Pub Date : 2026-01-16DOI: 10.1016/j.phrs.2026.108103
Mengli Wang , Honglan Yang , Zhongzheng Li , Sen Zeng , Ke Xu , Binghao Wang , Yongzhi Xie , Qingping Wang , Zhuolin Su , Mingri Zhao , Yiti Zhang , Mujun Liu , Beisha Tang , Xionghao Liu , Ruxu Zhang
MORC2 mutations are associated with a spectrum of neuromotor disorders, including Charcot-Marie-Tooth disease subtype 2Z (CMT2Z) and a spinal muscular atrophy (SMA)-like phenotype. However, the mechanisms underlying these conditions remain unclear. In this study, we used iPSC-derived motor neurons (iPSC-MNs) carrying three distinct MORC2 mutations, p.S87L (SMA-like), p.Q400R, and p.D466N (CMT2Z), to examine their effects on cellular processes. Our results show that MORC2 mutations induce apoptosis, DNA damage, and axonal pathology, including shortened neurites, elevated axonal breakage, and increased axonal swellings, with the most severe phenotypes observed in iPSC-MNs harboring p.S87L. Mechanistically, these mutations impair DNA repair by disrupting the interaction between MORC2 and PARP1, leading to reduced PARP1 activity and expression, as well as diminished DNA repair protein expression and recruitment. Notably, inhibition of PAR degradation with PDD restored PAR levels, reduced DNA damage accumulation, and ameliorated axonal pathology in p.S87L-mutant iPSC-MNs. These findings demonstrate that MORC2 mutations impair DNA repair through PARP1-dependent pathways, contributing to axonal degeneration. Targeting the PAR signaling pathway with inhibitors such as PDD may therefore represent a promising therapeutic avenue for MORC2-related neuromotor disorders.
{"title":"Impaired PARP1-dependent DNA repair in MORC2 mutations drives axonal degeneration in Charcot-Marie-Tooth disease subtype 2Z and spinal muscular atrophy-like neuromotor disorders","authors":"Mengli Wang , Honglan Yang , Zhongzheng Li , Sen Zeng , Ke Xu , Binghao Wang , Yongzhi Xie , Qingping Wang , Zhuolin Su , Mingri Zhao , Yiti Zhang , Mujun Liu , Beisha Tang , Xionghao Liu , Ruxu Zhang","doi":"10.1016/j.phrs.2026.108103","DOIUrl":"10.1016/j.phrs.2026.108103","url":null,"abstract":"<div><div><em>MORC2</em> mutations are associated with a spectrum of neuromotor disorders, including Charcot-Marie-Tooth disease subtype 2Z (CMT2Z) and a spinal muscular atrophy (SMA)-like phenotype. However, the mechanisms underlying these conditions remain unclear. In this study, we used iPSC-derived motor neurons (iPSC-MNs) carrying three distinct <em>MORC2</em> mutations, p.S87L (SMA-like), p.Q400R, and p.D466N (CMT2Z), to examine their effects on cellular processes. Our results show that <em>MORC2</em> mutations induce apoptosis, DNA damage, and axonal pathology, including shortened neurites, elevated axonal breakage, and increased axonal swellings, with the most severe phenotypes observed in iPSC-MNs harboring p.S87L. Mechanistically, these mutations impair DNA repair by disrupting the interaction between <em>MORC2</em> and PARP1, leading to reduced PARP1 activity and expression, as well as diminished DNA repair protein expression and recruitment. Notably, inhibition of PAR degradation with PDD restored PAR levels, reduced DNA damage accumulation, and ameliorated axonal pathology in p.S87L-mutant iPSC-MNs. These findings demonstrate that <em>MORC2</em> mutations impair DNA repair through PARP1-dependent pathways, contributing to axonal degeneration. Targeting the PAR signaling pathway with inhibitors such as PDD may therefore represent a promising therapeutic avenue for MORC2-related neuromotor disorders.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"224 ","pages":"Article 108103"},"PeriodicalIF":10.5,"publicationDate":"2026-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145980178","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 : 2026-01-14DOI: 10.1016/j.phrs.2026.108100
Gaolong Zuo , Feifei Chang , Xinyi Yuan , Yujie Shen , Xiaoli Guo , Bo Tang , Jian-an Huang , Zhonghua Liu , Yong Lin
Fu Brick Tea Polysaccharide (FBTP) ameliorates dextran sulfate sodium (DSS)-induced colitis in mice. However, the key intestinal bacterial strains and downstream molecular mechanisms mediating these protective effects remain unclear. In this study, FBTP ameliorated colitis and concurrent liver injury in a microbiota-dependent manner, primarily by enriching Akkermansia muciniphila (A. muciniphila) and depleting Bacteroides thetaiotaomicron (B. thetaiotaomicron). The essential role of the microbiota was confirmed through fecal microbiota transplantation. Mechanistically, A. muciniphila synergistically employed both its microbe-associated molecular patterns (MAMPs) and metabolic activity to activate the toll-like receptor 2 (TLR2)-Akt anti-inflammatory signaling pathway, favorably modulating Treg/Th17 immune homeostasis. However, challenging its established status as a beneficial commensal, B. thetaiotaomicron was found to activate the TLR2-NF-κB pro-inflammatory pathway driven primarily by its MAMPs, significantly exacerbating colitis, bacterial translocation, and liver injury. The pivotal role of TLR2 in mediating these divergent bacterial outcomes was confirmed through gene knockdown experiments. In conclusion, this study reveals that FBTP restores immune homeostasis by orchestrating a complex, TLR2-dependent interplay between beneficial (A. muciniphila) and pathobiontic (B. thetaiotaomicron) bacteria. This discovery not only clarifies the therapeutic mechanism of FBTP but also highlights the context-dependent risk of key commensals, offering critical insights for developing more precise microbiota-targeted interventions.
{"title":"Differential toll-like receptor 2 activation by Akkermansia muciniphila and Bacteroides thetaiotaomicron mediates the beneficial effects of Fu brick tea polysaccharide against colitis","authors":"Gaolong Zuo , Feifei Chang , Xinyi Yuan , Yujie Shen , Xiaoli Guo , Bo Tang , Jian-an Huang , Zhonghua Liu , Yong Lin","doi":"10.1016/j.phrs.2026.108100","DOIUrl":"10.1016/j.phrs.2026.108100","url":null,"abstract":"<div><div>Fu Brick Tea Polysaccharide (FBTP) ameliorates dextran sulfate sodium (DSS)-induced colitis in mice. However, the key intestinal bacterial strains and downstream molecular mechanisms mediating these protective effects remain unclear. In this study, FBTP ameliorated colitis and concurrent liver injury in a microbiota-dependent manner, primarily by enriching <em>Akkermansia muciniphila</em> (<em>A. muciniphila</em>) and depleting <em>Bacteroides thetaiotaomicron</em> (<em>B. thetaiotaomicron</em>). The essential role of the microbiota was confirmed through fecal microbiota transplantation. Mechanistically, <em>A. muciniphila</em> synergistically employed both its microbe-associated molecular patterns (MAMPs) and metabolic activity to activate the toll-like receptor 2 (TLR2)-Akt anti-inflammatory signaling pathway, favorably modulating Treg/Th17 immune homeostasis. However, challenging its established status as a beneficial commensal, <em>B. thetaiotaomicron</em> was found to activate the TLR2-NF-κB pro-inflammatory pathway driven primarily by its MAMPs, significantly exacerbating colitis, bacterial translocation, and liver injury. The pivotal role of TLR2 in mediating these divergent bacterial outcomes was confirmed through gene knockdown experiments. In conclusion, this study reveals that FBTP restores immune homeostasis by orchestrating a complex, TLR2-dependent interplay between beneficial (<em>A. muciniphila</em>) and pathobiontic (<em>B. thetaiotaomicron</em>) bacteria. This discovery not only clarifies the therapeutic mechanism of FBTP but also highlights the context-dependent risk of key commensals, offering critical insights for developing more precise microbiota-targeted interventions.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"224 ","pages":"Article 108100"},"PeriodicalIF":10.5,"publicationDate":"2026-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145980179","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 : 2026-01-14DOI: 10.1016/j.phrs.2026.108099
Anna Schettino , Anella Saviano , Noemi Marigliano , Martina Smimmo , Erika Esposito , Jenefa Begum , Areeba Fatima , Alyssa M. Urbanowski , Christopher Mahony , Amnah M. Khormi , Adel Abo Mansour , Tariq H. Iqbal , Helen M. McGettrick , Asif Jilani Iqbal , Francesco Maione
Current therapies for immune-mediated diseases often lack precision, causing broad immunosuppression. While Mangifera indica L. extract (here referred to as MIE) shows promise in resolving pain and modulating adaptive immunity, its direct impact on monocyte recruitment and macrophage polarization, remains elusive. Using a reverse translational approach, we examined the effects of MIE on primary human monocytes and macrophages from healthy donors and inflammatory bowel disease (IBD) patients. We assessed its ability to inhibit monocyte transmigration across TNF-α-activated endothelial monolayers and to modulate macrophage polarization along the M1/M2 phenotypes. Transcriptomic profiling via RNA-seq revealed several MIE-responsive pathways in human macrophages, which were subsequently validated functionally using murine peritoneal macrophages stimulated with a panel of distinct toll-like receptors (TLRs) agonists. MIE markedly impaired monocyte adhesion and transmigration across activated endothelium. In human macrophages, it selectively attenuated the pro-inflammatory M1 phenotype, robustly suppressing TNF-α secretion from both healthy donors and IBD patients, while exerting minimal effects on the M2 profile. Transcriptomic analysis revealed that MIE disrupts key inflammatory signalling networks, notably those governed by NF-κB and TLRs. Mechanistically, MIE did not exert broad TLR inhibition but instead acted as a precise immunological rheostat, dampening responses to murine TLR2, TLR4, and TLR6 agonists. TLR4-targeted modulation was mediated via downregulation of MyD88 and NF-κB expression, culminating in reduced pro-inflammatory cytokine production. We delineate a novel mechanism for MIE as a selective rheostat of the TLR2/4/6 axis for restoring innate immune homeostasis in inflammatory-based diseases.
{"title":"A Mangifera indica L. extract functions as a broad TLR2/4/6 signalling rheostat to attenuate MyD88/NF-κB-driven inflammation and macrophage polarization","authors":"Anna Schettino , Anella Saviano , Noemi Marigliano , Martina Smimmo , Erika Esposito , Jenefa Begum , Areeba Fatima , Alyssa M. Urbanowski , Christopher Mahony , Amnah M. Khormi , Adel Abo Mansour , Tariq H. Iqbal , Helen M. McGettrick , Asif Jilani Iqbal , Francesco Maione","doi":"10.1016/j.phrs.2026.108099","DOIUrl":"10.1016/j.phrs.2026.108099","url":null,"abstract":"<div><div>Current therapies for immune-mediated diseases often lack precision, causing broad immunosuppression. While <em>Mangifera indica</em> L. extract (here referred to as MIE) shows promise in resolving pain and modulating adaptive immunity, its direct impact on monocyte recruitment and macrophage polarization, remains elusive. Using a reverse translational approach, we examined the effects of MIE on primary human monocytes and macrophages from healthy donors and inflammatory bowel disease (IBD) patients. We assessed its ability to inhibit monocyte transmigration across TNF-α-activated endothelial monolayers and to modulate macrophage polarization along the M1/M2 phenotypes. Transcriptomic profiling via RNA-seq revealed several MIE-responsive pathways in human macrophages, which were subsequently validated functionally using murine peritoneal macrophages stimulated with a panel of distinct toll-like receptors (TLRs) agonists. MIE markedly impaired monocyte adhesion and transmigration across activated endothelium. In human macrophages, it selectively attenuated the pro-inflammatory M1 phenotype, robustly suppressing TNF-α secretion from both healthy donors and IBD patients, while exerting minimal effects on the M2 profile. Transcriptomic analysis revealed that MIE disrupts key inflammatory signalling networks, notably those governed by NF-κB and TLRs. Mechanistically, MIE did not exert broad TLR inhibition but instead acted as a precise immunological rheostat, dampening responses to murine TLR2, TLR4, and TLR6 agonists. TLR4-targeted modulation was mediated via downregulation of MyD88 and NF-κB expression, culminating in reduced pro-inflammatory cytokine production. We delineate a novel mechanism for MIE as a selective rheostat of the TLR2/4/6 axis for restoring innate immune homeostasis in inflammatory-based diseases.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"224 ","pages":"Article 108099"},"PeriodicalIF":10.5,"publicationDate":"2026-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145990281","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 : 2026-01-12DOI: 10.1016/j.phrs.2026.108098
Li Zhang , Wenping Song , Junting Wang , Yelin Zhao , Chenyu Yuan , Zhilong Ruan , Jiaqi Chen , Junyang Zhao , Hongjuan Yao , Hebing Chen , Chengyue Zhang , Liang Li
Recurrence of high-risk advanced retinoblastoma (RB) is still a major obstacle even after enucleation due to resistance to adjuvant chemotherapy, especially in China. To identify any germline alterations or candidate genes associated with RB prognosis, we obtained whole-exome sequencing (WES) and reduced-representation bisulfite sequencing (RRBS) profiles by using patient peripheral blood samples, followed by clinical validation and functional characterization. For follow-up studies, we selected 17 candidate genes from the WES and RRBS analyses. Among them, MBD4, which carries a germline loss-of-function mutation (rs140693), was identified for further clinical replication. MBD4 downregulation significantly impaired carboplatin or etoposide efficacy in vitro and in vivo, respectively. There were marked decreases in the expression of 5 related genes plus increased DNA methylation in their promoters in Y79 (MBD4-/-) cells, along with even more significant effects after carboplatin treatment. MBD4 affected the transcription and expression of its downstream genes, such as FADD and P21, via MBDCap-PCR, ChIPqPCR, and reporter gene assays. Moreover, the germline mutation was responsible for MBD4 instability with attenuated binding to USP7, thereby leading to impaired drug sensitivity. It was confirmed by the reinstated susceptibility of Y79 (MBD4-/-) cells after MBD4-WT was restored. In the present study, our findings indicate that depletion or mutation of MBD4 interferes with the activation of the cell cycle and apoptosis via epigenetic regulation, thereby reducing drug susceptibility. It provides new insights into the role in RB chemoresistance of MBD4 as an epigenetic regulator, which might fuel the development of new RB-targeted strategies.
{"title":"Study on epigenetic regulatory mechanism of MBD4 with a germline loss-of-function mutation (rs140693) responsible for retinoblastoma chemoresistance via the cell cycle and apoptotic pathways","authors":"Li Zhang , Wenping Song , Junting Wang , Yelin Zhao , Chenyu Yuan , Zhilong Ruan , Jiaqi Chen , Junyang Zhao , Hongjuan Yao , Hebing Chen , Chengyue Zhang , Liang Li","doi":"10.1016/j.phrs.2026.108098","DOIUrl":"10.1016/j.phrs.2026.108098","url":null,"abstract":"<div><div>Recurrence of high-risk advanced retinoblastoma (RB) is still a major obstacle even after enucleation due to resistance to adjuvant chemotherapy, especially in China. To identify any germline alterations or candidate genes associated with RB prognosis, we obtained whole-exome sequencing (WES) and reduced-representation bisulfite sequencing (RRBS) profiles by using patient peripheral blood samples, followed by clinical validation and functional characterization. For follow-up studies, we selected 17 candidate genes from the WES and RRBS analyses. Among them, <em>MBD4</em>, which carries a germline loss-of-function mutation (rs140693), was identified for further clinical replication. MBD4 downregulation significantly impaired carboplatin or etoposide efficacy in vitro and in vivo, respectively. There were marked decreases in the expression of 5 related genes plus increased DNA methylation in their promoters in Y79 (MBD4<sup>-/-</sup>) cells, along with even more significant effects after carboplatin treatment. MBD4 affected the transcription and expression of its downstream genes, such as FADD and P21, via MBDCap-PCR, ChIP<img>qPCR, and reporter gene assays. Moreover, the germline mutation was responsible for MBD4 instability with attenuated binding to USP7, thereby leading to impaired drug sensitivity. It was confirmed by the reinstated susceptibility of Y79 (MBD4<sup>-/-</sup>) cells after MBD4-WT was restored. In the present study, our findings indicate that depletion or mutation of MBD4 interferes with the activation of the cell cycle and apoptosis via epigenetic regulation, thereby reducing drug susceptibility. It provides new insights into the role in RB chemoresistance of MBD4 as an epigenetic regulator, which might fuel the development of new RB-targeted strategies.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"224 ","pages":"Article 108098"},"PeriodicalIF":10.5,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145980180","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 : 2026-01-10DOI: 10.1016/j.phrs.2026.108096
Andrea Mancini , Elisabetta Betterini , Matteo Bordi , Francesco Cecconi
Mitochondria are central hubs of cellular metabolism, integrating nutrient catabolism, ATP production, redox balance, and biosynthetic precursor supply. Recent work has revealed that their influence extends beyond canonical bioenergetics to include intimate connections with cytosolic multi-enzyme assemblies. Among these, the purinosome, the complex dedicated to de novo purine biosynthesis, has emerged as a paradigmatic example of how metabolic pathways achieve efficiency through spatial and functional coupling. This Review highlights the dynamic interplay between purinosomes and mitochondria. We describe how mitochondrial metabolism supplies key substrates, including aspartate, glycine, and formate, while oxidative phosphorylation provides the ATP required for nucleotide synthesis. We discuss how purinosomes assemble through liquid–liquid phase separation, position near mitochondria in response to energetic stress, and act as adaptive metabolic hubs that sense and integrate growth and nutrient signals. Finally, we examine how disruption of this mitochondrion–purinosome axis contributes to disease, from rare neurodevelopmental disorders to cancer and neurodegeneration.
{"title":"Purinosomes and mitochondria: Dynamic interactomes at the crossroads of metabolism, cell structure, and disease","authors":"Andrea Mancini , Elisabetta Betterini , Matteo Bordi , Francesco Cecconi","doi":"10.1016/j.phrs.2026.108096","DOIUrl":"10.1016/j.phrs.2026.108096","url":null,"abstract":"<div><div>Mitochondria are central hubs of cellular metabolism, integrating nutrient catabolism, ATP production, redox balance, and biosynthetic precursor supply. Recent work has revealed that their influence extends beyond canonical bioenergetics to include intimate connections with cytosolic multi-enzyme assemblies. Among these, the purinosome, the complex dedicated to <em>de novo</em> purine biosynthesis, has emerged as a paradigmatic example of how metabolic pathways achieve efficiency through spatial and functional coupling. This Review highlights the dynamic interplay between purinosomes and mitochondria. We describe how mitochondrial metabolism supplies key substrates, including aspartate, glycine, and formate, while oxidative phosphorylation provides the ATP required for nucleotide synthesis. We discuss how purinosomes assemble through liquid–liquid phase separation, position near mitochondria in response to energetic stress, and act as adaptive metabolic hubs that sense and integrate growth and nutrient signals. Finally, we examine how disruption of this mitochondrion–purinosome axis contributes to disease, from rare neurodevelopmental disorders to cancer and neurodegeneration.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"224 ","pages":"Article 108096"},"PeriodicalIF":10.5,"publicationDate":"2026-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145952794","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 : 2026-01-10DOI: 10.1016/j.phrs.2026.108095
Jiarong He , Fei Peng , Ying Xu , Zhongyue Liu , Kai Su , Yang Zhou , Yugang Jiang , Ming Wang
The DNA hydroxymethylation landscape is profoundly disrupted in gliomas, especially glioblastoma, marked by global loss of 5-hydroxymethylcytosine (5hmC) and impaired Ten-eleven translocation (TET) enzyme activity. This review synthesizes evidence that TET family expression and subcellular localization are systematically altered in glioma: TET1 undergoes nuclear exclusion, while TET2 and TET3 show reduced nuclear abundance, directly contributing to 5hmC depletion. The extent of 5hmC loss correlates with tumor grade yet exhibits subtype heterogeneity, including a unique “5hmC-high” glioblastoma subgroup, highlighting the importance of post-transcriptional control of TET protein levels. Upstream regulatory mechanisms involve transcription factors (e.g., SOX2-mediated repression and context-dependent STAT3 activation), non-coding RNAs (such as miR-10b), and epigenetic silencing of TET genes themselves, alongside metabolic and microenvironmental constraints (e.g., D-2-HG from IDH1/2 mutations, hypoxia) that restrict TET catalytic function. Downstream consequences include TET deficiency-driven promoter hypermethylation and MBD-mediated repression of tumor suppressor and differentiation genes, RNA hydroxymethylation-dependent regulation of mRNA stability and splicing, and chromatin reprogramming via interactions with complexes like OGT/COMPASS and PRC2. Functionally, TET inactivation promotes tumor initiation and progression, sustains glioma stem cells, enhances cellular plasticity, drives metabolic reprogramming, and facilitates immune evasion. Emerging therapeutic strategies encompass miRNA antagonists, vitamin C as a TET cofactor, DNMT and HDAC inhibitors, locus-specific epigenetic editing tools (e.g., CRISPR-dCas9 and engineered demethylases), brain-penetrant IDH inhibitors, and novel approaches such as PROTACs and TET mRNA delivery—all requiring precision application due to the context-dependent roles of TET proteins. We further identify critical research gaps, including single-cell and spatial mapping of TET/5hmC dynamics, microenvironmental regulation of TET activity, functional cooperation between TET isoforms, and the development of clinically feasible delivery systems and biomarkers. Addressing these challenges will be essential to translate TET pathway modulation into effective, individualized combination therapies for glioma patients.
{"title":"The TET/5hmC mediated epigenetic landscape in glioma: From molecular mechanisms to therapeutic targeting and future perspectives","authors":"Jiarong He , Fei Peng , Ying Xu , Zhongyue Liu , Kai Su , Yang Zhou , Yugang Jiang , Ming Wang","doi":"10.1016/j.phrs.2026.108095","DOIUrl":"10.1016/j.phrs.2026.108095","url":null,"abstract":"<div><div>The DNA hydroxymethylation landscape is profoundly disrupted in gliomas, especially glioblastoma, marked by global loss of 5-hydroxymethylcytosine (5hmC) and impaired Ten-eleven translocation (TET) enzyme activity. This review synthesizes evidence that TET family expression and subcellular localization are systematically altered in glioma: TET1 undergoes nuclear exclusion, while TET2 and TET3 show reduced nuclear abundance, directly contributing to 5hmC depletion. The extent of 5hmC loss correlates with tumor grade yet exhibits subtype heterogeneity, including a unique “5hmC-high” glioblastoma subgroup, highlighting the importance of post-transcriptional control of TET protein levels. Upstream regulatory mechanisms involve transcription factors (e.g., SOX2-mediated repression and context-dependent STAT3 activation), non-coding RNAs (such as miR-10b), and epigenetic silencing of TET genes themselves, alongside metabolic and microenvironmental constraints (e.g., D-2-HG from IDH1/2 mutations, hypoxia) that restrict TET catalytic function. Downstream consequences include TET deficiency-driven promoter hypermethylation and MBD-mediated repression of tumor suppressor and differentiation genes, RNA hydroxymethylation-dependent regulation of mRNA stability and splicing, and chromatin reprogramming via interactions with complexes like OGT/COMPASS and PRC2. Functionally, TET inactivation promotes tumor initiation and progression, sustains glioma stem cells, enhances cellular plasticity, drives metabolic reprogramming, and facilitates immune evasion. Emerging therapeutic strategies encompass miRNA antagonists, vitamin C as a TET cofactor, DNMT and HDAC inhibitors, locus-specific epigenetic editing tools (e.g., CRISPR-dCas9 and engineered demethylases), brain-penetrant IDH inhibitors, and novel approaches such as PROTACs and TET mRNA delivery—all requiring precision application due to the context-dependent roles of TET proteins. We further identify critical research gaps, including single-cell and spatial mapping of TET/5hmC dynamics, microenvironmental regulation of TET activity, functional cooperation between TET isoforms, and the development of clinically feasible delivery systems and biomarkers. Addressing these challenges will be essential to translate TET pathway modulation into effective, individualized combination therapies for glioma patients.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"224 ","pages":"Article 108095"},"PeriodicalIF":10.5,"publicationDate":"2026-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145959914","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 : 2026-01-10DOI: 10.1016/j.phrs.2026.108094
Eline Pottie , Christophe P. Stove
G protein-coupled receptors (GPCRs) remain among the most important drug targets. To characterize their ligands’ activity, a range of in vitro assays is available, all with their inherent advantages and limitations. In the Gαq signaling pathway, the interaction between Gαq and phospholipase C (PLC-)β is a receptor-proximal event, and its monitoring does not require modification of the GPCR. With this in mind, we set out to develop a luminescence-based assay gauging this interaction. The resulting assay format encompassed functional complementation of a split nanoluciferase following the interaction of SmBiT, N-terminally fused to PLC-β, with LgBiT, intramolecularly integrated within Gαq. When applied to assess activation of the Gαq-coupled serotonin 2 A receptor (5-HT2AR), an excellent assay performance was demonstrated, as evidenced by an auspicious Z’-factor of 0.75 and by confirming the specificity for both the GPCR and the Gαq signaling pathway. The optimized Gαq-PLC-β assay was successfully applied on a diverse panel of 5-HT2AR ligands and the resulting output was compared with that of a more upstream miniGαq recruitment assay, and more downstream IP1 accumulation and Ca2+ mobilization assays. Overall, the Gαq-PLC-β assay yielded efficacy, potency and relative activity data that correlated very well with those obtained with the IP1 accumulation and miniGαq recruitment assays, although with the former two assays consistently higher potencies and a smaller range of efficacies were observed. Comparison with the Ca2+ mobilization assay did not yield such good correlation, presumably because of kinetic implications. Last, the Gαq-PLC-β interaction assay allowed to detect signals emerging from endogenously expressed GPCRs, indicative of its broad applicability.
{"title":"Live cell luminescence-based Gαq-PLC-β interaction assay: Development and application at the serotonin 5-HT2A receptor","authors":"Eline Pottie , Christophe P. Stove","doi":"10.1016/j.phrs.2026.108094","DOIUrl":"10.1016/j.phrs.2026.108094","url":null,"abstract":"<div><div>G protein-coupled receptors (GPCRs) remain among the most important drug targets. To characterize their ligands’ activity, a range of <em>in vitro</em> assays is available, all with their inherent advantages and limitations. In the Gα<sub>q</sub> signaling pathway, the interaction between Gα<sub>q</sub> and phospholipase C (PLC-)β is a receptor-proximal event, and its monitoring does not require modification of the GPCR. With this in mind, we set out to develop a luminescence-based assay gauging this interaction. The resulting assay format encompassed functional complementation of a split nanoluciferase following the interaction of SmBiT, N-terminally fused to PLC-β, with LgBiT, intramolecularly integrated within Gα<sub>q</sub>. When applied to assess activation of the Gα<sub>q</sub>-coupled serotonin 2 A receptor (5-HT<sub>2A</sub>R), an excellent assay performance was demonstrated, as evidenced by an auspicious Z’-factor of 0.75 and by confirming the specificity for both the GPCR and the Gα<sub>q</sub> signaling pathway. The optimized Gα<sub>q</sub>-PLC-β assay was successfully applied on a diverse panel of 5-HT<sub>2A</sub>R ligands and the resulting output was compared with that of a more upstream miniGα<sub>q</sub> recruitment assay, and more downstream IP<sub>1</sub> accumulation and Ca<sup>2+</sup> mobilization assays. Overall, the Gα<sub>q</sub>-PLC-β assay yielded efficacy, potency and relative activity data that correlated very well with those obtained with the IP<sub>1</sub> accumulation and miniGα<sub>q</sub> recruitment assays, although with the former two assays consistently higher potencies and a smaller range of efficacies were observed. Comparison with the Ca<sup>2+</sup> mobilization assay did not yield such good correlation, presumably because of kinetic implications. Last, the Gα<sub>q</sub>-PLC-β interaction assay allowed to detect signals emerging from endogenously expressed GPCRs, indicative of its broad applicability.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"224 ","pages":"Article 108094"},"PeriodicalIF":10.5,"publicationDate":"2026-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145959941","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 : 2026-01-10DOI: 10.1016/j.phrs.2026.108097
Kaylee Hough , Marzia Friuli , Nicole M. Avena , Adele Romano
The concept of addiction, traditionally confined to substances such as drugs and alcohol, has expanded to encompass behavioral patterns such as compulsive eating. Emerging evidence suggests that ultra-processed foods (UPFs), particularly those high in refined sugars and saturated fats, may elicit neurobiological responses akin to those observed in substance use disorders. This review explores the hypothesis that food addiction shares common clinical and neurochemical mechanisms with traditional forms of addiction, drawing from DSM-5 diagnostic criteria and recent findings in neuropharmacology. Animal and human studies have demonstrated that excessive consumption of palatable foods can induce behaviors characteristic of addiction—bingeing, craving, tolerance, and withdrawal—accompanied by significant dopaminergic alterations within the mesolimbic reward circuitry. Neuroimaging and molecular studies further reveal that chronic overconsumption of UPFs alters dopaminergic tone, disrupts prefrontal control, and activates stress pathways, thereby reinforcing compulsive intake. The Yale Food Addiction Scale (YFAS) and its pediatric adaptations provide structured tools for identifying food addiction phenotypes in clinical and research settings. Moreover, parallels between binge eating disorder and substance dependence highlight overlapping neurobehavioral mechanisms. As the obesity epidemic intensifies, particularly among populations with limited access to nutritious foods, understanding the pharmacological underpinnings of food addiction becomes critical. This review underscores the need to reframe UPFs as potentially addictive agents and calls for integrative therapeutic strategies and policy-driven reforms aimed at mitigating their impact on public health.
{"title":"The addicted brain: How processed foods hijack reward pathways","authors":"Kaylee Hough , Marzia Friuli , Nicole M. Avena , Adele Romano","doi":"10.1016/j.phrs.2026.108097","DOIUrl":"10.1016/j.phrs.2026.108097","url":null,"abstract":"<div><div>The concept of addiction, traditionally confined to substances such as drugs and alcohol, has expanded to encompass behavioral patterns such as compulsive eating. Emerging evidence suggests that ultra-processed foods (UPFs), particularly those high in refined sugars and saturated fats, may elicit neurobiological responses akin to those observed in substance use disorders. This review explores the hypothesis that food addiction shares common clinical and neurochemical mechanisms with traditional forms of addiction, drawing from DSM-5 diagnostic criteria and recent findings in neuropharmacology. Animal and human studies have demonstrated that excessive consumption of palatable foods can induce behaviors characteristic of addiction—bingeing, craving, tolerance, and withdrawal—accompanied by significant dopaminergic alterations within the mesolimbic reward circuitry. Neuroimaging and molecular studies further reveal that chronic overconsumption of UPFs alters dopaminergic tone, disrupts prefrontal control, and activates stress pathways, thereby reinforcing compulsive intake. The Yale Food Addiction Scale (YFAS) and its pediatric adaptations provide structured tools for identifying food addiction phenotypes in clinical and research settings. Moreover, parallels between binge eating disorder and substance dependence highlight overlapping neurobehavioral mechanisms. As the obesity epidemic intensifies, particularly among populations with limited access to nutritious foods, understanding the pharmacological underpinnings of food addiction becomes critical. This review underscores the need to reframe UPFs as potentially addictive agents and calls for integrative therapeutic strategies and policy-driven reforms aimed at mitigating their impact on public health.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"224 ","pages":"Article 108097"},"PeriodicalIF":10.5,"publicationDate":"2026-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145959931","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 : 2026-01-08DOI: 10.1016/j.phrs.2026.108092
Chen Chen , Yuezhen Li , Wenling Wang , Chunrong Liu , Qiumei Luo , Yan Ren , Yiquan Xiong , Xin Sun , Jing Tan
Purpose
Herbal medicines are widely used during pregnancy, yet their potential effects on offspring remain uncertain. This systematic review aimed to comprehensively evaluate both the potential benefits and risks of prenatal herbal medicine use on offspring outcomes by synthesizing evidence from randomized controlled trials (RCTs) and observational studies.
Methods
We searched PubMed, Embase, and the Cochrane Central Register of Controlled Trials from inception to November 9, 2024. Eligible studies reported maternal use of herbal medicines during pregnancy and assessed offspring-related outcomes.
Results
A total of 111 studies met the inclusion criteria, comprising 39 RCTs, 36 cohort studies, 18 case–control studies, and 18 cross-sectional surveys. In RCTs, prenatal use of certain herbal medicines was associated the live birth rate (RR=1.14, 95 % CI: 1.05–1.24) and a lower risk of birth defects (RR=0.46, 95 % CI: 0.22–0.94), primarily among women undergoing assisted reproduction; reductions in miscarriage were observed among those with threatened or recurrent miscarriage. At the overall level, observational studies adjusted for confounding did not show significant associations between prenatal herbal medicine use and major adverse offspring outcomes (including birth defects, miscarriage, stillbirth, or preterm birth). Exploratory analyses of individual herbal products suggested that some specific herbs—such as almond oil and Glycyrrhiza (with preterm birth), betel quid (with low birth weight), An-Tai-Yin (with musculoskeletal malformations), khat (with nervous system malformations), and Coptidis Rhizoma (with nervous system and genital organ malformations)—may be linked to increased risks. However, these signals were based on a limited number of studies and should be interpreted with caution given variability in exposure definitions, study quality, and potential residual confounding.
Conclusions
For women undergoing assisted reproduction or those at increased risk of miscarriage, certain herbal medicines may offer potential benefits during pregnancy. Overall, evidence from RCTs and adjusted observational studies does not indicate a clear increase in adverse offspring outcomes associated with prenatal herbal medicine use. Nonetheless, a few herbs have been linked to potential safety concerns, although the supporting evidence remains limited and heterogeneous. Cautious use is advised, particularly for products without robust data on fetal and long-term postnatal safety.
{"title":"Benefits and risks of herbal medicine use during pregnancy on offspring outcomes: A systematic review and meta-analysis of randomized controlled trials and observational studies","authors":"Chen Chen , Yuezhen Li , Wenling Wang , Chunrong Liu , Qiumei Luo , Yan Ren , Yiquan Xiong , Xin Sun , Jing Tan","doi":"10.1016/j.phrs.2026.108092","DOIUrl":"10.1016/j.phrs.2026.108092","url":null,"abstract":"<div><h3>Purpose</h3><div>Herbal medicines are widely used during pregnancy, yet their potential effects on offspring remain uncertain. This systematic review aimed to comprehensively evaluate both the potential benefits and risks of prenatal herbal medicine use on offspring outcomes by synthesizing evidence from randomized controlled trials (RCTs) and observational studies.</div></div><div><h3>Methods</h3><div>We searched PubMed, Embase, and the Cochrane Central Register of Controlled Trials from inception to November 9, 2024. Eligible studies reported maternal use of herbal medicines during pregnancy and assessed offspring-related outcomes.</div></div><div><h3>Results</h3><div>A total of 111 studies met the inclusion criteria, comprising 39 RCTs, 36 cohort studies, 18 case–control studies, and 18 cross-sectional surveys. In RCTs, prenatal use of certain herbal medicines was associated the live birth rate (RR=1.14, 95 % CI: 1.05–1.24) and a lower risk of birth defects (RR=0.46, 95 % CI: 0.22–0.94), primarily among women undergoing assisted reproduction; reductions in miscarriage were observed among those with threatened or recurrent miscarriage. At the overall level, observational studies adjusted for confounding did not show significant associations between prenatal herbal medicine use and major adverse offspring outcomes (including birth defects, miscarriage, stillbirth, or preterm birth). Exploratory analyses of individual herbal products suggested that some specific herbs—such as almond oil and <em>Glycyrrhiza</em> (with preterm birth), betel quid (with low birth weight), An-Tai-Yin (with musculoskeletal malformations), khat (with nervous system malformations), and <em>Coptidis Rhizoma</em> (with nervous system and genital organ malformations)—may be linked to increased risks. However, these signals were based on a limited number of studies and should be interpreted with caution given variability in exposure definitions, study quality, and potential residual confounding.</div></div><div><h3>Conclusions</h3><div>For women undergoing assisted reproduction or those at increased risk of miscarriage, certain herbal medicines may offer potential benefits during pregnancy. Overall, evidence from RCTs and adjusted observational studies does not indicate a clear increase in adverse offspring outcomes associated with prenatal herbal medicine use. Nonetheless, a few herbs have been linked to potential safety concerns, although the supporting evidence remains limited and heterogeneous. Cautious use is advised, particularly for products without robust data on fetal and long-term postnatal safety.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"224 ","pages":"Article 108092"},"PeriodicalIF":10.5,"publicationDate":"2026-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145948872","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 : 2026-01-07DOI: 10.1016/j.phrs.2026.108091
Zilu Zhang , Hewei Qin
Several disease conditions are associated with the abnormal activation of pyroptosis, ferroptosis, necroptosis, cuproptosis, and disulfidptosis, as well as dysregulated macrophage polarization, which collectively serve as hallmarks of tissue damage and organ dysfunction. Importantly, these emerging forms of programmed cell death are closely linked to intestinal microbiota homeostasis. The gut microbiota constitutes a key ecosystem that regulates host metabolism, immunity, and overall physiological balance. When gut microbiota dysbiosis occurs, it promotes the production of harmful metabolites and activates inflammatory signaling pathways. This leads to metabolic disturbances and chronic inflammation, which in turn can induce pyroptosis, ferroptosis, necroptosis, cuproptosis, disulfidptosis, and polarization of macrophages toward the M1 phenotype. Therefore, a deeper understanding of the dynamic regulation of the gut microbiota in these forms of cell death and macrophage polarization is essential for comprehending the progression of related diseases. In this review, we systematically summarize the impact of gut microbiota and its metabolite alterations on the regulation of these novel programmed cell death pathways and macrophage polarization, aiming to advance the understanding of related disease pathogenesis and provide a theoretical foundation for potential therapeutic strategies.
{"title":"Crosstalk mechanisms among gut microbiota, novel programmed cell death, and macrophage polarization","authors":"Zilu Zhang , Hewei Qin","doi":"10.1016/j.phrs.2026.108091","DOIUrl":"10.1016/j.phrs.2026.108091","url":null,"abstract":"<div><div>Several disease conditions are associated with the abnormal activation of pyroptosis, ferroptosis, necroptosis, cuproptosis, and disulfidptosis, as well as dysregulated macrophage polarization, which collectively serve as hallmarks of tissue damage and organ dysfunction. Importantly, these emerging forms of programmed cell death are closely linked to intestinal microbiota homeostasis. The gut microbiota constitutes a key ecosystem that regulates host metabolism, immunity, and overall physiological balance. When gut microbiota dysbiosis occurs, it promotes the production of harmful metabolites and activates inflammatory signaling pathways. This leads to metabolic disturbances and chronic inflammation, which in turn can induce pyroptosis, ferroptosis, necroptosis, cuproptosis, disulfidptosis, and polarization of macrophages toward the M1 phenotype. Therefore, a deeper understanding of the dynamic regulation of the gut microbiota in these forms of cell death and macrophage polarization is essential for comprehending the progression of related diseases. In this review, we systematically summarize the impact of gut microbiota and its metabolite alterations on the regulation of these novel programmed cell death pathways and macrophage polarization, aiming to advance the understanding of related disease pathogenesis and provide a theoretical foundation for potential therapeutic strategies.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"224 ","pages":"Article 108091"},"PeriodicalIF":10.5,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145945567","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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