Copper Chelates Research Articles

Rapid and prolonged response of oligodendrocyte lineage cells in standard acute cuprizone demyelination model revealed by in situ hybridization

Dietary administration of a copper chelator, cuprizone (CPZ), has long been reported to induce intense and reproducible demyelination of several brain structures such as the corpus callosum. Despite the widespread use of CPZ as an animal model for demyelinating diseases such as multiple sclerosis (MS), the mechanism by which it induces demyelination and then allows robust remyelination is still unclear. An intensive mapping of the cell dynamics of oligodendrocyte (OL) lineage during the de- and remyelination course would be particularly important for a deeper understanding of this model. Here, using a panel of OL lineage cell markers as in situ hybridization (ISH) probes, including Pdgfra, Plp, Mbp, Mog, Enpp6, combined with immunofluorescence staining of CC1, SOX10, we provide a detailed dynamic profile of OL lineage cells during the entire course of the model from 1, 2, 3.5 days, 1, 2, 3, 4,5 weeks of CPZ treatment, as well as after 1, 2, 3, 4 weeks of recovery from CPZ treatment. The result showed an unexpected early death of mature OLs and response of OL progenitor cells (OPCs) in vivo upon CPZ challenge, and a prolonged upregulation of myelin-forming OLs compared to the intact control even 4 weeks after CPZ withdrawal. These data may serve as a basic reference system for future studies of the effects of any intervention on de- and remyelination using the CPZ model, and imply the need to optimize the timing windows for the introduction of pro-remyelination therapies in demyelinating diseases such as MS.

A Case Report on Wilson’s Disease

The accumulation of copper in the liver, brain, cornea, and kidneys is the hallmark of Wilson's disease, an uncommon autosomal recessive condition. There is no community-based research on the prevalence and incidence of Wilson's disease in India; this study is hospital-based. Overview of the Case: A 10-year-old girl with serious complaints of burning micturition, giddiness, loose stools and blood in stools, yellowish discolouration of skin and sclera, generalized body aches, fever and stomach pain with distension was brought to the paediatric department. Wilson's illness was established by abdominal USG using the increased levels of urine copper, whole blood picture, liver function tests, and serum electrolytes and decreased levels of ceruloplasmin. The prominent characteristic, which is less common in youngsters, is the Kayser Fleisher ring. It is identified by a discoloration of the corneal edge that is greenish-brown in colour and eventually goes away with treatment. Probiotics, an antibiotic, a hepatoprotective drug, and copper chelators (D-penicillamine and zinc) were used in her treatment. Gradually she showed improvement in clinical signs and LFT levels.

The Chemistry of Chelation for Built Heritage Cleaning: The Removal of Copper and Iron Stains.

Chelators are widely used in conservation treatments to remove metal stains from marble, travertine, and limestone surfaces. In the current review the chemical aspects underlying the use of chelators for the removal of copper and iron stains from built heritage are described and clear criteria for the selection of the most efficient stain removal treatment are given. The main chelator structural features are outlined and the operating conditions for effective metal stain removal (pH, time of application, etc.) discussed, with a particular emphasis on the ability to form stable metal complexes, the high selectivity towards the metal that should be removed, and the high sustainability for the environment. Dense matrices often host chelators for higher effectiveness, and further research is required to clarify their role in the cleaning process. Then, relevant case studies of copper and iron stain removal are discussed. On these bases, the most effective chelators for copper and stain removal are indicated, providing chemists and conservation scientists with scientific support for conservation operations on stone works of art and opening the way to the synthesis of new chelators.

Copper Chelation Therapy Attenuates Periodontitis Inflammation through the Cuproptosis/Autophagy/Lysosome Axis.

Periodontitis development arises from the intricate interplay between bacterial biofilms and the host's immune response, where macrophages serve pivotal roles in defense and tissue homeostasis. Here, we uncover the mitigative effect of copper chelator Tetrathiomolybdate (TTM) on periodontitis through inhibiting cuproptosis, a newly identified form of cell death which is dependent on copper. Our study reveals concurrent cuproptosis and a macrophage marker within murine models. In response to lipopolysaccharide (LPS) stimulation, macrophages exhibit elevated cuproptosis-associated markers, which are mitigated by the administration of TTM. TTM treatment enhances autophagosome expression and mitophagy-related gene expression, countering the LPS-induced inhibition of autophagy flux. TTM also attenuates the LPS-induced fusion of autophagosomes and lysosomes, the degradation of lysosomal acidic environments, lysosomal membrane permeability increase, and cathepsin B secretion. In mice with periodontitis, TTM reduces cuproptosis, enhances autophagy flux, and decreases Ctsb levels. Our findings underscore the crucial role of copper-chelating agent TTM in regulating the cuproptosis/mitophagy/lysosome pathway during periodontitis inflammation, suggesting TTM as a promising approach to alleviate macrophage dysfunction. Modulating cuproptosis through TTM treatment holds potential for periodontitis intervention.

Polydopamine reduced graphene oxide/ chitosan-based hydrogel for the therapy of diabetic wound

Diabetic foot ulcer (DFU) is a serious complication of diabetes, often leading to high risks of amputation and imposing considerable economic burdens on patients. Hyperglycemia induced impaired angiogenesis and increased susceptibility to bacterial infection are common obstacles in DFU wound healing, which impede the recovery process. In this work, a novel multifunctional polydopamine reduced graphene oxide chelating copper ions chitosan (PDA-rGO@Cu/CS) hydrogel was developed. Specifically, PDA-rGO@Cu/CS hydrogel dressing was facilitated efficient sterilization and angiogenesis, which attributed to the remarkable photothermal performance and the catalyzing NO release function of hydrogel. Experimental results indicated that the hydrogel accelerated the wound healing process in diabetic rats after topical application and the wound closure rate reached up to 91.57% (vs. 60% of the control) on day 14. Furthermore, in vitro/vivo antibacterial assays demonstrated that the hydrogel possessed antibacterial activity against E.coli and S.aureus, and improved infected wound healing as well as wound closure, which reached up to 90.42% on day 10. Mechanistically, H&E staining, Masson staining, immunofluorescent staining for CD31&α-SMA and IL-6 exhibited that the hydrogel accelerated full-thickness skin wound reconstruction by inhibiting inflammation, promoting collagen deposition and accelerating angiogenesis. Collectively, PDA-rGO@Cu/CS hydrogel provided a promising and efficient treatment strategy for DFU.

#2036 Mitochondrial copper overload promotes renal fibrosis via inhibiting pyruvate dehydrogenase activity

Abstract Background and Aims Copper is a trace element essential for numerous biological activities, whereas the mitochondria serve as both major sites of intracellular copper utilization and copper reservoir. Pyruvate dehydrogenase complex (PDHC) is a rate-limiting enzyme of glucose oxidation in mitochondrial matrix, converting pyruvate into acetyl-CoA and linking glycolysis to tricarboxylic acid (TCA) cycle. Dihydrolipoamide acetyltransferase (DLAT), the E2 component of the PDHC, requires lipoylation for enzymatic function and exhibits a high affinity for copper within its lipoyl moiety. Here, we investigated the impact of mitochondrial copper overload on the tricarboxylic acid cycle and renal senescence and fibrosis. Method Molecular dynamics simulation was used to explore the effect of copper ions on lipoylated DLAT protein. ICP-MS was used to detect copper content in mitochondria. Western blotting was used to detect the level of lipoylated DLAT dimer. Enzyme biopsy test kit, electron microscopy, mitoSOX Red staining and ATP content detection were used to evaluate mitochondrial function. Detect Collagen I, α-smooth muscle actin (α-SMA) expression levels and Masson staining to explore renal fibrosis. To reduce mitochondrial copper level, we used lentivirus to downregulate CRT1 expression or copper chelator tetrathiomolybdate in renal tubular epithelial cells (NRK-52E), and used CTR1 knockdown transgenic mice or tetrathiomolybdate in vivo. Results We found that copper ion levels are significantly elevated in the mitochondria in fibrotic kidney tissues, which are accompanied by reduced pyruvate dehydrogenase (PDH) activity, mitochondrial dysfunction, cellular senescence and renal fibrosis. Conversely, lowering mitochondrial copper levels through knocking-down of copper transporter 1 or treatment with the copper chelator tetrathiomolybdate effectively restore PDH enzyme activity, improve mitochondrial function, and mitigate cellular senescence and renal fibrosis. Mechanically, we found mitochondrial copper binds directly to lipoylated dihydrolipoamide acetyltransferase (DLAT), thereby changing the interaction between protein subunits, inducing lipoylated DLAT protein dimerization, and ultimately inhibiting PDH enzyme activity. Conclusion Our study indicates that mitochondrial copper overload could inhibit PDH activity, subsequently leading to mitochondrial dysfunction, cellular senescence and renal fibrosis. Reducing mitochondrial copper overload might therefore serve as a strategy to rescue renal fibrosis.

Role of copper chelating agents: between old applications and new perspectives in neuroscience.

The role of copper element has been an increasingly relevant topic in recent years in the fields of human and animal health, for both the study of new drugs and innovative food and feed supplements. This metal plays an important role in the central nervous system, where it is associated with glutamatergic signaling, and it is widely involved in inflammatory processes. Thus, diseases involving copper (II) dyshomeostasis often have neurological symptoms, as exemplified by Alzheimer's and other diseases (such as Parkinson's and Wilson's diseases). Moreover, imbalanced copper ion concentrations have also been associated with diabetes and certain types of cancer, including glioma. In this paper, we propose a comprehensive overview of recent results that show the importance of these metal ions in several pathologies, mainly Alzheimer's disease, through the lens of the development and use of copper chelators as research compounds and potential therapeutics if included in multi-target hybrid drugs. Seeing how copper homeostasis is important for the well-being of animals as well as humans, we shortly describe the state of the art regarding the effects of copper and its chelators in agriculture, livestock rearing, and aquaculture, as ingredients for the formulation of feed supplements as well as to prevent the effects of pollution on animal productions.

Cuproptosis in lung cancer: therapeutic options and prognostic models.

Lung cancer (LC) is a serious threat to mankind. The survival of LC patients is still poor despite the enormous efforts that have been made to develop novel treatments. A copper-dependent cell death termed cuproptosis is distinct from known programmed cell death (PCD). Cuproptosis is induced by the disruption of the binding of copper to lipoylated tricarboxylic acid (TCA) cycle proteins of mitochondrial respiratory chains. Potential approaches for treating LC are inducing cell cuproptosis and targeting cell copper death mechanisms. Thus, in this review, we summarize the systemic and cellular metabolic processes of copper. We highlight the possible therapeutic options of employing copper ionophores and chelators for inducing cuproptosis. Moreover, we summarize the prognostic models based on cuproptosis-related genes (CRGs) to identify promising biomarkers for tumor diagnosis and therapy. This review aims to provide a comprehensive summary of CRGs-based prognostic models and promising therapeutic options for cuproptosis induction in LC.

Human Serum Albumin Mediated Controllable Synthesis of Defect-Rich Copper Hydroxide Nanowire for Cuproptosis-Based Anti-Tumor Therapy.

Cuproptosis, as a newly identified form of programmed cell death, shows great promise in cancer treatment. Efficient Cu+ delivery while avoiding systemic toxicity and elimination of the resistance from over-expressed intracellular copper chelator glutathione (GSH) are critical for cuproptosis. Herein, this work innovatively constructs a biocompatible and defect-rich copper hydroxide nanowire (HCu nanowire) through a human serum albumin (HSA) mediated biomineralization method. This work finds that the morphology and size of HCu nanowires can be controlled adjusted by the feed ratio of HSA and Cu2+. Remarkably, except for outstanding biocompatibility, HSA coordination endows HCu nanowires abundant oxygen vacancies (OVs), and the defect-rich HCu nanowire possesses excellent GSH consumption efficiency. Density functional theory studies indicate that OVs change GSH absorption energy on defective HCu nanowires. In cancer cells, HCu nanowires deplete GSH and simultaneously produce sufficient free Cu+ for enhanced cuproptosis. Meanwhile, Cu+ can catalyze endogenous H2O2 into hydroxyl radicals (·OH) via a Fenton-like reaction. Thus, synergetic cuproptosis and ROS mediated apoptosis against tumor are achieved. The experimental results show that HCu nanowires have a better performance in both antitumor efficiency and safety compared with chemotherapeutic drug Dox at the same dose, demonstrating its great potential in clinical applications.

Cytotoxic Activity of the Red Grape Polyphenol Resveratrol against Human Prostate Cancer Cells: A Molecular Mechanism Mediated by Mobilization of Nuclear Copper and Generation of Reactive Oxygen Species.

Resveratrol, a polyphenolic compound found primarily in red grapes and pomegranates is known as an antioxidant but can act as a pro-oxidant when copper ions are present. Here, resveratrol is demonstrated to reduce cell growth (as evaluated by MTT assay) and promote apoptosis-like cell death (as measured by Histone/DNA ELISA) in prostate cancer cell lines PC3 and C42B. This effect is effectively inhibited by a copper chelator (neocuproine) and reactive oxygen species (ROS) scavengers (thiourea for hydroxyl radical, superoxide dismutase for superoxide anion, and catalase for hydrogen peroxide). These inhibitory effects provide evidence that intracellular copper reacts with resveratrol within cancer cells, resulting in DNA damage via the generation of reactive oxygen species. Additionally, it has been demonstrated that non-tumorigenic epithelial cell lines (MCF-10A) grown in media supplemented with copper are more susceptible to growth inhibition by resveratrol, as confirmed by the observed reduction in cell proliferation. Copper supplementation induces enhanced expression of the copper transporter CTR1 in MCF-10A cells, which is reduced by the addition of resveratrol to the media. The selective cell death of cancer cells generated by copper-mediated and ROS mechanisms may help to explain the anticancer properties of resveratrol.

Sleep fragmentation exacerbates myocardial ischemia‒reperfusion injury by promoting copper overload in cardiomyocytes

Sleep disorders increase the risk and mortality of heart disease, but the brain-heart interaction has not yet been fully elucidated. Cuproptosis is a copper-dependent type of cell death activated by the excessive accumulation of intracellular copper. Here, we showed that 16 weeks of sleep fragmentation (SF) resulted in elevated copper levels in the male mouse heart and exacerbated myocardial ischemia–reperfusion injury with increased myocardial cuproptosis and apoptosis. Mechanistically, we found that SF promotes sympathetic overactivity, increases the germination of myocardial sympathetic nerve terminals, and increases the level of norepinephrine in cardiac tissue, thereby inhibits VPS35 expression and leads to impaired ATP7A related copper transport and copper overload in cardiomyocytes. Copper overload further leads to exacerbated cuproptosis and apoptosis, and these effects can be rescued by excision of the sympathetic nerve or administration of copper chelating agent. Our study elucidates one of the molecular mechanisms by which sleep disorders aggravate myocardial injury and suggests possible targets for intervention.

Antitumor Activity and Mechanistic Insights of a Mitochondria-Targeting Cu(I) Complex.

Using copper-ionophores to translocate extracellular copper into mitochondria is a clinically validated anticancer strategy that has been identified as a new type of regulated cell death termed "cuproptosis." This study reports a mitochondria-targeting Cu(I) complex, Cu(I)Br(PPh3)3 (CBP), consisting of a cuprous ion coordinated by three triphenylphosphine moieties and a Br atom. CBP exhibited antitumor and antimetastatic efficacy in vitro and in vivo by specifically targeting mitochondria instigating mitochondrial dysfunction. The cytotoxicity of CBP could only be reversed by a copper chelator rather than inhibitors of the known cell death, indicating copper-dependent cytotoxicity. Furthermore, CBP induced the oligomerization of lipoylated proteins and the loss of Fe-S cluster proteins, consistent with characteristic features of cuproptosis. Additionally, CBP induced remarkable intracellular generation of reactive oxygen species (ROS) through a Fenton-like reaction, indicating a complex antitumor mechanism. This is a proof-of-concept study exploiting the antitumor activity and mechanism of the Cu(I)-based mitochondria-targeting therapy.

Retinoic acid mitigates the NSC319726-induced spermatogenesis dysfunction through cuproptosis-independent mechanisms

Copper ionophore NSC319726 has attracted researchers' attention in treating diseases, particularly cancers. However, its potential effects on male reproduction during medication are unclear. This study aimed to determine whether NSC319726 exposure affected the male reproductive system. The reproductive toxicity of NSC319726 was evaluated in male mice following a continuous exposure period of 5 weeks. The result showed that NSC319726 exposure caused testis index reduction, spermatogenesis dysfunction, and architectural damage in the testis and epididymis. The exposure interfered with spermatogonia proliferation, meiosis initiation, sperm count, and sperm morphology. The exposure also disturbed androgen synthesis and blood testis barrier integrity. NSC319726 treatment could elevate the copper ions in the testis to induce cuproptosis in the testis. Copper chelator rescued the elevated copper ions in the testis and partly restored the spermatogenesis dysfunction caused by NSC319726. NSC319726 treatment also decreased the level of retinol dehydrogenase 10 (RDH10), thereby inhibiting the conversion of retinol to retinoic acid, causing the inability to initiate meiosis. Retinoic acid treatment could rescue the meiotic initiation and spermatogenesis while not affecting the intracellular copper ion levels. The study provided an insight into the bio-safety of NSC319726. Retinoic acid could be a potential therapy for spermatogenesis impairment in patients undergoing treatment with NSC319726.

Wilson Disease: Copper-Mediated Cuproptosis, Iron-Related Ferroptosis, and Clinical Highlights, with Comprehensive and Critical Analysis Update.

Wilson disease is a genetic disorder of the liver characterized by excess accumulation of copper, which is found ubiquitously on earth and normally enters the human body in small amounts via the food chain. Many interesting disease details were published on the mechanistic steps, such as the generation of reactive oxygen species (ROS) and cuproptosis causing a copper dependent cell death. In the liver of patients with Wilson disease, also, increased iron deposits were found that may lead to iron-related ferroptosis responsible for phospholipid peroxidation within membranes of subcellular organelles. All topics are covered in this review article, in addition to the diagnostic and therapeutic issues of Wilson disease. Excess Cu2+ primarily leads to the generation of reactive oxygen species (ROS), as evidenced by early experimental studies exemplified with the detection of hydroxyl radical formation using the electron spin resonance (ESR) spin-trapping method. The generation of ROS products follows the principles of the Haber-Weiss reaction and the subsequent Fenton reaction leading to copper-related cuproptosis, and is thereby closely connected with ROS. Copper accumulation in the liver is due to impaired biliary excretion of copper caused by the inheritable malfunctioning or missing ATP7B protein. As a result, disturbed cellular homeostasis of copper prevails within the liver. Released from the liver cells due to limited storage capacity, the toxic copper enters the circulation and arrives at other organs, causing local accumulation and cell injury. This explains why copper injures not only the liver, but also the brain, kidneys, eyes, heart, muscles, and bones, explaining the multifaceted clinical features of Wilson disease. Among these are depression, psychosis, dysarthria, ataxia, writing problems, dysphagia, renal tubular dysfunction, Kayser-Fleischer corneal rings, cardiomyopathy, cardiac arrhythmias, rhabdomyolysis, osteoporosis, osteomalacia, arthritis, and arthralgia. In addition, Coombs-negative hemolytic anemia is a key feature of Wilson disease with undetectable serum haptoglobin. The modified Leipzig Scoring System helps diagnose Wilson disease. Patients with Wilson disease are well-treated first-line with copper chelators like D-penicillamine that facilitate the removal of circulating copper bound to albumin and increase in urinary copper excretion. Early chelation therapy improves prognosis. Liver transplantation is an option viewed as ultima ratio in end-stage liver disease with untreatable complications or acute liver failure. Liver transplantation finally may thus be a life-saving approach and curative treatment of the disease by replacing the hepatic gene mutation. In conclusion, Wilson disease is a multifaceted genetic disease representing a molecular and clinical challenge.

Development and translation of thiometallate sulfide donors using a porcine model of coronary occlusion and reperfusion

Sulfide-releasing compounds reduce reperfusion injury by decreasing mitochondria-derived reactive oxygen species production. We previously characterised ammonium tetrathiomolybdate (ATTM), a clinically used copper chelator, as a sulfide donor in rodents. Here we assessed translation to large mammals prior to clinical testing. In healthy pigs an intravenous ATTM dose escalation revealed a reproducible pharmacokinetic/pharmacodynamic (PK/PD) relationship with minimal adverse clinical or biochemical events. In a myocardial infarction (1-h occlusion of the left anterior descending coronary artery)-reperfusion model, intravenous ATTM or saline was commenced just prior to reperfusion. ATTM protected the heart (24-h histological examination) in a drug-exposure-dependent manner (r2 = 0.58, p < 0.05). Blood troponin T levels were significantly (p < 0.05) lower in ATTM-treated animals while myocardial glutathione peroxidase activity, an antioxidant selenoprotein, was elevated (p < 0.05). Overall, our study represents a significant advance in the development of sulfides as therapeutics and underlines the potential of ATTM as a novel adjunct therapy for reperfusion injury. Mechanistically, our study suggests that modulating selenoprotein activity could represent an additional mode of action of sulfide-releasing drugs.

Dendritic Pyridine-Imine Copper Complexes as Metallo-Drugs.

Since the discovery of cisplatin in the 1960s, the search for metallo-drugs that are more efficient than platinum complexes with negligible side effects has attracted much interest. Among the other metals that have been examined for potential applications as anticancer agents is copper. The interest in copper was recently boosted by the discovery of cuproptosis, a recently evidenced form of cell death mediated by copper. However, copper is also known to induce the proliferation of cancer cells. In view of these contradictory results, there is a need to find the most suitable copper chelators, among which Schiff-based derivatives offer a wide range of possibilities. Gathering several metal complexes in a single, larger entity may provide enhanced properties. Among the nanometric objects suitable for such purpose are dendrimers, precisely engineered hyperbranched macromolecules, which are outstanding candidates for improving therapy and diagnosis. In this review article, we present an overview of the use of a particular Schiff base, namely pyridine-imine, linked to the surface of dendrimers, suitable for complexing copper, and the use of such dendrimer complexes in biology, in particular against cancers.

Initial Steps in Methanobactin Biosynthesis: Substrate Binding by the Mixed-Valent Diiron Enzyme MbnBC.

The MbnBC enzyme complex converts cysteine residues in a peptide substrate, MbnA, to oxazolone/thioamide groups during the biosynthesis of copper chelator methanobactin (Mbn). MbnBC belongs to the mixed-valent diiron oxygenase (MVDO) family, of which members use an Fe(II)Fe(III) cofactor to react with dioxygen for substrate modification. Several crystal structures of the inactive Fe(III)Fe(III) form of MbnBC alone and in complex with MbnA have been reported, but a mechanistic understanding requires determination of the oxidation states of the crystallographically observed Fe ions in the catalytically active Fe(II)Fe(III) state, along with the site of MbnA binding. Here, we have used electron nuclear double resonance (ENDOR) spectroscopy to determine such structural and electronic properties of the active site, in particular, the mode of substrate binding to the MV state, information not accessible by X-ray crystallography alone. The oxidation states of the two Fe ions were determined by 15N ENDOR analysis. The presence and locations of both bridging and terminal exogenous solvent ligands were determined using 1H and 2H ENDOR. In addition, 2H ENDOR using an isotopically labeled MbnA substrate indicates that MbnA binds to the Fe(III) ion of the cluster via the sulfur atom of its N-terminal modifiable cysteine residue, with displacement of a coordinated solvent ligand as shown by complementary 1H ENDOR. These results, which underscore the utility of ENDOR in studying MVDOs, provide a molecular picture of the initial steps in Mbn biosynthesis.

In vitro immune analysis of serum from the hemolymph of the anomuran crab Albunea symmysta (Linnaeus, 1758) displayed diversified reactions

The present investigation aims to substantiate that serum from the hemolymph of anomuran crab Albunea symmysta encompasses multiple immunological reactions in in vitro condition. The serum highly agglutinated human O erythrocytes in the presence of Ba2+. Distinct and unique sugar binding capacity of serum towards laminarin, N-acetyl sugars and higher binding specificity towards a glycoprotein, fetuin was inferred. In vitro enhancement of melanin synthesis due to enhanced oxidation of 3, 4-dihydroxy-dl-phenylalanine (dl-DOPA) by preincubation of nonself molecules with serum phenoloxidase (PO) was documented. Similarly, dl-DOPA oxidation by serum PO was reduced when preincubated with chemical inhibitors and copper chelators. Further, the crab serum lysed the vertebrate erythrocytes with maximum hemolysis against chicken and it unveiled dependency on divalent cation, serum concentration, ionic strength, pH, temperature and time interval. Occurrence of maximum hemolysis at a concentration of 30 µl, pH 8.0, temperature 37 °C and time interval of 60 min in the presence of Ba2+ were documented. Interestingly, serum hemolysis was reduced by different osmoprotectants suggesting a colloid-osmotic mechanism involving in hemolysis. It was observed that A. symmysta serum had antimicrobial activity against Gram-positive Staphylococcus aureus and fungal pathogen Candida albicans. The serum showed higher glycan content, potent lysozyme and free radical scavenging activity suggesting the existence of potential immune molecules of therapeutic use. These results clearly demonstrated the diversified immunogenicity of A. symmysta serum confirming a highly conserved non-specific immunity of crustaceans

Molecular Imaging of Diffuse Cardiac Fibrosis with a Radiotracer That Targets Proteolyzed Collagen IV.

Purpose To develop an approach for in vivo detection of interstitial cardiac fibrosis using PET with a peptide tracer targeting proteolyzed collagen IV (T-peptide). Materials and Methods T-peptide was conjugated to the copper chelator MeCOSar (chemical name, 5-(8-methyl-3,6,10,13,16,19-hexaaza-bicyclo[6.6.6]icosan-1-ylamino)-5-oxopentanoic acid) and radiolabeled with copper 64 (64Cu). PET/CT scans were acquired following intravenous delivery of 64Cu-T-peptide-MeCOSar (0.25 mg/kg; 18 MBq ± 2.7 [SD]) to male transgenic mice overexpressing β2-adrenergic receptors with intermediate (7 months of age; n = 4 per group) to severe (10 months of age; n = 11 per group) cardiac fibrosis and their wild-type controls. PET scans were also performed following coadministration of the radiolabeled probe with nonlabeled T-peptide in excess to confirm binding specificity. PET data were analyzed by t tests for static scans and analysis of variance tests (one- or two-way) for dynamic scans. Results PET/CT scans revealed significantly elevated (2.24-4.26-fold; P < .05) 64Cu-T-peptide-MeCOSar binding in the fibrotic hearts of aged transgenic β2-adrenergic receptor mice across the entire 45-minute acquisition period compared with healthy controls. The cardiac tracer accumulation and presence of diffuse cardiac fibrosis in older animals were confirmed by gamma counting (P < .05) and histologic evaluation, respectively. Coadministration of a nonradiolabeled probe in excess abolished the elevated radiotracer binding in the aged transgenic hearts. Importantly, PET tracer accumulation was also detected in younger (7 months of age) transgenic mice with intermediate cardiac fibrosis, although this was only apparent from 20 minutes following injection (1.6-2.2-fold binding increase; P < .05). Conclusion The T-peptide PET tracer targeting proteolyzed collagen IV provided a sensitive and specific approach of detecting diffuse cardiac fibrosis at varying degrees of severity in a transgenic mouse model. Keywords: Diffuse Cardiac Fibrosis, Molecular Peptide Probe, Molecular Imaging, PET/CT © RSNA, 2024.

In situ assembly FeS2-tetrathiomolybdate nanosheets for imaging-guided tumor vascular collapse and amplified catalytic therapy

Catalytic therapy has recently gained considerable attention as a novel tumor microenvironment (TME)-responsive treatment. While conventional nano-catalysts have demonstrated the ability to induce the death of tumor cells through oxidative damage via the generation of reactive oxygen species (ROS), their therapeutic efficacy is impeded by several factors, including limited tissue penetration depth and suboptimal catalytic efficiency. Herein, the FeS2-tetrathiomolybdate (FeS2-TTM) nanosheet was synthesized via in-situ self-assembled in the specific redox TME using metal precursors of divalent iron and tetrathiomolybdate, and these metal precursors could easily enter tumor cells through vascular penetration to avoid the blood-brain barrier. This nanosheet has been proved to possess peroxidase (POD)-like catalytic activity, which overcomes the limitations of traditional nanoparticals by the bimetallic electron transfer effect in the TME to amplify the catalytic treatment effect. Importantly, it retains the chelating copper characteristics of TTM, and inhibits tumor angiogenesis by depriving the necessary copper in cells and angiogenesis, resulting in vascular embolization to cause tumor blood vessels to collapse. Additionally, it can also act as a nanoprobe that supports both real-time fluorescence imaging monitoring and T1/T2 dual-modality magnetic resonance imaging (MRI). As a promising nanomaterial, this new type of in-situ self-assembled nanosheet provides more varieties for the construction of an integrative platform of tumor diagnosis and treatment.