Pub Date : 2026-01-07DOI: 10.1016/j.phrs.2025.108084
Claudia Llinas del Torrent , Iu Raïch , Berta Carrasco-Martinez , Jaume Lillo , Maria Gallo , David Andreu , Leonardo Pardo , Gemma Navarro
From the approximately 800 members of the G protein-coupled receptor (GPCR) family, more than 100 remain orphans (oGPCRs). There is evidence indicating that some oGPCRs may carry out a physiological role independently from endogenous ligands; this includes forming heteromers with other GPCRs and altering their functional and pharmacological properties via allosteric interactions. Recent studies have shown that some of these oGPCRs, e.g. GPR88 and GPR139, allosterically inhibit opioid activity by interacting with the μ-opioid receptor (μOR). Here, we have focused on the characterization of the interaction between GPR88 and µOR and the allosteric mechanism of inhibition. We confirmed that GPR88 inhibits µOR function in striatal neuronal primary cultures. Moreover, using a peptide-interfering approach combined with biophysical and biochemical techniques, we identified that GPR88 and µOR interact via transmembrane helix 6. A combination of molecular dynamic simulations and site-directed mutagenesis have allowed to propose that the negative regulatory role of GPR88 on µOR is due to the Q2986.49 side chain of GPR88.
{"title":"Mechanism of μ-opioid receptor inhibition by orphan GPR88","authors":"Claudia Llinas del Torrent , Iu Raïch , Berta Carrasco-Martinez , Jaume Lillo , Maria Gallo , David Andreu , Leonardo Pardo , Gemma Navarro","doi":"10.1016/j.phrs.2025.108084","DOIUrl":"10.1016/j.phrs.2025.108084","url":null,"abstract":"<div><div>From the approximately 800 members of the G protein-coupled receptor (GPCR) family, more than 100 remain orphans (oGPCRs). There is evidence indicating that some oGPCRs may carry out a physiological role independently from endogenous ligands; this includes forming heteromers with other GPCRs and altering their functional and pharmacological properties via allosteric interactions. Recent studies have shown that some of these oGPCRs, e.g. GPR88 and GPR139, allosterically inhibit opioid activity by interacting with the μ-opioid receptor (μOR). Here, we have focused on the characterization of the interaction between GPR88 and µOR and the allosteric mechanism of inhibition. We confirmed that GPR88 inhibits µOR function in striatal neuronal primary cultures. Moreover, using a peptide-interfering approach combined with biophysical and biochemical techniques, we identified that GPR88 and µOR interact via transmembrane helix 6. A combination of molecular dynamic simulations and site-directed mutagenesis have allowed to propose that the negative regulatory role of GPR88 on µOR is due to the Q298<sup>6.49</sup> side chain of GPR88.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"224 ","pages":"Article 108084"},"PeriodicalIF":10.5,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145940633","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 : 2026-01-05DOI: 10.1016/j.phrs.2026.108088
Dan-dan Wang , Jin Qian , Hui-zhen Zou , Hao Tian , Jia Cai , Cui-cui Hao , Xiao-wen Huang , Ming Li , Yan Dai , Min Zhang , Gao-ming Li , Song-tao Wang , Meng-meng Yang , Ruo-hong Liu , Ce-shi Chen , Xia Kang , Xiao-wei Qi
Plant-derived exosomes-like nanoparticles (ELNs) have been proven to be utilized as a promising therapy for varieties of diseases and conditions with ideal biocompatibility and biosecurity. Fig (Ficus carica) was reported to exert an anti-tumor effect, however, the active components and the underlying mechanism are still unclear. Herein, we isolated and characterized Fig-releasing ELNs (Fig-ELNs). Then, we found Fig-ELNs can prevent the growth of both human and murine breast cancer (BC) cells and induce M1 polarization of macrophages in bone metastasis murine model of BC. Mechanically, peu-miR-2916-p3 was identified as the important component in Fig-ELNs to inhibit the progression of bone metastasis of BC. Peu-miR-2916-p3 can promote the degradation of RN7SL1 and induce the apoptosis of BC cells. On the other hand, it also directly targeted Stab1 and promote the activation of non-canonical NF-κB pathway to facilitate M1 polarization. Our study demonstrated that Fig-ELNs can be a promising therapeutical target of bone metastasis of BC through directly inhibiting the growth of BC cells and remodeling tumor microenvironment, implying as safe and effective adjuvant therapy.
{"title":"Fig-derived exosome-like nanoparticles attenuating bone metastasis of breast cancer through establishing an anti-tumor microenvironment","authors":"Dan-dan Wang , Jin Qian , Hui-zhen Zou , Hao Tian , Jia Cai , Cui-cui Hao , Xiao-wen Huang , Ming Li , Yan Dai , Min Zhang , Gao-ming Li , Song-tao Wang , Meng-meng Yang , Ruo-hong Liu , Ce-shi Chen , Xia Kang , Xiao-wei Qi","doi":"10.1016/j.phrs.2026.108088","DOIUrl":"10.1016/j.phrs.2026.108088","url":null,"abstract":"<div><div>Plant-derived exosomes-like nanoparticles (ELNs) have been proven to be utilized as a promising therapy for varieties of diseases and conditions with ideal biocompatibility and biosecurity. Fig (Ficus carica) was reported to exert an anti-tumor effect, however, the active components and the underlying mechanism are still unclear. Herein, we isolated and characterized Fig-releasing ELNs (Fig-ELNs). Then, we found Fig-ELNs can prevent the growth of both human and murine breast cancer (BC) cells and induce M1 polarization of macrophages in bone metastasis murine model of BC. Mechanically, peu-miR-2916-p3 was identified as the important component in Fig-ELNs to inhibit the progression of bone metastasis of BC. Peu-miR-2916-p3 can promote the degradation of <em>RN7SL1</em> and induce the apoptosis of BC cells. On the other hand, it also directly targeted Stab1 and promote the activation of non-canonical NF-κB pathway to facilitate M1 polarization. Our study demonstrated that Fig-ELNs can be a promising therapeutical target of bone metastasis of BC through directly inhibiting the growth of BC cells and remodeling tumor microenvironment, implying as safe and effective adjuvant therapy.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"224 ","pages":"Article 108088"},"PeriodicalIF":10.5,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145918206","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 : 2026-01-05DOI: 10.1016/j.phrs.2026.108086
Yu Zhang, Yingjie Wang
{"title":"Response letter to Chi-Tung Lu et al.’s Comment on “Efficacy and safety of Gutong Patch compared with NSAIDs for knee osteoarthritis: A real-world multicenter, prospective cohort study in China”","authors":"Yu Zhang, Yingjie Wang","doi":"10.1016/j.phrs.2026.108086","DOIUrl":"10.1016/j.phrs.2026.108086","url":null,"abstract":"","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"224 ","pages":"Article 108086"},"PeriodicalIF":10.5,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145918201","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 : 2026-01-02DOI: 10.1016/j.phrs.2025.108085
Hao Xie , Hong Sheng Cheng , Jia Xun Jarryl Ng , Shuang Zhang , Joseph Han Sol Kim , Soon Heng Tan , Choon-Hong Tan , Nguan Soon Tan
Pharmacotherapies for metabolic dysfunction-associated steatotic liver disease (MASLD) remain limited. Although resmetirom and semaglutide have approvals for MASH, gut-liver axis options are still needed. Fatty Acid Esters of Hydroxy Fatty Acids (FAHFAs) offer anti-inflammatory and metabolic benefits but are constrained by poor stability and synthesis complexity. We develop a modular, scalable chemistry platform that installs bioisosteric linkages to generate orally stable, gut-retentive FAHFAs. High-throughput screening identifies lead candidates (12-TAASA, 12-HDTZSA) that selectively inhibit intestinal lipid handling while sparing glucose absorption. In a diet-induced MASLD model, oral dosing reduces weight gain, lowers hepatic triglycerides, improves steatosis histology and liver injury markers, and enhances glycemic control, achieving efficacy comparable to semaglutide. Mechanistically, we identify an intestine-anchored dual-brake mechanism. First, 12-TAASA slows and diminishes gut-to-liver lipid flux in vivo, directly reducing the dietary lipid burden reaching the liver. Second, 12-TAASA and 12-HDTZSA remodel the gut microbiome toward short-chain fatty acid (SCFA)–producing consortia and increase circulating, bacterially derived SCFAs, providing a complementary, microbiota-mediated route to systemic metabolic benefit. Multi-omics integration further implicates a CD44-centered epithelial program, together with allied lipid-handling pathways, as a key intestinal target network governing flux control. These findings position stabilized FAHFAs as gut-localized agents that couple epithelial lipid-uptake restraint with microbiome-derived SCFA signals to reduce gut-to-liver lipid flux, establishing an orally active, dual-action strategy for MASLD.
{"title":"A gut-liver lipid flux checkpoint mediates FAHFA protection from MASLD","authors":"Hao Xie , Hong Sheng Cheng , Jia Xun Jarryl Ng , Shuang Zhang , Joseph Han Sol Kim , Soon Heng Tan , Choon-Hong Tan , Nguan Soon Tan","doi":"10.1016/j.phrs.2025.108085","DOIUrl":"10.1016/j.phrs.2025.108085","url":null,"abstract":"<div><div>Pharmacotherapies for metabolic dysfunction-associated steatotic liver disease (MASLD) remain limited. Although resmetirom and semaglutide have approvals for MASH, gut-liver axis options are still needed. Fatty Acid Esters of Hydroxy Fatty Acids (FAHFAs) offer anti-inflammatory and metabolic benefits but are constrained by poor stability and synthesis complexity. We develop a modular, scalable chemistry platform that installs bioisosteric linkages to generate orally stable, gut-retentive FAHFAs. High-throughput screening identifies lead candidates (12-TAASA, 12-HDTZSA) that selectively inhibit intestinal lipid handling while sparing glucose absorption. In a diet-induced MASLD model, oral dosing reduces weight gain, lowers hepatic triglycerides, improves steatosis histology and liver injury markers, and enhances glycemic control, achieving efficacy comparable to semaglutide. Mechanistically, we identify an intestine-anchored dual-brake mechanism. First, 12-TAASA slows and diminishes gut-to-liver lipid flux in vivo, directly reducing the dietary lipid burden reaching the liver. Second, 12-TAASA and 12-HDTZSA remodel the gut microbiome toward short-chain fatty acid (SCFA)–producing consortia and increase circulating, bacterially derived SCFAs, providing a complementary, microbiota-mediated route to systemic metabolic benefit. Multi-omics integration further implicates a CD44-centered epithelial program, together with allied lipid-handling pathways, as a key intestinal target network governing flux control. These findings position stabilized FAHFAs as gut-localized agents that couple epithelial lipid-uptake restraint with microbiome-derived SCFA signals to reduce gut-to-liver lipid flux, establishing an orally active, dual-action strategy for MASLD.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"224 ","pages":"Article 108085"},"PeriodicalIF":10.5,"publicationDate":"2026-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145898128","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 : 2026-01-01DOI: 10.1016/j.phrs.2025.108077
Andrew J. Elmendorf , Mostafa Yousefian , Il-Man Kim , J. Andrew Hardaway , Kirk Habegger , Jonathan N. Flak
The epidemics of metabolic disease, in the form of obesity and type 2 diabetes, are a growing public health concern. However, incretin-based therapeutics have transformed our ability to address these diseases. While this current generation of incretin analogues show weight regain upon cessation of treatment, the amount of which can depend on the treatment and patient, iterative advancements may improve weight loss durability in the long term. In this review, we discuss the development of glucagon like peptide-1 receptor (GLP-1R) agonists and GLP-1R/ glucose-dependent insulinotropic polypeptide receptor (GIPR) co-agonists, and how future generations will leverage this strategy. We focus our review on glucagon receptor (GCGR) agonism, which has recently been combined with both GLP-1R and GLP-1R/GIPR agonism to generate dual (e.g. survodutide, cotatutide, mazdutide, etc) and triple agonists (e.g. retatrutide, etc) for improved body weight loss via energy expenditure stimulation. We rely on largely pre-clinical evidence for action because clinical data is extremely limited for GCGR agonism. Herein, we review mechanisms by which glucagon receptor agonists act to increase energy expenditure. Finally, we discuss future improvements to incretin-based therapeutics, and how they can include strategies that target the GCGR. The purpose of this review is to discuss mechanisms by which GCGR agonism can reduce body weight and put them in the context of the combination with incretin receptor agonists. Mechanistic data has only currently been evaluated in preclinical rodent models and evidence for similar processes in humans is limited. We also provide perspectives about how treatments can improve for future advancement of obesity treatment.
{"title":"IUPHAR review: From foe to friend: Repurposing glucagon to treat obesity and type 2 diabetes","authors":"Andrew J. Elmendorf , Mostafa Yousefian , Il-Man Kim , J. Andrew Hardaway , Kirk Habegger , Jonathan N. Flak","doi":"10.1016/j.phrs.2025.108077","DOIUrl":"10.1016/j.phrs.2025.108077","url":null,"abstract":"<div><div>The epidemics of metabolic disease, in the form of obesity and type 2 diabetes, are a growing public health concern. However, incretin-based therapeutics have transformed our ability to address these diseases. While this current generation of incretin analogues show weight regain upon cessation of treatment, the amount of which can depend on the treatment and patient, iterative advancements may improve weight loss durability in the long term. In this review, we discuss the development of glucagon like peptide-1 receptor (GLP-1R) agonists and GLP-1R/ glucose-dependent insulinotropic polypeptide receptor (GIPR) co-agonists, and how future generations will leverage this strategy. We focus our review on glucagon receptor (GCGR) agonism, which has recently been combined with both GLP-1R and GLP-1R/GIPR agonism to generate dual (e.g. survodutide, cotatutide, mazdutide, etc) and triple agonists (e.g. retatrutide, etc) for improved body weight loss via energy expenditure stimulation. We rely on largely pre-clinical evidence for action because clinical data is extremely limited for GCGR agonism. Herein, we review mechanisms by which glucagon receptor agonists act to increase energy expenditure. Finally, we discuss future improvements to incretin-based therapeutics, and how they can include strategies that target the GCGR. The purpose of this review is to discuss mechanisms by which GCGR agonism can reduce body weight and put them in the context of the combination with incretin receptor agonists. Mechanistic data has only currently been evaluated in preclinical rodent models and evidence for similar processes in humans is limited. We also provide perspectives about how treatments can improve for future advancement of obesity treatment.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"223 ","pages":"Article 108077"},"PeriodicalIF":10.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145889625","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 : 2026-01-01DOI: 10.1016/j.phrs.2025.108076
Hamsaletchumi Rajan , Bey-Hing Goh , Yatinesh Kumari , Lai Ti Gew , Hooi-Leng Ser
Oxidative stress results from an imbalance between free radicals—such as reactive oxygen species (ROS) and reactive nitrogen species (RNS)—and the body’s antioxidant defenses. This imbalance contributes to the progression of diseases affecting the nervous, cardiovascular, and respiratory systems. Cyclodipeptides (CDPs) have exhibited significant antioxidant, cytoprotective, and neuroprotective properties, making them promising candidates for mitigating oxidative damage. Their ability to modulate oxidative stress pathways highlights their potential as therapeutic agents in oxidative damage-related diseases. This review discusses the role of free radicals in oxidative stress before exploring the importance of different types of CDPs in counteracting oxidative damage in various diseases.
{"title":"Potential of cyclodipeptides in combating oxidative stress in chronic diseases","authors":"Hamsaletchumi Rajan , Bey-Hing Goh , Yatinesh Kumari , Lai Ti Gew , Hooi-Leng Ser","doi":"10.1016/j.phrs.2025.108076","DOIUrl":"10.1016/j.phrs.2025.108076","url":null,"abstract":"<div><div>Oxidative stress results from an imbalance between free radicals—such as reactive oxygen species (ROS) and reactive nitrogen species (RNS)—and the body’s antioxidant defenses. This imbalance contributes to the progression of diseases affecting the nervous, cardiovascular, and respiratory systems. Cyclodipeptides (CDPs) have exhibited significant antioxidant, cytoprotective, and neuroprotective properties, making them promising candidates for mitigating oxidative damage. Their ability to modulate oxidative stress pathways highlights their potential as therapeutic agents in oxidative damage-related diseases. This review discusses the role of free radicals in oxidative stress before exploring the importance of different types of CDPs in counteracting oxidative damage in various diseases.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"223 ","pages":"Article 108076"},"PeriodicalIF":10.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145810840","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 : 2026-01-01DOI: 10.1016/j.phrs.2025.108075
Forum Kayastha , Noah B. Herrington , Anirban Roychowdhury , Nahid M. Nanaji , Won Sok Lee , Glen E. Kellogg , Bandish Kapadia , Ronald B. Gartenhaus
Deubiquitinases (DUBs) have long been viewed through the narrow lens of enzymatic catalysis, but emerging evidence reveals their non-catalytic domains as master regulators of oncogenic signaling. USP11, a structurally modular DUB, exemplifies this duality: beyond its canonical role in DNA repair, USP11 scaffolds key translational effectors such as eIF4B, sustaining the expression of pro-survival oncogenes in aggressive lymphomas. Here, we unveil RBF4 and RBF11, first-in-class, non-catalytic USP11 inhibitors discovered through pharmacophore-guided virtual screening anchored on the UBL domain interface. These small molecules selectively bind USP11 without disrupting its catalytic activity yet interrupt critical interactions essential for eIF4B stabilization and oncogenic translation. Mechanistically, USP11 inhibition collapses MYC-driven translational networks, destabilizes DNA repair factors, rewires calcium homeostasis, and induces a post-transcriptional apoptotic program while sparing non-malignant cells. RBF4, chemically identical to the FDA-approved anti-arrhythmic agent Dronedarone, exhibits potent antitumor efficacy in orthotopic EμMyc lymphoma models, suppressing tumor growth, metastatic spread, and ascites formation with no overt toxicity. Transcriptomic analyses reveal broad rewiring of EMT, immune, and metabolic programs, underscoring USP11’s role as a nodal regulator of tumor cell identity and plasticity. These findings establish the UBL domain of USP11 as a druggable scaffold, redefining DUBs not merely as enzymes but as structural signaling platforms. RBF4 emerges as a clinically actionable prototype for dismantling USP11-driven oncogenic circuits, illuminating a new therapeutic axis in lymphoid malignancies and beyond.
{"title":"Discovery, development, and characterization of potent and selective USP11 inhibitors","authors":"Forum Kayastha , Noah B. Herrington , Anirban Roychowdhury , Nahid M. Nanaji , Won Sok Lee , Glen E. Kellogg , Bandish Kapadia , Ronald B. Gartenhaus","doi":"10.1016/j.phrs.2025.108075","DOIUrl":"10.1016/j.phrs.2025.108075","url":null,"abstract":"<div><div>Deubiquitinases (DUBs) have long been viewed through the narrow lens of enzymatic catalysis, but emerging evidence reveals their non-catalytic domains as master regulators of oncogenic signaling. USP11, a structurally modular DUB, exemplifies this duality: beyond its canonical role in DNA repair, USP11 scaffolds key translational effectors such as eIF4B, sustaining the expression of pro-survival oncogenes in aggressive lymphomas. Here, we unveil RBF4 and RBF11, first-in-class, non-catalytic USP11 inhibitors discovered through pharmacophore-guided virtual screening anchored on the UBL domain interface. These small molecules selectively bind USP11 without disrupting its catalytic activity yet interrupt critical interactions essential for eIF4B stabilization and oncogenic translation. Mechanistically, USP11 inhibition collapses MYC-driven translational networks, destabilizes DNA repair factors, rewires calcium homeostasis, and induces a post-transcriptional apoptotic program while sparing non-malignant cells. RBF4, chemically identical to the FDA-approved anti-arrhythmic agent Dronedarone, exhibits potent antitumor efficacy in orthotopic EμMyc lymphoma models, suppressing tumor growth, metastatic spread, and ascites formation with no overt toxicity. Transcriptomic analyses reveal broad rewiring of EMT, immune, and metabolic programs, underscoring USP11’s role as a nodal regulator of tumor cell identity and plasticity. These findings establish the UBL domain of USP11 as a druggable scaffold, redefining DUBs not merely as enzymes but as structural signaling platforms. RBF4 emerges as a clinically actionable prototype for dismantling USP11-driven oncogenic circuits, illuminating a new therapeutic axis in lymphoid malignancies and beyond.</div></div><div><h3>One sentence summary</h3><div>Potent, selective USP11 inhibitors exhibit anti-tumor activity.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"223 ","pages":"Article 108075"},"PeriodicalIF":10.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145857383","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 : 2026-01-01DOI: 10.1016/j.phrs.2025.108082
Yudan Zhao , Hongyuan Lu , Xiaowen Jiang
With the global population growing and aging, along with increasing environmental, metabolic, and lifestyle-related risk factors, the worldwide incidence of stroke, Alzheimer's disease (AD) and other dementias, meningitis, and other neurological disorders-along with associated mortality-has risen significantly. Proanthocyanidins (PCs), which are oligomers and polymers of flavan-3-ols, are widely distributed across the plant kingdom, including in grape seeds, cinnamon, apples, cranberries, lotus seeds, and pine bark. They represent the second most abundant class of polyphenols in nature, after lignin. A substantial body of preclinical evidence indicates that PCs exert significant neuroprotective effects through multiple mechanisms. This review provides a systematic overview of the sources, structural characteristics, and bioavailability of PCs, with a focus on their pharmacological mechanisms in nervous system disease. Specifically, it examines their roles in regulating oxidative stress, neuroinflammation, protein homeostasis, apoptosis, autophagy, and key signaling pathways, including Nrf2/HO-1, CREB/BDNF, PI3K/Akt, MAPK, and NF-κB. Furthermore, this review systematically summarized the distinct structural forms of PCs, including monomers, dimers, trimers, and polymers, and explores their structure-activity relationships (SARs) in modulating the gut-brain axis. Additionally, recent advances in PCS-based nano-delivery systems and clinical studies related to neurological disorders are summarized. Growing evidence indicates that microbial metabolism in the gut serves as a key mechanism underlying their neuroprotective effects. Finally, the potential applications of PCs as promising dietary supplements or therapeutic agents for the prevention and treatment of nervous system diseases are discussed, along with existing challenges and future perspectives.
{"title":"Advance in neuroprotective effects of proanthocyanidins (PCs): Structure, absorption, bioactivities, mechanism, and perspectives","authors":"Yudan Zhao , Hongyuan Lu , Xiaowen Jiang","doi":"10.1016/j.phrs.2025.108082","DOIUrl":"10.1016/j.phrs.2025.108082","url":null,"abstract":"<div><div>With the global population growing and aging, along with increasing environmental, metabolic, and lifestyle-related risk factors, the worldwide incidence of stroke, Alzheimer's disease (AD) and other dementias, meningitis, and other neurological disorders-along with associated mortality-has risen significantly. Proanthocyanidins (PCs), which are oligomers and polymers of flavan-3-ols, are widely distributed across the plant kingdom, including in grape seeds, cinnamon, apples, cranberries, lotus seeds, and pine bark. They represent the second most abundant class of polyphenols in nature, after lignin. A substantial body of preclinical evidence indicates that PCs exert significant neuroprotective effects through multiple mechanisms. This review provides a systematic overview of the sources, structural characteristics, and bioavailability of PCs, with a focus on their pharmacological mechanisms in nervous system disease. Specifically, it examines their roles in regulating oxidative stress, neuroinflammation, protein homeostasis, apoptosis, autophagy, and key signaling pathways, including Nrf2/HO-1, CREB/BDNF, PI3K/Akt, MAPK, and NF-κB. Furthermore, this review systematically summarized the distinct structural forms of PCs, including monomers, dimers, trimers, and polymers, and explores their structure-activity relationships (SARs) in modulating the gut-brain axis. Additionally, recent advances in PCS-based nano-delivery systems and clinical studies related to neurological disorders are summarized. Growing evidence indicates that microbial metabolism in the gut serves as a key mechanism underlying their neuroprotective effects. Finally, the potential applications of PCs as promising dietary supplements or therapeutic agents for the prevention and treatment of nervous system diseases are discussed, along with existing challenges and future perspectives.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"223 ","pages":"Article 108082"},"PeriodicalIF":10.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145912657","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 : 2026-01-01DOI: 10.1016/j.phrs.2025.108071
Emanuela Bottani , Francesca Ciarpella , Benedetta Lucidi , Giulia Pedrotti , Chiara Santanatoglia , Eros Rossi , Enrica Cappellozza , Elisa De Tomi , Sissi Dolci , Giovanni Malerba , Giorgio Malpeli , Ilaria Decimo
Thyroid hormone (T3) deficiency during central nervous system development leads to severe and often incurable human pathologies, including intellectual disability and motor dysfunction. Using murine dorsal forebrain organoids, we showed that T3 is required to activate mitochondrial β-oxidation and OXPHOS biogenesis to sustain neuronal development, while its absence caused profound neurodevelopmental defects such as defective maturation, astrogliosis, and reduced spontaneous activity. Mechanistically, we identified the transcriptional coactivator PGC-1α as a central mediator of the T3 effect. Pharmacological inhibition of β-oxidation in T3-supplemented organoids recapitulated the T3-deficient phenotype, whereas Ppargc1a gene augmentation rescued neuronal development under T3-deprived conditions. Most importantly, pharmacological stimulation of the PGC-1α axis with Nicotinamide Riboside or Bezafibrate rescues mitochondrial bioenergetics and neuronal development, effectively correcting aberrant brain organoid maturation despite T3 deficiency. These findings reveal for the first time the role of T3 in supporting neurodevelopment via activation of mitochondrial β-oxidation and OXPHOS biogenesis, and identify the PGC-1α axis as a promising therapeutic avenue for otherwise intractable disorders linked to thyroid hormone deficiency.
{"title":"Targeting PGC-1α axis rescues aberrant development from thyroid hormone defect in brain organoids","authors":"Emanuela Bottani , Francesca Ciarpella , Benedetta Lucidi , Giulia Pedrotti , Chiara Santanatoglia , Eros Rossi , Enrica Cappellozza , Elisa De Tomi , Sissi Dolci , Giovanni Malerba , Giorgio Malpeli , Ilaria Decimo","doi":"10.1016/j.phrs.2025.108071","DOIUrl":"10.1016/j.phrs.2025.108071","url":null,"abstract":"<div><div>Thyroid hormone (T3) deficiency during central nervous system development leads to severe and often incurable human pathologies, including intellectual disability and motor dysfunction. Using murine dorsal forebrain organoids, we showed that T3 is required to activate mitochondrial β-oxidation and OXPHOS biogenesis to sustain neuronal development, while its absence caused profound neurodevelopmental defects such as defective maturation, astrogliosis, and reduced spontaneous activity. Mechanistically, we identified the transcriptional coactivator PGC-1α as a central mediator of the T3 effect. Pharmacological inhibition of β-oxidation in T3-supplemented organoids recapitulated the T3-deficient phenotype, whereas <em>Ppargc1a</em> gene augmentation rescued neuronal development under T3-deprived conditions. Most importantly, pharmacological stimulation of the PGC-1α axis with Nicotinamide Riboside or Bezafibrate rescues mitochondrial bioenergetics and neuronal development, effectively correcting aberrant brain organoid maturation despite T3 deficiency. These findings reveal for the first time the role of T3 in supporting neurodevelopment <em>via</em> activation of mitochondrial β-oxidation and OXPHOS biogenesis, and identify the PGC-1α axis as a promising therapeutic avenue for otherwise intractable disorders linked to thyroid hormone deficiency.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"223 ","pages":"Article 108071"},"PeriodicalIF":10.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145794250","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 : 2026-01-01DOI: 10.1016/j.phrs.2025.108072
Sebastiano A. Torrisi , Maria Rosaria Tropea , Silvia Rizzo , Mattia Giovenzana , Chiara Magri , Alessandro Barbon , Jessica Mingardi , Clizia Chinello , Lisa Pagani , Isabella Piga , Loredana Leggio , Nunzio Iraci , Walter Gulisano , Filippo Drago , Daniela Puzzo , Laura Musazzi , Gian Marco Leggio
Although post-traumatic stress disorder (PTSD) occurs more in women than in men, how sex influences trauma susceptibility remains largely unknown. We developed the arousal-based individual screening (AIS) model, which identifies mice as susceptible/resilient to PTSD-like phenotypes, based on changes in startle reactivity induced by 24-hour-restraint. To test the hypothesis that sex drives trauma susceptibility/resilience, we applied a multidisciplinary approach involving electrophysiological, structural, and synaptoproteomic analyses of the hippocampus in susceptible and resilient mice of both sexes. Female mice were more susceptible to the trauma than male mice and exhibited long-lasting PTSD-like phenotypes. Long-term potentiation (LTP) was impaired in hippocampal slices of both male and female susceptible mice, whereas short-term presynaptic forms of plasticity and vesicle recycling remained unchanged. Increased apical dendritic length and augmented basal dendritic spine density of pyramidal neurons were found in CA1 of male susceptible mice, while decreased dendritic length of granule neurons was uncovered in the dentate gyrus of female resilient mice. Although minor synaptoproteomic changes were observed, bioinformatic analysis suggested sex- and susceptibility/resilience-dependent profiles. Notably, several pathways involving RHO Family GTPases were found to be upregulated exclusively in susceptible male mice. Accordingly, the Rac1/Rac3 GTPases inhibitor EHop-016 rescued the hippocampal LTP impairment in susceptible male mice but not in susceptible female mice. Our findings suggest that the AIS model mirrors sex differences in PTSD susceptibility/resilience highlighting associated functional, molecular and structural alterations. This model may represent a critical first step for studying sex-dependent pathophysiological mechanisms subserving PTSD susceptibility and for sex-tailored drug development.
{"title":"Functional, synaptoproteomic and structural adaptations underlying sex-dependent traumatic stress susceptibility/resilience in the hippocampus","authors":"Sebastiano A. Torrisi , Maria Rosaria Tropea , Silvia Rizzo , Mattia Giovenzana , Chiara Magri , Alessandro Barbon , Jessica Mingardi , Clizia Chinello , Lisa Pagani , Isabella Piga , Loredana Leggio , Nunzio Iraci , Walter Gulisano , Filippo Drago , Daniela Puzzo , Laura Musazzi , Gian Marco Leggio","doi":"10.1016/j.phrs.2025.108072","DOIUrl":"10.1016/j.phrs.2025.108072","url":null,"abstract":"<div><div>Although post-traumatic stress disorder (PTSD) occurs more in women than in men, how sex influences trauma susceptibility remains largely unknown. We developed the arousal-based individual screening (AIS) model, which identifies mice as susceptible/resilient to PTSD-like phenotypes, based on changes in startle reactivity induced by 24-hour-restraint. To test the hypothesis that sex drives trauma susceptibility/resilience, we applied a multidisciplinary approach involving electrophysiological, structural, and synaptoproteomic analyses of the hippocampus in susceptible and resilient mice of both sexes. Female mice were more susceptible to the trauma than male mice and exhibited long-lasting PTSD-like phenotypes. Long-term potentiation (LTP) was impaired in hippocampal slices of both male and female susceptible mice, whereas short-term presynaptic forms of plasticity and vesicle recycling remained unchanged. Increased apical dendritic length and augmented basal dendritic spine density of pyramidal neurons were found in CA1 of male susceptible mice, while decreased dendritic length of granule neurons was uncovered in the dentate gyrus of female resilient mice. Although minor synaptoproteomic changes were observed, bioinformatic analysis suggested sex- and susceptibility/resilience-dependent profiles. Notably, several pathways involving RHO Family GTPases were found to be upregulated exclusively in susceptible male mice. Accordingly, the Rac1/Rac3 GTPases inhibitor EHop-016 rescued the hippocampal LTP impairment in susceptible male mice but not in susceptible female mice. Our findings suggest that the AIS model mirrors sex differences in PTSD susceptibility/resilience highlighting associated functional, molecular and structural alterations. This model may represent a critical first step for studying sex-dependent pathophysiological mechanisms subserving PTSD susceptibility and for sex-tailored drug development.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"223 ","pages":"Article 108072"},"PeriodicalIF":10.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145843846","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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