Betulinic Acid Attenuates T-2-Toxin-Induced Testis Oxidative Damage Through Regulation of the JAK2/STAT3 Signaling Pathway in Mice

Wu, Jing; Yang, Chenglin; Liu, Juan; Chen, Jiaxin; Huang, Chao; Wang, Ji; Liang, Zengenni; Wen, Lixin; Yi, Jine

doi:10.3390/biom9120787

Cited by 36 publications

(32 citation statements)

References 42 publications

(35 reference statements)

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“…Subsequently, we wanted to examine the molecular mechanism of pancreas injury. Considering that the Stat3, MAPK, and Akt-mTOR pathways play a prominent role in oxidative stress, inflammatory response, and cell apoptosis 33 , 34 , we measured the levels of Stat3, p38/JNK, mTOR and their corresponding phosphorylated protein expression. Importantly, the results showed that the mice of the STZ+circPPM1F group exhibited significantly enhanced levels of phosphorylated Stat3, p38, and JNK expression compared with control, STZ and STZ+pZW1 groups.…”

Section: Resultsmentioning

confidence: 99%

Circular RNA circPPM1F modulates M1 macrophage activation and pancreatic islet inflammation in type 1 diabetes mellitus

Zhang¹,

et al. 2020

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Rationale: Macrophages play critical roles in the pathogenesis of type 1 diabetes mellitus (T1DM). Circular RNAs (circRNAs) are a novel class of endogenous RNAs with covalently closed loop structures, implicated in various disease processes. However, their impact on macrophage activation and T1DM pathogenesis remains elusive. Methods: circRNA expression profiles of peripheral blood mononuclear cells (PBMCs) from T1DM children were determined by whole transcriptome microarray. Bioinformatics, quantitative real-time PCR, Western blot, RNA immunoprecipitation (RIP), cell co-culture, cell proliferation, and cell apoptosis assays were performed to investigate the expression, function, and regulatory mechanisms of circPPM1F in vitro . The regulatory role of circPPM1F in vivo was evaluated in the streptozocin-induced diabetic mouse model. Results: We identified 27 upregulated and 31 downregulated differentially expressed circRNAs in T1DM patients. circPPM1F , a circRNA with unknown function, was dominantly expressed in monocytes and significantly upregulated in T1DM patients. Functionally, circPPM1F promoted lipopolysaccharide (LPS)-induced M1 macrophage activation via enhancement of the NF-κB signaling pathway. Mechanistically, circPPM1F competitively interacted with HuR to impair the translation of protein phosphatase, Mg 2+ /Mn 2+ dependent 1F (PPM1F), thus alleviating the inhibitory effect of PPM1F on the NF-κB pathway. Moreover, eukaryotic initiation factor 4A-III (EIF4A3) and fused in sarcoma (FUS) coordinately regulated circPPM1F expression during M1 macrophage activation. In addition, circPPM1F could exacerbate pancreas injury in the streptozocin-induced diabetic mice by activation of M1 macrophages in vivo . Conclusions: circPPM1F is a novel positive regulator of M1 macrophage activation through the circPPM1F -HuR-PPM1F-NF-κB axis. Overexpression of circPPM1F could promote pancreatic islet injury by enhancing M1 macrophage activation and circPPM1F may serve as a novel potential therapeutic target for T1DM in children.

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Section: Resultsmentioning

confidence: 99%

Circular RNA circPPM1F modulates M1 macrophage activation and pancreatic islet inflammation in type 1 diabetes mellitus

Zhang¹,

et al. 2020

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“…Besides, research has shown that intraperitoneal injection of T-2 toxin also causes oxidative stress [ 31 ]. Our previous study found that intraperitoneal injection of 4 mg/kg T-2 toxin could cause oxidative damage in testicular tissue [ 32 ]. Based on these studies, an intraperitoneal injection of 4 mg/kg T-2 toxin was used to establish an oxidative damage model of the thymus in this study.…”

Section: Discussionmentioning

confidence: 99%

“…Fifty male Kunming mice (4–5 w) were provided by Hunan Silaike Jingda Laboratory Animal Co., Ltd. (Changsha, Hunan, China). The duration of treatment and the doses of T-2 toxin and BA were chosen from previous studies and preliminary experiments [ 23 , 32 ]. The mice were placed individually in a room with controlled humidity (50–70%) and temperature (22–25 °C).…”

Section: Methodsmentioning

confidence: 99%

Betulinic Acid Attenuates Oxidative Stress in the Thymus Induced by Acute Exposure to T-2 Toxin via Regulation of the MAPK/Nrf2 Signaling Pathway

Zhu

et al. 2020

Toxins

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T-2 toxin, the most toxic of the trichothecenes, is widely found in grains and feeds, and its intake poses serious risks to the health of humans and animals. An important cytotoxicity mechanism of T-2 toxin is the production of excess free radicals, which in turn leads to oxidative stress. Betulinic acid (BA) has many biological activities, including antioxidant activity, which is a plant-derived pentacyclic triterpenoid. The protective effects and mechanisms of BA in blocking oxidative stress caused by acute exposure to T-2 toxin in the thymus of mice was studied. BA pretreatment reduced ROS production, decreased the MDA content, and increased the content of IgG in serum and the levels of SOD and GSH in the thymus. BA pretreatment also reduced the degree of congestion observed in histopathological tissue sections of the thymus induced by T-2 toxin. Besides, BA downregulated the phosphorylation of the p38, JNK, and ERK proteins, while it upregulated the expression of the Nrf2 and HO-1 proteins in thymus tissues. The results indicated that BA could protect the thymus against the oxidative damage challenged by T-2 toxin by activating Nrf2 and suppressing the MAPK signaling pathway.

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“…Besides, some reports revealed that betulinic acid could regulate STAT3 in many cancer types [51,52]. In central nervous system cancer cell lines, compounds nakiterpiosin and cucurbitacin I had a positive correlation coefficient greater than 0.3 (higher expression of STAT3 related to resistance).…”

Section: Stat3 Expression and Drug Responsementioning

confidence: 99%

Significance of STAT3 in Immune Infiltration and Drug Response in Cancer

et al. 2020

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Signal transducer and activator of transcription 3 (STAT3) is a transcription factor and regulates tumorigenesis. However, the functions of STAT3 in immune and drug response in cancer remain elusive. Hence, we aim to reveal the impact of STAT3 in immune infiltration and drug response comprehensively by bioinformatics analysis. The expression of STAT3 and its relationship with tumor stage were explored by Tumor Immune Estimation Resource (TIMER), Human Protein Altas (HPA), and UALCAN databases. The correlations between STAT3 and immune infiltration, gene markers of immune cells were analyzed by TIMER. Moreover, the association between STAT3 and drug response was evaluated by the Cancer Cell Line Encyclopedia (CCLE) and Cancer Therapeutics Response Portal (CTRP). The results suggested that the mRNA transcriptional level of STAT3 was lower in tumors than normal tissues and mostly unrelated to tumor stage. Besides, the protein expression of STAT3 decreased in colorectal and renal cancer compared with normal tissues. Importantly, STAT3 was correlated with immune infiltration and particularly regulated tumor-associated macrophage (TAM), M2 macrophage, T-helper 1 (Th1), follicular helper T (Treg), and exhausted T-cells. Remarkably, STAT3 was closely correlated with the response to specified inhibitors and natural compounds in cancer. Furthermore, the association between STAT3 and drug response was highly cell line type dependent. Significantly, the study provides thorough insight that STAT3 is associated with immunosuppression, as well as drug response in clinical treatment.

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Betulinic Acid Attenuates T-2-Toxin-Induced Testis Oxidative Damage Through Regulation of the JAK2/STAT3 Signaling Pathway in Mice

Cited by 36 publications

References 42 publications

Circular RNA circPPM1F modulates M1 macrophage activation and pancreatic islet inflammation in type 1 diabetes mellitus

Circular RNA circPPM1F modulates M1 macrophage activation and pancreatic islet inflammation in type 1 diabetes mellitus

Betulinic Acid Attenuates Oxidative Stress in the Thymus Induced by Acute Exposure to T-2 Toxin via Regulation of the MAPK/Nrf2 Signaling Pathway

Significance of STAT3 in Immune Infiltration and Drug Response in Cancer

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