Pharmacological research最新文献

{"title":"Pain signaling via sensory neurons drives breast cancer progression through neuropeptide release and κ-opioid counter-regulation","authors":"Hitoshi Makabe ,&nbsp;Michiko Narita ,&nbsp;Yasuyuki Nagumo ,&nbsp;Masanori Fujiwara ,&nbsp;Yusuke Hamada ,&nbsp;Jion Takise ,&nbsp;Takumi Yoshizawa ,&nbsp;Sakura Sano ,&nbsp;Shin Iizuka ,&nbsp;Eri Asaba ,&nbsp;Yukari Suda ,&nbsp;Tomohisa Mori ,&nbsp;Tsuyoshi Saitoh ,&nbsp;Hiroshi Nagase ,&nbsp;Vivianne L. Tawfik ,&nbsp;Shigehiro Yagishita ,&nbsp;Akinobu Hamada ,&nbsp;Kan Yonemori ,&nbsp;Shin Takayama ,&nbsp;Masayuki Yoshida ,&nbsp;Minoru Narita","doi":"10.1016/j.phrs.2026.108113","DOIUrl":"10.1016/j.phrs.2026.108113","url":null,"abstract":"<div><div>Severe pain in patients with breast cancer is associated with poorer survival outcomes, yet the mechanisms linking nociceptive signaling to tumor progression remain unclear. In a clinical cohort, breast cancer patients whose moderate or severe pain improved under specialized palliative care exhibited significantly longer survival than those with persistent pain. Serum levels of calcitonin gene-related peptide (CGRP) and substance P (SP), neuropeptides that can be released from sensory neurons, were elevated in breast cancer patients with uncontrolled pain, correlating positively with pain intensity and negatively with overall survival. <em>In vitro</em>, supernatants from depolarized human iPSC-derived sensory neurons containing CGRP, SP, and the endogenous κ-opioid receptor (KOR) ligand dynorphin attenuated docetaxel efficacy, promoted epithelial-mesenchymal transition, and enhanced migration in human triple-negative breast cancer (TNBC) cells, accompanied by Gi protein-coupled activation of the PI3K-Akt signaling pathway. <em>In vivo</em>, optogenetic activation of sensory neurons significantly accelerated tumor growth following orthotopic transplantation of murine TNBC cells, whereas combined blockade of CGRP and SP receptors suppressed this effect. Similarly, in patient-derived xenograft models of TNBC, dual receptor blockade effectively abrogated tumor progression. Conversely, <em>in vitro</em> treatment with dynorphin enhanced the cytotoxic efficacy of docetaxel, accompanied by the inhibition of PI3K-Akt signaling, whereas <em>in vivo</em> administration of the peripherally restricted KOR agonist nalfurafine methiodide markedly suppressed tumor growth. These findings establish a bidirectional neural-tumor axis in breast cancer progression. Therapeutically, combined blockade of CGRP/SP signaling with peripheral KOR agonism may present a novel strategy to enhance chemotherapy efficacy in TNBC patients.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"225 ","pages":"Article 108113"},"PeriodicalIF":10.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146093549","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}

{"title":"Pevonedistat targeting NEDDylation activating enzyme for human diseases: Underlying mechanisms, clinical studies, and future directions","authors":"Dong-Jun Fu,&nbsp;Yu-Jie Wu,&nbsp;Cong Chen,&nbsp;Cai Zhang,&nbsp;Ze-Qi Su,&nbsp;Ting Wang","doi":"10.1016/j.phrs.2026.108134","DOIUrl":"10.1016/j.phrs.2026.108134","url":null,"abstract":"<div><div>NEDDylation is a crucial post-translational modification wherein the ubiquitin-related molecule NEDD8 is added to lysine residues in substrate proteins via a stepwise enzymatic cascade with the participation of the NEDDylation activating enzyme (NAE, E1), E2 conjugating enzymes, and E3 ligases. Many significant proteins in the NEDDylation process are highly expressed in several human diseases, and suppression of NEDDylation is an attractive strategy to develop novel therapeutic drugs for these diseases. Although a variety of small-molecule inhibitors targeting NEDDylation have been discovered, pevonedistat (also known as MLN4924) is the only NEDDylation inhibitor to date to enter phase III clinical trials. Moreover, many preclinical studies and over 40 clinical trials have fully investigated the potential therapeutic effects of pevonedistat, which has been proven safe for human diseases. A literature search was conducted in X-mol, Web of Science and PubMed, and the keywords to retrieve the literature were pevonedistat and MLN4924. Stepwise enzymatic cascades involved in the NEDDylation process and specific mechanisms underlying pevonedistat binding to NAE were investigated. Crucially, this review also details the research progress of pevonedistat, including the discovery process and design strategies. Through the inhibition of NEDDylation pathway, pevonedistat can alleviate various human diseases, including cancers, metabolic diseases, viral diseases, neurological disorders, cardiac diseases, and autoimmune diseases. Review offers new perspectives for the future research on pevonedistat. By a systematic understanding of relevant findings, this review highlights the immense potential of pevonedistat for human diseases and facilitates the promotion of targeting NEDDylation as a new and effective therapeutic strategy.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"225 ","pages":"Article 108134"},"PeriodicalIF":10.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146195361","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}

{"title":"Cytokine epigenetics network for gastric cancer progression and chemoresistance","authors":"Ganji Purnachandra Nagaraju ,&nbsp;Seema Kumari ,&nbsp;Mundla Srilatha ,&nbsp;Irina Nakashidze ,&nbsp;Bassel F. El-Rayes","doi":"10.1016/j.phrs.2026.108136","DOIUrl":"10.1016/j.phrs.2026.108136","url":null,"abstract":"<div><div>Gastric cancer (GC) is a leading cause of cancer mortality due to late diagnosis, metastasis, and therapy resistance. Epigenetic modifications rewire the cytokine network, facilitating the development, progression, and chemoresistance of GC. Cytokines regulate immune and inflammatory responses through various pathways, including the IL-6/JAK/STAT pathway, MAP Kinase, NF-κB signaling, IL-8/NF-κB, and the TGF-β axis, which sustain persistent inflammation and oncogenic signaling. The expression of these regulatory molecules is tightly controlled by epigenetic changes, including DNA methylation, histone modification, chromatin remodeling, and miRNA sponging. In addition, this is influenced by long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs), which impact the tumor microenvironment and tumor survival. <em>H. pylori</em> and EBV further remodel cytokine epigenetic networks, promoting tumor progression. LncRNA and circRNAs can play dual roles, acting as both oncogenic and tumor-suppressive agents, where oncogenic ncRNAs, via drug efflux, apoptosis inhibition, autophagy, PD-L1 stabilization, and CSC maintenance, whereas tumor-suppressive ncRNAs restore chemosensitivity and antitumor immunity by reactivating PTEN, MHC-I, and apoptosis, proving to be promising biomarkers and therapeutic targets. Various clinical trials are also discussed in this review.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"225 ","pages":"Article 108136"},"PeriodicalIF":10.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146195368","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}

{"title":"Manipulating metabolism-reprogrammed monocytic-MDSCs prevents colitis-associated dysplasia by IL-10/HIF-1α/DLL4 signaling","authors":"Yirui Wang ,&nbsp;Jiahui Ni ,&nbsp;Guize Feng ,&nbsp;Yan You ,&nbsp;Keyuan You ,&nbsp;Weilian Bao ,&nbsp;Tongqing Chen ,&nbsp;Lijie Zhang ,&nbsp;Xinyue Cao ,&nbsp;Xu Wang ,&nbsp;Yuran Huang ,&nbsp;Hong Li ,&nbsp;Zhiwen Yang ,&nbsp;Yuan Qi ,&nbsp;Xiaoyan Shen","doi":"10.1016/j.phrs.2026.108143","DOIUrl":"10.1016/j.phrs.2026.108143","url":null,"abstract":"<div><div>Dysplasia has been described in various inflammatory environments. However, the mechanisms underlying the dysplastic transformation of the intestinal epithelium and the increased risk of colorectal cancer in colitis patients are not yet fully understood. In this study, we observed that IL-10 was negatively correlated with aberrant proliferation and differentiation of colonic epithelium in colitis patients. Deficiency of myeloid IL-10 resulted in a marked accumulation of intestinal myeloid-derived suppressor cells (MDSCs) and colitis-associated dysplasia, which could be mitigated by intra-bone marrow injection of AAV9-mIL-10. Mechanistically, IL-10-deficient monocytic-MDSCs (M-MDSCs) displayed a distinct pro-inflammatory phenotype with unique metabolic properties characterized by HIF-1α overexpression-induced vibrant glycolysis. This metabolic shift was accompanied by DLL4 transcription through direct binding to its promoter and subsequently skewed the differentiation of intestinal stem cells (ISCs) toward absorptive enterocytes, thereby potentially contributing to intestinal dysplasia. Furthermore, a small-molecule drug screen identified the plant flavonoid Sophoraflavanone G (SG) as a potential DLL4 antagonist, which attenuated the abnormal lineage differentiation of ISCs and ameliorated dysplasia in colitis by inhibiting Notch1 signaling pathway overactivation. Our study highlights a critical role of myeloid IL-10 in monocyte development and homeostasis maintenance of the intestinal epithelium, suggesting potential complementary therapeutic strategies for intestinal dysplasia in colitis patients.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"225 ","pages":"Article 108143"},"PeriodicalIF":10.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146219106","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}

{"title":"Multiple protease-activated probody-drug conjugates for treating CD147-positive ovarian cancer with limited toxicity","authors":"Bo Wang ,&nbsp;Qiangzhe Zhang ,&nbsp;Yuqing Yang ,&nbsp;Chenhui Wang ,&nbsp;Guiyu Deng ,&nbsp;Ying Chen ,&nbsp;Zichang Xu ,&nbsp;Zhinan Chen ,&nbsp;Chuanzheng Zhou ,&nbsp;Sihe Zhang","doi":"10.1016/j.phrs.2026.108120","DOIUrl":"10.1016/j.phrs.2026.108120","url":null,"abstract":"<div><div>Traditional antibody-drug conjugates (ADCs) that target antigens expressed not only on tumor cells but also on nonmalignant cells are often associated with unavoidable on-target off-tumor toxicities. Probodies are masked antibody prodrugs that remain inactive until proteolytically activated in the tumor microenvironment (TME). However, most probodies are produced on the basis of a monoresponsive design and achieve a narrow therapeutic index owing to tumor heterogeneity and nonspecific payload-conjugation. Here, we generated different probodies targeting the cluster of differentiation 147 (CD147) antigen based on the design of multiple-protease-activated linker peptide and HcHAb18 antibody epitope-derived masking peptides. Three anti-CD147 probody-drug conjugates (PDCs) were produced via site-specific conjugation with cytotoxic monomethyl auristatin E (MMAE) through mild cysteine-selective chemical reactions. The created probodies and PDCs can be activated through cleavage by the proteases legumain, matrix-metalloproteinases 9, and urokinase-type plasminogen activator, but exhibit different CD147-targeting potentials. Importantly, PDC1, one of the conditional antibody architectures, exhibits highly selective targeting and strongest cytotoxicity to ovarian cancer cells. More importantly, PDC1 demonstrated promising targeting selectivity and improved the tumor-inhibition efficiency in ovarian cancer-xenograft mouse models without systemic toxicity. This multiple protease-activated, disulfide-bridging PDC strategy provides a novel, precise and safe ADC-targeted therapeutics against ovarian cancer.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"225 ","pages":"Article 108120"},"PeriodicalIF":10.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146097469","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}

{"title":"Pterostilbene alleviates doxorubicin-induced cardiotoxicity by inhibiting cardiomyocytes pyroptosis mediated by the IL-6/STAT3-caspase-3/GSDME axis and M1 polarization of macrophages","authors":"Xiaoxia Huang ,&nbsp;Yuelei Chen ,&nbsp;Yanan Zhang ,&nbsp;Xinyi Hu ,&nbsp;Wenhui Yang ,&nbsp;Tingting Pan ,&nbsp;Wei Gao ,&nbsp;Kidong Eom ,&nbsp;Peng Chen ,&nbsp;Jing Dong ,&nbsp;Lin Li","doi":"10.1016/j.phrs.2026.108129","DOIUrl":"10.1016/j.phrs.2026.108129","url":null,"abstract":"<div><div>Doxorubicin (DOX)-induced cardiotoxicity (DIC) is a major dose-limiting complication of chemotherapy, in which pyroptosis is considered a key pathological mechanism. The natural stilbene compound pterostilbene (PTE) has demonstrated cardioprotective potential, but its role in DOX-induced pyroptosis remains unclear. This study, using both <em>in vitro</em> H9C2 cardiomyocyte and <em>in vivo</em> C57BL/6 mouse models of DIC, confirmed that PTE effectively inhibits DOX-induced cardiomyocyte pyroptosis and alleviates cardiac injury. Mechanistically, DOX activates the IL-6/STAT3 signaling pathway, promoting the nuclear translocation of phosphorylated STAT3 (pSTAT3). CUT&amp;Tag and dual-luciferase reporter assays further revealed that activated STAT3 directly binds to the core promoter regions of the <em>caspase-3</em> and <em>Gasdermin E (GSDME)</em> genes, thereby upregulating their expression at the transcriptional level and ultimately activating the caspase-3/GSDME-mediated pyroptosis pathway. PTE effectively blocks this pyroptotic execution pathway by inhibiting the activation of the IL-6/STAT3 pathway. Furthermore, this study elucidated a critical interaction between cardiomyocytes and immune cells: GSDME-mediated cardiomyocyte pyroptosis releases various soluble factors, with IL-6 being a key cytokine that drives the polarization of macrophages toward the pro-inflammatory M1 phenotype, thereby amplifying the myocardial inflammatory response. By inhibiting cardiomyocyte pyroptosis, particularly by reducing IL-6 release, PTE effectively interrupts this “cardiomyocyte pyroptosis-M1 macrophage polarization” vicious cycle and restores myocardial homeostasis. In summary, our research elucidates a signaling cascade driving DOX-induced cardiotoxicity: IL-6/STAT3-caspase-3/GSDME. We confirmed that PTE is an effective inhibitor of this pathway, not only directly protecting cardiomyocytes but also suppressing the subsequent pyroptosis-driven inflammatory response, thereby highlighting its significant therapeutic potential in mitigating DIC.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"225 ","pages":"Article 108129"},"PeriodicalIF":10.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146137765","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}

{"title":"The SAM-m6A axis as an unexplored therapeutic hub for plant-derived regulation of disease metabolism","authors":"Yuxuan Zhao ,&nbsp;Jingyimei Liang ,&nbsp;Wanning Ma ,&nbsp;Jianbo Xiao ,&nbsp;Hui Cao","doi":"10.1016/j.phrs.2026.108114","DOIUrl":"10.1016/j.phrs.2026.108114","url":null,"abstract":"<div><div>S-adenosylmethionine (SAM) is the main cellular methyl donor and a core product of one-carbon metabolism. Its balance with S-adenosylhomocysteine (SAH) defines methylation potential and shapes epigenetic and epitranscriptomic outputs. RNA N⁶-methyladenosine (m⁶A) directly depends on SAM and is controlled by a writer-reader-eraser system. This review summarizes how altered SAM supply, SAH accumulation, and shifts in the SAM/SAH ratio can reprogram m⁶A landscapes. These changes can occur in cancer, metabolic disease, inflammation, and neurodegeneration. We integrate metabolic control of SAM generation and consumption with regulation of METTL3/METTL14, WTAP and related cofactors, and the erasers FTO and ALKBH5. We also assess plant-derived bioactive compounds proposed to act on this coupling. Most phytochemicals do not behave as potent, selective m⁶A enzyme inhibitors. They more often act upstream by reshaping one-carbon metabolism, redox state, and protein expression. This profile contrasts with canonical synthetic inhibitors that block a single node with higher affinity and more predictable pharmacodynamics. Together, the evidence supports the SAM-m⁶A axis as a practical framework to connect nutrient state with RNA fate decisions. It also highlights key gaps for translation, including target engagement, dose-exposure alignment, and causal validation of m⁶A-dependent phenotypes.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"225 ","pages":"Article 108114"},"PeriodicalIF":10.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146081503","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}

{"title":"Inhibition of Kdm2a with Daminozide suppresses high myopia progression and related neuropsychiatric comorbidities by epigenetically modulating the gut-eye axis","authors":"Zixuan Li ,&nbsp;Hao Li ,&nbsp;Shibo Zhang ,&nbsp;Xixi Wang ,&nbsp;Xinpei Ji ,&nbsp;Jianping Zhang ,&nbsp;Dengyong Hou ,&nbsp;Mengya Fan ,&nbsp;Ruisang Liu ,&nbsp;Yan Xiang ,&nbsp;Yuyu Jiang ,&nbsp;Yingying Ding ,&nbsp;Yanbin Zhan ,&nbsp;Liben Fang ,&nbsp;Bin Sun ,&nbsp;Huafei Li ,&nbsp;Xingguang Liu ,&nbsp;Yunkai Zhang ,&nbsp;Xiaomeng Ren","doi":"10.1016/j.phrs.2026.108137","DOIUrl":"10.1016/j.phrs.2026.108137","url":null,"abstract":"<div><div>High myopia (HM) poses a growing public health challenge due to its increasing prevalence and the associated risks of blinding complications and psychological comorbidities. While traditionally considered an isolated ocular condition, emerging evidence implicates systemic mechanisms, notably through the gut–eye axis and immune factors, play important part in the pathogenesis of HM. Histone demethylase Kdm2a, the key H3K36me2 modification eraser, is critically involved in various inflammatory diseases, yet its specific role in the gut–eye axis and HM remains elusive. To address this, the HM model was successfully established. HM mice exhibited significant scleral thinning, reduced collagen protein, and prominent anxiety-like behaviors. Crucially, they were suffering from gut microbial dysbiosis and intestinal barrier impairment. Intriguingly, upregulated Kdm2a and correspondingly decreased H3K36me2 levels were observed in the intestinal epithelial cells (IECs) of HM mice. Treatment with Daminozide (DA), the selective inhibitor of Kdm2a, effectively suppressed myopia progression and ameliorated psychological comorbidities. Mechanistically, DA restored gut microbiota homeostasis, colonic morphology, and barrier integrity. The transcriptomic profiling further revealed the protective effects of Kdm2a inhibition on modulating key pathways involved in intestinal inflammation and tissue remodeling. Collectively, this work elucidates a novel gut–eye pathway in HM pathogenesis and identifies Kdm2a in IECs as a promising therapeutic target for HM and its associated psychological comorbidities.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"225 ","pages":"Article 108137"},"PeriodicalIF":10.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146207157","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}

{"title":"Semaglutide attenuates autistic-like behaviors in BTBR mice through the shaping of gut microbiota","authors":"Jiayin Liu ,&nbsp;Tianyao Liu ,&nbsp;Lina Nie ,&nbsp;Lianyu Zhou ,&nbsp;Jing Luo ,&nbsp;Li Guo ,&nbsp;Xinggao Zhang ,&nbsp;Meifeng Gong ,&nbsp;Zhenyang Chen ,&nbsp;Xin Li ,&nbsp;Xiaotang Fan","doi":"10.1016/j.phrs.2026.108149","DOIUrl":"10.1016/j.phrs.2026.108149","url":null,"abstract":"<div><div>Autism spectrum disorder (ASD) is a multifaceted neurodevelopmental condition characterized by deficits in social communication and the presence of repetitive behaviors. The significance of the gut-brain axis in the pathogenesis of ASD often points to a relationship with gut dysbiosis and metabolic disruptions in affected individuals. This study investigates the potential of the glucagon-like peptide-1 receptor agonist, semaglutide, to modulate gut microbiota, metabolic pathways, and neurodevelopmental outcomes using the BTBR T(+) Itpr3(tf)/J (BTBR) mouse model of ASD. Our findings indicate that administration of semaglutide during an early neurodevelopmental stage leads to significant improvements in social behavior, cognitive function, and repetitive behaviors in BTBR mice. This therapeutic effect is associated with the restoration of gut microbiota, as demonstrated by fecal microbiota transplantation from C57BL/6 J controls and semaglutide-treated BTBR mice, which ameliorated the ASD behaviors in BTBR mice. Metabolomic profiling identified adrenic acid (AdA) as a crucial mediator; AdA levels in BTBR mice were lower but returned to normal following semaglutide treatment. Additionally, RNA sequencing revealed that hippocampal neurogenesis is associated with semaglutide treatment, and AdA supplementation restored social behaviors and hippocampal neurogenesis. These results highlight the critical role of the gut microbiota-brain axis in the therapeutic effects of semaglutide on ASD and suggest that targeting this axis alongside AdA may represent a promising strategy for ASD.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"225 ","pages":"Article 108149"},"PeriodicalIF":10.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147271771","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}

{"title":"Apoptosis and motor deficits in SPG76 hereditary spastic paraplegia: Calpain 2 inhibition as therapeutic strategy","authors":"Francesca Brivio ,&nbsp;Giulia Guarato ,&nbsp;Elena Panzeri ,&nbsp;Fiore Manganelli ,&nbsp;Massimiliano Filosto ,&nbsp;Chiara Vantaggiato ,&nbsp;Maria Teresa Bassi","doi":"10.1016/j.phrs.2026.108115","DOIUrl":"10.1016/j.phrs.2026.108115","url":null,"abstract":"<div><div>SPG76 is a complicated form of hereditary spastic paraplegia (HSP) associated with mutations in the <em>CAPN1</em> gene. The encoded protein, calpain 1, is a calcium-activated cysteine protease that catalyzes the proteolytic cleavage of a variety of cellular proteins and is involved in a wide range of biological processes. Calpain 1 and calpain 2 isoforms are highly expressed in various tissues and have opposite effects on survival: calpain 1 induces the activation of Akt and ERK pro-survival pathways, regulates autophagy and is neuroprotective, while calpain 2 induces neurodegeneration. We characterized fibroblast cells derived from two SPG76 patients carrying a homozygous mutation (p.Tyr320Leufs73*) in the <em>CAPN1</em> gene that leads to the absence of the protein. Loss of calpain 1 in SPG76 patient’s derived cells increased calpain 2 activation and induced autophagosome formation and accumulation, inhibited Akt and ERK1/2 pro-survival pathways, reducing GSK3β inhibition, and increased cell susceptibility to ER stress. In ER stress conditions, SPG76 cells presented unfolded protein response (UPR) activation, increased apoptosis and cell death. We analysed the potential of targeting calpain 2 and the Akt pro-survival pathway to rescue the SPG76 deranged pathways in patient’s derived cells. We found that the calpain inhibitors olesoxime and MDL28170, naringenin and the GSK3β inhibitor tideglusib were the most effective in increasing Akt activation and GSK3β inhibition and in rescuing apoptosis and cell death in SPG76 cells. Among these, olesoxime and MDL28170 reduced calpain activity, rescued apoptosis and locomotor deficits <em>in vivo</em> in a CalpB KO <em>Drosophila</em> model that replicates the SPG76 phenotype.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"225 ","pages":"Article 108115"},"PeriodicalIF":10.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146081502","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}