Apoptosis perturbations and expression of regulatory inflammatory factors in cisplatin-depleted rat livers under l-arginine protection

Hepatic injury is one of the most common complications associated with cisplatin (CIS) use. Recently, liver protection lines are being discovered to stop the hepatic cell death due to inflammatory and apoptotic perturbations. l-arginine has protective effects in several models of liver injury. This study was designed to investigate the possible protective effect of l-arginine against CIS-induced acute hepatic injury in rats. Rats were divided into 4 groups: control, l-arginine, CIS, l-arginine + CIS. Liver function, oxidative stress, inflammatory cytokines, and apoptosis markers were assessed. l-arginine pretreatment protected the liver against CIS-induced toxicity as indicated by significantly alleviating the changes in liver function along with restoration of the antioxidant status. This finding was confirmed with the markedly improved pathological changes. l-arginine showed anti-inflammatory effect through the reduction of liver expression of iNOS, TNF-α, and NF-κβ, which were ameliorated to significant levels. Furthermore, l-arginine administration downregulated the liver expression of the apoptotic marker, caspase-3. The results recommend l-arginine as a hepatoprotective agent against CIS toxicity. Mostly, this hepatoprotective effect of l-arginine involved anti-inflammatory and anti-apoptotic activities.

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Protective Effects of Total Saponins of Aralia elata (Miq.) on Endothelial Cell Injury Induced by TNF-α via Modulation of the PI3K/Akt and NF-κB Signalling Pathways

International Journal of Molecular Sciences ◽

10.3390/ijms20010036 ◽

2018 ◽

Vol 20 (1) ◽

pp. 36 ◽

Cited By ~ 13

Author(s):

Ping Zhou ◽

Weijie Xie ◽

Yun Luo ◽

Shan Lu ◽

Ziru Dai ◽

...

Keyword(s):

Endothelial Cell ◽

Cell Injury ◽

Inflammatory Responses ◽

Inflammatory Factors ◽

Early Event ◽

Protective Effects ◽

Bax Protein ◽

Aralia Elata ◽

Tnf Α ◽

Anti Inflammatory

Atherosclerosis is an arterial disease associated with inflammation. Hence, the discovery of novel therapeutic agents for suppressing inflammatory responses is urgent and vital for the treatment of atherosclerosis in cardiovascular diseases. The total saponins of Aralia elata (Miq.) Seem. (TAS) are the main components extracted from the Chinese traditional herb Longya Aralia chinensis L., a folk medicine used in Asian countries for treating numerous diseases, enhancing energy and boosting immunity. However, the protective effects of TAS against inflammation-triggered vascular endothelial dysfunction, a critical early event during the course of atherosclerosis, and the potential mechanisms of this protection have been not demonstrated. Accordingly, the aim of this study was to investigate the anti-inflammatory and anti-apoptotic effects and the protective mechanisms of TAS, and show how TAS ameliorates human umbilical vein endothelial cell (HUVEC) damage caused by tumour necrosis factor-α (TNF-α). The results indicated that TAS exerted cytoprotective effects by inhibiting TNF-α-triggered HUVEC apoptosis, mitochondrial membrane potential depolarisation, and the regulation of inflammatory factors (IL-6, MCP-1, and VCAM-1) while suppressing NF-κB transcription. Furthermore, this phenomenon was related to activation of the phosphoinositide 3-kinase (PI3K)/Akt signalling pathway. Blocking the Akt pathway with LY294002, a PI3K inhibitor, reversed the cytoprotective effect of TAS against TNF-α-induced endothelial cell death. Moreover, LY294002 partially abolished the effects of TAS on the upregulation of the Bcl-2 family of proteins and the downregulation of Bax protein expression. In conclusion, the results of our study suggest that TAS suppresses the inflammation and apoptosis of HUVECs induced by TNF-α and that PI3K/Akt signalling plays a key role in promoting cell survival and anti-inflammatory reactions during this process.

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Metformin ameliorates scleroderma via inhibiting Th17 cells and reducing mTOR-STAT3 signaling in skin fibroblasts

Journal of Translational Medicine ◽

10.1186/s12967-021-02860-z ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Jeonghyeon Moon ◽

Seon-yeong Lee ◽

Jeong Won Choi ◽

A Ram Lee ◽

Jin Hee Yoo ◽

...

Keyword(s):

Inflammatory Cytokines ◽

Th17 Cells ◽

Skin Fibroblasts ◽

Inflammatory Factors ◽

Metformin Treatment ◽

Protective Effects ◽

Stat3 Signaling ◽

Tnf Α ◽

Anti Inflammatory ◽

Pro Inflammatory Cytokines

AbstractScleroderma is an autoimmune disease that causes dermal fibrosis. It occurs when collagen accumulates in tissue as a result of persistent inflammation. Th17 cells and pro-inflammatory cytokines such as IL-1β, IL-6, IL-17, and TNF-α play important roles in the pathogenesis of scleroderma. Because metformin, a medication used to treat diabetes, has effective immunoregulatory functions, we investigated its therapeutic function in scleroderma. Mice in a model of bleomycin-induced scleroderma were treated with metformin for 2 weeks. Histological assessment demonstrated protective effects of metformin against scleroderma. Metformin decreased the expression of pro-inflammatory factors in dermal tissue and lymphocytes. It also decreased mRNA expression of pro-inflammatory cytokines (IL-1β, IL-6, IL-17, and TNF-α) and fibrosis-inducing molecules both in vivo and in vitro. These results suggest that metformin treatment has anti-inflammatory effects on lymphocytes via the inhibition of IL-17 and cytokines related to Th17 differentiation, such as IL-1β, IL-6, and TNF-α. To investigate how metformin modulates the inflammatory process in skin fibroblasts, we measured mTOR-STAT3 signaling in skin fibroblasts and found that phosphorylated mTOR and phosphorylated STAT3 protein expression were decreased by metformin treatment. These results suggest that metformin has potential to treat scleroderma by inhibiting pro-inflammatory cytokines and anti-inflammatory activity mediated by mTOR-STAT3 signaling.

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TLR4-MyD88-NF-κB signaling pathway contributes to the progression of secondary hepatic injury and fibrosis in hepatolithiasis

European Journal of Inflammation ◽

10.1177/20587392211014762 ◽

2021 ◽

Vol 19 ◽

pp. 205873922110147

Author(s):

Yuan Fang ◽

Lulu Zhou ◽

Xiaoxuan Hu ◽

Jingyun Guo ◽

Jinmao Liao ◽

...

Keyword(s):

Liver Function ◽

Signaling Pathway ◽

Hepatic Injury ◽

Bile Duct Ligation ◽

Inflammatory Factors ◽

Pathological Changes ◽

Duct Ligation ◽

Tnf Α ◽

Serum Biochemical ◽

Liver Tissues

This paper focused on evaluating the effect of TLR4-MyD88-NF-κB signaling pathway in the progression of secondary hepatic injury and fibrosis in hepatolithiasis. The levels of inflammatory factors (IL-1β, IL-6, TNF-α) and serum biochemical values (ALT, AST, Tbil, Dbil, ALP, GGT) were detected by ELISA. IHC was used to detected the expression level of TLR4 in liver tissues of hepatolithiasis patients and mice. The pathological changes of liver tissue were observed by HE staining. The levels of MyD88, NF-κB, IκB, Laminin (LN), and chitosan enzyme 3-like protein 1 (CHI3L1) were detected by western blotting. In hepatolithiasis patients, the levels of TNF-α, IL-1β, and IL-6 were distinctly raised and proteins associated with TLR4-MyD88-NF-κB signaling pathway (such as TLR4, MyD88, NF-κB, and IκB) in liver tissues were significantly up-regulated. In Bile duct ligation (BDL) model of mice, the results showed that in addition to the significant increase of inflammatory factors, liver function indexes, and fibrosis indexes in BDL mice were also significantly up-regulated. Additionally, TLR4-MyD88-NF-κB signaling pathway was activated in BDL mice. After TLR4 knockdown in BDL mice, inflammatory factors, liver function indexes, and fibrosis indexes were significantly down-regulated. TLR4-MyD88-NF-κB signaling pathway proteins were restrained. TLR4-MyD88-NF-κB signaling pathway took part in the progression of secondary hepatic injury and fibrosis in hepatolithiasis. Inhibition of TLR4-MyD88-NF-κB signaling pathway can reduce the progression of secondary hepatic injury and fibrosis in hepatolithiasis.

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Abstract 353: High Density Lipoprotein Regulates Tumor Necrosis Factor Alpha and Jun Kinase Signaling Pathway in Adipocytes

Circulation Research ◽

10.1161/res.127.suppl_1.353 ◽

2020 ◽

Vol 127 (Suppl_1) ◽

Author(s):

Qiaoqing Zhong

Keyword(s):

Tumor Necrosis ◽

Density Lipoprotein ◽

High Density ◽

Inflammatory Factors ◽

Necrosis Factor Alpha ◽

Tnf Α ◽

Factor Alpha ◽

Anti Inflammatory ◽

Necrosis Factor ◽

Inflammatory Effect

Background: High-density lipoproteins (HDL) is presumed to exhibit cardiovascular protection, since HDL mediate the reverse transport of cholesterol and exhibit strong anti-inflammatory potential. Previous studies have found that HDL can reduce the level of IL-8 secreted by the inflammatory adipocytes, as well as affect the expression of adiponectin and tumor necrosis factor-alpha (TNF-α) under the inflammatory condition in adipocytes. These studies indicate that HDL is closely related to the inflammatory response of adipose tissue, yet its mechanism has not been fully understood. Secretory leucocyte protease inhibitor (SLPI), a nonglycosylated single-chain polypeptide protein, may play an important role in diet-induced obesity and adipocyte inflammation. Purpose: To study the role of SLPI in HDL anti-inflammatory action in the adipocytes, and explore the mechanism of the action. Methods: 3T3-L1 Adipocytes were induced to differentiation and maturation by culturing. Acute inflammation in adipocytes was induced by LPS (100 ng/ml, 6h), and then the adipocytes were pretreated with HDL and/or SLPI-siRNA. The protein and mRNA levels of SLPI, TNF-α and JNK were examined by Western blotting and qRT-PCR assay, respectively. In addition, the levels of inflammatory factors were measured by ELISA. Results: HDL up-regulated SLPI expression, down-regulated TNF-α expression, and inhibited the secretion of inflammatory factors such as IL-1, IL-6, IL-8 and MCP-1 in 3T3-L1 Adipocytes pre-treated by LPS. Silencing of SLPI by its siRNA effectively abolished the anti-inflammatory effect of HDL. JNK inhibitor (SP600125) partially restored the anti-inflammatory effects of HDL decreased by SLPI knockdown and decreased the secretion of inflammatory factors. Conclusions: These data suggest that HDL up-regulate the expression of SLPI and inhibit the inflammation in 3T3-L1 Adipocytes pre-treated by LPS. The anti-inflammatory effect of HDL, including inhibition of the secretion of inflammatory factors via TNF-α/JNK signaling pathway, probably viat up-regulating the SLPI expression. Key words: high-density lipoprotein, Inflammation, Adipocytes

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Extracts from Fermented Black Garlic Exhibit a Hepatoprotective Effect on Acute Hepatic Injury

Molecules ◽

10.3390/molecules24061112 ◽

2019 ◽

Vol 24 (6) ◽

pp. 1112 ◽

Cited By ~ 6

Author(s):

Jen-Chieh Tsai ◽

Yi-An Chen ◽

Jung-Tsung Wu ◽

Kuan-Chen Cheng ◽

Ping-Shan Lai ◽

...

Keyword(s):

Hepatic Injury ◽

Interleukin 1 ◽

Water Layer ◽

Hepatoprotective Effect ◽

Protective Effects ◽

Necrosis Factor Alpha ◽

Tnf Α ◽

Acute Hepatic Injury ◽

Factor Alpha ◽

Anti Inflammatory

The mechanism of hepatoprotective compounds is usually related to its antioxidant or anti-inflammatory effects. Black garlic is produced from garlic by heat treatment and its anti-inflammatory activity has been previously reported. Therefore, the aim of this study was to investigate the hepatoprotective effect of five different extracts of black garlic against carbon tetrachloride (CCl4)-induced acute hepatic injury (AHI). In this study, mice in the control, CCl4, silymarin, and black garlic groups were orally administered distilled water, silymarin, and different fraction extracts of black garlic, respectively, after CCl4 was injected intraperitoneally to induce AHI. The results revealed that the n-butanol layer extract (BA) and water layer extract (WS) demonstrated a hepatoprotective effect by reducing the levels of alanine aminotransferase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP), and hepatic malondialdehyde (MDA). Furthermore, the BA and WS fractions of black garlic extract increased the activity of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), glutathione reductase (GSH-Rd), tumor necrosis factor alpha (TNF-α), and the interleukin-1 (IL-1β) level in liver. It was concluded that black garlic exhibited significant protective effects on CCl4-induced acute hepatic injury.

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Metformin Ameliorates Scleroderma Via Inhibiting Th17 Cells and Reducing mTOR-STAT3 Signaling in Skin Fibroblasts

10.21203/rs.3.rs-139863/v1 ◽

2021 ◽

Author(s):

Jeonghyeon Moon ◽

Seon-yeong Lee ◽

Jeong Won Choi ◽

Aram Lee ◽

Jin Hee Yoo ◽

...

Keyword(s):

Inflammatory Cytokines ◽

Th17 Cells ◽

Skin Fibroblasts ◽

Inflammatory Factors ◽

Metformin Treatment ◽

Protective Effects ◽

Stat3 Signaling ◽

Tnf Α ◽

Anti Inflammatory ◽

Pro Inflammatory Cytokines

Abstract Scleroderma is an autoimmune disease that causes dermal fibrosis. It occurs when collagen accumulates in tissue as a result of persistent inflammation. Th17 cells and pro-inflammatory cytokines such as IL-1β, IL-6, IL-17, and TNF-α play important roles in the pathogenesis of scleroderma. Because metformin, a medication used to treat diabetes, has effective immunoregulatory functions, we investigated its therapeutic function in scleroderma. Mice in a model of bleomycin-induced scleroderma were treated with metformin for 2 weeks. Histological assessment demonstrated protective effects of metformin against scleroderma. Metformin decreased the expression of pro-inflammatory factors in dermal tissue and lymphocytes. It also decreased mRNA expression of pro-inflammatory cytokines (IL-1β, IL-6, IL-17, and TNF-α) and fibrosis-inducing molecules both in vivo and in vitro. These results suggest that metformin treatment has anti-inflammatory effects on lymphocytes via the inhibition of IL-17 and cytokines related to Th17 differentiation, such as IL-1β, IL-6, and TNF-α. To investigate how metformin modulates the inflammatory process in skin fibroblasts, we measured mTOR-STAT3 signaling in skin fibroblasts and found that mTOR and STAT3 protein expression were decreased by metformin treatment. These results suggest that metformin has potential to treat scleroderma by inhibiting pro-inflammatory cytokines and anti-inflammatory activity mediated by mTOR-STAT3 signaling.

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Dipterocarpus tuberculatus Roxb. Ethanol Extract Has Anti-Inflammatory and Hepatoprotective Effects In Vitro and In Vivo by Targeting the IRAK1/AP-1 Pathway

Molecules ◽

10.3390/molecules26092529 ◽

2021 ◽

Vol 26 (9) ◽

pp. 2529

Author(s):

Haeyeop Kim ◽

Woo Seok Yang ◽

Khin Myo Htwe ◽

Mi-Nam Lee ◽

Young-Dong Kim ◽

...

Keyword(s):

Ethanol Extract ◽

Serum Levels ◽

Hepatoprotective Activity ◽

Tnf Α ◽

Anti Inflammatory ◽

Related Proteins ◽

Pro Inflammatory Cytokines ◽

Inflammatory Effect

Dipterocarpus tuberculatus Roxb. has been used traditionally as a remedy for many diseases, especially inflammation. Therefore, we analyzed and explored the mechanism of the anti-inflammatory effect of a Dipterocarpus tuberculatus Roxb. ethanol extract (Dt-EE). Dt-EE clearly and dose-dependently inhibited the expression of pro-inflammatory cytokines such as IL-6, TNF-α, and IL-1β in lipopolysaccharide (LPS)-treated RAW264.7 cells. Also, Dt-EE suppressed the activation of the MyD88/TRIF-mediated AP-1 pathway and the AP-1 pathway related proteins JNK2, MKK4/7, and TAK1, which occurred as a result of inhibiting the kinase activity of IRAK1 and IRAK4, the most upstream factors of the AP-1 pathway. Finally, Dt-EE displayed hepatoprotective activity in a mouse model of hepatitis induced with LPS/D-galactosamine (D-GalN) through decreasing the serum levels of alanine aminotransferase and suppressing the activation of JNK and IRAK1. Therefore, our results strongly suggest that Dt-EE could be a candidate anti-inflammatory herbal medicine with IRAK1/AP-1 inhibitory and hepatoprotective properties.

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Biomimetic nanotherapy: core–shell structured nanocomplexes based on the neutrophil membrane for targeted therapy of lymphoma

Journal of Nanobiotechnology ◽

10.1186/s12951-021-00922-4 ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Qiangqiang Zhao ◽

Duanfeng Jiang ◽

Xiaoying Sun ◽

Qiuyu Mo ◽

Shaobin Chen ◽

...

Keyword(s):

Mesoporous Silica Nanoparticles ◽

Treatment Options ◽

Inflammatory Factors ◽

Main Method ◽

Tnf Α ◽

Good Biocompatibility ◽

Inflammatory Drugs ◽

Anti Inflammatory ◽

New Treatment ◽

Lymphoma Therapy

Abstract Background Non-Hodgkin’s lymphoma (NHL) is a malignant disease of lymphoid tissue. At present, chemotherapy is still the main method for the treatment of NHL. R-CHOP can significantly improve the survival rate of patients. Unfortunately, DOX is the main cytotoxic drug in R-CHOP and it can lead to adverse reactions. Therefore, it is particularly important to uncover new treatment options for NHL. Results In this study, a novel anti-tumor nanoparticle complex Nm@MSNs-DOX/SM was designed and constructed in this study. Mesoporous silica nanoparticles (MSNs) loaded with Doxorubicin (DOX) and anti-inflammatory drugs Shanzhiside methylester (SM) were used as the core of nanoparticles. Neutrophil membrane (Nm) can be coated with multiple nanonuclei as a shell. DOX combined with SM can enhance the anti-tumor effect, and induce apoptosis of lymphoma cells and inhibit the expression of inflammatory factors related to tumorigenesis depending on the regulation of Bcl-2 family-mediated mitochondrial pathways, such as TNF-α and IL-1β. Consequently, the tumor microenvironment (TME) was reshaped, and the anti-tumor effect of DOX was amplified. Besides, Nm has good biocompatibility and can enhance the EPR effect of Nm@MSNs-DOX/SM and increase the effect of active targeting tumors. Conclusions This suggests that the Nm-modified drug delivery system Nm@MSNs-DOX/SM is a promising targeted chemotherapy and anti-inflammatory therapy nanocomplex, and may be employed as a specific and efficient anti-Lymphoma therapy.

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From Inflammation to the Onset of Fibrosis through A2A Receptors in Kidneys from Deceased Donors

International Journal of Molecular Sciences ◽

10.3390/ijms21228826 ◽

2020 ◽

Vol 21 (22) ◽

pp. 8826

Author(s):

Elena Guillén-Gómez ◽

Irene Silva ◽

Núria Serra ◽

Francisco Caballero ◽

Jesús Leal ◽

...

Keyword(s):

Deceased Donor ◽

Inflammatory Factors ◽

Mrna Levels ◽

A2a Adenosine Receptor ◽

A2a Receptors ◽

Tnf Α ◽

Anti Inflammatory ◽

Pka Pathway ◽

Tgf Β1 ◽

M2 Phenotype

Pretransplant graft inflammation could be involved in the worse prognosis of deceased donor (DD) kidney transplants. A2A adenosine receptor (A2AR) can stimulate anti-inflammatory M2 macrophages, leading to fibrosis if injury and inflammation persist. Pre-implantation biopsies of kidney donors (47 DD and 21 living donors (LD)) were used to analyze expression levels and activated intracellular pathways related to inflammatory and pro-fibrotic processes. A2AR expression and PKA pathway were enhanced in DD kidneys. A2AR gene expression correlated with TGF-β1 and other profibrotic markers, as well as CD163, C/EBPβ, and Col1A1, which are highly expressed in DD kidneys. TNF-α mRNA levels correlated with profibrotic and anti-inflammatory factors such as TGF-β1 and A2AR. Experiments with THP-1 cells point to the involvement of the TNF-α/NF-κB pathway in the up-regulation of A2AR, which induces the M2 phenotype increasing CD163 and TGF-β1 expression. In DD kidneys, the TNF-α/NF-κB pathway could be involved in the increase of A2AR expression, which would activate the PKA–CREB axis, inducing the macrophage M2 phenotype, TGF-β1 production, and ultimately, fibrosis. Thus, in inflamed DD kidneys, an increase in A2AR expression is associated with the onset of fibrosis, which may contribute to graft dysfunction and prognostic differences between DD and LD transplants.

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In vitro evidence for the involvement of H2S pathway in the effect of clodronate during inflammatory response

Scientific Reports ◽

10.1038/s41598-021-94228-y ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Rosangela Montanaro ◽

Alessio D’Addona ◽

Andrea Izzo ◽

Carlo Ruosi ◽

Vincenzo Brancaleone

Keyword(s):

Inflammatory Markers ◽

In Vitro Study ◽

Inos Expression ◽

Beneficial Effects ◽

Tnf Α ◽

Inflammatory State ◽

Anti Inflammatory ◽

Underlying Mechanisms ◽

Inflammatory Effect

AbstractClodronate is a bisphosphonate agent commonly used as anti-osteoporotic drug. Throughout its use, additional anti-inflammatory and analgesic properties have been reported, although the benefits described in the literature could not solely relate to their inhibition of bone resorption. Thus, the purpose of our in vitro study is to investigate whether there are underlying mechanisms explaining the anti-inflammatory effect of clodronate and possibly involving hydrogen sulphide (H2S). Immortalised fibroblast-like synoviocyte cells (K4IM) were cultured and treated with clodronate in presence of TNF-α. Clodronate significantly modulated iNOS expression elicited by TNF-α. Inflammatory markers induced by TNF-α, including IL-1, IL-6, MCP-1 and RANTES, were also suppressed following administration of clodronate. Furthermore, the reduction in enzymatic biosynthesis of CSE-derived H2S, together with the reduction in CSE expression associated with TNF-α treatment, was reverted by clodronate, thus rescuing endogenous H2S pathway activity. Clodronate displays antinflammatory properties through the modulation of H2S pathway and cytokines levels, thus assuring the control of the inflammatory state. Although further investigation is needed to stress out how clodronate exerts its control on H2S pathway, here we showed for the first the involvement of H2S in the additive beneficial effects observed following clodronate therapy.

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