The efficacy of mesenchymal stem cell (MSC) transplantation has been reported for various diseases. We previously developed a drug delivery system targeting mitochondria (MITO-Porter) by using a microfluidic device to encapsulate Coenzyme Q₁₀ (CoQ₁₀) on a large scale. The current study aimed to confirm if treatment with CoQ₁₀ encapsulated by MITO-Porter enhanced mitochondrial functions in MSCs, with the potential to improve MSC transplantation therapy. We used highly purified human bone marrow-derived MSCs, described as rapidly expanding clones (RECs), and attempted to control and increase the amount of CoQ₁₀ encapsulated in the MITO-Porter using microfluidic device system. We treated these RECs with CoQ₁₀ encapsulated MITO-Porter, and evaluated its cellular uptake, co-localization with mitochondria, changes in mitochondrial respiratory capacity, and cellular toxicity. There was no significant change in mitochondrial respiratory capacity following treatment with the previous CoQ₁₀ encapsulated MITO-Porter; however, mitochondrial respiratory capacity in RECs was significantly increased by treatment with CoQ₁₀-rich MITO-Porter. Utilization of a microfluidic device enabled the amount of CoQ₁₀ encapsulated in MITO-Porter to be controlled, and treatment with CoQ₁₀-rich MITO-Porter successfully activated mitochondrial functions in MSCs. The MITO-Porter system thus provides a promising tool to improve MSC cell transplantation therapy.

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.

2022-01-01·Phytotherapy Research2区 · 医学

Esculetin: A review of its pharmacology and pharmacokinetics

2区 · 医学

Review

作者: Xie, Qingxuan ; Zhang, Linlin ; Li, Xiaofang

AbstractEsculetin is a natural dihydroxy coumarin; it is mainly extracted from twig skin and the trunk bark of the Chinese herbal medicineFraxinus rhynchophyllaHance. Emerging evidence suggests that esculetin has a wide range of pharmacological activities. Based on its fundamental properties, including antioxidant, antiinflammatory, antiapoptotic, anticancer, antidiabetic, neuroprotective, and cardiovascular protective activities, as well as antibacterial activity, among others, esculetin is expected to be a therapeutic drug for specific disease indications, such as cancer, diabetes, atherosclerosis, Alzheimer's disease (AD), Parkinson's disease (PD), nonalcoholic fatty liver disease (NAFLD), and other diseases. The oral bioavailability of esculetin was shown by studies to be low. The extensive glucuronidation was described to be the main metabolic pathway of esculetin and C‐7 phenolic hydroxyl to be its major metabolic site. With the development of scientific research technology, the pharmacological effects of esculetin are identified and its potential for the treatment of diseases is demonstrated. The underlining mechanisms of action and biological activities as well as the pharmacokinetic data of the analyzed compound reported so far are highlighted in this review with the aim of becoming a proven, and applicable insight and reference for further studies on the utilization of esculetin.

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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