AbstractSepsis‐induced acute lung injury (SALI) is characterized by a high incidence and mortality rate, which has caused a serious medical burden. The pharmacological effects of esculetin (ELT), such as antibacterial and anti‐inflammatory actions, have been widely confirmed. However, the therapeutic effects and mechanisms of ELT on SALI still need to be further clarified. In this study, we first evaluated the therapeutic potential of ELT on a caecal ligation and puncture (CLP) induced septic rat model, particularly in the treatment of acute lung injury. Afterwards, we explored the effect of ELT on macrophage polarization in vivo and in vitro. Then, we investigated the anti‐inflammatory mechanism of ELT based on modulating the metabolic reprogramming of macrophage (the effect on glycolysis in M1, and the effect on fatty acid β‐oxidation in M2). In addition, macrophage metabolic inhibitors (glycolysis inhibitor: 2‐DG, and fatty acid β‐oxidation inhibitor: etomoxir) were used to verify the regulatory effect of ELT on macrophage metabolic reprogramming. Our results proved that ELT intervention could effectively improve the survival rate of SALI rats and ameliorate pathological injury. Next, we found that ELT intervention inhibited M1 polarization and promoted M2 polarization of macrophages in vivo and in vitro, including the downregulation of M1‐related markers (CD86, iNOS), the decrease of pro‐inflammatory factors (nitric oxide, IL‐1β, IL‐6, and TNF‐α), the upregulation of M2‐related markers (CD206, ARG‐1), the increase of immunomodulatory factors (IL‐4 and IL‐10). Subsequently, seahorse analysis showed that ELT intervention inhibited the glycolytic capacity in M1, and promoted the ability of fatty acid β‐oxidation in M2. Besides, ELT intervention inhibited the level of glycolysis product (lactic acid), and the expression of glycolysis‐related genes (Glut1, Hk2, Pfkfb1, Pkm and Ldha) and promoted the expression of fatty acid β‐oxidation related genes (Cpt1a, Cpt2, Acox1). In addition, we found that the inhibitory effect of ELT on M1 polarization was comparable to that of 2‐DG, while intervention with etomoxir abolished the promoting effect of ELT on M2 polarization. ELT inhibited the inflammatory response in SALI by correcting macrophage polarization (inhibiting M1 and promoting M2). The mechanism of ELT on macrophage polarization was associated with regulating metabolic reprogramming (inhibiting glycolysis in M1 and promoting fatty acid β‐oxidation in M2).

2024-10-26·Biological and Pharmaceutical Bulletin

Different Effects of Berberine Delivery to Mitochondria on Cells Derived from the Neural Crest

Article

作者: Hori, Ikuma ; Harashima, Hideyoshi ; Yamada, Yuma

Energy metabolism is crucial for cell polarity and pathogenesis. Mitochondria, which are essential for maintaining energy homeostasis within cells, can be targeted by drug delivery to regulate energy metabolism. However, there is a lack of research comparing how mitochondria control energy metabolism in different cell types derived from the neural crest. Understanding the effects of berberine (BBR), a compound that acts on mitochondria, on energy metabolism in neural crest-derived cells is important. This study reports how MITO-Porter, a mitochondria-targeted liposome, affects neuroblasts (Neuro2a cells) and normal human epidermal melanocytes (NHEMs) when loaded with BBR. We found that treatment with MITO-Porter containing BBR reduced mitochondrial respiration in Neuro2a cells, while it caused a slight increase in NHEMs. Additionally, the treatment shifted the ATP production pathway in Neuro2a cells to rely more on glycolysis, while in NHEMs, there was a slight decrease in the reliance on glycolysis. We also observed a significant decrease in ATP production in Neuro2a cells, while NHEMs showed a tendency to increase ATP production. Importantly, on the basis of the results of the Premix WST-1 assay, the study found that BBR treatment was not toxic to either cell type. It is important to take note of the varied effects of BBR treatment on different cell types derived from the neural crest. These findings necessitate attention when utilizing NHEMs as a cell model in the development of therapeutic strategies for neurodegenerative diseases, including the use of BBR for metabolic control.

2023-11-01·International Immunopharmacology

Therapeutic efficacy of mitochondria-targeted esculetin in the improvement of NAFLD-NASH via modulating AMPK-SIRT1 axis

Article

作者: Pulipaka, Sriravali ; Kotamraju, Srigiridhar ; Singuru, Gajalakshmi ; Thennati, Rajamannar ; Balaji Andugulapati, Sai ; Shaikh, Altab

Mitochondrial dysfunction due to deregulated production of mitochondria-derived ROS is implicated in the development and progression of non-alcoholic fatty liver disease (NAFLD) to non-alcoholic steatohepatitis (NASH). Recently, we synthesized a novel mitochondria-targeted esculetin (Mito-Esc) and investigated its dose-response therapeutic efficacy in mitigating high-fat diet (HFD)-induced NAFLD and NASH in Apoe^-/- mice. Mito-Esc administration, compared to simvastatin and pioglitazone, dose-dependently caused a significant reduction in body weight, improved lipid profile, glucose homeostasis, and pro-inflammatory cytokines level. Mito-Esc administration reduced adipose tissue hypertrophy and lipid accumulation presumably by regulating the levels of CD36, PPAR-γ, EBP-α, and their target genes. Mechanistically, Mito-Esc-induced activation of the AMPK1α-SIRT1 axis inhibited pre-adipocyte differentiation. Conversely, Mito-Esc failed to regulate pre-adipocyte differentiation under AMPK/SIRT1 depleted conditions. In parallel, Mito-Esc administration ameliorated HFD-induced steatosis, fibrosis of the liver, and NAFLD-associated atheromatous plaque formation in the aorta. Importantly, Mito-Esc administration inhibited HFD-induced infiltration of macrophages, a marker of steatohepatitis, in the adipose and liver tissues. The results of the in vitro studies showed that Mito-Esc treatment significantly inhibits TGF-β-induced hepatic stellate cell differentiation as well as the fibrotic markers. Consistent with the above observations, Mito-Esc treatment by activating the AMPK-SIRT1 pathway markedly reversed palmitate-induced mitochondrial superoxide production, depolarization of mitochondrial membrane potential, and lipid accumulation in HepG2 cells. Together, the therapeutic efficacy of Mito-Esc in the mitigation of HFD-induced lipotoxicity, and the associated NASH is in part, mediated by potentiating the AMPK-SIRT1 axis.

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适应症	最高研发状态	国家/地区	公司	日期
动脉粥样硬化	临床前	-	CSIR-Indian Institute of Chemical Biology	2024-05-17
动脉粥样硬化	临床前	-	Academy of Scientific & Innovative Research	2024-05-17