bims-supasi 2025-03-30 papers

bims-supasi

Biomed News

on Sulfation pathways and signalling

Issue of 2025–03–30
fourteen papers selected by
Jonathan Wolf Mueller, University of Birmingham

CANT1 Is Involved in Collagen Fibrogenesis in Tendons by Regulating the Synthesis of Dermatan/Chondroitin Sulfate Attached to the Decorin Core Protein.
Functional Testing and Localization of Tyrosine Sulfation in a Trispecific Antibody.
Sulfatase 2 inhibition sensitizes triple-negative breast cancer cells to paclitaxel through augmentation of extracellular ATP.
Cellular SLC35B4 promotes internalization during influenza A virus entry.
3D-Printed Biomimetic Vascular Scaffold Crosslinked with Heparan Sulfate for Sustained Release of PDGFB-LG4 Fusion Protein Promotes Bone Regeneration.
Polymerization of Poly(3,4-ethylenedioxythiophene) on Sulfated Cellulose Nanofiber and Its Conducting Property.
Targets and Potential Mechanism of Chondroitin Sulfate A-selenium Nanoparticle on Kashin-Beck Disease Chondrocytes.
Deconjugation of Polychlorinated Biphenyl Sulfates to Hydroxylated PCBs by Anaerobically Cultured Mouse and Human Gut Microbiota.
Chondroitin sulfate nanoparticles based on co-delivery dual drug induced ferroptosis in lung cancer cells by disrupting mitochondrial oxidative homeostasis.
Structural basis for cholesterol sensing of LYCHOS and its interaction with indoxyl sulfate.
Estimation of Proximal Tubular Function by Stimulation of Organic Anion and Cation Transporters.
A Cost-Effective and Easy to Assemble 3D Human Microchannel Blood-Brain Barrier Model and Its Application in Tumor Cell Adhesion Under Flow.
Chondroitin Sulfate-Based Imatinib Nanoparticles Targeting Activated Hepatic Stellate Cells Against Hepatic Fibrosis.
Adrenal cortex senescence: an ageing-related pathology?

Int J Mol Sci. 2025 Mar 10. pii: 2463. [Epub ahead of print]26(6):

CANT1 Is Involved in Collagen Fibrogenesis in Tendons by Regulating the Synthesis of Dermatan/Chondroitin Sulfate Attached to the Decorin Core Protein.

Rina Yamashita, Saki Tsutsui, Shuji Mizumoto, Takafumi Watanabe, Noritaka Yamamoto, Kenta Nakano, Shuhei Yamada, Tadashi Okamura, Tatsuya Furuichi.

  Tendons are connective tissues that join muscles and bones and are rich in glycosaminoglycans (GAGs). Decorin is a proteoglycan with one dermatan sulfate (DS) or chondroitin sulfate (CS) chain (a type of GAG) attached to its core protein and is involved in regulating the assembly of collagen fibrils in the tendon extracellular matrix (ECM). Calcium-activated nucleotidase 1 (CANT1), a nucleotidase that hydrolyzes uridine diphosphate into uridine monophosphate and phosphate, plays an important role in GAG synthesis in cartilage. In the present study, we performed detailed histological and biochemical analyses of the tendons from Cant1 knockout (Cant1-/-) mice. No abnormalities were observed in the tendons on postnatal day 1 (P1); however, remarkable hypoplasia was observed on P30 and P180. The collagen fibrils were more angular and larger in the Cant1-/- tendons than in the control (Ctrl) tendons. In the Cant1-/- tendons, the DS/CS content was significantly reduced, and the DC/CS chains attached to the decorin core protein became shorter than those in the Ctrl tendons. No abnormalities were observed in the proliferation and differentiation of tendon fibroblasts (tenocytes) in the Cant1-/- mice. These results strongly suggest that CANT1 dysfunction causes defective DS/CS synthesis, followed by impairment of decorin function, which regulates collagen fibrogenesis in the tendon ECM. Multiple joint dislocations are a clinical feature of Desbuquois dysplasia type 1 caused by human CANT1 mutations. The multiple joint dislocations associated with this genetic disorder may be attributed to tendon fragility resulting from CANT1 dysfunction.

Keywords:  CANT1; Desbuquois dysplasia; chondroitin sulfate; collagen fibril; decorin; dermatan sulfate; glycosaminoglycan; proteoglycan; tendon

DOI:  https://doi.org/10.3390/ijms26062463
J Am Soc Mass Spectrom. 2025 Mar 25.

Functional Testing and Localization of Tyrosine Sulfation in a Trispecific Antibody.

Armelle Martelet, Valerie Garrigue, Hélène Le Borgne, Claire Borel, Sylvie Alexandre, Ronan Crépin, Bruno Genet, Haichuan Liu, Yuzhuo Zhang, Séverine Clavier.

  Mass spectrometry (MS) is a tool of choice for the in-depth characterization of new biotherapeutic molecules such as a complex naturally derived trispecific antibody (tsAb) that presents a tyrosine sulfation within the variable domain. Although tyrosine sulfation is an important post-translational modification responsible for strengthening protein-protein interactions, its localization is challenging, as the sulfate group is very labile using conventional positive ion mode fragmentation techniques. In this work, we describe the combination of functional testing and MS-based methods to study the impact of tyrosine sulfation in the tsAb. The presence of sulfation was confirmed by intact mass and peptide mapping analyses. For unambiguous localization of the sulfate group, electron activated dissociation (EAD) MS/MS experiments were employed to generate diagnostic fragments carrying an intact sulfate group. We also demonstrated that a significant decrease in binding of the tsAb to the target antigen was observed following the sulfatase treatment. Taken together, the results from this study support the notion that tyrosine sulfation plays an important role in protein-protein interactions.

Keywords:  EAD; HIV; biotherapeutics; mass spectrometry; post-translational modification; sulfotyrosine

DOI:  https://doi.org/10.1021/jasms.4c00432
Cancer Biol Ther. 2025 Dec;26(1): 2483989

Sulfatase 2 inhibition sensitizes triple-negative breast cancer cells to paclitaxel through augmentation of extracellular ATP.

Jasmine M Manouchehri, Jharna Datta, Lynn M Marcho, Daniel Stover, Ramesh K Ganju, Bhuvaneswari Ramaswamy, William E Carson, Arjun Mittra, Xiaoli Zhang, Patrick M Schnell, Yu Yue, Mark P Rubinstein, Mathew A Cherian.

  The highest incidence and cancer-related mortality rate among women worldwide is due to breast cancer. Triple-negative breast cancers (TNBC) are associated with more inferior outcomes than other breast cancers because of their progressive nature and the deficit in available therapies. Therefore, there is a need for new therapeutic approaches. Our lab determined that chemotherapy induces the release of extracellular adenosine triphosphate (eATP), and, hence, augments TNBC cells' response to chemotherapy. Despite this, eATP concentrations are restricted by a variety of extracellular ATPases. We propose that, as an ATPase inhibitor, heparan sulfate (HS) would augment eATP concentrations and TNBC vulnerability induced by chemotherapy. Sulfatase 2 (SULF2) removes sulfate from HS, the functional group essential for ATPase inhibition. Consequently, we propose that TNBC cell death and eATP release induced by chemotherapy would be intensified by SULF2 inhibitors. We examined eATP and cell viability in paclitaxel-treated TNBC and nontumorigenic immortal mammary epithelial MCF-10A cells in the presence of OKN-007, a selective SULF2 inhibitor, and/or heparan sodium sulfate. Furthermore, sulfatase 1 (SULF1) and SULF2 protein expressions were ascertained. We found that the expression of SULF2 was greater in TNBC cell lines when compared to MCF-10A cells. The release of eATP and loss of TNBC cell viability induced by chemotherapy was enhanced by OKN-007. The co-treatment of chemotherapy and OKN-007 also attenuated cancer-initiating cells. This data implies that the combination of SULF2 inhibitors with chemotherapy augments eATP and decreases cell viability of TNBC greater than chemotherapy alone.

Keywords:  ATP; Chemotherapy; breast cancer; heparan sodium sulfate; purinergic signaling; sulfatases

DOI:  https://doi.org/10.1080/15384047.2025.2483989
mBio. 2025 Mar 25. e0019425

Cellular SLC35B4 promotes internalization during influenza A virus entry.

Guangwen Wang, Li Jiang, Ya Yan, Fandi Kong, Qibing Li, Jie Zhang, Shuangshuang Hou, Bo Wang, Xiurong Wang, Huihui Kong, Guohua Deng, Jianzhong Shi, Guobin Tian, Xianying Zeng, Hualan Chen, Chengjun Li.

  SLC35B4, a nucleotide sugar transporter that mediates the transport of UDP-GlcNAc and UDP-xylose, was found to be required for the replication of influenza A virus (IAV) of the H5N1 subtype in our genome-wide siRNA library screen. We found that defective IAV replication in SLC35B4-deficient A549 cells was independent of virus strain specificity, and the virulence of IAV in Slc35b4 knockdown mice was also decreased. By examining the individual stages of the IAV replication cycle, we discovered that the amount of internalized IAV was significantly reduced in SLC35B4-knockout A549 cells. Mechanistically, SLC35B4 facilitated IAV replication by transporting UDP-xylose, which attaches to the serine residue of heparan sulfate proteoglycans (HSPGs) in the heparan sulfate (HS) biosynthesis pathway. Knockdown of associated host factors (i.e., XYLT2, B4GALT7, EXT1, and EXT2) in the HS biosynthesis pathway also impaired IAV replication. Furthermore, we revealed that AGRN, a unique HSPG family member, was important for the endocytosis of IAV in A549 cells. Moreover, we found that the homeostasis of the AGRN protein was regulated by HS modification mediated by the initial UDP-xylose transporter SLC35B4, thereby affecting the expression level of endocytic adapter AP2B1 to influence IAV internalization. Collectively, these findings establish that SLC35B4 is an important regulator of IAV replication and uncover the underlying mechanisms by which SLC35B4 employs UDP-xylose transport activity to promote IAV internalization.IMPORTANCEThe entry process of IAV represents a favorable target for drug development. In this study, we identified SLC35B4 as an important host factor for the efficient replication of different subtypes of IAV in vitro and for the virulence of IAV in mice. We revealed that SLC35B4 employed its UDP-xylose transport activity to promote the HS biosynthesis pathway, thereby assisting IAV internalization into target cells in the early stage of viral infection. Consistently, several downstream factors in the HS biosynthesis pathway, i.e., XYLT2, B4GALT7, EXT1, and EXT2, as well as a specific HSPG member AGRN were also important for the replication of IAV. Furthermore, the UDP-xylose-transporting activity of SLC35B4 was involved in the regulation of the homeostasis of the AGRN protein by HS modification, which influenced virus internalization by affecting the expression levels of AP2B1. Together, the identification of the SLC35B4-XYLT2-B4GALT7-EXT1-EXT2-AGRN-AP2B1 axis may shed light on the development of potential anti-IAV therapeutics.

Keywords:  AGRN; AP2B1; SLC35B4; heparan sulfate modification; influenza A virus; internalization

DOI:  https://doi.org/10.1128/mbio.00194-25
Adv Sci (Weinh). 2025 Mar 27. e2414362

3D-Printed Biomimetic Vascular Scaffold Crosslinked with Heparan Sulfate for Sustained Release of PDGFB-LG4 Fusion Protein Promotes Bone Regeneration.

Jiahua Duan, Gaofei Qian, Huikang Zhang, Feifan Wang, Qiang Tian, Dong Lei, Jianning Zhao.

  A central focus of bone tissue engineering is the construction of vascular systems, which provide nutrients for cell survival, remove metabolic waste, and accelerate tissue regeneration. Platelet-derived growth factor-BB (PDGFB) has the ability to stimulate both vascularization and bone regeneration; however, its clinical application has been hindered by side effects and low efficacy due to suboptimal delivery systems. In this study, a biomimetic vascular scaffold crosslinked with heparan sulfate (HS) is developed to enable sustained delivery of the PDGFB-LG4 fusion protein, targeting the regeneration of critically sized bone defects. The scaffold is designed with a vascular-like hierarchical structure, incorporating a customized 3D framework, multibranched microchannels, and permeable porous walls, which facilitates mass exchange and cell infiltration. PDGFB-LG4 exhibits superior osteoinductive and angiogenic activity compared to PDGFB. In a calvarial defect model, the composite scaffold (PCLHS-PDGFB-LG4) significantly enhances both vascularization and bone regeneration, demonstrating improved efficacy at lower doses compared to PDGFB. This approach may be applicable to other growth factors and gelatin-based materials, offering the potential for a wide range of applications in regenerative medicine.

Keywords:  biomimetic vascular scaffold; bone regeneration; fusion protein; heparan sulfate; vascularization

DOI:  https://doi.org/10.1002/advs.202414362
Materials (Basel). 2025 Mar 13. pii: 1273. [Epub ahead of print]18(6):

Polymerization of Poly(3,4-ethylenedioxythiophene) on Sulfated Cellulose Nanofiber and Its Conducting Property.

Naofumi Takahashi, Atsuya Ogo, Takeshi Shimomura.

  Recent research on incorporating biomass resources into functional polymers has garnered significant attention. Poly(3,4-ethylenedioxythiophene)/poly(styrene sulfonate) (PEDOT:PSS) is the most commercially successful conducting polymer composed of over 70 wt% petroleum-derived PSS, which presents an opportunity for partial replacement with biomass-based resources. In this study, a complex of PEDOT and sulfated cellulose nanofiber (PEDOT:s-CNF) was synthesized, and the relationship between its conductivity and doping conditions was investigated. PEDOT was synthesized on s-CNF, which was used in place of PSS, and the results indicate that conductivity increases as PEDOT polymerization progresses; however, excessive polymerization reduces electrical conductivity. Based on X-ray photoelectron spectroscopy and zeta potential measurements, the doping concentration decreases as PEDOT polymerization progresses to an excess state. This decrease is attributed to the depletion of sulfate groups, which act as dopants on s-CNFs, occurring as a consequence of the addition of PEDOT monomers. Enhancing the degree of sulfate group substitution on s-CNFs and incorporating additional dopants containing sulfonic groups improved conductivity. Specifically, adding p-toluenesulfonic acid (PTSA) as a dopant increased conductivity, reaching approximately 10 mS cm-1. However, at higher PTSA concentrations, the strong acidity of sulfonic groups reduced the degree of sulfate group dissociation, leading to a decline in doping efficiency.

Keywords:  PEDOT; bio-based polymer; cellulose nanofiber; conducting polymer; sulfated cellulose

DOI:  https://doi.org/10.3390/ma18061273
Biol Trace Elem Res. 2025 Mar 26.

Targets and Potential Mechanism of Chondroitin Sulfate A-selenium Nanoparticle on Kashin-Beck Disease Chondrocytes.

Huan Deng, Feidan Deng, Xinyue Wen, Yude Jiang, Abebe Feyissa Amhare, Lichun Qiao, Miaoqian Li, Ping Wan, Jun Wang, Jing Han.

  Kashin-Beck disease (KBD) is a chronic and deformable osteoarthropathy linked to low selenium. Limited cartilage regeneration poses challenges for its treatment. Previous studies have found that chondroitin sulfate A-selenium nanoparticle (CSA-SeNP) protects chondrocytes. This study used label-free LC-MS/MS quantitative proteomics to identify differentially expressed proteins and pathways in KBD chondrocytes post-CSA-SeNP treatment. Western blot (WB) was used to verify the key differential proteins, and transmission electron microscopy (TEM) was used to observe the ultrastructure of chondrocytes. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis revealed proteins mainly involved in RNA processing, translation, peptide biosynthesis, gene expression, rRNA metabolism, and ribonucleoprotein complex biogenesis. Notably, 121 proteins were up-regulated, 27 down-regulated, and 117 specifically expressed in the CSA-SeNP group. Enriched KEGG pathways included ribosome biogenesis, mRNA surveillance, endoplasmic reticulum protein processing, and endocytosis. Proteins related to autophagy, ER stress, cell homeostasis, protein processing and transport, including PELO, WES1, PLAA, RRBP1, ARC1B, ARFGAP2, and SH3KBP1, were significantly up-regulated in the CSA-SeNP group. In conclusion, our results demonstrated that CSA-SeNP may exert protective effects on chondrocytes in adult patients with KBD mainly through the regulation of target proteins and pathways related to ribosome biogenesis, mRNA surveillance, endoplasmic reticulum protein processing, endocytosis, autophagy, ER stress, and cell homeostasis. Further studies with larger sample size and in vivo to identify, screen and verify the regulatory effects of target proteins and pathways may provide more information for elucidating the mechanism of CSA-SeNP in the treatment of KBD.

Keywords:  Chondrocyte; Chondroitin sulfate A-selenium nanoparticle; Homeostasis; Kashin-Beck disease; Proteomics

DOI:  https://doi.org/10.1007/s12011-025-04584-3
Chem Res Toxicol. 2025 Mar 25.

Deconjugation of Polychlorinated Biphenyl Sulfates to Hydroxylated PCBs by Anaerobically Cultured Mouse and Human Gut Microbiota.

Xueshu Li, Joe J Lim, Cayen Rong, Hans-Joachim Lehmler, Julia Yue Cui.

The role of the gut microbiome in metabolizing polychlorinated biphenyls (PCBs), toxic environmental contaminants, and their metabolites remains unclear. This study used mouse and human microbiomes in anaerobic cultures to investigate the metabolism of PCB sulfate to hydroxylated PCBs (OH-PCBs). All microbiomes enzymatically hydrolyzed PCB sulfates. Higher chlorinated PCB sulfates were metabolized more readily. Male mouse microbiomes exhibited more PCB sulfate hydrolysis to OH-PCBs than female mouse microbiomes. Human microbiomes metabolized PCB sulfates to a more considerable extent than mouse microbiomes. They also showed variability in PCB sulfate metabolism, depending on the microbial communities. These findings suggest that the microbiome contributes to PCB metabolism.

DOI: https://doi.org/10.1021/acs.chemrestox.5c00016
Mater Today Bio. 2025 Apr;31 101632

Chondroitin sulfate nanoparticles based on co-delivery dual drug induced ferroptosis in lung cancer cells by disrupting mitochondrial oxidative homeostasis.

He Wang, Shuimu Lin, Jiacui Xie, Xuming Chen, Yating Deng, Pei Huang, Kanglong Peng, Wenhui Gao, Guodong Ye, Guihua Wang, Xiyong Yu, Huaying Wen, Linghao Qin, Yi Zhou.

  Mitochondrial REDOX homeostasis is unbalanced by large amounts of reactive oxygen species production and reduced glutathione, leading to lipid oxidation-induced ferroptosis, which enhanced cancer immunotherapy. Thus, disrupting mitochondrial redox homeostasis represents a promising strategy for the treatment of lung cancer. In this study, a co-delivery system of based on chondroitin sulfate (CS) (CS-CA-CUR-TPP, CCCT) for natural medicines (Curcumin, CUR; and Cinnamaldehyde CA) was successfully constructed, which resulted in elevated ROS levels in cancer cells. Under the action of CS specifically targeting tumor cells, CCCT NPs is enriched and taken up by lung cancer cells. Acid responsiveness causes the CCCT NPs to break and escape from the lysosome, and CUR targets and destroys mitochondria under the action of mitochondrial target head triphenylphosphine (TPP). CA collaborates with CUR to produce large amounts of ROS and reduce GSH in a time-dependent manner in mitochondria for disruption of REDOX homeostasis, and triggers ferroptosis by reducing the expression of GXP4 and xCT proteins. The immunogenic cell death (ICD) after ferroptosis promotes interferon γ (IFN-γ), TNF-a, and IL-6 secretion. Our results desmontrat CCCT can promote inhibition of tumor growth by enhancing tumor immunogenicity. This study may provide a potential avenue for the advancement of self-delivery nanoparticles to overcome resistance to apoptosis in tumor therapy.

Keywords:  Chondroitin sulfate; Cinnamaldehyde; Curcumin; Ferroptosis; Mitochondrial REDOX homeostasis

DOI:  https://doi.org/10.1016/j.mtbio.2025.101632
Nat Commun. 2025 Mar 21. 16(1): 2815

Structural basis for cholesterol sensing of LYCHOS and its interaction with indoxyl sulfate.

Zhenhua Wang, Jingjing He, Yufan Yang, Yonglin He, Hongwu Qian.

The lysosome serves as an essential nutrient-sensing hub within the cell, where the mechanistic target of rapamycin complex 1 (mTORC1) is activated. Lysosomal cholesterol signaling (LYCHOS), a lysosome membrane protein, has been identified as a cholesterol sensor that couples cholesterol concentration to mTORC1 activation. However, the molecular basis is unknown. Here, we determine the cryo-electron microscopy (cryo-EM) structure of human LYCHOS at a resolution of 3.1 Å, revealing a cholesterol-like density at the interface between the permease and G-protein coupled receptor (GPCR) domains. Advanced 3D classification reveals two distinct states of LYCHOS. Comparative structural analysis between these two states demonstrated a cholesterol-related movement of GPCR domain relative to permease domain, providing structural insights into how LYCHOS senses lysosomal cholesterol levels. Additionally, we identify indoxyl sulfate (IS) as a binding ligand to the permease domain, confirmed by the LYCHOS-IS complex structure. Overall, our study provides a foundation and indicates additional directions for further investigation of the essential role of LYCHOS in the mTORC1 signaling pathway.

DOI: https://doi.org/10.1038/s41467-025-58087-9
J Am Soc Nephrol. 2025 Mar 24.

Estimation of Proximal Tubular Function by Stimulation of Organic Anion and Cation Transporters.

Magdalena Madero, Ana Karen Fernández-Yepez, Aldo Arturo Reséndiz-Albor, José Alberto Rivera Chávez, Jesse C Seegmiller, Bernardo Rodriguez-Iturbe.

BACKGROUND: Tubular pathophysiology plays a critical role in the progression of chronic kidney disease (CKD). Exogenous stimulation of proximal tubule organic anion (OAT) and cation (OCT) transporters may be used to evaluate their responses independently of glomerular filtration rate (GFR) and their relation with clearance of protein-bound solutes and other biomarkers of tubular function.
METHODS: A proof of principle study was conducted in nine healthy volunteers and 22 patients with CKD classified by their GFR in KDIGO stages. They were studied hourly during 4 hours with water-induced diuresis, after the ingestion of 5g of creatinine and intravenous injection of 1-1.5mg/kg of furosemide, as means to stimulate OCTs and OATs, respectively. GFR determination (iohexol urinary clearance) was done in hours 2 to 3 and 3 to 4 of the study. Indoxyl sulfate, pCresol sulfate and urinary biomarkers of tubular function were studied in the first hour.
RESULTS: GFR was stable during the study. Maximal values of tubular secretion of creatinine (TScr) and furosemide (TSfuro) were obtained in the first hour. The KDIGO categories of GFR were widely distributed throughout the range of tubular secretory responses. One-hour stimulated response of organic anion transporters was negatively correlated with serum levels of Indoxyl sulfate (r=-0.59, p=0.005) and pCresol sulfate (r=-0.59, p=0.004). Urinary epidermal growth factor, ammonium, alpha 1 microglobulin, and uromodulin correlated with the increment of TScr and TSfuro. The urinary excretion rate of creatinine in the first hour after the ingestion of 5g of creatinine was strongly correlated with the TScr (r=0.836, p<0.001).
CONCLUSIONS: The functions of OATs and OCTs of the proximal tubule varied considerably between patients with similar GFRs and their impaired response was associated with retention of protein-bound uremic solutes and urine biomarkers of tubular dysfunction. The response of OCTs may be estimated by the urinary excretion of creatinine 1-hour after the ingestion of 5g of creatinine.

DOI: https://doi.org/10.1681/ASN.0000000686
Cells. 2025 Mar 19. pii: 456. [Epub ahead of print]14(6):

A Cost-Effective and Easy to Assemble 3D Human Microchannel Blood-Brain Barrier Model and Its Application in Tumor Cell Adhesion Under Flow.

Yunfei Li, Bingmei M Fu.

  By utilizing polydimethylsiloxane (PDMS), collagen hydrogel, and a cell line for human cerebral microvascular endothelial cells, we produced a 3D microchannel blood-brain barrier (BBB) model under physiological flow. This 3D BBB has a circular-shaped cross-section and a diameter of ~100 μm, which can properly mimic the cerebral microvessel responsible for material exchange between the circulating blood and brain tissue. The permeability of the 3D microchannel BBB to a small molecule (sodium fluorescein with a molecular weight of 376) and that to a large molecule (Dex-70k) are the same as those of rat cerebral microvessels. This 3D BBB model can replicate the effects of a plasma protein, orosomucoid, a cytokine, vascular endothelial growth factor (VEGF), and an enzyme, heparinase III, on either rat cerebral or mesenteric microvessesels in terms of permeability and the modulation of glycocalyx (heparan sulfate). It can also replicate the adhesion of a breast cancer cell, MDA-MB-231, in rat mesenteric microvessels under no treatment or treatments with VEGF, orosomucoid, and heparinase III. Because of difficulties in accessing human cerebral microvessels, this inexpensive and easy to assemble 3D human BBB model can be applied to investigate BBB-modulating mechanisms in health and in disease and to develop therapeutic interventions targeting tumor metastasis to the brain.

Keywords:  MDA-MB-231; dextran-70k; engineered microvessel; glycocalyx; heparan sulfate; microfluidic device; sodium fluorescein; solute permeability; tumor cell adhesion

DOI:  https://doi.org/10.3390/cells14060456
Pharmaceutics. 2025 Mar 09. pii: 351. [Epub ahead of print]17(3):

Chondroitin Sulfate-Based Imatinib Nanoparticles Targeting Activated Hepatic Stellate Cells Against Hepatic Fibrosis.

Xunzhi Liu, Changlong Fang, Hongling Yu, Lu Huang, Jiaxing Feng, Shiqin Luo, Li Song, Mengying Wu, Yulu Tan, Jianxia Dong, Tao Gong, Peihong Xiao.

  Background: Activated hepatic stellate cells (aHSCs) play a significant role during the onset of hepatic fibrosis, ultimately leading to excessive deposition of extracellular matrix (ECM) and other typical pathological features, and thus have become a popular target for the treatment of hepatic fibrosis. However, current aHSC-centric therapy strategies achieve unsatisfactory results, mainly due to the lack of approved anti-fibrosis drugs and sufficiently efficient aHSC-targeted delivery systems. In this study, our aim was to develop an Imatinib-loaded nanoparticle delivery system based on a chondroitin sulfate derivative to enhance aHSC targeting efficiency, improve the therapeutic effect for hepatic fibrosis, and investigate the underlying mechanism. Methods: The carboxyl group of chondroitin sulfate and the amino group of 1-hexadecylamine were linked by an amide bond in this study to produce the amphiphilic carrier CS-HDA. Then, the Imatinib-loaded nanoparticles (IM-CS NPs) were designed to efficiently target aHSCs through CD44-mediated endocytosis and effectively inhibit HSC overactivation via PDGF and TGF-β signaling pathways. Results: Both in vitro cellular uptake experiments and in vivo distribution experiments demonstrated that CS-HDA-modified nanoparticles (IM-CS NPs) exhibited a better targeting ability for aHSCs, which were subsequently utilized to treat carbon tetrachloride-induced hepatic fibrosis mouse models. Finally, significant fibrosis resolution was observed in the carbon tetrachloride-induced hepatic fibrosis mouse models after tail vein injection of the IM-CS NPs, along with their outstanding biocompatibility and biological safety. Conclusions: IM-loaded NPs based on an amphiphilic CS derivative have remarkable antifibrotic effects, providing a promising avenue for the clinical treatment of advanced hepatic fibrosis.

Keywords:  1-hexadecamine modified chondroitin sulfate; CD44 receptors; activated hepatic stellate cells; imatinib; liver fibrosis

DOI:  https://doi.org/10.3390/pharmaceutics17030351
J Endocrinol Invest. 2025 Mar 25.

Adrenal cortex senescence: an ageing-related pathology?

Emma Short, Ramzi Ajjan, Thomas M Barber, Ian Benson, Victoria Higginbotham, Robert Huckstepp, Venkateswarlu Kanamarlapudi, Natasha Mumwiro, Stuart R G Calimport, Barry Bentley.

  The adrenal glands are a pair of endocrine organs that produce and secrete mineralocorticoids, glucocorticoids, sex hormones, adrenaline, and noradrenaline. They have a vital role in a range of physiological processes including regulating electrolyte balance, blood pressure and metabolism, immunomodulation, sexual development and the stress response. Adrenal cortex senescence describes the ageing-related decline in the normal functioning of the adrenal cortex, characterised by an alteration in the output of adrenal cortical hormones, in particular reduced secretion of dehydroepiandrosterone (DHEA) and sulfated dehydroepiandrosterone (DHEAS). Such endocrine aberrations may be implicated in adverse clinical outcomes including mood disturbances, impairment in cognitive functioning, metabolic dysfunction and osteopenia. This paper shall address whether adrenal cortex senescence should be recognised as an ageing-related pathology, which has recently been defined as one that develops and/or progresses with increasing chronological age, that is associated with, or contributes to, functional decline, and is evidenced by studies in humans.

Keywords:  Adrenal cortex ageing; Adrenal cortex senescence; Healthy longevity; Senescence

DOI:  https://doi.org/10.1007/s40618-025-02566-9