Stattic alleviates acute hepatic damage induced by LPS/d-galactosamine in mice

Increasing evidence indicates that signal transducer and activator of transcription 3 (STAT3), a vital transcription factor, plays crucial roles in the regulation of inflammation. STAT3 has become a novel therapeutic target for intervention in inflammation-related disorders. However, it remains unclear whether STAT3 plays a part in acute hepatic damage. To investigate the effects of STAT3 here, LPS/d-GalN-induced hepatic damage was induced in mice, the STAT3 inhibitor Stattic was administered, and the degree of liver injury, inflammation, and hepatocyte apoptosis were investigated. The results showed that Stattic mitigated the hepatic morphologic abnormalities and decreased the level of aminotransferase in LPS/D-GalN-insulted mice. The results also indicated that Stattic decreased the levels of TNF-α and IL-6, prevented the activation of the caspase cascade, suppressed cleavage of PARP, and decreased the quantity of TUNEL-positive cells. These results suggest that Stattic provided protective benefits in LPS/d-GalN-induced hepatic damage, and the protective effects might be associated with its anti-inflammatory and anti-apoptotic effects. Therefore, STAT3 might become a novel target for intervening in inflammation-based and apoptosis-based hepatic disorders.

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Succinate dehydrogenase inhibitor dimethyl malonate alleviates LPS/d-galactosamine-induced acute hepatic damage in mice

Innate Immunity ◽

10.1177/1753425919873042 ◽

2019 ◽

Vol 25 (8) ◽

pp. 522-529 ◽

Cited By ~ 1

Author(s):

Yongqiang Yang ◽

Ruyue Shao ◽

Li Tang ◽

Longjiang Li ◽

Min Zhu ◽

...

Keyword(s):

Liver Injury ◽

Succinate Dehydrogenase ◽

Hepatic Damage ◽

Hepatocyte Apoptosis ◽

Dimethyl Malonate ◽

Tnf Α ◽

Novel Target ◽

Succinate Dehydrogenase Inhibitor ◽

And Oxidative Stress ◽

Pro Inflammatory Cytokines

In addition to its energy-supplying function, increasing evidence suggests that mitochondria also play crucial roles in the regulation of inflammation. Succinate dehydrogenase is also known as mitochondrial complex II, and inhibition of succinate dehydrogenase by dimethyl malonate has been reported to suppress the production of pro-inflammatory cytokines. In the present study, the potential anti-inflammatory benefits of dimethyl malonate were investigated in a mouse model with LPS/d-galactosamine-induced acute hepatic damage. Male BALB/c mice were injected i.p. with LPS and d-galactosamine to cause liver injury. The degree of liver injury, inflammatory response and oxidative stress and the survival of the experimental animals were determined. The results indicated dimethyl malonate decreased the level of aminotransferases in plasma, alleviated histological abnormalities in liver, inhibited the induction of TNF-α and IL-6 in plasma, suppressed hepatocyte apoptosis and improved the survival of LPS/d-galactosamine-exposed mice. Therefore, inhibition of succinate dehydrogenase by dimethyl malonate significantly alleviated LPS/d-galactosamine-induced hepatic damage, which suggests that succinate dehydrogenase might become a novel target for the intervention of inflammation-based hepatic disorders.

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The Role of Signal Transducer and Activator of Transcription 3 (STAT3) and Its Targeted Inhibition in Hematological Malignancies

Cancers ◽

10.3390/cancers10090327 ◽

2018 ◽

Vol 10 (9) ◽

pp. 327 ◽

Cited By ~ 39

Author(s):

Loukik Arora ◽

Alan Kumar ◽

Frank Arfuso ◽

Wee Chng ◽

Gautam Sethi

Keyword(s):

Hematological Malignancies ◽

Signal Transducer ◽

Therapeutic Approaches ◽

Janus Kinases ◽

Constitutive Activation ◽

Targeted Inhibition ◽

Transcription Activators ◽

Apoptotic Effects ◽

Transcription 3

Signal transducer and activator of transcription 3 (STAT3), a member of the STAT protein family, can be phosphorylated by receptor-associated Janus kinases (JAKs) in response to stimulation by cytokines and growth factors. It forms homo- or heterodimers that can translocate to the cell nucleus where they act as transcription activators. Constitutive activation of STAT3 has been found to be associated with initiation and progression of various cancers. It can exert proliferative as well as anti-apoptotic effects. This review focuses on the role of STAT3 in pathogenesis i.e., proliferation, differentiation, migration, and apoptosis of hematological malignancies viz. leukemia, lymphoma and myeloma, and briefly highlights the potential therapeutic approaches developed against STAT3 activation pathway.

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Hypoxia-mediated activation of signal transducer and activator of transcription 3 (STAT3) in ovarian cancer: A novel therapeutic strategy using HO-3867, a STAT3 inhibitor

Gynecologic Oncology ◽

10.1016/j.ygyno.2010.12.062 ◽

2011 ◽

Vol 120 ◽

pp. S25

Author(s):

G. McCann ◽

K. Selvendiran ◽

K. Hideg ◽

D. Cohn ◽

P. Kuppusamy

Keyword(s):

Ovarian Cancer ◽

Therapeutic Strategy ◽

Signal Transducer ◽

Transcription 3 ◽

Novel Therapeutic

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Attenuation of STAT3 Signaling Cascade by Daidzin Can Enhance the Apoptotic Potential of Bortezomib against Multiple Myeloma

Biomolecules ◽

10.3390/biom10010023 ◽

2019 ◽

Vol 10 (1) ◽

pp. 23 ◽

Cited By ~ 8

Author(s):

Min Hee Yang ◽

Sang Hoon Jung ◽

Arunachalam Chinnathambi ◽

Tahani Awad Alahmadi ◽

Sulaiman Ali Alharbi ◽

...

Keyword(s):

Multiple Myeloma ◽

Therapeutic Strategy ◽

Tyrosine Phosphatase ◽

Signaling Cascade ◽

Signal Transducer ◽

Stat3 Signaling ◽

Anti Cancer ◽

Prostate Cancers ◽

Apoptotic Effects ◽

Transcription 3

Daidzin (DDZ) extracted from Pueraria lobate (Fabaceae) is a widely known phytoestrogen. DDZ can display anti-cancer activities against breast and prostate cancers, but its anti-oncogenic actions in multiple myeloma (MM) cells have not been studied. The signal transducer and activator of transcription 3 (STAT3) can control key processes including proliferation, differentiation, and survival in MM cells. Here, we noted that DDZ abrogated STAT3 activation (both constitutive as well as inducible) at Tyr705 and Ser727 in MM cells. Additionally, DDZ mitigated the phosphorylation of STAT3 upstream Janus-activated kinases (JAK1/2) and c-Src kinases. Pervanadate (tyrosine phosphatase blocker) exposure altered the DDZ-induced inhibition of STAT3 activation, thus affecting the action of this phytoestrogen on apoptosis. Moreover, DDZ impeded proliferation and augmented the apoptotic effects of bortezomib (Bor) in MM cells. Overall, the data indicate that DDZ may act as a potent suppressor of STAT3 signaling cascade, and the co-treatment of DDZ and Bor could be a promising therapeutic strategy, specifically in MM.

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Protective Effects of Estradiol on Ethanol-Induced Bone Loss Involve Inhibition of Reactive Oxygen Species Generation in Osteoblasts and Downstream Activation of the Extracellular Signal-Regulated Kinase/Signal Transducer and Activator of Transcription 3/Receptor Activator of Nuclear Factor-κB Ligand Signaling Cascade

Journal of Pharmacology and Experimental Therapeutics ◽

10.1124/jpet.107.130351 ◽

2007 ◽

Vol 324 (1) ◽

pp. 50-59 ◽

Cited By ~ 58

Author(s):

Jin-Ran Chen ◽

Kartik Shankar ◽

Shanmugam Nagarajan ◽

Thomas M. Badger ◽

Martin J. J. Ronis

Keyword(s):

Reactive Oxygen Species Generation ◽

Nuclear Factor Κb ◽

Nuclear Factor ◽

Oxygen Species ◽

Protective Effects ◽

Signal Transducer ◽

Extracellular Signal Regulated Kinase ◽

Extracellular Signal ◽

Receptor Activator ◽

Transcription 3

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Signal Transducer and Activator of Transcription 3 in Liver Diseases: A Novel Therapeutic Target

International Journal of Biological Sciences ◽

10.7150/ijbs.7.536 ◽

2011 ◽

Vol 7 (5) ◽

pp. 536-550 ◽

Cited By ~ 152

Author(s):

Hua Wang ◽

Fouad Lafdil ◽

Xiaoni Kong ◽

Bin Gao

Keyword(s):

Therapeutic Target ◽

Liver Diseases ◽

Signal Transducer ◽

Transcription 3 ◽

Novel Therapeutic

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SHED ameliorated concanavalin A-induced autoimmune hepatitis by protecting hepatocytes from apoptosis

10.21203/rs.3.rs-17847/v1 ◽

2020 ◽

Author(s):

Yikun Zhou ◽

Ruili Yang ◽

Lingsu Zhu ◽

Huaming Huang ◽

Shengjie Cui ◽

...

Keyword(s):

Liver Injury ◽

Autoimmune Hepatitis ◽

Concanavalin A ◽

Acute Liver Injury ◽

Deciduous Teeth ◽

Protective Effects ◽

Hepatocyte Apoptosis ◽

Con A ◽

Tnf Α ◽

Ifn Γ

Abstract Background：Autoimmune hepatitis (AIH) is serious autoimmune liver diseases that threaten people’s health worldwide, emphasizing the need to identify novel treatment. Stem cells from human exfoliated deciduous teeth (SHED), which is easy to obtain and non-invasive, showed pronounced proliferation and immunomodulation capacity. This study aims to investigate the effect of SHED on ConA-induced AIH and the potential underlying mechanisms.Methods: We used a concanavalin A (ConA) induced acute hepatitis mouse model and in vitro co-culture system to study the protective effects of SHED on ConA-induced autoimmune hepatitis and the underlying mechanisms.Results: SHED infusion could prevent aberrant histopathological architecture of liver with infiltration of abundant of CD3+, CD4+, TNF-α+ and IFN-γ+ inflammatory cells induced by ConA. The expression of ALT and AST which indicated the liver function significantly elevated in hepatitis mice. While SHED infusion could block the elevation of ALT and AST induced by ConA. Mechanistically, Con-A upregulated TNF-α and IFN-γ expression activated NF-κB pathways to induced hepatocyte apoptosis, resulting in acute liver injury. SHED administration protected hepatocytes from Con-A-induced apoptosis. Conclusions: These results demonstrated that SHED alleviated ConA-induced acute liver injury via inhibition of hepatocyte apoptosis mediated by the NF-κB pathways. Our findings could provide a potential prevention and therapeutic strategy for hepatitis and acute hepatic injury.

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A Michael Acceptor Analogue, SKSI-0412, Down-Regulates Inflammation and Proliferation Factors through Suppressing Signal Transducer and Activator of Transcription 3 Signaling in IL-17A-Induced Human Keratinocyte

International Journal of Molecular Sciences ◽

10.3390/ijms22168813 ◽

2021 ◽

Vol 22 (16) ◽

pp. 8813

Author(s):

A-Ram Kim ◽

Seungbeom Lee ◽

Jung U Shin ◽

Seung Hui Seok ◽

Young-Ger Suh ◽

...

Keyword(s):

Cell Proliferation ◽

Therapeutic Strategy ◽

Signal Transducer ◽

Synthetic Compounds ◽

Human Keratinocyte ◽

Stat3 Phosphorylation ◽

Michael Acceptor ◽

Transcription 3 ◽

Psoriatic Lesions ◽

Novel Therapeutic

The activation of signal transducer and activator of transcription 3 (STAT3), as well as up-regulation of cytokines and growth factors to promote STAT3 activation, have been found in the epidermis of psoriatic lesions. Recently, a series of synthetic compounds possessing the Michael acceptor have been reported as STAT3 inhibitors by covalently binding to cysteine of STAT3. We synthesized a Michael acceptor analog, SKSI-0412, and confirmed the binding affinity between STAT3 and SKSI-0412. We hypothesized that the SKSI-0412 can inhibit interleukin (IL)-17A-induced inflammation in keratinocytes. The introduction of IL-17A increased the phosphorylation of STAT3 in keratinocytes, whereas the inactivation of STAT3 by SKSI-0412 reduced IL-17A-induced STAT3 phosphorylation and IκBζ expression. In addition, human β defensin-2 and S100A7, which are regulated by IκBζ, were significantly decreased with SKSI-0412 administration. We also confirmed that SKSI-0412 regulates cell proliferation, which is the major phenotype of psoriasis. Based on these results, we suggest targeting STAT3 with SKSI-0412 as a novel therapeutic strategy to regulate IL-17A-induced psoriatic inflammation in keratinocytes.

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