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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 -
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 -
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 -
International Journal of Molecular... Dec 2023Obesity prevalence is becoming a serious global health and economic issue and is a major risk factor for concomitant diseases that worsen the quality and duration of...
Obesity prevalence is becoming a serious global health and economic issue and is a major risk factor for concomitant diseases that worsen the quality and duration of life. Therefore, the urgency of the development of novel therapies is of a particular importance. A previous study of ours revealed that the natural pterocarpan, maackiain (MACK), significantly inhibits adipogenic differentiation in human adipocytes through a peroxisome proliferator-activated receptor gamma (PPARγ)-dependent mechanism. Considering the observed anti-adipogenic potential of MACK, we aimed to further elucidate the molecular mechanisms that drive its biological activity in a obesity model. Therefore, in the current study, the anti-obesogenic effect of MACK (25, 50, and 100 μM) was compared to orlistat (ORST, 12 μM) as a reference drug. Additionally, the hybrid combination between the ORST (12 μM) and MACK (100 μM) was assessed for suspected synergistic interaction. Mechanistically, the observed anti-obesogenic effect of MACK was mediated through the upregulation of the key metabolic regulators, namely, the nuclear hormone receptor 49 () that is a functional homologue of the mammalian PPARs and the AMP-activated protein kinase (aak-2/AMPK) in . Collectively, our investigation indicates that MACK has the potential to limit lipid accumulation and control obesity that deserves future developments.
Topics: Animals; Humans; Caenorhabditis elegans; Pterocarpans; Caloric Restriction; AMP-Activated Protein Kinases; Caenorhabditis elegans Proteins; Obesity; Lipids; Mammals
PubMed: 38139270
DOI: 10.3390/ijms242417442 -
Foods (Basel, Switzerland) Dec 2023Fu brick tea (FBT), a product of microbial fermentation from primary dark tea, also known as raw material tea (RMT), has been extensively studied for its functional...
Fu brick tea (FBT), a product of microbial fermentation from primary dark tea, also known as raw material tea (RMT), has been extensively studied for its functional properties. However, its potential as a staple food supplement for weight loss remains poorly understood. This study compared the weight loss effects of orlistat, traditional plain noodles (NN), and noodles supplemented with varying amounts of RMT (RMTN) and FBT (FBTN), with the aim to elucidate their lipid-reducing effects and underlying mechanisms. Experimental trials on high fat diet fed mice revealed significant weight loss, lipid-lowering, and hypoglycemic effects upon supplementation with orlistat, RMTN, and FBTN. Moreover, supplementation with orlistat, RMTN, and FBTN effectively restored serum and liver-related index levels, mitigating high-fat diet-induced dyslipidemia. Additionally, these supplements ameliorated liver and kidney damage by inhibiting oxidative stress and inflammatory responses. Furthermore, orlistat, RMTN, and FBTN exert their anti-obesity effects primarily by modulating genes associated with lipid metabolism and inflammatory responses and through regulation of the composition and structure of the gut microbiota. Importantly, FBTN demonstrated a significantly stronger lipid-lowering effect compared to RMTN, particularly at higher tea addition ratios. In contrast, NN supplementation exhibited minimal to no weight loss effects. Based on these findings, it could be inferred that FBT holds promise as a staple food supplement to ameliorate high-fat diet-induced obesity and its associated health conditions.
PubMed: 38137292
DOI: 10.3390/foods12244488 -
Skeletal Muscle Dec 2023Cross-sectional studies have demonstrated the association of skeletal muscle mass with metabolic-associated fatty liver disease (MAFLD), while longitudinal data are...
AIMS
Cross-sectional studies have demonstrated the association of skeletal muscle mass with metabolic-associated fatty liver disease (MAFLD), while longitudinal data are scarce. We aimed to explore the impact of changes in relative skeletal muscle mass on the MAFLD treatment response.
METHODS
MAFLD patients undergoing magnetic resonance imaging-based proton density fat fraction for liver fat content (LFC) assessments and bioelectrical impedance analysis before and after treatment (orlistat, meal replacement, lifestyle modifications) were enrolled. Appendicular muscle mass (ASM) was adjusted by weight (ASM/W).
RESULTS
Overall, 256 participants were recruited and divided into two groups: with an ASM/W increase (n=166) and without an ASM/W increase (n=90). There was a great reduction in LFC in the group with an ASM/W increase (16.9% versus 8.2%, P < 0.001). However, the change in LFC in the group without an ASM/W increase showed no significant difference (12.5% versus 15.0%, P > 0.05). △ASM/W [odds ratio (OR)=1.48, 95% confidence interval (CI) 1.05-2.07, P = 0.024] and △total fat mass (OR=1.45, 95% CI 1.12-1.87, P = 0.004) were independent predictors for steatosis improvement (relative reduction of LFC ≥ 30%). The subgroup analysis showed that, despite without weight loss, decrease in HOMA-IR (OR=6.21, 95% CI 1.28-30.13, P=0.023), △total fat mass (OR=3.48, 95% CI 1.95-6.21, P <0.001 and △ASM/W (OR=2.13, 95% CI 1.12-4.05, P=0.022) independently predicted steatosis improvement.
CONCLUSIONS
ASM/W increase and loss of total fat mass benefit the resolution of liver steatosis, independent of weight loss for MAFLD.
Topics: Humans; Sarcopenia; Muscle, Skeletal; Cross-Sectional Studies; Non-alcoholic Fatty Liver Disease; Weight Loss
PubMed: 38115119
DOI: 10.1186/s13395-023-00333-z -
Journal of Medicine and Life Sep 2023Obesity is a world health concern and a serious risk factor for several chronic diseases. is a plant with reported anti-obesity properties. However, the preclinical...
Obesity is a world health concern and a serious risk factor for several chronic diseases. is a plant with reported anti-obesity properties. However, the preclinical anti-obesity effect of ethanolic extract of Iraqi has not been studied yet. This study aimed to evaluate the preclinical anti-obesity properties of Iraqi extract, alone or in combination with orlistat, on high-fat diet-induced obesity in male rats. Male rats were divided into five groups: control, induction, ethanolic extract of Iraqi (250 mg/kg and 500 mg/kg), orlistat (Xenical) alone (10 mg/kg), and a combination of the extract (250 mg/kg) with Xenical. The rats were fed a high-fat diet to induce obesity, and treatments were given orally for 8 weeks. Body weight, food intake, serum lipid profile, and liver enzymes were measured. Administration of ethanolic extract of Iraqi (250 mg/kg and 500 mg/kg), Xenical alone (10 mg/kg), and combination with the extract (250 mg/kg) for 8 weeks significantly reduced body weight, food intake, serum triglycerides, total cholesterol, low-density lipoprotein cholesterol, and liver enzymes (aspartate transaminase and alanine transaminase) when compared to the induction group. The ethanolic extract of Iraqi showed anti-obesity effects and could be a potential therapeutic agent in managing obesity. However, further studies are needed to evaluate its clinical efficacy and safety.
Topics: Rats; Animals; Orlistat; Diet, High-Fat; Hibiscus; Iraq; Plant Extracts; Obesity; Body Weight; Cholesterol
PubMed: 38107717
DOI: 10.25122/jml-2023-0140