15-Lipoxygenase-2 Deficiency Induces a Dysfunction in Macrophages That Can Be Restored by Salidroside

Abstract 15-Lipoxygenase-2(15-LOX-2) is thought to regulate inflammation and immunological function however, its mechanisms of action are still unclear. Furthermore, it has been reported that salidroside has anti inflammatory properties , but its role in macrophage function has not been understood yet In this study, we aimed to determine how 15-LOX-2 expression level s affect the function of macrophages and the effect of salidroside on 15-LOX-2 deficient macrophages We used multiple functional genetic strategies to determine 15-LOX-2 function in macrophages. 15-LOX-2 deficiency promotes phagocytosis and proliferation of macrophages and impairs their apoptosis Mechanistically, t he expression levels of cyclophilinB (CypB) were upregulated in 15-LOX-2 deficient Ana 1 macrophages, whereas those of caspase 3 were down regulated. Furthermore, RNA-seq analysis showed that inflammation, complement, and TNF-α signaling pathway s were all activated in 15-LOX-2 deficient Ana 1 macrophages. Treatment of 15-LOX-2 deficient macrophages with salidroside, a natural product derived from Rhodiola species, effectively reversed the effects of 15-LOX-2 deficiency on caspase 3 and CypB levels, as well as on apoptosis and proliferation. In conclusion, our study shows that there is a newly identified link between 15-LOX-2 deficiency and salidroside in regulating macrophage survival, proliferation, and function. Salidroside may be a promising therapeutic strategy for treating inflammation related diseases resulting from 15-LOX-2 deficiency.

Download Full-text

Oxymatrine protects against sepsis-induced myocardial injury via inhibition of the TNF-α/p38-MAPK/caspase-3 signaling pathway

Molecular Medicine Reports ◽

10.3892/mmr.2016.5250 ◽

2016 ◽

Vol 14 (1) ◽

pp. 551-559 ◽

Cited By ~ 15

Author(s):

MINGHAO ZHANG ◽

XIUYU WANG ◽

BIN BAI ◽

RUI ZHANG ◽

YUNHONG LI ◽

...

Keyword(s):

Signaling Pathway ◽

P38 Mapk ◽

Myocardial Injury ◽

Caspase 3 ◽

Tnf Α

Download Full-text

Electroacupuncture stimulation at Yanglingquan acupoint ameliorates hepatic ischemia-reperfusion injury by down-regulating ET-1 to inhibit TAK1-JNK/p38 pathway

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00012.2021 ◽

2021 ◽

Author(s):

Lai Wei ◽

Yinyin Su ◽

Siyou Tan ◽

Yi Zou ◽

Yixun Tang ◽

...

Keyword(s):

Reperfusion Injury ◽

Signaling Pathway ◽

Caspase 3 ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Expression Patterns ◽

Hepatic Ischemia ◽

Tnf Α ◽

Hepatic Ischemia Reperfusion ◽

Liver Tissues

The current study set out to investigate the molecular mechanism of electroacupuncture (EA) stimulation at Yanglingquan acupoint (GB34) in hepatic ischemia-reperfusion injury (HIRI) in rats via regulation of the endothelin-1 (ET-1) mediated transforming growth factor-β-activated kinase-1 (TAK1)-c-Jun NH2-terminal kinase (JNK)/p38 signaling pathway. First, EA stimulation was applied to the constructed rat model of HIRI at GB34. Subsequently, the activities of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) and myeloperoxidase (MPO) in liver tissues were measured. Apoptotic changes in liver tissues in rats with HIRI were observed using TUNEL staining. Western blot assay was employed to determine the expression patterns of Bcl-2, Bax, c-caspase-3 and the activation of TAK1-JNK/p38 signaling pathway, and immunohistochemistry was conducted to determine the protein expression patterns of c-caspase-3 and ET-1. In addition, ELISA was performed to determine the levels of tumor necrosis factor-α (TNF-α), interleukin (IL)-1β and IL-6 in serum. The results demonstrated a significant decline in the activities of AST and ALT and hepatocyte apoptosis in rats with HIRI following EA stimulation. Meanwhile, EA stimulation brought about decreases in the expression levels of Bcl-2, Bax and c-caspase-3, MPO activity, TNF-α, IL-1β and IL-6 in serum, and diminished those of ET-1 in liver tissues, in addition to inhibiting the TAK1-JNK/p38 signaling pathway. Over-expression of ET-1 could counter the inhibitory effects of EA stimulation of HIRI in rats. Together, our findings indicate that EA stimulation at GB34 down-regulates the expression of ET-1, which inhibits the TAK1-JNK/p38 signaling pathway, consequently alleviating HIRI in rats.

Download Full-text

Marine furanocembranoids-inspired macrocycles enabled by Pd-catalyzed unactivated C(sp3)-H olefination mediated by donor/donor carbenes

Nature Communications ◽

10.1038/s41467-021-21484-x ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Jiping Hao ◽

Xueying Guo ◽

Shijun He ◽

Zhongliang Xu ◽

Lu Chen ◽

...

Keyword(s):

Dft Calculations ◽

Natural Product ◽

Organic Synthesis ◽

Diazo Compounds ◽

Assembly Strategy ◽

Tnf Α ◽

Anti Inflammatory ◽

And Function

AbstractBiomimetic modularization and function-oriented synthesis of structurally diversified natural product-like macrocycles in a step-economical fashion is highly desirable. Inspired by marine furanocembranoids, herein, we synthesize diverse alkenes substituted furan-embedded macrolactams via a modular biomimetic assembly strategy. The success of this assembly is the development of crucial Pd-catalyzed carbene coupling between ene-yne-ketones as donor/donor carbene precursors and unactivated Csp3‒H bonds which represents a great challenge in organic synthesis. Notably, this method not only obviates the use of unstable, explosive, and toxic diazo compounds, but also can be amenable to allenyl ketones carbene precursors. DFT calculations demonstrate that a formal 1,4-Pd shift could be involved in the mechanism. Moreover, the collected furanocembranoids-like macrolactams show significant anti-inflammatory activities against TNF-α, IL-6, and IL-1β and the cytotoxicity is comparable to Dexamethasone.

Download Full-text

Marine Furanocembranoids-Inspired Macrocycles Enabled by Pd-catalyzed Unactivated C(sp3)-H Insertion Reaction of Donor/Donor Carbenes

10.21203/rs.3.rs-58031/v1 ◽

2020 ◽

Author(s):

Jiping Hao ◽

Xueying Guo ◽

Shijun He ◽

Zhongliang Xu ◽

Lu Chen ◽

...

Keyword(s):

Dft Calculations ◽

Natural Product ◽

Organic Synthesis ◽

Diazo Compounds ◽

Insertion Reaction ◽

Assembly Strategy ◽

Tnf Α ◽

Anti Inflammatory ◽

Low Cytotoxicity ◽

And Function

Abstract Biomimetic modularization and function-oriented synthesis of structurally diversified natural product-like macrocycles in a step-economical fashion is highly desirable. Inspired by marine furanocembranoids, herein, we unprecedentedly synthesized diverse alkenes substituted furan-embedded macrolactams via a modular biomimetic assembly strategy. The success of this assembly is the development of crucial Pd-catalyzed carbene coupling between ene-yne-ketones as donor/donor carbene precursors and unactivated Csp3‒H bonds which represents a great challenge in organic synthesis. Notably, this method not only obviates the use of unstable, explosive, and toxic diazo compounds, but also can be amenable to allenyl ketones carbene precursors. DFT calculations demonstrated that a 1,4-Pd shift could be involved in the mechanism. Moreover, the collected furanocembranoids-like macrolactams showed significant anti-inflammatory activities against TNF-α, IL-6, and IL-1β and the low cytotoxicity is comparable to Dexamethasone.

Download Full-text

Exploratory Investigation of Intestinal Structure and Function after Stroke in Mice

Mediators of Inflammation ◽

10.1155/2021/1315797 ◽

2021 ◽

Vol 2021 ◽

pp. 1-12

Author(s):

Diya Ye ◽

Yuting Hu ◽

Ning Zhu ◽

Weizhong Gu ◽

Gao Long ◽

...

Keyword(s):

Ischemic Stroke ◽

Intestinal Mucosa ◽

Caspase 3 ◽

Disease Model ◽

Death Receptor ◽

Intestinal Barrier ◽

Structure And Function ◽

Intestinal Barrier Function ◽

Tnf Α ◽

And Function

Stroke is the second leading cause of death worldwide. Patients who have a stroke are susceptible to many gastrointestinal (GI) complications, such as dysphagia, GI bleeding, and fecal incontinence. However, there are few studies focusing on the GI tract after stroke. The current study is to investigate the changes of intestinal structure and function in mice after ischemic stroke. Ischemic stroke was made as a disease model in mice, in which brain and ileal tissues were collected for experiments on the 1st and 7th day after stroke. Intestinal motility of mice was inhibited, and intestinal permeability was increased after stroke. Hematoxylin-eosin (HE) staining showed the accumulation of leucocytes in the intestinal mucosa. Myeloperoxidase (MPO) activity and inflammatory proteins (nuclear factor kappa-B (NF-κB), inducible nitric oxide synthase (iNOS)) in the small intestine were significantly increased in mice after stroke. The expression of tight junction (TJ) proteins (zonula occludens-1 (ZO-1), occludin, and claudin-1) was downregulated, and transmission electron microscopy (TEM) showed broken TJ of the intestinal mucosa after stroke. Glial fibrillary acidic protein (GFAP) and the apoptosis-associated proteins (tumor necrosis factor (TNF-α), caspase-3, and cleaved caspase-3) were notably upregulated as well. Ischemic stroke led to negative changes on intestinal structure and function. Inflammatory mediators and TNF-α-induced death receptor signaling pathways may be involved and disrupt the small intestinal barrier function. These results suggest that stroke patients should pay attention to GI protection.

Download Full-text

Nano-Curcumin Protects Against Sodium Nitrite–Induced Lung Hypoxia Through Modulation of Mitogen-Activated Protein Kinases/c-Jun NH2-Terminal Kinase Signaling Pathway

Dose-Response ◽

10.1177/15593258211033148 ◽

2021 ◽

Vol 19 (3) ◽

pp. 155932582110331

Author(s):

Ahlam Alhusaini ◽

Sara Alhumaidan ◽

Renad Almogren ◽

Shaikha Alsaif ◽

Ebtesam Alsultan ◽

...

Keyword(s):

Signaling Pathway ◽

Protein Kinases ◽

Sodium Nitrite ◽

Caspase 3 ◽

Tissue Inhibitors Of Metalloproteinases ◽

Control Group ◽

Mitogen Activated Protein Kinases ◽

Tnf Α ◽

Mitogen Activated Protein ◽

Hypoxic Group

Background and objective This study was designed to compare the efficacy of curcumin (CRN) with that of nano-curcumin (N-CRN) in the mitigation of various biochemical indices in hypoxic lung induced by sodium nitrite (SN) in rats. Methods Twenty-four adult male albino rats were divided into 4 groups. Group 1: control group received carboxy methyl cellulose; Group 2: hypoxic group injected with single dose of SN (60 mg/kg, s.c.); Group 3: SN-intoxicated rats pre-injected with CRN (100 mg/kg, i.p.); and Group 4: SN-intoxicated rats pre-injected with N-CRN (100 mg/kg, i.p.). Curcumin and N-CRN were administered intraperitoneally 2 hour prior to SN intoxication. Hemoglobin concentration, serum tumor necrosis factor-alpha (TNF-α), and caspase-3 were analyzed. Gene expression of hypoxia inducible factor-1 (HIF-1α), matrix metallo-proteinases (MMP)-2, and tissue inhibitors of metalloproteinases (TIMPs)-2, as well as the protein expression of mitogen-activated protein kinases (MAPKs) and c-Jun NH2-terminal kinase (JNK) were examined in lung tissues. Results Hemoglobin level was markedly reduced, and serum TNF-α and caspase-3 were significantly elevated post SN intoxication. The lung MMP-2 and HIF-1α mRNA were overexpressed in the hypoxic group; while TIMP-2 mRNA was downregulated. Sodium nitrite administration increased proteins’ expressions of MAPK and JNK. Pretreatment with CRN or N-CRN markedly mitigated those alterations. These results were supported by histopathological examinations of lung tissue. Conclusion Interestingly, N-CRN exhibited a pronounced protective effect via suppression of inflammatory and apoptotic biomarkers and modulation of MAPK/JNK signaling pathway.

Download Full-text

Simvastatin Protects Hepatocytes From Apoptosis by Suppressing the TNF-α/Caspase-3 Signaling Pathway in Mice With Burn Injury

Annals of Surgery ◽

10.1097/sla.0b013e318273fdca ◽

2013 ◽

Vol 257 (6) ◽

pp. 1129-1136 ◽

Cited By ~ 6

Author(s):

Gaofeng Zhao ◽

Yong-Ming Yu ◽

Masao Kaneki ◽

Ronald G. Tompkins ◽

Alan J. Fischman

Keyword(s):

Signaling Pathway ◽

Caspase 3 ◽

Burn Injury ◽

Tnf Α

Download Full-text

Upregulation of microRNA-96 alleviates the neurological damage in acute seizure rats by down-regulating RAC1 and inhibiting the activation of RhoA/ROCK signaling pathway

10.21203/rs.2.19156/v1 ◽

2019 ◽

Author(s):

Zhihan Wang ◽

Wei Jiang ◽

Dabin Ren ◽

Wei Chen ◽

Ping Zheng

Keyword(s):

Signaling Pathway ◽

Caspase 3 ◽

Rat Hippocampus ◽

Luciferase Assay ◽

Neurological Damage ◽

Altered Expression ◽

Tnf Α ◽

Acute Seizure ◽

Related Proteins

Abstract Objective Today, the research about the involvement of non-coding RNAs on neurological disorders is still scarce. Hence, we aimed to investigate the effect of miR-96 targeted RAC1 to mediate RhoA/ROCK signaling pathway in neurological damage in acute seizure rats.MethodsThe acute seizure rat model was constructed by using classical chlorinated-pilocarpine injection, which was treated with miR-96 mimics, RAC1-siRNA or their controls. The number of BrdU positive cells, neuronal changes and apoptosis, expression of NGF, BDNF and GFAP were detected by different staining assays. At the same time, the activity of SOD, the content of MDA and the protein contents of TNF-α and IL-6 in rat hippocampus were detected as well. Next, the expression of NGF, BDNF, GFAP, Bax, Bcl-2, caspase-3, RAC1, RhoA and ROCK were determined by RT-qPCR and western blot analysis. Then, the binding site between miR-96 and RAC1 was analyzed by bioinformatics software and luciferase assay. Finally, the altered expression of miRNAs was investigated in exosomes released from excitotoxic neurons with a customized rat miRNA chipset.Results After upregulation of miR-96 or downregulation RAC1, BrdU-positive cells, TUNEL-positive cells, NGF, GFAP, MDA, TNF-α, IL-6, Bax, caspase-3, and pathway related proteins in rat hippocampus decreased while Bcl-2, BDNF, and the activity of SOD increased. Furthermore, RAC1 was found to be the target gene of miR-96 and their relationship was validated in in-vitro studies. Finally, the decreased expression of miR-96 in exosomes from kainic acid treated neurons was identified as well.Conclusion This study suggests that upregulation of miR-96 could downregulate RAC1 and inhibit the activation of RhoA/ROCK signaling pathway, thus alleviated the neurological damage in acute seizure rats.

Download Full-text

YQWY Decoction Improves Myocardial Remodeling via Activating the IL-10/Stat3 Signaling Pathway

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2020/7532892 ◽

2020 ◽

Vol 2020 ◽

pp. 1-10

Author(s):

He Li ◽

Zhi-Jun Gong ◽

Yun He ◽

Jing-Jing Huang ◽

Yu-Ning Jiang ◽

...

Keyword(s):

Left Ventricular Function ◽

Ventricular Function ◽

Signaling Pathway ◽

Myocardial Fibrosis ◽

Caspase 3 ◽

Left Ventricular ◽

Collagen I ◽

Stat3 Signaling ◽

Stat3 Signaling Pathway ◽

Tnf Α

Heart failure (HF) has been known as a global health problem, and cardiac remodeling plays an essential role in the development of HF. We hypothesized that YQWY decoction might exert a cardioprotective effect against myocardium inflammation, fibrosis, and apoptosis via activating the interleukin-10 (IL-10)/Stat3 signaling pathway. To test this hypothesis, the HF model in rats was established by pressure overload through the minimally invasive transverse aortic constriction (MTAC). Echocardiography was performed to assess the left ventricular function of rats. Myocardial fibrosis in rats was observed by Masson and Picrosirius red staining, and the degree of myocardial apoptosis was detected via TUNEL staining. In addition, expression levels of IL-10, tumor necrosis factor-α (TNF-α), Stat3 (P-Stat3), P65 (P-P65), CD68, collagen I, TGF-β, CTGF, Bax, Bcl-2, cleaved caspase-3, and PARP in rat serum and myocardium samples were examined by ELISA, western blot, and immunohistochemistry, respectively. YQWY decoction treatment significantly improved left ventricular function in HF rats, especially in those of the high-dose group (LVEF%: 51.29 ± 5.876 vs. 66.02 ± 1.264, P < 0.01 ;, LVFS%: 27.75 ± 3.757 vs. 37.76 ± 1.137, P < 0.01 ). Furthermore, YQWY decoction markedly inhibited MTAC-induced myocardial fibrosis as evidenced by downregulated collagen I, TGF-β, and CTGF in myocardium and alleviated apoptosis (downregulated caspase-3 and PARP and increased Bcl-2/Bax ratio in cardiomyocytes). In addition, YQWY decoction decreased the level of the proinflammatory cytokine TNF-α in both circulating blood and myocardium and attenuated infiltration of inflammatory cells in heart tissue from HF rats. Most importantly, YQWY decoction suppressed MTAC-induced NF-κB activation and phosphorylated Stat3 by upregulating IL-10 in rat heart tissues. Our study showed that YQWY decoction could attenuate MTAC-induced myocardial inflammation, fibrosis, apoptosis, and reverse the impairment of cardiac function in rats by activating the IL-10/Stat3 signaling pathway and improving myocardium remodeling. Our findings suggested a therapeutic potential of YQWY decoction in HF.

Download Full-text

Transcriptome profiling unveils GAP43 regulates ABC transporters and EIF2 signaling in colorectal cancer cells

BMC Cancer ◽

10.1186/s12885-020-07728-x ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Xi Chen ◽

Hongjin Wu ◽

Jia Feng ◽

Ying Li ◽

Jiao Lv ◽

...

Keyword(s):

Colorectal Cancer ◽

Signaling Pathway ◽

Abc Transporters ◽

Transcriptome Profiling ◽

Receptor Interaction ◽

Genomic Sequencing ◽

Rna Seq ◽

Bisulfite Genomic Sequencing ◽

Transcriptional Alterations ◽

And Function

Abstract Background The growth- and plasticity-associated protein-43 (GAP43) is biasedly expressed in indigestive system and nervous system. Recent study has shown that GAP43 is responsible for the development of neuronal growth and axonal regeneration in normal nervous tissue, while serves as a specific biomarker of relapsed or refractory neuroblastoma. However, its expression pattern and function in digestive system cancer remains to be clarified. Methods In this study, we examined the GAP43 status with qRT-PCR and bisulfite genomic sequencing in colorectal cancer (CRC). We investigated the effect of overexpressed GAP43 in CRC cells with RNA-seq. The RNA-seq data was analyzed with DAVID and IPA. Results GAP43 was downregulated in CRC compared to the adjacent tissues. DNA methylase inhibitor 5-Aza-CdR treatment could significantly induce GAP43, indicated that the silencing of GAP43 gene in CRC is closely related to DNA methylation. Bisulfite genomic sequencing confirmed the promoter methylation of GAP43 in CRC. To explore the transcriptional alterations by overexpressed GAP43 in CRC, we performed RNA-seq and found that upregulated genes were significantly enriched in the signaling pathways of ABC transporters and ECM-receptor interaction, while downregulated genes were significantly enriched in Ribosome signaling pathway. Further Ingenuity Pathway Analysis (IPA) showed that EIF2 signaling pathway was significantly repressed by overexpression of GAP43. Conclusion Our findings provide a novel mechanistic insight of GAP43 in CRC. Transcriptome profiling of overexpressed GAP43 in CRC uncovered the functional roles of GAP43 in the development of human CRC.

Download Full-text