Pub Date : 2025-02-01DOI: 10.1016/j.phrs.2025.107577
Yanqing Liu , Jie Chen , Xiang Li , Yu Fan , Cheng Peng , Xiaochun Ye , Yingshuang Wang , Xin Xie
RAS proteins, as pivotal signal transduction molecules, are frequently mutated and hyperactivated in various human cancers, closely associated with tumor cell proliferation, survival, and metastasis. Despite extensive research on RAS targeted therapies, developing effective RAS inhibitors remains a significant challenge. Natural products, endowed with unique chemical structures and diverse biological activities through long-term natural selection, have emerged as a vital resource for discovering novel RAS-targeted therapeutic drugs. This review focuses on the latest advancements in targeting RAS with natural products and categorizes these natural products based on their mechanisms of action. Additionally, we discuss the challenges faced by these natural products during clinical translation, including issues related to pharmacokinetics. Strategies such as combination therapy, structural optimization, and drug delivery systems are anticipated to enhance efficacy and overcome these challenges.
{"title":"Natural products targeting RAS by multiple mechanisms and its therapeutic potential in cancer: An update since 2020","authors":"Yanqing Liu , Jie Chen , Xiang Li , Yu Fan , Cheng Peng , Xiaochun Ye , Yingshuang Wang , Xin Xie","doi":"10.1016/j.phrs.2025.107577","DOIUrl":"10.1016/j.phrs.2025.107577","url":null,"abstract":"<div><div>RAS proteins, as pivotal signal transduction molecules, are frequently mutated and hyperactivated in various human cancers, closely associated with tumor cell proliferation, survival, and metastasis. Despite extensive research on RAS targeted therapies, developing effective RAS inhibitors remains a significant challenge. Natural products, endowed with unique chemical structures and diverse biological activities through long-term natural selection, have emerged as a vital resource for discovering novel RAS-targeted therapeutic drugs. This review focuses on the latest advancements in targeting RAS with natural products and categorizes these natural products based on their mechanisms of action. Additionally, we discuss the challenges faced by these natural products during clinical translation, including issues related to pharmacokinetics. Strategies such as combination therapy, structural optimization, and drug delivery systems are anticipated to enhance efficacy and overcome these challenges.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"212 ","pages":"Article 107577"},"PeriodicalIF":9.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142932481","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.2025.107585
Andrea Ebersberger, Hans-Georg Schaible
Musculoskeletal pain has a high prevalence of transition to chronic pain and/or persistence as chronic pain for years or even a lifetime. Possible mechanisms for the development of such pain states are often reflected in inflammatory or neuropathic processes involving, among others, cytokines and other molecules. Since biologics such as blockers of TNF or IL-6 can attenuate inflammation and pain in a subset of patients with rheumatoid arthritis, the question arises to what extent cytokines are involved in the generation of pain in human musculoskeletal diseases. In numerous experimental non-human studies, cytokines have been shown to alter neuronal sensitivity in the peripheral and central nociceptive systems. In this review, we addressed the involvement of cytokines in postoperative pain, complex regional pain syndrome, rheumatoid arthritis, osteoarthritis, temporomandibular joint disease, low back pain and fibromyalgia using PubMed searches including meta-analyses of data. There is evidence that certain pro- and anti-inflammatory cytokines are regulated in all of these diseases, often in both acute and chronic disease states. However, within these data, we found a great deal of heterogeneity in the association between cytokine levels and pain. Neutralization of cytokines showed antinociceptive effects in subgroups of patients with chronic pain (e.g., in a proportion of patients with rheumatoid arthritis), but failed to reduce chronic pain in other diseases (e.g., osteoarthritis). More systematic studies are needed to unravel the pathogenic role of cytokines in human musculoskeletal pain, taking into account the disease process and the mechanisms of pain initiation and maintenance.
{"title":"Do cytokines play a role in the transition from acute to chronic musculoskeletal pain?","authors":"Andrea Ebersberger, Hans-Georg Schaible","doi":"10.1016/j.phrs.2025.107585","DOIUrl":"10.1016/j.phrs.2025.107585","url":null,"abstract":"<div><div>Musculoskeletal pain has a high prevalence of transition to chronic pain and/or persistence as chronic pain for years or even a lifetime. Possible mechanisms for the development of such pain states are often reflected in inflammatory or neuropathic processes involving, among others, cytokines and other molecules. Since biologics such as blockers of TNF or IL-6 can attenuate inflammation and pain in a subset of patients with rheumatoid arthritis, the question arises to what extent cytokines are involved in the generation of pain in human musculoskeletal diseases. In numerous experimental non-human studies, cytokines have been shown to alter neuronal sensitivity in the peripheral and central nociceptive systems. In this review, we addressed the involvement of cytokines in postoperative pain, complex regional pain syndrome, rheumatoid arthritis, osteoarthritis, temporomandibular joint disease, low back pain and fibromyalgia using PubMed searches including meta-analyses of data. There is evidence that certain pro- and anti-inflammatory cytokines are regulated in all of these diseases, often in both acute and chronic disease states. However, within these data, we found a great deal of heterogeneity in the association between cytokine levels and pain. Neutralization of cytokines showed antinociceptive effects in subgroups of patients with chronic pain (e.g., in a proportion of patients with rheumatoid arthritis), but failed to reduce chronic pain in other diseases (e.g., osteoarthritis). More systematic studies are needed to unravel the pathogenic role of cytokines in human musculoskeletal pain, taking into account the disease process and the mechanisms of pain initiation and maintenance.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"212 ","pages":"Article 107585"},"PeriodicalIF":9.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142952938","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.2025.107595
Mar Garcia–Zamora, Gemma García–Lluch, Lucrecia Moreno, Consuelo Cháfer–Pericas, Juan Pardo
{"title":"Response to letter to the editor: Expanding perspectives on the relationship between statin potency and lipophilicity in Alzheimer’s disease management","authors":"Mar Garcia–Zamora, Gemma García–Lluch, Lucrecia Moreno, Consuelo Cháfer–Pericas, Juan Pardo","doi":"10.1016/j.phrs.2025.107595","DOIUrl":"10.1016/j.phrs.2025.107595","url":null,"abstract":"","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"212 ","pages":"Article 107595"},"PeriodicalIF":9.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142971892","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}
It has been established that cross-fostering impacts the development of hypertension in spontaneously hypertensive rats (SHR). However, the ability of the cross-fostering protocol to shape gut microbiota profile in SHR and impact hypertension is not known. In this sense, the current study explored the influence of normotensive and hypertensive postnatal environments on the intestinal microbiota structure, composition, and functional capacity of SHR and Wistar rats. Our findings revealed significant differences in the microbiota's composition and its metabolic activity in young non-fostered SHR (SS) vs. Wistar (WW) rats, even before hypertension onset, characterized by a reduction of the “low-abundance” bacterial genera, a diminished availability of fecal butyrate and elevated hydrogen sulfide (H2S) production by the SS gut microbiota. Despite influencing the microbiota of both strains, cross-fostering did not fully replicate the microbiota composition of the naturally reared groups in the SHR nursed by Wistar mothers (SW), or in the Wistar rats breastfed by SHR mothers (WS). The SW group had fewer significant genera identified at the Partial Least Squares Discriminant Analysis (PLS-DA), despite resembling the genera profile identified in the normotensive group. While sharing bacterial genera with both SS and WW groups, the WS group is distinguished by its unique microbial composition, particularly by a greater diversity of the ‘low-abundance’ bacterial genera. Moreover, decreased systolic blood pressure was observed in the SW group compared to the SS group in adulthood. Thus, we could establish a link between microbiota composition and hypertension development, associating it with the loss of the "low-abundance" bacterial taxa. Our data suggest that the postnatal environment is pivotal to promoting gut microbiota compositional changes and contributes to hypertension development.
{"title":"Changes in the intestinal microbiota induced by the postnatal environment and their association with hypertension","authors":"Patrizia Dardi , Camille Perella Coutinho , Sarah de Oliveira , Simone Aparecida Teixeira , Renaide Rodrigues Ferreira Gacek , Eduardo Purgatto , Marco Aurélio Ramirez Vinolo , Marcelo Nicolás Muscará , Luciana Venturini Rossoni","doi":"10.1016/j.phrs.2025.107621","DOIUrl":"10.1016/j.phrs.2025.107621","url":null,"abstract":"<div><div>It has been established that cross-fostering impacts the development of hypertension in spontaneously hypertensive rats (SHR). However, the ability of the cross-fostering protocol to shape gut microbiota profile in SHR and impact hypertension is not known. In this sense, the current study explored the influence of normotensive and hypertensive postnatal environments on the intestinal microbiota structure, composition, and functional capacity of SHR and Wistar rats. Our findings revealed significant differences in the microbiota's composition and its metabolic activity in young non-fostered SHR (SS) <em>vs.</em> Wistar (WW) rats, even before hypertension onset, characterized by a reduction of the “low-abundance” bacterial genera, a diminished availability of fecal butyrate and elevated hydrogen sulfide (H<sub>2</sub>S) production by the SS gut microbiota. Despite influencing the microbiota of both strains, cross-fostering did not fully replicate the microbiota composition of the naturally reared groups in the SHR nursed by Wistar mothers (SW), or in the Wistar rats breastfed by SHR mothers (WS). The SW group had fewer significant genera identified at the Partial Least Squares Discriminant Analysis (PLS-DA), despite resembling the genera profile identified in the normotensive group. While sharing bacterial genera with both SS and WW groups, the WS group is distinguished by its unique microbial composition, particularly by a greater diversity of the ‘low-abundance’ bacterial genera. Moreover, decreased systolic blood pressure was observed in the SW group compared to the SS group in adulthood. Thus, we could establish a link between microbiota composition and hypertension development, associating it with the loss of the \"low-abundance\" bacterial taxa. Our data suggest that the postnatal environment is pivotal to promoting gut microbiota compositional changes and contributes to hypertension development.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"212 ","pages":"Article 107621"},"PeriodicalIF":9.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143028870","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.2025.107603
Li Zhu , Yong-Ping Liu , Yuan-Wang , Bo-Xuan Sun , Yu-Ting Huang , Ji-Kai Zhao , Jian-Feng Liu , Li-Ming Yu , Hui-Shan Wang
Numerous studies conducted in recent years indicate that mammalian E3 ubiquitin ligases serve as key regulators in the maintenance of cellular homeostasis by targeting the ubiquitination of substrate proteins and activating downstream signaling pathways. SYVN1, an E3 ubiquitin ligase, is characterized by its significant functions in regulating various biological processes, including molecular mechanisms related to gene expression, signaling pathways, and cell death, among others. Consequently, SYVN1 plays a crucial role in both normal human physiology and the pathogenesis of various diseases, such as oncogenesis, cardiovascular disorders, immune regulation, skeletal anomalies, and neurological diseases. This review synthesizes recent findings regarding the physiological and pathophysiological roles of SYVN1, offering new insights into potential strategies for the prevention and treatment of human diseases, as well as suggesting avenues for future drug development. In this Review, we summarize the latest findings regarding the physiological and pathophysiological roles of SYVN1, elucidating the mechanisms by which SYVN1 can regulate the progression of various diseases in humans. These important findings provide new avenues for further investigation of SYVN1 protein, new insights into potential strategies to prevent and treat human diseases, and new directions for future drug development.
{"title":"E3 ubiquitin ligase SYVN1 as a promising therapeutic target for diverse human diseases","authors":"Li Zhu , Yong-Ping Liu , Yuan-Wang , Bo-Xuan Sun , Yu-Ting Huang , Ji-Kai Zhao , Jian-Feng Liu , Li-Ming Yu , Hui-Shan Wang","doi":"10.1016/j.phrs.2025.107603","DOIUrl":"10.1016/j.phrs.2025.107603","url":null,"abstract":"<div><div>Numerous studies conducted in recent years indicate that mammalian E3 ubiquitin ligases serve as key regulators in the maintenance of cellular homeostasis by targeting the ubiquitination of substrate proteins and activating downstream signaling pathways. SYVN1, an E3 ubiquitin ligase, is characterized by its significant functions in regulating various biological processes, including molecular mechanisms related to gene expression, signaling pathways, and cell death, among others. Consequently, SYVN1 plays a crucial role in both normal human physiology and the pathogenesis of various diseases, such as oncogenesis, cardiovascular disorders, immune regulation, skeletal anomalies, and neurological diseases. This review synthesizes recent findings regarding the physiological and pathophysiological roles of SYVN1, offering new insights into potential strategies for the prevention and treatment of human diseases, as well as suggesting avenues for future drug development. In this Review, we summarize the latest findings regarding the physiological and pathophysiological roles of SYVN1, elucidating the mechanisms by which SYVN1 can regulate the progression of various diseases in humans. These important findings provide new avenues for further investigation of SYVN1 protein, new insights into potential strategies to prevent and treat human diseases, and new directions for future drug development.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"212 ","pages":"Article 107603"},"PeriodicalIF":9.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143009623","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}
Metabolic syndrome (MetS) encompasses metabolic risk factors like elevated blood glucose, abnormal lipid levels, and hypertension. Nanocurcumin, a nanoscale formulation of curcumin, may offer therapeutic benefits for MetS management. This systematic review and meta-analysis evaluates the impact of nanocurcumin supplementation on key MetS parameters.
Methods
A systematic literature search identified 20 randomized controlled trials (RCTs) with 1394 participants. Data were pooled using a random-effects model, and standardized mean differences (SMDs) were calculated for key outcomes.
Results
Nanocurcumin supplementation significantly improved waist circumference (WC) (standardized mean difference (SMD): −0.30 cm), fasting blood sugar (FBS) (SMD: −0.34 mg/dL), HbA1c (SMD: −0.33 %), and quantitative insulin sensitivity check index (QUICKI) score (SMD: 0.73). Lipid profile parameters, including total cholesterol (SMD: −0.18 mg/dL), LDL-C (SMD: −0.16 mg/dL), and HDL-C (SMD: 0.32 mg/dL), also reduced significantly. Improvement in diastolic blood pressure (DBP) (SMD: −0.32 mmHg), total antioxidant capacity (TAC) (SMD: 0.44 mmol/L), malondialdehyde (MDA) (SMD: −0.37 mmol/L), tumor necrosis factor-α (TNF-α) (SMD: −2.30 ng/L), interleukin-6 (IL-6) (SMD: −1.07 ng/L), and high-sensitivity C-reactive protein (hs-CRP) (SMD: −0.34 mg/L) were observed.
Conclusion
Nanocurcumin supplementation significantly improves multiple MetS-related parameters, including anthropometric measures, glycemic control, lipid profile, blood pressure, oxidative stress markers, and inflammatory biomarkers. These findings highlight nanocurcumin's potential as an effective adjunctive therapy for managing MetS. However, the variability in study participant ages, treatment durations, and sample sizes suggests the need for further well-designed RCTs to establish optimal usage guidelines.
{"title":"Effects of nanocurcumin supplementation on metabolic syndrome: A systematic review and meta-analysis of randomized controlled trials","authors":"Gofarana Wilar , Cecep Suhandi , Kohji Fukunaga , Masanori Shigeno , Ichiro Kawahata , Rizky Abdulah , Takuya Sasaki","doi":"10.1016/j.phrs.2025.107641","DOIUrl":"10.1016/j.phrs.2025.107641","url":null,"abstract":"<div><h3>Background</h3><div>Metabolic syndrome (MetS) encompasses metabolic risk factors like elevated blood glucose, abnormal lipid levels, and hypertension. Nanocurcumin, a nanoscale formulation of curcumin, may offer therapeutic benefits for MetS management. This systematic review and meta-analysis evaluates the impact of nanocurcumin supplementation on key MetS parameters.</div></div><div><h3>Methods</h3><div>A systematic literature search identified 20 randomized controlled trials (RCTs) with 1394 participants. Data were pooled using a random-effects model, and standardized mean differences (SMDs) were calculated for key outcomes.</div></div><div><h3>Results</h3><div>Nanocurcumin supplementation significantly improved waist circumference (WC) (standardized mean difference (SMD): −0.30 cm), fasting blood sugar (FBS) (SMD: −0.34 mg/dL), HbA1c (SMD: −0.33 %), and quantitative insulin sensitivity check index (QUICKI) score (SMD: 0.73). Lipid profile parameters, including total cholesterol (SMD: −0.18 mg/dL), LDL-C (SMD: −0.16 mg/dL), and HDL-C (SMD: 0.32 mg/dL), also reduced significantly. Improvement in diastolic blood pressure (DBP) (SMD: −0.32 mmHg), total antioxidant capacity (TAC) (SMD: 0.44 mmol/L), malondialdehyde (MDA) (SMD: −0.37 mmol/L), tumor necrosis factor-α (TNF-α) (SMD: −2.30 ng/L), interleukin-6 (IL-6) (SMD: −1.07 ng/L), and high-sensitivity C-reactive protein (hs-CRP) (SMD: −0.34 mg/L) were observed.</div></div><div><h3>Conclusion</h3><div>Nanocurcumin supplementation significantly improves multiple MetS-related parameters, including anthropometric measures, glycemic control, lipid profile, blood pressure, oxidative stress markers, and inflammatory biomarkers. These findings highlight nanocurcumin's potential as an effective adjunctive therapy for managing MetS. However, the variability in study participant ages, treatment durations, and sample sizes suggests the need for further well-designed RCTs to establish optimal usage guidelines.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"213 ","pages":"Article 107641"},"PeriodicalIF":9.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143080820","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 : 2025-01-31DOI: 10.1016/j.phrs.2025.107636
Qian Fang , Xiaoying Hou , Limei Fan , Yufei Deng , Xiaoxuan Li , Hongyun Zhang , Haiping Wang , Zhengqi Fu , Binlian Sun , Xiji Shu , Hongzhi Du , Yuchen Liu
FOLFOX (5-Fluorouracil, Calcium Folinate combined with Oxaliplatin) is a preferred chemotherapy regimen for colon cancer, but its limited efficacy remains a major challenge, significantly impairs patient outcomes. There is an urgent need to identify strategies to improve its therapeutic effectiveness. Our previous studies have suggested that gut microbiota-derived bile acids may be involved in the anticancer effect of FOLFOX in vitro, however, the underlying mechanism remains unclear. In this study, we investigated the role of bile acids in modulating FOLFOX efficacy and the related mechanisms. We first demonstrated that bile acids depletion (cholestyramine treatment) enhanced FOLFOX efficacy in an orthotopic colon cancer mouse model, suggesting that bile acids play a key role in FOLFOX’s therapeutic effects. Further, based on the system screen of 15 bile acids on FOLFOX efficacy via MTT, colony formation and flow cytometry assay, Deoxycholic Acid (DCA) and Glycodeoxycholic Acid (GDCA) were annotated as potential modulators of FOLFOX efficacy. Among these, DCA was further validated to significantly enhance FOLFOX’s anti-colon cancer effects in vivo. Transcriptomic analysis and subsequent biological experiments revealed that DCA enhanced FOLFOX efficacy via Ugt1a6b. In conclusion, our findings establish that gut microbiota-derived DCA enhances the efficacy of FOLFOX potentially via Ugt1a6b mediated enterohepatic circulation, providing novel insights into a synergistic therapeutic strategy for improving colon cancer treatment.
{"title":"Gut microbiota derived DCA enhances FOLFOX efficacy via Ugt1a6b mediated enterohepatic circulation in colon cancer","authors":"Qian Fang , Xiaoying Hou , Limei Fan , Yufei Deng , Xiaoxuan Li , Hongyun Zhang , Haiping Wang , Zhengqi Fu , Binlian Sun , Xiji Shu , Hongzhi Du , Yuchen Liu","doi":"10.1016/j.phrs.2025.107636","DOIUrl":"10.1016/j.phrs.2025.107636","url":null,"abstract":"<div><div>FOLFOX (5-Fluorouracil, Calcium Folinate combined with Oxaliplatin) is a preferred chemotherapy regimen for colon cancer, but its limited efficacy remains a major challenge, significantly impairs patient outcomes. There is an urgent need to identify strategies to improve its therapeutic effectiveness. Our previous studies have suggested that gut microbiota-derived bile acids may be involved in the anticancer effect of FOLFOX <em>in vitro</em>, however, the underlying mechanism remains unclear. In this study, we investigated the role of bile acids in modulating FOLFOX efficacy and the related mechanisms. We first demonstrated that bile acids depletion (cholestyramine treatment) enhanced FOLFOX efficacy in an orthotopic colon cancer mouse model, suggesting that bile acids play a key role in FOLFOX’s therapeutic effects. Further, based on the system screen of 15 bile acids on FOLFOX efficacy via MTT, colony formation and flow cytometry assay, Deoxycholic Acid (DCA) and Glycodeoxycholic Acid (GDCA) were annotated as potential modulators of FOLFOX efficacy. Among these, DCA was further validated to significantly enhance FOLFOX’s anti-colon cancer effects <em>in vivo</em>. Transcriptomic analysis and subsequent biological experiments revealed that DCA enhanced FOLFOX efficacy via Ugt1a6b. In conclusion, our findings establish that gut microbiota-derived DCA enhances the efficacy of FOLFOX potentially via Ugt1a6b mediated enterohepatic circulation, providing novel insights into a synergistic therapeutic strategy for improving colon cancer treatment.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"213 ","pages":"Article 107636"},"PeriodicalIF":9.1,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143079869","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 : 2025-01-30DOI: 10.1016/j.phrs.2025.107618
Lixin Liu , Siwen Chen , Yantao Song , Longwei Cui , Yiman Chen , Jiangli Xia , Yibo Fan , Liqun Yang , Lina Yang
As the population ages, musculoskeletal diseases (MSK) have emerged as a significant burden for individuals, healthcare systems, and social care systems. Recently, regenerative medicine has exhibited vast potential in age-related MSK, with mesenchymal stromal cells (MSCs) and their derived exosomes (Exos) therapies showing distinct advantages. However, these therapies face several limitations, including issues related to ensuring stability and effective distribution within the body. Hydrogels, acting as an ideal carrier, can enhance the therapeutic effects and application range of MSCs and Exos derived from MSCs (MSC-Exos). Therefore, this review comprehensively summarizes the application progress of MSCs and MSC-Exos combined with hydrogels in age-related MSK disease research. It aims to provide a detailed perspective, showcasing the functional enhancement of MSCs and MSC-Exos when incorporated into hydrogels. Additionally, this review explores their potential and challenges in treating age-related MSK diseases, offering references for future research directions and potential innovative strategies.
{"title":"Hydrogels empowered mesenchymal stem cells and the derived exosomes for regenerative medicine in age-related musculoskeletal diseases","authors":"Lixin Liu , Siwen Chen , Yantao Song , Longwei Cui , Yiman Chen , Jiangli Xia , Yibo Fan , Liqun Yang , Lina Yang","doi":"10.1016/j.phrs.2025.107618","DOIUrl":"10.1016/j.phrs.2025.107618","url":null,"abstract":"<div><div>As the population ages, musculoskeletal diseases (MSK) have emerged as a significant burden for individuals, healthcare systems, and social care systems. Recently, regenerative medicine has exhibited vast potential in age-related MSK, with mesenchymal stromal cells (MSCs) and their derived exosomes (Exos) therapies showing distinct advantages. However, these therapies face several limitations, including issues related to ensuring stability and effective distribution within the body. Hydrogels, acting as an ideal carrier, can enhance the therapeutic effects and application range of MSCs and Exos derived from MSCs (MSC-Exos). Therefore, this review comprehensively summarizes the application progress of MSCs and MSC-Exos combined with hydrogels in age-related MSK disease research. It aims to provide a detailed perspective, showcasing the functional enhancement of MSCs and MSC-Exos when incorporated into hydrogels. Additionally, this review explores their potential and challenges in treating age-related MSK diseases, offering references for future research directions and potential innovative strategies.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"213 ","pages":"Article 107618"},"PeriodicalIF":9.1,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143075199","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 : 2025-01-30DOI: 10.1016/j.phrs.2025.107632
Fengjuan Li , Haowen Ye , Lanlan Li , Qingling Chen , Xianwu Lan , Liangxiu Wu , Bin Li , Lishan Li , Chuxian Guo , Milad Ashrafizadeh , Gautam Sethi , Jun Guo , Liangyan Wu
Dysfunction of keratinocytes affects diabetic wound healing, but underlying mechanisms have not been understood. This study examines crotonylation's role in ferroptosis and autophagy in keratinocytes, particularly regarding ACSL4, using STZ-induced diabetic rats and high glucose-exposed keratinocytes to assess these processes. The ACSL4 knockdown was achieved using adenovirus in wounds to examine the impact of ferroptosis modulation on healing diabetic wounds. MB-3 was utilized to block the H3K27 crotonylation (H3K27cr) in order to clarify the regulatory function of crotonylation in both autophagy and ferroptosis. In STZ-induced diabetic skin and high glucose-exposed keratinocytes, ferroptosis mediated by ACSL4 and suppression of autophagic flux were demonstrated. Moreover, the downregulation of ACSL4 triggered ferroptosis in adjacent wounds of diabetic rats and improved wound healing. The degradation of ACSL4 may be observed via the autophagy-lysosome pathway in keratinocytes. Downregulation of SQSTM1 in diabetic keratinocytes leads to autophagy inhibition and modulates the protein level of ACSL4. Mechanistically, total crotonylation levels and H3K27cr were remarkably elevated in the skin and keratinocytes of diabetic rats; blocking high glucose-induced H3K27cr with MB-3 can enhance SQSTM1 transcription and expression while promoting autophagy and reducing ACSL4-induced ferroptosis in keratinocytes. Therefore, H3K27cr influences autophagy by adjusting SQSTM1 to facilitate ACSL4-triggered ferroptosis in diabetic keratinocytes. This study clarifies the relationships between acylation modifications, autophagy, and ferroptosis, while also offering mechanistic insights and potential therapeutic targets for issues associated with diabetic wound healing.
{"title":"Histone lysine crotonylation accelerates ACSL4-mediated ferroptosis of keratinocytes via modulating autophagy in diabetic wound healing","authors":"Fengjuan Li , Haowen Ye , Lanlan Li , Qingling Chen , Xianwu Lan , Liangxiu Wu , Bin Li , Lishan Li , Chuxian Guo , Milad Ashrafizadeh , Gautam Sethi , Jun Guo , Liangyan Wu","doi":"10.1016/j.phrs.2025.107632","DOIUrl":"10.1016/j.phrs.2025.107632","url":null,"abstract":"<div><div>Dysfunction of keratinocytes affects diabetic wound healing, but underlying mechanisms have not been understood. This study examines crotonylation's role in ferroptosis and autophagy in keratinocytes, particularly regarding ACSL4, using STZ-induced diabetic rats and high glucose-exposed keratinocytes to assess these processes. The ACSL4 knockdown was achieved using adenovirus in wounds to examine the impact of ferroptosis modulation on healing diabetic wounds. MB-3 was utilized to block the H3K27 crotonylation (H3K27cr) in order to clarify the regulatory function of crotonylation in both autophagy and ferroptosis. In STZ-induced diabetic skin and high glucose-exposed keratinocytes, ferroptosis mediated by ACSL4 and suppression of autophagic flux were demonstrated. Moreover, the downregulation of ACSL4 triggered ferroptosis in adjacent wounds of diabetic rats and improved wound healing. The degradation of ACSL4 may be observed via the autophagy-lysosome pathway in keratinocytes. Downregulation of SQSTM1 in diabetic keratinocytes leads to autophagy inhibition and modulates the protein level of ACSL4. Mechanistically, total crotonylation levels and H3K27cr were remarkably elevated in the skin and keratinocytes of diabetic rats; blocking high glucose-induced H3K27cr with MB-3 can enhance SQSTM1 transcription and expression while promoting autophagy and reducing ACSL4-induced ferroptosis in keratinocytes. Therefore, H3K27cr influences autophagy by adjusting SQSTM1 to facilitate ACSL4-triggered ferroptosis in diabetic keratinocytes. This study clarifies the relationships between acylation modifications, autophagy, and ferroptosis, while also offering mechanistic insights and potential therapeutic targets for issues associated with diabetic wound healing.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"213 ","pages":"Article 107632"},"PeriodicalIF":9.1,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143075197","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 : 2025-01-30DOI: 10.1016/j.phrs.2025.107630
Xinye Li , Xin Su , Wanping Liang , Li Wang , Chao Yuan , Juping Xu , Yijun Zhang , Yan Liu , Ning Ma , Fan Yang , Yiyuan Yang , Liyuan Tao , Shipeng Sun , Hongcai Shang , Yanwei Xing
Anthracycline chemotherapy leads to cardiotoxicity in patients with breast cancer. We performed a double-blind randomized controlled trial to assess the efficacy of crocin (crocin tablets) in reducing anthracycline-induced cardiotoxicity in breast cancer patients. Eligible patients were randomly assigned to receive either treatment with crocin tablets or placebo for 6 months. Primary efficacy outcome was the proportion of patients with a drop in left ventricular ejection fraction (LVEF) of at least 10 % from baseline until 6 months. We randomized 200 patients; 7 of them had no valid randomization as the change in chemotherapy scheme. A total of 193 eligible participants (mean [SD] age, 50.9 [9.6] years; all women) were randomly assigned to receive crocin tablets or placebo. The incidence of the primary efficacy outcome was 7.2 % (7/97) in the crocin group and 17.7 % (17/96) in the placebo group (P = 0.027). At 6 months, there were significant differences in the mean change of N-terminal pro–brain natriuretic peptide (NT-pro BNP) between the groups (3.06 [-25.18–6.95] vs. 3.06 [-4.85–24.98] pg/ml; P = 0.017). The changes in heart rate from baseline to 6 months showed a significant difference as the mean difference of −4.00 (95 %CI, −6.95 to −1.05) bpm (P = 0.008). Conclusively, among patients with breast cancer treated with anthracycline-based chemotherapy, crocin tablets reduced the incidence of LVEF reduction. This finding indicated that crocin tablets might be a safe and effective therapy to prevent the cardiotoxicity in this population. (Chictr.org.cn, ID Number: ChiCTR2000041134).
{"title":"Cardioprotective effect of crocin in patients with breast cancer receiving anthracycline-based chemotherapy: A randomized, double-blind, placebo-controlled study","authors":"Xinye Li , Xin Su , Wanping Liang , Li Wang , Chao Yuan , Juping Xu , Yijun Zhang , Yan Liu , Ning Ma , Fan Yang , Yiyuan Yang , Liyuan Tao , Shipeng Sun , Hongcai Shang , Yanwei Xing","doi":"10.1016/j.phrs.2025.107630","DOIUrl":"10.1016/j.phrs.2025.107630","url":null,"abstract":"<div><div>Anthracycline chemotherapy leads to cardiotoxicity in patients with breast cancer. We performed a double-blind randomized controlled trial to assess the efficacy of crocin (crocin tablets) in reducing anthracycline-induced cardiotoxicity in breast cancer patients. Eligible patients were randomly assigned to receive either treatment with crocin tablets or placebo for 6 months. Primary efficacy outcome was the proportion of patients with a drop in left ventricular ejection fraction (LVEF) of at least 10 % from baseline until 6 months. We randomized 200 patients; 7 of them had no valid randomization as the change in chemotherapy scheme. A total of 193 eligible participants (mean [SD] age, 50.9 [9.6] years; all women) were randomly assigned to receive crocin tablets or placebo. The incidence of the primary efficacy outcome was 7.2 % (7/97) in the crocin group and 17.7 % (17/96) in the placebo group (<em>P</em> = 0.027). At 6 months, there were significant differences in the mean change of N-terminal pro–brain natriuretic peptide (NT-pro BNP) between the groups (3.06 [-25.18–6.95] vs. 3.06 [-4.85–24.98] pg/ml; <em>P</em> = 0.017). The changes in heart rate from baseline to 6 months showed a significant difference as the mean difference of −4.00 (95 %CI, −6.95 to −1.05) bpm (<em>P</em> = 0.008). Conclusively, among patients with breast cancer treated with anthracycline-based chemotherapy, crocin tablets reduced the incidence of LVEF reduction. This finding indicated that crocin tablets might be a safe and effective therapy to prevent the cardiotoxicity in this population. (Chictr.org.cn, ID Number: ChiCTR2000041134).</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"213 ","pages":"Article 107630"},"PeriodicalIF":9.1,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143075183","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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