammation. Finally, Fsp27 silencing rescued hypoketonemia and other metabolic phenotypes in KD-fed HKO mice. Our data suggest that the Sirt6-Crebh-Fsp27 axis is pivotal for hepatic lipid metabolism and inflammation. Sirt6 may be a pharmacological target to remedy metabolic diseases.

SKLB023 as an iNOS inhibitor alleviated liver fibrosis by inhibiting the TGF-beta/Smad signaling pathway.

Nonalcoholic steatohepatitis (NASH)-related liver fibrosis has been suggested to be a physiological consequence of chronic hepatic injury, necrosis, inflammation and unbalanced intrahepatic lipid metabolism. Accumulated evidence demonstrates that inducible nitric oxide synthase (iNOS) is highly expressed in advanced liver fibrosis, and the knockout of iNOS inhibits the progression of hepatic fibrosis. In our previous study, (Z)-N-(3-chlorophenyl)-2-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)phenoxy)acetamide (SKLB023), a novel small-molecule inhibitor of iNOS, blocked joint inflammation and cartilage destruction in arthritis. However, the role and function of SKLB023 in liver fibrosis have not been fully elucidated. In the present study, methionine- and choline-deficient (MCD) diet-induced NASH mice and LX-2 hepatic stellate cells were chosen to investigate the pharmacological effects of SKLB023 against liver fibrosis and the associated mechanism. Our results show that SKLB023 significantly alleviated MCD diet-induced liver injury, lipid accumulation and liver fibrosis. SKLB023 could suppress the activation of hepatic stellate cells by interfering with TGF-ß/Smad pathways. Importantly, SKLB023 inhibited the level of TGF-ß1 and Smad2/3 phosphorylation by blocking the expression of iNOS. These results suggest that SKLB023 might be an effective drug candidate for the treatment of liver fibrosis.

Fat-Specific Sirt6 Ablation Sensitizes Mice to High-Fat Diet-Induced Obesity and Insulin Resistance by Inhibiting Lipolysis.

Sirt6 is an NAD+-dependent deacetylase that is involved in the control of energy metabolism. However, the tissue-specific function of Sirt6 in the adipose tissue remains unknown. In this study, we showed that fat-specific Sirt6 knockout (FKO) sensitized mice to high-fat diet-induced obesity, which was attributed to adipocyte hypertrophy rather than adipocyte hyperplasia. The adipocyte hypertrophy in FKO mice likely resulted from compromised lipolytic activity as an outcome of decreased expression of adipose triglyceride lipase (ATGL), a key lipolytic enzyme. The suppression of ATGL in FKO mice was accounted for by the increased phosphorylation and acetylation of FoxO1, which compromises the transcriptional activity of this positive regulator of ATGL. Fat-specific Sirt6 KO also increased inflammation in the adipose tissue, which may have contributed to insulin resistance in high-fat diet-fed FKO mice. We also observed that in obese patients, the expression of Sirt6 expression is reduced, which is associated with a reduction of ATGL expression. Our results suggest Sirt6 as an attractive therapeutic target for treating obesity and obesity-related metabolic disorders.

Activation of Constitutive Androstane Receptor Prevents Cholesterol Gallstone Formation.

Cholesterol gallstone disease (CGD) is one of the most common gastrointestinal diseases. Lithogenic hepatic bile secretion precedes the formation of cholesterol gallstones. Constitutive androstane receptor (CAR), a member of nuclear family, plays an important role in cholesterol and bile acid metabolism. To examine whether activation of CAR can prevent cholesterol gallstone formation, we treated C57BL6/J mice maintained on a lithogenic diet with CAR agonist 1,4-bis-[2-(3, 5-dichlorpyridyloxy)] benzene and performed bile duct cannulation to study the dynamics of biliary lipids. We report that activation of CAR decreases the biliary cholesterol concentration and prevents CGD formation. The lower biliary cholesterol level was largely attributed to suppressed Abcg5 and Abcg8 expression in CAR-activated mice. CAR activation also promoted cholesterol conversion into bile acids by increasing the expression of Cyp7a1, a rate-limiting enzyme in bile acid biosynthesis. Activation of CAR enhanced bile acid re-absorption via increasing the expression of bile acid transporters Asbt and Ostß in the ileum. The hepatic steatosis was also improved in the liver of CAR-activated mice. Furthermore, activation of CAR protected the mice against the liver X receptor α-sensitized CGD through suppressing the expression of Abcg5/8. Collectively, CAR plays an important role in maintaining the homeostasis of cholesterol, bile acids, and triglycerides levels, and it might be a promising therapeutic target for preventing or treating CGD.