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Cell Death Discovery Jan 2024Liver metastasis is the major reason for most of colorectal cancer (CRC) related deaths. Accumulating evidence indicates that CRC patients with non-alcoholic fatty liver...
Liver metastasis is the major reason for most of colorectal cancer (CRC) related deaths. Accumulating evidence indicates that CRC patients with non-alcoholic fatty liver disease (NAFLD) are at a greater risk of developing liver metastasis. With the growing prevalence of NAFLD, a better understanding of the molecular mechanism in NAFLD-driven CRC liver metastasis is needed. In this study, we demonstrated that NAFLD facilitated CRC liver metastasis as a metabolic disorder and promoted the stemness of metastatic CRC cells for their colonization and outgrowth in hepatic niches. Metabolically, the lipid-rich microenvironment in NAFLD activated de novo palmitate biosynthesis in metastatic CRC cells via upregulating fatty acid synthase (FASN). Moreover, increased intracellular palmitate bioavailability promoted EGFR palmitoylation to enhance its protein stability and plasma membrane localization. Furthermore, we demonstrated that the FDA-approved FASN inhibitor orlistat could reduce NAFLD-activated endogenous palmitate production, thus inhibiting palmitoylation of EGFR to suppress CRC cell stemness and restrict liver metastasis in synergy with conventional chemotherapy. These findings reveal that the NAFLD metabolic microenvironment boosts endogenous palmitate biosynthesis in metastatic CRC cells and promotes cell stemness via EGFR palmitoylation, and FASN inhibitor orlistat could be a candidate adjuvant drug to suppress liver metastasis in CRC patients with NAFLD.
PubMed: 38263401
DOI: 10.1038/s41420-023-01770-x -
BioRxiv : the Preprint Server For... Jan 2024Malaria, caused by remains a significant health burden. A barrier for developing anti-malarial drugs is the ability of the parasite to rapidly generate resistance. We...
Malaria, caused by remains a significant health burden. A barrier for developing anti-malarial drugs is the ability of the parasite to rapidly generate resistance. We demonstrated that Salinipostin A (SalA), a natural product, kills parasites by inhibiting multiple lipid metabolizing serine hydrolases, a mechanism with a low propensity for resistance. Given the difficulty of employing natural products as therapeutic agents, we synthesized a library of lipidic mixed alkyl/aryl phosphonates as bioisosteres of SalA. Two constitutional isomers exhibited divergent anti-parasitic potencies which enabled identification of therapeutically relevant targets. We also confirm that this compound kills parasites through a mechanism that is distinct from both SalA and the pan-lipase inhibitor, Orlistat. Like SalA, our compound induces only weak resistance, attributable to mutations in a single protein involved in multidrug resistance. These data suggest that mixed alkyl/aryl phosphonates are a promising, synthetically tractable anti-malarials with a low-propensity to induce resistance.
PubMed: 38260474
DOI: 10.1101/2024.01.11.575224 -
Pharmaceuticals (Basel, Switzerland) Jan 2024Orlistat (ORL) is an effective irreversible inhibitor of the lipase enzyme, and it possesses anticancer effects and limited aqueous solubility. This study was designed...
Fabrication of Nanocrystals for Enhanced Distribution of a Fatty Acid Synthase Inhibitor (Orlistat) as a Promising Method to Relieve Solid Ehrlich Carcinoma-Induced Hepatic Damage in Mice.
BACKGROUND
Orlistat (ORL) is an effective irreversible inhibitor of the lipase enzyme, and it possesses anticancer effects and limited aqueous solubility. This study was designed to improve the aqueous solubility, oral absorption, and tissue distribution of ORL via the formulation of nanocrystals (NCs).
METHODS
ORL-NC was prepared using the liquid antisolvent precipitation method (bottom-up technology), and it demonstrated significantly improved solubility compared with that of the blank crystals (ORL-BCs) and untreated ORL powder. The biodistribution and relative bioavailability of ORL-NC were investigated via the radiolabeling technique using Technetium-99m (Tc). Female Swiss albino mice were used to examine the antitumor activity of ORL-NC against solid Ehrlich carcinoma (SEC)-induced hepatic damage in mice.
RESULTS
The prepared NCs improved ORL's solubility, bioavailability, and tissue distribution, with evidence of 258.70% relative bioavailability. In the in vivo study, the ORL-NC treatment caused a reduction in all tested liver functions (total and direct bilirubin, AST, ALT, and ALP) and improved modifications in liver sections that were marked using hematoxylin and eosin staining (H&E) and immunohistochemical staining (Ki-67 and ER-α) compared with untreated SEC mice.
CONCLUSIONS
The developed ORL-NC could be considered a promising formulation approach to enhance the oral absorption tissue distribution of ORL and suppress the liver damage caused by SEC.
PubMed: 38256929
DOI: 10.3390/ph17010096 -
Foods (Basel, Switzerland) Jan 2024Fu tea is receiving increasing attention for its specific aroma, flavor, and dramatic functional benefits. Herein, we explored the effects and underlying mechanisms of...
Fu tea is receiving increasing attention for its specific aroma, flavor, and dramatic functional benefits. Herein, we explored the effects and underlying mechanisms of Fu loose tea (FLT), Fu brick tea (FBT), and diet pills (orlistat) on a high-fat diet (HFD)-induced obesity. The results indicated that FLT and FBT administration effectively inhibited weight gain, glucose metabolic dysregulation, fat accumulation in organs, hepatic and kidney injury, and oxidative stress induced by HFD. Additionally, FLT and FBT treatments improved the lipid profiles and reduced the production of proinflammatory cytokines by regulating the expression levels of lipid metabolism- and inflammation-related genes. Furthermore, FLT and FBT ameliorated the gut microbiota dysbiosis in HFD-mice in a dose-dependent relationship by increasing the abundance of family Verrucomicrobiaceae and genus and and simultaneously reducing the abundance of family Erysipelotrichaceae and genus ; in contrast, orlistat did not exert a regulatory effect on gut microbiota similar to FLT and FBT to improve HFD-induced obesity. KEGG analysis of gut microbiota annotation revealed that "metabolism" was the most enriched category. This study further provides a theoretical basis for FLT and FBT to be potential supplements to alleviate diet-induced obesity.
PubMed: 38254507
DOI: 10.3390/foods13020206 -
Archiv Der Pharmazie Apr 2024A series of 1,1'-biphenyl-3-carboxamide and furan-phenyl-carboxamide analogs were synthesized using an optimized scheme and confirmed by H and C nuclear magnetic...
A series of 1,1'-biphenyl-3-carboxamide and furan-phenyl-carboxamide analogs were synthesized using an optimized scheme and confirmed by H and C nuclear magnetic resonance and high-resolution mass spectrometry techniques. The synthesized peptidomimetics analogs were screened in vitro to understand the inhibitory potential of pancreatic lipase (PL). Analogs were assessed for the PL inhibitory activity based on interactions, geometric complementarity, and docking score. Among the synthesized analogs, 9, 29, and 24 were found to have the most potent PL inhibitory activity with IC values of 3.87, 4.95, and 5.34 µM, respectively, compared to that of the standard drug, that is, orlistat, which inhibits PL with an IC value of 0.99 µM. The most potent analog, 9, exhibited a competitive-type inhibition with an inhibition constant (K) of 2.72 µM. In silico molecular docking of analog 9 with the PL (PDB ID:1LPB) showed a docking score of -11.00 kcal/mol. Analog 9 formed crucial hydrogen bond interaction with Ser152, His263, π-cation interaction with Asp79, Arg256, and π-π stacking with Phe77, Tyr114 at the protein's active site. The molecular dynamic simulation confirmed that analog 9 forms stable interactions with PL at the end of 200 ns with root mean square deviation values of 2.5 and 6 Å. No toxicity was observed for analog 9 (concentration range of 1-20 µM) when tested by MTT assay in RAW 264.7 cells.
Topics: Humans; Structure-Activity Relationship; Peptidomimetics; Molecular Docking Simulation; Lipase; Obesity; Enzyme Inhibitors
PubMed: 38251950
DOI: 10.1002/ardp.202300503 -
The Journal of Nutrition Mar 2024A high incidence of obesity and surplus body fat has been observed in wealthy countries for many decades. It is generally recognized that these excesses contribute to...
A high incidence of obesity and surplus body fat has been observed in wealthy countries for many decades. It is generally recognized that these excesses contribute to serious disease states, including type 2 diabetes and cardiovascular diseases. On the other hand, the adipose tissue stores relatively safely many environmental lipophilic toxins. However, rapid weight loss mobilizes these toxins to the blood to be exposed to vital organs, such as the brain, lungs, and others. With the introduction of potent diabetic drugs causing rapid weight reduction, the question of mobilization of lipophilic toxins to the blood should be considered. In this commentary, we raised this mobilization of adipose tissue toxins to the readers. Also, we discussed how these toxins may be eliminated from the body through the use of nondigestible fat, such as olestra or lipase inhibitors, such as Xenical.
Topics: Humans; Diabetes Mellitus, Type 2; Obesity; Adipose Tissue; Orlistat; Weight Loss; Body Weight
PubMed: 38244860
DOI: 10.1016/j.tjnut.2024.01.018 -
Journal of Ethnopharmacology Apr 2024Irvingia gabonensis (Aubry-Lecomte ex O'Rorke) Baill., also known as "African mango" or "bush mango", belonging to family Irvingiaceae, has been mostly used as food and...
A mechanistic exploration of the metabolome of African mango seeds and its potential to alleviate cognitive impairment induced by high-fat/high-carbohydrate diets: Involvement of PI3K/AKT/GSK-3β/CREB, PERK/CHOP/Bcl-2, and AMPK/SIRT-1/mTOR Axes.
ETHNOPHARMACOLOGICAL RELEVANCE
Irvingia gabonensis (Aubry-Lecomte ex O'Rorke) Baill., also known as "African mango" or "bush mango", belonging to family Irvingiaceae, has been mostly used as food and traditional medicine for weight loss and to enhance the health.
AIM OF THE STUDY
The overconsumption of high-fat and high-carbohydrate (HFHC) food induces oxidative stress, leading to neurological and cognitive dysfunction. Consequently, there is an immediate need for effective treatment. Hence, this study explored the efficacy of orlistat, metformin, and I. gabonensis seeds' total aqueous extract (IG SAE) in addressing HFHC-induced cognitive impairment by mitigating oxidative stress and their underlying mechanistic pathways.
MATERIALS AND METHODS
Initially, the secondary metabolite profile of IG SAE is determined using high-performance liquid chromatography coupled with a mass detector (UHPLC/MS). The in vivo study involves two phases: an established model phase with control (10 rats on a standard diet) and HFHC diet group (50 rats) for 3 months. In the study phase, HFHC is divided into 5 groups. The first subgroup receives HFHC diet only, while the remaining groups each receive HFHC diet with either Orlistat, metformin, or IG SAE at doses of 100 mg/kg and 200 mg/kg, respectively, for 28 days.
RESULTS
More than 150 phytoconstituents were characterized for the first holistic approach onto IG metabolome. Characterization of IG SAE revealed that tannins dominate metabolites in the plant. Total phenolics and flavonoids were estimated to standardize our extract (77.12 ± 7.09 μg Gallic acid equivalent/mg extract and 8.039 ± 0.53 μg Rutin equivalent/mg extract, respectively). Orlistat, metformin, and IG SAE successfully reduced the body weight, blood glucose level, lipid profile, oxidative stress and neurotransmitters levels leading to improved behavioral functions as well as histological alternation. Also, IG SAE halted inflammation, apoptosis, and endoplasmic reticulum stress, together with promoting autophagy, via modulation of PI3K/AKT/GSK-3β/CREB, PERK/CHOP/Bcl-2 and AMPK/SIRT-1/m-TOR pathways.
CONCLUSION
Metformin, orlistat, and IG SAE offer a promising multi-target therapy to mitigate HFHC diet-induced oxidative stress, addressing cognitive function. This involves diverse molecular mechanisms, particularly the modulation of inflammation, ER stress, and both PI3K/AKT/GSK-3β/CREB and AMPK/SIRT-1/m-TOR pathways. Furthermore, the higher dose of IG SAE demonstrated effects comparable to orlistat and metformin across most studied parameters.
Topics: Rats; Animals; Proto-Oncogene Proteins c-akt; Glycogen Synthase Kinase 3 beta; AMP-Activated Protein Kinases; Phosphatidylinositol 3-Kinases; Orlistat; Mangifera; TOR Serine-Threonine Kinases; Cognitive Dysfunction; Seeds; Metformin; Inflammation; Metabolome; Diet
PubMed: 38218500
DOI: 10.1016/j.jep.2024.117747 -
Phytochemistry Mar 2024Ten previously undescribed compounds were isolated from the fruits of Amomum tsao-ko (Zingiberaceae), including nine undescribed flavanol-fatty alcohol hybrids (1-6,...
Ten previously undescribed compounds were isolated from the fruits of Amomum tsao-ko (Zingiberaceae), including nine undescribed flavanol-fatty alcohol hybrids (1-6, 10-11, 13), and a flavanol-monoterpenoid hybrid (14), along with seven known flavanol hybrids (7-9, 12, 15-17). The structures of these compounds were determined using various analyses, such as HRESIMS, 1D/2D NMR, and ECD calculations. In terms of biological activity, compounds 1, 2, 5, and 6 exhibited inhibitions of human pancreatic lipase (HPL), with IC values ranging from 0.017 to 0.193 mM. Some of these values were found to be stronger than that of the positive control, orlistat (IC, 0.067 mM). Molecular docking studies were also conducted to investigate the interactions between these compounds and HPL. The docking simulations revealed the importance of the orientation of the 3,4-dihydroxyphenyl in binding with HPL. Additionally, compound 9 demonstrated cytotoxicity against HepG2, with a CC value of 14.96 ± 0.62 μM as determined by the MTT assay. Flow cytometry analysis indicated that compound 9 induced apoptosis in HepG2 cells. Western blot results showed an up-regulation of apoptosis-related proteins, such as p53 protein, Bax and Caspase-3 proteins, while the expression of Bcl-2 protein was down-regulated.
Topics: Humans; Amomum; Fatty Alcohols; Molecular Docking Simulation; Fruit; Lipase
PubMed: 38215812
DOI: 10.1016/j.phytochem.2024.113982 -
Gut Jun 2024Whether and how the PI3K-AKT pathway, a central node of metabolic homeostasis, is responsible for high-fat-induced non-alcoholic steatohepatitis (NASH) and...
OBJECTIVE
Whether and how the PI3K-AKT pathway, a central node of metabolic homeostasis, is responsible for high-fat-induced non-alcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC) remain a mystery. Characterisation of AKT regulation in this setting will provide new strategies to combat HCC.
DESIGN
Metabolite library screening disclosed that palmitic acid (PA) could activate AKT. In vivo and in vitro palmitoylation assay were employed to detect AKT palmitoylation. Diverse cell and mouse models, including generation of and knock-in cells, and knockout mice and knock-in mice were employed. Human liver tissues from patients with NASH and HCC, hydrodynamic transfection mouse model, high-fat/high-cholesterol diet (HFHCD)-induced NASH/HCC mouse model and high-fat and methionine/choline-deficient diet (HFMCD)-induced NASH mouse model were also further explored for our mechanism studies.
RESULTS
By screening a metabolite library, PA has been defined to activate AKT by promoting its palmitoyl modification, an essential step for growth factor-induced AKT activation. Biologically, a high-fat diet could promote AKT kinase activity, thereby promoting NASH and liver cancer. Mechanistically, palmitoyl binding anchors AKT to the cell membrane in a PIP3-independent manner, in part by preventing AKT from assembling into an inactive polymer. The palmitoyltransferases ZDHHC17/24 were characterised to palmitoylate AKT to exert oncogenic effects. Interestingly, the anti-obesity drug orlistat or specific penetrating peptides can effectively attenuate AKT palmitoylation and activation by restricting PA synthesis or repressing AKT modification, respectively, thereby antagonising liver tumorigenesis.
CONCLUSIONS
Our findings elucidate a novel fine-tuned regulation of AKT by PA-ZDHHC17/24-mediated palmitoylation, and highlight tumour therapeutic strategies by taking PA-restricted diets, limiting PA synthesis, or directly targeting AKT palmitoylation.
Topics: Animals; Proto-Oncogene Proteins c-akt; Diet, High-Fat; Mice; Non-alcoholic Fatty Liver Disease; Carcinoma, Hepatocellular; Liver Neoplasms; Humans; Lipoylation; Palmitic Acid; Carcinogenesis; Mice, Knockout; Disease Models, Animal; Male; Signal Transduction
PubMed: 38191266
DOI: 10.1136/gutjnl-2023-330826 -
Diabetology & Metabolic Syndrome Jan 2024Obesity is a chronic, recurring, progressive disease and a major public health problem associated with several other diseases that lead to disability, morbidity, and...
Obesity is a chronic, recurring, progressive disease and a major public health problem associated with several other diseases that lead to disability, morbidity, and mortality. The prevalence of obesity has increased at pandemic levels, along with increasing weight-related comorbidities and deaths worldwide. Lifestyle interventions alone provide clinically significant long-term weight loss in only a small proportion of individuals, and bariatric surgery is not suitable or desirable for all patients. Historically, anti-obesity medications achieved a mean efficacy with weight loss between 5 and 10%, which significantly impacted several comorbidities and risk factors, but the average efficacy of these medications remained lower than that expected by both patients and health care professionals and eventually curbed long-term use. Moreover, there is no direct evidence on the impact of anti-obesity medications on cardiovascular outcomes. Semaglutide is a newer anti-obesity medication that changes the overall landscape, as phase 3 studies show a mean weight loss near the 15% threshold and significant proportions of patients with a weight loss of greater than 20%. In this review, we focus on the currently available anti-obesity medications, discuss the results of semaglutide, and present perspectives on the future of obesity treatment after semaglutide.
PubMed: 38172940
DOI: 10.1186/s13098-023-01233-4