Nitric oxide facilitates the targeting Kupffer cells of a nano-antioxidant for the treatment of NASH

Maeda, Hitoshi; Ishima, Yu; Saruwatari, Junji; Mizuta, Yuki; Minayoshi, Yuki; Ichimizu, Shota; Yanagisawa, Hiroki; Nagasaki, Taisei; Yasuda, Kengo; Oshiro, Shun; Taura, Manabu; McConnell, Matthew; Oniki, Kentaro; Sonoda, Kayoko; Wakayama, Tomohiko; Kinoshita, Manabu; Shuto, Tsuyoshi; Kai, Hirofumi; Tanaka, Motohiko; Sasaki, Yutaka; Iwakiri, Yasuko; Otagiri, Masaki; Watanabe, Hiroshi; Maruyama, Toru

doi:10.1016/j.jconrel.2021.11.039

“…Hyperglycemia, mainly caused by insulin resistance, induces the generation of free radicals by the activated Kupffer cells (phagocytic hepatic macrophages) that help in maintaining the integrity of liver cells [ 88 ]. However, these cells are highly susceptible to the effects of the free radicals generated by their own immune reactions and the surrounding cells [ 89 ]. The excessive ROS production results in irreversible oxidative alterations of macromolecules including the carbohydrates, lipids, and proteins [ 90 ], thereby leading to increased oxidative stress and triggering the cascade of inflammatory events that activates the transcription of proapoptotic genes and damages hepatocytes [ 91 , 92 ].…”

Section: Resultsmentioning

confidence: 99%

“…Oxidative Medicine and Cellular Longevity immune reactions and the surrounding cells [89]. The excessive ROS production results in irreversible oxidative alterations of macromolecules including the carbohydrates, lipids, and proteins [90], thereby leading to increased oxidative stress and triggering the cascade of inflammatory events that activates the transcription of proapoptotic genes and damages hepatocytes [91,92].…”

Section: The Dietl-eth_t Garckeana Exhibited Antioxidantmentioning

confidence: 99%

Luteolin-Rich Extract of Thespesia garckeana F. Hoffm. (Snot Apple) Contains Potential Drug-Like Candidates and Modulates Glycemic and Oxidoinflammatory Aberrations in Experimental Animals

Alozieuwa

¹

,

Lawal

²

,

Sani³

et al. 2022

Oxidative Medicine and Cellular Longevity

10

2

0

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The present study evaluated the polyphenolic contents and hypoglycemic, antioxidant, and anti-inflammatory effects of the diethyl ether fraction of Thespesia garckeana using various in vitro and in vivo models. Total phenol and flavonoid contents of the extract were 613.65 ± 2.38 and 152.83 ± 1.56 mg/100 g dry weight, respectively. The extract exhibited in vitro antioxidant activities against DPPH, FRAP, LPO, and ABTS with respective half-maximal inhibitory concentration (IC50) values of 30.91 ± 0.23 , 16.81 ± 0.51 , 41.29 ± 1.82 , and 42.39 ± 2.24 μg/mL. In vitro anti-inflammatory studies using membrane stabilization, protein denaturation, and proteinase activities revealed the effectiveness of the extract with respective IC50 values of 54.45 ± 2.89 , 93.62 ± 3.04 , and 56.60 ± 2.34 μg/mL, while in vitro hypoglycemic analysis of the extract revealed inhibition of α-amylase (IC50 64.59 ± 3.29 μg/mL) and enhancement of glucose uptake by yeast cells. Interestingly, the extract demonstrated in vivo hypoglycemic and anti-inflammatory effects in streptozotocin- (STZ-) induced diabetic and xylene-induced ear swelling models, respectively. In addition, the extract improved insulin secretion, attenuated pancreatic tissue distortion and oxidative stress, and increased the activities of superoxide dismutase (SOD), catalase, and reduced glutathione (GSH), while reducing the concentration of LPO in the diabetic rats. A high-performance liquid chromatography (HPLC) analysis identified the presence of catechin ( 6.81 e − 1 ppm), rutin ( 8.46 e − 1 ppm), myricetin, apigenin ( 4.019 e − 1 ppm), and luteolin (15.09 ppm) with respective retention times (RTs) of 13.64, 24.269, 27.781, 29.58, and 32.23 min, and these were subjected to a pharmacoinformatics analysis, which revealed their drug-likeness and good pharmacokinetic properties. A docking analysis hinted at the potential of luteolin, the most abundant compound in the extract, for targeting glucose-metabolizing enzymes. Thus, the present study provides preclinical insights into the bioactive constituents of T. garckeana, its antioxidant and anti-inflammatory effects, and its potential for the treatment of diabetes.

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“…In addition, the NO released by s-nitrosation of the nanoparticles restored the liver blood flow, increased the expression of MRC2, and improved the oxidative stress related pathology of the NASH model mice through combined treatment. 213 Because of these excellent properties, organic nanomaterials have shown great application value as effective carriers in the delivery of anti-liver fibrosis drugs. However, low drug loading remains a major challenge for polymers and lipid nanoparticles in the delivery of hydrophobic drugs.…”

Section: Synthetic Nanomaterialsmentioning

confidence: 99%

“…In addition, the NO released by s-nitrosation of the nanoparticles restored the liver blood flow, increased the expression of MRC2, and improved the oxidative stress related pathology of the NASH model mice through combined treatment. 213…”

Section: Therapeutic Nanoagents For the Treatment Of Liver Fibrosismentioning

confidence: 99%

Liver fibrosis: pathological features, clinical treatment and application of therapeutic nanoagents

Chen,

Guo,

Mao

et al. 2024

J. Mater. Chem. B

1

0

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“…KCs and ROS have an interactive relationship, and KCs are known to release bioactive mediators, such as ROS, to surrounding hepatocytes and stellate cells through the activation of NOX2 and TLR signaling pathways ( Liang et al, 2016 ); ( Luangmonkong et al, 2018 ; Maeda et al, 2022 ). In NASH patients, the accumulation of fat and increased levels of LPS polarize KCs towards the M1 phenotype and result in increased production of ROS and cytokines ( Ma et al, 2021 ).…”

Section: Activation Of Kcsmentioning

confidence: 99%

Activation of Kupffer cells in NAFLD and NASH: mechanisms and therapeutic interventions

Xu

¹

,

Wei

²

,

Zhao

³

et al. 2023

Front. Cell Dev. Biol.

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Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are emerging as the leading causes of liver disease worldwide. These conditions can lead to cirrhosis, liver cancer, liver failure, and other related ailments. At present, liver transplantation remains the sole treatment option for end-stage NASH, leading to a rapidly growing socioeconomic burden. Kupffer cells (KCs) are a dominant population of macrophages that reside in the liver, playing a crucial role in innate immunity. Their primary function includes phagocytosing exogenous substances, presenting antigens, and triggering immune responses. Moreover, they interact with other liver cells during the pathogenesis of NAFLD, and this crosstalk may either delay or exacerbate disease progression. Stimulation by endogenous signals triggers the activation of KCs, resulting in the expression of various inflammatory factors and chemokines, such as NLRP3, TNF-α, IL-1B, and IL-6, and contributing to the inflammatory cascade. In the past 5 years, significant advances have been made in understanding the biological properties and immune functions of KCs in NAFLD, including their interactions with tissue molecules, underlying molecular mechanisms, signaling pathways, and relevant therapeutic interventions. Having a comprehensive understanding of these mechanisms and characteristics can have enormous potential in guiding future strategies for the prevention and treatment of NAFLD.

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Nitric oxide facilitates the targeting Kupffer cells of a nano-antioxidant for the treatment of NASH

Cited by 8 publications

References 98 publications

Luteolin-Rich Extract of Thespesia garckeana F. Hoffm. (Snot Apple) Contains Potential Drug-Like Candidates and Modulates Glycemic and Oxidoinflammatory Aberrations in Experimental Animals

Luteolin-Rich Extract of Thespesia garckeana F. Hoffm. (Snot Apple) Contains Potential Drug-Like Candidates and Modulates Glycemic and Oxidoinflammatory Aberrations in Experimental Animals

Liver fibrosis: pathological features, clinical treatment and application of therapeutic nanoagents

Activation of Kupffer cells in NAFLD and NASH: mechanisms and therapeutic interventions

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