Search Results (83)

The stomach has been a highly conserved organ throughout vertebrate evolution; however, there are now over 20 lineages composed of monotremes, lungfish and teleost fish displaying a secondary loss of stomach function and morphology. This “agastric phenotype” has evolved convergently and is typified by a loss of gastric glands and gastric acid secretion and a near-to-complete loss of storage capacity of the stomach. All agastric species have lost the genes for gastric enzymes (Pga and Pgc) and proton pump subunits (Atp4a and Atp4b), and gastrin (Gast) has been lost in monotremes. As a key gastric hormone, the conservation of gastrin has not yet been investigated in the lungfish or agastric teleosts, and it is unclear how the loss of gastrin affects the evolution and selection of the native receptor (Cckbr), gastrin-releasing peptide (Grp) and gastrin-releasing peptide receptor (Grpr) in vertebrates. Furthermore, there are still many genes implicated in gastric development and function which have yet to be associated with the agastric phenotype. We analysed the evolution, selection and conservation of the gastrin pathway and a novel gastric gene repertoire (Gkn1, Gkn2, Tff1, Tff2, Vsig1 and Anxa10) to determine the correlation with the agastric phenotype. We found that the loss of gastrin or its associated genes does not correlate with the agastric phenotype, and their conservation is due to multiple pleiotropic roles throughout vertebrate evolution. We found a loss of the gastric gene repertoire in the agastric phenotype, except in the echidna, which retained several genes (Gkn1, Tff2 and Vsig1). Our findings suggest that the gastrin physiological pathway evolved differently in pleiotropic roles throughout vertebrate evolution and support the convergent evolution of the agastric phenotype through shared independent gene-loss events. Full article

Background/Objectives: Gastrin-releasing peptide receptor (GRPR) is overexpressed in breast cancer and might be used as a theranostics target. The expression of GRPR strongly correlates with estrogen receptor (ER) expression. Visualization of GRPR-expressing breast tumors might help to select the optimal treatment. Developing GRPR-specific probes for SPECT would permit imaging-guided therapy in regions with restricted access to PET facilities. In this first-in-human study, we evaluated the safety, biodistribution, and dosimetry of the [^99mTc]Tc-DB8 GRPR-antagonistic peptide. We also addressed the important issue of finding the optimal injected peptide mass. Methods: Fifteen female patients with ER-positive primary breast cancer were enrolled and divided into three cohorts receiving [^99mTc]Tc-DB8 (corresponding to three distinct doses of 40, 80, or 120 µg DB8) comprising five patients each. Additionally, four patients with ER-negative primary tumors were injected with 80 µg [^99mTc]Tc-DB8. The injected activity was 360 ± 70 MBq. Planar scintigraphy was performed after 2, 4, 6, and 24 h, and SPECT/CT scans followed planar imaging 2, 4, and 6 h after injection. Results: No adverse events were associated with [^99mTc]Tc-DB8 injections. The effective dose was 0.009–0.014 mSv/MBq. Primary tumors and all known lymph node metastases were visualized irrespective of injected peptide mass. The highest uptake in the ER-positive tumors was 2 h after injection of [^99mTc]Tc-DB8 at a 80 µg DB8 dose (SUV_max 5.3 ± 1.2). Injection of [^99mTc]Tc-DB8 with 80 µg DB8 provided significantly (p < 0.01) higher uptake in primary ER-positive breast cancer lesions than injection with 40 µg DB8 (SUV_max 2.0 ± 0.3) or 120 µg (SUV_max 3.2 ± 1.4). Tumor-to-contralateral breast ratio after injection of 80 μg was also significantly (p < 0.01, ANOVA test) higher than ratios after injection of other peptide masses. The uptake in ER-negative lesions was significantly lower (SUV_max 2.0 ± 0.3) than in ER-positive tumors. Conclusions: Imaging using [^99mTc]Tc-DB8 is safe, tolerable, and associated with low absorbed doses. The tumor uptake is dependent on the injected peptide mass. The injection of an optimal mass (80 µg) provides the highest uptake in ER-positive tumors. At optimal dosing, the uptake was significantly higher in ER-positive than in ER-negative lesions. Full article

Targeted radioligand therapy (RLT) is an emerging field in anticancer therapeutics with great potential across tumor types and stages of disease. While much progress has focused on agents targeting somatostatin receptors and prostate-specific membrane antigen (PSMA), the same advanced radioconjugation methods and molecular targeting have spurred the development of numerous theranostic combinations for other targets. A number of the most promising agents have progressed to clinical trials and are poised to change the landscape of positron emission tomography (PET) imaging. Here, we present recent data on some of the most important emerging molecular targeted agents with their exemplar clinical images, including agents targeting fibroblast activation protein (FAP), hypoxia markers, gastrin-releasing peptide receptors (GRPrs), and integrins. These radiopharmaceuticals share the promising characteristic of being able to image multiple types of cancer. Early clinical trials have already demonstrated superiority to ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) for some, suggesting the potential to supplant this longstanding PET radiotracer. Here, we provide a primer for practicing radiologists, particularly nuclear medicine clinicians, to understand novel PET imaging agents and their clinical applications, as well as the availability of companion targeted radiotherapeutics, the status of their regulatory approval, the potential challenges associated with their use, and the future opportunities and perspectives. Full article

Background/Objectives: Radiolabeled biomolecules specifically targeting overexpressed structures on tumor cells hold great potential for prostate cancer (PCa) imaging and therapy. Due to heterogeneous target expression, single radiopharmaceuticals may not detect or treat all lesions, while simultaneously applying two or more radiotracers potentially improves staging, stratification, and therapy of cancer patients. This study explores a dual-tracer SPECT approach using [¹¹¹In]In-RM2 (targeting the gastrin-releasing peptide receptor, GRPR) and [^99mTc]Tc-PSMA-I&S (targeting the prostate-specific membrane antigen, PSMA) as a proof of concept. To mimic heterogeneous tumor lesions in the same individual, we aimed to establish a dual xenograft mouse model for preclinical evaluation. Methods: CHO-K1 cells underwent lentiviral transduction for human GRPR or human PSMA overexpression. Six-to-eight-week-old female immunodeficient mice (NOD SCID) were subsequently inoculated with transduced CHO-K1 cells in both flanks, enabling a dual xenograft with similar target density and growth of both xenografts. Respective dual-isotope imaging and γ-counting protocols were established. Target expression was analyzed ex vivo by Western blotting. Results: In vitro studies showed similar target-specific binding and internalization of [¹¹¹In]In-RM2 and [^99mTc]Tc-PSMA-I&S in transduced CHO-K1 cells compared to reference lines PC-3 and LNCaP. However, in vivo imaging showed negligible tumor uptake in xenografts of the transduced cell lines. Ex vivo analysis indicated a loss of the respective biomarkers in the xenografts. Conclusions: Although the technical feasibility of a dual-tracer SPECT imaging approach using ¹¹¹In and ^99mTc has been demonstrated, the potential of [^99mTc]Tc-PSMA-I&S and [¹¹¹In]In-RM2 in a dual-tracer cocktail to improve PCa diagnosis could not be verified. The animal model, and in particular the transduced cell lines developed exclusively for this project, proved to be unsuitable for this purpose. The in/ex vivo experiments indicated that results from an in vitro model may not necessarily be successfully transferred to an in vivo setting. To assess the potential of this dual-tracer concept to improve PCa diagnosis, optimized in vivo models are needed. Nevertheless, our strategies address key challenges in dual-tracer applications, aiming to optimize future SPECT imaging approaches. Full article

Cisplatin (CIS) is a widely used chemotherapeutic agent that is highly effective against various cancers. However, its clinical application is frequently limited by its substantial nephrotoxic side effects. The gastrin-releasing peptide receptor (GRPR), a critical regulator in inflammatory diseases, has been identified as a promising therapeutic target. Our previous studies have demonstrated that the GRPR antagonists PD176252 and RH-1402 can mitigate CIS-induced nephrotoxicity through anti-inflammatory mechanisms. Based on these findings, we designed and synthesized a series of 2-arylpropanoic acid-L-tryptophan derivatives to enhance the therapeutic effects. Among these compounds, 3m exhibited superior renal protection by significantly improving mouse renal tubular epithelial cell (mRTEC) viability from 50.2 ± 2.6% to 80.5 ± 3.9%, surpassing PD176252 (70.8 ± 1.4%) and RH-1402 (73.9 ± 3.7%). Moreover, compound 3m markedly reduced the expression of kidney injury molecule-1 (KIM-1) and inflammatory cytokines [Tumor Necrosis Factor-α (TNF-α), Interleukin-6 (IL-6), Monocyte Chemoattractant Protein-1 (MCP-1)]. Finally, molecular docking results revealed that 3m exhibited a high binding affinity for GRPR. Computational predictions using SwissADME further indicated that 3m possesses favorable drug-like properties, thereby supporting its potential as a promising candidate for mitigating CIS-induced nephrotoxicity. Full article

Effective molecular imaging and targeted cancer therapy rely on receptor-specific targeted delivery systems that are both metabolically stable and kinetically inert for optimal in vivo performance. Until now, no single metal complexing agent has demonstrated the versatility to coordinate metals across the periodic table while maintaining the kinetic inertness required for clinical theranostic applications. Therefore, enhancing the in vivo kinetic stability of radiolabeled, cell-targeting, biologically active compounds remains a critical goal to minimize unintended accumulation of radioactivity in collateral tissues. This review describes the usage of NOTA [NOTA = 1,4,7-triazacyclononane-1,4,7-triacetic acid] and derivatives of NOTA, a metal complexing agent that has been found to have the ability to effectively coordinate with a wide range of radiometals, including metal-radiohalogens, to form stable complexes. This enables the development of new cell-targeting small molecule and peptide conjugates with the potential to resist demetallation in vivo, thereby reducing radionuclide uptake in non-target tissues. Herein, we discuss the design and development of NOTA-based, cell-targeting, small molecules having very high affinity and selectivity for the GRPR (Gastrin-Releasing Peptide Receptor), the SSTR2 (Somatostatin Receptor Subtype 2), and the MC1R (Melanocortin-1) receptors that are present on the surfaces of numerous solid primary human tumors and their metastatic counterparts. Full article

The peptidergic systems are involved in neuroblastoma. Peptides (angiotensin II, neuropeptide Y, neurotensin, substance P) act as oncogenic agents in neuroblastoma, whereas others (adrenomedullin, corticotropin-releasing factor, urocortin, orexin) exert anticancer effects against neuroblastoma. This plethora of peptidergic systems show the functional complexity of the mechanisms regulated by peptides in neuroblastoma. Peptide receptor antagonists act as antineuroblastoma agents since these compounds counteracted neuroblastoma cell growth and migration and the angiogenesis promoted by oncogenic peptides. Other therapeutic approaches (signaling pathway inhibitors, focal adhesion kinase inhibitors, peptide receptor knockdown, acetic acid analogs) that also counteract the beneficial effects mediated by the oncogenic peptides in neuroblastoma are discussed, and future research lines to be developed in neuroblastoma (interactions between oncogenic and anticancer peptides, combination therapy using peptide receptor antagonists and chemotherapy/radiotherapy) are also suggested. Although the data regarding the involvement of the peptidergic systems in neuroblastoma are, in many cases, fragmentary or very scarce for a particular peptidergic system, taken together, they are quite promising with respect to potentiating and developing this research line with the aim of developing new therapeutic strategies to treat neuroblastoma in the future. Peptidergic systems are potential and promising targets for the diagnosis and treatment of neuroblastoma. Full article

Background/Objectives: Gastrin-releasing peptide receptor is a promising target for cancer diagnosis and therapy. However, the high pancreas uptake of reported GRPR-targeted radioligands limits their clinical applications. Our group previously reported one ⁶⁸Ga-labeled GRPR antagonist, [⁶⁸Ga]Ga-TacsBOMB5 (⁶⁸Ga-DOTA-Pip-[D-Phe⁶,NMe-Gly¹¹,Leu¹³ψThz¹⁴]Bombesin(6–14)), and two agonists, [⁶⁸Ga]Ga-LW01110 (⁶⁸Ga-DOTA-Pip-[D-Phe⁶,Tle¹⁰,NMe-His¹²,Thz¹⁴]Bombesin(6–14)) and [⁶⁸Ga]Ga-LW01142 (⁶⁸Ga-DOTA-Pip-[D-Phe⁶,His⁷,Tle¹⁰,NMe-His¹²,Thz¹⁴]Bombesin(6–14)) showing minimal pancreas uptake. Thus, in this study, we prepared their ¹⁷⁷Lu-labeled analogs, evaluated their therapeutic potentials, and compared them with the clinically evaluated [¹⁷⁷Lu]Lu-AMBA. Methods: GRPR binding affinities were determined by in vitro competition binding assay using PC-3 prostate cancer cells. Longitudinal SPECT/CT imaging and ex vivo biodistribution studies were conducted in PC-3 tumor-bearing mice. Dosimetry data were calculated from the biodistribution results. Results: The K_i(GRPR) values of Lu-TacsBOMB5, Lu-LW01110, Lu-LW01142, and Lu-AMBA were 12.6 ± 1.02, 3.07 ± 0.15, 2.37 ± 0.28, and 0.33 ± 0.16 nM, respectively. SPECT/CT images and biodistribution results demonstrated good tumor accumulation of [¹⁷⁷Lu]Lu-TacsBOMB5, [¹⁷⁷Lu]Lu-LW01110, and [¹⁷⁷Lu]Lu-LW01142 at early time points with rapid clearance over time. The pancreas uptake of all three [Thz¹⁴]Bombesin(6–14)-derived ligands was significantly lower than that of [¹⁷⁷Lu]Lu-AMBA at all time points. The calculated absorbed doses of [¹⁷⁷Lu]Lu-TacsBOMB5, [¹⁷⁷Lu]Lu-LW01110, and [¹⁷⁷Lu]Lu-LW01142 in PC-3 tumor xenografts were 87.1, 312, and 312 mGy/MBq, respectively, higher than that of [¹⁷⁷Lu]Lu-AMBA (79.1 mGy/MBq), but lower than that of the previously reported [¹⁷⁷Lu]Lu-RM2 (429 mGy/MBq). Conclusions: Our data suggest that [¹⁷⁷Lu]Lu-TacsBOMB5 and [¹⁷⁷Lu]Lu-LW01142 reduce radiation exposure to the pancreas. However, further optimizations are needed for both radioligands to prolong their tumor retention and enhance treatment efficacy. Full article

Royal jelly (RJ) has long been considered a crucial dietary component in dictating caste differentiation in honeybees. As a nutritional additive, royal jelly imparts a broad range of benefits to mammals and humans; however, its precise impact on the social hierarchy of these advanced animals is not yet fully understood. This study aims to determine whether the benefits of royal jelly can be transferred to rats to alter their social ranks and uncover the underlying mechanisms. A submissive model was established by inducing dysbiosis in rats, via the persistent exposure of vancomycin. Royal jelly at a dose of 2.5 g/kg was daily administered to the subject rats during postnatal weeks (PNW) 6 and 7. At the end of the intervention, animals were subjected to agonistic, water and tube competition tests, in order to assess their dominance status. As revealed by the results, the RJ treatment significantly improved the social rank of the dysbiotic rats, demonstrating that RJ can elicit positive effect on the social behaviors (caused by dysbiosis) of rats. All behavioral paradigms yielded consistent results, with no notable differences in body weight or anxiety levels. Regarding gut microbiome, vancomycin exposure caused the dysbiosis of the subject rats, which was partially reversed by treatment with royal jelly. Specifically, the intestinal presence of Proteobacteria was profoundly attenuated by the RJ supplementation, resulting in a comparable level with the intact/dominant rats. At the genus level, both Escherichia and Clostridium displayed similar dynamics in relation to Proteobacteria, implying their involvement with the RJ-mediated dominance switching. Transcriptomic analysis in the medial prefrontal context showed that the expression of a broad range of genes was influenced by RJ intake, embodying various pathways related to neuronal transmission such as neuroactive ligan–receptor interaction, the synaptic vesicle cycle, etc. By virtue of correlation analysis, Escherichia, Akkermansia and Clostridium were strongly associated with a set of gene modules around gastrin releasing peptide (Grp) and signaling pathways around Rps6ka3, establishing an intrinsic gut–brain communication. Furthermore, the infection trials of Escherichia significantly degraded the social ranks of the RJ-remedied rats in tube tests, while a series of cerebral genes like Grpr and Grpel1, as well as prefrontal spine density, were concordantly altered, underscoring the critical role of the gut–brain link in deciding the outcomes of the dyadic contests. In summary, this is an intriguing example of how royal jelly can influence the social ranks of mammals, emphasizing the importance of microbe–host interaction in mediating this species-spanning function of royal jelly in shaping social hierarchy. Full article

Bombesin receptor subtype-3 (BRS-3) is a type 1 G-protein-coupled receptor (GPCR). BRS-3 is an orphan GPCR that is structurally related to neuromedin B and gastrin-releasing peptide receptors. When activated, BRS-3 causes phosphatidylinositol turnover in lung cancer cells. BRS-3 stimulates tyrosine the phosphorylation of the epidermal growth-factor receptor (ErbB1); however, it is unknown whether it transactivates ErbB2/HER2. Adding the nonpeptide BRS-3 allosteric agonist MK-5046 or the peptide agonist BA1 to the lung cancer cell line NCI-H727 or to BRS-3-transfected NCI-H1299 lung cancer cells increased the tyrosine phosphorylation of HER2/ERK2. This increase was antagonized by the BRS-3 peptide antagonist Bantag-1 and the small-molecule BRS-3 antagonist ML-18. The increase in HER2/ERK phosphorylation caused by MK-5046 was inhibited by the ROS inhibitors N-acetylcysteine and Tiron (superoxide scavengers). Adding MK-5046 to lung cancer cells increased reactive oxygen species, which was inhibited by NAC or Tiron. MK-5046 and BA1 increased non-small lung cancer cell (NSCLC) colony formation, whereas Bantag-1/ML-18 inhibited proliferation. These results indicate that in lung cancer cells, the activation of BRS-3 regulates HER2 transactivation in an ROS-dependent manner, which can mediate tumor growth. These results raise the possibility that the use of HER2-inhibiting compounds alone or in combination with other agents could represent a novel approach to the treatment of these tumors. Full article

Background/Objectives: Overexpressed in various solid tumors, the gastrin-releasing peptide receptor (GRPR) is a promising target for cancer diagnosis and therapy. However, the high pancreas uptake of the current clinically evaluated GRPR-targeted radiopharmaceuticals limits their applications. In this study, we replaced the Pro¹⁴ residue in our previously reported GRPR-targeted LW02056 and ProBOMB5 with 4,4-difluoroproline (diF-Pro) to obtain an agonist LW02060 (DOTA-Pip-[D-Phe⁶,Tle¹⁰,NMe-His¹²,diF-Pro¹⁴]Bombesin(6–14)) and an antagonist LW02080 (DOTA-Pip-[D-Phe⁶,NMe-Gly¹¹,Leu¹³(ψ)diF-Pro¹⁴]Bombesin(6–14)), respectively. Methods/Results: The binding affinities (K_i) of Ga-LW02060, Ga-LW02080, Lu-LW02060, and Lu-LW02080 were measured by in vitro competition binding assays using PC-3 cells and were found to be 5.57 ± 2.47, 21.7 ± 6.69, 8.00 ± 2.61, and 32.1 ± 8.14 nM, respectively. The ⁶⁸Ga- and ¹⁷⁷Lu-labeled ligands were obtained in 36–75% decay-corrected radiochemical yields with >95% radiochemical purity. PET imaging, SPECT imaging, and ex vivo biodistribution studies were conducted in PC-3 tumor-bearing mice. Both [⁶⁸Ga]Ga-LW02060 and [⁶⁸Ga]Ga-LW02080 enabled clear tumor visualization in PET images at 1 h post-injection (pi). Tumor uptake values of [⁶⁸Ga]Ga-LW02060 and [⁶⁸Ga]Ga-LW02080 at 1 h pi were 16.8 ± 2.70 and 7.36 ± 1.33 %ID/g, respectively, while their pancreas uptake values were 3.12 ± 0.89 and 0.38 ± 0.04 %ID/g, respectively. Compared to [¹⁷⁷Lu]Lu-LW02080, [¹⁷⁷Lu]Lu-LW02060 showed higher tumor uptake at all time points (1, 4, 24, 72, and 120 h pi). However, fast tumor clearance was observed for both [¹⁷⁷Lu]Lu-LW02060 and [¹⁷⁷Lu]Lu-LW02080. Conclusions: Our data demonstrate that [⁶⁸Ga]Ga-LW02060 is promising for clinical translation for the detection of GRPR-expressing tumor lesions. However, further optimizations are needed for [¹⁷⁷Lu]Lu-LW02060 and [¹⁷⁷Lu]Lu-LW02080 to prolong tumor retention for therapeutic applications. Full article

Metastasis is a leading cause of lung adenocarcinoma (LUAD)-related mortality and presents significant challenges for treatment. The gastrin-releasing peptide receptor (GRPR), a member of the G protein-coupled receptor (GPCR) family, has an unclear role in LUAD progression. This study aimed to investigate the function and underlying mechanisms of GRPR in LUAD metastasis. Our findings revealed that GRPR levels were significantly elevated in tumor tissues, and higher GRPR expression was associated with worse overall survival outcomes. Functional assays demonstrated that GRPR overexpression enhanced LUAD cell invasion, while GRPR knockdown inhibited invasion both in vitro and in vivo. RNA sequencing and gene set enrichment analysis (GSEA) identified an enrichment of metastasis-promoting genes in GRPR-overexpressing cells, with CRABP2 and FNDC4 emerging as key targets. Clinical analyses further confirmed a positive correlation between GRPR expression and the levels of CRABP2 and FNDC4 in LUAD patients. These results suggest that GRPR could serve as both a prognostic marker and a therapeutic target to inhibit metastasis in LUAD. Full article

Background/Objectives: Prostate cancer (PC) represents the second most diagnosed form of cancer in men on a global scale. Despite the theranostic efficacy of prostate-specific membrane antigen (PSMA) radioligands, there is a spectrum of PC disease in which PSMA expression is low or absent. The gastrin-releasing peptide receptor (GRPR), also known as the bombesin type 2 receptor, has been identified as a target in both the early and advanced stages of PC. The objective of this study was to prepare and preclinically evaluate [^99mTc]Tc-iPSMA-Bombesin ([^99mTc]Tc-iPSMA-BN), estimate dosimetry in healthy subjects, and assess the diagnostic efficacy of the radiotracer in patients with metastatic PC, with the hypothesis of non-inferiority to one of the gold standards, [¹⁸F]-PSMA-1007. Moreover, the potential of [^99mTc]Tc-iPSMA-BN as a theranostic pair with [¹⁷⁷Lu]Lu-iPSMA-BN was investigated. Methods: [^99mTc]Tc-iPSMA-BN was prepared under GMP conditions with radiochemical purities > 95%, showing specific recognition by PSMA and GRP receptors in prostate cancer cells and mice bearing PC tumors. Six healthy volunteers were enrolled, and [^99mTc]Tc-iPSMA-BN SPECT/CT imaging (740 MBq) was performed to estimate the dosimetry. The pilot clinical study included seven mCRPC and four mCSPC patients with prior androgen deprivation therapy. All patients had a recent [¹⁸F]-PSMA-PET/CT scan and were enrolled in this prospective study on their own signed behalf. Volumetric lesion target-to-background ratios (TBRs) were obtained from PET/CT and SPECT/CT images. Results: [^99mTc]Tc-iPSMA-BN effective radiation dose was 1.94 ± 0.39 mSv/740 MBq. A total of 178 lesions were detected via CT, 162 via [¹⁸F]-PSMA-1007 PET, and 155 via [^99mTc]Tc-iPSMA-BN SPECT. Three patients with mCRPC had higher TBR values on SPECT than on PET. [^99mTc]Tc-iPSMA-BN appears to have better lesion detection in patients with aggressive histologic transformation. Two-way ANOVA analysis revealed a significant difference in TBR values between patients with mCRPC and mCSPC (p < 0.05) but no difference between [¹⁸F]-PSMA-1007 and [^99mTc]Tc-iPSMA-BN (p > 0.05). In one patient, [¹⁷⁷Lu]Lu-iPSMA-BN showed a high correlation with [^99mTc]Tc-iPSMA-BN for lesions that concentrated radioactivity. Conclusions: [^99mTc]Tc-iPSMA-BN SPECT/CT is a promising alternative not only for diagnostic purposes but also for broadening the spectrum of PC patients who may benefit from radionuclide theranostics. The results justify the development of a clinical trial involving a significant number of patients with PC. Full article

Background: The concept of radiotheranostics relies on the overexpression of a biomolecular target on malignant cells to direct diagnostic/therapeutic radionuclide-carriers specifically to cancer lesions. The concomitant expression of more than one target in pathological lesions may be elegantly exploited to improve diagnostic sensitivity and therapeutic efficacy. Toward this goal, we explored a first example of a combined application of [^99mTc]Tc-DT11 (DT11, N₄-Lys(MPBA-PEG4)-Arg-Arg-Pro-Tyr-Ile-Leu-OH; NTS₁R-specific) and [^99mTc]Tc-DB7(DB7, N₄-PEG2-DPhe-Gln-Trp-Ala-Val-Gly-His-Leu-NHEt; GRPR-specific) in prostate cancer models. Methods: Accordingly, the behavior of [^99mTc]Tc-DT11 was compared with that of the [^99mTc]Tc-DT11+[^99mTc]Tc-DB7 mixture in prostate adenocarcinoma PC-3 cells and xenografts in mice. The impact of stabilizing both radiotracers by Entresto^®, as a source of the potent neprilysin inhibitor sacubitrilat, was also investigated. Results: The PC-3 cell binding of the [^99mTc]Tc-DT11+[^99mTc]Tc-DB7 mixture surpassed that of [^99mTc]Tc-DT11. Likewise, the PC-3 tumor uptake of the [^99mTc]Tc-DT11+[^99mTc]Tc-DB7 mixture at 4 h post-injection was superior (7.70 ± 0.89%IA/g) compared with [^99mTc]Tc-DT11 (4.23 ± 0.58%IA/g; p < 0.0001). Treatment with Entresto^® led to further enhancement of the tumor uptake (to 11.57 ± 1.92%IA/g; p < 0.0001). Conclusions: In conclusion, this first preclinical study on prostate cancer models revealed clear advantages of dual NTS₁R/GRPR targeting, justifying further assessment of this promising concept in other cancer models. Full article

Naringenin (NRG) is widely found in citrus fruits and has anti-inflammatory, hypoglycemic, and immunomodulatory effects. Previous studies have shown that NRG promotes gastrointestinal motility in mice constipation models, but there are few systematic evaluations of its effects on normal animals. This study first clarified the promotive effects of NRG on gastric emptying and small intestine propulsion (p < 0.01). NRG can also regulate the release of gastrointestinal hormones, including enhancing gastrin (GAS) and motilin (MTL) (p < 0.01), while reducing vasoactive intestinal peptide (VIP) secretion (p < 0.01). Using NRG to stimulate the isolated stomach, duodenum, and colon showed similar promotive effects to those observed in vivo (p < 0.01). A Western blot analysis indicated that this effect may be mediated by increasing the expression of stem cell factor (SCF) and its receptor (c-Kit) in these three segments, thus regulating their downstream pathways. It is worth noting that NRG can also increase the proportion of beneficial bacteria (Planococcaceae, Bacteroides acidifaciens, Clostridia_UCG-014) in the intestine and reduce the quantity of harmful bacteria (Staphylococcus). These findings provide a new basis for the application of NRG. Full article