bims-supasi 2024-08-04 papers

bims-supasi

Biomed News

on Sulfation pathways and signalling

Issue of 2024–08–04
fiveteen papers selected by
Jonathan Wolf Mueller, University of Birmingham

Anti-inflammatory potential of low-molecular-weight and high-sulfation-degree sulfated polysaccharides extracted from Antrodia cinnamomea.
Chondroitin sulfate-tocopherol succinate modified exosomes for targeted drug delivery to CD44-positive cancer cells.
Sulfated Alginate for Biomedical Applications.
In vitro assessment of protamine toxicity with neural cells, its therapeutic potential to counter chondroitin sulfate mediated neuron inhibition, and its effects on reactive astrocytes.
Association between polymorphisms of DNA repair genes and intracranial aneurysms: A systematic review and meta‑analysis.
[The value of dehydroepiandrosterone sulfate in the differential diagnosis of primary bilateral adrenal macronodular hyperplasia].
Two Preparation Methods for Peptide Thioester Containing Tyr(SO3H) Residue(s) without the Use of Protecting Group for Sulfate Moiety.
Diverse and multifunctional roles for perlecan (HSPG2) in repair of the intervertebral disc.
Pre-analytical stability and physiological fluctuations affect plasma steroid hormone outcomes: a real-world study.
Gut microbiota metabolite indole-3-acetic acid maintains intestinal epithelial homeostasis through mucin sulfation.
Circulating glycocalyx shedding products as biomarkers for evaluating prognosis of patients with out-of-hospital cardiac arrest after return of spontaneous circulation.
Extracellular Matrix Sulfation in the Tumor Microenvironment Stimulates Cancer Stemness and Invasiveness.
Galectin-3 contributes to pathogenesis of IgA nephropathy.
Hepatocyte growth factor delivery to injured cervical spinal cord using an engineered biomaterial protects respiratory neural circuitry and preserves functional diaphragm innervation.
Revisiting X-linked congenital ichthyosis.

Int J Biol Macromol. 2024 Jul 31. pii: S0141-8130(24)05165-1. [Epub ahead of print] 134360

Anti-inflammatory potential of low-molecular-weight and high-sulfation-degree sulfated polysaccharides extracted from Antrodia cinnamomea.

Wei-Lun Qiu, Chi-Hsein Chao, Yu-Chi Hsu, Mei-Kuang Lu.

  Two novel sulfated polysaccharides (SPs), N10 and K5 were isolated from ammonium sulfate or potassium sulfate at concentrations of 10 mM and 5 mM in liquid cultures of Antrodia cinnamomea, respectively. N10 and K5 were galactoglucans with a galactose:glucose molar ratio of approximately 1:3. In lipopolysaccharide (LPS)-stimulated RAW264.7 cells, N10 and K5 exhibited strong anti-inflammatory potential, of 56 % and 23 % maximal inhibition of IL-6 and TNF-α production, respectively. Mechanical analysis revealed differences between N10 and K5, with N10 inhibiting the LPS-stimulated phosphorylation of ERK and p38 in RAW264.7 cells. K5 inhibited the LPS-stimulated phosphorylation of AKT and TGFβR-II. N10 and K5 were fragmented into F1, F2, and F3, the molecular weights of which were 455, 24, 0.9, and 327, 36, 1.9 kDa, respectively. K5 F2 and K5 F3 exhibited high degrees of sulfation of 1:3 and 1:8, resulting in strong anti-inflammation, of 83 % and 37 % highest inhibition of IL-6 and TNF-α production, respectively. Therefore, low-molecular-weight and high-sulfation-degree SPs exhibited strong anti-inflammatory activity. Specifically, K5 F2 inhibited the phosphorylation of p38, and K5 F3 suppressed the signaling pathway of p38/JNK. Overall, the sulfation degree of SPs is concluded to affect the anti-inflammatory responses.

Keywords:  Anti-inflammation; Antrodia cinnamomea; Sulfated polysaccharide

DOI:  https://doi.org/10.1016/j.ijbiomac.2024.134360
Int J Biol Macromol. 2024 Jul 05. pii: S0141-8130(24)04430-1. [Epub ahead of print] 133625

Chondroitin sulfate-tocopherol succinate modified exosomes for targeted drug delivery to CD44-positive cancer cells.

Amir Hossein Mohammadi, Fatemeh Bagheri, Kaveh Baghaei.

  Exosomes (Exos), natural nanovesicles released by various cell types, show potential as an effective drug delivery platform due to their intrinsic role as transporters of biomolecules between different cells. However, Exos functionalization with targeting ligands is a critical step to enhance their targeting capability, which could be challenging. In this study, Exos were modified to specifically bind to CD44-positive cells by anchoring chondroitin sulfate (CS) to their surface. Exo modification was facilitated with CS conjugation with alpha-tocopherol succinate (TOS) as an anchorage. The modified Exos were utilized for delivering curcumin (Cur) to pancreatic cancer (PC) cells. In vitro Cur release studies revealed that Exos play a crucial role in maintaining Cur within themselves, demonstrating their potential as effective carriers for drug delivery to targeted locations. Notably, Cur loaded into the modified Exos exhibited enhanced cytotoxicity compared to unmodified Exo-Cur. Meanwhile, Exo-Cur-TOS-CS induced apoptosis more effectively in AsPC-1 cells than unmodified Exos (70.2 % versus 56.9 %). It is worth mentioning that with CD44-mediated cancer-specific targeting, Exo-CS enabled increased intracellular accumulation in AsPC-1 cells, showing promise as a targeted platform for cancer therapy. These results confirm that Exo modification has a positive impact on enhancing the therapeutic efficacy and cytotoxicity of drugs.

Keywords:  Chondroitin sulfate; Exosome; Targeted drug delivery

DOI:  https://doi.org/10.1016/j.ijbiomac.2024.133625
Macromol Biosci. 2024 Jul 30. e2400237

Sulfated Alginate for Biomedical Applications.

Alexandra L Mutch, Jiankun Yang, Vito Ferro, Anitha A, Lisbeth Grøndahl.

  Alginate (Alg) polymers have received much attention due to the mild conditions required for gel formation and their good bio-acceptability. However, due to limited interactions with cells, many drugs, and biomolecules, chemically modified alginates are of great interest. Sulfated alginate (S-Alg) is a promising heparin-mimetic that continues to be investigated both as a drug molecule and as a component of biomaterials. Herein, the S-Alg literature of the past five years (2017-2023) is reviewed. Several methods used to synthesize S-Alg are described, with a focus on new advances in characterization and stereoselectivity. Material fabrication is another focus and spans bulk materials, particles, scaffolds, coatings, and part of multicomponent biomaterials. The new application of S-Alg as an antitumor agent is highlighted together with studies evaluating safety and biodistribution. The high binding affinity of S-Alg for various drugs and heparin-binding proteins is exploited extensively in biomaterial design to tune the encapsulation and release of these agents and this aspect is covered in detail. Recommondations include publishing key material properties to allow reproducibility, careful selection of appropriate sulfation strategies, the use of cross-linking strategies other than ionic cross-linking for material fabrication, and more detailed toxicity and biodistribution studies to inform future work.

Keywords:  alginate sulfate; biomaterials; heparin‐binding proteins; propylene glycol alginate sodium sulfate (PSS); therapeutic delivery

DOI:  https://doi.org/10.1002/mabi.202400237
Adv Ther (Weinh). 2024 Feb;pii: 2300242. [Epub ahead of print]7(2):

In vitro assessment of protamine toxicity with neural cells, its therapeutic potential to counter chondroitin sulfate mediated neuron inhibition, and its effects on reactive astrocytes.

Derek W Nelson, Jessica L Funnell, Conrad H Cheung, Geraldine B Quinones, Christina S Mendoza, Marvin Bentley, Ryan J Gilbert.

  Multiple therapies have been studied to ameliorate the neuroinhibitory cues present after traumatic injury to the central nervous system. Two previous in vitro studies have demonstrated the efficacy of the FDA-approved cardiovascular therapeutic, protamine (PRM), to overcome neuroinhibitory cues presented by chondroitin sulfates; however, the effect of a wide range of PRM concentrations on neuronal and glial cells has not been evaluated. In this study, we investigate the therapeutic efficacy of PRM with primary cortical neurons, hippocampal neurons, mixed glial cultures, and astrocyte cultures. We show the threshold for PRM toxicity to be at or above 10 μg/ml depending on the cell population, that 10 μg/ml PRM enables neurons to overcome the inhibitory cues presented by chondroitin sulfate type A, and that soluble PRM allows neurons to more effectively overcome inhibition compared to a PRM coating. We also assessed changes in gene expression of reactive astrocytes with soluble PRM and determined that PRM does not increase their neurotoxic phenotype and that PRM may reduce brevican production and serpin transcription in cortical and spinal cord astrocytes. This is the first study to thoroughly assess the toxicity threshold of PRM with neural cells and study astrocyte response after acute exposure to PRM in vitro.

Keywords:  astrocyte reactivity; drug toxicity; neurotherapy; protamine sulfate salt; traumatic CNS injury

DOI:  https://doi.org/10.1002/adtp.202300242
Med Int (Lond). 2024 Nov-Dec;4(6):4(6): 59

Association between polymorphisms of DNA repair genes and intracranial aneurysms: A systematic review and meta‑analysis.

Mohamed M Montasr, George Fotakopoulos, Vasiliki Epameinondas Georgakopoulou, Ourania Fotakopoulou, Nikolaos Trakas, Pagona Sklapani, Kostas N Fountas.

  Intracranial aneurysms (IAs) are present in ~2% of the general population, and genetic factors cannot be excluded for the risk of their development. The gene factors that result in the changes in the vascular extracellular matrix (ECM) may also be a key reason for IAs being hereditary. The VCAN gene [also known as chondroitin sulfate proteoglycan 2 (CSPG2)] plays various roles in maintaining ECM functions. The present systematic review and meta-analysis aimed to investigate all eligible articles involving IAs on the association with germ line SNPs of DNA repair genes (up to January, 2024). The total number of patients was 2,308 [987 cases (poor outcomes) and 1,321 controls (good outcomes)]. The results revealed that rs2287926 G/G genotype and G allele and rs251124 T/T genotype and minor allele T increased the risk of developing IAs. However, further studies are required to examine these gene polymorphisms as screening markers for IAs.

Keywords:  aneurysms; chondroitin sulfate proteoglycan 2 gene; gene associations; intracranial aneurysms; single nucleotide polymorphisms

DOI:  https://doi.org/10.3892/mi.2024.183
Zhonghua Yi Xue Za Zhi. 2024 Aug 06. 104(30): 2830-2836

[The value of dehydroepiandrosterone sulfate in the differential diagnosis of primary bilateral adrenal macronodular hyperplasia].

X J Rao, D Y Jiang, L Zang, Q H Guo, Z H Lyu, Y M Mu.

Objective: To investigate the value of serum dehydroepiandrosterone sulfate (DHEAS) in the differential diagnosis of primary bilateral macronodular adrenal hyperplasia (PBMAH) from nonfunctional adenoma tumors (NFA), adrenocortical adenoma (ADA) and Cushing's disease (CD). Methods: A cross-sectional study. The clinical data of 302 patients with PBMAH, NFA, ADA and CD diagnosed and treated in the First Medical Center of PLA General Hospital from January 2010 to June 2021 were retrospectively analyzed. Among them, 97 were males and 205 were females, aged (45.7±7.2) years. The area under receiver operating characteristic (ROC) curve was used to evaluate the DHEAS ratio (serum DHEAS value divided by the lower limit of normal reference range for the corresponding age and sex) and the 8∶00 adrenocorticotropic hormone (ACTH) level in the differential diagnosis of PBMAH from NFA, ADA and CD. The maximum value of Youden index was cut-off value. Results: Among the 302 patients, 33 were in PBMAH group, 125 were in NFA group, 67 were in ADA group, and 77 were in CD group. The DHEAS ratio in CD group, NFA group, PBMAH group and ADA group decreased successively, with values of 6.34(4.44, 9.93), 3.37(2.24, 4.79), 1.14(1.04, 2.40) and 0.58(0.27, 1.05), respectively. There was statistical significance among all groups (all P<0.01). The area under the ROC curve for distinguishing PBMAH from NFA, ADA and CD were 0.803, 0.741 and 0.930, and the cut-off value were 2.59, 0.99 and 2.92, respectively. The sensitivity was 66.1%, 64.2% and 87.9%, respectively. The specificity was 81.8%, 81.2% and 85.7%. According to the level of 8∶00 ACTH, PBMAH was divided into ACTH-inhibited group (ACTH<2.2 pmol/L,n=18) and ACTH-non-inhibited group (ACTH≥2.2 pmol/L, n=15).The DHEAS ratio in ACTH-non-inhibited PBMAH group was higher than that in ACTH-inhibited PBMAH group(P<0.01).The area under ROC curve of DHEAS ratio for identifying ACTH-non-inhibited PBMAH and CD was 0.877, the cut-off value was 4.55, the sensitivity was 93.3%, and the specificity was 75.3%. If the DHEAS ratio combined with 8∶00 ACTH was used as a differential diagnostic indicator, the area under the ROC curve for distinguishing ACTH-non-inhibitory PBMAH from CD can reach 0.967, with the sensitivity of 100.0% and the specificity of 81.8%. Conclusions: DHEAS ratios is different in PBMAH, NFA, ADA and CD patients, which can assist in the differential diagnosis of PBMAH from NFA、ADA and CD patients, especially in the differential diagnosis of ACTH-non-inhibited PBMAH patients and CD patients.

DOI: https://doi.org/10.3760/cma.j.cn112137-20240201-00248
Chem Pharm Bull (Tokyo). 2024 ;72(7): 700-710

Two Preparation Methods for Peptide Thioester Containing Tyr(SO3H) Residue(s) without the Use of Protecting Group for Sulfate Moiety.

Yumi Sekigawa, Shinichi Asada, Yurie Ichikawa, Kazuaki Tsubokawa, Shoh Watanabe, Shinobu Honzawa, Kouki Kitagawa.

  We report two methods for the preparation of peptide thioesters containing Tyr(SO3H) residue(s), without use of a protecting group for the sulfate moiety. The first was based on direct thioesterification using carbodiimide on a fully protected peptide acid, prepared on a 2-chlorotrityl (Clt) resin with fluoren-9-ylmethoxycarbonyl (Fmoc)-based solid-phase peptide synthesis (Fmoc-SPPS). Subsequent deprotection of the protecting groups with trifluoroacetic acid (TFA) (0 °C, 4 h) yielded peptide thioesters containing Tyr(SO3H) residue(s). Peptide thioesters containing one to three Tyr(SO3H) residue(s), prepared by this method, were used as building blocks for the synthesis of the Nα-Fmoc-protected N-terminal part of P-selectin glycoprotein ligand 1 (PSGL-1) (Fmoc-PSGL-1(43-74)) via silver-ion mediated thioester segment condensation. The other method was based on the thioesterification of peptide azide, derived from a peptide hydrazide prepared on a NH2NH-Clt-resin with Fmoc-SPPS. Peptide thioester containing two Tyr(SO3H) residues, prepared via this alternative method, was used as a building block for the one-pot synthesis of the N-terminal extracellular portion of CC-chemokine receptor 5 (CCR5(9-26)) by native chemical ligation (NCL). The two methods for the preparation of peptide thioesters containing Tyr(SO3H) residue(s) described herein are applicable to the synthesis of various types of sulfopeptides.

Keywords:  Tyr(SO3H)-containing peptide; native chemical ligation; peptide azide; peptide thioester; silver-ion mediated segment condensation; thioesterification

DOI:  https://doi.org/10.1248/cpb.c24-00212
JOR Spine. 2024 Sep;7(3): e1362

Diverse and multifunctional roles for perlecan (HSPG2) in repair of the intervertebral disc.

James Melrose, Farshid Guilak.

  Perlecan is a widely distributed, modular, and multifunctional heparan sulfate proteoglycan, which facilitates cellular communication with the extracellular environment to promote tissue development, tissue homeostasis, and optimization of biomechanical tissue functions. Perlecan-mediated osmotic mechanotransduction serves to regulate the metabolic activity of cells in tissues subjected to tension, compression, or shear. Perlecan interacts with a vast array of extracellular matrix (ECM) proteins through which it stabilizes tissues and regulates the proliferation or differentiation of resident cell populations. Here we examine the roles of the HS-proteoglycan perlecan in the normal and destabilized intervertebral disc. The intervertebral disc cell has evolved to survive in a hostile weight bearing, acidic, low oxygen tension, and low nutrition environment, and perlecan provides cytoprotection, shields disc cells from excessive compressive forces, and sequesters a range of growth factors in the disc cell environment where they aid in cellular survival, proliferation, and differentiation. The cells in mechanically destabilized connective tissues attempt to re-establish optimal tissue composition and tissue functional properties by changing the properties of their ECM, in the process of chondroid metaplasia. We explore the possibility that perlecan assists in these cell-mediated tissue remodeling responses by regulating disc cell anabolism. Perlecan's mechano-osmotic transductive property may be of potential therapeutic application.

Keywords:  chondroid metaplasia; homeostasis; intervertebral disc; intervertebral disc degeneration; mechanotransduction; osmoregulation; perlecan

DOI:  https://doi.org/10.1002/jsp2.1362
J Steroid Biochem Mol Biol. 2024 Jul 30. pii: S0960-0760(24)00144-4. [Epub ahead of print] 106596

Pre-analytical stability and physiological fluctuations affect plasma steroid hormone outcomes: a real-world study.

Jian Zhong, Danchen Wang, Shaowei Xie, Ming Li, Yicong Yin, Jialei Yu, Chaochao Ma, SongLin Yu, Ling Qiu.

  Since steroids are crucial for diagnosing endocrine disorders, the lack of research on factors that affect hormone levels makes interpreting the results difficult. Our study aims to assess the stability of the pre-analytical procedure and the impact of hormonal physiological fluctuations using real-world data. The dataset was created using 12,418 records from individuals whose steroid hormone measurements were taken in our laboratory between September 2019 and March 2024. We routinely measured 22 steroid hormones in plasma using well-validated liquid chromatography and tandem mass spectrometry techniques. After normalization transformation, outlier removal, and z-score normalization, generalized additive models were constructed to evaluate preanalytic stability and age, sex, and sample time-dependent hormonal fluctuations. Most hormones exhibit significant variability with age, particularly steroid hormone precursors, sex hormones, and certain corticosteroids such as aldosterone. 18-hydroxycortisol, 18-oxocortisol, Sex hormones varied between male and female. Levels of certain hormones, including cortisol, cortisone, 11-deoxycortisol, 18-hydroxycortisol, 18-oxocortisol, corticosterone, aldosterone, estrone, testosterone, dihydrotestosterone, dehydroepiandrosterone sulfate, 11-ketotestosterone, and 11-hydroxytestosterone, fluctuated with sampling time. Moreover, levels of pregnenolone and progesterone decreased within 1hour of sampling, with pregnenolone becoming unstable with storage time at 4 degrees after centrifugation, while other hormone levels remained relatively stable for a short period of time without or after centrifugation of the sample. This is the first time that real-world data have been used to assess the pre-analytic stability of plasma hormones and to assess the effect of physiological factors on steroid hormones.

Keywords:  adrenal diseases; generalized additive model; hormonal fluctuation; pre-analytical stability; steroid hormones

DOI:  https://doi.org/10.1016/j.jsbmb.2024.106596
Gut Microbes. 2024 Jan-Dec;16(1):16(1): 2377576

Gut microbiota metabolite indole-3-acetic acid maintains intestinal epithelial homeostasis through mucin sulfation.

Mengfan Li, Yiyun Ding, Jingge Wei, Yue Dong, Jingyi Wang, Xin Dai, Jing Yan, Feifei Chu, Kexin Zhang, Fanyi Meng, Jiahui Ma, Weilong Zhong, Bangmao Wang, Yunhuan Gao, Rongcun Yang, Xinjuan Liu, Xiaomin Su, Hailong Cao.

  The global incidence and prevalence of inflammatory bowel disease (IBD) are gradually increasing. A high-fat diet (HFD) is known to disrupt intestinal homeostasis and aggravate IBD, yet the underlying mechanisms remain largely undefined. Here, a positive correlation between dietary fat intake and disease severity in both IBD patients and murine colitis models is observed. A HFD induces a significant decrease in indole-3-acetic acid (IAA) and leads to intestinal barrier damage. Furthermore, IAA supplementation enhances intestinal mucin sulfation and effectively alleviates colitis. Mechanistically, IAA upregulates key molecules involved in mucin sulfation, including 3'-phosphoadenosine 5'-phosphosulfate synthase 2 (Papss2) and solute carrier family 35 member B3 (Slc35b3), the synthesis enzyme and the transferase of 3'-phosphoadenosine-5'-phosphosulfate (PAPS), via the aryl hydrocarbon receptor (AHR). More importantly, AHR can directly bind to the transcription start site of Papss2. Oral administration of Lactobacillus reuteri, which can produce IAA, contributes to protecting against colitis and promoting mucin sulfation, while the modified L. reuteri strain lacking the iaaM gene (LactobacillusΔiaaM) and the ability to produce IAA fail to exhibit such effects. Overall, IAA enhances intestinal mucin sulfation through the AHR-Papss2-Slc35b3 pathway, contributing to the protection of intestinal homfeostasis.

Keywords:  Inflammatory bowel disease; aryl hydrocarbon receptor; indole-3-acetic acid; mucin; sulfation

DOI:  https://doi.org/10.1080/19490976.2024.2377576
Sci Rep. 2024 Jul 30. 14(1): 17582

Circulating glycocalyx shedding products as biomarkers for evaluating prognosis of patients with out-of-hospital cardiac arrest after return of spontaneous circulation.

Jun Li, Zhijiang Qi, Changan Sun, Yi Zhang, Lei Gong, Yang Li, Haibin Dong, Wenjuan Jia, Lin Zhong, Jun Yang.

  The endothelial glycocalyx is damaged in postcardiac arrest syndrome (PCAS), but the prognostic value is unknown. We aimed to observe the expression and prognostic value of glycocalyx shedding products, including syndecan-1 (SDC-1), hyaluronan (HA), and heparan sulfate (HS) in PCAS. Data on clinical and 28-day outcomes of seventy-one consecutive patients with out-of-hospital cardiac arrest (OHCA) after the return of spontaneous circulation (ROSC) were collected. SDC-1, HA, and HS were measured on days 0, 1, and 3 after ROSC. Thirty healthy individuals were controls. Glycocalyx shedding was observed in human umbilical vein endothelial cells (HUVECs) stimulated during hypoxia and reoxygenation in vitro. Within 4 h of ROSC, SDC-1 and HA levels, significantly increased. In the 28-day non-survivors, HA levels showed a gradual upward trend, SDC-1 remained at a high level, and HS levels first increased, then decreased. Kaplan-Meier curves and binary logistic regression analysis showed the prognostic value of SDC-1 levels on days 0, 1, and 3, HA levels on days 1 and 3, and HS levels on day 1. Only HS levels on day 1 showed a prognostic value for 28-day neurological outcomes. SDC-1 and HA levels were positively correlated with the no-flow time. In vitro, HUVECs showed shedding of SDC-1 and HS during a prolonged duration of hypoxia. After ROSC, SDC-1, HA, and HS levels may predict the 28-day survival after PCAS, and HS levels are associated with functional outcomes.

Keywords:  Glycocalyx; Heparan sulfate; Hyaluronan; Neurological outcome; Out-of-hospital cardiac arrest; Postcardiac arrest syndrome; Syndecan-1

DOI:  https://doi.org/10.1038/s41598-024-68738-4
Adv Sci (Weinh). 2024 Jul 31. e2309966

Extracellular Matrix Sulfation in the Tumor Microenvironment Stimulates Cancer Stemness and Invasiveness.

Alican Kuşoğlu, Deniz Örnek, Aslı Dansık, Ceren Uzun, Sena Nur Özkan, Sevgi Sarıca, Kardelen Yangın, Şevval Özdinç, Duygu Turan Sorhun, Nuriye Solcan, Efe Can Doğanalp, Øystein Arlov, Katherine Cunningham, Ismail C Karaoğlu, Seda Kizilel, Ihsan Solaroğlu, Pınar Bulutay, Pınar Fırat, Suat Erus, Serhan Tanju, Şükrü Dilege, Gordana Vunjak-Novakovic, Nurcan Tuncbag, Ece Öztürk.

  Tumor extracellular matrices (ECM) exhibit aberrant changes in composition and mechanics compared to normal tissues. Proteoglycans (PG) are vital regulators of cellular signaling in the ECM with the ability to modulate receptor tyrosine kinase (RTK) activation via their sulfated glycosaminoglycan (sGAG) side chains. However, their role on tumor cell behavior is controversial. Here, it is demonstrated that PGs are heavily expressed in lung adenocarcinoma (LUAD) patients in correlation with invasive phenotype and poor prognosis. A bioengineered human lung tumor model that recapitulates the increase of sGAGs in tumors in an organotypic matrix with independent control of stiffness, viscoelasticity, ligand density, and porosity, is developed. This model reveals that increased sulfation stimulates extensive proliferation, epithelial-mesenchymal transition (EMT), and stemness in cancer cells. The focal adhesion kinase (FAK)-phosphatidylinositol 3-kinase (PI3K) signaling axis is identified as a mediator of sulfation-induced molecular changes in cells upon activation of a distinct set of RTKs within tumor-mimetic hydrogels. The study shows that the transcriptomic landscape of tumor cells in response to increased sulfation resembles native PG-rich patient tumors by employing integrative omics and network modeling approaches.

Keywords:  cancer; extracellular matrix (ECM); hydrogels; tissue engineering; tumor microenvironment (TME); tumor models

DOI:  https://doi.org/10.1002/advs.202309966
Kidney Int. 2024 Jul 29. pii: S0085-2538(24)00527-1. [Epub ahead of print]

Galectin-3 contributes to pathogenesis of IgA nephropathy.

Yu-Ling Chou, Hung-Lin Chen, Bang-Gee Hsu, Chih-Yu Yang, Cheng-Hsu Chen, Yu-Ching Lee, I-Lin Tsai, Chih-Chien Sung, Chia-Chao Wu, Shin-Ruen Yang, Yusuke Suzuki, Edwin Yates, Kuo-Feng Hua, Lu-Gang Yu, Fu-Tong Liu, Ann Chen, Shuk-Man Ka.

  IgA nephropathy (IgAN) is the most common type of glomerulonephritis that frequently progresses to kidney failure. However, the molecular pathogenesis underlying IgAN remains largely unknown. Here, we investigated the role of galectin-3 (Gal-3), a galactoside-binding protein in IgAN pathogenesis and showed that Gal-3 expression by the kidney was significantly enhanced in patients with IgAN. In both TEPC-15 hybridoma-derived IgA-induced, passive, and spontaneous "grouped" ddY IgAN models, Gal-3 expression was clearly increased with disease severity in the glomeruli, peri-glomerular regions, and some kidney tubules. Gal-3 knockout (KO) in the passive IgAN model had significantly improved proteinuria, kidney function and reduced severity of kidney pathology, including neutrophil infiltration and decreased differentiation of Th17 cells from kidney-draining lymph nodes, despite increased percentages of regulatory T cells. Gal-3 KO also inhibited the NLRP3 inflammasome, yet it enhanced autophagy and improved kidney inflammation and fibrosis. Moreover, administration of 6-de-O-sulfated, N-acetylated low-molecular-weight heparin, a competitive Gal-3 binding inhibitor, restored kidney function and improved kidney lesions in passive IgAN mice. Thus, our results suggest that Gal-3 is critically involved in IgAN pathogenesis by activating the NLRP3 inflammasome and promoting Th17 cell differentiation. Hence, targeting Gal-3 action may represent a new therapeutic strategy for treatment of this kidney disease.

Keywords:  Galectin-3; IgA nephropathy; Low-molecular-weight heparin; NLRP3 inflammasome; TEPC-15 hybridoma; Th17; Therapeutic target; “grouped” ddY mice

DOI:  https://doi.org/10.1016/j.kint.2024.06.023
J Neurotrauma. 2024 Jul 30.

Hepatocyte growth factor delivery to injured cervical spinal cord using an engineered biomaterial protects respiratory neural circuitry and preserves functional diaphragm innervation.

Samantha J Thomas, Biswarup Ghosh, Zhicheng Wang, Mengxi Yang, Jia Nong, Jenna Severa, Megan C Wright, Yinghui Zhong, Angelo C Lepore.

  A major portion of spinal cord injury (SCI) cases occur in the cervical region where essential components of respiratory neural circuitry are located. Phrenic motor neurons (PhMNs) housed at cervical spinal cord level C3-C5 directly innervate the diaphragm, and SCI-induced damage to these cells severely impairs respiratory function. In this study, we tested a biomaterial-based approach aimed at preserving this critical phrenic motor circuitry after cervical SCI by locally delivering hepatocyte growth factor (HGF). HGF is a potent mitogen that promotes survival, proliferation, migration, repair and regeneration of a number of different cell and tissue types in response to injury. We developed a hydrogel-based HGF delivery system that can be injected into the intrathecal space for local delivery of high levels of HGF without damaging the spinal cord. Implantation of HGF hydrogel after unilateral C5 contusion-type SCI in rats preserved diaphragm function, as assessed by in vivo recordings of both compound muscle action potentials and inspiratory electromyography amplitudes. HGF hydrogel also preserved PhMN innervation of the diaphragm, as assessed by both retrograde PhMN tracing and detailed neuromuscular junction morphological analysis. Furthermore, HGF hydrogel significantly decreased lesion size and degeneration of cervical motor neuron cell bodies, as well as reduced levels surrounding the injury site of scar-associated chondroitin sulfate proteoglycan (CSPG) molecules that limit axon growth capacity. Our findings demonstrate that local biomaterial-based delivery of HGF hydrogel to injured cervical spinal cord is an effective strategy for preserving respiratory circuitry and diaphragm function.

Keywords:  DEGENERATION; GROWTH FACTORS; IN VIVO STUDIES; THERAPEUTIC APPROACHES FOR THE TREATMENT OF CNS INJURY; spinal cord injury

DOI:  https://doi.org/10.1089/neu.2024.0084
Int J Dermatol. 2024 Jul 31.

Revisiting X-linked congenital ichthyosis.

Baishun Zhou, Cancan Liang, Peiyao Li, Heng Xiao.

  X-linked recessive ichthyosis (XLI) is a hereditary skin disease characterized by generalized dryness and scaling of the skin, with frequent extracutaneous manifestations. It is the second most common type of ichthyosis, with a prevalence of 1/6,000 to 1/2,000 in males and without any racial or geographical differences. The causative gene for XLI is the steroid sulfatase gene (STS), located on Xp22.3. STS deficiency causes an abnormal cholesterol sulfate (CS) accumulation in the stratum corneum (SC). Excess CS induces epidermal permeability barrier dysfunction and scaling abnormalities. This review summarizes XLI's genetic, clinical, and pathological features, pathogenesis, diagnosis and differential diagnoses, and therapeutic perspectives. Further understanding the role of the STS gene pathogenic variants in XLI may contribute to a more accurate and efficient clinical diagnosis of XLI and provide novel strategies for its treatment and prenatal diagnosis.

Keywords:  STS gene; XLI; X‐linked recessive ichthyosis; dermatopathology; diagnosis; gene pathogenic variants; gene therapy; genetic skin disorders; treatment

DOI:  https://doi.org/10.1111/ijd.17396