Angiotensin-converting enzyme 2 (ACE2) is an important factor in coronavirus disease (COVID-19) interactions. Losartan (LOS) belongs to the angiotensin receptor blocker (ARB) family. Additionally, ...the protective role of ACE2 restored by LOS has been suggested and clinically examined in the treatment of COVID-19 patients. Furthermore, clinical trials with LOS have been conducted. However, the mechanism through which LOS enhances ACE2 expression remains unclear. In addition, the response of ACE2 to LOS differs among patients. Our LOS-treated patient data revealed a correlated mechanism of ACE2 with components of the renin-angiotensinogen system. We observed a significant positive regulation of MAS1 and ACE2 expression. In the context of LOS treatment of COVID-19, ACE2 expression could depend on LOS regulated MAS1. Thus, MAS1 expression could predict the COVID-19 treatment response of LOS.
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•Prenatal exposure to Polyethylene (PE) lead to Autism spectrum disorder (ASD) like traits in mice.•Exposure to PE leads to impaired social interaction and repetitive behaviors in ...mice model.•Exposure to PE leads to disturbance of metabolites and gene expression in brain.•Exposure to PE leads gut microbiome change revealed ASD like traits in mice.•Our finding on ASD in prenatal model was well supported based on already revealed findings.
In common with the increase in environmental pollution in the past 10 years, there has also been a recent increase in the prevalence of autism spectrum disorder (ASD). In this regard, we hypothesized that exposure to microplastics is a potential risk factor for ASD. To evaluate the validity of this hypothesis, we initially examined the accumulation of polyethylene (PE) in the brains of mice and then assessed the behavioral effects using mouse models at different life stages, namely, prenatal, post-weaning, puberty, and adult models. Based on typical behavioral assessments of autistic traits in the model mice, we established that ASD-like traits were induced in mice after PE feeding. In addition, we examined the induction of ASD-like traits in response to microplastic exposure using positron emission tomography, magnetic resonance spectroscopy, quantitative real-time polymerase chain reaction, microarray, and microbiome analysis. We believe these findings provide evidence in microplastics as a potential risk factor for ASD.
Recent studies showed the presence of microplastic in human lungs. There remains an unmet need to identify the biodistribution of microplastic after inhalation. In this study, we traced the ...biodistribution of inhaled micro-sized polystyrene (mPS) and/or nano-sized PS (nPS) using .sup.64Cu with PET in mice. We used 0.2-0.3-microm sized mPS and 20-nm sized nPS throughout. .sup.64Cu-DOTA-mPS, .sup.64Cu-DOTA-nPS and/or .sup.64CuCl.sub.2 were used to trace the distribution in the murine inhalation model. PET images were acquired using an INVEON PET scanner at 1, 12, 24, 48, and 72 h after intratracheal instillation, and the SUV.sub.max for interesting organs were determined, biodistribution was then determined in terms of percentage injected dose/gram of tissue (%ID/g). Ex vivo tissue-radio thin-layer chromatography (Ex vivo-radioTLC) was used to demonstrate the existence of .sup.64Cu-DOTA-PS in tissue. PET image demonstrated that the amount of .sup.64Cu-DOTA-mPS retained within the lung was significantly higher than .sup.64Cu-DOTA-nPS until 72 h; SUV.sub.max values of .sup.64Cu-DOTA-mPS in lungs was 11.7 + or - 5.0, 48.3 + or - 6.2, 65.5 + or - 2.3, 42.2 + or - 13.1, and 13.2 + or - 2.3 at 1, 12, 24, 48, and 72 h respectively whereas it was 31.2 + or - 3.1, 17.3 + or - 5.9, 10.0 + or - 3.4, 8.1 + or - 2.4 and 8.9 + or - 3.6 for .sup.64Cu-DOTA-nPS at the corresponding timepoints. The biodistribution data supported the PET data with a similar pattern of clearance of the radioactivity from the lung. nPS cleared rapidly post instillation in comparison to mPS within the lungs. Higher accumulation of %ID/g for nPS (roughly 2 times) were observed compared to mPS in spleen, liver, intestine, thymus, kidney, brain, salivary gland, ovary, and urinary bladder. Ex vivo-radioTLC was used to demonstrate that the detected gamma rays originated from .sup.64Cu-DOTA-mPS or nPS. PET image demonstrated the differences in accumulations of mPS and/or nPS between lungs and other interesting organs. The information provided may be used as the basis for future studies on the toxicity of mPS and/or nPS.
Combination radioimmunotherapy is an emerging approach for the treatment of solid tumors where radio immunotherapy alone has proven to be reasonably ineffective. Radioimmunotherapy (RIT) using ...monoclonal antibodies (mAbs) labeled with radionuclides is an attractive approach for cancer treatment because tumor-associated mAbs with cytotoxic radionuclides can selectively bind to tumor antigens. However, due to various limitations, mAbs cannot reach solid tumors, consequently reducing RIT efficacy. Combination RIT is a pragmatic approach through which the addition of drugs or other agents not only help mAbs to reach the targeted site but also improves its efficacy. Thus, the combination of drugs or moieties with RIT can be applied to overcome the barriers that RIT faces for solid tumors. This review covers the RIT approach, along with the mechanism of action of mAb used in RIT, limitations of solid tumors, and strategies that can be used in combination RIT to enhance the treatment regimen for solid tumors.
For optimum radioimmunotherapy (RIT), deep penetration and uniform distribution into the tumor core is important. The solid tumor microenvironment, consisting of a highly fibrotic or desmoplastic ...tumor, abnormal tumor vasculature, high fluid pressure, and the absence of fluid lymphatics, limits the distribution of monoclonal antibodies mAbs to the tumor core. To investigate the optimal rationale for therapeutic mAbs administration and the microdistribution of mAbs, single and serial fractional dosage regimens of Cu-64-trastuzumab (TRZ) with paclitaxel were evaluated. Groups of nude mice were inoculated with gastric cancer cell line NCI-N87 tumor cells. When the tumor size reached 200 ± 20 mm
, the mice were divided into two groups for injection of Alexa-647-TRZ. One group (
= 5) was injected with 15 mg/kg in a single dose (SD), and the other group (
= 5) with two doses of 7.5 mg/kg (fractionated dose (FD)). In both cases, the injections were done intravenously in combination with intraperitoneal paclitaxel either as a SD of 70 mg/kg or fractionated into two doses of 40 and 30 mg/kg. Tumors were harvested, flash frozen, and sectioned (8 µm) five days after Alexa-647-TRZ injection. Rhodamine lectin (rhodamine-labeled
agglutinin I, 1 mg in 0.2 mL of phosphate-buffered saline (PBS)) was intravenously injected to delineate the functional vessel for a wait time of 5 min before animal euthanization. Microscopic images were acquired with an IN Cell Analyzer. The amount of TRZ that penetrated the tumor surface and the tumor vessel was calculated by area under the curve (AUC) analysis. For RIT efficacy (
= 21), Cu-64-TRZ was injected following the same dose schedule to observe tumor volume and survival ratio for 30 days. The SD and FD regimens of Alexa-647-TRZ were observed to have no significant difference in penetration of mAbs from the tumor edge and vessel, nor was the total accumulation across the whole tumor tissue significantly different. Additionally, the SD and FD regimens of Cu-64-TRZ were not proven to be significantly efficacious. Our study reveals that SD and FD in a treatment design with Cu-64-TRZ and paclitaxel shows no significant difference in therapeutic efficacy on tumor growth inhibition in vivo in mice bearing human gastric cancer xenografts overexpressing HER2 antigen.
Backgrounds: Radioimmunotherapy (RIT) serves as a targeted therapy for non-Hodgkin lymphomas (NHL). Although HIF(Hypoxia-inducible factors)-1α is an important biomarker during radiation therapy, its ...role in NHL is unclear. Atorvastatin (ATV) is used as a combination drug for chemotherapy. Methods: We investigated whether ATV downregulated tumor radio-resistance and enhanced the anticancer effect of 131I-RTX (rituximab) in Raji xenograft mouse models. First, the increased uptake and enhanced therapeutic effect of 131I-RTX by ATV was confirmed using molecular imaging in Raji xenograft subcutaneous model and orthotropic model with SPECT and IVIS images. Second, we examined the profile of differentially expressed miRNAs using miRNA array. Results: We found that miR-346 inhibited HIF-1α/VEGF (Vascular endothelial growth factor) during ATV combination therapy with 131I-RTX. The underlying mechanism of ATV involved induction of anti-angiogenesis and radiosensitivity by downregulating HIF-1α in Raji cells. Conclusion: Our findings suggested that combination therapy with ATV and 131I-RTX is a promising strategy for enhancing the potency of 131I-RTX therapy in poorly responding patients and those with radio-resistance.
Fludeoxyglucose-18-(3-fluoropropyl)-2
β
-carboxymethoxy-3
β
-(4-iodophenyl) nortropane positron emission tomography (F-18 FP CIT PET) was used for the diagnosis of Parkinson’s disease in nuclear ...medicine. However, no study of the effect of reconstruction parameters on the quality images obtained using F-18 FP CIT PET has been done. For that reason, this study compares the quality of F-18 FP CIT PET images reconstructed with different algorithms in terms of the recovery coefficient (RC), maximum PET counts, and binding potential (BP). The RCs of images were measured according to the National Electrical Manufacturers Association (NEMA) standard NU 4-2008 (NEMA NU4-2008). The PET images of the phantoms were reconstructed using various reconstruction algorithms (OSEM2D, FBP, 3DRP and OSEM3D/MAP) and filters. For the FBP reconstruction, the ramp, Butterworth (order: 1), Hamming, Hanning, Parzen, and SheppLogan filters were used. The cutoff frequency was 0.5 (even though the, ramp filter needed no cut-off frequency). For the OSEM3D/MAP reconstruction, various smoothing factors (
β
= 0.05, 0.5 and 1.5) were used with 18 iterations number. The
β
value was provided as a penalty function for constraint on neighboring voxels during the MAP algorithm. The
β
values of 0.05, 0.5 and 1.5 corresponded to predicted target resolutions of 1.5 mm, 2 mm, and 2.3 mm for the OSEM3D/MAP reconstruction algorithm, respectively. For the 3DRP reconstruction, Hanning filters were used. We used OSEM2D with 4 iterations and 16 subsets (default number in Siemens Inveon PET scanner) in this study for OSEM2D method. To compare the chosen parameters between the F-18 FP CIT PET images and phantoms, we used BALB nude mice (20 g body weight) were used to obtain mouse images. For evaluating the reconstruction methods, the maximum PET counts (counts/s/voxel) and BP (for image contrast ratio with striatum and cerebellum) of each reconstruction algorithm the striatal diameter of mice was observed to be 3 mm. Therefore, the RC values of the phantoms with a diameter of 3 mm were chosen. For phantoms with Φ = 3 mm, the OSEM2D provided the most appropriate 0.95 of RC value. Moreover, the maximum PET counts and the BP of the striatum with the OSEM2D reconstruction were observed to be high compared to the value for the other reconstruction methods. OSEM3D/MAP also showed high values for the maximum PET counts and the BP; however, the RC of OSEM3D/MAP (
β
= 0.05) exceeded 1 at Φ = 3 mm, and other OSEM3D/MAPs (
β
= 1.5 and 0.5) were lower than those of OSEM2D. Therefore, OSEM3D/MAP was not considered for decisions regarding the optimal reconstruction method. Through actual PET images we verified that the images with OSEM2D were identified more clearly and with higher image contrast. The OSEM2D reconstruction algorithm provided the best values (0.95) on reconstructed PET data; thus, OSE2D would be suitable for quantification of F-18 FP CIT PET images of mice obtained with a Siemens Inveon PET.
While the hazardous effects of microplastics (MPs) are increasingly reported, it remains uncertain if MPs induce inner ear dysfunction. Nonetheless, prevalence of inner ear dysfunction was observed ...across all age groups. In this study, we investigated whether MP polyethylene affect inner ear function in a murine model. To detect hearing loss and balance defect after polyethylene (PE) exposure, we evaluated hearing threshold levels, assessed cerebral glucose metabolism, conducted transcriptome analysis, and performed behavioral studies. C57BL/6 J mice (5-week-old) were grouped into control (n = 10) and PE-fed groups (n = 10). Mice were orally administered 100 ppm/100 μL (equivalent to 10 μg) of PE every day for 4 months. We identified the accumulation of PE in the cochlea and vestibular region. The fragmented PE in inner ear was 3.00 ± 0.38 µm in size; the administered PE concentration was 1.14 ± 1.06 mg/g. Fourier transform infrared spectrometry confirmed that the properties of the MP were identical with those of PE fed to the mice. Transcriptomic analysis showed up-regulation of PER1, NR4A3 and CEBPB at the PE exposed inner ear tissue and it was confirmed using qRT-PCR, western blotting, and immunofluorescence staining. We observed abnormalities in balance related behavior assessment in the PE group. Exposure to PE increased the hearing thresholds and decreased glucose metabolism in the bilateral lateral entorhinal cortex, right primary auditory cortex, and right secondary auditory cortex. We can conclude that PE exposure induced inner ear dysfunction such as hearing loss and balance disorder.
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•Microplastic polyethylene induced hearing loss and balance defects in a murine model.•Upregulated gene expression of PER1, NR4A3 and CEBPB with polyethylene exposure.
In the previous study (Im et al., 2022), we revealed microplastic (MP) was accumulated and cleared through the kidneys via PET imaging. Here, we aimed to identify the renal dysfunction due to ...polyethylene (PE) MP in the kidney tissue. Mice were exposed to 100 ppm (∼equivalent to 0.1 mg/mL)/100 μL of PE for 12 weeks (n = 10). PE uptake in the kidney tissues was confirmed using confocal microscopy. QuantSeq analysis was performed to determine gene expression. Renal function assessment was performed using 99mTc-Diethylene triamine penta acetic acid or 99mTc-Dimercaptosuccinic acid. Measurement of creatinine, BUN, and albumin levels in serum and urine samples was also estimated. 18F-FDG was also acquired. PE increased expression of Myc, CD44, Programmed Death-Ligand 1 (PD-L1), and Hypoxia-Inducible Factor (HIF)-1α, which indicates a potential link to an increased risk of early-onset cancer. An increase in glucose metabolism of 18F-FDG were observed. We assessed renal failure using 99mTc-Diethylene triamine penta acetic acid and 99mTc-Dimercaptosuccinic acid scintigraphy to determine the renal function. Renal failure was confirmed using serum and urine creatinine, serum blood urea nitrogen levels, serum albumin levels, and urine albumin levels in PE exposed mice, relative to the control. In sum, PE exposure induced renal dysfunction in a murine model.
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•99mTc-DMSA and 99mTc-DTPA identified renal dysfunction induced by PE exposure.•Administration of PE to mice resulted in altered gene expression in the kidneys.•PE exposure increased the risk of renal cancer onset.
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