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Heliyon Mar 2024The rate of vincristine (VCR) resistance in the treatment of retinoblastoma (RB) is relatively high, and the exact role and mechanism of autophagy and fatty acid (FA)...
The rate of vincristine (VCR) resistance in the treatment of retinoblastoma (RB) is relatively high, and the exact role and mechanism of autophagy and fatty acid (FA) metabolism in RB are still unknown. The aim of this study was to elucidate the molecular mechanism by which acyl-CoA thioesterase 7 (ACOT7) regulates FA metabolism and autophagy, which may lead to potential therapeutic strategies for RB. In the present study, the relationship between FA metabolism and cellular drug sensitivity was evaluated through ACOT7 overexpression or inhibition tests in RB-resistant cells. The lipase inhibitor orlistat and the autophagy inhibitor CQ were used to determine the effects of ACOT7 on FA metabolism, autophagy, and cellular drug sensitivity, as well as the therapeutic value of ACOT7 targeting. The results showed that ACOT7 was upregulated in VCR-resistant RB cells, significantly enhancing cell resistance and indicating that ACOT7 may serve as a biomarker for VCR resistance in RB cells. Knockdown of ACOT7 inhibited FA metabolism and reduced cell viability in VCR-resistant RB cells. The effect of ACOT7 overexpression was opposite to that of ACOT7 knockdown, and ACOT7 overexpression promoted autophagy in VCR-resistant RB cells. After treatment with orlistat or CQ, FA metabolism in VCR-resistant RB cells decreased, cell viability and autophagy were inhibited, EMT was inhibited, and the sensitivity of RB cells to VCR was increased. In conclusion, ACOT7 knockdown can mediate FA metabolism to inhibit autophagy and the migration of RB cells, thereby improving the sensitivity of RB cells to VCR.
PubMed: 38463820
DOI: 10.1016/j.heliyon.2024.e27156 -
Frontiers in Microbiology 2024The dietary protein level plays a crucial role in maintaining the equilibrium of rumen microbiota in yaks. To explore the association between dietary protein levels,...
INTRODUCTION
The dietary protein level plays a crucial role in maintaining the equilibrium of rumen microbiota in yaks. To explore the association between dietary protein levels, rumen microbiota, and muscle metabolites, we examined the rumen microbiome and muscle metabolome characteristics in yaks subjected to varying dietary protein levels.
METHODS
In this study, 36 yaks were randomly assigned to three groups ( = 12 per group): low dietary protein group (LP, 12% protein concentration), medium dietary protein group (MP, 14% protein concentration), and high dietary protein group (HP, 16% protein concentration).
RESULTS
16S rDNA sequencing revealed that the HP group exhibited the highest Chao1 and Observed_species indices, while the LP group demonstrated the lowest. Shannon and Simpson indices were significantly elevated in the MP group relative to the LP group ( < 0.05). At the genus level, the relative abundance of in the HP group was notably greater than that in the LP and MP groups ( < 0.05). Conversely, the relative abundance of displayed an increasing tendency with escalating feed protein levels. Muscle metabolism analysis revealed that the content of the metabolite Uric acid was significantly higher in the LP group compared to the MP group ( < 0.05). The content of the metabolite L-(+)-Arabinose was significantly increased in the MP group compared to the HP group ( < 0.05), while the content of D-(-)-Glutamine and L-arginine was significantly reduced in the LP group ( < 0.05). The levels of metabolites 13-HPODE, Decanoylcarnitine, Lauric acid, L-(+)-Arabinose, and Uric acid were significantly elevated in the LP group relative to the HP group ( < 0.05). Furthermore, our observations disclosed correlations between rumen microbes and muscle metabolites. The relative abundance of was negatively correlated with Orlistat concentration; the relative abundance of was positively correlated with D-(-)-Glutamine and L-arginine concentrations.
DISCUSSION
Our findings offer a foundation for comprehending the rumen microbiome of yaks subjected to different dietary protein levels and the intimately associated metabolic pathways of the yak muscle metabolome. Elucidating the rumen microbiome and muscle metabolome of yaks may facilitate the determination of dietary protein levels.
PubMed: 38419639
DOI: 10.3389/fmicb.2024.1275865 -
Cells Feb 2024The oral consumption of alcohol (ethanol) has a long tradition in humans and is an integral part of many cultures. The causal relationship between ethanol consumption...
The oral consumption of alcohol (ethanol) has a long tradition in humans and is an integral part of many cultures. The causal relationship between ethanol consumption and numerous diseases is well known. In addition to the well-described harmful effects on the liver and pancreas, there is also evidence that ethanol abuse triggers pathological skin conditions, including acne. In the present study, we addressed this issue by investigating the effect of ethanol on the energy metabolism in human SZ95 sebocytes, with particular focus on qualitative and quantitative lipogenesis. It was found that ethanol is a strong trigger for lipogenesis, with moderate effects on cell proliferation and toxicity. We identified the non-oxidative metabolism of ethanol, which produced fatty acid ethyl esters (FAEEs), as relevant for the lipogenic effect-the oxidative metabolism of ethanol does not contribute to lipogenesis. Correspondingly, using the Seahorse extracellular flux analyzer, we found an inhibition of the mitochondrial oxygen consumption rate as a measure of mitochondrial ATP production by ethanol. The ATP production rate from glycolysis was not affected. These data corroborate that ethanol-induced lipogenesis is independent from oxygen. In sum, our results give a causal explanation for the prevalence of acne in heavy drinkers, confirming that alcoholism should be considered as a systemic disease. Moreover, the identification of key factors driving ethanol-dependent lipogenesis may also be relevant in the treatment of acne vulgaris.
Topics: Humans; Lipogenesis; Sebaceous Glands; Acne Vulgaris; Ethanol; Adenosine Triphosphate
PubMed: 38391942
DOI: 10.3390/cells13040328 -
Journal of Advanced Veterinary and... Dec 2023Various disease complications are a risk of overweight or obesity, so losing weight can reduce the risk of diseases caused by obesity. Binahong leaf ethanol extract ()...
OBJECTIVE
Various disease complications are a risk of overweight or obesity, so losing weight can reduce the risk of diseases caused by obesity. Binahong leaf ethanol extract () is a weight-loss herbal preparation.
AIM
This study aims to analyze whether extract is effective in losing weight by affecting the mechanism of adipogenesis in an animal obesity model.
MATERIALS AND METHODS
Animals were grouped into six groups as follows: the normal diet (K1), the negative control group (K2), the positive control group with Orlistat at a dose of 20 mg/kg BW (K3), an ethanol extract of leaves at doses of 50 mg/kg BW (P1), 100 mg/kg BW group (P2), and 150 mg/kg BW (P3). All rats were fed a diet that consisted of high fat for eight weeks, except K1. Afterward, the treatments were given based on group distribution. Then, the rats were treated based on their groups for 4 weeks, and the high-fat diet was still given during the treatment for the control groups (K2). Anthropometric examinations such as body weight, length, and the circumference of the abdomen were measured. Metabolic parameters, including blood glucose, cholesterol levels, triglyceride levels, and abdominal fat weight, were measured using molecular parameters that measured PI3K levels and Extracellular signal-regulated kinase (ERK) in abdominal fat tissue samples using the ELISA method.
RESULTS
ERK levels of abdominal fat were lowered in the treatment group using the extract of (50 mg/kg BW (P1) and 100 mg/kg BW (P2)) compared to the control group that was given a high-fat diet without treatment. The control group, which was fed a high-fat diet without treatment, had an average ERK level of 10.17 ± 2.98 ng/ml, P1 (50 mg/kg BW). Furthermore, when ethanol extracts were used as opposed to the control group, which received a high-fat diet without treatment, there was an increase in phosphoinositide three-kinase (PI3K) levels (K2). The control group received 9.35 ± 2.87 ng/ml, the treatment group received 100 mg/kg BW (P2) 9.48 ± 1.54 ng/ml, and the treatment group received 150 mg/kg BW (P3) 7.87 ± 1.79 ng/ml. The weight of fat in the abdomen differed between the groups that received a high-fat diet without treatment (K2) and those that received a high-fat diet with treatment (P1, P2, P3; < 0.05).
CONCLUSION
extract possesses anti-obesity activities by decreasing ERK and increasing PI3K levels, as well as reducing abdominal fat weight.
PubMed: 38370901
DOI: 10.5455/javar.2023.j737 -
MSMR Jan 2024The U.S. military has witnessed rising obesity among active component service members. The Department of Defense authorized coverage of weight loss medications in 2018,...
The U.S. military has witnessed rising obesity among active component service members. The Department of Defense authorized coverage of weight loss medications in 2018, but no study has evaluated prescription prevalence within the active component. This descriptive retrospective cohort study analyzed data from active component U.S. military service members from January 2018 through June 2023. The study used data from the Defense Medical Surveillance System to determine prescription period prevalence of weight loss medication. Data on demographics, body mass index, and history of diabetes were considered. The study revealed a 100-fold increase in the prescription period prevalence of weight loss agents in the active component from their initial authorization date. Demographics associated with higher prescription period prevalence were non-Hispanic Black race and ethnicity, female sex, and older age. Service members in the health care occupations and the Navy had higher prevalence compared to other service branches and occupations. The findings indicate a significant rise in the period prevalence of weight loss prescriptions over time. Further research is recommended to assess the effectiveness, safety, and use in austere military environments.
Topics: Female; Humans; United States; Prevalence; Retrospective Studies; Military Personnel; Anti-Obesity Agents; Weight Loss
PubMed: 38359359
DOI: No ID Found -
International Journal of Molecular... Feb 2024Infertility is a modern health problem. Obesity is another expanding health issue associated with chronic diseases among which infertility is also included. This review... (Review)
Review
Infertility is a modern health problem. Obesity is another expanding health issue associated with chronic diseases among which infertility is also included. This review will focus on the effects of weight loss by medical therapy on fertility regarding reproductive hormonal profile, ovulation rates, time to pregnancy, implantation rates, pregnancy rates, normal embryo development, and live birth rates. We comprised medicine already used for weight loss, such as orlistat and metformin, and emerging medical treatments, such as Glucagon-Like Peptide-1 receptor agonists (GLP-1 RA). Their use is not recommended during a planned pregnancy, and they should be discontinued in such cases. The main outcomes of this literature review are the following: modest weight loss after medication and the duration of the treatment are important factors for fertility improvement. The fecundity outcomes upon which medical-induced weight loss provides significant results are the female reproductive hormonal profile, menstrual cyclicity, ovulation and conception rates, and pregnancy rates. Regarding the male reproductive system, the fertility outcomes that feature significant alterations after medically induced weight loss are as follows: the male reproductive hormonal profile, sperm motility, movement and morphology, weight of reproductive organs, and sexual function. The newer promising GLP-1 RAs show expectations regarding fertility improvement, as they have evidenced encouraging effects on improving ovulation rates and regulating the menstrual cycle. However, more human studies are needed to confirm this. Future research should aim to provide answers about whether medical weight loss therapies affect fertility indirectly through weight loss or by a possible direct action on the reproductive system.
Topics: Pregnancy; Humans; Male; Female; Infertility, Female; Sperm Motility; Reproduction; Weight Loss; Glucagon-Like Peptide 1
PubMed: 38339186
DOI: 10.3390/ijms25031909 -
Scientific Reports Feb 2024Lipase inhibition is one of the directions to control obesity. In vitro assays have confirmed the inhibitory effect of selected xanthophylls, including astaxanthin,...
Lipase inhibition is one of the directions to control obesity. In vitro assays have confirmed the inhibitory effect of selected xanthophylls, including astaxanthin, fucoxanthinol, fucoxanthin, and neoxanthin. Similarly, an in-silico study also demonstrated the successful inhibition of pancreatic lipase by astaxanthin. Unfortunately, the efficacy of these protocols in the emulsion state typical of lipid digestion remains untested. To address this issue, the current study employed the pH-stat test, which mimics lipid digestion in the gastrointestinal tract, to evaluate native and prepared sea buckthorn and rapeseed oils with varying xanthophyll contents from 0 to 1400 mg/kg oil. Furthermore, a molecular docking of zeaxanthin and violaxanthin (commonly found in plant-based foods), astaxanthin (widely distributed in foods of marine origin) and orlistat (approved as a drug) was performed. The in-silico studies revealed comparable inhibitory potential of all tested xanthophylls (variation from - 8.0 to - 9.3 kcal/mol), surpassing that of orlistat (- 6.5 kcal/mol). Nonetheless, when tested in an emulsified state, the results of pH-stat digestion failed to establish the inhibitory effect of xanthophylls in the digested oils. In fact, lipolysis of native xanthophyll-rich sea buckthorn oil was approximately 22% higher than that of the xanthophyll-low preparation. The key insight derived from this study is that the amphiphilic properties of xanthophylls during the digestion of xanthophyll-rich lipids/meals facilitate emulsion formation, which leads to enhanced fat lipolysis.
Topics: Hydrolysis; Orlistat; Emulsions; Molecular Docking Simulation; Xanthophylls; Lipase; Lutein; Lipids; Oils; Digestion
PubMed: 38302772
DOI: 10.1038/s41598-024-53312-9 -
Advances in Pharmacological and... 2024Obesity, characterized by excessive adipose tissue accumulation, has emerged as a crucial determinant for a wide range of chronic medical conditions. The identification...
Obesity, characterized by excessive adipose tissue accumulation, has emerged as a crucial determinant for a wide range of chronic medical conditions. The identification of effective interventions for obesity is of utmost importance. Widely researched antiobesity agents focus on pancreatic lipase, a significant therapeutic target. This study presented the evaluation of ten flavonoid compounds in terms of their inhibitory activities against pancreatic lipase, utilizing both and approaches. The results indicated that all tested compounds demonstrated modest and weaker inhibitory activities compared to the reference compound, orlistat. Among the compounds investigated, F01 exhibited the highest potency, with an IC value of 17.68 ± 1.43 M. The enzymatic inhibition kinetic analysis revealed that F01 operated through a competitive inhibition mechanism with a determined of 7.16 M. This value suggested a moderate binding affinity for the pancreatic lipase enzyme. Furthermore, the associated value was quantified at 0.03272 ΔA·min. studies revealed that F01 displayed a binding mode similar to that of orlistat, despite lacking an active functional group capable of forming a covalent bond with Ser152 of the catalytic triad. However, F01 formed a hydrogen bond with this crucial amino acid. Furthermore, F01 interacted with other significant residues at the enzyme's active site, particularly those within the lid domain. Based on these findings, F01 demonstrates substantial potential as a candidate for further investigations.
PubMed: 38298460
DOI: 10.1155/2024/6655996 -
International Journal of Obesity (2005) May 2024This study aimed to assess the cost-effectiveness of weight-management pharmacotherapies approved by Canada Health, i.e., orlistat, naltrexone 32 mg/bupropion 360 mg...
OBJECTIVES
This study aimed to assess the cost-effectiveness of weight-management pharmacotherapies approved by Canada Health, i.e., orlistat, naltrexone 32 mg/bupropion 360 mg (NB-32), liraglutide 3.0 mg and semaglutide 2.4 mg as compared to the current standard of care (SoC).
METHODS
Analyses were conducted using a cohort with a mean starting age 50 years, body mass index (BMI) 37.5 kg/m, and 27.6% having type 2 diabetes. Using treatment-specific changes in surrogate endpoints from the STEP trials (BMI, glycemic, blood pressure, lipids), besides a network meta-analysis, the occurrence of weight-related complications, costs, and quality-adjusted life-years (QALYs) were projected over lifetime.
RESULTS
From a societal perspective, at a willingness-to-pay (WTP) threshold of CAD 50 000 per QALY, semaglutide 2.4 mg was the most cost-effective treatment, at an incremental cost-utility ratio (ICUR) of CAD 31 243 and CAD 29 014 per QALY gained versus the next best alternative, i.e., orlistat, and SoC, respectively. Semaglutide 2.4 mg extendedly dominated other pharmacotherapies such as NB-32 or liraglutide 3.0 mg and remained cost-effective both under a public and private payer perspective. Results were robust to sensitivity analyses varying post-treatment catch-up rates, longer treatment durations and using real-world cohort characteristics. Semaglutide 2.4 mg was the preferred intervention, with a likelihood of 70% at a WTP threshold of CAD 50 000 per QALY gained. However, when the modeled benefits of weight-loss on cancer, mortality, cardiovascular disease (CVD) or osteoarthritis surgeries were removed simultaneously, orlistat emerged as the best value for money compared with SoC, with an ICUR of CAD 35 723 per QALY gained.
CONCLUSION
Semaglutide 2.4 mg was the most cost-effective treatment alternative compared with D&E or orlistat alone, and extendedly dominated other pharmacotherapies such as NB-32 or liraglutide 3.0 mg. Results were sensitive to the inclusion of the combined benefits of mortality, cancer, CVD, and knee osteoarthritis.
Topics: Humans; Cost-Benefit Analysis; Canada; Middle Aged; Obesity; Female; Anti-Obesity Agents; Male; Orlistat; Quality-Adjusted Life Years; Liraglutide; Diabetes Mellitus, Type 2; Bupropion; Naltrexone; Glucagon-Like Peptides
PubMed: 38291203
DOI: 10.1038/s41366-024-01467-w