Biomedicine & Pharmacotherapy最新文献

{"title":"Enhancing non-viral gene delivery to human T cells through tuning nanoparticles physicochemical features, modulation cellular physiology, and refining transfection strategies","authors":"Abazar Roustazadeh ,&nbsp;Maryam Askari ,&nbsp;Mohammad Hossein Heidari ,&nbsp;Majid Kowsari ,&nbsp;Fatemeh Askari ,&nbsp;Jalil Mehrzad ,&nbsp;Saman Hosseinkhani ,&nbsp;Mohsen Alipour ,&nbsp;Hassan Bardania","doi":"10.1016/j.biopha.2025.117820","DOIUrl":"10.1016/j.biopha.2025.117820","url":null,"abstract":"<div><div>Genetically engineered immune cells hold great promise for treating immune-related diseases, but their development is hindered by technical challenges, primarily related to nucleic acid delivery. Polyethylenimine (PEI) is a cost-effective transfection agent, yet it requires significant optimization for effective T cell transfection. In this study, we comprehensively fine-tuned the characteristics of PEI/DNA nanoparticles, culture conditions, cellular physiology, and transfection protocols to enhance gene delivery into T cells. Gel retardation and dynamic light scattering (DLS) analyses confirmed that PEI effectively bound to DNA, forming size- and charge-adjustable particles based on the N/P ratio, which remained stable in RPMI 1640 medium for 3 days at 25°C. At an N/P ratio of 8.0, these nanoparticles achieved an optimal transfection rate, which improved further with adjustments in DNA dosage and complex volume. Additionally, increasing the cell seeding density and adding complete media shortly after transfection significantly boosted PEI-mediated gene delivery. Notably, reversing the transfection in vials resulted in a 20-fold increase in cellular uptake and transfection efficiency compared to the conventional direct transfection method in culture plates. Finally, modifying cellular physiology with hypotonic extracellular media at pH 9.0 dramatically enhanced transfection rates while maintaining minimal cytotoxicity. These findings could reduce the cost and complexity of preparing engineered T cells, potentially accelerating the development of immune cell therapies for human diseases.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"183 ","pages":"Article 117820"},"PeriodicalIF":6.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143018049","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dimethyl Fumarate attenuates synovial inflammation, reduces nociception, and inhibits the development of post-traumatic osteoarthritis","authors":"Nazir M. Khan ,&nbsp;Jarred M. Kaiser ,&nbsp;Samir Chihab ,&nbsp;Tracy Eng ,&nbsp;Hicham Drissi","doi":"10.1016/j.biopha.2025.117865","DOIUrl":"10.1016/j.biopha.2025.117865","url":null,"abstract":"<div><div>There is currently no cure or disease-modifying treatment for post-traumatic osteoarthritis (PTOA). This study aims to assess the efficacy of dimethyl fumarate (DMF), a US-FDA approved drug for multiple sclerosis, as a treatment for PTOA. PTOA was induced in male Lewis rats by medial meniscal transection (MMT) surgery, and DMF was intra-articularly administered once, one week following surgery. PTOA progression was evaluated using histological, molecular, and radiographic analyses, while secondary allodynia was measured longitudinally, and pain-related markers expression were analyzed in dorsal root ganglion (DRG). 3D radiographic imaging by µCT analysis revealed that DMF treatment attenuated cartilage degradation by decreasing cartilage lesions, surface roughness, and osteophyte formation in the proximal tibiae. Histological analysis showed that DMF markedly inhibited cartilage erosion and cartilage surface fibrillation. Gene expression and Luminex analysis indicated that DMF suppressed joint inflammation by inhibiting inflammatory cytokines. DMF mitigated allodynic pain behavior at 6 weeks and repressed pain mediator expression (Calca, Tac1, Trpv1) in lumbar DRGs. Additionally, DMF treatment inhibited inflammatory gene expression and cytokine secretion induced by IL1β stimulation of human articular chondrocytes <em>in vitro</em>. Mechanistically, DMF treatment reduced colony-stimulating factor 2 (CSF2 or GM-CSF) level in the synovial fluid <em>in vivo</em> and inhibited its expression in human OA chondrocytes. Furthermore, siRNA targeting of CSF2 reduced inflammatory gene expression in human chondrocytes. The findings suggest that DMF reduced inflammatory gene expression, inhibited cartilage degeneration, and mitigated PTOA development in rats. It also alleviated pain behavior indicating its potential as a disease-modifying therapy for PTOA.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"183 ","pages":"Article 117865"},"PeriodicalIF":6.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143043814","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transcriptomic insights into the anti-inflammatory mechanisms of Protaetia brevitarsis seulensis larvae in IL-1β-driven chondrosarcoma cells","authors":"Jin Mi Chun ,&nbsp;Jun Hong Park ,&nbsp;Byeong Cheol Moon ,&nbsp;Su–Jin Baek","doi":"10.1016/j.biopha.2025.117866","DOIUrl":"10.1016/j.biopha.2025.117866","url":null,"abstract":"<div><div>Osteoarthritis (OA) is a complex, degenerative, multi-factorial joint disease. Because of the difficulty in treating OA, developing new targeting strategies that can be used to understand its molecular mechanisms is critical. <em>Protaetia brevitarsis seulensis</em> larvae offer much therapeutic value; however, the presence of various active compounds and the multi-factorial risk factors for OA render the precise mechanisms of action unclear. A systematic transcriptome analysis was used to investigate the key mechanisms of action of <em>P. brevitarsis seulensis</em> larvae aqueous extract (PBSL) and its compounds on OA. Major mechanisms and transcription factors of PBSL were analyzed by profiling gene expression changes in interleukin (IL)-1β-induced human chondrosarcoma cell (SW1353) treated with PBSL. An in vitro assay was performed to validate the efficacy of the novel mechanism and targets of PBSL. PBSL exerted anti-inflammatory effects on SW1353 cells by regulating many molecular pathways. The IL-6/JAK/STAT3 pathway was significantly downregulated by PBSL, and STAT3 was identified as a major transcription factor regulating PBSL-induced target gene expression. Of the six PBSL compounds, the major compound was regulated by the IL-6/JAK/STAT3 pathway. This study provided potential novel mechanisms and transcription factors for PBSL and its active compounds against OA and indicated that inhibiting the IL-6/JAK/STAT3 pathway is a therapeutic target for treating OA.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"183 ","pages":"Article 117866"},"PeriodicalIF":6.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143043885","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Engineered PepFect14 analog for efficient cellular delivery of oligonucleotides","authors":"Abhijit Biswas ,&nbsp;Kapilraj Periyasamy ,&nbsp;Maria Maloverjan ,&nbsp;Ly Porosk ,&nbsp;Geeta Arya ,&nbsp;Sudhichan Mehta ,&nbsp;Hanna Andla ,&nbsp;Raivo Raid ,&nbsp;Vambola Kisand ,&nbsp;Margus Rätsep ,&nbsp;Jesper Wengel ,&nbsp;Ana Rebane ,&nbsp;Margus Pooga","doi":"10.1016/j.biopha.2025.117872","DOIUrl":"10.1016/j.biopha.2025.117872","url":null,"abstract":"<div><div>The broad use of oligonucleotides (ON) in therapeutic and biotechnological applications is limited due to inefficient delivery methods. In parallel with lipids and polymeric carriers, cell-penetrating peptides (CPPs) are efficient vehicles for delivering nucleic acids of various types and activity into cells. In the current work, we examined the structural motifs required for the high efficacy of PepFect14, an often-used CPP for ON delivery, by introducing point mutations into the peptide sequence. We predicted the characteristics of modified CPPs, and analyzed their structure and ability to condense ONs into nanoparticles (NPs) using biophysical methods. We evaluated the ability of new PF14 analogs to deliver splicing switching oligonucleotides (SCO) and small interfering RNA (siRNA) in reporter cell lines, as well as microRNA miR-146a in human primary keratinocytes and in a mouse skin inflammation <em>in vivo</em>. Our findings indicate that the α-helical structure of PF14 is essential for efficient ON delivery, and mutations that disrupt the hydrophobic or cationic face in the peptide abolish NP formation and cellular internalization. PF14-Lys, an analog containing lysine residues instead of original ornithines, yielded a higher biological response to SCO and siRNA in the respective reporter cells than PF14. Furthermore, PF14-Lys efficiently delivered miRNA into keratinocytes and led to the subsequent downregulation of the target genes. Importantly, subcutaneously administered PF14-Lys-miR-146a NPs suppressed the inflammatory responses in mouse model of irritant contact dermatitis. In conclusion, our results suggest that PF14-Lys is a highly promising delivery vector for various oligonucleotides, applicable both <em>in vitro</em> and <em>in vivo</em>.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"184 ","pages":"Article 117872"},"PeriodicalIF":6.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143076699","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Oxaliplatin reversibly and differentially affects electrogenic activity of small IB4(+) of male and female rat sensory neurons","authors":"Eva Villalba-Riquelme ,&nbsp;Roberto de la Torre-Martínez ,&nbsp;Asia Fernández-Carvajal ,&nbsp;Antonio Ferrer-Montiel","doi":"10.1016/j.biopha.2025.117849","DOIUrl":"10.1016/j.biopha.2025.117849","url":null,"abstract":"<div><div>Oxaliplatin-induced peripheral neuropathy (OIPN) is a prevalent drug side effect with unclear molecular mechanism and sex differences. We report that a 48-hour exposure of 1 µg·mL⁻¹ oxaliplatin potently and reversibly increased the excitability of IB4(+) male and female nociceptors. In females, oxaliplatin augmented spontaneous and tonic activity, increased the overshoot and amplitude of action potentials, depolarized the membrane potential, reduced the rheobase, and raised the firing frequency, primarily due to the depolarization of K_V currents and a mild up-regulation of TTX-resistant (TTX-r) Na_V currents. In males, oxaliplatin reduced the rheobase, augmented the firing frequency, and prolonged the action potential peak time, mediated by increased TTX-r Na_V currents, hyperpolarization of their activation curve, and a faster recovery from inactivation. Oxaliplatin also up-regulated TRPV1 currents in male and female IB4(+) nociceptors and augmented TRPA1 responses in male IB4(+) neurons. These findings highlight Na_V1.8, TRPV1, and TRPA1 as therapeutic targets to mitigate OIPN and validate the use of long-term nociceptor cultures as preclinical models for studying peripheral neuropathies.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"183 ","pages":"Article 117849"},"PeriodicalIF":6.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143230265","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Isoniazid and nicotinic hydrazide hybrids mitigate trehalose-6,6’-dimycolate-induced inflammatory responses and pulmonary granulomas via Syk/PI3K pathways: A promising host-directed therapy for tuberculosis","authors":"Ha-Yeon Song ,&nbsp;Bo-Gyeong Yoo ,&nbsp;Yuna Lee ,&nbsp;Jae Yoon Lim ,&nbsp;Eun Ji Gu ,&nbsp;Jongho Jeon ,&nbsp;Eui-Baek Byun","doi":"10.1016/j.biopha.2024.117798","DOIUrl":"10.1016/j.biopha.2024.117798","url":null,"abstract":"<div><div>Granulomas, dense clusters of immune cells and bacteria, are critical barriers in tuberculosis (TB) treatment. Recent advancements in TB management have highlighted granuloma control as a potential host-directed therapy (HDT) strategy. Although isoniazid (INH) is the first-line drug for TB therapy, its efficacy is limited to non-replicating <em>Mycobacterium tuberculosis</em> (Mtb) under granulomatous conditions, necessitating the development of more effective derivatives. In this study, hybrid compounds of isoniazid, designated as INH-D1 and INH-D2, were synthesized and evaluated for their effects on controlling inflammatory responses and pulmonary granuloma lesions induced by trehalose-6,6′-dimycolate (TDM), a glycolipid of Mtb. Both INH-D1 and INH-D2 demonstrated stronger inhibitory effects on inflammatory mediators (TNF-α, interleukin-6, co-stimulatory molecules, and MHC class I) in TDM-stimulated macrophages compared to original INH. These anti-inflammatory effects were mediated by the inhibition of Syk, p38, PI3K, and NF-κB transcription. INH-D1 and INH-D2 exhibited stronger binding energies to Syk and PI3Kα/β than INH, which are known as proximal kinases and key mediator in TDM-mediated inflammatory responses. Oral administration of INH-D2 successfully relieved TDM-induced pulmonary granuloma pathology by reducing innate immune cell infiltration, hypoxic conditions in the lungs, and systemic inflammation by decreasing serum cytokines and chemokines. In contrast, original INH and INH-D1 did not effectively alleviate pulmonary granuloma pathology. These findings demonstrate that the novel molecule INH-D2 is effective in treating pulmonary granulomas owing to its strong anti-inflammatory effects, highlighting it as a promising HDT candidate for the management of pulmonary tuberculosis, thereby providing a strategic alternative to standard anti-TB antibiotics.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"183 ","pages":"Article 117798"},"PeriodicalIF":6.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143230635","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"New insights into gold nanoparticles in virology: A review of their applications in the prevention, detection, and treatment of viral infections","authors":"Hossein Teimouri ,&nbsp;Shiva Taheri ,&nbsp;Fatemeh Eivazzadeh Saidabad ,&nbsp;Gerson Nakazato ,&nbsp;Yazdan Maghsoud ,&nbsp;Abouzar Babaei","doi":"10.1016/j.biopha.2025.117844","DOIUrl":"10.1016/j.biopha.2025.117844","url":null,"abstract":"<div><div>Viral infections have led to the deaths of millions worldwide and come with significant economic and social burdens. Emerging viral infections, as witnessed with coronavirus disease 2019 (COVID-19), can profoundly affect all aspects of human life, highlighting the imperative need to develop diagnostic, therapeutic, and effective control strategies in response. Numerous studies highlight the diverse applications of nanoparticles in diagnosing, controlling, preventing, and treating viral infections. Due to favorable and flexible physicochemical properties, small size, immunogenicity, biocompatibility, high surface-to-volume ratio, and the ability to combine with antiviral agents, gold nanoparticles (AuNPs) have shown great potential in the fight against viruses. The physical and chemical properties, the adjustability of characteristics based on the type of application, the ability to cross the blood-brain barrier, the ability to infiltrate cells such as phagocytic and dendritic cells, and compatibility for complexing with various compounds, among other features, transform AuNPs into a suitable tool for combating and addressing pathogenic viral agents through multiple applications. In recent years, AuNPs have been employed in various applications to fight viral infections. However, a comprehensive review article on the applications of AuNPs against viral infections has yet to be available. Given their versatility, AuNPs present an appealing option to address various gaps in combating viral infections. Hence, this review explores the attributes, antiviral properties, contributions to drug delivery, vaccine development, and diagnostic uses of AuNPs.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"183 ","pages":"Article 117844"},"PeriodicalIF":6.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143018228","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mechanism and therapeutic potential of hippo signaling pathway in type 2 diabetes and its complications","authors":"Ziqi Zhao,&nbsp;Weijie Wu,&nbsp;Qianyi Zhang,&nbsp;Tiancheng Xing,&nbsp;Yiling Bai,&nbsp;Shuoqi Li,&nbsp;Dandan Zhang,&nbsp;Huilian Che,&nbsp;Xiaohui Guo","doi":"10.1016/j.biopha.2025.117817","DOIUrl":"10.1016/j.biopha.2025.117817","url":null,"abstract":"<div><div>Loss of pancreatic islet cell mass and function is one of the most important factors in the development of type 2 diabetes mellitus, and hyperglycemia-induced lesions in other organs are also associated with apoptosis or hyperproliferation of the corresponding tissue cells. The Hippo signaling pathway is a key signal in the regulation of cell growth, proliferation and apoptosis, which has been shown to play an important role in the regulation of diabetes mellitus and its complications. Excessive activation of the Hippo signaling pathway under high glucose conditions triggered apoptosis and decreased insulin secretion in pancreatic islet cells, while dysregulation of the Hippo signaling pathway in the cells of other organ tissues led to proliferation or apoptosis and promoted tissue fibrosis, which aggravated the progression of diabetes mellitus and its complications. This article reviews the mechanisms of Hippo signaling, its individual and reciprocal regulation in diabetic pancreatic pathology, and its emerging role in the pathophysiology of diabetic complications. Potential therapeutics for diabetes mellitus that have been shown to target the Hippo signaling pathway are also summarized to provide information for the clinical management of type 2 diabetes mellitus.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"183 ","pages":"Article 117817"},"PeriodicalIF":6.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143026108","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Insights from animal studies exploring the efficacy and safety of topical losartan, in prophylaxis and treatment of corneal scarring fibrosis","authors":"Valeria Villabona-Martinez ,&nbsp;Barbara Araujo Lima Dutra ,&nbsp;Steven E. Wilson","doi":"10.1016/j.biopha.2025.117857","DOIUrl":"10.1016/j.biopha.2025.117857","url":null,"abstract":"<div><div>Several studies in rabbits demonstrated the efficacy and safety of topical losartan, an angiotensin II receptor blockers (ARB) that modulates the TGF-β intracellular signaling pathways by inhibiting the activation of Extracellular Signal-regulated Kinase (ERK), in preventing or treating stromal fibrosis after a range of injuries such as Descemetorhexis, alkali burns, incisions, and photorefractive keratectomy (PRK). Several case reports have shown that topical losartan treatment is also efficacious and safe in humans to prevent or treat stromal fibrosis after many different injuries or diseases. Topical losartan penetrates the full thickness of the cornea and, therefore, can treat both anterior and posterior stromal fibrosis. These rabbit studies have demonstrated that there can be epithelial and stromal toxicity to losartan at dosages greater than 0.8 mg/ml and that higher dosages will not accelerate the return to transparency of fibrotic corneas. In corneas with an epithelial defect, it is likely safer to use 0.2 mg/ml losartan six times a day until the epithelium closes to further decrease the risk of epithelial toxicity before going to the 0.8 mg/ml six times a day dosage. Future clinical studies will explore additional questions, such as whether four times a day dosing is less effective than six times a day dosing in the treatment of stromal fibrosis.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"183 ","pages":"Article 117857"},"PeriodicalIF":6.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143018204","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Phosphodiesterase 4D inhibition improves the functional and molecular outcome in a mouse and human model of Charcot Marie Tooth disease 1 A","authors":"Melissa Schepers ,&nbsp;Tim Vangansewinkel ,&nbsp;Karen Libberecht ,&nbsp;Hanne Jeurissen ,&nbsp;Darren Jacobs ,&nbsp;Elisabeth Piccart ,&nbsp;Robert Prior ,&nbsp;Roberta Ricciarelli ,&nbsp;Chiara Brullo ,&nbsp;Ernesto Fedele ,&nbsp;Olga Bruno ,&nbsp;Jos Prickaerts ,&nbsp;Ivo Lambrichts ,&nbsp;Ludo Van Den Bosch ,&nbsp;Tim Vanmierlo ,&nbsp;Esther Wolfs","doi":"10.1016/j.biopha.2025.117828","DOIUrl":"10.1016/j.biopha.2025.117828","url":null,"abstract":"<div><div>Charcot-Marie-Tooth disease type 1A (CMT1A) is an inherited peripheral neuropathy caused by a duplication of the peripheral myelin protein 22 (PMP22) gene. It is primarily marked by Schwann cell dedifferentiation and demyelination, leading to motor and sensory deficits. Cyclic adenosine monophosphate (cAMP) is crucial for Schwann cell differentiation and maturation. Therefore, increasing cAMP by inhibiting its degraders, phosphodiesterases (PDE), is a potential therapeutic strategy for CMT1A. This study investigated the therapeutic potential of the specific PDE4D inhibitor Gebr32a using the C3-PMP22 mouse model for CMT1A and patient-induced Pluripotent Stem Cell (iPSC)-derived Schwann cells. C3-PMP22 mice, injected subcutaneously with Gebr32a twice a day for 10 weeks, showed significantly increased nerve conduction in sciatic nerves compared to vehicle-injected controls, indicating improved myelination. Additionally, Gebr32a-treated C3-PMP22 mice exhibited improved sensorimotor functions. Grip strength analysis revealed significantly increased strength in all limbs of Gebr32a-treated C3-PMP22 mice. Post-mortem histological and ultrastructural analysis confirmed enhanced myelination in the sciatic nerve of treated mice compared to controls. In primary mouse CMT1A Schwann cells, Gebr32a dose-dependently increased the expression of pro-myelinating genes such as <em>oct6, Krox20, Mbp, Mpz</em>, and <em>Plp</em>, while downregulating the dedifferentiation marker <em>c-Jun</em> and human <em>PMP22</em>. Similar effects on gene expression were observed in iPSC-derived Schwann cells from a CMT1A patient, highlighting the clinical relevance of our findings. In conclusion, inhibition of PDE4D with Gebr32a improves the functional and molecular outcomes in mouse and human models of CMT1A, highlighting its potential as a new therapeutic strategy for CMT1A disease management.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"183 ","pages":"Article 117828"},"PeriodicalIF":6.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143018238","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}