A rapid and accurate identification of necrotic myocardium is of great importance for diagnosis, risk stratification, clinical decision-making, and prognosis evaluation of myocardial infarction. Here, we explored technetium-99m labeled rhein derivatives for rapid imaging of the necrotic myocardium. Three hydrazinonicotinic acid-linker-rhein (HYNIC-linker-rhein) derivatives were synthesized, and then, these synthetic compounds were labeled with technetium-99m using ethylenediaminediacetic acid (EDDA) and tricine as coligands [Tc(EDDA)-HYNIC-linker-rhein]. The necrosis avidity of the three Tc-labeled rhein derivatives was tested in a mouse model of ethanol-induced muscular necrosis by gamma counting, histochemical staining, and autoradiography. A lead tracer for visualization of necrotic myocardium was assessed by single photon emission computed tomography/computed tomography (SPECT/CT) imaging in a rat model with reperfused myocardial infarction. The necrosis avidity mechanism of the tracer was explored by DNA binding studies in vitro and blocking experiments in vivo. Results showed that the uptake in necrotic muscles of the threeTc-compounds was higher than that in viable muscles (P < 0.001). Autoradiography and histochemical staining results were consistent with selective uptake of the radiotracer in the necrotic regions. Among the these tracers, Tc(EDDA)-HYNIC-ethylenediamine-rhein [Tc(EDDA)-HYNIC-2C-rhein] displayed the best distribution profiles for imaging. The necrotic myocardium lesions were clearly visualized by SPECT/CT using Tc(EDDA)-HYNIC-2C-rhein at 1 h after injection. The necrotic-to-viable myocardium and necrotic myocardium-to-blood uptake ratios ofTc(EDDA)-HYNIC-2C-rhein were 4.79 and 3.02 at 1 h after injection. DNA binding studies suggested HYNIC-linker-rhein bound to DNA through intercalation. The uptake of Tc(EDDA)-HYNIC-2C-rhein in necrotic muscle was significantly blocked by excessive unlabeled rhein, with 77.61% decline at 1 h after coinjection. These findings suggestedTc(EDDA)-HYNIC-2C-rhein emerged as a "hot spot" imaging probe that has a potential for rapid imaging of necrotic myocardium. The necrosis avidity mechanism of Tc(EDDA)-HYNIC-linker-rhein may be due to its interaction with exposed DNA in necrotic tissues.

Early and accurate assessment of therapeutic response to anticancer therapy plays an important role in determining treatment planning and patient management in clinic. Magnetic rseonance imaging (MRI) of necrosis that occurs after cancer therapies provides chances for that. Here, we reported three novel MRI contrast agents, GdL 1 , GdL 2 , and GdL 3 , by conjugating rhein with gadolinium 2-[4,7,10-tris(carboxymethyl)-1,4,7,10tetraazacyclododec-1-yl]acetic acid (Gd-DOTA) through different linkers. The T1 relaxivities of three probes (7.28, 7.35, and 8.03 mM −1 s −1 ) were found to be higher than that of Gd-DOTA (4.28 mM −1 s −1 ). Necrosis avidity of GdL 1 was evaluated on the rat models of reperfused liver infarction (RLI) by MRI, which showed an increase of T1-weighted contrast between necrotic and normal liver during 0.5−12 h. Besides, L 1 was also labeled with 64 Cu to assess its necrosis avidity on rat models of RLI and muscle necrosis (MN) by a γ-counter. The uptakes of 64 CuL 1 in necrotic liver and muscle were higher than those in normal liver and muscle (P < 0.05). Then, the ability of GdL 1 to assess therapeutic response was tested on rats bearing Walker 256 breast carcinoma injected with a vascular disrupting agent CA4P by MR imaging. The signal intensity of tumoral necrosis was strongly enhanced, and the contrast ratio between necrotic and viable tumor was 1.63 ± 0.11 at 3 h after administration of GdL 1 . Besides, exposed DNA in necrosis cells may be an important mechanism of three probes targeting to necrosis cells. In summary, GdL 1 may serve as a promising MRI contrast agent for accurate assessment of treatment response.

No abstract

Cell death plays important roles in living organisms and is a hallmark of numerous disorders such as cardiovascular diseases, sepsis and acute pancreatitis. Moreover, cell death also plays a pivotal role in the treatment of certain diseases, for example, cancer. Noninvasive visualization of cell death contributes to gained insight into diseases, development of individualized treatment plans, evaluation of treatment responses, and prediction of patient prognosis. On the other hand, cell death can also be targeted for the treatment of diseases. Although there are many ways for a cell to die, only apoptosis and necrosis have been extensively studied in terms of cell death related theranostics. This review mainly focuses on molecular imaging and therapeutic strategies directed against necrosis. Necrosis shares common morphological characteristics including the rupture of cell membrane integrity and release of cellular contents, which provide potential biomarkers for visualization of necrosis and necrosis targeted therapy. In the present review, we summarize the updated joint efforts to develop molecular imaging probes and therapeutic strategies targeting the biomarkers exposed by necrotic cells. Moreover, we also discuss the challenges in developing necrosis imaging probes and propose several biomarkers of necrosis that deserve to be explored in future imaging and therapy research.

Cell death plays a prominent role in the treatment of cancer, because most anticancer therapies act by the induction of cell death including apoptosis, necrosis, and other pathways of cell death. Imaging cell death helps to identify treatment responders from nonresponders and thus enables patient-tailored therapy, which will increase the likelihood of treatment response and ultimately lead to improved patient survival. By taking advantage of molecular probes that specifically target the biomarkers/biochemical processes of cell death, cell death imaging can be successfully achieved. In recent years, with the increased understanding of the molecular mechanism of cell death, a variety of well-defined biomarkers/biochemical processes of cell death have been identified. By targeting these established cell death biomarkers/biochemical processes, a set of molecular imaging probes have been developed and evaluated for early monitoring treatment response in tumors. In this review, we mainly present the recent advances in identifying useful biomarkers/biochemical processes for both apoptosis and necrosis imaging and in developing molecular imaging probes targeting these biomarkers/biochemical processes, with a focus on their application in early evaluation of tumor response to therapy.

Purpose Early evaluation of tumor response to thermal ablation therapy can help identify untreated tumor cells and then perform repeated treatment as soon as possible. The purpose of this work was to explore the potential of rhein‐based necrosis‐avid contrast agents (NACAs) for early evaluation of tumor response to microwave ablation (MWA). Methods 3‐[4,5‐dimethylthiazol‐2‐yl]‐2,5‐diphenyl tetrazolium bromide (MTT) assay was performed to test the cytotoxicity of rhein‐based NACAs against HepG2 cells. Rat models of liver MWA were used for investigating the effectiveness of rhein‐based NACAs in imaging the MWA lesion, the optimal time period for post‐MWA MRI examination, and the metabolic behaviors of 68Ga‐labeled rhein‐based NACAs. Rat models of orthotopic liver W256 tumor MWA were used for investigating the time window of rhein‐based NACAs for imaging the MWA lesion, the effectiveness of these NACAs in distinguishing the residual tumor and the MWA lesion, and their feasibility in early evaluating the tumor response to MWA. Results Gadolinium 2,2',2''‐(10‐(2‐((4‐(4,5‐Dihydroxy‐9,10‐dioxo‐9,10‐dihydroanthracene‐2‐carboxamido)butyl)amino)‐2‐oxoethyl)‐1,4,7,10‐tetraazacyclododecane‐1,4,7‐triyl)triacetic acid (GdL2) showed low cytotoxicity and high quality in imaging the MWA region. The optimal time period for post‐MWA MRI examination using GdL2 was 2 to 24 h after the treatment. During 2.5 to 3.5 h postinjection, GdL2 can better visualize the MWA lesion in comparison with gadolinium 2‐[4,7,10‐tris(carboxymethyl)‐1,4,7,10‐tetraazacyclododec‐1‐yl]acetic acid (Gd‐DOTA), and the residual tumor would not be enhanced. The tumor response to MWA as evaluated by using GdL2‐enhanced MRI was consistent with histological examination. Conclusion GdL2 appears to be a promising NACA for the tumor response assessment after thermal ablation therapies.

No abstract

This study aimed to assess the effects of triterpene extract of Cyclocarya paliurus (Batal.) Iljinskaja (CPT) on diabetes-induced hepatic inflammation and to unveil the underlying mechanisms. Diabetes in db/db mice was alleviated after CPT administration, as assessed by the oral glucose tolerance test. In addition, treatment with CPT dramatically reduced serum insulin, aspartate amino-transaminase, alanine aminotransferase, triglyceride, and total cholesterol amounts. Besides, serum levels of interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α were also reduced after CPT administration. Western blot analysis revealed that CPT treatment significantly reversed the protein expression levels of Rho, ROCK1, ROCK2, p-P65, p-IκBα, p-IKKα, and p-IKKβ in liver samples obtained from db/db mice. Upon palmitic acid stimulation, the protective effects of CPT on the liver were further assessed in HepG2 and LO2 cells, and no appreciable cytotoxic effects were found. Therefore, these findings indicate that CPT alleviates liver inflammation via Rho-kinase signaling. Chemical compounds evaluated in this report: Metformin (PubChem CID: 4091); Fasudil (PubChem CID: 3547); Palmitic acid (PubChem CID: 985).