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1.
Front Endocrinol (Lausanne) ; 15: 1344262, 2024.
Article in English | MEDLINE | ID: mdl-38559696

ABSTRACT

Obesity, a multifactorial disease with many complications, has become a global epidemic. Weight management, including dietary supplementation, has been confirmed to provide relevant health benefits. However, experimental evidence and mechanistic elucidation of dietary supplements in this regard are limited. Here, the weight loss efficacy of MHP, a commercial solid beverage consisting of mulberry leaf aqueous extract and Hippophae protein peptides, was evaluated in a high-fat high-fructose (HFF) diet-induced rat model of obesity. Body component analysis and histopathologic examination confirmed that MHP was effective to facilitate weight loss and adiposity decrease. Pathway enrichment analysis with differential metabolites generated by serum metabolomic profiling suggests that PPAR signal pathway was significantly altered when the rats were challenged by HFF diet but it was rectified after MHP intervention. RNA-Seq based transcriptome data also indicates that MHP intervention rectified the alterations of white adipose tissue mRNA expressions in HFF-induced obese rats. Integrated omics reveals that the efficacy of MHP against obesogenic adipogenesis was potentially associated with its regulation of PPARγ and FGFR1 signaling pathway. Collectively, our findings suggest that MHP could improve obesity, providing an insight into the use of MHP in body weight management.


Subject(s)
Hippophae , Morus , Rats , Animals , PPAR gamma/genetics , PPAR gamma/metabolism , Hippophae/metabolism , Morus/metabolism , Diet, High-Fat/adverse effects , Obesity/metabolism , Adipose Tissue, White/metabolism , Signal Transduction , Weight Loss
2.
J Nutr Biochem ; 128: 109626, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38527560

ABSTRACT

Along with the increasing prevalence of obesity worldwide, the deleterious effects of high-calorie diet are gradually recognized through more and more epidemiological studies. However, the concealed and chronic causality whitewashes its unhealthy character. Given an ingenious mechanism orchestrates the metabolic adaptation to high-fat high-fructose (HFF) diet and connive its lipotoxicity, in this study, an experimental rat/mouse model of obesity was induced and a comparative transcriptomic analysis was performed to probe the mystery. Our results demonstrated that HFF diet consumption altered the transcriptomic pattern as well as different high-calorie diet fed rat/mouse manifested distinct hepatic transcriptome. Validation with RT-qPCR and Western blotting confirmed that SREBP1-FASN involved in de novo lipogenesis partly mediated metabolic self-adaption. Moreover, hepatic ACSL1-CPT1A-CPT2 pathway involved in fatty acids ß-oxidation, played a key role in the metabolic adaption to HFF. Collectively, our findings enrich the knowledge of the chronic adaptation mechanisms and also shed light on future investigations. Meanwhile, our results also suggest that efforts to restore the fatty acids metabolic fate could be a promising avenue to fight against obesity and associated steatosis and insulin resistance challenged by HFF diet.


Subject(s)
Diet, High-Fat , Fatty Acid Synthase, Type I , Fructose , Liver , Obesity , Sterol Regulatory Element Binding Protein 1 , Transcriptome , Animals , Fructose/adverse effects , Diet, High-Fat/adverse effects , Male , Liver/metabolism , Obesity/metabolism , Sterol Regulatory Element Binding Protein 1/metabolism , Sterol Regulatory Element Binding Protein 1/genetics , Lipogenesis , Mice, Inbred C57BL , Rats , Mice , Rats, Sprague-Dawley , Fatty Acids/metabolism
3.
Chem Biodivers ; 21(3): e202301315, 2024 Mar.
Article in English | MEDLINE | ID: mdl-38189169

ABSTRACT

Thousands of years ago, humans started to use propolis because of its medicinal properties, and modern science has successfully identified several bioactive molecules within this resinous bee product. However, a natural propolis extract which has been removed the adhesive glue and preserved propolis bioactive compounds is urgently needed to maximise the therapeutic opportunities. In this study, a novel ultrafiltrate fraction from Brazilian green propolis, termed P30K, was demonstrated with anti-inflammatory properties, both in vitro and in vivo. Total flavonoids and total phenolic acids content in P30K were 244.6 mg/g and 275.8 mg/g respectively, while the IC50 value of inhibition of cyclooxygenase-2 (COX-2) was 8.30 µg/mL. The anti-inflammatory activity of P30K was furtherly corroborated in experimental models of lipopolysaccharides (LPS)-induced acute liver and lung injury. Mechanistically, integrated GC-MS and LC-MS based serum metabolomics analysis revealed that P30K modulated citrate cycle (TCA), pyruvate, glyoxylate and dicarboxylate metabolism pathways to inhibit secretion of pro-inflammatory cytokines. Results of network pharmacology and molecular docking suggested that P30K targeted catechol-O-methyltransferases (COMT), 11ß-hydroxysteroid dehydrogenases (HSD11B1), and monoamine oxidases (MAOA and MAOB) to promote cellular metabolomic rewiring. Collectively, our work reveals P30K as an efficient therapeutic agent against inflammatory conditions and its efficacy is related to metabolic rewiring.


Subject(s)
Propolis , Humans , Propolis/pharmacology , Molecular Docking Simulation , Flavonoids/pharmacology , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/therapeutic use , Brazil
4.
Aging Cell ; 23(2): e14046, 2024 Feb.
Article in English | MEDLINE | ID: mdl-37990605

ABSTRACT

A major goal of healthy aging is to prevent declining resilience and increasing frailty, which are associated with many chronic diseases and deterioration of stress response. Here, we propose a loss-or-gain survival model, represented by the ratio of cumulative stress span to life span, to quantify stress resilience at organismal level. As a proof of concept, this is demonstrated by reduced survival resilience in Caenorhabditis elegans exposed to exogenous oxidative stress induced by paraquat or with endogenous proteotoxic stress caused by polyglutamine or amyloid-ß aggregation. Based on this, we reveal that a hidden peptide ("cryptide")-AbaPep#07 (SETYELRK)-derived from abalone hemocyanin not only enhances survival resilience against paraquat-induced oxidative stress but also rescues proteotoxicity-mediated behavioral deficits in C. elegans, indicating its capacity against stress and neurodegeneration. Interestingly, AbaPep#07 is also found to increase cost-free longevity and age-related physical fitness in nematodes. We then demonstrate that AbaPep#07 can promote nuclear localization of SKN-1/Nrf, but not DAF-16/FOXO, transcription factor. In contrast to its effects in wild-type nematodes, AbaPep#07 cannot increase oxidative stress survival and physical motility in loss-of-function skn-1 mutant, suggesting an SKN-1/Nrf-dependent fashion of these effects. Further investigation reveals that AbaPep#07 can induce transcriptional activation of immune defense, lipid metabolism, and metabolic detoxification pathways, including many SKN-1/Nrf target genes. Together, our findings demonstrate that AbaPep#07 is able to boost stress resilience and reduce behavioral frailty via SKN-1/Nrf-governed transcriptional reprogramming, and provide an insight into the health-promoting potential of antioxidant cryptides as geroprotectors in aging and associated conditions.


Subject(s)
Caenorhabditis elegans Proteins , Frailty , Resilience, Psychological , Animals , Caenorhabditis elegans/metabolism , Caenorhabditis elegans Proteins/genetics , Caenorhabditis elegans Proteins/metabolism , DNA-Binding Proteins/metabolism , Longevity/genetics , Metabolic Reprogramming , Oxidative Stress/genetics , Paraquat/toxicity , Peptides/metabolism
5.
Chem Biodivers ; 21(2): e202301333, 2024 Feb.
Article in English | MEDLINE | ID: mdl-38116898

ABSTRACT

Propolis is one functional supplement with hundreds of years of usage. However, it's rarely consumed directly for its resinous property. Herein, a pre-treated process which can remove the impurity while preserve its bioactivities is needed to maximise its therapeutic opportunities. In the present study, a membrane-based ultrafiltration process was developed on a KM1812-NF experimental instrument. Using Brazilian green propolis as testing material, all experimental steps and parameters were sequentially optimized. In addition, a mathematical model was developed to fit the process. As a result, the optimum solvent was 60 % ethanol adjusted to pH 8-9, while the optimum MWCO (molecular weight cut-off) value of membrane was 30 KDa. The membrane filtration dynamic model fitted with the function y=(ax+b)/(1+cx+dx2 ). The resulting propolis ultrafiltrate from Brazilian green propolis, termed P30K, contains the similar profile of flavonoids and phenolic acids as raw propolis. Meanwhile, the ORAC (oxygen radical absorbance capacity) value of P30K is 11429.45±1557.58 µM TE/g and the IC50 value of inhibition of fluorescent AGEs (advanced glycation end products) formation is 0.064 mg/mL. Our work provides an innovative alternative process for extraction of active compounds from propolis and reveals P30K as an efficient therapeutic antioxidant.


Subject(s)
Antioxidants , Propolis , Antioxidants/pharmacology , Antioxidants/chemistry , Propolis/pharmacology , Propolis/chemistry , Flavonoids/chemistry , Ethanol/chemistry , Solvents
6.
J Biomol Struct Dyn ; : 1-17, 2023 Nov 09.
Article in English | MEDLINE | ID: mdl-37942992

ABSTRACT

Fufang Zhenzhu Tiaozhi (FTZ) capsules have been prescribed for treating glucose and lipid metabolism disorders such as type 2 diabetes mellitus (T2DM). However, the underlying mechanism remains unknown. In this study, network pharmacology and experimental verification were combined to investigate the mechanisms of FTZ in treating T2DM. A total of 176 active ingredients and 1169 corresponding targets were screened using biological databases. 598 potential targets of T2DM were retrieved from GeneCards, PharmGKB, OMIM, Drugbank, and TTD. The Venn diagram was employed to identify the 194 intersection targets, which were employed to construct the "Herb-Compound-Target" interacting networks. These common targets were also used to prepare a protein-protein interaction (PPI) network to uncover potential targets. The four core targets were docked to their corresponding targets for binding analysis. Additionally, the top-ranked poses of ingredients and the positive compounds from each protein were evaluated for stability using molecular dynamics. Our results suggest that core active ingredients such as kaempferol, luteolin, and baicalein have high binding affinity and stability with AKT1, PTGS2 (also known as COX-2), DPP4, and PAPRG. GO and KEGG analyses indicated that the treatment T2DM by FTZ might be related to different pathway like AMPK and EGFR pathways. The experimental validation results proved that kaempferol, luteolin, and baicalein could significantly inhibit the activity of DPP4 and COX-2, kaempferol and luteolin were also able to activate AKT and AMPK signaling pathway. This study further validated previous findings and enhanced our understanding of the potential effects of FTZ on T2DM.Communicated by Ramaswamy H. Sarma.

10.
Molecules ; 27(24)2022 Dec 08.
Article in English | MEDLINE | ID: mdl-36557828

ABSTRACT

Pectolinarin and linarin are two major flavone O-glycosides of Cirsium japonicum, which has been used for thousands of years in traditional Chinese medicine. Pharmacological research on pectolinarin and linarin is meaningful and necessary. Here, a process for the purification of pectolinarin and linarin from C. japonicum was established using macroporous resin enrichment followed by prep-HPLC separation. The results show the purity of pectolinarin and linarin reached 97.39% and 96.65%, respectively. The in vitro bioactivities result shows the ORAC values of pectolinarin and linarin are 4543 and 1441 µmol TE/g, respectively, meanwhile their inhibition rate of BSA-MGO-derived AGEs is 63.58% and 19.31% at 2 mg/mL, which is 56.03% and 30.73% in the BSA-fructose system, respectively. The COX-2 inhibition rate at 50 µg/mL of linarin and pectolinarin reached 55.35% and 40.40%, respectively. Furthermore, the in vivo bioassay combining of histopathologic evaluation and biochemical analysis of liver glutamic oxaloacetic transaminase, serum creatinine and TNF-α show pectolinarin can alleviate lipopolysaccharide (LPS)-induced acute liver and kidney injury in mice. Metabolomics analysis shows that pectolinarin attenuates LPS-challenged liver and kidney stress through regulating the arachidonic acid metabolism and glutathione synthesis pathways. Collectively, our work presents a solid process for pectolinarin and linarin purification and has discovered a promising natural therapeutic agent-pectolinarin.


Subject(s)
Cirsium , Mice , Animals , Lipopolysaccharides , Glycosides/pharmacology
11.
Front Microbiol ; 13: 984019, 2022.
Article in English | MEDLINE | ID: mdl-36212891

ABSTRACT

Background: The gut microbiome affects the occurrence and development of NAFLD, but its mechanism has not yet been fully elucidated. Chinese medicine is a new treatment strategy to improve NAFLD by regulating the gut microbiome. Tianhuang formula (TH) has been proved to have a lipid-lowering effect in which constituents of ginsenoside Rb1, ginsenoside Rg1, ginsenoside Rb, ginsenoside Re, and ginsenoside R1 from Panax notoginseng and berberine, palmatine, and coptisine from Coptis chinensis have low drug permeability, which results in poor intestinal absorption into the human body, and are thus able to come into contact with the gut microflora for a longer time. Therefore, it might be able to influence the gut microbial ecosystem, but it still needs to be investigated. Method: The characteristics of the gut microbiome were represented by 16S rRNA sequencing, and the metabolites in intestinal contents and liver were discovered by non-targeted metabolomics. Correlation analysis and fermentation experiments revealed the relationship between the gut microbiome and metabolites. Blood biochemical indicators, liver function indicators, and oxidation-related indicators were assayed. H&E staining and Oil Red O staining were used to analyze the characteristics of hepatic steatosis. RT-qPCR and western blotting were used to detect the expression of genes and proteins in liver tissues, and fecal microbial transplantation (FMT) was performed to verify the role of the gut microbiome. Results: Gut microbiome especially Lactobacillus reduced, metabolites such as 5-Methoxyindoleacetate (5-MIAA) significantly reduced in the liver and intestinal contents, the level of hepatic GSH and SOD reduced, MDA increased, and the protein expression of Nrf2 also reduced in NAFLD mice induced by high-fat diet (HFD). The normal diet mice transplanted with NAFLD mice feces showed oxidative liver injury, indicating that the NAFLD was closely related to the gut microbiome. TH and TH-treated mice feces both can reshape the gut microbiome, increase the abundance of Lactobacillus and the content of 5-MIAA in intestinal contents and liver, and improve oxidative liver injury. This indicated that the effect of TH improving NAFLD was related to the gut microbiome, especially Lactobacillus. 5-MIAA, produced by Lactobacillus, was proved with fermentation experiments in vitro. Further experiments proved that 5-MIAA activated the Nrf2 pathway to improve oxidative stress in NAFLD mice induced by HFD. TH reshaped the gut microbiome, increased the abundance of Lactobacillus and its metabolite 5-MIAA to alleviate oxidative stress, and improved NAFLD. Conclusion: The study has demonstrated a mechanism by which the gut microbiome modulated oxidative stress in NAFLD mice induced by HFD. The traditional Chinese medicine TH improved NAFLD by regulating the gut microbiome, and its mechanism was related to the "Lactobacillus-5-MIAA-Nrf2" pathway. It provided a promising way for the intervention of NAFLD.

12.
Apoptosis ; 27(11-12): 1004-1014, 2022 12.
Article in English | MEDLINE | ID: mdl-36103026

ABSTRACT

Cuproptosis is a newly discovered cell death induced by excessive copper in mitochondria distinct from any known forms of apoptosis. Role of cuproptosis has not been well-reported in cancer, especially in clear-cell renal cell carcinoma (ccRCC). We comprehensively interrogated cuproptotic gene signature in ccRCC by reproducing multi-omics datasets and found cuproptosis was decreased in ccRCC compared with normal kidney. Cuproptosis identified a subgroup with significantly better prognosis. Functional annotation supported increased tricarboxylic acid cycle activity and decreased hypoxia signaling corroborated by metabolomics. Cuproptotic tumors showed decreased angiogenesis but were sensitive to Sunitinib and Sorafenib. Cuproptotic level in ccRCC cell lines showed robust negative correlation with copper ionophore Elesclomol. All findings support a respiratory subtype of ccRCC identified by cuproptosis.


Subject(s)
Carcinoma, Renal Cell , Kidney Neoplasms , Humans , Carcinoma, Renal Cell/genetics , Carcinoma, Renal Cell/metabolism , Copper , Apoptosis/genetics , Kidney Neoplasms/metabolism , Sunitinib
13.
Cell Signal ; 100: 110470, 2022 Dec.
Article in English | MEDLINE | ID: mdl-36122885

ABSTRACT

Trefoil factor 3 (TFF3, also known as intestinal trefoil factor) is a small-molecule peptide containing a typical trefoil structure. TFF3 has several biological effects, such as wound healing, immune regulation, neuroprotection, and cell migration and proliferation promotion. Although TFF3 binding sites were identified in rat kidneys more than a decade ago, the specific effects of this small-molecule peptide on kidneys remain unclear. Until recently, much of the research on TFF3 in the kidney field has focused exclusively on its role as a biomarker. Notably, a large prospective randomized study of patients with 29 common clinical diseases revealed that chronic kidney disease (CKD) was associated with the highest serum TFF3 levels, which were 3-fold higher than in acute gastroenteritis, which had the second-highest levels. Examination of each stage of CKD revealed that urine and serum TFF3 levels significantly increased with the progression of CKD. These results suggest that the role of TFF3 in CKD needs further research. The present review summarizes the renal physiological expression, biological functions, and downstream signaling of TFF3, as well as the upstream events that lead to high expression of TFF3 in CKD.

14.
Zhongguo Zhong Yao Za Zhi ; 47(14): 3853-3862, 2022 Jul.
Article in Chinese | MEDLINE | ID: mdl-35850844

ABSTRACT

This study aims to explore the potential mechanism of Liangfu Pills in the treatment of functional dyspepsia(FD) based on network pharmacology and molecular docking, and verify the mechanism by animal experiment. The active components of Liangfu Pills were screened from Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(TCMSP), and the targets of Liangfu Pills were predicted by SwissTargetPrediction. The targets of FD were retrieved from GeneCards. On this basis, the common targets of the disease and the pills were yielded and the protein interaction was retrieved based on STRING. The core targets were screened out, followed by Gene Oncology(GO) term enrichment and Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment analysis with DAVID. Finally, molecular docking was carried out with the help of AutoDock Tools to predict the binding degree between the effective components of Liangfu Pills and core targets. A total of 19 active components of Liangfu Pills and 591 FD-related targets were screened out by network pharmacology, of which 253 were common targets of the disease and the prescription. Liangfu Pills was mainly involved in the biological processes of response to drug, negative regulation of transcription, positive regulation of apoptotic process, and cell surface receptor signaling pathway, and the KEGG pathways of hypoxia-inducible factor-1(HIF-1) signaling pathway, serotonergic synapse, tumor necrosis factor(TNF) signaling pathway, cyclic adenosine monophosphate(cAMP) signaling pathway, calcium signal pathway, and inflammatory mediator regulation of transient receptor potential(TRP) channels. The results of molecular docking showed that the key active components of Liangfu Pills had certain binding activity to the targets mitogen-activated protein kinase 1(MAPK1), protein kinase B(AKT1), transient receptor potential cation channel subfamily V member 1(TRPV1), 5-hydroxytryptamine receptor 1 A(HTR1 A), and 5-hydroxytryptamine receptor 2 A(HTR2 A). FD was induced in rats, and then Liangfu Pills was given to FD rats for 7 days. The results showed that Liangfu Pills could significantly relieve the symptoms of FD rats, significantly increase the expression of 5-hydroxytryptamine(5-HT), and down-regulate the expression of TRPV1. Through network pharmacology, molecular docking, and experimental verification, this study proved that Liangfu Pills improved FD through multiple components and multiple targets. The result lays a basis for further research on the mechanism and clinical application of Liangfu Pills in the treatment of FD.


Subject(s)
Drugs, Chinese Herbal , Dyspepsia , Animals , Drugs, Chinese Herbal/chemistry , Drugs, Chinese Herbal/pharmacology , Drugs, Chinese Herbal/therapeutic use , Dyspepsia/drug therapy , Medicine, Chinese Traditional , Molecular Docking Simulation , Network Pharmacology , Rats
15.
Front Immunol ; 13: 853088, 2022.
Article in English | MEDLINE | ID: mdl-35651604

ABSTRACT

Aim: The action of immune checkpoint inhibition (ICI) largely depends on antibody-dependent cellular phagocytosis (ADCP). We thus aim to develop ADCP-based ccRCC risk stratification as both prognostic and therapeutic markers of ICI. Method: Genomic data from multiple public datasets (TCGA, etc.) were integrated. A cancer-intrinsic ADCP gene set for ccRCC tailored from a recent report was constructed based on the association with prognosis, immune infiltrates, and response to ICI. Therapeutic potential was profiled using genome-drug sensitivity datasets. Results: ADCP genes were selected from a recent CRISPR/Cas9 screen report. Following a four-module panel based on clinical traits, we generated a six-gene signature (ARPC3, PHF19, FKBP11, MS4A14, KDELR3, and CD1C), which showed a strong correlation with advanced grade and stage and worsened prognosis, with a nomogram showing predictive efficacies of 0.911, 0.845, and 0.867 (AUC) at 1, 3, and 5 years, respectively. Signatures were further dichotomized, and groups with a higher risk score showed a positive correlation with tumor mutation burden, higher expressions of inhibitory checkpoint molecules, and increased antitumor immune infiltrates and were enriched for antitumor immune pathways. The high risk-score group showed better response to ICI and could benefit from TKIs of axitinib, tivozanib, or sorafenib, preferentially in combination, whereas sunitinib and pazopanib would better fit the low risk-score group. Conclusion: Here we showed a six-gene ADCP signature that correlated with prognosis and immune modulation in ccRCC. The signature-based risk stratification was associated with response to both ICI and tyrosine kinase inhibition in ccRCC.


Subject(s)
Carcinoma, Renal Cell , Kidney Neoplasms , Biomarkers, Tumor/genetics , Biomarkers, Tumor/metabolism , Carcinoma, Renal Cell/drug therapy , Carcinoma, Renal Cell/genetics , Carcinoma, Renal Cell/pathology , Humans , Kidney Neoplasms/drug therapy , Kidney Neoplasms/genetics , Kidney Neoplasms/pathology , Phagocytosis , Prognosis
16.
Mol Nutr Food Res ; 66(7): e2100950, 2022 04.
Article in English | MEDLINE | ID: mdl-35072983

ABSTRACT

SCOPE: Ample evidence supports the prominent role of gut-liver axis in perpetuating pathological networks of high-fat high-fructose (HFF) diet induced metabolic disorders, however, the molecular mechanisms are still not fully understood. Herein, this study aims to present a holistic delineation and scientific explanation for the crosstalk between the gut and liver, including the potential mediators involved in orchestrating the metabolic and immune systems. METHODS AND RESULTS: An experimental obesity-associated metaflammation rat model is induced with a HFF diet. An integrative multi-omics analysis is then performed. Following the clues illustrated by the multi-omics discoveries, putative pathways are subsequently validated by RT-qPCR and Western blotting. HFF diet leads to obese phenotypes in rats, as well as histopathological changes. Integrated omics analysis shows that there exists a strong interdependence among gut microbiota composition, intestinal metabolites, and innate immunity regulation in the liver. Some carboxylic acids may contribute to gut-liver communication. Moreover, activation of the hepatic LPS-TLR4 pathway in obesity is confirmed. CONCLUSION: HFF-intake disturbs gut flora homeostasis. Crosstalk between gut microbiota and innate immune system mediates hepatic metaflammation in obese rats, associated with LPS-TLR4 signaling pathway activation. Moreover, α-hydroxyisobutyric acid and some other organic acids may play a role as messengers in the liver-gut axis.


Subject(s)
Gastrointestinal Microbiome , Animals , Diet, High-Fat/adverse effects , Fructose/adverse effects , Gastrointestinal Microbiome/physiology , Homeostasis , Metabolome , Models, Theoretical , Obesity/etiology , Obesity/metabolism , Rats
17.
J Hepatol ; 76(2): 407-419, 2022 02.
Article in English | MEDLINE | ID: mdl-34656650

ABSTRACT

BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease worldwide. The advanced stage of NAFLD, non-alcoholic steatohepatitis (NASH), has been recognized as a leading cause of end-stage liver injury for which there are no FDA-approved therapeutic options. Glutathione S-transferase Mu 2 (GSTM2) is a phase II detoxification enzyme. However, the roles of GSTM2 in NASH have not been elucidated. METHODS: Multiple RNA-seq analyses were used to identify hepatic GSTM2 expression in NASH. In vitro and in vivo gain- or loss-of-function approaches were used to investigate the role and molecular mechanism of GSTM2 in NASH. RESULTS: We identified GSTM2 as a sensitive responder and effective suppressor of NASH progression. GSTM2 was significantly downregulated during NASH progression. Hepatocyte GSTM2 deficiency markedly aggravated insulin resistance, hepatic steatosis, inflammation and fibrosis induced by a high-fat diet and a high-fat/high-cholesterol diet. Mechanistically, GSTM2 sustained MAPK pathway signaling by directly interacting with apoptosis signal-regulating kinase 1 (ASK1). GSTM2 directly bound to the N-terminal region of ASK1 and inhibited ASK1 N-terminal dimerization to subsequently repress ASK1 phosphorylation and the activation of its downstream JNK/p38 signaling pathway under conditions of metabolic dysfunction. CONCLUSIONS: These data demonstrated that hepatocyte GSTM2 is an endogenous suppressor that protects against NASH progression by blocking ASK1 N-terminal dimerization and phosphorylation. Activating GSTM2 holds promise as a therapeutic strategy for NASH. CLINICAL TRIAL NUMBER: IIT-2021-277. LAY SUMMARY: New therapeutic strategies for non-alcoholic steatohepatitis are urgently needed. We identified that the protein GSTM2 exerts a protective effect in response to metabolic stress. Therapies that aim to increase the activity of GSTM2 could hold promise for the treatment of non-alcoholic steatohepatitis.


Subject(s)
Glutathione Transferase/pharmacology , MAP Kinase Kinase Kinase 5/antagonists & inhibitors , Non-alcoholic Fatty Liver Disease/prevention & control , Animals , Biopsy/methods , Biopsy/statistics & numerical data , Disease Models, Animal , Gene Targeting/methods , Gene Targeting/standards , Gene Targeting/statistics & numerical data , Glutathione Transferase/metabolism , Hepatocytes/metabolism , Hepatocytes/physiology , Liver/pathology , MAP Kinase Kinase Kinase 5/therapeutic use , Mice , Non-alcoholic Fatty Liver Disease/drug therapy , Sequence Analysis, RNA/methods , Sequence Analysis, RNA/statistics & numerical data
19.
J Exp Clin Cancer Res ; 40(1): 308, 2021 Sep 30.
Article in English | MEDLINE | ID: mdl-34593007

ABSTRACT

BACKGROUND: Kinases play critical role in clear-cell renal cell carcinoma (ccRCC). We aim to exploit novel kinase that is both protumorigenic and drugable in ccRCC. METHODS: Reproduction of public datasets with validation using microarray was performed to identify candidate gene. Functionality was studied using multi-omics with validation in vitro and in vivo. RESULTS: 6-Phosphofructo-2-Kinase/Fructose-2,6-Biphosphatase 4 (PFKFB4) was differentially expressed showing significantly higher expression in tumor than in normal kidney. PFKFB4 overexpression was associated with advanced tumor grade, stage and worsened prognosis. PFKFB4-knockdown significantly impaired fitness in cell proliferation, migration and wound healing. Despite being recurrently deleted on 3p, PFKFN4 mRNA remained actively transcribed by HIF1α. Metabolomics showed overexpressed PFKFB4 showed enriched metabolites in pentose phosphate pathway (PPP). Phosphoproteomics and immunoprecipitation showed PFKFB4 also phosphorylated NCOA3 which interacted with FBP1 to counteract overactive PPP flux, forming a regulatory loop. PFKFB4-knockdown overcame resistance to Sunitinib in vitro and in vivo both in xenograft and tail-vein injection murine models. CONCLUSION: We concluded PFKFB4 was associated with PPP activity and the fine-tuning of which was mediated by its phosphorylation of NCOA3. Targeting PFKFB4 held promise to combat resistance to Sunitinib.


Subject(s)
Carcinoma, Renal Cell/pathology , Gene Expression Regulation, Neoplastic/drug effects , Lung Neoplasms/secondary , Metabolome/drug effects , Pentose Phosphate Pathway/drug effects , Phosphofructokinase-2/metabolism , Sunitinib/pharmacology , Animals , Antineoplastic Agents/pharmacology , Apoptosis , Carcinoma, Renal Cell/drug therapy , Carcinoma, Renal Cell/genetics , Carcinoma, Renal Cell/metabolism , Cell Cycle , Cell Movement , Cell Proliferation , Female , Humans , Kidney Neoplasms/drug therapy , Kidney Neoplasms/genetics , Kidney Neoplasms/metabolism , Kidney Neoplasms/pathology , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Lung Neoplasms/metabolism , Male , Mice , Mice, Inbred BALB C , Mice, Nude , Middle Aged , Phosphofructokinase-2/genetics , Phosphorylation , Prognosis , Survival Rate , Tumor Cells, Cultured , Xenograft Model Antitumor Assays
20.
Aging (Albany NY) ; 13(18): 22286-22297, 2021 09 18.
Article in English | MEDLINE | ID: mdl-34536950

ABSTRACT

Adrenocortical carcinoma (ACC) is a rare but aggressive disease that lacks definitive treatment. We aim to evaluate role of ASXL1 in ACC and exploit its therapeutic merits therein. We performed in silico reproduction of datasets of the Cancer Genome Atlas (TCGA), GDSC (Genomics of Drug Sensitivity in Cancer) and Human Protein Atlas using platforms of cBioPortal, UALCAN, NET-GE, GSEA and GEPIA. Validation in ACC was performed in tissue, in vitro and in vivo using the NCI-H295R and SW-13 cells. ASXL1 was gained in over 50% of ACC cases with its mRNA overexpressed in DNA gained cases. ASXL1 overexpression was associated with recurrence and worsened prognosis in ACC. ASXL1 gain was associated with resistance to etoposide, doxorubicin and cisplatin (EDP). ASXL1 expression was positively correlated with FSCN1 expression. Targeting ASXL1 significantly impaired fitness of ACC cells, which could be in part rescued by FSCN1 overexpression. Targeting FSCN1 however could not rescue resistance to EDP induced by ASXL1 overexpression. Targeting ASXL1 sensitized ACC cells to EDP regimen but constitutive ASXL3 overexpression in SW-13 cells could induce resistance upon prolonged treatment. Functional gain of ASXL1 was common in ACC and exerted pro-tumorigenic and chemoresistance role. Targeting ASXL1 hold promise to ACC treatment.


Subject(s)
Adrenal Cortex Neoplasms/metabolism , Adrenocortical Carcinoma/metabolism , Drug Resistance, Neoplasm , Adrenal Cortex Neoplasms/drug therapy , Adrenal Cortex Neoplasms/genetics , Adrenocortical Carcinoma/drug therapy , Adrenocortical Carcinoma/genetics , Antibiotics, Antineoplastic/therapeutic use , Antineoplastic Agents/therapeutic use , Antineoplastic Agents, Phytogenic/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Cisplatin/therapeutic use , Datasets as Topic , Doxorubicin/therapeutic use , Etoposide/therapeutic use , Humans , Repressor Proteins/genetics
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