AcidoCEST-UTE MRI Reveals an Acidic Microenvironment in Knee Osteoarthritis

Lombardi, Alecio; Ma, Yajun; Jang, Hyungseok; Jerban, Saeed; Tang, Qingbo; Searleman, Adam C.; Meyer, R. Scott; Du, Jiang; Chang, Eric Y.

doi:10.3390/ijms23084466

Cited by 23 publications

(11 citation statements)

References 48 publications

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“…This accumulation of lactate in the cytoplasm further lowers the pH value of the already acidic microenvironment, leading to extracellular acidosis (Richardson et al, 2010 ). Research indicates that patients with osteoarthritis have lower pH levels and lower pH measurements are associated with more severe symptoms and impaired knee function (Lombardi et al, 2022 ).…”

Section: Discussionmentioning

confidence: 99%

Analysis of the mechanism of curcumin against osteoarthritis using metabolomics and transcriptomics

Deng,

He,

Zhang

2023

Naunyn-Schmiedeberg's Arch Pharmacol

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Curcumin, a polyphenolic compound derived from the turmeric plant (Curcuma longa), has been extensively studied for its anti-inflammatory and anti-proliferative properties. The safety and efficacy of curcumin have been thoroughly validated. Nevertheless, the underlying mechanism for treating osteoarthritis remains ambiguous. This study aims to reveal the potential mechanism of curcumin in treating osteoarthritis by using metabolomics and transcriptomics. Firstly, we validated the effect of curcumin on inflammatory factors in human articular chondrocytes. Secondly, we explored the cellular metabolism mechanism of curcumin against osteoarthritis using cell metabolomics. Thirdly, we assessed the differences in gene expression of human articular chondrocytes through transcriptomics. Lastly, to evaluate the essential targets and elucidate the potential mechanism underlying the therapeutic effects of curcumin in osteoarthritis, we conducted a screening of the proteins within the shared pathway of metabolomics and transcriptomics. Our results demonstrated that curcumin significantly decreased the levels of inflammatory markers, such as IL-β, IL-6, and TNF-α, in human articular chondrocytes. Cell metabolomics identified 106 differential metabolites, including beta-aminopropionitrile, 3-amino-2-piperidone, pyrrole-2-carboxaldehyde, and various other components. The transcriptomic analysis yielded 1050 differential mRNAs. Enrichment analysis showed that the differential metabolites and mRNAs were significantly enriched in seven pathways, including glycine, serine, and threonine metabolism; pentose and glucuronate interconversions; glycerolipid metabolism; histidine metabolism; mucin-type o-glycan biosynthesis; inositol phosphate metabolism; and cysteine and methionine metabolism. A total of 23 key targets were identified to be involved in these pathways. We speculate that curcumin may alleviate osteoarthritis by targeting key proteins involved in glycine, serine, and threonine metabolism; inhibiting pyruvate production; and modulating glycolysis.

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Section: Discussionmentioning

confidence: 99%

Analysis of the mechanism of curcumin against osteoarthritis using metabolomics and transcriptomics

Deng,

He,

Zhang

2023

Naunyn-Schmiedeberg's Arch Pharmacol

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“…For in vivo assessment of tumor pHe, 4 T1 breast or H292 lung tumor bearing mice ( n = 4 per group; NSPS vs vehicle saline) described above were imaged via magnetic resonance imaging (MRI) at 7 Tesla using the chemical exchange saturation transfer (CEST) approach, an established method for measuring extracellular pH 42 , 43 , 44 , 45 , 46 , 47 in vivo. Clinical grade iohexol; 300 mg/mL Iodine (300 mgI/mL Omnipaque, GE Healthcare, purchased from VUMC pharmacy) was injected (0.2 mL) intraperitoneally and another 0.2 mL were injected directly into the tumors similar to Chen et al 43 The mice were scanned at baseline and immediately following an intravenous injection, via jugular vein catheter, of either a test dose of 25 mg/kg (0.6 mg) NSPS in 0.05 mL saline or vehicle (0.05 mL saline).…”

Section: Methodsmentioning

confidence: 99%

Tumor therapy by targeting extracellular hydroxyapatite using novel drugs: A paradigm shift

Tantawy,

McIntyre,

Yull

et al. 2024

Cancer Medicine

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BackgroundIt has been shown that tumor microenvironment (TME) hydroxyapatite (HAP) is typically associated with many malignancies and plays a role in tumor progression and growth. Additionally, acidosis in the TME has been reported to play a key role in selecting for a more aggressive tumor phenotype, drug resistance and desensitization to immunotherapy for many types of cancers. TME‐HAP is an attractive target for tumor detection and treatment development since HAP is generally absent from normal soft tissue. We provide strong evidence that dissolution of hydroxyapatite (HAP) within the tumor microenvironment (TME‐HAP) using a novel therapeutic can be used to kill cancer cells both in vitro and in vivo with minimal adverse effects.MethodsWe developed an injectable cation exchange nano particulate sulfonated polystyrene solution (NSPS) that we engineered to dissolve TME‐HAP, inducing localized acute alkalosis and inhibition of tumor growth and glucose metabolism. This was evaluated in cell culture using 4T1, MDA‐MB‐231 triple negative breast cancer cells, MCF10 normal breast cells, and H292 lung cancer cells, and in vivo using orthotopic mouse models of cancer that contained detectable microenvironment HAP including breast (MMTV‐Neu, 4T1, and MDA‐MB‐231), prostate (PC3) and colon (HCA7) cancer using 18F‐NaF for HAP and 18F‐FDG for glucose metabolism with PET imaging. On the other hand, H292 lung tumor cells that lacked detectable microenvironment HAP and MCF10a normal breast cells that do not produce HAP served as negative controls. Tumor microenvironment pH levels following injection of NSPS were evaluated via Chemical Exchange Saturation (CEST) MRI and via ex vivo methods.ResultsWithin 24 h of adding the small concentration of 1X of NSPS (~7 μM), we observed significant tumor cell death (~ 10%, p < 0.05) in 4T1 and MDA‐MB‐231 cell cultures that contain HAP but ⟨2% in H292 and MCF10a cells that lack detectable HAP and in controls. Using CEST MRI, we found extracellular pH (pHe) in the 4T1 breast tumors, located in the mammary fat pad, to increase by nearly 10% from baseline before gradually receding back to baseline during the first hour post NSPS administration. in the tumors that contained TME‐HAP in mouse models, MMTV‐Neu, 4T1, and MDA‐MB‐231, PC3, and HCA7, there was a significant reduction (p<0.05) in 18F‐Na Fuptake post NSPS treatment as expected; 18F‐ uptake in the tumor = 3.8 ± 0.5 %ID/g (percent of the injected dose per gram) at baseline compared to 1.8 ±0.5 %ID/g following one‐time treatment with 100 mg/kg NSPS. Of similar importance, is that 18F‐FDG uptake in the tumors was reduced by more than 75% compared to baseline within 24 h of treatment with one‐time NSPS which persisted for at least one week. Additionally, tumor growth was significantly slower (p < 0.05) in the mice treated with one‐time NSPS. Toxicity showed no evidence of any adverse effects, a finding attributed to the absence of HAP in normal soft tissue and to our therapeutic NSPS having limited penetration to access HAP within skeletal bone.ConclusionDissolution of TME‐HAP using our novel NSPS has the potential to provide a new treatment paradigm to enhance the management of cancer patients with poor prognosis.

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“…In OA lesioned joints, synovial fluid pH decreases from 7.4 to 6.0 owing to local tissue hypoxia metabolism and acidosis 112 , 113 . Even in different areas of the lesion, the pH of the joint tissue reflects some variability 114 . Articular cartilage (6.3) had a slightly lower pH than the meniscus (6.5) 114 .…”

Section: Responsive Biomaterials In Osteoarthritismentioning

confidence: 99%

“…Even in different areas of the lesion, the pH of the joint tissue reflects some variability 114 . Articular cartilage (6.3) had a slightly lower pH than the meniscus (6.5) 114 . This significant pH shift in the pathological microenvironment is considered as an ideal response condition to modulate drug delivery 115 , 116 .…”

Section: Responsive Biomaterials In Osteoarthritismentioning

confidence: 99%

Targeted and responsive biomaterials in osteoarthritis

Li¹,

Zhang²,

Han³

et al. 2023

Theranostics

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Osteoarthritis (OA) is a degenerative disease characterized by loss of articular cartilage and chronic inflammation, involving multiple cellular dysfunctions and tissue lesions. The non-vascular environment and dense cartilage matrix in the joints tend to block drug penetration, resulting in low drug bioavailability. There is a desire to develop safer and more effective OA therapies to meet the challenges of an aging world population in the future. Biomaterials have achieved satisfactory results in improving drug targeting, prolonging the duration of action, and achieving precision therapy. This article reviews the current basic understanding of the pathological mechanisms and clinical treatment dilemmas of OA, summarizes and discusses the advances for different kinds of targeted and responsive biomaterials in OA, seeking to provide new perspectives for the treatment of OA. Subsequently, limitations and challenges in clinical translation and biosafety are analyzed to guide the development of future therapeutic strategies for OA. As the need for precision medicine rises over time, emerging multifunctional biomaterials based on tissue targeting and controlled release will become an irreplaceable part of OA management.

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AcidoCEST-UTE MRI Reveals an Acidic Microenvironment in Knee Osteoarthritis

Cited by 23 publications

References 48 publications

Analysis of the mechanism of curcumin against osteoarthritis using metabolomics and transcriptomics

Analysis of the mechanism of curcumin against osteoarthritis using metabolomics and transcriptomics

Tumor therapy by targeting extracellular hydroxyapatite using novel drugs: A paradigm shift

Targeted and responsive biomaterials in osteoarthritis

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