Element Binding Protein Research Articles

Exploring the inhibitory activity and mechanism on lipid production in 3T3-L1 cells by hot water extract derived from Acacia confusa flowers.

Acacia confusa Merr. (Fabaceae) (A. confusa) is a native tree species of Taiwan, commonly found in the low-altitude mountains and hilly areas of the Hengchun Peninsula. This evergreen, perennial, and large-sized tree was the focus of a study that employed various chromatographic and spectroscopic methods to analyze the hot water extract of its flowers. The analysis revealed that the major components of the extract were myricitrin, quercitrin, europetin-3-O-rhamnoside, and chalconaringenin-2'-xyloside, with respective concentrations of approximately 0.22, 0.02, 0.26, and 0.10mg/g of the flowers. Subsequent cell assays were conducted to assess the inhibitory effect of the extract on lipid synthesis in fat cells. Oil Red O staining results indicated that the extract significantly suppressed fatty acid accumulation in 3T3-L1 cells, with the most pronounced effect observed at a concentration of 180μg/ml. Furthermore, the hot water extract of A. confusa flowers was found to increase the phosphorylation of AMP-activated protein kinase (AMPK), decrease the phosphorylation of cAMP response element-binding protein (CREB), and reduce the expression of glucocorticoid receptor (GR) protein. This, in turn, inhibited the expression of downstream transcription factors such as CCAT/ehancer binding proteins α (C/EBPα), CCAT/ehancer binding proteins β (C/EBPβ), CCAT/ehancer binding proteins δ (C/EBPδ), peroxisome proliferation-actived receptor γ (PPARγ), and sterol regulatory element binding proteins-1 (SREBP-1). Consequently, the expression of lipid synthesis-related proteins acetyl-CoA carboxylase (ACC), fatty acid synthase (FAS), and fatty acid translocase (CD36) was reduced, ultimately inhibiting lipid generation. Therefore, the hot water extract of A. confusa flowers shows potential for development as a weight-loss tea.

The Effects of Warm Acupuncture on the Expression of AMPK in High-Fat Diet-Induced MAFLD Rats.

This study investigated the effects of acupuncture and warm acupuncture on the expression and mechanism of the AMP-activated protein kinase (AMPK) signalling pathway associated with lipid accumulation in the liver tissue of rats with metabolic dysfunction-associated fatty liver disease (MAFLD) induced by a high-fat diet. Sprague-Dawley rats were categorised into four groups: control (CON), untreated MAFLD (MAFLD), and two MAFLD groups treated with acupuncture (ACU) and warm acupuncture (WA). The treatment groups underwent 16 application sessions over 8 weeks at the SP9 and BL18 acupoints. We measured the expression levels of AMPK, sterol regulatory element-binding protein1 (SREBP1), acetyl-coenzyme A carboxylase (ACC), peroxisome proliferator-activated receptorα (PPARα), carnitine palmitoyltransferase1 (CPT1), and CPT2. AMPK was activated in both ACU and WA groups. WA downregulated both SREBP1 and ACC expression at the protein level, whereas the acupuncture treatment downregulated SREBP1 expression. Additionally, WA selectively induced the activation of signalling pathways related to AMPK, PPARα, CPT1, and CPT2 at the mRNA level. Histological observations confirmed that fat accumulation was reduced in both the ACU and the WA groups compared to the MAFLD group. The WA treatment-promoted amelioration of HFD-induced MAFLD may be related to the activation of the AMPK/SREBP1/ACC pathway in the liver.

GR113808, a serotonin receptor 4 antagonist, prevents high-fat-diet-induced obesity, fatty liver formation, and insulin resistance in C57BL/6J mice

BackgroundThe burden of nonalcoholic fatty liver disease is increasing, and limited therapeutic drugs are available for its treatment. Serotonin binds to approximately 14 serotonin receptors (HTR) and plays diverse roles in obesity and metabolic complications. In this study, we focused on the function of HTR4 on nonalcoholic fatty liver disease using GR113808, a selective HTR4 antagonist.MethodsMale C57BL/6J mice were fed high-fat diet for 12 weeks with intraperitoneal GR113808 injection, and HTR expression, weight changes, glucose and lipid metabolism, hepatic fat accumulation, changes in adipose tissue, the changes in transcriptional factors of signaling pathways, and inflammations were assessed. Hep3B cells and 3T3-L1 cells were treated with siRNA targeting HTR4 to downregulate its expression and then cultured with palmitate to mimic a high-fat diet. The changes in transcriptional factors of signaling pathways, and inflammations were assessed in those cells.ResultsAfter feeding a high-fat diet to male C57BL/6J mice, HTR4 expression in the liver and adipose tissues decreased. GR113808 suppressed body weight gain and improved glucose intolerance. Furthermore, GR113808 not only decreased fatty liver formation but also reduced adipose tissue size. Additionally, GR113808 reduced inflammatory cytokine serum levels and inflammasome complex formation in both tissues. Palmitate treatment in HTR4-downregulated Hep3B cells, also reduced peroxisome proliferator-activated receptor γ and sterol regulatory element-binding protein-1 pathway induction as well as inflammasome complex formation, thus decreasing inflammatory cytokine levels. HTR4 downregulation in 3T3-L1 cells also reduced palmitate-induced inflammasome complex formation and inflammatory cytokine production. Palmitate-induced insulin resistance in Hep3B cells, but not in 3T3-L1 cells, was improved by HTR4 downregulation.ConclusionsIn summary, GR113808 protected against fatty liver formation and improved inflammation in the liver and adipose tissue. Downregulation of HTR4 ameliorated insulin resistance in the liver. These results suggest that HTR4 could serve as a promising therapeutic target for metabolic diseases.

Inflammatory profile of eosinophils in asthma-COPD overlap and eosinophilic COPD: a multi-omics study.

Elevated blood eosinophil levels in patients with chronic obstructive pulmonary disease (COPD) with or without asthma are linked to increased exacerbations and the effectiveness of inhaled corticosteroid treatment. This study aimed to delineate the inflammatory cellular properties of eosinophils in patients with asthma-COPD overlap (ACO) and eosinophilic COPD (eCOPD). Eosinophils were isolated from the peripheral blood of healthy volunteers, patients with non-eCOPD, and those with ACO/eCOPD. Multi-omics analysis involving transcriptomics, proteomics, and lipidomics was performed, followed by bioinformatic data analyses. In vitro experiments using eosinophils from healthy volunteers were conducted to investigate the molecular mechanisms underlying cellular alterations in eosinophils. Proteomics and transcriptomics analyses revealed cellular characteristics in overall COPD patients represented by viral infection (elevated expression of sterol regulatory element-binding protein-1) and inflammatory responses (elevated levels of IL1 receptor-like 1, Fc epsilon receptor Ig, and transmembrane protein 176B). Cholesterol metabolism enzymes were identified as ACO/eCOPD-related factors. Gene Ontology and pathway enrichment analyses demonstrated the key roles of antiviral responses, cholesterol metabolism, and inflammatory molecules-related signaling pathways in ACO/eCOPD. Lipidomics showed the impaired synthesis of cyclooxygenase-derived mediators including prostaglandin E2 (PGE2) in ACO/eCOPD. In vitro assessment confirmed that IL-33 or TNF-α stimulation combined with IL-5 and IFN-γ stimulation induced cellular signatures in eosinophils in ACO/eCOPD. Atorvastatin, dexamethasone, and PGE2 differentially modulated these inflammatory changes. ACO/eCOPD is associated with viral infection and an inflammatory milieu. Therapeutic strategies using statins and inhaled corticosteroids are recommended to control these pathogenic changes.

Coffee Bioactive N-Methylpyridinium: Unveiling Its Antilipogenic Effects by Targeting De Novo Lipogenesis in Human Hepatocytes.

Type 2 diabetes and nonalcoholic fatty liver diseases (NAFLDs) are promoted by insulin resistance (IR), which alters lipid homeostasis in the liver. This study aims to investigate the effect of N-methylpyridinium (NMP), a bioactive alkaloid of coffee brew, on lipid metabolism in hepatocytes. The effect of NMP in modulating lipid metabolism is evaluated at physiological concentrations in a diabetes cell model represented by HepG2 cells cultured in a high-glucose medium. Hyperglycemia triggers lipid droplet accumulation in cells and enhances the lipogenic gene expression, which is transactivated by sterol regulatory element binding protein-1 (SREBP-1). Lipid droplet accumulation alters the redox status and endoplasmic reticulum (ER) stress, leading to the activation of the unfolded protein response and antioxidative pathways by X-Box Binding Protein 1(XBP-1)/eukaryotic Initiation Factor 2 alpha (eIF2α) Protein Kinase RNA-Like ER Kinase and nuclear factor erythroid 2-related factor 2 (NRF2), respectively. NMP induces the phosphorylation of AMP-dependent protein kinase (AMPK) and acetyl-CoA carboxylase α (ACACA), and improves the redox status and ER homeostasis, essential steps to reduce lipogenesis and lipid droplet accumulation. These results suggest that NMP may be beneficial for the management of T2D and NAFLD by ameliorating the cell oxidative and ER homeostasis and lipid metabolism.

The human milk oligosaccharide 3'sialyllactose reduces low-grade inflammation and atherosclerosis development in mice.

Macrophages contribute to the induction and resolution of inflammation and play a central role in chronic low-grade inflammation in cardiovascular diseases caused by atherosclerosis. Human milk oligosaccharides (HMOs) are complex unconjugated glycans unique to human milk that benefit infant health and act as innate immune modulators. Here, we identify the HMO 3'sialyllactose (3'SL) as a natural inhibitor of Toll-Like Receptor (TLR) 4-induced low-grade inflammation in macrophages and endothelium. Transcriptome analysis in macrophages revealed that 3'SL attenuates mRNA levels of a selected set of inflammatory genes and promotes the activity of Liver X Receptor (LXR) and Sterol Regulatory Element-binding Protein-1 (SREBP). These acute anti-inflammatory effects of 3'SL were associated with reduced histone H3K27 acetylation at a subset of lipopolysaccharide (LPS)-inducible enhancers distinguished by preferential enrichment for CCCTC-binding factor (CTCF), Interferon Regulatory Factor 2 (IRF2), B-cell lymphoma 6 (BCL6), and other transcription factor recognition motifs. In a murine atherosclerosis model, both subcutaneous and oral administration of 3'SL significantly reduced atherosclerosis development and the associated inflammation. This study provides evidence that 3'SL attenuates inflammation by a transcriptional mechanism to reduce atherosclerosis development in the context of cardiovascular disease.

J147 treatment protects against traumatic brain injury by inhibiting neuronal endoplasmic reticulum stress potentially via the AMPK/SREBP-1 pathway

Endoplasmic reticulum (ER) stress is recognized as a crucial contributor to the progression of traumatic brain injury (TBI) and represents a potential target for therapeutic intervention. This study aimed to assess the potential of J147, a novel neurotrophic compound, in alleviating ER stress by modulating related signaling pathways, thereby promoting functional recovery in TBI. To this end, adult mice underwent controlled cortical impact (CCI) injury to induce TBI, followed by oral administration of J147 one-hour post-injury, with daily dosing for 3 to 7 days. Multiple behavioral assessments were conducted over 35 days, revealing a significant, dose-dependent improvement in neurofunctional recovery with J147 treatment. The neuropathological analysis demonstrated reduced acute neurodegeneration (observed at three days through FJC staining), enhanced long-term neuron survival (H&E and Nissl staining), and improved neuroplasticity (Golgi staining) at 35 days post-TBI. At the molecular level, TBIinduced AMP-activated protein kinase (AMPK) dephosphorylation, sterol regulatory element binding protein-1 (SREBP-1) activation, and upregulation of ER stress marker proteins, including phosphorylated eukaryotic initiation factor-2α (p-eIF2a), activating transcription factor 4 (ATF4), and C/EBP homologous protein (CHOP) in perilesional cortex neurons at three days post-injury. Notably, the J147 treatment significantly attenuated AMPK dephosphorylation, SERBP-1 activation, and expression of the ER stress markers. In summary, this study reveals the therapeutic promise of J147 in mitigating secondary brain damage associated with TBI and improving long-term functional recovery by modulating ER stress pathways.

Analysis of expression characteristics and identification of interaction proteins of transcription factor BnaABI5 in Brassica napus.

Rapeseed is one important oil crop in China. However, its planting benefit is frequently affected by environmental stresses such as drought in the northwest region of China. The abscisic acid(ABA) signaling pathway plays an important role in plant abiotic stress response and tolerance, and ABFs/AREBs(ABA-responsive element binding factors/ABA-responsive element binding proteins) are the core transcription factors that regulate the expression of ABA-responsive genes. To dissect the key transcription factors mediated abiotic stress, we mainly characterized abscisic acid insensitive 5(BnaABI5) in rapeseed, including its subcellular localization, expression pattern in response to various stress and tissue-specific expression analysis, transcriptional activity analysis as well as interaction screening with BnaMPKs(mitogen-activated protein kinases). Our results showed that the BnaABI5-GFP fusion protein was localized in the nucleus, and its transcript level is induced by drought stress and was mainly expressed in the roots of rapeseed. Furthermore, BnaABI5 showed transcriptional activation activity through a yeast transactivation assay and it also activated the promoter activity of EM6 target gene in the transient expression system in tobacco leaves. Moreover, BnaABI5 interacted with BnaMPK6 and BnaMPK13 through BiFC and Y2H analysis. This study preliminarily explored the expression characteristics of transcription factor BnaABI5 and its interaction with BnaMPKs, which might help us for further understanding the function of BnaABI5.

Kurarinol restrains non-alcoholic fatty liver disease-associated hepatocellular carcinoma (HCC) progression by suppressing EGFR signaling

Non-alcoholic fatty liver disease (NAFLD) is a hepatic manifestation of metabolic syndrome and a key factor for hepatocellular carcinoma (HCC) development. As a metabolic hepatic damage, there is still a lack of efficient therapy for NAFLD-HCC. Kurarinol (KUR) is a flavanone extracted from the root of Sophora flavescens, and exerts excellent hepatoprotective and lipid-lowering activities. But its potential on NAFLD-HCC still remains unclear, and thus was explored in our present study. Firstly, in vitro experiments revealed that KUR treatments markedly reduced lipid deposition and inflammatory response in hepatocytes under palmitate and oleic acid stimulation (PO) with decreased expression levels of fatty acid synthesis markers including fatty acid synthase (FASN), stearoyl-CoA desaturase-1 (SCD1) and sterol receptor element binding protein-1 (SREBP-1). Importantly, the proliferation of HCC cell lines was strongly limited by KUR in a dose-dependent manner. Of note, PO stimulation accelerated the proliferative capacity of HCC cells, whereas being significantly suppressed by KUR. Mechanistically, we found that epidermal growth factor receptor (EGFR) and its phosphorylation protein expression levels were highly down-regulated in hepatocytes and HCC cell lines under PO stimuli. More importantly, the functions of KUR to restrain lipid accumulation and HCC cell proliferation were diminished upon EGFR overexpression, confirming that EGFR suppression was necessary for KUR to treat NAFLD-HCC. Murine mouse models were finally established by the use of diethylnitrosamine (DEN) with high-fat/high-cholesterol diet (HFHC) feeding to determine the role of KUR in NAFLD-HCC. Oral gavage of KUR efficiently suppressed NAFLD-HCC formation in mice, as evidenced by the decreased tumor number and loading. KUR also ameliorated lipid accumulation, liver dysfunction, fibrosis and HCC cell proliferation in DEN/HFHC-challenged mice, along with decreased EGFR expression. Collectively, KUR may be an effective strategy for NAFLD-HCC prevention via EGFR signaling suppression.

Dietary supplementation with 25-hydroxyvitamin D3 regulates productive performance, lipid metabolism and gut microbiota in aged laying ducks

The aim of this study was to investigate the effect of dietary supplementation with 25-hydroxyvitamin D3 (25(OH)D3) on productive performance, lipid metabolism and gut microbiota in aged laying ducks. A total of 432 healthy Longyan ducks at 60-week of age were randomly allotted to 6 groups, each with 6 replicates of 12 ducks. Ducks were given a basal diet (without added 25(OH)D3) or that diet supplemented with 800, 1600, 2400, 3200, or 4000 IU/kg 25(OH)D3 for a total of 16 wk. Dietary supplementation with 25(OH)D3 improved egg production, egg mass and average daily feed intake, and decreased the feed conversion ratio (FCR) of ducks during the whole trial period (linear, quadratic; P < 0.05). Supplementation with 25(OH)D3 decreased very low-density lipoprotein (VLDL) content in yolk (P = 0.008), decreased high-density lipoprotein and low-density lipoprotein (LDL) content in plasma (P = 0.002). Hepatic index, VLDL, LDL, triglyceride and total cholesterol content in liver, nonalcoholic fatty liver activity score of liver and alanine aminotransferase content in plasma were decreased with supplementation of 25(OH)D3 (linear or quadratic; P < 0.05). The decreased hepatic apolipoprotein B 100 and lipoprotein lipase expression, and increased hepatic peroxisome proliferator-activated receptor-α and sterol regulatory element binding protein-1 expression resulted from 25(OH)D3 supplementation (linear, quadratic; P < 0.05). Moreover, 25(OH)D3 supplementation increased the villus/crypt ratio (linear, quadratic; P < 0.05) and expression of zonula occludens protein 1 and nuclear factor-κ-gene binding in duodenum (P < 0.05). The supplementation of 25(OH)D3 reduced the abundance of Wittenberg polluted soil-2 bacteria, Synergistota, Bacteroidales, Colidextribacter, Eggerthellaceae, Oscillospira, Oscillibacter, UCG-009, Barnesiellaceae and Lachnospiraceae_UCG-010 in cecal contents (P < 0.05). Dietary requirements for 25(OH)D3 for ducks (60 to 76 wk), were estimated to be 3377 IU/kg for egg production, 3434 IU/kg for egg mass, and 3256 IU/kg for FCR. In summary, dietary 25(OH)D3 supplementation improved productive performance and influenced liver and plasma lipid homeostasis in aged laying ducks, which may be associated with the reduction of bacteria involved in carbohydrate metabolism in the cecum. Supplementing the basal diet with 3250 to 3450 IU/kg 25(OH)D3 is recommended for aged laying ducks (60 to 76 wk).

Effects of dietary fish oil replacement with rice bran oil on growth performance, serum biochemical index, antioxidant capacity, lipid metabolism and inflammatory response of large yellow croaker (Larimichthys crocea) juveniles

Fish oil (FO) replacement has become a top priority with the increasing growth of aquaculture and the decline of FO production. Dietary rice bran oil (RBO) has been marked with good application prospects and development potential in humans and terrestrial animals. Hence, this study was geared towards ascertaining the effects of replacing dietary FO with RBO in fish feeds. In this study, a 74-day feeding trial was conducted with large yellow croaker (Larimichthys crocea) juveniles to ascertain the effects of dietary FO replaced by different levels (0%, 25%, 50%, 75% and 100%) of RBO. Each diet was randomly fed to triplicate groups of large yellow croaker juveniles (120 fish per group) with an initial mean body weight of 13.02 ± 0.02 g. Fish fed with dietary RBO 25% showed significantly higher final body weight, weight gain rate, specific growth rate, and feed intake compared to other treatments. Also, fish fed diets with RBO showed significantly higher antioxidant capacity compared to the control. Interestingly, fish fed with RBO 25% diet showed a significantly improved serum lipid profile when compared to the control. Moreover, the hepatic mRNA expression of sterol regulatory element-binding protein-1 (srebp-1), and fatty acid synthase (fas) was significantly upregulated in RBO 25% replacement, while peroxisome proliferator-activated receptor α (pparα), was significantly suppressed in fish fed RBO 100% compared to the control. Furthermore, fish fed RBO 100% had significantly increased Interleukin-1β (il-1β), Tumour necrosis factor-α (tnf-α), and Interferon-γ (ifn-γ), and significantly decreased transcript levels of Interleukin-10 (il-10). Therefore, the results of the present study showed that RBO could promote the performance of large yellow croaker juveniles, by improving the growth indexes, serum biochemical properties, antioxidant capacity, and alleviating liver inflammation.

HPP-1S attenuates oleic acid-induced steatosis in HepG2 cells and nonalcoholic fatty liver disease in a rat model of high-fat diet-induced obesity

HPP-1S is a new polysaccharide that was isolated and purified from the gonads of sea urchins in our laboratory. The aim of this study was to investigate the therapeutic effect of the polysaccharide HPP-1S on nonalcoholic fatty liver disease (NAFLD). The results showed that HPP-1S suppressed lipid accumulation in oleic acid (OA)-treated HepG2 cells. In vivo experiments shown that treatment with HPP-1S can reduce lipid accumulation and inhibit liver damage. Further mechanistic investigation indicated that HPP-1S treatment increased the phosphorylation of AMP-activated protein kinase (AMPK). Additionally, the expression of sterol regulatory element-binding protein-1 (SREBP1) and fatty acid synthase (FAS) decreased. After treatment with HPP-1S, the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and Sirtuin 1 (SIRT1) increased. These results reveal the promising role of HPP-1S in the prevention and treatment of NAFLD. These findings contribute to the development of new therapeutic strategies for the clinical treatment of NAFLD.

Neuroanatomical evidence and a mouse calcitonin gene-related peptide model in line with human functional magnetic resonance imaging data support the involvement of peptidergic Edinger-Westphal nucleus in migraine.

The urocortin 1 (UCN1)-expressing centrally projecting Edinger-Westphal (EWcp) nucleus is influenced by circadian rhythms, hormones, stress, and pain, all known migraine triggers. Our study investigated EWcp's potential involvement in migraine. Using RNAscope in situ hybridization and immunostaining, we examined the expression of calcitonin gene-related peptide (CGRP) receptor components in both mouse and human EWcp and dorsal raphe nucleus (DRN). Tracing study examined connection between EWcp and the spinal trigeminal nucleus (STN). The intraperitoneal CGRP injection model of migraine was applied and validated by light-dark box, and von Frey assays in mice, in situ hybridization combined with immunostaining, were used to assess the functional-morphological changes. The functional connectivity matrix of EW was examined using functional magnetic resonance imaging in control humans and interictal migraineurs. We proved the expression of CGRP receptor components in both murine and human DRN and EWcp. We identified a direct urocortinergic projection from EWcp to the STN. Photophobic behavior, periorbital hyperalgesia, increased c-fos gene-encoded protein immunoreactivity in the lateral periaqueductal gray matter and trigeminal ganglia, and phosphorylated c-AMP-responsive element binding protein in the STN supported the efficacy of CGRP-induced migraine-like state. Calcitonin gene-related peptide administration also increased c-fos gene-encoded protein expression, Ucn1 mRNA, and peptide content in EWcp/UCN1 neurons while reducing serotonin and tryptophan hydroxylase-2 levels in the DRN. Targeted ablation of EWcp/UCN1 neurons induced hyperalgesia. A positive functional connectivity between EW and STN as well as DRN has been identified by functional magnetic resonance imaging. The presented data strongly suggest the regulatory role of EWcp/UCN1 neurons in migraine through the STN and DRN with high translational value.

Research on the mechanism of sea buckthorn leaf Fu tea in the treatment of hyperlipidemia

BackgroundHyperlipidemia (HLP) presents a significant challenge to global public health. Mounting evidence suggests that statins, the recommended first-line lipid-lowering agents, have significant adverse effects. Consequently, the quest for natural and efficacious alternative therapies is steadily emerging as a research priority for HLP prevention and treatment. Consumption of tea, which is rich in diverse biologically active compounds with the capacity to regulate lipid metabolism and combat obesity, has emerged as a promising alternative therapy. Sea buckthorn leaves are rich in a multitude of biologically active substances, have a hypolipidemic effect, and can be used as a raw material for tea because of their unique flavor. There is a suggestion that combining Aspergillus cristatus with tea could modify or boost the lipid-lowering active compounds present in tea, thereby increasing its efficacy in regulating lipid metabolism. ResultsSea Buckthorn Leaf Fu Tea (SBLFT) was obtained by fermentation when sea buckthorn leaves contained 42 % moisture, inoculated with Aspergillus cristatus 0.2 mL/g, and incubated for 8 d at constant temperature. Animal experiments demonstrated that SBLFT significantly inhibited body weight gain in HLP rats and reduced lipid content and serum oxidative stress. In addition, liver tissue sections and functional indices showed that SBLFT can improve liver morphology and function abnormalities. Reverse transcription-polymerase chain reaction results indicated that the expression of Liver kinase B1 (LKB1), adenosine 5‘-monophosphate (AMP)-activated protein kinase (AMPK), acetyl CoA carboxylase 1 (ACC1), and sterol-regulatory element binding protein-1 (SREBP1c) gene related to lipid metabolism was altered. ConclusionSBLFT improved HLP, specifically via promoting the expression of LKB1 in the liver of HLP rats, activating AMPK, and inhibiting ACC1 and SREBP1c expression, resulting in the inhibition of fatty acid and triglyceride synthesis-related enzymes at the transcriptional level.

Design, synthesis, and biological evaluation of (E)-3-(3-methoxy-4-substituted phenyl)-acrylic acid derivatives: Role of compound S17 in regulating lipid accumulation via AMPK activation

Non-alcoholic fatty liver disease (NAFLD) is increasingly recognized as a global public health concern characterized by excessive lipid accumulation in the liver. Ferulic acid (FA), a common foodborne phenolic acid, has been shown to reduce lipid accumulation by activating adenosine monophosphate-activated protein kinase (AMPK) and suppressing the expression of sterol regulatory element-binding protein-1 (SREBP-1). In this study, we synthesized a new class of (E)-3-(3-methoxy-4-substituted phenyl)-acrylic acid derivatives as AMPK activators. Among these derivatives, compound S17 demonstrated a more potent inhibitory effect on lipid accumulation compared to its counterparts. Specifically, S17 notably diminished intracellular triglyceride (TG) levels and the activities of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), which are indicators of liver function. In addition, S17 curtailed intracellular lipid accumulation by activating the AMPK signaling pathway and down-regulating the protein expression of SREBP-1 in free fatty acid (FFA)-induced HepG2 cells. Therefore, findings from this study strongly suggest that compound S17 may serve as a promising therapeutic candidate for the treatment of NAFLD.

Effects of a diet supplemented with polysaccharides from Pogostemon cablin on growth performance, meat quality, and antioxidant capacity in Chongren Partridge chickens.

In this study, the Pogostemon cablin polysaccharides (PCPs) were heteropolysaccharides with molecular weights of 63.17 kDa and 8.99 kDa, and their total carbohydrate content was 76.17 ± 0.23%, uronic acid content was 19.92 ± 0.42%, and protein content was 1.24 ± 0.07%. PCP is composed of arabinose, galactose, glucose, and glucuronic acid, with a molar ratio of 0.196:0.249:0.451:0.104. In addition, we further investigated the effects of the diet supplemented with different doses of PCP on growth performance, meat quality, and anti-oxidant capacity in Chongren Partridge chickens. A total of 200 chickens were randomly allocated into 4 treatments, and fed with a basal diet of 0 (CON), 200 (LPCP), 400 (MPCP), and 800 (HPCP) mg/kg PCP for a 14-day prefeeding period and a formal experimental period of 56 days. Results showed that dietary PCP significantly increased final body weight (BW), average daily gain (ADG), and decreased feed-to-gain ratio (F/G) from days 1 to 56. Meanwhile, dietary PCP reduced yellowness (b∗) values and increased redness (a∗) values at 24 h in breast muscles (p < 0.05). Furthermore, LPCP and MPCP significantly increased the level of guanylic acid (GMP) (p < 0.05). MPCP increased the content of free amino acids (isoleucine, leucine, lysine, methionine, threonine, valine, alanine, glutamic acid, serine, cysteine), total essential amino acid (EAA), total flavor amino acid (FAA), total AA, the content of fatty acids (c14:1, c16:1, and c22:2), and monounsaturated fatty acids (MUFAs) in the breast muscle when compared to CON (p < 0.05). In addition, MPCP significantly reduced the content of malondialdehyde (MDA) and increased the transcript abundances of fatty acid desaturase 2 (FADS2), fatty acid synthase (FAS), lipoprotein lipase (LPL), and sterol regulatory element binding protein-1 (SREBP-1) in the breast muscles of the chickens (p < 0.05). In light of the aforementioned results, PCP at 400 mg/kg could be used as an effective additive because it not only promotes the growth performance of Chongren Partridge chickens but also shows a conducive role in meat quality, especially in meat flavor.

Exercise, mTOR Activation, and Potential Impacts on the Liver in Rodents.

The literature offers a consensus on the association between exercise training (ET) protocols based on the adequate parameters of intensity and frequency, and several adaptive alterations in the liver. Indeed, regular ET can reverse glucose and lipid metabolism disorders, especially from aerobic modalities, which can decrease intrahepatic fat formation. In terms of molecular mechanisms, the regulation of hepatic fat formation would be directly related to the modulation of the mechanistic target of rapamycin (mTOR), which would be stimulated by insulin signaling and Akt activation, from the following three different primary signaling pathways: (I) growth factor, (II) energy/ATP-sensitive, and (III) amino acid-sensitive signaling pathways, respectively. Hyperactivation of the Akt/mTORC1 pathway induces lipogenesis by regulating the action of sterol regulatory element binding protein-1 (SREBP-1). Exercise training interventions have been associated with multiple metabolic and tissue benefits. However, it is worth highlighting that the mTOR signaling in the liver in response to exercise interventions remains unclear. Hepatic adaptive alterations seem to be most outstanding when sustained by chronic interventions or high-intensity exercise protocols.

Network pharmacology combined with molecular docking and molecular dynamic simulation to reveal the potential mechanism of lentinan ameliorating hyperlipidemia

Hyperlipidemia is closely related to multiple diseases and is characterized by abnormal serum lipid profiles. The biological function of lentinan in mice and rats was studied, but the mechanism of its lipid-lowering effect was not completely clear. In this study, network pharmacological analysis, molecular docking, and molecular dynamics simulation were used to explore the potential mechanism of its lipid-lowering effect and high-fat diet (HFD) mice was used to confirm the predicted mechanism. Our results indicated that lentinan could ameliorate hyperlipidemia by regulating peroxisome proliferator-activated receptors (PPARs), sterol response element-binding protein-1 (SREBP1), and nuclear factor kappa-B (NF-κB) in the hepatic tissues of mices. Further animal experiment showed that lentinan could regulate the mRNA expressions of lipid metabolism-related genes, such as PPARα, PPARδ, PPARγ, cluster of differentiation 36 (CD36) and SREBP-1c. Moreover, lentinan supplementation could reduce the expressions of inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and inducible nitric oxide sythase (iNOS). In cell model, lentinan also could inhibit oleic acid-induced lipid droplet formation and the expressions of lipid metabolism-related genes and reduced inflammatory factor expressions in HepG2 cells, which further approved the results of animal experiment. Taken together, our results suggest that lentinan can ameliorate hyperlipidemia via regulating lipid metabolism-related gene expressions and reduce obesity-induced inflammatory response.

Discovery of Novel Binders to Sterol Regulatory Element-Binding Protein-1 by High-Throughput Screening.

Sterol regulatory element-binding protein-1 (SREBP-1) is a transcription factor that regulates the expression of genes related to fatty acid biosynthesis. Its high expression and activation in obesity and associated metabolic diseases make it a potential therapeutic target. However, the role of SREBP-1 in the development and exacerbation of these diseases remains unclear, partly because of the impossibility of inhibiting its function because of the lack of specific inhibitors. Here, we aimed to identify small-molecule compounds that directly bind to SREBP-1 using the recombinant N-terminal region of SREBP-1a, which is required for its transcriptional activity. A high-throughput screening campaign was conducted using a thermal shift assay and surface plasmon resonance assay to evaluate the compound affinity and specificity, which resulted in the identification of two compounds. Future analysis of their structure-activity relationships may lead to the development of specific SREBP-1 inhibitors, thereby potentially validating SREBP-1 as a therapeutic target for obesity and resultant atherosclerotic diseases.

Glucagon-like peptide-1 analog liraglutide reduces fat deposition in chicken adipocytes

Previously, we reported that glucagon-like peptide-1 (GLP-1) and its analog liraglutide could inhibit fat de novo synthesis in the liver and reduce abdominal fat accumulation in broiler chickens. Nevertheless, the impact of GLP-1 on adipocyte fat deposition remains enigmatic. This study aimed to investigate the effects of GLP-1, via its analog liraglutide, on chicken chicken adipocytes in vitro. Chemical assays, quantitative real-time polymerase chain reaction (qRT-PCR), and western blot were employed to assess the proliferation, differentiation, and fat deposition of chicken adipocytes. Our findings indicated that liraglutide significantly suppressed cell proliferation and promoted preadipocyte differentiation in comparison to the control group. This was evidenced by elevated triglyceride (TG) content and upregulated mRNA expression of lipogenesis-related enzymes, such as acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS), as well as regulators including peroxisome proliferator-activated receptor γ (PPARγ), sterol regulatory element binding protein-1 (SREBP1) and CCAAT/enhancer binding protein α (CEBPα). In mature adipocytes, liraglutide attenuated fat deposition by inhibiting fat de novo synthesis, evidenced by decreased mRNA expression of ACC, FAS, PPARγ, C/EBPα, and SREBP1, and concurrent upregulation of phosphorylated AMP-activated protein kinase (p-AMPK) and phosphorylated ACC (p-ACC). This resulted in reduced accumulation of lipid droplets and TG content in mature adipocytes. Collectively, our findings indicate that liraglutide suppresses the proliferation of preadipocytes, enhances their differentiation, and concurrently inhibits de novo lipogenesis in mature adipocytes. This observation offers profound insights into the mechanisms that underlie liraglutide's anti-adipogenic effects, which could have significant implications for the treatment of obesity in broiler chickens.