Cytokine最新文献_第2页

Hydrogen combined with needle-embedding therapy alleviates traumatic brain injury by inhibiting NLRP3 inflammasome activation via STING signaling pathway

IF 3.7 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Cytokine

Pub Date : 2025-04-04 DOI: 10.1016/j.cyto.2025.156931

Fan Wu , Wenting Su , Xin Wang , Chenhui Wang , Yongxing Sun , Baoguo Wang

Background

Traumatic brain injury (TBI) is a primary cause of disability and death worldwide and with unmet effective therapies. Molecular hydrogen (H₂) exerts latent therapeutic means for TBI. Nevertheless, few studies have illustrated the roles of hydrogen combined with needle-embedding therapy (H₂ + NET) in TBI and its exact mechanism remains unclear. Here, we elucidated the underlying mechanisms of H₂ + NET in the TBI progression.

Methods

Controlled cortical impact (CCI) method was conducted to construct TBI mouse model. The mNSS test was used for neurological function measurement. Nissl staining for evaluating neuronal injury, TUNEL assay for determining neuronal apoptosis and ELISA assay was applied for adenosine, ATP level and inflammatory cytokines determination. The relative mRNA levels of inflammatory elements were assessed by qRT-PCR analysis. Iba-1, NLRP3 and STING expression were determined through immunofluorescence staining. The expression of NLRP3 inflammasome related proteins and STING signaling pathway associated proteins were evaluated using Western blot.

Results

H₂ or NET treatment mitigated brain injury and reduced brain water content in CCI-induced TBI mouse model. CCI induction promoted microglia activation and inflammatory response, thereby activating the NLRP3 inflammasome activity and STING signaling pathway, which was partly reversed by H₂ or NET treatment. However, H₂ + NET significantly ameliorated brain oedema, and further inhibited inflammatory response, NLRP3 inflammasome activation and STING pathway activation in TBI mice when compared to the H₂ or NET alone treatment group.

Conclusion

Hydrogen combined with needle-embedding therapy acts as a promising intervention method for TBI through inhibiting NLRP3 inflammasome activation via STING signaling pathway.

{"title":"Hydrogen combined with needle-embedding therapy alleviates traumatic brain injury by inhibiting NLRP3 inflammasome activation via STING signaling pathway","authors":"Fan Wu , Wenting Su , Xin Wang , Chenhui Wang , Yongxing Sun , Baoguo Wang","doi":"10.1016/j.cyto.2025.156931","DOIUrl":"10.1016/j.cyto.2025.156931","url":null,"abstract":"<div><h3>Background</h3><div>Traumatic brain injury (TBI) is a primary cause of disability and death worldwide and with unmet effective therapies. Molecular hydrogen (H<sub>2</sub>) exerts latent therapeutic means for TBI. Nevertheless, few studies have illustrated the roles of hydrogen combined with needle-embedding therapy (H<sub>2</sub> + NET) in TBI and its exact mechanism remains unclear. Here, we elucidated the underlying mechanisms of H<sub>2</sub> + NET in the TBI progression.</div></div><div><h3>Methods</h3><div>Controlled cortical impact (CCI) method was conducted to construct TBI mouse model. The mNSS test was used for neurological function measurement. Nissl staining for evaluating neuronal injury, TUNEL assay for determining neuronal apoptosis and ELISA assay was applied for adenosine, ATP level and inflammatory cytokines determination. The relative mRNA levels of inflammatory elements were assessed by qRT-PCR analysis. Iba-1, NLRP3 and STING expression were determined through immunofluorescence staining. The expression of NLRP3 inflammasome related proteins and STING signaling pathway associated proteins were evaluated using Western blot.</div></div><div><h3>Results</h3><div>H<sub>2</sub> or NET treatment mitigated brain injury and reduced brain water content in CCI-induced TBI mouse model. CCI induction promoted microglia activation and inflammatory response, thereby activating the NLRP3 inflammasome activity and STING signaling pathway, which was partly reversed by H<sub>2</sub> or NET treatment. However, H<sub>2</sub> + NET significantly ameliorated brain oedema, and further inhibited inflammatory response, NLRP3 inflammasome activation and STING pathway activation in TBI mice when compared to the H<sub>2</sub> or NET alone treatment group.</div></div><div><h3>Conclusion</h3><div>Hydrogen combined with needle-embedding therapy acts as a promising intervention method for TBI through inhibiting NLRP3 inflammasome activation via STING signaling pathway.</div></div>","PeriodicalId":297,"journal":{"name":"Cytokine","volume":"190 ","pages":"Article 156931"},"PeriodicalIF":3.7,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143767689","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The synergistic effects of prostaglandin and IL-1β on myometrial and cervical stromal cells at the onset of labor

IF 3.7 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Cytokine

Pub Date : 2025-04-03 DOI: 10.1016/j.cyto.2025.156927

Qian Huang, Pin Li, Zheng Zheng, Xiaoyan Sha, Lele Wang, Baohua Lin, Junjie Bao, Yanmin Jiang , Huishu Liu

Inflammatory cytokines such as IL-1β and prostaglandins (PGs) are pivotal in the initiation of labor. Nevertheless, the synergistic interaction between PGs and IL-1β remains to be fully elucidated. Labor is defined as regular and gradually increasing uterine contractions accompanied by progressive dilation of the cervix, and descent of the fetal. This study employed Luminex to monitor alterations in inflammatory cytokine levels within myometrial tissue (n = 10) during labor compared to non-labor (n = 10) conditions. And the synergistic relationship between PGs and IL-1β by investigating the primary myometrium cells and cervical stromal cells culture. The results showed that the inflammatory cytokines of IL-1β, IL-6, IL-8 and TNF-α in the myometrium tissue were increased in labor group. In myometrium cells, PGF2α and IL-1β synergistically up-regulated COX-2 mRNA, upregulated the transcription of PRA and PRB, PGF2α alleviated that IL-1β up-regulated IL-8 mRNA. In cervical stromal cells, IL-1β up-regulated the COX-2 and PRB protein expression. PGE2 abated that IL-1β up-regulated IL-8 mRNA. PGE increased the expression of PRs, which is more pronounced with the prolonged duration. Ratio of PRA/PRB show an increased trend with IL-1β and PGE2 co-regulated. This study further clarified the synergistic regulatory mechanism of IL-1β and PGs, offering a theoretical foundation for the development of strategies aimed at labor induction and the prevention and treatment of preterm birth.

{"title":"The synergistic effects of prostaglandin and IL-1β on myometrial and cervical stromal cells at the onset of labor","authors":"Qian Huang, Pin Li, Zheng Zheng, Xiaoyan Sha, Lele Wang, Baohua Lin, Junjie Bao, Yanmin Jiang , Huishu Liu","doi":"10.1016/j.cyto.2025.156927","DOIUrl":"10.1016/j.cyto.2025.156927","url":null,"abstract":"<div><div>Inflammatory cytokines such as IL-1β and prostaglandins (PGs) are pivotal in the initiation of labor. Nevertheless, the synergistic interaction between PGs and IL-1β remains to be fully elucidated. Labor is defined as regular and gradually increasing uterine contractions accompanied by progressive dilation of the cervix, and descent of the fetal. This study employed Luminex to monitor alterations in inflammatory cytokine levels within myometrial tissue (<em>n</em> = 10) during labor compared to non-labor (n = 10) conditions. And the synergistic relationship between PGs and IL-1β by investigating the primary myometrium cells and cervical stromal cells culture. The results showed that the inflammatory cytokines of IL-1β, IL-6, IL-8 and TNF-α in the myometrium tissue were increased in labor group. In myometrium cells, PGF2α and IL-1β synergistically up-regulated <em>COX</em>-2 mRNA, upregulated the transcription of PRA and PRB, PGF2α alleviated that IL-1β up-regulated <em>IL-8</em> mRNA. In cervical stromal cells, IL-1β up-regulated the COX-2 and PRB protein expression. PGE2 abated that IL-1β up-regulated <em>IL-8</em> mRNA. PGE increased the expression of PRs, which is more pronounced with the prolonged duration. Ratio of PRA/PRB show an increased trend with IL-1β and PGE2 co-regulated. This study further clarified the synergistic regulatory mechanism of IL-1β and PGs, offering a theoretical foundation for the development of strategies aimed at labor induction and the prevention and treatment of preterm birth.</div></div>","PeriodicalId":297,"journal":{"name":"Cytokine","volume":"190 ","pages":"Article 156927"},"PeriodicalIF":3.7,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143761168","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Shedding new light on BACE1-mediated modulation of IL-6 signaling: Implications for neural activity and synaptic plasticity in mice

IF 3.7 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Cytokine

Pub Date : 2025-04-03 DOI: 10.1016/j.cyto.2025.156925

Buket Ucar Franke , Kai Kummer , Stefan Rose-John , Stefan F. Lichtenthaler , Michaela Kress

The pleiotropic cytokine IL-6 regulates numerous processes in the body, including neuronal functions. IL-6 either binds to membrane-bound receptor (mIL-6R) and triggers signaling via heteromerization with the signal transducer gp130 (classical signaling), or binds to its soluble form (sIL-6R) to act on cells that do not express mIL-6R (trans-signaling). The ß-secretase BACE1 can cleave gp130 as well as IL-6R and we hypothesized that BACE1 may alter neuron activity and synaptic transmission via modulation of IL-6 signaling.

We used multielectrode array (MEA) recordings to monitor electrical activity of neuronal networks in acute cerebellar slices as well as long-term potentiation (LTP) induced by high-frequency stimulation in the hippocampus and to assess how exposure to IL-6 affects these processes. A pharmacological approach was applied to elucidate the contribution of trans-signaling involving BACE1.

Spontaneous neuronal activity in cerebellar slices significantly decreased upon perfusion with IL-6 but not LIF and recovered during wash out. BACE1 inhibitors verubecestat or AZD3839 abolished the inhibitory effects of IL-6. Furthermore, IL-6 and LIF reversibly inhibited LTP in hippocampal slices, and in contrast to cerebellar neurons, BACE1 inhibitors verubecestat or AZD3839 did not abolish the inhibitory effect of IL-6 on LTP. Interestingly, a dramatic rebound effect on excitatory postsynaptic potentials was observed with BACE1 inhibitor AZD3839 but not verubecestat during wash out.

Our results support relevant and differential roles of IL-6, LIF and BACE1 in pathways modulating neuronal discharge activity in the cerebellum and the synaptic plasticity in the hippocampus, and a possible involvement of this interaction in deficits of memory and learning.

{"title":"Shedding new light on BACE1-mediated modulation of IL-6 signaling: Implications for neural activity and synaptic plasticity in mice","authors":"Buket Ucar Franke , Kai Kummer , Stefan Rose-John , Stefan F. Lichtenthaler , Michaela Kress","doi":"10.1016/j.cyto.2025.156925","DOIUrl":"10.1016/j.cyto.2025.156925","url":null,"abstract":"<div><div>The pleiotropic cytokine IL-6 regulates numerous processes in the body, including neuronal functions. IL-6 either binds to membrane-bound receptor (mIL-6R) and triggers signaling via heteromerization with the signal transducer gp130 (classical signaling), or binds to its soluble form (sIL-6R) to act on cells that do not express mIL-6R (trans-signaling). The ß-secretase BACE1 can cleave gp130 as well as IL-6R and we hypothesized that BACE1 may alter neuron activity and synaptic transmission via modulation of IL-6 signaling.</div><div>We used multielectrode array (MEA) recordings to monitor electrical activity of neuronal networks in acute cerebellar slices as well as long-term potentiation (LTP) induced by high-frequency stimulation in the hippocampus and to assess how exposure to IL-6 affects these processes. A pharmacological approach was applied to elucidate the contribution of trans-signaling involving BACE1.</div><div>Spontaneous neuronal activity in cerebellar slices significantly decreased upon perfusion with IL-6 but not LIF and recovered during wash out. BACE1 inhibitors verubecestat or AZD3839 abolished the inhibitory effects of IL-6. Furthermore, IL-6 and LIF reversibly inhibited LTP in hippocampal slices, and in contrast to cerebellar neurons, BACE1 inhibitors verubecestat or AZD3839 did not abolish the inhibitory effect of IL-6 on LTP. Interestingly, a dramatic rebound effect on excitatory postsynaptic potentials was observed with BACE1 inhibitor AZD3839 but not verubecestat during wash out.</div><div>Our results support relevant and differential roles of IL-6, LIF and BACE1 in pathways modulating neuronal discharge activity in the cerebellum and the synaptic plasticity in the hippocampus, and a possible involvement of this interaction in deficits of memory and learning.</div></div>","PeriodicalId":297,"journal":{"name":"Cytokine","volume":"190 ","pages":"Article 156925"},"PeriodicalIF":3.7,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143761167","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Exploring the genetic association between inflammatory cytokines and primary ovarian insufficiency: A Mendelian randomization study

IF 3.7 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Cytokine

Pub Date : 2025-04-03 DOI: 10.1016/j.cyto.2025.156937

Jie Wu , Yancheng Fu , Zhengqi Qiu

Purpose: This study aims to investigate the genetic underpinnings of Primary Ovarian Insufficiency (POI) by examining the association between 91 inflammatory cytokines identified through genome-wide association studies (GWAS) and POI, using Mendelian randomization (MR) to explore potential causal relationships.

Methods: We utilized Mendelian Randomization (MR) to investigate the causative links between inflammatory cytokines and POI, selecting genetic variants associated with cytokine levels as instrumental variables.

Results: Utilizing the Inverse Variance Weighted (IVW) method, our Mendelian Randomization (MR) study elucidated the influence of inflammatory cytokines on POI. We discovered that certain cytokines exhibit a protective association: CC motif chemokine 19 (CCL19) [OR 0.58; 95 % CI: 0.36–0.93; p = 0.024], Interleukin-10 (IL-10) [OR 0.41; 95 % CI: 0.23–0.72; p = 0.002], Interleukin-17 A (IL-17 A) [OR 0.44; 95 % CI: 0.20–0.96; p = 0.040], and Monocyte chemotactic protein 3 (MCP-3) [OR 0.51; 95 % CI: 0.29–0.89; p = 0.018]. Conversely, an elevated level of interleukin-33 in blood plasma was identified as a risk factor for POI [OR 2.83; 95 % CI: 1.23–6.50; p = 0.015].

Conclusion: Our findings indicate a significant correlation between specific inflammatory cytokines and the risk of developing POI. The negative association of cytokines such as CCL19, IL-10, IL-17 A, and MCP-3 suggests a protective effect against POI, whereas the positive association of IL-33 levels implies a potential adverse impact. These insights could guide future research towards targeted immunomodulatory therapies for the management and prevention of POI.

{"title":"Exploring the genetic association between inflammatory cytokines and primary ovarian insufficiency: A Mendelian randomization study","authors":"Jie Wu , Yancheng Fu , Zhengqi Qiu","doi":"10.1016/j.cyto.2025.156937","DOIUrl":"10.1016/j.cyto.2025.156937","url":null,"abstract":"<div><div><strong>Purpose:</strong> This study aims to investigate the genetic underpinnings of Primary Ovarian Insufficiency (POI) by examining the association between 91 inflammatory cytokines identified through genome-wide association studies (GWAS) and POI, using Mendelian randomization (MR) to explore potential causal relationships.</div><div><strong>Methods:</strong> We utilized Mendelian Randomization (MR) to investigate the causative links between inflammatory cytokines and POI, selecting genetic variants associated with cytokine levels as instrumental variables.</div><div><strong>Results:</strong> Utilizing the Inverse Variance Weighted (IVW) method, our Mendelian Randomization (MR) study elucidated the influence of inflammatory cytokines on POI. We discovered that certain cytokines exhibit a protective association: C<img>C motif chemokine 19 (CCL19) [OR 0.58; 95 % CI: 0.36–0.93; <em>p</em> = 0.024], Interleukin-10 (IL-10) [OR 0.41; 95 % CI: 0.23–0.72; <em>p</em> = 0.002], Interleukin-17 A (IL-17 A) [OR 0.44; 95 % CI: 0.20–0.96; <em>p</em> = 0.040], and Monocyte chemotactic protein 3 (MCP-3) [OR 0.51; 95 % CI: 0.29–0.89; <em>p</em> = 0.018]. Conversely, an elevated level of interleukin-33 in blood plasma was identified as a risk factor for POI [OR 2.83; 95 % CI: 1.23–6.50; <em>p</em> = 0.015].</div><div><strong>Conclusion:</strong> Our findings indicate a significant correlation between specific inflammatory cytokines and the risk of developing POI. The negative association of cytokines such as CCL19, IL-10, IL-17 A, and MCP-3 suggests a protective effect against POI, whereas the positive association of IL-33 levels implies a potential adverse impact. These insights could guide future research towards targeted immunomodulatory therapies for the management and prevention of POI.</div></div>","PeriodicalId":297,"journal":{"name":"Cytokine","volume":"190 ","pages":"Article 156937"},"PeriodicalIF":3.7,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143761170","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Effects of botulinum toxin type a on nucleotide binding oligomerization domain-like receptor 3 inflammasome in trigeminal ganglion of a rat migraine model

IF 3.7 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Cytokine

Pub Date : 2025-04-02 DOI: 10.1016/j.cyto.2025.156934

Jun Shen , Xiaofeng Zhu , Lei Xia , Jin Shang , Ming Wei , Qiu Han

Background

Botulinum toxin type A (BTX-A) has been used in the prevention and treatment of chronic migraine, but the detailed mechanism was not clear completely.

Objective

The effects of BTX-A on nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome and interleukin-1 beta (IL-1β) were explored in the trigeminal ganglion of migraine model rats.

Methods

Healthy adult male Sprague-Dawley (SD) rats were randomly divided into groups. Von Frey fiber filaments were used to detect the periorbital pain area of rats. The immunoblotting and Immunofluorescence were used to detect the expression of NLRP3 inflammasome and IL-1β in the trigeminal ganglia of rats.

Results

The periorbital pain area of rats in the migraine model group was significantly lower than that of the Sham group, and the difference was statistically significant (p < 0.05). Compared with the Sham group, the expressions of NLRP3, pro-caspase-1, caspase-1 and mature IL-1β in the migraine model group were significantly increased, and the difference was statistically significant (p < 0.05). Compared with the IA control group, the expressions of NLRP3, pro-caspase-1, caspase-1 and mature IL-1β in 5 U/kg BTX and 10 U/kg BTX-A group were significantly reduced (p < 0.05).

Conclusion

BTX-A inhibits the synthesis of NLRP3 inflammasome and mature IL-1β in the trigeminal ganglion from rat migraine models. Its inhibitory effect on the inflammation of the primary nociceptive neurons of the trigeminal nerve may be one of its important mechanisms for the prevention of migraine.

{"title":"Effects of botulinum toxin type a on nucleotide binding oligomerization domain-like receptor 3 inflammasome in trigeminal ganglion of a rat migraine model","authors":"Jun Shen , Xiaofeng Zhu , Lei Xia , Jin Shang , Ming Wei , Qiu Han","doi":"10.1016/j.cyto.2025.156934","DOIUrl":"10.1016/j.cyto.2025.156934","url":null,"abstract":"<div><h3>Background</h3><div>Botulinum toxin type A (BTX-A) has been used in the prevention and treatment of chronic migraine, but the detailed mechanism was not clear completely.</div></div><div><h3>Objective</h3><div>The effects of BTX-A on nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome and interleukin-1 beta (IL-1β) were explored in the trigeminal ganglion of migraine model rats.</div></div><div><h3>Methods</h3><div>Healthy adult male Sprague-Dawley (SD) rats were randomly divided into groups. Von Frey fiber filaments were used to detect the periorbital pain area of rats. The immunoblotting and Immunofluorescence were used to detect the expression of NLRP3 inflammasome and IL-1β in the trigeminal ganglia of rats.</div></div><div><h3>Results</h3><div>The periorbital pain area of rats in the migraine model group was significantly lower than that of the Sham group, and the difference was statistically significant (<em>p</em> < 0.05). Compared with the Sham group, the expressions of NLRP3, pro-caspase-1, caspase-1 and mature IL-1β in the migraine model group were significantly increased, and the difference was statistically significant (<em>p</em> < 0.05). Compared with the IA control group, the expressions of NLRP3, pro-caspase-1, caspase-1 and mature IL-1β in 5 U/kg BTX and 10 U/kg BTX-A group were significantly reduced (<em>p</em> < 0.05).</div></div><div><h3>Conclusion</h3><div>BTX-A inhibits the synthesis of NLRP3 inflammasome and mature IL-1β in the trigeminal ganglion from rat migraine models. Its inhibitory effect on the inflammation of the primary nociceptive neurons of the trigeminal nerve may be one of its important mechanisms for the prevention of migraine.</div></div>","PeriodicalId":297,"journal":{"name":"Cytokine","volume":"190 ","pages":"Article 156934"},"PeriodicalIF":3.7,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143761166","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The role of TNF in metabolic disorders and liver diseases

IF 3.7 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Cytokine

Pub Date : 2025-04-01 DOI: 10.1016/j.cyto.2025.156933

Chuze Xu , Sohaib Hasan Abdullah Ezzi , Xiaodi Zou , Yanzhao Dong , Ahmad Alhaskawi , Haiying Zhou , Vishnu Goutham Kota , Mohamed Hasan Abdulla Hasan Abdulla , Sahar Ahmed Abdalbary , Hui Lu

Tumor necrosis factor (TNF) is identified as a pro-inflammatory cytokine critical to the pathology of liver disease. In the carbohydrate metabolism, TNF has been demonstrated to impede the insulin signaling pathway, thereby precipitating glucose intolerance and insulin resistance. In lipid metabolism, TNF upregulates genes implicated in fatty acid synthesis, resulting in increased lipid accumulation within the liver. In amino acid metabolism, TNF has shown to promote the gene expression for amino acid catabolism, leading to decreased protein synthesis. Additionally, TNF stimulates the production of other chemokines and inflammatory cytokines that can further exacerbate liver injury. Overall, TNF is crucial in developing liver diseases by disrupting various metabolic pathways in the liver, causing insulin resistance, lipid accumulation, and decreased protein synthesis. This review summarizes the present understanding of TNF's role in the regulation of carbohydrate, lipid and amino acid metabolism in liver disease together with its potential therapeutic implications.

{"title":"The role of TNF in metabolic disorders and liver diseases","authors":"Chuze Xu , Sohaib Hasan Abdullah Ezzi , Xiaodi Zou , Yanzhao Dong , Ahmad Alhaskawi , Haiying Zhou , Vishnu Goutham Kota , Mohamed Hasan Abdulla Hasan Abdulla , Sahar Ahmed Abdalbary , Hui Lu","doi":"10.1016/j.cyto.2025.156933","DOIUrl":"10.1016/j.cyto.2025.156933","url":null,"abstract":"<div><div>Tumor necrosis factor (TNF) is identified as a pro-inflammatory cytokine critical to the pathology of liver disease. In the carbohydrate metabolism, TNF has been demonstrated to impede the insulin signaling pathway, thereby precipitating glucose intolerance and insulin resistance. In lipid metabolism, TNF upregulates genes implicated in fatty acid synthesis, resulting in increased lipid accumulation within the liver. In amino acid metabolism, TNF has shown to promote the gene expression for amino acid catabolism, leading to decreased protein synthesis. Additionally, TNF stimulates the production of other chemokines and inflammatory cytokines that can further exacerbate liver injury. Overall, TNF is crucial in developing liver diseases by disrupting various metabolic pathways in the liver, causing insulin resistance, lipid accumulation, and decreased protein synthesis. This review summarizes the present understanding of TNF's role in the regulation of carbohydrate, lipid and amino acid metabolism in liver disease together with its potential therapeutic implications.</div></div>","PeriodicalId":297,"journal":{"name":"Cytokine","volume":"190 ","pages":"Article 156933"},"PeriodicalIF":3.7,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143747949","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Progress of IL-10 and liver metastasis

IF 3.7 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Cytokine

Pub Date : 2025-03-31 DOI: 10.1016/j.cyto.2025.156932

Chuanfei Zeng , Fengyuan Niu , Huan Li, Ziyin Huang, Yujia Ke, Linxin Yu, Mingkai Chen

Liver metastasis can occur in a wide range of cancers and have a significant impact on patient survival and prognosis. Once liver metastasis occurs, patients often lose the opportunity for surgery, and although a small percentage of patients can undergo hepatic resection to prolong survival, the benefit is not great. There were also many factors affecting liver metastasis, including reprogramming of the primary tumor metabolism, disturbances in the immune microenvironment and immune cells, alterations in the gut microbiota, and epigenetic changes. Interleukin-10 (IL-10) has a dual role as a cytokine that has been found in recent years to be pro-inflammatory as well as pro-liver metastasis. IL-10 exerts pro-metastatic effects mainly by regulating the polarization of tumor macrophages in the tumor microenvironment, especially by promoting the polarization of M2 macrophages. However, the role of IL-10 in tumorigenesis and progression remains controversial and the molecular mechanism involved in promoting liver metastasis is currently unclear. In view of the increasing role of IL-10 in promoting liver metastasis, this review summarizes the role of IL-10 in liver metastasis of colorectal cancer, breast cancer and other tumors in recent years, and provides ideas for subsequent clinical practice and basic research.

{"title":"Progress of IL-10 and liver metastasis","authors":"Chuanfei Zeng , Fengyuan Niu , Huan Li, Ziyin Huang, Yujia Ke, Linxin Yu, Mingkai Chen","doi":"10.1016/j.cyto.2025.156932","DOIUrl":"10.1016/j.cyto.2025.156932","url":null,"abstract":"<div><div>Liver metastasis can occur in a wide range of cancers and have a significant impact on patient survival and prognosis. Once liver metastasis occurs, patients often lose the opportunity for surgery, and although a small percentage of patients can undergo hepatic resection to prolong survival, the benefit is not great. There were also many factors affecting liver metastasis, including reprogramming of the primary tumor metabolism, disturbances in the immune microenvironment and immune cells, alterations in the gut microbiota, and epigenetic changes. Interleukin-10 (IL-10) has a dual role as a cytokine that has been found in recent years to be pro-inflammatory as well as pro-liver metastasis. IL-10 exerts pro-metastatic effects mainly by regulating the polarization of tumor macrophages in the tumor microenvironment, especially by promoting the polarization of M2 macrophages. However, the role of IL-10 in tumorigenesis and progression remains controversial and the molecular mechanism involved in promoting liver metastasis is currently unclear. In view of the increasing role of IL-10 in promoting liver metastasis, this review summarizes the role of IL-10 in liver metastasis of colorectal cancer, breast cancer and other tumors in recent years, and provides ideas for subsequent clinical practice and basic research.</div></div>","PeriodicalId":297,"journal":{"name":"Cytokine","volume":"190 ","pages":"Article 156932"},"PeriodicalIF":3.7,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143739772","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Endothelial barrier disruptive effect of IFN-Ƴ and TNF-α: Synergism of pro-inflammatory cytokines

IF 3.7 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Cytokine

Pub Date : 2025-03-29 DOI: 10.1016/j.cyto.2025.156922

Chin Theng Ng , Lai Yen Fong , Jun Jie Tan , Muhammad Nazrul Hakim Abdullah

Crosstalk and synergy between interferon-γ (IFN-Ƴ) and tumor necrosis factor-α (TNF-α) in endothelial cells have previously been documented, however, there is an absence of articles reviewing the synergistic effect of IFN-Ƴ and TNF-α in regulating the endothelial barrier function. This review discusses the regulatory mechanisms and recent evidence of the synergism of IFN-γ and TNF-α in causing destabilization of endothelial junctions in various clinical studies and preclinical models. Articles were retrieved from electronic databases such as Web of Science, PubMed, Google Scholar, and Scopus. The search terms used were “interferon”, “interferon-gamma”, “tumor necrosis factor-α”, “vascular inflammation”, “endothelial barrier”, “endothelial permeability” and “synergism”. We selected articles published between 2004 and 2024. Through the Rho-associated protein kinase (ROCK) and p38 mitogen-activated protein (MAP) kinase pathways, our results showed that IFN-γ controls the remodeling of actin and the stability of junctions. In comparison to IFN-γ, the signaling cascades triggered by TNF-α involve a variety of pathways such as nuclear factor-kappa B (NF-κB), small GTPases, tyrosine kinases, integrin receptors, and barrier-stabilizing molecules such as Ras-related proteins 1A (Rap1A) and Rac family small GTPase 1 (Rac1). In the context of IFN-γ and TNF-α synergism, combined IFN-γ and TNF-α alter adherens and tight junctions. It is deduced that c-Jun N-terminal kinase (JNK), signal transducers and activators of transcription (STAT1), and caspase signaling pathways regulate endothelial barrier disruption caused by IFN-γ and TNF-α. Collectively, the mechanism underlying the synergistic action of IFN-γ and TNF-α is still lacking. Future work is needed to explore the crosstalk pathways of IFN-γ and TNF-α involved in the regulation of endothelial barrier function such as modulation of extracellular matrix (ECM) structure, involvement of tyrosine kinases and roles of small GTPases.

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引用次数: 0

Tumor-educated Neutrophils Induce Epithelial-mesenchymal Transition and Metastasis in Colorectal Cancer Through Interleukin-17a Secretion

IF 3.7 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Cytokine

Pub Date : 2025-03-28 DOI: 10.1016/j.cyto.2025.156928

Yibing Gong , Qingshuang Luo , Haiqi Tan , Jingyi Long , Longtai Hu , Moyed abd alhussain Hamza Al-saadawe , Jinke Yao , Xiaoming Lyu , Lizhen Qiu , Gongfa Wu

The role of neutrophils in defending against infections and regulating immune responses is well-known. In cancer, tumor-associated neutrophils also play a significant role in the progression of tumors. However, the specific mechanisms of their interaction with human colorectal tumors have not been fully elucidated. Our study found that tumor-educated neutrophils can activate the STAT3 signaling pathway in colorectal cancer cells by secreting IL-17a. This leads to increased migration and invasion of colorectal cancer cells, promoting tumor growth by triggering epithelial-to-mesenchymal transition (EMT). These findings suggest that IL-17a secreted by tumor-educated neutrophils contributes to the development of colorectal cancer through the IL-17a/STAT3 signaling pathway. This provides new insights for potential treatments for colorectal cancer.

引用次数: 0

Self-assembling sequentially administered tumor targeted Split IL-12p35 and p40 subunits to improve the therapeutic index of systemically delivered IL-12 therapy for cancer

IF 3.7 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Cytokine

Pub Date : 2025-03-27 DOI: 10.1016/j.cyto.2025.156912

P.S. Gurel, R.G. Newman, S. Pearson, K. Dreaden, C. Wang, S.S. Donatelli, Y. Zhao, J. Chamoun, J.F. Heiber

IL-12, also called IL-12p70, is a highly potent, proinflammatory heterodimeric cytokine that can mediate many beneficial anti-tumor effects. In preclinical studies, recombinant IL-12, as well as IL-12 gene therapies, have demonstrated notable anti-tumor results across various tumor types; however, IL-12 clinical benefit has been limited by its poor tolerability at potentially efficacious doses. We have developed a novel approach to mitigate the toxicity of IL-12 by engineering tumor-targeted split IL-12 that preferentially localizes IL-12 activity to the tumor microenvironment. The functionally inactive IL-12 subunits, p35 and p40, are separately fused to antibody fragments targeting a highly expressed tumor-associated antigen, uPAR. The goal of this strategy is to drive assembly and activity of the IL-12 heterodimer into the tumor site through sequential administration of the targeted subunits, reducing systemic exposure and thereby potentially reducing associated toxicities. We use in vitro activity assays along with in vivo pharmacokinetic and pharmacodynamic studies in mice and non-human primates to demonstrate that the split IL-12 anti-uPAR fusions are capable of assembly and activity in vivo. The targeted p35 and p40 subunits are capable of complexing to form IL-12p70 and inducing STAT4 phosphorylation when applied to cultured immune cells, indicating in vitro IL-12 activity. Furthermore, sequential administration of subunits in in vivo mouse models demonstrates rapid serum clearance of IL-12 while extending retention in the tumor. Finally, dosing in non-human primates shows molecules are functionally active in vivo. This is a unique strategy with great clinical promise to harness the therapeutic potential of IL-12 while potentially avoiding the toxicity associated with systemic delivery.

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引用次数: 0