Anti‐tumour effect of Odoroside A and its derivative on human leukaemia cells through the ROS/JNK pathway

Abstract Background Hyperhomocysteinemia (HHcy) plays an important role in the progression of many kidney diseases; however, the relationship between HHcy and ischemia-reperfusion injury (IRI)-induced acute kidney injury (IRI-induced AKI) is far from clear. In this study, we try to investigate the effect and possible mechanisms of HHcy on IRI-induced AKI. Methods Twenty C57/BL6 mice were reared with a regular diet or high methionine diet for 2 weeks (to generate HHcy mice); after that, mice were subgrouped to receive sham operation or ischemia-reperfusion surgery. Twenty four hour after reperfusion, serum creatinine, blood urea nitrogen, and Malondialdehyde (MDA) were measured. H&E staining for tubular injury, western blot for γH2AX, JNK, p-JNK, and cleaved caspase 3, and TUNEL assay for tubular cell apoptosis were also performed. Results Our results showed that HHcy did not influence the renal function and histological structure, as well as the levels of MDA, γH2AX, JNK, p-JNK, and tubular cell apoptosis in control mice. However, in IRI-induced AKI mice, HHcy caused severer renal dysfunction and tubular injury, higher levels of oxidative stress, DNA damage, JNK pathway activation, and tubular cell apoptosis. Conclusion Our results demonstrated that HHcy could exacerbate IRI-induced AKI, which may be achieved through promoting oxidative stress, DNA damage, JNK pathway activation, and consequent apoptosis.

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The AF-6 Homolog Canoe Acts as a Rap1 Effector During Dorsal Closure of the Drosophila Embryo

Genetics ◽

10.1093/genetics/165.1.159 ◽

2003 ◽

Vol 165 (1) ◽

pp. 159-169

Author(s):

Benjamin Boettner ◽

Phoebe Harjes ◽

Satoshi Ishimaru ◽

Michael Heke ◽

Hong Qing Fan ◽

...

Keyword(s):

Molecular Mechanisms ◽

Genetic Interaction ◽

Critical Role ◽

Adherens Junction ◽

Small Gtpases ◽

Drosophila Embryo ◽

Dorsal Closure ◽

Cell Sheets ◽

Jnk Pathway

Abstract Rap1 belongs to the highly conserved Ras subfamily of small GTPases. In Drosophila, Rap1 plays a critical role in many different morphogenetic processes, but the molecular mechanisms executing its function are unknown. Here, we demonstrate that Canoe (Cno), the Drosophila homolog of mammalian junctional protein AF-6, acts as an effector of Rap1 in vivo. Cno binds to the activated form of Rap1 in a yeast two-hybrid assay, the two molecules colocalize to the adherens junction, and they display very similar phenotypes in embryonic dorsal closure (DC), a process that relies on the elongation and migration of epithelial cell sheets. Genetic interaction experiments show that Rap1 and Cno act in the same molecular pathway during DC and that the function of both molecules in DC depends on their ability to interact. We further show that Rap1 acts upstream of Cno, but that Rap1, unlike Cno, is not involved in the stimulation of JNK pathway activity, indicating that Cno has both a Rap1-dependent and a Rap1-independent function in the DC process.

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The Mechanism of Jian-Gan-Xiao-Zhi Decoction in Insulin Resistant Adipocytes and Its Component Analysis

Natural Product Communications ◽

10.1177/1934578x21997678 ◽

2021 ◽

Vol 16 (3) ◽

pp. 1934578X2199767

Author(s):

Fang Fang ◽

Wei-Bo Wen ◽

Xue-Hua Xie ◽

Ling Yang ◽

Xu Zhang ◽

...

Keyword(s):

Lipid Synthesis ◽

Glucose Consumption ◽

Astragaloside Iv ◽

Serum Samples ◽

Rat Serum ◽

Jnk Pathway ◽

Alcoholic Fatty Liver ◽

Insulin Resistant ◽

Glucose Levels ◽

Main Components

Background: Jian-Gan-Xiao-Zhi decoction (JGXZ) is a traditional Chinese medicine formula to treat patients with non-alcoholic fatty liver disease (NAFLD). The study aimed to analyze the mechanism of JGXZ in adipocytes and detect the main components of the drug in rat serum. Methods: 3T3-L1 preadipocytes were used to establish an insulin resistant (IR) adipocyte model. Lipid accumulation in adipocytes was detected by oil red O staining. After JGXZ treatment, glucose consumption, total cholesterol (TC), and triglyceride (TG) were analyzed using the corresponding kits. ROS levels were measured by flow cytometry. In addition, Western blot was used to assess LKB1/AMPK and JNK/IRS/PI3k/AKT expressions. The main components of JGXZ in rat serum samples were detected by LC-MS/MS using a Phenomenex Luna C18 column, a mobile phase of methanol and 0.1% formic acid solution, and ESI detection. Results: JGXZ significantly decreased glucose levels and adipogenesis, accompanied by decreased IR ( P < 0.01). Besides, JGXZ markedly affected ROS, LKB1/AMPK, and JNK/IRS/PI3k/AKT levels ( P < 0.01). R1, Rg1, paeoniflorin, Rb1, astragaloside IV, and tanshinone could be significantly quantified. Conclusions: JGXZ decreased glucose and lipid synthesis, possibly via the ROS/AMPK/JNK pathway. R1, Rg1, paeoniflorin, Rb1, astragaloside IV, and tanshinone in JGXZ could play major roles in treating NAFLD, which could assist in the study of the mechanism of JGXZ in treating NAFLD.

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Targeting autophagy enhances atezolizumab-induced mitochondria-related apoptosis in osteosarcoma

Cell Death and Disease ◽

10.1038/s41419-021-03449-6 ◽

2021 ◽

Vol 12 (2) ◽

Author(s):

Zhuochao Liu ◽

Hongyi Wang ◽

Chuanzhen Hu ◽

Chuanlong Wu ◽

Jun Wang ◽

...

Keyword(s):

Reactive Oxygen Species ◽

Antitumor Immunity ◽

Reactive Oxygen ◽

Oxygen Species ◽

Specific Monoclonal Antibody ◽

Osteosarcoma Cells ◽

Jnk Pathway ◽

In Vivo Experiments

AbstractIn this study, we identified the multifaceted effects of atezolizumab, a specific monoclonal antibody against PD-L1, in tumor suppression except for restoring antitumor immunity, and investigated the promising ways to improve its efficacy. Atezolizumab could inhibit the proliferation and induce immune-independent apoptosis of osteosarcoma cells. With further exploration, we found that atezolizumab could impair mitochondria of osteosarcoma cells, resulting in increased release of reactive oxygen species and cytochrome-c, eventually leading to mitochondrial-related apoptosis via activating JNK pathway. Nevertheless, the excessive release of reactive oxygen species also activated the protective autophagy of osteosarcoma cells. Therefore, when we combined atezolizumab with autophagy inhibitors, the cytotoxic effect of atezolizumab on osteosarcoma cells was significantly enhanced in vitro. Further in vivo experiments also confirmed that atezolizumab combined with chloroquine achieved the most significant antitumor effect. Taken together, our study indicates that atezolizumab can induce mitochondrial-related apoptosis and protective autophagy independently of the immune system, and targeting autophagy is a promising combinatorial approach to amplify its cytotoxicity.

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Transient Receptor Potential Melastatin 7 Promotes Vascular Adventitial Fibroblasts Phenotypic Transformation and Inflammatory Reaction Induced by Mechanical Stretching Stress via p38 MAPK/JNK Pathway

Journal of Vascular Research ◽

10.1159/000512595 ◽

2021 ◽

pp. 1-13

Author(s):

Jiachen Liu ◽

Laijiang Chen ◽

Jun Huang ◽

Shujie Guo ◽

Dingliang Zhu ◽

...

Keyword(s):

Transient Receptor Potential ◽

Receptor Potential ◽

P38 Map Kinase ◽

Inflammatory Factors ◽

Jnk Pathway ◽

Transient Receptor Potential Melastatin ◽

Adventitial Fibroblasts ◽

Phenotypic Transformation ◽

Transient Receptor ◽

Mechanical Stretching

Remodeling of the arteries is one of the pathological bases of hypertension. We have previously shown that transient receptor potential melastatin 7 (TRPM7) aggravates the vascular adventitial remodeling caused by pressure overload in the transverse aortic constriction (TAC) model. In this study, we sought to explore the functional expression and downstream signaling of TRPM7 in vascular adventitial fibroblasts (AFs) stimulated by mechanical stretching stress (MSS). The expression of TRPM7 was upregulated with a concomitant translocation to the cytoplasm in the AFs stimulated with 20% MSS. Meanwhile, the expression of α-smooth muscle actin (α-SMA), a marker of transformation from AFs to myofibroblasts (MFs) was also increased. Moreover, AF-conditioned medium caused a significant migration of macrophages after treatment with MSS and contained high levels of monocyte chemotactic protein-1 (MCP-1), interleukin-6 (IL-6), interleukin-8 (IL-8), and tumor necrosis factor-α (TNF-α). Pharmacological and RNA interference approaches using the TRPM7 inhibitor 2-aminoethoxydiphenyl borate (2-APB) and speciﬁc anti-TRPM7 small interfering RNA (siRNA-TRPM7) abrogated these changes significantly. Further exploration uncloaked that inhibition of TRPM7 reduced the phosphorylation of p38 MAP kinase (p38MAPK) and c-Jun N-terminal kinase (JNK) in the AFs stimulated with MSS. Furthermore, inhibition of the phosphorylation of p38MAPK or JNK could also alleviate the MSS-induced expression of α-SMA and secretion of inflammatory factors. These observations indicate that activated TRPM7 participates in the phenotypic transformation and inflammatory action of AFs in response to MSS through the p38MAPK/JNK pathway and suggest that TRPM7 may be a potential therapeutic target for vascular remodeling caused by hemodynamic changes in hypertension.

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ZSCAN16-AS1 expedites hepatocellular carcinoma progression via modulating the miR-181c-5p/SPAG9 axis to activate the JNK pathway

Cell Cycle ◽

10.1080/15384101.2021.1919828 ◽

2021 ◽

pp. 1-13

Author(s):

Jianwen Liu ◽

Ruiqing Liu ◽

Yuyan Liu ◽

Lupeng Li ◽

Huicun Cao ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Jnk Pathway

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In silico analysis of selenoprotein N (Gallus gallus): absence of EF-hand motif and the role of CUGS-helix domain in antioxidant protection

Metallomics ◽

10.1093/mtomcs/mfab004 ◽

2021 ◽

Vol 13 (3) ◽

Author(s):

Shi-Yong Zhu ◽

Li-Li Liu ◽

Yue-Qiang Huang ◽

Xiao-Wei Li ◽

Milton Talukder ◽

...

Keyword(s):

In Silico ◽

Common Ancestor ◽

In Silico Analysis ◽

Antioxidant Protection ◽

Jnk Pathway ◽

Downstream Target ◽

Ef Hand ◽

Silico Analysis

Abstract Selenoprotein N (SEPN1) is critical to the normal muscular physiology. Mutation of SEPN1 can raise congenital muscular disorder in human. It is also central to maturation and structure of skeletal muscle in chicken. However, human SEPN1 contained an EF-hand motif, which was not found in chicken. And the biochemical and molecular characterization of chicken SEPN1 remains unclear. Hence, protein domains, transcription factors, and interactions of Ca2+ in SEPN1 were analyzed in silico to provide the divergence and homology between chicken and human in this work. The results showed that vertebrates’ SEPN1 evolved from a common ancestor. Human and chicken's SEPN1 shared a conserved CUGS-helix domain with function in antioxidant protection. SEPN1 might be a downstream target of JNK pathway, and it could respond to multiple stresses. Human's SEPN1 might not combine with Ca2+ with a single EF-hand motif in calcium homeostasis, and chicken SEPN1 did not have the EF-hand motif in the prediction, indicating the EF-hand motif malfunctioned in chicken SEPN1.

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Vindesine receptors in cells of a human leukaemia cell line

British Journal of Cancer ◽

10.1038/bjc.1982.215 ◽

1982 ◽

Vol 46 (3) ◽

pp. 392-396 ◽

Cited By ~ 4

Author(s):

K Totsuka ◽

K Oshimi ◽

H Mizoguchi

Keyword(s):

Cell Line ◽

Leukaemia Cell ◽

Leukaemia Cell Line ◽

Human Leukaemia Cell ◽

Human Leukaemia ◽

In Cells

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Utidelone inhibits growth of colorectal cancer cells through ROS/JNK signaling pathway

Cell Death and Disease ◽

10.1038/s41419-021-03619-6 ◽

2021 ◽

Vol 12 (4) ◽

Author(s):

Fuli Li ◽

Tinglei Huang ◽

Yao Tang ◽

Qingli Li ◽

Jianzheng Wang ◽

...

Keyword(s):

Colorectal Cancer ◽

Tumor Growth ◽

Xenograft Model ◽

Jnk Pathway ◽

Epothilone B ◽

Colorectal Cancer Cells ◽

M Phase ◽

Jnk Signaling Pathway ◽

Microtubule Stabilizing Agent

AbstractUtidelone (UTD1), a novel microtubule stabilizing agent, is an epothilone B analogue which was produced by genetic engineering. UTD1 has exhibited broad antitumor activity in multiple solid tumors. However, its activity and mechanism in colorectal cancer (CRC) remain to be studied. In this study, UTD1 dramatically inhibited CRC cell proliferation (with 0.38 µg/ml, 0.77 µg/ml IC50 in RKO and HCT116, respectively) in vitro. Immunofluorescence staining showed that UTD1 induced the formation of microtubule bundling and asters in RKO cells. Flow cytometry analysis demonstrated that UTD1 induced cell cycle to arrest in G2/M phase, subsequent apoptosis. Significantly, UTD1 exhibited stronger effect on inducing apoptosis than paclitaxel and 5-FU, especially in HCT15 cells which is ABCB1 high-expression. UTD1 exposure cleaved caspase-3 and poly ADP-ribose polymerase (PARP), decreased mitochondrial membrane potential, released cytochrome c, increased the production of active oxygen and activated c-Jun N-terminal kinase (JNK), suggesting ROS/JNK pathway was involved in this process. Moreover, UTD1 inhibited tumor growth and was more effective and safer compared with paclitaxel and 5-FU in RKO xenograft in nude mice. Taken together, our findings first indicate that UDT1 inhibits tumor growth in CRC xenograft model and may be a promising agent for CRC treatment.

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