Biomedicine & Pharmacotherapy最新文献

{"title":"Targeting of bowel tissue by fully human antibodies cross-reactive with human and mouse GPA33 antigen","authors":"Genki Hichiwa ,&nbsp;Abdur Rafique ,&nbsp;Asaki Nagashima ,&nbsp;Yayan Wang ,&nbsp;Kanako Kazuki ,&nbsp;Ryohei Ogihara ,&nbsp;Muhammad Feisal Jatnika ,&nbsp;Ryosuke Shimamoto ,&nbsp;Yumi Iwai ,&nbsp;Narumi Uno ,&nbsp;Hiroyuki Satofuka ,&nbsp;Kazuma Tomizuka ,&nbsp;Yuji Ito ,&nbsp;Yasuhiro Kazuki","doi":"10.1016/j.biopha.2025.118336","DOIUrl":"10.1016/j.biopha.2025.118336","url":null,"abstract":"<div><div>Monoclonal antibodies are indispensable therapeutic agents for various diseases, including cancer, autoimmune disorders, and infectious diseases. Glycoprotein A33 (GPA33), a cell surface antigen highly expressed in colorectal cancer, provides a compelling therapeutic target; however, the species-specificity of anti-GPA33 antibodies has limited their utility in preclinical models, thus inhibiting their development. Here, we generated and characterized fully human, cross-reactive anti-GPA33 antibodies using phage-display technology with transchromosomic antibody-producing animals. The resulting single-chain variable fragment and single-chain variable fragment crystallizable antibodies exhibited high specificity and affinity for both human and mouse GPA33. <em>In vivo</em> imaging confirmed their targeted retention in mouse intestine, indicating their potential for developing targeted therapeutic approaches. The ability of these antibodies to recognize both human and murine GPA33 enhances their applicability in preclinical models, improving their translation from experimental to clinical applications. These results highlight the feasibility of developing cross-reactive, fully human antibodies and support the advancement of GPA33-targeted diagnostic approaches and the exploration of novel therapeutic strategies for relevant gastrointestinal diseases.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"189 ","pages":"Article 118336"},"PeriodicalIF":6.9,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144631541","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":"TRPML2 channel modulation by PI(3,5)P₂ and small-molecule agonists controls endosomal vesicle dynamics","authors":"Zi-Qi Gu ,&nbsp;Hsuan-Ti Wang ,&nbsp;Yanfen Li ,&nbsp;Einar Krogsaeter ,&nbsp;Alice C. Lin ,&nbsp;Jackson Lin ,&nbsp;Yi-Shan Liu ,&nbsp;Wei-Shuan Lin ,&nbsp;William Burton ,&nbsp;Mu-Lin Liu ,&nbsp;Colin Feldmann ,&nbsp;Rachel Tang ,&nbsp;Ching-Wen Po ,&nbsp;Pei-Shan Hou ,&nbsp;Neng-Yu Lin ,&nbsp;Jing-Yi Lin ,&nbsp;Tai-Ling Chao ,&nbsp;Sui-Yuan Chang ,&nbsp;Zhuo Yang ,&nbsp;Marco Keller ,&nbsp;Cheng-Chang Chen","doi":"10.1016/j.biopha.2025.118350","DOIUrl":"10.1016/j.biopha.2025.118350","url":null,"abstract":"<div><div>TRPML2 is an endolysosomal calcium-permeable channel gated by phosphatidylinositol 3,5-bisphosphate (PI(3,5)P₂). However, its subcellular localization and functional contribution to compartment-specific vesicle trafficking remain incompletely defined. In this study, we identify Rab4-positive recycling endosomes as a key site of TRPML2 activity and regulation. We further examined a PI(3,5)P₂-insensitive TRPML2 mutant (R310A), which exhibited reduced channel activity, accumulated perinuclear vesicles, and impaired Rab4 + endosomal motility. To restore channel function, we employed two selective small-molecule TRPML2 agonists, ML2-SA1 and ML2-SA2. Endolysosomal patch-clamp recordings confirmed that both compounds activate wild-type TRPML2 and effectively restore channel activity in the R310A mutant. Functional imaging further demonstrated that ML2-SA2 treatment rescues vesicle redistribution, reduces Golgi accumulation, and promotes peripheral vesicle dynamics. Notably, these effects were observed even in the absence of functional PI(3,5)P₂ gating, indicating that small-molecule agonists can bypass endogenous lipid regulation to restore TRPML2 activity. Our findings identify TRPML2 as a druggable ion channel whose activity is essential for maintaining Rab4-dependent vesicle trafficking. This study establishes a mechanistic link between phosphoinositide sensitivity, TRPML2 activation, and endosomal motility, and highlights a potential therapeutic strategy for correcting trafficking defects caused by impaired lipid signaling in immune cells or other pathophysiological contexts involving endosomal stress.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"189 ","pages":"Article 118350"},"PeriodicalIF":6.9,"publicationDate":"2025-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144631556","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":"Iron chelation prior to static cold storage decreases lipid peroxidation and improves gluconeogenesis during NMP in isolated porcine kidneys","authors":"L.P. Gartzke ,&nbsp;T.H. de Boer ,&nbsp;S.S.M. Wolfswinkel ,&nbsp;S.E. Wink ,&nbsp;R. Kalashnik ,&nbsp;A. van Buiten ,&nbsp;M. Goris ,&nbsp;P.J. Ottens ,&nbsp;G. Krenning ,&nbsp;G.J. Nieuwenhuijs-Moeke ,&nbsp;H.G.D. Leuvenink ,&nbsp;R.H. Henning","doi":"10.1016/j.biopha.2025.118343","DOIUrl":"10.1016/j.biopha.2025.118343","url":null,"abstract":"<div><div>Despite alternative graft preservation techniques, static cold storage (SCS) remains the most widely used kidney preservation method. Nevertheless, the molecular mechanisms of SCS’ drawbacks remain poorly understood. One of the mechanisms that drives delayed graft function (DGF) and poorer transplant outcomes is suggested to entail increased oxidative stress due to prolonged cold ischemia, thus driving lipid peroxidation and ferroptosis via iron-mediated Fenton chemistry. Here, we investigate whether iron chelation with deferasirox can prevent the Fenton reaction and thereby mitigate lipid peroxidation and improve kidney preservation. Porcine kidneys underwent 24 h of SCS in University of Wisconsin (UW) solution with or without deferasirox (60 µmol), followed by 3 h of normothermic machine perfusion (NMP). Deferasirox-treated kidneys exhibited significantly lower lipid peroxidation, as evidenced by reduced 4-hydroxy-nonenal (4HNE)-protein adduct levels, without altering antioxidative capacity manifested by glutathione peroxidase 4 (GPx4) expression. Metabolic stability was enhanced, with increased glucose availability and a higher glucose-to-lactate ratio, suggesting improved oxidative phosphorylation. Adenosine triphosphate (ATP) levels remained stable, indicating no adverse mitochondrial effects. Additionally, deferasirox reduced kidney weight gain, which may reflect lower edema formation, and strongly improved glomerular integrity and reduced tubular dilation. By reducing lipid peroxidation and maintaining metabolic function, deferasirox may help mitigate ischemia-reperfusion injury (IRI), enhance early graft function, and improve transplant outcomes. These findings strengthen the role of iron in cold-induced oxidative damage, and imply that iron chelation is a promising adjunct to improve graft preservation.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"189 ","pages":"Article 118343"},"PeriodicalIF":6.9,"publicationDate":"2025-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144623319","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":"α6GABAA receptor positive allosteric modulators targeting trigeminal ganglia for preventing and aborting chronic periorbital allodynia and cephalic pain in both sexes: A mechanistic and comparative preclinical study","authors":"Xin-Chen Chang ,&nbsp;Chen-Jiun Yeh ,&nbsp;Yi-Ting Pan ,&nbsp;Yueh-Peng Chen ,&nbsp;Dishary Sharmin ,&nbsp;James Cook ,&nbsp;Yu-Cheng Pei ,&nbsp;Lih-Chu Chiou","doi":"10.1016/j.biopha.2025.118344","DOIUrl":"10.1016/j.biopha.2025.118344","url":null,"abstract":"<div><div>Migraine remains an unmet medical need, even with new calcitonin gene-related peptide (CGRP)-targeting treatments. The α6 subunit (Gabra6)-containing GABA_A receptors (α6GABA_ARs) are abundant in trigeminal ganglia (TG). We evaluated the possible anti-migraine efficacy and mechanism of DK-I-56–1, a druggable α6GABA_AR-selective positive allosteric modulator (PAM), using a chronic migraine model induced by repeated intermittent nitroglycerin (riNTG) injections (10 mg/kg, <em>i.p.</em>, every 2 days for a total of 5 doses). Chronic and acute allodynic responses of riNTG-treated ICR mice of both sexes were assessed by reduced mechanical withdrawal thresholds in their periorbital areas, and their chronic cephalic pain by elevated grimace scores. riNTG induced long-lasting chronic periorbital allodynia and cephalic pain, and one NTG injection caused acute allodynia. Daily DK-I-56–1 prevented chronic allodynia and cephalic pain, and abolished acute allodynia in both sexes. Anti-allodynic and cephalic pain-relieving effects of DK-I-56–1 (10 mg/kg, <em>i.p.</em>) were mimicked by topiramate (30 mg/kg, <em>i.p.</em>), antagonized by <em>i.p.</em> furosemide, an α6GABA_AR antagonist, and nullified in <em>Gabra6</em>-knockout ICR mice. However, olcegepant (1 mg/kg, <em>i.p.</em>) only partially prevented cephalic pain. In dissociated TG neurons, DK-I-56–1 induced a furosemide-sensitive potentiation of GABA-induced current and depolarization. However, DK-I-56–1 did not altered increased inflammatory cytokines, down-regulated glutamate decarboxylase 65 kDa (GAD65), and Gabra6 protein levels in TG of riNTG-treated mice. Therefore, DK-I-56–1 may have the potential to prevent and abort migraines by potentiating GABA-induced depolarization in TG neurons via α6GABA_ARs, offering efficacy comparable to that of topiramate but superior to olcegepant as a novel migraine therapy.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"189 ","pages":"Article 118344"},"PeriodicalIF":6.9,"publicationDate":"2025-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144614016","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":"Oral apigenin prevents obesity-related muscular atrophy, but not obesity itself, in middle-aged rats fed a high-calorie diet","authors":"Josimar Macedo de Castro ,&nbsp;Alanis da Silva Melo ,&nbsp;Beatriz Lima Silveira ,&nbsp;Igor Antônio Souza Martins ,&nbsp;Maielli Martins Marçal ,&nbsp;Tenille Dal Bosco ,&nbsp;Melina Belén Keingeski ,&nbsp;Elisa Carolina Lange de Oliveira ,&nbsp;Mario Reis Alvares-da-Silva ,&nbsp;Patrick Türck ,&nbsp;Alex Sander da Rosa Araujo ,&nbsp;Layane Ramos Ayres ,&nbsp;Lucas Stahlhöfer Kowalewski ,&nbsp;Mariana Kras Borges Russo ,&nbsp;Mauricio Krause ,&nbsp;Dirson João Stein ,&nbsp;Iraci L.S. Torres","doi":"10.1016/j.biopha.2025.118342","DOIUrl":"10.1016/j.biopha.2025.118342","url":null,"abstract":"<div><div>Obesity constitutes a growing global health concern, affecting individuals during the aging process. Flavonoids that increase tissue NAD+ levels, such as apigenin (Api), are proposed for the treatment of obesity and age-related diseases. Thus, this study aimed to provide initial preclinical evidence of Api in this setting using middle-aged rats induced to obesity by a high-calorie diet (HCD). Forty-seven 15-month-old male Wistar rats were assigned to five groups: standard diet (SD) or HCD, each with (Api at 50 mg/kg) or without treatment (vehicle), plus vehicle control group. Obesity induction and therapeutic intervention were conducted concurrently for 88 days. Biometric, cardiac, adiposity, muscular, and blood biochemical parameters were analyzed. Eighty-eight days post HCD rats had hyperglycemia, hypertriglyceridemia, increased visceral and subcutaneous fat, and heart hypertrophy, indicating obesity and related disorders (<em>p</em> &lt; 0.05 for all). The gastrocnemius of these rats exhibits reduced mass, smaller myocytes, and fibrosis (<em>p</em> &lt; 0.05), indicating sarcopenia, likely caused or worsened by obesity. In parallel, preemptive Api treatment failed to prevent obesity and did not affect key adipose tissue browning genes, cardiac oxidative stress markers, or sirtuin and CD38 levels. However, it mitigated muscle loss and hypotrophy, in addition to elevating p70S6K levels in HCD-fed rats (<em>p</em> &lt; 0.05 for both). These preclinical results suggest that although Api may not prevent some HCD-induced disturbances, it may attenuate age- and obesity-related atrophy via p70S6K anabolic signaling in middle-aged rats. To support clinical translation, particularly in sarcopenia subtypes, further mechanistic and therapeutic investigations on Api are required to elucidate its effects on skeletal muscle.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"189 ","pages":"Article 118342"},"PeriodicalIF":6.9,"publicationDate":"2025-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144605689","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":"Liposomal formulation of the CDK9 PROTAC THAL-SNS-032 enhances the antitumor activity in breast cancer cell lines","authors":"María Arenas-Moreira ,&nbsp;María del Mar Noblejas-López ,&nbsp;Consuelo Ripoll ,&nbsp;Carmen Moya-López ,&nbsp;Cristina Díaz-Tejeiro ,&nbsp;Alberto Ocaña ,&nbsp;Luis Martin-Ezama ,&nbsp;Iván Bravo ,&nbsp;Carlos Alonso-Moreno","doi":"10.1016/j.biopha.2025.118352","DOIUrl":"10.1016/j.biopha.2025.118352","url":null,"abstract":"<div><div>PROTAC technology presents promising options for treating various diseases, including cancer. Several PROTAC molecules are currently being tested in clinical trials for metastatic breast cancer and metastatic castration-resistant prostate cancer. Despite this progress, challenges such as poor bioavailability, off-tumor and/or off-target toxicity, and instability in biological environments hinder their therapeutic potential. Enhancing the therapeutic index of PROTACs is crucial, and one promising approach is converting PROTACs into nanomedicines. Cyclin-dependent kinase 9 (CDK9) is a key cell cycle regulator implicated in various cancers. THAL-SNS-032 (THAL), a CDK9 degrader PROTAC, has shown effectiveness in preclinical models, but its clinical translation is limited by on-target off-tumor toxicity. This study aimed to convert THAL into nanomedicines to improve its preclinical profile for breast cancer treatment. To do so, loaded lipid-based nanoparticle formulations (LBNPs) were designed, liposomal formulation (cLIP-THAL), free-cholesterol liposomal formulation (LIP-THAL), and solid-lipid nanoparticles (SLN-THAL). These formulations demonstrated high stability and controlled drug release of THAL, with cLIP-THAL showing the most promising results. Biological assessments on breast cancer cell lines indicated that the nanomedicines were as effective as the free PROTAC in reducing cell viability, with lower toxicity in non-transformed cells. Overall, incorporating THAL-SNS-032 into nanomedicines offers a comprehensive approach with potential benefits in dose optimization, safety, and targeted delivery. These findings support the further development of nanomedicine-based PROTAC therapies for cancer treatment.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"189 ","pages":"Article 118352"},"PeriodicalIF":6.9,"publicationDate":"2025-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144606106","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":"Mitochondrial homeostasis: Exploring their impact on skin disease pathogenesis","authors":"Hajar Ahmad Jamil,&nbsp;Norwahidah Abdul Karim","doi":"10.1016/j.biopha.2025.118349","DOIUrl":"10.1016/j.biopha.2025.118349","url":null,"abstract":"<div><div>Mitochondria play a vital impact in maintaining the well-being of the skin, by regulating key cellular activities and processes in various skin cell types, including keratinocytes, fibroblasts, and melanocytes. Understanding their activity and dysfunction is essential for comprehending the pathophysiology of skin diseases and establishing viable therapeutic approaches. This review synthesizes current knowledge on the role of mitochondria in skin cells and their impact on disease progression. In keratinocytes, mitochondria support differentiation and skin barrier formation. In fibroblasts, they are essential for collagen synthesis and maintaining redox balance. In melanocytes, mitochondria facilitate melanin synthesis and protect against UV-induced oxidative damage. Mitochondrial dysfunction, characterized by generation of reactive oxygen species (ROS), alterations in mitochondrial DNA (mtDNA), and changes in biogenesis and dynamics, has been linked to skin diseases such as psoriasis, atopic dermatitis, and vitiligo. These dysfunctions disrupt cellular energy metabolism and stress responses, compromising skin structure and function. Mitochondria are therefore integral not only to energy production and oxidative stress regulation but also to the overall biosynthetic and protective functions of the skin. Future research should aim to deepen our understanding of mitochondrial dysfunction in skin cells and explore targeted strategies to restore mitochondrial health in skin diseases.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"189 ","pages":"Article 118349"},"PeriodicalIF":6.9,"publicationDate":"2025-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144606104","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":"Design, synthesis, and evaluation of the effect of potential peptides against CD38: An in silico and in vitro study","authors":"Mohsen Nabi-Afjadi ,&nbsp;Bahareh Dabirmanesh ,&nbsp;S. Mohsen Asghari ,&nbsp;Sorour Ramezanpour ,&nbsp;Yaghoub Fathollahi ,&nbsp;Khosro Khajeh","doi":"10.1016/j.biopha.2025.118347","DOIUrl":"10.1016/j.biopha.2025.118347","url":null,"abstract":"<div><div>The transmembrane glycoprotein known as CD38 (cluster of differentiation 38) is a desirable target for targeted therapeutics as it is essential for immune response and cell signaling, especially in hematological malignancies. The current study aimed to design antibody/nanobody-derived peptides using bioinformatic tools and experimentally investigate their specific binding and impact on the extracellular CD38 expressing cells. Following the synthesis of one of the peptides that indicated somewhat better <em>in silico</em> results, known as CDR3a23 (L-pep), and its circular version as C-pep, flow cytometry was used to assess each one's specific binding to CD38. MTT and trypan blue exclusion assays were then used to investigate the peptide's impact. The peptide's anti-proliferative mechanism was also confirmed by cell cycle analysis and apoptosis after annexin V-fluorescein isothiocyanate (FITC) and propidium iodide (PI) double staining. Finally, the L-pep with K_d of 630 nm, indicated high affinity to CD38. The IC₅₀ values of the L-pep and C-pep against the HL-60 cells were achieved as 540 nM and 780 nM (<em>P</em> &lt; 0.0001), respectively. Also, when the peptides combined with 1 µM ATRA, these values significantly decreased to 390 nM and 630 nM (<em>P</em> &lt; 0.0001), respectively. During arresting the cells at the G1 phase, the total apoptosis of the L-pep and C-pep achieved as 47.5 % and 34.3 %, respectively, which significantly increased to 72.5 % and 55.3 %, respectively, in combination with 1 µM ATRA. Through their specific binding and suppression of cell growth, our research identified potential peptides against cells exhibiting high levels of CD38.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"189 ","pages":"Article 118347"},"PeriodicalIF":6.9,"publicationDate":"2025-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144605688","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":"Protein-functionalized nanoparticles: Emerging strategies in drug delivery","authors":"Anna Wietrzyk ,&nbsp;Agata Hutny ,&nbsp;Laura Jonderko ,&nbsp;Karol Biliński ,&nbsp;Małgorzata Makieła ,&nbsp;Jarosław Kalinin ,&nbsp;Barbara Jachimska ,&nbsp;Julita Kulbacka","doi":"10.1016/j.biopha.2025.118337","DOIUrl":"10.1016/j.biopha.2025.118337","url":null,"abstract":"<div><div>The constantly developing field of protein-functionalized nanoparticles seems to be the future of medicine, as was proved by the Nobel Prize in 2022 for the development of “click chemistry”. This method offers enormous possibilities for developing strategies for functionalizing nanoparticles with proteins. We scrutinize this field by exploring the latest advancements, methodologies, and applications in imaging, diagnostics, cancer treatment, and drug delivery. The research involves a comprehensive review of diverse strategies for functionalization, including in situ surface modification, post-synthesis techniques, and emerging click chemistry covalent and non-covalent coupling methods. Additionally, our review involves the importance of active targeting uptake. The flexibility and adaptability of PFNPs present encouraging prospects for numerous medical domains, notwithstanding the various obstacles encountered in implementing the solutions discussed. Our review highlights the need for further development to increase the universal applications of protein-functionalized nanoparticles while summarizing the remarkable advancements in this field.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"189 ","pages":"Article 118337"},"PeriodicalIF":6.9,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144597559","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":"A brain-penetrant CDK4/6 inhibitor - AU3-14 shows robust anti-tumor efficacy against glioblastoma","authors":"Laychiluh B. Mekonnen ,&nbsp;Theodosia Teo ,&nbsp;Benjamin Noll ,&nbsp;Muhammed H. Rahaman ,&nbsp;Jimma Lenjisa ,&nbsp;Sunita Basnet ,&nbsp;Ramin Hassankhani ,&nbsp;Robert Milne ,&nbsp;Briony L. Gliddon ,&nbsp;Melinda N. Tea ,&nbsp;Stuart M. Pitson ,&nbsp;Yan Zhou ,&nbsp;Lijun Wei ,&nbsp;Hui Wang ,&nbsp;Jun Liu ,&nbsp;Xiang Zhou ,&nbsp;Ke Wang ,&nbsp;Shudong Wang","doi":"10.1016/j.biopha.2025.118340","DOIUrl":"10.1016/j.biopha.2025.118340","url":null,"abstract":"<div><div>The cyclin D-CDK4/6-INK4-Rb pathway is frequently dysregulated in glioblastoma (GBM), the most aggressive and poorly prognosed brain malignancy. Despite extensive research, advances in GBM treatment have seen limited progress, with current therapy largely reliant on temozolomide (TMZ), underscoring the need for novel therapeutic strategies. This study explores the therapeutic potential of AU3–14, a potent and selective CDK4/6 inhibitor, for GBM. In CDK4-amplified GBM cell lines, AU3–14 significantly reduced phosphorylation of Rb and levels of cell cycle-related proteins, resulting in G₁/G₀ cell cycle arrest and senescence. Biopharmaceutical analysis indicated that AU3–14 has high membrane permeability and low P-glycoprotein substrate potential. More extensive pharmacokinetic studies revealed that AU3–14 efficiently crosses the blood-brain barrier, with an unbound brain-to-plasma concentration ratios (<em>K</em>_p,uu) of 1.2 and 0.63 at single oral doses of 10 and 30 mg/kg, respectively, which were 2–4 times higher than those of abemaciclib. In subcutaneous and orthotopic GBM mouse models, AU3–14 demonstrated substantial anti-tumor efficacy and safety. Further toxicokinetic studies in rats and cynomolgus monkeys following 28-day repeated doses demonstrated that AU3–14 is well-tolerated, with a low risk of hematological toxicities, such as neutropenia, which are commonly associated with other CDK4/6 inhibitors. Moreover, AU3–14 enhances TMZ’s anti-tumor efficacy and delays the onset of TMZ resistance. These findings support the clinical phase I/IIa investigation of AU3–14 for the treatment of GBM (ACTRN12621000479808).</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"189 ","pages":"Article 118340"},"PeriodicalIF":6.9,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144597560","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}