Curcumin enhances the anti-obesogenic activity of orlistat through SKN-1/NRF2-dependent regulation of nutrient metabolism in Caenorhabditis elegans
Related Articles
Role of pancreatic lipase inhibition in obesity treatment: mechanisms and challenges towards current insights and future directions
The worldwide health emergency of obesity is closely connected to how dietary fats are metabolized, whereas the process is significantly influenced by pancreatic lipase (PL), an enzyme critical for lipid hydrolysis into fatty acids. This narrative review employs a methodological approach utilizing literature searches of PubMed data up to March 2024. The search term criteria encompasses keywords related to the role, mechanism, challenges, and current and future treatments of pancreatic lipase in obesity with an overall references is 106. This paper offers a comprehensive explanation of the role of PL, underlining its significance in the digestive process and lipid imbalances that contribute to obesity and by extension, its impact on obesity development and progression. Additionally, it delves into the dual functionality of the pancreas, emphasizing its impact on metabolism and energy utilization which, when dysregulated, promotes obesity. A focal point of this review is the investigation into the efficacy, challenges, and adverse effects of current pancreatic lipase inhibitors, with orlistat being highlighted as a primary current drug delivery. By discussing advanced obesity treatments, including the exploration of novel anti-obesity medications that target specific biological pathways, this review underscores the complexity of obesity treatment and the necessity for a multifaceted approach. In conclusion, this paper emphasizing the importance of understanding the role of enzymes like pancreatic lipase mechanistic and adopting a multidisciplinary approach to treatment and side effects of current obesity drugs and explore new emerging therapeutic strategies for more effective obesity management.
Acyl-CoA thioesterase 8 induces gemcitabine resistance via regulation of lipid metabolism and antiferroptotic activity in pancreatic ductal adenocarcinoma
Pancreatic ductal adenocarcinoma (PDAC) comprises a group of highly malignant tumors of the pancreas. Metabolic reprogramming in tumors plays a pivotal role in promoting cancer progression. However, little is known about the metabolic alterations in tumors that drive cancer drug resistance in patients with PDAC. Here, we identified acyl-CoA thioesterase 8 (ACOT8) as a key player in driving PDAC gemcitabine (GEM) resistance. The expression of ACOT8 is significantly upregulated in GEM-resistant PDAC tissues and is closely associated with poor survival in patients with PDAC. Gain- and loss-of-function studies have shown that ACOT8 drives PDAC GEM resistance both in vitro and in vivo. Mechanistically, ACOT8 regulates cellular cholesterol ester (CE) levels, decreases the levels of phosphatidylethanolamines (PEs) that bind to polyunsaturated fatty acids and promote peroxisome activation. The knockdown of ACOT8 promotes ferroptosis and increases the chemosensitivity of tumors to GEM by inducing ferroptosis-associated pathway activation in PDAC cell lines. The combination of orlistat, an ACOT8 inhibitor, and GEM significantly inhibited tumor growth in PDAC organoid and mouse models. This study reveals the biological importance of ACOT8 and provides a potential combination therapy for treating patients with advanced GEM-resistant PDAC.
Iron homeostasis and ferroptosis in muscle diseases and disorders: mechanisms and therapeutic prospects
The muscular system plays a critical role in the human body by governing skeletal movement, cardiovascular function, and the activities of digestive organs. Additionally, muscle tissues serve an endocrine function by secreting myogenic cytokines, thereby regulating metabolism throughout the entire body. Maintaining muscle function requires iron homeostasis. Recent studies suggest that disruptions in iron metabolism and ferroptosis, a form of iron-dependent cell death, are essential contributors to the progression of a wide range of muscle diseases and disorders, including sarcopenia, cardiomyopathy, and amyotrophic lateral sclerosis. Thus, a comprehensive overview of the mechanisms regulating iron metabolism and ferroptosis in these conditions is crucial for identifying potential therapeutic targets and developing new strategies for disease treatment and/or prevention. This review aims to summarize recent advances in understanding the molecular mechanisms underlying ferroptosis in the context of muscle injury, as well as associated muscle diseases and disorders. Moreover, we discuss potential targets within the ferroptosis pathway and possible strategies for managing muscle disorders. Finally, we shed new light on current limitations and future prospects for therapeutic interventions targeting ferroptosis.
An integrative data-driven model simulating C. elegans brain, body and environment interactions
The behavior of an organism is influenced by the complex interplay between its brain, body and environment. Existing data-driven models focus on either the brain or the body–environment. Here we present BAAIWorm, an integrative data-driven model of Caenorhabditis elegans, which consists of two submodels: the brain model and the body–environment model. The brain model was built by multicompartment models with realistic morphology, connectome and neural population dynamics based on experimental data. Simultaneously, the body–environment model used a lifelike body and a three-dimensional physical environment. Through the closed-loop interaction between the two submodels, BAAIWorm reproduced the realistic zigzag movement toward attractors observed in C. elegans. Leveraging this model, we investigated the impact of neural system structure on both neural activities and behaviors. Consequently, BAAIWorm can enhance our understanding of how the brain controls the body to interact with its surrounding environment.
Targeted temperature management alleviates post-resuscitation myocardial dysfunction by inhibiting ferroptosis
Targeted temperature management (TTM) is a vital intervention for cardiac arrest survivors to mitigate post-resuscitation myocardial dysfunction (PRMD). However, the optimal temperature for TTM remains a topic of debate. This study investigates the effects of TTM at different temperatures and explores the underlying mechanisms using in vivo and in vitro models of myocardial ischemia/reperfusion (I/R) injury following cardiac arrest (CA) and cardiopulmonary resuscitation (CPR). We found that TTM at 33 °C significantly improved post-resuscitation hemodynamics and myocardial function, reducing both myocardial and mitochondrial damage in the rat model of CA/CPR. Additionally, Deferoxamin (DFO), as an iron chelating agent, also demonstrated protective effects against PRMD. Both in vitro and in vivo experiments confirmed that hypothermia at 33 °C and DFO mitigated mitochondrial damage, oxidative stress, lipid peroxidation, and iron overload, while suppressing ferritinophagy and ferroptosis. Furthermore, TTM at 33 °C and DFO facilitated the nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2), with Nrf2 activation leading to inhibited ferritinophagy and enhanced iron export. Our findings indicate that TTM at 33° C, as opposed to 36° C, significantly alleviates PRMD and reduced myocardial damage by inhibiting ferroptosis. Theses protective effects are associated with Nrf2 activation and modulation of iron homeostasis. Moreover, DFO not only suppressed ferroptosis through its iron chelation properties but also by activating the Nrf2 axis.
Responses