Pub Date : 2025-02-01DOI: 10.1016/j.phrs.2025.107598
Xiayi Zhu, Jie Qiu, Ya Zhang, Chunni Lin, Xiaohui Wang, Xiwei Shi, Siya Yang, Qiaoyan Wu, Li Cong
Background
Neoadjuvant chemoimmunotherapy emerged as a promising treatment for locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN). However, a comparison of clinical outcomes with neoadjuvant chemotherapy was lacking.
Objective
To provide evidence supporting clinical decision-making for neoadjuvant chemoimmunotherapy in LA-SCCHN treatment.
Methods
Literature was retrieved from PubMed, Web of Science, Embase, and the Cochrane Library for studies on the efficacy and safety of neoadjuvant chemoimmunotherapy and chemotherapy in LA-SCCHN published before August 10, 2024. The study was registered in the PROSPERO (CRD42024573816).
Results
A total of 28 clinical trials with 2021 patients were included. The neoadjuvant chemoimmunotherapy group had significantly higher pathologic complete response (pCR) (33 % vs. 18 %, P = 0.04) and partial response (PR) (65 % vs. 38 %, P < 0.01). No significant differences were found in overall survival (OS) (hazard ratio: 0.85, 95 % CI: 0.77–0.93) and progression-free survival (PFS) (hazard ratio: 0.72, 95 % CI: 0.61–0.86). Regarding safety outcomes, in the single-arm trials, grade 3–4 treatment-related adverse events (TRAEs) occurred in 14 % of the chemoimmunotherapy group and 13 % of the chemotherapy group, with grade 5 TRAEs at 0 % and 4 %, respectively, showing no significant difference (P = 0.80; P = 0.08). In both RCTs and non-RCT, chemoimmunotherapy had a higher Risk Ratio (RR) for grade 3–4 TRAEs (RR: 1.42, 95 % CI: 0.87–2.31).
Conclusion
Neoadjuvant chemoimmunotherapy has shown promising efficacy and safety for LA-SCCHN, but further randomized trials are needed to confirm long-term survival benefits.
背景：新辅助化学免疫治疗是治疗局部晚期头颈部鳞状细胞癌（LA-SCCHN）的一种很有希望的治疗方法。然而，缺乏与新辅助化疗的临床结果的比较。目的：为LA-SCCHN新辅助化疗的临床决策提供依据。方法：检索PubMed、Web of Science、Embase和Cochrane图书馆，检索2024年8月10日前发表的关于LA-SCCHN新辅助化疗、免疫治疗和化疗的疗效和安全性的文献。该研究已在PROSPERO注册（CRD42024573816）。结果：共纳入28项临床试验，2021例患者。新辅助化疗组病理完全缓解（pCR） （33% vs. 18%, P = 0.04）和部分缓解（PR） （65% vs. 38%, P < 0.01）明显高于化疗组。总生存期（OS）（风险比：0.85,95% CI: 0.77-0.93）和无进展生存期（PFS）（风险比：0.72,95% CI: 0.61-0.86）无显著差异。关于安全性结局，在单臂试验中，化疗免疫治疗组和化疗组发生3 - 4级治疗相关不良事件（TRAEs）的比例分别为14%和13%，其中5级TRAEs分别为0%和4%，差异无统计学意义(P = 0.80；P = 0.08)。在随机对照试验和非随机对照试验中，化疗免疫治疗对3 - 4级TRAEs的风险比（RR）更高（RR: 1.42, 95% CI: 0.87-2.31）。结论：新辅助化疗免疫治疗对LA-SCCHN具有良好的疗效和安全性，但需要进一步的随机试验来证实长期生存益处。
{"title":"Neoadjuvant chemoimmunotherapy for locally advanced squamous cell carcinoma of the head and neck: Systematic review and meta-analysis","authors":"Xiayi Zhu, Jie Qiu, Ya Zhang, Chunni Lin, Xiaohui Wang, Xiwei Shi, Siya Yang, Qiaoyan Wu, Li Cong","doi":"10.1016/j.phrs.2025.107598","DOIUrl":"10.1016/j.phrs.2025.107598","url":null,"abstract":"<div><h3>Background</h3><div>Neoadjuvant chemoimmunotherapy emerged as a promising treatment for locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN). However, a comparison of clinical outcomes with neoadjuvant chemotherapy was lacking.</div></div><div><h3>Objective</h3><div>To provide evidence supporting clinical decision-making for neoadjuvant chemoimmunotherapy in LA-SCCHN treatment.</div></div><div><h3>Methods</h3><div>Literature was retrieved from PubMed, Web of Science, Embase, and the Cochrane Library for studies on the efficacy and safety of neoadjuvant chemoimmunotherapy and chemotherapy in LA-SCCHN published before August 10, 2024. The study was registered in the PROSPERO (CRD42024573816).</div></div><div><h3>Results</h3><div>A total of 28 clinical trials with 2021 patients were included. The neoadjuvant chemoimmunotherapy group had significantly higher pathologic complete response (pCR) (33 % vs. 18 %, <em>P</em> = 0.04) and partial response (PR) (65 % vs. 38 %, <em>P</em> < 0.01). No significant differences were found in overall survival (OS) (hazard ratio: 0.85, 95 % CI: 0.77–0.93) and progression-free survival (PFS) (hazard ratio: 0.72, 95 % CI: 0.61–0.86). Regarding safety outcomes, in the single-arm trials, grade 3–4 treatment-related adverse events (TRAEs) occurred in 14 % of the chemoimmunotherapy group and 13 % of the chemotherapy group, with grade 5 TRAEs at 0 % and 4 %, respectively, showing no significant difference (<em>P</em> = 0.80; <em>P</em> = 0.08). In both RCTs and non-RCT, chemoimmunotherapy had a higher Risk Ratio (RR) for grade 3–4 TRAEs (RR: 1.42, 95 % CI: 0.87–2.31).</div></div><div><h3>Conclusion</h3><div>Neoadjuvant chemoimmunotherapy has shown promising efficacy and safety for LA-SCCHN, but further randomized trials are needed to confirm long-term survival benefits.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"212 ","pages":"Article 107598"},"PeriodicalIF":9.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142979402","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 : 2025-02-01DOI: 10.1016/j.phrs.2024.107570
Yuanyuan Liu , Zerong Zhang , Xiaoyan Li , Qinghong Hu , Zhangyu Jiang , Jia Lv , Jiayi Xue , Dongyu Wang , Jianxiong Cao , Lingyu Li , Xiaowen Ou , Lijun Zhu , Zhongqiu Liu , Tao Su
Wogonin is a flavonoid with efficacy in ulcerative colitis (UC), while the mechanism of its action remains to be fully elucidated. Previous research has indicated that the triple recycling significantly enhances the bioavailability of flavonoids. The efflux transporters, breast cancer resistance protein (BCRP) and multidrug resistance-associated protein 2 (MRP2) are critical regulatory molecules within the enterohepatic triple recycling pathways. Therefore, we investigated the regulatory impact of wogonin on BCRP and MRP2, as well as the roles of these transporters in wogonin's therapeutic efficacy in UC. Using dextran sulfate sodium (DSS)-induced UC model, we found that the anti-UC efficacy of wogonin was diminished in Bcrp-/--Mrp2-/- mice compared to wild-type (WT) mice. In these knockout mice, the content of wogonin was increased in the plasma but decreased in the colon tissues, suggesting that deficiencies in BCRP and MRP2 hinder the efflux of wogonin, resulting in elevated content in the plasma. Moreover, in vitro results showed that after knockout of BCRP and MRP2, the concentration of wogonin increased, and its UGT metabolite wogonoside decreased in both cells and mitochondria. These indicate that inhibiting efflux transporters suppresses cellular and mitochondrial glucuronidation metabolism. Interestingly, proteomic sequencing of mitochondrial subcellular organelles revealed that wogonin exhibited anti-UC effects by inhibiting afamin (AFM), with these effects modulated by BCRP and MRP2. These findings not only suggest a new mechanism for the anti-UC effects of wogonin, but also provide a pharmacological foundation for the clinical use of wogonin in treating UC.
{"title":"Wogonin effects on the efflux transporters BCRP and MRP2, explain its effectiveness in ulcerative colitis: Implications for metabolic and transport interactions","authors":"Yuanyuan Liu , Zerong Zhang , Xiaoyan Li , Qinghong Hu , Zhangyu Jiang , Jia Lv , Jiayi Xue , Dongyu Wang , Jianxiong Cao , Lingyu Li , Xiaowen Ou , Lijun Zhu , Zhongqiu Liu , Tao Su","doi":"10.1016/j.phrs.2024.107570","DOIUrl":"10.1016/j.phrs.2024.107570","url":null,"abstract":"<div><div>Wogonin is a flavonoid with efficacy in ulcerative colitis (UC), while the mechanism of its action remains to be fully elucidated. Previous research has indicated that the triple recycling significantly enhances the bioavailability of flavonoids. The efflux transporters, breast cancer resistance protein (BCRP) and multidrug resistance-associated protein 2 (MRP2) are critical regulatory molecules within the enterohepatic triple recycling pathways. Therefore, we investigated the regulatory impact of wogonin on BCRP and MRP2, as well as the roles of these transporters in wogonin's therapeutic efficacy in UC. Using dextran sulfate sodium (DSS)-induced UC model, we found that the anti-UC efficacy of wogonin was diminished in <em>Bcrp</em><sup><em>-/-</em></sup><em>-Mrp2</em><sup><em>-/-</em></sup> mice compared to wild-type (WT) mice. In these knockout mice, the content of wogonin was increased in the plasma but decreased in the colon tissues, suggesting that deficiencies in BCRP and MRP2 hinder the efflux of wogonin, resulting in elevated content in the plasma. Moreover, <em>in vitro</em> results showed that after knockout of BCRP and MRP2, the concentration of wogonin increased, and its UGT metabolite wogonoside decreased in both cells and mitochondria. These indicate that inhibiting efflux transporters suppresses cellular and mitochondrial glucuronidation metabolism. Interestingly, proteomic sequencing of mitochondrial subcellular organelles revealed that wogonin exhibited anti-UC effects by inhibiting afamin (AFM), with these effects modulated by BCRP and MRP2. These findings not only suggest a new mechanism for the anti-UC effects of wogonin, but also provide a pharmacological foundation for the clinical use of wogonin in treating UC.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"212 ","pages":"Article 107570"},"PeriodicalIF":9.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142922495","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 : 2025-02-01DOI: 10.1016/j.phrs.2025.107580
Daniel Segelcke , Julia R. Sondermann , Christin Kappert , Bruno Pradier , Dennis Görlich , Manfred Fobker , Jan Vollert , Peter K. Zahn , Manuela Schmidt , Esther M. Pogatzki-Zahn
A significant number of patients develop chronic pain after surgery, but prediction of those who are at risk is currently not possible. Thus, prognostic prediction models that include bio-psycho-social and physiological factors in line with the complex nature of chronic pain would be urgently required. Here, we performed a translational study in male volunteers before and after an experimental incision injury. We determined multi-modal features ranging from pain characteristics and psychological questionnaires to blood plasma proteomics. Outcome measures included pain intensity ratings and the extent of the area of hyperalgesia to mechanical stimuli surrounding the incision, as a proxy of central sensitization. A multi-step logistic regression analysis was performed to predict outcome measures based on feature combinations using data-driven cross-validation and prognostic model development. Phenotype-based stratification resulted in the identification of low and high responders for both outcome measures. Regression analysis revealed prognostic proteomic, specific psychophysical, and psychological features. A combinatorial set of distinct features enabled us to predict outcome measures with increased accuracy compared to using single features. Remarkably, in high responders, protein network analysis suggested a protein signature characteristic of low-grade inflammation. Alongside, in silico drug repurposing highlighted potential treatment options employing antidiabetic and anti-inflammatory drugs. Taken together, we present here an integrated pipeline that harnesses bio-psycho-physiological data for prognostic prediction in a translational approach. This pipeline opens new avenues for clinical application with the goal of stratifying patients and identifying potential new targets, as well as mechanistic correlates, for postsurgical pain.
{"title":"Blood proteomics and multimodal risk profiling of human volunteers after incision injury: A translational study for advancing personalized pain management after surgery","authors":"Daniel Segelcke , Julia R. Sondermann , Christin Kappert , Bruno Pradier , Dennis Görlich , Manfred Fobker , Jan Vollert , Peter K. Zahn , Manuela Schmidt , Esther M. Pogatzki-Zahn","doi":"10.1016/j.phrs.2025.107580","DOIUrl":"10.1016/j.phrs.2025.107580","url":null,"abstract":"<div><div>A significant number of patients develop chronic pain after surgery, but prediction of those who are at risk is currently not possible. Thus, prognostic prediction models that include bio-psycho-social and physiological factors in line with the complex nature of chronic pain would be urgently required. Here, we performed a translational study in male volunteers before and after an experimental incision injury. We determined multi-modal features ranging from pain characteristics and psychological questionnaires to blood plasma proteomics. Outcome measures included pain intensity ratings and the extent of the area of hyperalgesia to mechanical stimuli surrounding the incision, as a proxy of central sensitization. A multi-step logistic regression analysis was performed to predict outcome measures based on feature combinations using data-driven cross-validation and prognostic model development. Phenotype-based stratification resulted in the identification of low and high responders for both outcome measures. Regression analysis revealed prognostic proteomic, specific psychophysical, and psychological features. A combinatorial set of distinct features enabled us to predict outcome measures with increased accuracy compared to using single features. Remarkably, in high responders, protein network analysis suggested a protein signature characteristic of low-grade inflammation. Alongside, <em>in silico</em> drug repurposing highlighted potential treatment options employing antidiabetic and anti-inflammatory drugs. Taken together, we present here an integrated pipeline that harnesses bio-psycho-physiological data for prognostic prediction in a translational approach. This pipeline opens new avenues for clinical application with the goal of stratifying patients and identifying potential new targets, as well as mechanistic correlates, for postsurgical pain.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"212 ","pages":"Article 107580"},"PeriodicalIF":9.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142932437","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 : 2025-02-01DOI: 10.1016/j.phrs.2024.107575
Emma F. Magavern , Harshal Deshmukh , Geraldine Asselin , Elizabeth Theusch , Stella Trompet , Xiaohui Li , Raymond Noordam , Y.-D. Ida Chen , Teresa E. Seeman , Kent D. Taylor , Wendy S. Post , Jean-Claude Tardif , Dirk S. Paul , Emelia J. Benjamin , Nancy L. Heard-Costa , Ramachandran S. Vasan , Jerome I. Rotter , Ronald M. Krauss , J.Wouter Jukema , Paul M. Ridker , Helen R. Warren
Statins are first-line treatments in the primary and secondary prevention of cardiovascular disease. Clinical studies show statins act independently of lipid-lowering mechanisms to decrease C-reactive protein (CRP), an inflammation marker. We aim to elucidate genetic loci associated with CRP statin response.
CRP statin response is the change in log-CRP between off-treatment and on-treatment measurements. Cohort-level Genome-Wide Association Studies (GWAS) of CRP response were performed using 1000 Genomes imputed data, testing ∼10 million common genetic variants. GWAS meta-analysis combined results from seven cohorts and clinical trials totalling 14,070 statin-treated individuals of European ancestry within the GIST consortium. Secondary analyses included statin-by-placebo interaction analyses, and lookups in African ancestry cohorts.
Our GWAS identified two genome-wide significant (P < 5e-8) loci: APOE and HNF1A for CRP statin response corrected for baseline CRP. The missense lead variant rs429358 at APOE, contributing to the APOE-E4 haplotype, is a risk locus for dyslipidaemia, Alzheimer’s and coronary artery disease (CAD). The HNF1A locus is associated with diabetes, cholesterol levels, and CAD. Both loci are also associated with baseline CRP levels, and neither locus achieved a significant (P < 0.05) result from the statin v. placebo interaction meta-analysis using randomized clinical trial data. However, the interaction result (P-int=0.09) for APOE was suggestive and possibly underpowered.
The APOE-E4 signal may therefore be associated with both CRP and LDL-cholesterol statin response. Combined with suggestions in the literature that APOE also leads to differential statin benefit in Alzheimer’s, the APOE locus warrants further investigation for potential genetic effects on healthcare with statin treatment.
{"title":"GWAS of CRP response to statins further supports the role of APOE in statin response: A GIST consortium study","authors":"Emma F. Magavern , Harshal Deshmukh , Geraldine Asselin , Elizabeth Theusch , Stella Trompet , Xiaohui Li , Raymond Noordam , Y.-D. Ida Chen , Teresa E. Seeman , Kent D. Taylor , Wendy S. Post , Jean-Claude Tardif , Dirk S. Paul , Emelia J. Benjamin , Nancy L. Heard-Costa , Ramachandran S. Vasan , Jerome I. Rotter , Ronald M. Krauss , J.Wouter Jukema , Paul M. Ridker , Helen R. Warren","doi":"10.1016/j.phrs.2024.107575","DOIUrl":"10.1016/j.phrs.2024.107575","url":null,"abstract":"<div><div>Statins are first-line treatments in the primary and secondary prevention of cardiovascular disease. Clinical studies show statins act independently of lipid-lowering mechanisms to decrease C-reactive protein (CRP), an inflammation marker. We aim to elucidate genetic loci associated with CRP statin response.</div><div>CRP statin response is the change in log-CRP between off-treatment and on-treatment measurements. Cohort-level Genome-Wide Association Studies (GWAS) of CRP response were performed using 1000 Genomes imputed data, testing ∼10 million common genetic variants. GWAS meta-analysis combined results from seven cohorts and clinical trials totalling 14,070 statin-treated individuals of European ancestry within the GIST consortium. Secondary analyses included statin-by-placebo interaction analyses, and lookups in African ancestry cohorts.</div><div>Our GWAS identified two genome-wide significant (P < 5e-8) loci: <em>APOE</em> and <em>HNF1A</em> for CRP statin response corrected for baseline CRP. The missense lead variant rs429358 at <em>APOE</em>, contributing to the <em>APOE</em>-E4 haplotype, is a risk locus for dyslipidaemia, Alzheimer’s and coronary artery disease (CAD). The <em>HNF1A</em> locus is associated with diabetes, cholesterol levels, and CAD. Both loci are also associated with baseline CRP levels, and neither locus achieved a significant (P < 0.05) result from the statin v. placebo interaction meta-analysis using randomized clinical trial data. However, the interaction result (P-int=0.09) for <em>APOE</em> was suggestive and possibly underpowered.</div><div>The <em>APOE</em>-E4 signal may therefore be associated with both CRP and LDL-cholesterol statin response. Combined with suggestions in the literature that <em>APOE</em> also leads to differential statin benefit in Alzheimer’s, the <em>APOE</em> locus warrants further investigation for potential genetic effects on healthcare with statin treatment.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"212 ","pages":"Article 107575"},"PeriodicalIF":9.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142971874","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 : 2025-02-01DOI: 10.1016/j.phrs.2025.107609
Bruno Pradier , Daniel Segelcke , Nathalie Just , Mirjam Augustin , Nina Nagelmann , Cornelius Faber , Esther Pogatzki-Zahn
Post-surgical pain affects millions each year, hindering recovery and quality of life. Surgical procedures cause tissue damage and inflammation, leading to peripheral and central sensitization, resulting in pain at rest or mechanical and heat hyperalgesia. In a rat model for post-surgical pain, spinal GABAergic transmission via GABAA receptors reduces mechanical hypersensitivity but has no effect on pain at rest. While fMRI studies show consistent brain activity changes during mechanical stimulation in post-surgical pain, central processing of pain at rest and the role of spinal GABAergic circuits on surgical pain processing is currently unclear. The aim of this study was to evaluate the influence of an acute surgical incision injury, a proxy for post-surgical pain, on the cerebral processing of pain at rest and mechanical hypersensitivity, and to assess the influence of spinal GABAA-circuits on this processing. In rats, a unilateral incision affected sensorimotor and thalamo-limbic subnetworks at rest and following mechanical stimulation, indicating changes in neural processing relevant to pain at rest and mechanical hypersensitivity in post-surgical pain. Enhancing spinal GABAergic tone increased functional connectivity (FC) in parts of these subnetworks during mechanical stimulation, but not at rest, highlighting spino-cerebral interactions in pain regulation relevant for mechanical hypersensitivity and potentially the transisition to chronic pain after surgery but likely not for pain at rest. These findings underscore the complex and interconnected nature of brain networks in post-surgical pain processing, and provide insights into potential spinal targets for pharmacological intervention to alleviate post-surgical pain and prevent it's chronification.
{"title":"How spinal GABAergic circuits modulate cerebral processing of postsurgical pain","authors":"Bruno Pradier , Daniel Segelcke , Nathalie Just , Mirjam Augustin , Nina Nagelmann , Cornelius Faber , Esther Pogatzki-Zahn","doi":"10.1016/j.phrs.2025.107609","DOIUrl":"10.1016/j.phrs.2025.107609","url":null,"abstract":"<div><div>Post-surgical pain affects millions each year, hindering recovery and quality of life. Surgical procedures cause tissue damage and inflammation, leading to peripheral and central sensitization, resulting in pain at rest or mechanical and heat hyperalgesia. In a rat model for post-surgical pain, spinal GABAergic transmission via GABA<sub>A</sub> receptors reduces mechanical hypersensitivity but has no effect on pain at rest. While fMRI studies show consistent brain activity changes during mechanical stimulation in post-surgical pain, central processing of pain at rest and the role of spinal GABAergic circuits on surgical pain processing is currently unclear. The aim of this study was to evaluate the influence of an acute surgical incision injury, a proxy for post-surgical pain, on the cerebral processing of pain at rest and mechanical hypersensitivity, and to assess the influence of spinal GABA<sub>A</sub>-circuits on this processing. In rats, a unilateral incision affected sensorimotor and thalamo-limbic subnetworks at rest and following mechanical stimulation, indicating changes in neural processing relevant to pain at rest and mechanical hypersensitivity in post-surgical pain. Enhancing spinal GABAergic tone increased functional connectivity (FC) in parts of these subnetworks during mechanical stimulation, but not at rest, highlighting spino-cerebral interactions in pain regulation relevant for mechanical hypersensitivity and potentially the transisition to chronic pain after surgery but likely not for pain at rest. These findings underscore the complex and interconnected nature of brain networks in post-surgical pain processing, and provide insights into potential spinal targets for pharmacological intervention to alleviate post-surgical pain and prevent it's chronification.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"212 ","pages":"Article 107609"},"PeriodicalIF":9.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143009261","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 : 2025-02-01DOI: 10.1016/j.phrs.2025.107615
Mingxue Song , Yao Bai , Fuyong Song
In recent years, increasing evidence has supported that high-fat diet (HFD) can induce the chronic, low-grade neuroinflammation in the brain, which is closely associated with the impairment of cognitive function. As the key organelles responsible for energy metabolism in the cell, mitochondria are believed to involved in the pathogenesis of a variety of neurological disorders. This review summarizes the current progress in the field of the relationship between HFD exposure and neurodegenerative diseases, and outline the major routines of HFD induced neuroinflammation and its pathological significance in the pathogenesis of neurodegenerative diseases. Furthermore, the article highlights the pivotal role of mitochondrial dysfunction in driving the neuroinflammation in the setting of HFD. Danger-associated molecular patterns (DAMPs) from damaged mitochondria can activate innate immune signaling pathways, while mitochondrial dysfunction itself can lead to metabolic remodeling of inflammatory cells, thus inducing neuroinflammation. More importantly, mitochondrial damage, neuroinflammation, and insulin resistance caused by HFD form a mutually reinforcing vicious cycle, ultimately leading to the death of neurons and promoting the progression of neurodegenerative diseases. Thus, in-depth elucidation of the role and underlying mechanisms of mitochondrial dysfunction in HFD-induced metabolic disorders may not only expand our understanding of the mechanistic linkages between HFD and etiology of neurodegenerative diseases, but also help develop the specific strategies for the prevention and treatment of neurodegenerative diseases.
{"title":"High-fat diet and neuroinflammation: The role of mitochondria","authors":"Mingxue Song , Yao Bai , Fuyong Song","doi":"10.1016/j.phrs.2025.107615","DOIUrl":"10.1016/j.phrs.2025.107615","url":null,"abstract":"<div><div>In recent years, increasing evidence has supported that high-fat diet (HFD) can induce the chronic, low-grade neuroinflammation in the brain, which is closely associated with the impairment of cognitive function. As the key organelles responsible for energy metabolism in the cell, mitochondria are believed to involved in the pathogenesis of a variety of neurological disorders. This review summarizes the current progress in the field of the relationship between HFD exposure and neurodegenerative diseases, and outline the major routines of HFD induced neuroinflammation and its pathological significance in the pathogenesis of neurodegenerative diseases. Furthermore, the article highlights the pivotal role of mitochondrial dysfunction in driving the neuroinflammation in the setting of HFD. Danger-associated molecular patterns (DAMPs) from damaged mitochondria can activate innate immune signaling pathways, while mitochondrial dysfunction itself can lead to metabolic remodeling of inflammatory cells, thus inducing neuroinflammation. More importantly, mitochondrial damage, neuroinflammation, and insulin resistance caused by HFD form a mutually reinforcing vicious cycle, ultimately leading to the death of neurons and promoting the progression of neurodegenerative diseases. Thus, in-depth elucidation of the role and underlying mechanisms of mitochondrial dysfunction in HFD-induced metabolic disorders may not only expand our understanding of the mechanistic linkages between HFD and etiology of neurodegenerative diseases, but also help develop the specific strategies for the prevention and treatment of neurodegenerative diseases.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"212 ","pages":"Article 107615"},"PeriodicalIF":9.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143024317","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 : 2025-02-01DOI: 10.1016/j.phrs.2025.107612
Yiming Liu , Karim Valji , Wayne Monsky , Chuansheng Zheng , Xiaoming Yang
Over recent decades, optical imaging (OI) has become an integral part of medical imaging, offering significant advantages over other modalities, such as computed tomography (CT) and magnetic resonance imaging (MRI). OI is distinguished by its real-time imaging capability, cost-effectiveness, portability, absence of ionizing radiation, and high patient acceptability. The introduction of advanced optical dyes (including FDA-approved agents like indocyanine green, Cytalux, and Gleolan) has greatly enhanced its clinical utility. OI has shown clear benefits in the management of patients with cancer, originally by open surgery and now extending to minimally invasive, image-guided interventional procedures. This review highlights recent developments in OI for oncology, emphasizing its benefits for clinicians in guiding surgical and interventional procedures.
{"title":"Optical imaging guidance in oncologic surgery and interventional oncology","authors":"Yiming Liu , Karim Valji , Wayne Monsky , Chuansheng Zheng , Xiaoming Yang","doi":"10.1016/j.phrs.2025.107612","DOIUrl":"10.1016/j.phrs.2025.107612","url":null,"abstract":"<div><div>Over recent decades, optical imaging (OI) has become an integral part of medical imaging, offering significant advantages over other modalities, such as computed tomography (CT) and magnetic resonance imaging (MRI). OI is distinguished by its real-time imaging capability, cost-effectiveness, portability, absence of ionizing radiation, and high patient acceptability. The introduction of advanced optical dyes (including FDA-approved agents like indocyanine green, Cytalux, and Gleolan) has greatly enhanced its clinical utility. OI has shown clear benefits in the management of patients with cancer, originally by open surgery and now extending to minimally invasive, image-guided interventional procedures. This review highlights recent developments in OI for oncology, emphasizing its benefits for clinicians in guiding surgical and interventional procedures.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"212 ","pages":"Article 107612"},"PeriodicalIF":9.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143009585","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 : 2025-02-01DOI: 10.1016/j.phrs.2025.107637
Yaojun Ren , Min Xue , Xinhui Hui , Xiuyu Liu , Muhammad Asad Farooq , Yiran Chen , Yuzhou Ji , Yixin Duan , Iqra Ajmal , Jie Yao , Wenzheng Jiang
Gastric cancer remains a significant global health burden, characterized by regional variations in incidence and poor survival prospects in advanced stages. Natural killer (NK) cells play a crucial role in the body’s anti-cancer defense, and chimeric antigen receptor (CAR)–NK cell therapy is gaining attention as a cutting-edge and promising treatment method. This study aims to tackle the challenge of TGF-β-mediated tumor immune evasion within the immunosuppressive tumor microenvironment by designing a novel chimeric cytokine receptor TRII/21 R, which consists of extracellular domains of TGF-β receptor II (TRII) and transmembrane and intracellular domains of IL-21 receptor (21 R) and can convert the immunosuppressive signal from TGF-β in the tumor microenvironment (TME) into an NK cell activation signal through the IL-21R-STAT3 pathway. We successfully constructed NKG2D-CAR-NK cells expressing TRII/21 R and demonstrated strong anti-tumor activity against cancer cells both in vitro and in vivo. The co-expression of TRII/21 R in CAR-NK cells enhanced the cytotoxicity, promoted proliferation and survival capabilities, and reduced the expression of exhaustion markers. In the xenograft mouse model, TRII/21R-CAR-NK cells significantly inhibited tumor growth and improved the survival rate of tumor-bearing mice compared to the mice receiving control CAR-NK cells. Additionally, TRII/21 R co-expression enhanced NK cells' infiltration, activation, and persistence within the tumor, indicating a robust anti-tumor response mediated by the JAK-STAT3 signaling pathway. This study underscores the therapeutic potential of TRII/21R-modified CAR-NK cells as a breakthrough strategy for combating cancer.
{"title":"Chimeric cytokine receptor TGF-β RⅡ/IL-21R improves CAR-NK cell function by reversing the immunosuppressive tumor microenvironment of gastric cancer","authors":"Yaojun Ren , Min Xue , Xinhui Hui , Xiuyu Liu , Muhammad Asad Farooq , Yiran Chen , Yuzhou Ji , Yixin Duan , Iqra Ajmal , Jie Yao , Wenzheng Jiang","doi":"10.1016/j.phrs.2025.107637","DOIUrl":"10.1016/j.phrs.2025.107637","url":null,"abstract":"<div><div>Gastric cancer remains a significant global health burden, characterized by regional variations in incidence and poor survival prospects in advanced stages. Natural killer (NK) cells play a crucial role in the body’s anti-cancer defense, and chimeric antigen receptor (CAR)–NK cell therapy is gaining attention as a cutting-edge and promising treatment method. This study aims to tackle the challenge of TGF-β-mediated tumor immune evasion within the immunosuppressive tumor microenvironment by designing a novel chimeric cytokine receptor TRII/21 R, which consists of extracellular domains of TGF-β receptor II (TRII) and transmembrane and intracellular domains of IL-21 receptor (21 R) and can convert the immunosuppressive signal from TGF-β in the tumor microenvironment (TME) into an NK cell activation signal through the IL-21R-STAT3 pathway. We successfully constructed NKG2D-CAR-NK cells expressing TRII/21 R and demonstrated strong anti-tumor activity against cancer cells both in vitro and in vivo. The co-expression of TRII/21 R in CAR-NK cells enhanced the cytotoxicity, promoted proliferation and survival capabilities, and reduced the expression of exhaustion markers. In the xenograft mouse model, TRII/21R-CAR-NK cells significantly inhibited tumor growth and improved the survival rate of tumor-bearing mice compared to the mice receiving control CAR-NK cells. Additionally, TRII/21 R co-expression enhanced NK cells' infiltration, activation, and persistence within the tumor, indicating a robust anti-tumor response mediated by the JAK-STAT3 signaling pathway. This study underscores the therapeutic potential of TRII/21R-modified CAR-NK cells as a breakthrough strategy for combating cancer.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"212 ","pages":"Article 107637"},"PeriodicalIF":9.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143067195","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 : 2025-02-01DOI: 10.1016/j.phrs.2025.107591
Huifang Sun , Tengyuan Xia , Shuting Ma , Tao Lv, Yuhong Li
The hallmarks of aging encompass a variety of molecular categories (genomic, telomeric, and epigenetic), organelles (proteostasis, autophagy, and mitochondria), cellular components (including stem cells), systems (such as intercellular communication and chronic inflammation), and environmental factors (dysbiosis and nutrient sensing). These hallmarks play a crucial role in the aging process. Despite their intricate interconnections, the relationships among the hallmarks of aging remain unclear. Although the boundaries between these hallmarks may be indistinct, they exhibit interdependence, with the influence of one hallmark extending to others. Building on this foundation, we investigated the interrelations among the various hallmarks of aging and provided a systematic overview of their logical relationships, proposing that cellular communication plays a crucial role in the aging process. Exosomes function as a primary mode of cellular communication and significantly impact the aging process. Therefore, we propose utilizing exosomes as valuable tools for understanding the mechanisms of aging and addressing age-related concerns. Exosomes may represent a novel approach for the treatment and diagnosis of aging-related conditions in animals. Furthermore, our research reveals that exocytosis in young nematodes slows the aging process, while exocytosis in aged nematodes has the opposite effect, accelerating aging. In conclusion, exosomes act as intercellular messengers that influence the maintenance of a healthy aging process and link the hallmarks of aging with indicators of well-being.
{"title":"Intercellular communication is crucial in the regulation of healthy aging via exosomes","authors":"Huifang Sun , Tengyuan Xia , Shuting Ma , Tao Lv, Yuhong Li","doi":"10.1016/j.phrs.2025.107591","DOIUrl":"10.1016/j.phrs.2025.107591","url":null,"abstract":"<div><div>The hallmarks of aging encompass a variety of molecular categories (genomic, telomeric, and epigenetic), organelles (proteostasis, autophagy, and mitochondria), cellular components (including stem cells), systems (such as intercellular communication and chronic inflammation), and environmental factors (dysbiosis and nutrient sensing). These hallmarks play a crucial role in the aging process. Despite their intricate interconnections, the relationships among the hallmarks of aging remain unclear. Although the boundaries between these hallmarks may be indistinct, they exhibit interdependence, with the influence of one hallmark extending to others. Building on this foundation, we investigated the interrelations among the various hallmarks of aging and provided a systematic overview of their logical relationships, proposing that cellular communication plays a crucial role in the aging process. Exosomes function as a primary mode of cellular communication and significantly impact the aging process. Therefore, we propose utilizing exosomes as valuable tools for understanding the mechanisms of aging and addressing age-related concerns. Exosomes may represent a novel approach for the treatment and diagnosis of aging-related conditions in animals. Furthermore, our research reveals that exocytosis in young nematodes slows the aging process, while exocytosis in aged nematodes has the opposite effect, accelerating aging. In conclusion, exosomes act as intercellular messengers that influence the maintenance of a healthy aging process and link the hallmarks of aging with indicators of well-being.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"212 ","pages":"Article 107591"},"PeriodicalIF":9.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142971890","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}
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