In China, Chinese herbal medicines (CHMs) have been widely used in the treatment of psoriatic arthritis (PsA), showing great therapeutic effects in clinical practice. However, due to the great heterogeneity of PsA and the diversity of CHM combination patterns, there is little high-level evidence-based medical research on the treatment of PsA with CHMs. This study aims to explore the beneficial effects of CHMs on the immune inflammation in PsA and its specific mechanism.
Methods
The data mining method was performed to analyze the real-world data of 91 PsA clinical cases. Network pharmacology, molecular docking, and cellular experiments were used to explore the mechanism of CHMs and its active ingredient wogonin in improving PsA immune inflammation.
Results
Data mining results showed that in PsA, immune inflammation was disturbed and relevant indexes were significantly correlated. After CHM treatment, the level of HCRP, C4, IL-12, IL-17, IL-23, TNF-α, TGF-β1, P65, P50, and IKBα was markedly improved, which was highly correlated with the application of CHMs. In addition, the core prescription containing 10 CHMs was screened, and the action mechanisms of the active ingredient wogonin on the immune inflammation in PsA were identified with network pharmacology and molecular docking. Cell experiments revealed that wogonin reduced M5-induced HaCaT cell viability and TNF-α and IL-1β expressions by blocking the PI3K/AKT pathway in a dose-dependent manner.
Conclusion
Our findings strongly confirmed the enormous promise of CHMs as a therapy for PsA and may provide support for developing drugs and targets for PsA treatment.
{"title":"Chinese herbal medicines and its active ingredient wogonin can improve immune inflammation in psoriatic arthritis","authors":"Xian-Heng Zhang , Jian Liu , Xiang Ding , Xiao-Lu Chen","doi":"10.1016/j.intimp.2024.113984","DOIUrl":"10.1016/j.intimp.2024.113984","url":null,"abstract":"<div><h3>Objective</h3><div>In China, Chinese herbal medicines (CHMs) have been widely used in the treatment of psoriatic arthritis (PsA), showing great therapeutic effects in clinical practice. However, due to the great heterogeneity of PsA and the diversity of CHM combination patterns, there is little high-level evidence-based medical research on the treatment of PsA with CHMs. This study aims to explore the beneficial effects of CHMs on the immune inflammation in PsA and its specific mechanism.</div></div><div><h3>Methods</h3><div>The data mining method was performed to analyze the real-world data of 91 PsA clinical cases. Network pharmacology, molecular docking, and cellular experiments were used to explore the mechanism of CHMs and its active ingredient wogonin in improving PsA immune inflammation.</div></div><div><h3>Results</h3><div>Data mining results showed that in PsA, immune inflammation was disturbed and relevant indexes were significantly correlated. After CHM treatment, the level of HCRP, C4, IL-12, IL-17, IL-23, TNF-α, TGF-β1, P65, P50, and IKBα was markedly improved, which was highly correlated with the application of CHMs. In addition, the core prescription containing 10 CHMs was screened, and the action mechanisms of the active ingredient wogonin on the immune inflammation in PsA were identified with network pharmacology and molecular docking. Cell experiments revealed that wogonin reduced M5-induced HaCaT cell viability and TNF-α and IL-1β expressions by blocking the PI3K/AKT pathway in a dose-dependent manner.</div></div><div><h3>Conclusion</h3><div>Our findings strongly confirmed the enormous promise of CHMs as a therapy for PsA and may provide support for developing drugs and targets for PsA treatment.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"147 ","pages":"Article 113984"},"PeriodicalIF":4.8,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142927148","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-06DOI: 10.1016/j.intimp.2025.114029
Kejia Xu , Juan Tan , Dongyang Lin , Haoran Jiang , Yimin Chu , Luting Zhou , Junjie Zhang , Yinzhong Lu
Intestinal perforations lead to a high risk of sepsis-associated morbidity and multi-organ dysfunctions. A perforation allows intestinal contents (IC) to enter the peritoneal cavity, causing abdominal infections. Right- and left-sided perforations have different prognoses in humans, but the mechanisms associated with different cecum and colon perforations remain unclear. This study investigates how gut flora influences outcomes from perforations at different sites in mice. Using fecal-induced peritonitis mouse model, isolated IC from the cecum or colon was injected peritoneally at 2 mg/kg. Bacterial burden was quantified with quantitative PCR, and microbial communities were analyzed using 16S rRNA gene sequencing. Survival rates were monitored, and blood biochemical indices, histological changes, cytokines expression, immunological signaling and multiple-organ damage were assessed at 16 h post-injections. The results showed cecum IC developed more severe sepsis than colon IC, with shorter median survival time and greater multi-organ damage. Mice treated with cecum IC displayed elevated tissue damage markers in the liver, heart, and kidneys, contributing to worsened pathology. This was likely driven by systematic inflammatory cytokines production and lung inflammation. Mechanistically, cecum IC triggered stronger cGAS-STING and TBK1-NF-κB signaling, promoting systemic inflammation compared to the colon IC. Moreover, bacterial analysis demonstrated that cecum IC carry a higher bacterial burden than colon IC and exhibit a different microbial community. A detailed microbiome comparison revealed an increased abundance of potentially pathogenic bacteria in the cecum IC. These findings suggest that the site of intestinal perforation influences sepsis severity, with the cecum being associated with a higher bacterial burden and a relatively increased abundance of potentially pathogenic bacteria compared to the colon. Our findings first compared the lethality associated with the microbial composition of the cecum and colon, indicating the perforation site could help providers predict the severity of sepsis, thereby introducing a novel perspective to microbiology and sepsis research.
{"title":"Gut microbes of the cecum versus the colon drive more severe lethality and multi-organ damage","authors":"Kejia Xu , Juan Tan , Dongyang Lin , Haoran Jiang , Yimin Chu , Luting Zhou , Junjie Zhang , Yinzhong Lu","doi":"10.1016/j.intimp.2025.114029","DOIUrl":"10.1016/j.intimp.2025.114029","url":null,"abstract":"<div><div>Intestinal perforations lead to a high risk of sepsis-associated morbidity and multi-organ dysfunctions. A perforation allows intestinal contents (IC) to enter the peritoneal cavity, causing abdominal infections. Right- and left-sided perforations have different prognoses in humans, but the mechanisms associated with different cecum and colon perforations remain unclear. This study investigates how gut flora influences outcomes from perforations at different sites in mice. Using fecal-induced peritonitis mouse model, isolated IC from the cecum or colon was injected peritoneally at 2 mg/kg. Bacterial burden was quantified with quantitative PCR, and microbial communities were analyzed using 16S rRNA gene sequencing. Survival rates were monitored, and blood biochemical indices, histological changes, cytokines expression, immunological signaling and multiple-organ damage were assessed at 16 h post-injections. The results showed cecum IC developed more severe sepsis than colon IC, with shorter median survival time and greater multi-organ damage. Mice treated with cecum IC displayed elevated tissue damage markers in the liver, heart, and kidneys, contributing to worsened pathology. This was likely driven by systematic inflammatory cytokines production and lung inflammation. Mechanistically, cecum IC triggered stronger cGAS-STING and TBK1-NF-κB signaling, promoting systemic inflammation compared to the colon IC. Moreover, bacterial analysis demonstrated that cecum IC carry a higher bacterial burden than colon IC and exhibit a different microbial community. A detailed microbiome comparison revealed an increased abundance of potentially pathogenic bacteria in the cecum IC. These findings suggest that the site of intestinal perforation influences sepsis severity, with the cecum being associated with a higher bacterial burden and a relatively increased abundance of potentially pathogenic bacteria compared to the colon. Our findings first compared the lethality associated with the microbial composition of the cecum and colon, indicating the perforation site could help providers predict the severity of sepsis, thereby introducing a novel perspective to microbiology and sepsis research.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"147 ","pages":"Article 114029"},"PeriodicalIF":4.8,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142964535","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-06DOI: 10.1016/j.intimp.2025.114037
Xiaoxuan Yang , Jie Yang , Qian Zhou , Liang Kang , Xiaoya Li , Wanjun Guo , Fulun Li , Yu Deng
Psoriasis is a chronic inflammatory skin disease. Consistent activation of Signal Transducer and Activator of Transcription 3 (STAT3) in epidermal keratinocyte transactivates various keratinocyte-derived pro-inflammatory cytokines and elicits spontaneous psoriasis-like skin inflammation. In the current study, we first report that topical application of protocatechuic aldehyde (PA), the bioactive compound from Salvia miltiorrhiza (Danshen), significantly improved psoriasis-like skin symptoms and reduced immune cell infiltration in psoriatic lesions. Further molecular mechanism studies demonstrated that PA inactivated STAT3 and inhibited STAT3-mediated transactivation of interleukin-1α (IL-1α) and C-X-C motif chemokine ligand 9 (CXCL9) in epidermal keratinocyte both in vivo and in vitro. Knockdown of STAT3 attenuated the repression effect on IL-1α and CXCL9 by PA. Our results suggested that PA repressed the transactivation of IL-1α and CXCL9 through inhibiting STAT3 in keratinocyte. PA could be potentially used for psoriasis topical treatment or be as a lead compound for drug development.
{"title":"Protocatechuic aldehyde ameliorates psoriasis-like skin inflammation and represses keratinocyte-derived IL-1α and CXCL9 via inhibiting STAT3 activation","authors":"Xiaoxuan Yang , Jie Yang , Qian Zhou , Liang Kang , Xiaoya Li , Wanjun Guo , Fulun Li , Yu Deng","doi":"10.1016/j.intimp.2025.114037","DOIUrl":"10.1016/j.intimp.2025.114037","url":null,"abstract":"<div><div>Psoriasis is a chronic inflammatory skin disease. Consistent activation of Signal Transducer and Activator of Transcription 3 (STAT3) in epidermal keratinocyte transactivates various keratinocyte-derived pro-inflammatory cytokines and elicits spontaneous psoriasis-like skin inflammation. In the current study, we first report that topical application of protocatechuic aldehyde (PA), the bioactive compound from <em>Salvia miltiorrhiza</em> (Danshen), significantly improved psoriasis-like skin symptoms and reduced immune cell infiltration in psoriatic lesions. Further molecular mechanism studies demonstrated that PA inactivated STAT3 and inhibited STAT3-mediated transactivation of interleukin-1α (IL-1α) and C-X-C motif chemokine ligand 9 (CXCL9) in epidermal keratinocyte both <em>in vivo</em> and <em>in vitro</em>. Knockdown of STAT3 attenuated the repression effect on IL-1α and CXCL9 by PA. Our results suggested that PA repressed the transactivation of IL-1α and CXCL9 through inhibiting STAT3 in keratinocyte. PA could be potentially used for psoriasis topical treatment or be as a lead compound for drug development.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"147 ","pages":"Article 114037"},"PeriodicalIF":4.8,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142964548","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-06DOI: 10.1016/j.intimp.2025.114033
Tingting Meng , Ting Gao , Fangxia Qiao , Hongxia Xu , Na Yu , Wenbao Zuo , Jianhong Yang
Herpes zoster is an acute infectious skin disease caused by the reactivation of latent varicella-zoster virus, vaccination, such as subunit vaccine with good safety, can effectively prevent shingles through increasing immunity of the body. However, protein antigens are prone to degradation and inactivation, which alone is generally not sufficient to induce potent immune effect. In this study, the liposomal vaccine platform modified with mPLA (TLR4 agonist) was developed to improve the immunogenicity of glycoprotein E (VZV-gE) derived from herpes zoster virus. The thin-film dispersion and freeze-drying methods were employed to encapsulate VZV-gE against degradation, enhance liposomal stability, and achieve better redissolution effects with an optimized cryoprotectant. The in vitro results presented that mPLA could effectively enhance the uptake of VZV-gE with DC2.4. In vivo immune effect evaluation showed that the prepared subunit vaccines could induce stronger IgG, IgG1, and IgG2a antibody levels in the mouse serum, improving humoral immune effects. And the secretion levels of Th1 cytokines (IFN-γ, IL-2) and Th2 cytokines (IL-4, IL-10) in the splenocytes were significantly increased, inducing protective cellular immune responses. Overall, this work presented that combining immunomodulatory adjuvants decorated nanocarriers to develop subunit vaccine platforms was a promising strategy to prevent the occurrence of herpes zoster effectively.
{"title":"A VZV-gE subunit vaccine decorated with mPLA elicits protective cellular immmune responses against varicella-zoster virus","authors":"Tingting Meng , Ting Gao , Fangxia Qiao , Hongxia Xu , Na Yu , Wenbao Zuo , Jianhong Yang","doi":"10.1016/j.intimp.2025.114033","DOIUrl":"10.1016/j.intimp.2025.114033","url":null,"abstract":"<div><div>Herpes zoster is an acute infectious skin disease caused by the reactivation of latent varicella-zoster virus, vaccination, such as subunit vaccine with good safety, can effectively prevent shingles through increasing immunity of the body. However, protein antigens are prone to degradation and inactivation, which alone is generally not sufficient to induce potent immune effect. In this study, the liposomal vaccine platform modified with mPLA (TLR4 agonist) was developed to improve the immunogenicity of glycoprotein E (VZV-gE) derived from herpes zoster virus. The thin-film dispersion and freeze-drying methods were employed to encapsulate VZV-gE against degradation, enhance liposomal stability, and achieve better redissolution effects with an optimized cryoprotectant. The <em>in vitro</em> results presented that mPLA could effectively enhance the uptake of VZV-gE with DC2.4. <em>In vivo</em> immune effect evaluation showed that the prepared subunit vaccines could induce stronger IgG, IgG1, and IgG2a antibody levels in the mouse serum, improving humoral immune effects. And the secretion levels of Th1 cytokines (IFN-γ, IL-2) and Th2 cytokines (IL-4, IL-10) in the splenocytes were significantly increased, inducing protective cellular immune responses. Overall, this work presented that combining immunomodulatory adjuvants decorated nanocarriers to develop subunit vaccine platforms was a promising strategy to prevent the occurrence of herpes zoster effectively.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"147 ","pages":"Article 114033"},"PeriodicalIF":4.8,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142970771","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-06DOI: 10.1016/j.intimp.2025.114012
Xue Han , Minyi Zhao , Kexin Wang , Weiwei Ma , Binghuo Wu , Yueyang Yu , Xiaomei Liang , Wenjian Mo , Xiaowei Chen , Ming Zhou , Yumiao Li , Shilin Xu , Uet Yu , Yalan Yang , Peng Lei , Ruiqing Zhou , Shunqing Wang
Inflammation stimulation regulates the activity of hematopoietic stem cells (HSCs) through direct-sensing and cytokine-mediation. It is known that HSCs directly sense lipopolysaccharide (LPS), a classical infection-related inflammatory signal, via toll like receptor 4 (TLR4) and subsequently become active. However, the mechanism underlying the activity change of HSCs induced by LPS remains incompletely disclosed. Here we explored that under LPS stimulation, the activation of interferon alpha (IFNα) signal pathway resulted in the activation and exhaustion of HSCs in vitro, indicating HSCs directly responded to LPS through the downstream IFNα signal pathway. We also discovered the increased production of IFNα in mice bone marrow and expression of interferon-α/β receptor (IFNAR) on mice HSCs after LPS stimulation. Creatine, an IFNα inhibitor, could reverse the activation and prevent the exhaustion of HSCs caused by LPS by suppressing the expressions of genes associated with the IFNα signal pathway both in vitro and in vivo. Furthermore, we found that the IFNAR deficiency in mice effectively protected HSCs from activation, elevated apoptosis and impaired reconstitution ability under LPS stimulation in vivo. This finding further supports the notion that LPS activates and injures HSCs indirectly via promoting IFNα secretion in the bone marrow environment. Overall, our findings reveal that LPS causes the injury to HSCs either through direct or cytokine-mediated indirect activation of the IFNα signal pathway.
{"title":"IFN alpha signaling drives hematopoietic stem cells malfunction under acute inflammation","authors":"Xue Han , Minyi Zhao , Kexin Wang , Weiwei Ma , Binghuo Wu , Yueyang Yu , Xiaomei Liang , Wenjian Mo , Xiaowei Chen , Ming Zhou , Yumiao Li , Shilin Xu , Uet Yu , Yalan Yang , Peng Lei , Ruiqing Zhou , Shunqing Wang","doi":"10.1016/j.intimp.2025.114012","DOIUrl":"10.1016/j.intimp.2025.114012","url":null,"abstract":"<div><div>Inflammation stimulation regulates the activity of hematopoietic stem cells (HSCs) through direct-sensing and cytokine-mediation. It is known that HSCs directly sense lipopolysaccharide (LPS), a classical infection-related inflammatory signal, via toll like receptor 4 (TLR4) and subsequently become active. However, the mechanism underlying the activity change of HSCs induced by LPS remains incompletely disclosed. Here we explored that under LPS stimulation, the activation of interferon alpha (IFNα) signal pathway resulted in the activation and exhaustion of HSCs in vitro, indicating HSCs directly responded to LPS through the downstream IFNα signal pathway. We also discovered the increased production of IFNα in mice bone marrow and expression of interferon-α/β receptor (IFNAR) on mice HSCs after LPS stimulation. Creatine, an IFNα inhibitor, could reverse the activation and prevent the exhaustion of HSCs caused by LPS by suppressing the expressions of genes associated with the IFNα signal pathway both in vitro and in vivo. Furthermore, we found that the IFNAR deficiency in mice effectively protected HSCs from activation, elevated apoptosis and impaired reconstitution ability under LPS stimulation in vivo. This finding further supports the notion that LPS activates and injures HSCs indirectly via promoting IFNα secretion in the bone marrow environment. Overall, our findings reveal that LPS causes the injury to HSCs either through direct or cytokine-mediated indirect activation of the IFNα signal pathway.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"147 ","pages":"Article 114012"},"PeriodicalIF":4.8,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143052380","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-06DOI: 10.1016/j.intimp.2024.113969
Shihao Bao , Yifan Zhang , Jingtong Zeng , Bo Zhang , Hanqing Wang , Xianjie Li , Hao Zhang , Yuan Cheng , Wei Xia , Xiaohong Xu , Lingling Zu , Song Xu , Zuoqing Song
Background
Esophageal squamous cell carcinoma (ESCC) is among the most prevalent malignant tumors; it is associated with dismal prognosis, and effective therapeutic agents are lacking. Depression is prevalent concern among cancer patients and is linked to diminished quality of life, poor adherence to treatment, heightened risk of suicide, and poorer prognosis. Imipramine (IM) is a tricyclic antidepressant with anti-inflammatory activity. Recent reports have indicated antitumor effects of IM in various cancers, although its role in ESCC remains unclear.
Methods
The depression status of patients with ESCC was graded with the Patient Health Questionnaire-9, and the effects of antidepressants (moclobemide, milnacipran, venlafaxine, escitalopram, amitriptyline, trazodone, fluvoxamine, and IM) on cell viability were evaluated through CCK-8 assays. The effects of IM on cell proliferation were evaluated through clone formation assays, whereas Transwell assays were used to assess effects on ESCC cell migration and invasion. IM-induced apoptosis was confirmed with annexin V-FITC/Caspase-3 assays, and immunofluorescence staining was used to investigate the formation of IM-induced autophagosomes. Furthermore, western blotting analysis was conducted to determine the expression levels of apoptosis- and autophagy-related proteins. RNA sequencing (RNA-seq) was used to examine signaling pathway changes. Finally, we investigated the influence of IM on tumor progression in vivo in a xenograft model.
Results
The PHQ-9 scores of patients with ESCC were higher than those of healthy controls and positively correlated with the TNM stage of ESCC. Among the antidepressants examined in our study, IM demonstrated the most potent inhibitory effect on ESCC cell viability, and effectively suppressed the proliferation, migration, and invasion of ESCC cells. Additionally, IM treatment induced apoptosis and autophagy in ESCC cells. Furthermore, blocking autophagy with chloroquine (CQ) intensified IM-induced apoptosis, thereby suggesting a protective role of cellular autophagy against apoptosis. RNA-seq results indicated that the Hippo pathway was associated with IM treatment. Upregulation of YAP reversed the apoptosis and autophagy triggered by IM, and targeting YAP intensified this effect. Finally, in animal experiments, IM hindered the growth of ESCC cells and promoted apoptosis and autophagy in tumors while causing minimal toxicity.
Conclusion
Our findings provide the first reported evidence that IM triggers apoptosis and protective autophagy in ESCC cells via the Hippo signaling pathway, thus suggesting that IM may offer a promising therapeutic approach for patients with ESCC and depression.
{"title":"Innovative role of the antidepressant imipramine in esophageal squamous cell carcinoma treatment: Promoting apoptosis and protective autophagy","authors":"Shihao Bao , Yifan Zhang , Jingtong Zeng , Bo Zhang , Hanqing Wang , Xianjie Li , Hao Zhang , Yuan Cheng , Wei Xia , Xiaohong Xu , Lingling Zu , Song Xu , Zuoqing Song","doi":"10.1016/j.intimp.2024.113969","DOIUrl":"10.1016/j.intimp.2024.113969","url":null,"abstract":"<div><h3>Background</h3><div>Esophageal squamous cell carcinoma (ESCC) is among the most prevalent malignant tumors; it is associated with dismal prognosis, and effective therapeutic agents are lacking. Depression is prevalent concern among cancer patients and is linked to diminished quality of life, poor adherence to treatment, heightened risk of suicide, and poorer prognosis. Imipramine (IM) is a tricyclic antidepressant with anti-inflammatory activity. Recent reports have indicated antitumor effects of IM in various cancers, although its role in ESCC remains unclear.</div></div><div><h3>Methods</h3><div>The depression status of patients with ESCC was graded with the Patient Health Questionnaire-9, and the effects of antidepressants (moclobemide, milnacipran, venlafaxine, escitalopram, amitriptyline, trazodone, fluvoxamine, and IM) on cell viability were evaluated through CCK-8 assays. The effects of IM on cell proliferation were evaluated through clone formation assays, whereas Transwell assays were used to assess effects on ESCC cell migration and invasion. IM-induced apoptosis was confirmed with annexin V-FITC/Caspase-3 assays, and immunofluorescence staining was used to investigate the formation of IM-induced autophagosomes. Furthermore, western blotting analysis was conducted to determine the expression levels of apoptosis- and autophagy-related proteins. RNA sequencing (RNA-seq) was used to examine signaling pathway changes. Finally, we investigated the influence of IM on tumor progression in vivo in a xenograft model.</div></div><div><h3>Results</h3><div>The PHQ-9 scores of patients with ESCC were higher than those of healthy controls and positively correlated with the TNM stage of ESCC. Among the antidepressants examined in our study, IM demonstrated the most potent inhibitory effect on ESCC cell viability, and effectively suppressed the proliferation, migration, and invasion of ESCC cells. Additionally, IM treatment induced apoptosis and autophagy in ESCC cells. Furthermore, blocking autophagy with chloroquine (CQ) intensified IM-induced apoptosis, thereby suggesting a protective role of cellular autophagy against apoptosis. RNA-seq results indicated that the Hippo pathway was associated with IM treatment. Upregulation of YAP reversed the apoptosis and autophagy triggered by IM, and targeting YAP intensified this effect. Finally, in animal experiments, IM hindered the growth of ESCC cells and promoted apoptosis and autophagy in tumors while causing minimal toxicity.</div></div><div><h3>Conclusion</h3><div>Our findings provide the first reported evidence that IM triggers apoptosis and protective autophagy in ESCC cells via the Hippo signaling pathway, thus suggesting that IM may offer a promising therapeutic approach for patients with ESCC and depression.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"147 ","pages":"Article 113969"},"PeriodicalIF":4.8,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143052382","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-06Epub Date: 2025-01-13DOI: 10.1016/j.intimp.2024.113701
Dayanne Carla Fernandes, Felipe Silva-de-França, Paula Cristiane Pohl, Silas Fernandes Eto, Luiz Roberto Sardinha, John D Lambris, Denise V Tambourgi
The complement system plays a crucial role in various pathophysiological conditions, including snake envenomation. In this study, we investigated the effects of Bitis arietans venom on the complement system using an ex vivo human whole blood model. Our findings demonstrate that B. arietans venom was able to activate the complement system, leading to a significant increase in the production of anaphylatoxins (C3a/C3a-desArg, C5a/C5a-desArg) and the soluble Terminal Complement Complex (sTCC). Inhibition of the C3 component by Cp40, a C3-C3b inhibitor, resulted in the reduction of C3a/C3a-desArg, C5a/C5a-desArg, and sTCC levels to baseline in venom-stimulated samples. Furthermore, treatment with Cp40 promoted a substantial decrease in the production of pro-inflammatory mediators, such as Prostaglandin E2 (PGE2), IL-8/CXCL8, MCP-1/CCL2, and MIG/CXCL9. To further elucidate the molecular mechanisms, we utilized the THP-1 cell line differentiated into M0 macrophages. Incubation of these macrophages with human plasma, from the human whole blood treated with B. arietans venom, resulted in the expression of the NLRP3 inflammasome and the production of IL-8 and IL-1β. Importantly, Cp40 was able to diminish the production of these cytokines, as well as the levels of ASC and caspase-1 proteins. In conclusion, our results indicate that the inhibition of the complement by Cp40 at C3/C3b level can modulate the inflammatory response and inflammasome activation induced by B. arietans venom. These findings suggest that complement inhibition may be a promising therapeutic approach for managing the inflammatory complications associated with this snake envenomation.
{"title":"Cp40-mediated complement C3 inhibition dampens inflammasome activation and inflammatory mediators storm induced by Bitis arietans venom.","authors":"Dayanne Carla Fernandes, Felipe Silva-de-França, Paula Cristiane Pohl, Silas Fernandes Eto, Luiz Roberto Sardinha, John D Lambris, Denise V Tambourgi","doi":"10.1016/j.intimp.2024.113701","DOIUrl":"10.1016/j.intimp.2024.113701","url":null,"abstract":"<p><p>The complement system plays a crucial role in various pathophysiological conditions, including snake envenomation. In this study, we investigated the effects of Bitis arietans venom on the complement system using an ex vivo human whole blood model. Our findings demonstrate that B. arietans venom was able to activate the complement system, leading to a significant increase in the production of anaphylatoxins (C3a/C3a-desArg, C5a/C5a-desArg) and the soluble Terminal Complement Complex (sTCC). Inhibition of the C3 component by Cp40, a C3-C3b inhibitor, resulted in the reduction of C3a/C3a-desArg, C5a/C5a-desArg, and sTCC levels to baseline in venom-stimulated samples. Furthermore, treatment with Cp40 promoted a substantial decrease in the production of pro-inflammatory mediators, such as Prostaglandin E<sub>2</sub> (PGE<sub>2</sub>), IL-8/CXCL8, MCP-1/CCL2, and MIG/CXCL9. To further elucidate the molecular mechanisms, we utilized the THP-1 cell line differentiated into M0 macrophages. Incubation of these macrophages with human plasma, from the human whole blood treated with B. arietans venom, resulted in the expression of the NLRP3 inflammasome and the production of IL-8 and IL-1β. Importantly, Cp40 was able to diminish the production of these cytokines, as well as the levels of ASC and caspase-1 proteins. In conclusion, our results indicate that the inhibition of the complement by Cp40 at C3/C3b level can modulate the inflammatory response and inflammasome activation induced by B. arietans venom. These findings suggest that complement inhibition may be a promising therapeutic approach for managing the inflammatory complications associated with this snake envenomation.</p>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"147 ","pages":"113701"},"PeriodicalIF":4.8,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142983298","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-06Epub Date: 2025-01-13DOI: 10.1016/j.intimp.2025.114076
Yeying Wang, Bin Liao, Xuesong Shan, Haonan Ye, Yuqi Wen, Hua Guo, Feng Xiao, Hong Zhu
The pathological mechanisms of Parkinson's disease (PD) is complex, and no definitive cure currently exists. This study identified Rutaecarpine (Rut), an alkaloid extracted from natural plants, as a potential therapeutic agent for PD. To elucidate its mechanisms of action and specific effects in PD, network pharmacology, molecular docking, and experimental validation methods were employed. Our findings demonstrated the efficacy of Rut in ameliorating PD symptoms. Network pharmacology analysis indicated that Rut exerts its therapeutic effects through the PPAR signaling pathway and the lipid pathway. Molecular docking results revealed that Rut forms stable protein-ligand complexes with PPARα and PPARγ. Animal experiments showed that Rut improved motor function in PD mice, protected dopaminergic neurons, ameliorated lipid metabolism disorders, and reduced neuroinflammation. This study identified the critical molecular mechanisms and therapeutic targets of Rut in the treatment of PD, providing a theoretical foundation for future investigations into the pharmacodynamics of Rut as a potential anti-PD agent.
{"title":"Revealing rutaecarpine's promise: A pathway to parkinson's disease relief through PPAR modulation.","authors":"Yeying Wang, Bin Liao, Xuesong Shan, Haonan Ye, Yuqi Wen, Hua Guo, Feng Xiao, Hong Zhu","doi":"10.1016/j.intimp.2025.114076","DOIUrl":"10.1016/j.intimp.2025.114076","url":null,"abstract":"<p><p>The pathological mechanisms of Parkinson's disease (PD) is complex, and no definitive cure currently exists. This study identified Rutaecarpine (Rut), an alkaloid extracted from natural plants, as a potential therapeutic agent for PD. To elucidate its mechanisms of action and specific effects in PD, network pharmacology, molecular docking, and experimental validation methods were employed. Our findings demonstrated the efficacy of Rut in ameliorating PD symptoms. Network pharmacology analysis indicated that Rut exerts its therapeutic effects through the PPAR signaling pathway and the lipid pathway. Molecular docking results revealed that Rut forms stable protein-ligand complexes with PPARα and PPARγ. Animal experiments showed that Rut improved motor function in PD mice, protected dopaminergic neurons, ameliorated lipid metabolism disorders, and reduced neuroinflammation. This study identified the critical molecular mechanisms and therapeutic targets of Rut in the treatment of PD, providing a theoretical foundation for future investigations into the pharmacodynamics of Rut as a potential anti-PD agent.</p>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"147 ","pages":"114076"},"PeriodicalIF":4.8,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142983300","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
With the exacerbation of global population aging, sarcopenia has become an increasingly recognized public health issue. Sarcopenia, characterized by a progressive decline in skeletal muscle mass, strength, and function, significantly impacts the quality of life in the elderly. Herein, we explore the role of chroniclow-gradeinflammation in the development of sarcopenia and its underlying molecular mechanisms, including chronic inflammation-associated signaling pathways, immunosenescence, obesity and lipid infiltration, gut microbiota dysbiosis and intestinal barrier disruption, and the decline of satellite cells. The interplay and interaction of these molecular mechanisms provide new perspectives on the complexity of the pathogenesis of sarcopenia and offer a theoretical foundation for the development of future therapeutic strategies.
{"title":"The role of chronic low-grade inflammation in the development of sarcopenia: Advances in molecular mechanisms.","authors":"Ying Cheng, Shangjin Lin, Ziyi Cao, Runzhi Yu, Yongqian Fan, Jie Chen","doi":"10.1016/j.intimp.2025.114056","DOIUrl":"10.1016/j.intimp.2025.114056","url":null,"abstract":"<p><p>With the exacerbation of global population aging, sarcopenia has become an increasingly recognized public health issue. Sarcopenia, characterized by a progressive decline in skeletal muscle mass, strength, and function, significantly impacts the quality of life in the elderly. Herein, we explore the role of chroniclow-gradeinflammation in the development of sarcopenia and its underlying molecular mechanisms, including chronic inflammation-associated signaling pathways, immunosenescence, obesity and lipid infiltration, gut microbiota dysbiosis and intestinal barrier disruption, and the decline of satellite cells. The interplay and interaction of these molecular mechanisms provide new perspectives on the complexity of the pathogenesis of sarcopenia and offer a theoretical foundation for the development of future therapeutic strategies.</p>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"147 ","pages":"114056"},"PeriodicalIF":4.8,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142970603","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-06Epub Date: 2025-01-03DOI: 10.1016/j.intimp.2024.113968
Dan Liao, Yumeng Cui, Lijuan Shi, Saitian Zeng, Huali Wang
Background: Cervical cancer is a prevalent form of cancer in women, and the inhibition of ferroptosis has been shown to promote the progression of cervical cancer tumours. This study aimed to investigate the role of PIN1 in regulating ferroptosis in cervical cancer, focusing on its ability to modulate the cGAS-STING pathway and the potential involvement of USP34 as an upstream regulator of PIN1.
Methods: PIN1-overexpressing and PIN1-knockdown cell lines were constructed. In addition to activating p-STING via PIN1 knockdown and inhibiting p-STING via PIN1 overexpression, cell activity was evaluated via CCK8, EdU, transwell and flow cytometry assays. The expression of USP34, PIN1, cGAS, p-STING, and STING was analysed through qRT-PCR and immunofluorescence. Western blot analysis was used to detect the regulatory effects of USP34, PIN1, cGAS, p-STING, and STING, as well as SUMOylation. Ferroptosis was detected by ROS immunofluorescence, the mitochondrial membrane potential, and mitochondrial electron microscopy. Furthermore, PIN1-knockdown cells were used to construct xenograft tumours in BALB/c male nude mice, and the relevant verification experiments were performed in vivo.
Results: PIN1 can increase the proliferation and invasion of cervical cancer cells by significantly inhibiting ferroptosis. The mechanism by which PIN1 promotes cancer is inhibition of the cGAS-STING pathway. Additionally, we found that USP34 could increase the expression of PIN1 via SUMOylation in cervical cancer cells.
Conclusion: This study confirmed that USP34 could upregulate PIN1 expression and SUMOylation, thereby inhibiting ferroptosis by suppressing the cGAS-STING pathway and in turn promoting the progression of cervical cancer.
{"title":"USP34 regulates PIN1-cGAS-STING axis-dependent ferroptosis in cervical cancer via SUMOylation.","authors":"Dan Liao, Yumeng Cui, Lijuan Shi, Saitian Zeng, Huali Wang","doi":"10.1016/j.intimp.2024.113968","DOIUrl":"10.1016/j.intimp.2024.113968","url":null,"abstract":"<p><strong>Background: </strong>Cervical cancer is a prevalent form of cancer in women, and the inhibition of ferroptosis has been shown to promote the progression of cervical cancer tumours. This study aimed to investigate the role of PIN1 in regulating ferroptosis in cervical cancer, focusing on its ability to modulate the cGAS-STING pathway and the potential involvement of USP34 as an upstream regulator of PIN1.</p><p><strong>Methods: </strong>PIN1-overexpressing and PIN1-knockdown cell lines were constructed. In addition to activating p-STING via PIN1 knockdown and inhibiting p-STING via PIN1 overexpression, cell activity was evaluated via CCK8, EdU, transwell and flow cytometry assays. The expression of USP34, PIN1, cGAS, p-STING, and STING was analysed through qRT-PCR and immunofluorescence. Western blot analysis was used to detect the regulatory effects of USP34, PIN1, cGAS, p-STING, and STING, as well as SUMOylation. Ferroptosis was detected by ROS immunofluorescence, the mitochondrial membrane potential, and mitochondrial electron microscopy. Furthermore, PIN1-knockdown cells were used to construct xenograft tumours in BALB/c male nude mice, and the relevant verification experiments were performed in vivo.</p><p><strong>Results: </strong>PIN1 can increase the proliferation and invasion of cervical cancer cells by significantly inhibiting ferroptosis. The mechanism by which PIN1 promotes cancer is inhibition of the cGAS-STING pathway. Additionally, we found that USP34 could increase the expression of PIN1 via SUMOylation in cervical cancer cells.</p><p><strong>Conclusion: </strong>This study confirmed that USP34 could upregulate PIN1 expression and SUMOylation, thereby inhibiting ferroptosis by suppressing the cGAS-STING pathway and in turn promoting the progression of cervical cancer.</p>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"147 ","pages":"113968"},"PeriodicalIF":4.8,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142926875","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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