bims-supasi 2024-07-21 papers

bims-supasi

Biomed News

on Sulfation pathways and signalling

Issue of 2024–07–21
seventeen papers selected by
Jonathan Wolf Mueller, University of Birmingham

Synthesis and Reactivity of Masked Organic Sulfates.
Design Principle of Heparanase Inhibitors: A Combined In Vitro and In Silico Study.
Sulfated vitamin D metabolites represent prominent roles in serum and in breastmilk of lactating women.
Androgenic Steroid Hormones and Endurance Exercise in Athletic Women.
Enhancement of the chondrogenic differentiation capacity of human dental pulp stem cells via chondroitin sulfate-coated polycaprolactone-MWCNT nanofibers.
Cartilage extracellular matrix polymers: hierarchical structure, osmotic properties, and function.
Chondroitin Sulfate and Hyaluronic Acid-Based PolyHIPE Scaffolds for Improved Osteogenesis and Chondrogenesis In Vitro.
Community consensus for Heparan sulfate as a biomarker to support accelerated approval in Neuronopathic Mucopolysaccharidoses.
Exploring Neuron-Specific Steroid Synthesis and DHEAS Therapy in Alzheimer's Disease.
Chondroitin sulfate proteoglycan 4 (CSPG4) increases invasion of recessive dystrophic epidermolysis bullosa-associated cutaneous squamous cell carcinoma by modifying TGFβ signaling.
Salivary uric acid dynamics are associated with stress response hormones among African American in an urban sample.
An unusual case of 17-hydroxylase deficiency presenting with short stature.
Chondroitin Sulfate-Modified Hydroxyapatite for Caspase-1 Activated Induced Pyroptosis through Ca Overload/ER Stress/STING/IRF3 Pathway in Colorectal Cancer.
Multifunctional Glycopeptide-Based Hydrogel via Dual-Modulation for the Prevention and Repair of Radiation-Induced Skin Injury.
Acceleration of chondrogenic differentiation utilizing biphasic core-shell alginate sulfate electrospun nanofibrous scaffold.
Global siRNA Screen Reveals Critical Human Host Factors of SARS-CoV-2 Multicycle Replication.
Pathogenesis and Mechanism of Uremic Vascular Calcification.

Chemistry. 2024 Jul 18. e202402268

Synthesis and Reactivity of Masked Organic Sulfates.

Bharath K Villuri, Umesh R Desai.

  Nature offers a variety of structurally unique, sulfated endobiotics including sulfated glycosaminoglycans, sulfated tyrosine peptides, sulfated steroids/bile acids/catecholamines. Sulfated molecules display a large number of biological activities including antithrombotic, antimicrobial, anticancer, anti-inflammatory, and others, which arise from modulation of intracellular signaling and enhanced in vivo retention of certain hormones. These characteristics position sulfated molecules very favorably as drug-like agents. However, few have reached the clinic. Major hurdles exist in realizing sulfated molecules as drugs. This state-of-the-art has been transformed through recent works on the development of sulfate masking technologies for both alkyl (sulfated carbohydrates, sulfated steroids) and aryl (sTyr-bearing peptides/proteins, sulfated flavonoids) sulfates. This review compiles the literature on different strategies implemented for different types of sulfate groups. Starting from early efforts in protection of sulfate groups to the design of newer SuFEx, trichloroethyl, and gem-dimethyl-based protection technologies, this review presents the evolution and application of concepts in realizing highly diverse, sulfated molecules as candidate drugs and/or prodrugs. Overall, the newer strategies for sulfate masking and demasking are likely to greatly enhance the design and development of sulfated molecules as non-toxic drugs of the future.

Keywords:  Glycosaminoglycans; Steroids; Synthesis; Tyrosines; Xenobiotics

DOI:  https://doi.org/10.1002/chem.202402268
ACS Med Chem Lett. 2024 Jul 11. 15(7): 1032-1040

Design Principle of Heparanase Inhibitors: A Combined In Vitro and In Silico Study.

Yuzhao Zhang, Meijun Xiong, Zixin Chen, Gustavo Seabra, Jun Liu, Chenglong Li, Lina Cui.

Heparanase (HPSE) is an enzyme that cleaves heparan sulfate (HS) side chains from heparan sulfate proteoglycans (HSPGs). Overexpression of HPSE is associated with various types of cancer, inflammation, and immune disorders, making it a highly promising therapeutic target. Previously developed HPSE inhibitors that have advanced to clinical trials are polysaccharide-derived compounds or their mimetics; however, these molecules tend to suffer from poor bioavailability, side effects via targeting other saccharide binding proteins, and heterogeneity. Few small-molecule inhibitors have progressed to the preclinical or clinical stages, leaving a gap in HPSE drug discovery. In this study, a novel small molecule that can inhibit HPSE activity was discovered through high-throughput screening (HTS) using an ultrasensitive HPSE probe. Computational tools were employed to elucidate the mechanisms of inhibition. The essential structural features of the hit compound were summarized into a structure-activity relationship (SAR) theory, providing insights into the future design of HPSE small-molecule inhibitors.

DOI: https://doi.org/10.1021/acsmedchemlett.3c00268
Clin Nutr. 2024 Jul 14. pii: S0261-5614(24)00237-1. [Epub ahead of print]43(9): 1929-1936

Sulfated vitamin D metabolites represent prominent roles in serum and in breastmilk of lactating women.

Carmen J Reynolds, Roy B Dyer, Sara S Oberhelman-Eaton, Brianna L Konwinski, Renee M Weatherly, Ravinder J Singh, Tom D Thacher.

   BACKGROUND: Concentrations of vitamin D (VitD) and 25-hydroxyvitamin D (25OHD) in breastmilk are low despite the essential role of VitD for normal infant bone development, yet additional metabolic forms of vitamin D may be present. This study evaluates the contribution of sulfated vitamin D metabolites, vitamin D3-sulfate (VitD3-S) and 25-hydroxyvitamin D3-sulfate (25OHD3-S) for lactating women and assesses the response to high-dose VitD3 supplementation.
METHODS: Serum and breastmilk were measured before and after 28 days with 5000 IU/day VitD3 intake in 20 lactating women. Concentrations of VitD3-S and 25OHD3-S in milk, and 25OHD2, 25OHD3, 25OHD3-S, VitD3 and VitD3-S in serum were determined by mass spectrometry.
RESULTS: Baseline vitamin D status was categorized as sufficient (mean ± SD serum 25OHD3 69 ± 19 nmol/L), and both serum VitD3 and 25OHD3 increased following supplementation (p < 0.001). 25OHD3-S was 91 ± 19 nmol/L in serum and 0.47 ± 0.09 nmol/L in breastmilk. VitD3-S concentrations were 2.92 ± 0.70 nmol/L in serum and 6.4 ± 3.9 nmol/L in breastmilk. Neither sulfated metabolite significantly changed with supplementation in either serum or breastmilk.
CONCLUSIONS: Sulfated vitamin D metabolites have prominent roles for women during lactation with 25OHD3-S highly abundant in serum and VitD3-S distinctly abundant in breastmilk. These data support the notion that 25OHD3-S and VitD3-S may have physiological relevance during lactation and nutritional usage for nursing infants.

Keywords:  Infant nutrition; Lactation; Rickets; Supplementation

DOI:  https://doi.org/10.1016/j.clnu.2024.07.008
Endocrines. 2024 Sep;5(3): 252-260

Androgenic Steroid Hormones and Endurance Exercise in Athletic Women.

Anthony C Hackney, Raul Cosme Ramos Prado, Eimear Dolan.

  This study investigated the impact of intensive endurance exercise on circulating androgenic steroid hormones in women. Fifteen normally menstruating athletic women participated. They completed intensive endurance exercise (treadmill running) until volitional fatigue in their follicular phase, with blood samples collected at pre-exercise, volitional fatigue, 90 min and 24 h into recovery. The steroid hormones (total, free testosterone, dehydroepiandrosterone [DHEA], and DHEA-sulfate [DHEA-S], cortisol) were analyzed in blood sera. Non-parametric statistics were used to assess changes across exercise and recovery. At volitional fatigue, all hormones, except free testosterone, were significantly (p < 0.05) increased compared to pre-exercise levels. Most hormones remained elevated through 90 min of recovery, with DHEA, DHEA-S, and total testosterone changes being significant (p < 0.05). At 24 h of recovery, hormonal levels were reduced; specifically, DHEA, DHEA-S, and total testosterone compared to baseline (p < 0.01 to 0.06). Increases in cortisol levels at volitional fatigue and 90 min of recovery were correlated with reductions in total testosterone, DHEA, and DHEA-S observed at 24 h of recovery (rho > -0.62, p < 0.05). In conclusion, in menstruating women performing intensive endurance exercise during their follicular phase, their androgenic steroid hormones remain elevated during early recovery but are suppressed at 24 h of recovery. The latter finding indicates that establishing a resting endocrine equilibrium requires a longer recovery period than 24 h.

Keywords:  adrenal; anabolism; endocrine; females; gonads; physical activity

DOI:  https://doi.org/10.3390/endocrines5030018
Sci Rep. 2024 Jul 16. 14(1): 16396

Enhancement of the chondrogenic differentiation capacity of human dental pulp stem cells via chondroitin sulfate-coated polycaprolactone-MWCNT nanofibers.

Ghada Nour Eldeen, Tarek A Elkhooly, Gehan T El Bassyouni, Tamer M Hamdy, Ahmed R Hawash, Riham M Aly.

  Most of the conditions involving cartilaginous tissues are irreversible and involve degenerative processes. The aim of the present study was to fabricate a biocompatible fibrous and film scaffolds using electrospinning and casting techniques to induce chondrogenic differentiation for possible application in cartilaginous tissue regeneration. Polycaprolactone (PCL) electrospun nanofibrous scaffolds and PCL film were fabricated and incorporated with multi-walled carbon nanotubes (MWCNTs). Thereafter, coating of chondroitin sulfate (CS) on the fibrous and film structures was applied to promote chondrogenic differentiation of human dental pulp stem cells (hDPSCs). First, the morphology, hydrophilicity and mechanical properties of the scaffolds were characterized by scanning electron microscopy (SEM), spectroscopic characterization, water contact angle measurements and tensile strength testing. Subsequently, the effects of the fabricated scaffolds on stimulating the proliferation of human dental pulp stem cells (hDPSCs) and inducing their chondrogenic differentiation were evaluated via electron microscopy, flow cytometry and RT‒PCR. The results of the study demonstrated that the different forms of the fabricated PCL-MWCNTs scaffolds analyzed demonstrated biocompatibility. The nanofilm structures demonstrated a higher rate of cellular proliferation, while the nanofibrous architecture of the scaffolds supported the cellular attachment and differentiation capacity of hDPSCs and was further enhanced with CS addition. In conclusion, the results of the present investigation highlighted the significance of this combination of parameters on the viability, proliferation and chondrogenic differentiation capacity of hDPSCs seeded on PCL-MWCNT scaffolds. This approach may be applied when designing PCL-based scaffolds for future cell-based therapeutic approaches developed for chondrogenic diseases.

Keywords:  Chondrogenic differentiation; Chondroitin sulfate; Human dental pulp stem cells; PCL scaffolds; Regeneration

DOI:  https://doi.org/10.1038/s41598-024-66497-w
Soft Matter. 2024 Jul 19.

Cartilage extracellular matrix polymers: hierarchical structure, osmotic properties, and function.

Ferenc Horkay, Peter J Basser, Erik Geissler.

Proteoglycans are hierarchically organized structures that play an important role in the hydration and the compression resistance of cartilage matrix. In this study, the static and dynamic properties relevant to the biomechanical function of cartilage are determined at different levels of the hierarchical structure, using complementary osmotic pressure, neutron scattering (SANS) and light scattering (DLS) measurements. In cartilage proteoglycans (PGs), two levels of bottlebrush structures can be distinguished: the aggrecan monomer, which consists of a core protein to which are tethered charged glycosaminoglycan (GAG) chains, and complexes formed of the aggrecan monomers attached around a linear hyaluronic acid backbone. The principal component of GAG, chondroitin sulfate (CS), is used as a baseline in this comparison. The osmotic modulus, measured as a function of the proteoglycan concentration, follows the order CS < aggrecan < aggrecan-HA complex. This order underlines the benefit of the increasing complexity at each level of the molecular architecture. The hierarchical bottlebrush configuration, which prevents interpenetration among the bristles of the aggrecan monomers, enhances both the mechanical properties and the osmotic resistance. The osmotic pressure of the collagen solution is notably smaller than in the proteoglycan systems. This is consistent with its known primary role to provide tensile strength to the cartilage and to confine the aggrecan-HA complexes, as opposed to load bearing. The collective diffusion coefficient D governs the rate of recovery of biological tissue after compressive load. In CS solutions the diffusion process is fast, D ≈ 3 × 10-6 cm2 s-1 at concentrations comparable with that of the GAG chains inside the aggrecan molecule. In CS solutions D is a weakly decreasing function of calcium ion concentration, while in aggrecan and its complexes with HA, the relaxation rate is insensitive to the presence of calcium.

DOI: https://doi.org/10.1039/d4sm00617h
ACS Appl Bio Mater. 2024 Jul 15.

Chondroitin Sulfate and Hyaluronic Acid-Based PolyHIPE Scaffolds for Improved Osteogenesis and Chondrogenesis In Vitro.

Isha Behere, Anuradha Vaidya, Ganesh Ingavle.

  Osteochondral damage, affecting the articular cartilage and the underlying subchondral bone, presents significant challenges in clinical treatment. Such defects, commonly seen in knee and ankle joints, vary from small localized lesions to larger defects. Current medical therapies encounter several challenges, such as donor shortages, drug side effects, high costs, and rejection problems, often resulting in only temporary relief. Highly porous emulsion-templated polymers (polyHIPEs) offer numerous potential benefits in the fabrication of scaffolds for tissue engineering and regenerative medicine. Polymeric scaffolds synthesized using a high internal phase emulsion (HIPE) technique, called PolyHIPEs, involve polymerizing a continuous phase surrounding a dispersed internal phase to form a solid, foam-like structure. A dense, porous design encourages cell ingrowth, nutrient delivery, and waste disposal from the scaffold, mimicking the cells' natural microenvironment. This study used hydroxyethyl methacrylate (HEMA) and acrylamide (AAM) polyHIPE scaffolds combined with extracellular matrix (ECM) components of the tissue, such as methacrylated hyaluronic acid (MHA) and methacrylated chondroitin sulfate (MCS), to prepare polyHIPE scaffolds. The mouse preosteoblast MC3T3-E1 cells and primary rat chondrocytes (harvested from male Wistar rats) were seeded on the scaffolds and cultured for 21 days to assess the osteogenesis and chondrogenesis in vitro. When compared to the AAM-MHA and AAM-MCS groups at day 21, scaffold groups HEMA-MHA and HEMA-MCS showed a significant rise in alkaline phosphatase (ALP) and calcium content. Chondrogenic markers such as glycosaminoglycan (GAG) and hydroxyproline were also assessed over a 21-day time point. On day 21, it was found that GAG and hydroxyproline production were considerably higher in the HEMA-MHA and HEMA-MCS scaffolds than in the AAM-MHA and AAM-MCS scaffolds. The overall studies showed that polyHIPE monolith scaffolds could favor cell adherence, survival ability, proliferation, differentiation, and ECM formation over 21 days. Thus, incorporating ECM components enhanced osteogenesis and chondrogenesis in vitro and can be further used as tissue repair models.

Keywords:  chondrogenesis; methacrylated chondroitin sulfate; monoliths; osteochondral defect; osteogenesis; polyHIPE

DOI:  https://doi.org/10.1021/acsabm.4c00393
Mol Genet Metab. 2024 Jul 10. pii: S1096-7192(24)00419-0. [Epub ahead of print]142(4): 108535

Community consensus for Heparan sulfate as a biomarker to support accelerated approval in Neuronopathic Mucopolysaccharidoses.

Joseph Muenzer, Carole Ho, Heather Lau, Mark Dant, Maria Fuller, Nidal Boulos, Patricia Dickson, N Matthew Ellinwood, Simon A Jones, Eric Zanelli, Cara O'Neill.

  Mucopolysaccharidoses (MPS) disorders are a group of ultra-rare, inherited, lysosomal storage diseases caused by enzyme deficiencies that result in accumulation of glycosaminoglycans (GAGs) in cells throughout the body including the brain, typically leading to early death. Current treatments do not address the progressive cognitive impairment observed in patients with neuronopathic MPS disease. The rarity and clinical heterogeneity of these disorders as well as pre-existing brain disease in clinically diagnosed patients make the development of new therapeutics utilizing a traditional regulatory framework extremely challenging. Children with neuronopathic MPS disorders will likely sustain irreversible brain damage if randomized to a placebo or standard-of-care treatment arm that does not address brain disease. The United States Food and Drug Administration (FDA) recognized these challenges, and, in 2020, issued final guidance for industry on slowly progressive, low-prevalence, rare diseases with substrate deposition that result from single enzyme defects, outlining a path for generating evidence of effectiveness to support accelerated approval based on reduction of substrate accumulation [1]. Neuronopathic MPS disorders, which are characterized by the accumulation of the GAG heparan sulfate (HS) in the brain, fit the intended disease characteristics for which this guidance was written, but to date, this guidance has not yet been applied to any therapeutic candidate for MPS. In February 2024, the Reagan-Udall Foundation for the FDA convened a public workshop for representatives from the FDA, patient advocacy groups, clinical and basic science research, and industry to explore a case study of using cerebrospinal fluid (CSF) HS as a relevant biomarker to support accelerated approval of new therapeutics for neuronopathic MPS disorders. This review provides a summary of the MPS presentations at the workshop and perspective on the path forward for neuronopathic MPS disorders.

Keywords:  CSF heparan sulfate; Community consensus; FDA accelerated approval; MPS therapeutic development; Neuronopathic MPS; Reagan-Udall Foundation

DOI:  https://doi.org/10.1016/j.ymgme.2024.108535
J Steroid Biochem Mol Biol. 2024 Jul 15. pii: S0960-0760(24)00133-X. [Epub ahead of print] 106585

Exploring Neuron-Specific Steroid Synthesis and DHEAS Therapy in Alzheimer's Disease.

Hong-Yi Lin, Yin-Hsun Feng, Tzu-Jen Kao, Hsien-Chung Chen, Guan-Yuan Chen, Chiung-Yuan Ko, Tsung-I Hsu.

  Alzheimer's Disease (AD) is a neurodegenerative disorder characterized by cognitive decline and memory loss. Recent studies have suggested a potential role for steroid synthesis in AD pathology. This study investigated the co-localization of steroidogenic enzymes in neuronal cells, changes in enzyme expression in an AD mouse model, and steroid expressions in human AD samples. Additionally, we conducted a steroidomic metabolomics analysis and evaluated the effects of dehydroepiandrosterone sulfate (DHEAS) treatment in an AD mouse model. Immunofluorescence analysis revealed significant co-localization of cytochrome P450 family 17 subfamily A member 1 (CYP17A1) and steroidogenic acute regulatory protein (StAR) proteins with α-synuclein in presynaptic neurons, suggesting active steroid synthesis in these cells. Conversely, such co-localization was absent in astrocytes. In the AD mouse model, a marked decrease in the expression of steroidogenic enzymes (Cyp11a1, Cyp17a1, Star) was observed, especially in areas with amyloid beta plaque accumulation. Human AD and MS brain tissues showed similar reductions in StAR and CYP17A1 expressions. Steroidomic analysis indicated a downregulation of key steroids in the serum of AD patients. DHEAS treatment in AD mice resulted in improved cognitive function and reduced Aβ accumulation. Our findings indicate a neuron-specific pathway for steroid synthesis, potentially playing a crucial role in AD pathology. The reduction in steroidogenic enzymes and key steroids in AD models and human samples suggests that impaired steroid synthesis is a feature of neurodegenerative diseases. The therapeutic potential of targeting steroid synthesis pathways, as indicated by the positive effects of DHEAS treatment, warrants further investigation.

Keywords:  Alzheimer's Disease; CYP17A1; DHEAS; StAR; Steroid Synthesis

DOI:  https://doi.org/10.1016/j.jsbmb.2024.106585
Br J Dermatol. 2024 Jul 17. pii: ljae295. [Epub ahead of print]

Chondroitin sulfate proteoglycan 4 (CSPG4) increases invasion of recessive dystrophic epidermolysis bullosa-associated cutaneous squamous cell carcinoma by modifying TGFβ signaling.

Allison R K Macaulay, Jianbo Yang, Matthew A Price, Colleen L Forster, Megan J Riddle, Christen L Ebens, Frank W Albert, Alessio Giubellino, James B McCarthy, Jakub Tolar.

BACKGROUND: Recessive dystrophic epidermolysis bullosa (RDEB) is a rare genetic skin-blistering disorder often progressing to metastatic cutaneous squamous cell carcinoma (cSCC) at chronic wound sites. Chondroitin sulfate proteoglycan 4 (CSPG4) is a cell-surface proteoglycan that is an oncoantigen in multiple malignancies, where it modulates oncogenic signaling, drives epithelial-to-mesenchymal transition (EMT), and enables cell motility.
OBJECTIVES: To evaluate CSPG4 expression and function in RDEB-cSCC.
METHODS: RDEB-cSCC cell lines were used to assess CSPG4-dependent changes in invasive potential, TGFβ1-stimulated signal activation, and clinically relevant cytopathology metrics in an in vitro full-thickness tumor model. CSPG4 expression in RDEB-cSCC and non-RDEB cSCC tumors was analyzed via immunohistochemistry and single-cell RNA sequencing (scRNA-seq), respectively.
RESULTS: Inhibiting CSPG4 expression reduced invasive potential in multiple RDEB-cSCC cell lines and altered membrane-proximal TGFβ signal activation through changes in SMAD3 phosphorylation. CSPG4 expression was uniformly localized to basal-layer keratinocytes in fibrotic RDEB skin and tumor cells at the tumor/stroma interface at the invasive front in RDEB-cSCC tumors in vivo. Analysis of published scRNA-seq data revealed that CSPG4 expression was correlated with an enhanced EMT transcriptomic signature in cells at the tumor/stroma interface of non-RDEB cSCC tumors. Cytopathological metrics, like nucleus:cell area ratio, were influenced by CSPG4 expression in in vitro tumor models.
CONCLUSIONS: We determined that CSPG4 expression in RDEB-cSCC cell lines enhanced invasive potential. Mechanistically, CSPG4 was found to enhance membrane-proximal TGFβ-stimulated signaling through SMAD3, which is a key mediator of EMT in RDEB-cSCC. The implication of these studies is that CSPG4 may represent a therapeutic target that can be leveraged for clinical management in patients with RDEB-cSCC.

DOI: https://doi.org/10.1093/bjd/ljae295
Psychoneuroendocrinology. 2024 Jul 02. pii: S0306-4530(24)00164-1. [Epub ahead of print]168 107120

Salivary uric acid dynamics are associated with stress response hormones among African American in an urban sample.

Stefan M M Goetz, Todd Lucas, Douglas A Granger.

  Acute physiological responses to psychosocial stressors are a potential pathway underlying racial disparities in stress-related illnesses. Uric acid (UA) is a potent antioxidant that has been linked to disparities in stress-related illnesses, and recent research has shown that UA is responsive to acute social stress. However, an examination of the relationships between the purinergic system and other commonly measured stress systems is lacking. Here, we measure and characterize associations of salivary uric acid (sUA) with markers of hypothalamic-pituitary-adrenal (HPA) axis activation, sympathetic-adreno-medullar (SAM) axis activation, and acute inflammation. A community sample of 103 African Americans (33 male, 70 female) completed the Trier Social Stress Test to induce social-evaluative threat. Passive drool collected before, during, and after the stressor task provided salivary reactivity measures of UA (sUA), cortisol, dehydroepiandrosterone sulfate (DHEAS), salivary alpha amylase (sAA - a surrogate marker of SAM activity) and C-reactive protein (sCRP). Multiple regressions revealed that total activation of cortisol, DHEAS, and sCRP were each positively associated with higher total activation of sUA. Additionally, DHEAS reactivity was positively associated with sUA reactivity. Relationships between HPA-axis markers and sUA were especially observed among younger and male participants. Overall, findings suggest potential coordination of stress systems with sUA in response to acute stress, which may further the contributions of biological stress processes to racial health disparities.

Keywords:  Health Disparities; Multisystem Stress; Purinergic Stress Response; Stress Reactivity; Trier Social Stress Test; Uric Acid

DOI:  https://doi.org/10.1016/j.psyneuen.2024.107120
Arch Pediatr. 2024 Jul 12. pii: S0929-693X(24)00089-7. [Epub ahead of print]

An unusual case of 17-hydroxylase deficiency presenting with short stature.

Fatma Özgüç Çömlek, Uğur Gümüş.

  17α-Hydroxylase and 17,20-lyase are enzymes encoded by the CYP17A1 gene and are necessary for the production of cortisol and sex steroids. Females with 17α-hydroxylase deficiency usually present with primary amenorrhea and delayed puberty accompanied by hypertension and electrolyte imbalance. Here, we report the case of a 14-year-old female patient who presented with severe short stature and delayed puberty without any complaint suggestive of 17-hydroxylase enzyme deficiency. Laboratory test results showed low cortisol and dehydroepiandrosterone sulfate (DHEA-S) along with high luteinizing hormone (LH) and follicle-stimulating hormone (FSH). Turner syndrome was excluded after genetic analysis showed a 46,XX karyotype, and 17α-hydroxylase deficiency was diagnosed by detecting a c.1319G>A (p.Arg440His) variation/alternation in the patient's CYP17A1 gene.

Keywords:  17-Alpha-hydroxylase deficiency; Delayed puberty; Short stature

DOI:  https://doi.org/10.1016/j.arcped.2024.03.007
Small. 2024 Jul 17. e2403201

Chondroitin Sulfate-Modified Hydroxyapatite for Caspase-1 Activated Induced Pyroptosis through Ca Overload/ER Stress/STING/IRF3 Pathway in Colorectal Cancer.

Qing Chen, Bin Peng, Lifan Lin, Jiawen Chen, Zhaojun Jiang, Yuanwei Luo, Liyong Huang, Jin Li, Yuping Peng, Jiaming Wu, Wei Li, Kangmin Zhuang, Min Liang.

  Immune checkpoint inhibitors, are the fourth most common therapeutic tool after surgery, chemotherapy, and radiotherapy for colorectal cancer (CRC). However, only a small proportion (≈5%) of CRC patients, those with "hot" (immuno-activated) tumors, benefit from the therapy. Pyroptosis, an innovative form of programmed cell death, is a potentially effective means to mediate a "cold" to "hot" transformation of the tumor microenvironment (TME). Calcium-releasing hydroxyapatite (HAP) nanoparticles (NPs) trigger calcium overload and pyroptosis in tumor cells. However, current limitations of these nanomedicines, such as poor tumor-targeting capabilities and insufficient calcium (Ca) ion release, limit their application. In this study, chondroitin sulfate (CS) is used to target tumors via binding to CD44 receptors and kaempferol (KAE) is used as a Ca homeostasis disruptor to construct CS-HAP@KAE NPs that function as pyroptosis inducers in CRC cells. CS-HAP@KAE NPs bind to the tumor cell membrane, HAP released Ca in response to the acidic environment of the TME, and kaempferol (KAE) enhances the influx of extracellular Ca, resulting in intracellular Ca overload and pyroptosis. This is associated with excessive endoplasmic reticulum stress triggered activation of the stimulator of interferon genes/interferon regulatory factor 3 pathway, ultimately transforming the TME from "cold" to "hot".

Keywords:  STING; calcium overload; colorectal cancer; pyroptosis; tumor immunotherapy

DOI:  https://doi.org/10.1002/smll.202403201
ACS Biomater Sci Eng. 2024 Jul 17.

Multifunctional Glycopeptide-Based Hydrogel via Dual-Modulation for the Prevention and Repair of Radiation-Induced Skin Injury.

Jiajun Guo, Xiaoguang Zhang, Ruiqi Mao, Hui Li, Yusen Hao, Jiamin Zhang, Wei Wang, Yumin Zhang, Jianfeng Liu.

  The radiation-induced skin injury (RISI) remains a great challenge for clinical wound management and care after radiotherapy, as patients will suffer from the acute radiation injury and long-term chronic inflammatory damage during the treatment. The excessive ROS in the early acute stage and prolonged inflammatory response in the late healing process always hinder therapeutic efficiency. Herein, we developed an extracellular matrix (ECM)-mimetic multifunctional glycopeptide hydrogel (oCP@As) to promote and accelerate RISI repair via a dual-modulation strategy in different healing stages. The oCP@As hydrogel not only can form an ECM-like nanofiber structure through the Schiff base reaction but also exhibits ROS scavenging and DNA double-strand break repair abilities, which can effectively reduce the acute radiation damage. Meanwhile, the introduction of oxidized chondroitin sulfate, which is the ECM polysaccharide-like component, enables regulation of the inflammatory response by adsorption of inflammatory factors, accelerating the repair of chronic inflammatory injury. The animal experiments demonstrated that oCP@As can significantly weaken RISI symptoms, promote epidermal tissue regeneration and angiogenesis, and reduce pro-inflammatory cytokine expression. Therefore, this multifunctional glycopeptide hydrogel dressing can effectively attenuate RISI symptoms and promote RISI healing, showing great potential for clinical applications in radiotherapy protection and repair.

Keywords:  DNA repairing; glycopeptide hydrogel; inflammatory response modulation; radiation-induced skin injury; wound healing

DOI:  https://doi.org/10.1021/acsbiomaterials.4c00698
Colloids Surf B Biointerfaces. 2024 Jul 09. pii: S0927-7765(24)00339-4. [Epub ahead of print]242 114080

Acceleration of chondrogenic differentiation utilizing biphasic core-shell alginate sulfate electrospun nanofibrous scaffold.

Elmira Omrani, Mohammad Amin Haramshahi, Najmeh Najmoddin, Mahdi Saeed, Mohamad Pezeshki-Modaress.

  Engineering new biomedical materials with tailored physicochemical, mechanical and biological virtues in order to differentiate stem cells into chondrocytes for cartilage regeneration has garnered much scientific interest. In this study, core/shell nanofibrous scaffold based on poly(ɛ-caprolactone) (PCL) as a core material and alginate sulfate (AlgS)-poly(vinyl alcohol) (PVA) blend as shell materials (AlgS-PVA/PCL) was fabricated by emulsion electrospinning. In this vein, the influence of AlgS to PVA ratio (30:70, 50:50), organic to aqueous phase ratio (1:2, 1:3 and 1:5) and acid concentration (0, 10, 20, 30, 40 and 50 %) on nanofibers morphology were investigated. SEM images depicted that AlgS to PVA ratio of 30:70 and 50:50, organic to aqueous phase ratio of 1:3 and 1:5 and acid concentration of 30 % led to uniform, bead-free fibrous mats. AlgS-PVA/PCL scaffolds with AlgS to PVA ratio of 30:70 and organic to aqueous phase ratio of 1:3, showed admirable mechanical features, high porosity (>90 %) with desirable swelling ratio in wet condition. In vitro assays indicated that the AlgS-PVA/PCL scaffold surface had desirable interaction with stem cells and promotes cells attachment, proliferation and differentiation. Thus, we envision that this salient structure could be an intriguing construction as a cartilage tissue-engineered scaffold.

Keywords:  Alginate sulfate; Cartilage tissue engineering; Core-shell fibers; Emulsion electrospinning; Stem cells

DOI:  https://doi.org/10.1016/j.colsurfb.2024.114080
bioRxiv. 2024 Jul 10. pii: 2024.07.10.602835. [Epub ahead of print]

Global siRNA Screen Reveals Critical Human Host Factors of SARS-CoV-2 Multicycle Replication.

Xin Yin, Yuan Pu, Shuofeng Yuan, Lars Pache, Christopher Churas, Stuart Weston, Laura Riva, Lacy M Simons, William Cisneros, Thomas Clausen, Paul de Jesus, Ha Na Kim, Daniel Fuentes, John Whitelock, Jeffrey Esko, Megan Lord, Ignacio Mena, Adolfo Garcia-Sastre, Judd Hultquist, Matthew Frieman, Trey Ideker, Dexter Pratt, Laura Martin-Sancho, Sumit Chanda.

Defining the subset of cellular factors governing SARS-CoV-2 replication can provide critical insights into viral pathogenesis and identify targets for host-directed antiviral therapies. While a number of genetic screens have previously reported SARS-CoV-2 host dependency factors, these approaches relied on utilizing pooled genome-scale CRISPR libraries, which are biased towards the discovery of host proteins impacting early stages of viral replication. To identify host factors involved throughout the SARS-CoV-2 infectious cycle, we conducted an arrayed genome-scale siRNA screen. Resulting data were integrated with published datasets to reveal pathways supported by orthogonal datasets, including transcriptional regulation, epigenetic modifications, and MAPK signalling. The identified proviral host factors were mapped into the SARS-CoV-2 infectious cycle, including 27 proteins that were determined to impact assembly and release. Additionally, a subset of proteins were tested across other coronaviruses revealing 17 potential pan-coronavirus targets. Further studies illuminated a role for the heparan sulfate proteoglycan perlecan in SARS-CoV-2 viral entry, and found that inhibition of the non-canonical NF-kB pathway through targeting of BIRC2 restricts SARS-CoV-2 replication both in vitro and in vivo. These studies provide critical insight into the landscape of virus-host interactions driving SARS-CoV-2 replication as well as valuable targets for host-directed antivirals.

DOI: https://doi.org/10.1101/2024.07.10.602835
Cureus. 2024 Jul;16(7): e64771

Pathogenesis and Mechanism of Uremic Vascular Calcification.

Yingjing Shen.

  This review elucidates the modeling and mechanistic studies of vascular calcification in chronic kidney disease - mineral and bone disorder. In patients with chronic kidney disease, metabolic abnormalities in uremic toxins, including phosphate and indole sulfate, are closely associated with vascular calcification. Vitamin K, vascular circadian clock, and autophagy are also key factors involved in vascular calcification. Furthermore, communication between endothelial cells and smooth muscle cells also plays a pivotal role in the regulation of this process. Together, these factors accelerate vascular calcification progression and increase the risk of cardiovascular events. Therefore, timely intervention for vascular calcification is essential for patients with chronic kidney disease.

Keywords:  cell communication; chronic kidney disease; chronic kidney disease-mineral and bone disorder; mechanism; uremic toxic substance; vascular calcification

DOI:  https://doi.org/10.7759/cureus.64771