Tissue Concentrations Research Articles

The therapeutic efficacy of 5-ALA based photodynamic therapy and chemotherapy combination in triple negative breast cancer cells

Triple negative breast cancer (TNBC) is one of the subtypes of breast cancer characterized by a heterogeneous and aggressive nature. Photodynamic therapy (PDT) has drawn significant attention in cancer treatment. However, solubility of photosensitizer, penetration problems into a target tissue and insufficient oxygen concentration limit the effectiveness of PDT. To overcome these limitations and to reduce the side effects of chemotherapy, combination treatment modalities play an essential role in cancer treatment. In this study, we aimed to investigate the combination efficacy of cisplatin-based chemotherapy and 5-Aminolevulinic acid (5-ALA)/PDT in TNBC cells and healthy breast cells in vitro. To determine the effect of the combination effects of cisplatin and 5-ALA/PDT on TNBC cells, two treatment protocols (simultaneous and sequential combination therapy) were evaluated compared with cisplatin and 5-ALA/PDT monotherapy and WST-1, Annexin V assay, acridine orange (AO) and mitochondrial staining were performed. Our findings showed that MDA-MB-231 TNBC cell viability was significantly decreased following simultaneous combination treatment compared to cisplatin and 5-ALA/PDT monotherapy. Additionally, simultaneous combination treatment was more effective than sequential combination treatment. The simultaneous combination treatment of 2.5 µM cisplatin and 5-ALA/PDT at 6 J/cm2 and 9 J/cm2 induced 46.78% and 53.6% total apoptotic death, respectively in TNBC cells compared with monotherapies (cisplatin (37.88%) and 5-ALA/PDT (6 J/cm2: 31.48% and 9 J/cm2: 37.78%). Additionally, cisplatin and 5-ALA/PDT combination treatment resulted in nuclear fragmentation and mitochondrial damage due to apoptosis. Our results suggest that cisplatin and 5-ALA/PDT simultaneous combination therapy could be a promising new alternative strategy for treating TNBC. However, further studies are required to assess the underlying molecular mechanisms of cisplatin and 5-ALA/PDT combination treatment at the molecular level.

Evaluating phytoremediation potential and nutrients status of Bassia indica (Wight) A. J. Scott (Indian Bassia) in a cadmium-contaminated saline soil.

Bassia indica (Wight) A. J. Scott is a fast-growing halophyte suitable for the remediation of saline lands on a large scale. However, no information is available regarding its phytoremediation potential for cadmium (Cd) alone or in combination with salinity. Besides evaluating phytoremediation, assessing micronutrient hemostasis as a crucial physiological insight into the mechanism involved in the tolerance of B. indica under saline soil contaminated with Cd was subjected. Under salinity stress, a considerable amount of sodium accumulates in the plant. Moreover, the accumulation of sodium increased by Cd stress levels. The increase in the exchangeable form of Cd in the rhizosphere in the presence of NaCl ions further elevated the Cd content in the plant tissues. For instance, compared to non-saline conditions, applying 2.5 and 5 g NaCl kg-1 to soil treated with 60 mg Cd kg-1 increased exchangeable Cd by 28.4 and 49.5% in rhizosphere soil, which led to increased cadmium content by 16.1 and 29.6% in the root (as amainpart of Cd accumulation), respectively. Under most stress conditions, potassium homeostasis in the shoot remained undisturbed. It was observed that this plant could transfer an optimal level of potassium from the roots to the shoots at a moderate salinity level. Changes and the distribution of Cu and Zn levels followed a similar pattern in the plant, indicating a common regulation mechanism for these nutrients. Generally, the plant could maintain an appropriate level of Fe, Zn, and Cu ions under most stressed conditions. However, the level of Mn decreased significantly under severe stress levels. Growth parameters, tolerance index, and the values of translocation factor < 1 and shoot bioconcentration factor > 1 under 5 mg Cd kg-1 soil treatment at different salinity levels indicated that B. indica could mitigate the detrimental effect of Cd toxicity and tolerate the NaCl stress via a phytostabilizer mechanism. However, the shoot bioconcentration factor values were very close to one at other Cd levels. Therefore, considering the obtained evidence and the innate ability of B. indica to remediation salinity, this plant is still recommended, even for higher Cd levels (even until 30 mg kg-1), in the presence of salinity.

The Role of Oxidative Stress and DNA Hydroxymethylation in the Pathogenesis of Benzo[a]pyrene-Impaired Reproductive Function in Male Mice.

Benzo[a]pyrene (BaP), a polycyclic aromatic hydrocarbon, is known to cause teratogenesis. Environmental exposure of BaP has led to wide public concerns due to their potential risk of reproductive toxicity. However, the exact mechanism is still not clear. We aimed to explore the alterations of oxidative stress and DNA hydroxymethylation during BaP-impaired reproductive function. BALB/c mice were intragastrically administered with different doses of BaP (0.01, 0.1, and 1 mg/kg/day, once a day), while control mice were administered with corn coil. Then, the reproductive function, alterations of oxidative stress, DNA methylation, and DNA hydroxymethylation of testis tissues were evaluated. We found that BaP caused obvious histopathological damages of testis tissues. As for sperm parameters after BaP administration, testis weight and the rate of teratosperm were increased, as well as sperm count and motility were decreased. In mechanism, BaP upregulated HO-1 and MDA levels and downregulated SOD and CAT activity and GSH content in testis tissues, indicating that oxidative stress was induced by BaP. Furthermore, a significant induction of hydroxymethylation and inhibition of methylation were observed in testis tissues after BaP exposure. Collectively, BaP-induced oxidative stress and hydroxymethylation were involved in impairing reproductive function, which may be the mechanism of the male infertility.

Inter- and intra-specific metal tolerance variation in ectomycorrhizal fungal Suillus species.

Soil metal contamination can affect growth, metabolism, and reproduction of organisms, and can lead to death. However, some fungi have evolved metal tolerance and are able to live in contaminated soils. Species in the ectomycorrhizal genus Suillus from Europe and Asia display variation in metal tolerance, yet it is unknown whether this is a widespread trait in the genus and whether it occurs in North America. Here we investigate cadmium (Cd) and zinc (Zn) tolerance in S. brevipes and S. tomentosus isolates collected from sites in the Rocky Mountains of Colorado displaying different metal content. In line with previous findings for other Suillus species, we hypothesized (1) S. brevipes and S. tomentosus to display intra-specific metal tolerance variation, (2) Zn and Cd tolerance to be correlated to soil metal content, and (3) tolerant isolates to show lower metal tissue content compared to sensitive isolates (due to increased metal exclusion). We found ample intra- and inter-specific Zn and Cd tolerance variation in both S. brevipes and S. tomentosus, but no correlation between soil metal content and tolerance. There was a negative correlation between tolerance level and Zn uptake, indicating an exclusion-based Zn tolerance strategy. Sensitive and tolerant isolates showed no difference in Cd accumulation, indicating that Cd tolerance in these species is likely not dependent on exclusion. Our study sets the groundwork for further investigation into the genetic basis of Suillus metal tolerance and whether and how it impacts pine mycorrhizal partners.

Lactobacillus rhamnosus GG and Tannic Acid Synergistically Promote the Gut Barrier Integrity in a Rat Model of Experimental Diarrhea via Selective Immunomodulatory Cytokine Targeting.

Diarrhea is a common health issue that contributes to a significant annual death rate among children and the elderly worldwide. The anti-diarrheal activity of Lactobacillus rhamnosus GG (LGG) and tannic acid (TA), alone or combined, is examined, in addition to their effect on intestinal barrier integrity. Fifty-six adult male Wistar rats are randomly assigned into seven groups: control, LGG alone, TA alone, diarrhea model, diarrhea+LGG, diarrhea+TA, and diarrhea+LGG+TA-treated groups. Diarrhea is induced by high-lactose diet (HLD) consumption. LGG (1x109 CFU/rat) and TA (100 mg Kg-1 d-1) were given orally 4 days after HLD feeding and continued for 10 days. Ileum specimens are processed for biochemical analysis of the local intestinal cytokines, polymerase chain reaction (PCR), and histological study. Also, immunohistochemistry-based identification of Proliferating Cell Nuclear Antigen (PCNA) and zonula occludens 1 (ZO-1) is performed. Compared to the diarrhea model group, both treatments maintain the intestinal mucosal structure and proliferative activity and preserve ZO-1 expression, with the combination group showing the maximal effect. However, LGG-treated diarrheic rats show a remarkable decrease in the intestinal tissue concentrations of tumor necrosis factor-alpha (TNF-α) and nuclear factor Kappa beta (NF-κB); meanwhile, TA treatment leads to a selective decrease of interferon-gamma (INF-γ) and transforming growth factor-beta (TGF-β1). Individual LGG and TA treatments significantly alleviate diarrhea, probably through a selective immunomodulatory cytokine-dependent mechanism, while the combination of both synergistically maintains the intestinal mucosa by keeping the intestinal epithelial barrier function and regenerative capability.

Penicillin Concentrations in Oropharyngeal and Frontal Sinus Tissue Following Enteral and Intravenous Administration Measured by Microdialysis in a Porcine Model

BackgroundPenicillin may be administered enterally or intravenously for the treatment of bacterial infections within the oropharynx and the frontal sinuses. We aimed to assess and compare penicillin concentrations in oropharyngeal and frontal sinus tissues following enteral and intravenous administration in a porcine model. MethodTwelve pigs were randomized to receive either enteral (0.8 g Penicillin V) or intravenous (1.2 g Penicillin G) penicillin. Microdialysis was used for sampling in oropharyngeal and frontal sinus tissues during a six-hour dosing interval. In addition, plasma samples were collected. The primary endpoints were time with drug concentration above the minimal inhibitory concentration (T>MIC) for two MIC targets: 0.125 (low target) and 0.5 (high target) μg/mL (covering Group A Streptococci, Fusobactarium necrophorum, Streptococcus pneumoniae and Hemophilus influenza) and attainment of these treatment targets for ≥50%T>MIC. ResultsFor both the low and high MIC targets, intravenous administration resulted in higher T>MIC in oropharyngeal and frontal sinus tissues compared to enteral administration. In oropharyngeal tissue, the treatment target (≥50% T>MIC) was achieved for both the low target (96%) and high target (68%) when penicillin was administrated intravenously. In frontal sinus tissue, the treatment target was reached for the low target (70%), but not the high target (35%) when administered intravenously. None of the two tissues reached the treatment targets when penicillin was administered enterally. ConclusionIntravenous administrated penicillin in standard dosage is superior to enteral administration of penicillin in standard dosage in achieving clinically important T>MIC as the majority of targets were achieved following intravenously administration, while none of the targets were achieved following enteral administration. These results support the general notion of higher tissue concentrations following intravenous compared to enteral administration.

Fatty Acids and Volatile Flavor Components of Adipose Tissue from Local Tibetan Sheep in Qinghai with Dietary Supplementation of Palm Kernel Meal (PKM)

Substituting traditional protein feed with palm kernel meal (PKM) in the diet of Tibetan sheep can be a cost-effective feeding strategy. To determine the impact of PKM on flavor development in different adipose tissues of Tibetan sheep, subjects were fed with 15% and 18% of PKM, while the control group received no PKM. The fatty acids and volatile compounds in the samples were then analyzed by GC-MS and HS-GC-IMS. Adding PKM to the diet significantly increased the C12:0, C14:0, C16:0 and C18:1N9 content in adipose tissues compared with the control, and most of these were associated with flavor formation (p &lt; 0.05). The flavor compounds in the adipose tissues predominantly consisted of alcohols, ketones, acids and aldehydes. In particular, including PKM in the diet increased the proportion of ketones but decreased the proportion of alcohols, acids and aldehydes in subcutaneous and tail fat. Specifically, the proportion of acetone, acetoin monomer, 2,3-butanedione, 2-butanone monomer, 2-methyl-2-propanol, 2-methyl-2-propanol and methyl acetate increased significantly in the subcutaneous and tail fat (p &lt; 0.05), while that of ethanol, 1-propanol monomer, butanol monomer, acetic acid monomer and acetic acid monomer decreased. Intermuscular fat exhibited variable results, mainly because the addition of PKM resulted in higher proportions of alcohols, including ethanol, 1-propanol and butanol monomer, especially at 15% PKM. In summary, the addition of PKM improved the flavor of Tibetan sheep fat and increased the amount of favorable volatile flavor compounds. This study can serve as reference for understanding the effects of dietary PKM on the adipose tissue flavor profile of Tibetan sheep.

Trends of Short- and Medium-Chain Chlorinated Paraffin Concentrations in Top Predator Fish Tissues from The Great Lakes

Trends of Short- and Medium-Chain Chlorinated Paraffin Concentrations in Top Predator Fish Tissues from The Great Lakes

Internal and external spatial analysis of trace elements in local crayfish

ABSTRACT Pollution in urban environments is a major health concern for humans as well as the local wildlife and aquatic species. Anthropogenic waste and discharge from storm drainage accumulate nutrients and environmental contaminants in local water systems. Locating contaminated sites using water samples over the vast landscape is a daunting task. Crayfish thrive in urban environments and have been used for biomonitoring pollutants. This study aimed to use crayfish as sentinels to monitor for elements in local environments. In this study, crayfish were used to measure metals and metalloids in lotic environments using ICP-OES analysis of abdominal and exoskeletal tissue. Using cluster analysis, geographical zones of trace element accumulation were determined. Eighteen total elements were analysed providing baseline data on local genera, biometric data, and element concentrations averaging 267.3 mg/kg Mn in the exoskeleton and with Zn averaging 6.88 mg/kg being significantly higher in the abdomen. Correlations of elements with biometric data allowed for internal analyses of elements. The elements As, Cr, Hg, Ni, and Tl demonstrated equivalent concentrations in both tissues. The crayfish locations with high abundance of elements allowed for the determination of contaminated areas with higher accumulations being areas of active urban development. These analyses gave measurable results of metal and metalloid to pinpoint potential sources of pollutants. Since crayfish are consumed globally as a food source, these methods can be used to determine the risk of toxic metals being passed through the food chain to the public.

Antioxidative effect of astragalosides on acute pancreatitis in mice

IntroductionThe research examined the antioxidative impact of astragalosides (AST) on experimental acute pancreatitis (AP) in mice. This study aims to assess the correlation between varying doses of astragalosides and superoxide dismutase (SOD) activity in an acute pancreatitis mouse model. By examining the interplay between astragaloside’s protective effects and its antioxidant properties, we aim to deepen our understanding of its therapeutic potential in acute pancreatitis.MethodsThe AP model in mice was induced by retrograde injection of sodium deoxycholate into the biliary and pancreatic ducts. Serum amylase activity was monitored at various time points following induction. Furthermore, 24 hours post-induction, levels of serum nitric oxide (NO), superoxide dismutase (SOD) activity, and malondialdehyde (MDA) content in pancreatic tissue were assessed.ResultsThe findings of this study illustrated that AST, while exhibiting a protective effect in experimental AP, could effectively lower the elevated serum NO levels, reduce MDA production, and enhance SOD activity in model mice. AST notably reduced MDA levels in the pancreatic tissue of AP mice, underscoring its ability to inhibit membrane peroxidation induced by oxygen free radicals. Furthermore, AST was observed to elevate SOD activity in scavenging oxygen free radicals in pancreatic tissue.ConclusionThese findings suggest that AST enhances recovery in an experimental acute pancreatitis mouse model by exerting antioxidative effects.

Evaluation of Glutathione S-transferases Expression as Biomarkers by Heavy Metals in Geloina expansa from Sepang Besar River, Selangor, Malaysia

Glutathione S-transferases (GSTs) are enzymes involved in phase II of detoxification metabolism and could be used as biomarkers for water pollution. This study aims to determine heavy metal concentrations in the soft tissue of the mangrove clam Geloina expansa, as well as the expression of GSTs in the species. The acid digestion method was used to digest the samples, followed by a standard USEPA 6010B procedure using inductively coupled plasma optical emission spectrometry (ICP-OES) to measure the heavy metal contents in the samples. GST enzyme activity was measured using 1-chloro-2, 4-dinitrobenzene (CDNB) as substrate. One-way ANOVA was performed to compare the mean values of heavy metal concentration, protein concentration, enzyme activity, and specific activity. There was a significant difference (p&lt;0.05) for Zn, total protein, and specific activity in G. expansa, but no significant difference in Pb, Cu and enzyme activity. GST enzyme activities were estimated at 0.16 ± 0.01 µmol/min, with a protein content of 1.24 ± 0.04 mg. The specific activity for GST was 0.13 ± 0.01 µmol/min/mg, calculated as the ratio of enzyme activity to the total protein. GST-specific activity positively correlates with Pb concentration in the soft tissue of G. expansa. Detailed studies on the effects of pollution on the expression of GST need to be further investigated for the future use of this species as an efficient biomarker model.

Activation of α7 Nicotinic Acetylcholine Receptor Improves Muscle Endurance by Upregulating Orosomucoid Expression and Glycogen Content in Mice.

There are presently no acknowledged therapeutic targets or official drugs for the treatment of muscle fatigue. The alpha7 nicotinic acetylcholine receptor (α7nAChR) is expressed in skeletal muscle, with an unknown role in muscle endurance. Here, we try to explore whether α7nAChR could act as a potential therapeutic target for the treatment of muscle fatigue. Results showed that nicotine and PNU-282987 (PNU), as nonspecific and specific agonists of α7nAChR, respectively, could both significantly increase C57BL6/J mice treadmill-running time in a time- and dose-dependent manner. The improvement effect of PNU on running time and ex vivo muscle fatigue index disappeared when α7nAChR deletion. RNA sequencing revealed that the differential mRNAs affected by PNU were enriched in glycolysis/gluconeogenesis signaling pathways. Further studies found that PNU treatment significantly elevates glycogen content and ATP level in the muscle tissues of α7nAChR+/+ mice but not α7nAChR-/- mice. α7nAChR activation specifically increased endogenous glycogen-targeting protein orosomucoid (ORM) expression both in vivo skeletal muscle tissues and in vitro C2C12 skeletal muscle cells. In ORM1 deficient mice, the positive effects of PNU on running time, glycogen and ATP content, as well as muscle fatigue index, were abolished. Therefore, the activation of α7nAChR could enhance muscle endurance via elevating endogenous anti-fatigue protein ORM and might act as a promising therapeutic strategy for the treatment of muscle fatigue.

Salivary metabolomic biomarkers for esophageal and gastric cancers by liquid chromatography-mass spectrometry.

Early detection of esophageal and gastric cancers is essential for patients' prognosis; however, optimal noninvasive screening tests are currently not available. Saliva is a biofluid that is readily available, allowing for frequent screening tests. Thus, we explored salivary diagnostic biomarkers for esophageal and gastric cancers using metabolomic analyses. Saliva samples were collected from patients with esophageal (n = 50) and gastric cancer (n = 63), and patients without cancer as controls (n = 20). Salivary metabolites were analyzed by liquid chromatography-mass spectrometry to identify salivary biomarkers. We also examined the metabolic profiles of gastric cancer tissues and compared them with the salivary biomarkers. The sensitivity of the diagnostic models based on salivary biomarkers was assessed by comparing it with that of serum tumor markers. Additionally, using postoperative saliva samples collected from patients with gastric cancer, we analyzed the changes in the biomarkers' concentrations before and after surgery. Cytosine was detected as a salivary biomarker for gastric cancer, and cytosine, 2-oxoglutarate, and arginine were detected as salivary biomarkers for esophageal cancer. Cytidine, a cytosine nucleotide, showed decreased concentrations in gastric cancer tissues. The sensitivity of the diagnostic models for esophageal and gastric cancers was 66.0% and 47.6%, respectively, while that of serum tumor markers was 40%. Salivary cytosine concentration increased significantly postoperatively relative to the preoperative value. In summary, we identified salivary biomarkers for esophageal and gastric cancers, which showed diagnostic sensitivity at least comparable to that of serum tumor markers. Salivary metabolomic tests could be promising screening tests for these types of cancer.

Zinc oxide nanoparticles and nano-hydroxyapatite enhanced Cd immobilization, activated antioxidant activity, improved wheat growth, and minimized dietary health risks in soil-wheat system

Cadmium (Cd) accumulation in alkaline soils has posed a serious global food safety and health threat. In this work, the effects of zinc oxide nanoparticles (ZnO NPs) and nano-hydroxyapatite (n-HAP) on Cd uptake by wheat in Cd-contaminated soils were evaluated by potting experiments. Results revealed that wheat grain yield increased with the application of nanomaterials (NPs), particularly at higher concentrations. The addition of ZnO NPs or n-HAP reduced Cd concentrations in wheat grains, shoots, and roots by 8.40∼44.54 %, 34.50∼57.28 %, 9.32∼41.26 % and 6.72∼14.29 %, 18.18∼32.19 %, and 1.08∼11.02 % compared with those in controls, respectively, while simultaneously increasing leaf antioxidative activity of SOD, POD, and CAT and decreasing MDA content. Soil pH increased and exchangeable Cd was transformed into more stable organically-bound and residual-bound Cd, thereby reducing soil available Cd content (0.1 g/kg ZnO NPs:16.97 %; 2.0 g/kg n-HAP:14.98 %). As a result, Cd enrichment in wheat tissues was reduced significantly by 0.1 g/kg ZnO NPs or 2.0 g/kg n-HAP. The health risk was assessed, and the Target Hazard Quotient (THQ) value was <1 with 0.1 g/kg ZnO NPs, which was within the safe range (P<0.05). Principal component analysis (PCA) suggested that ZnO NPs were more effective than n-HAP in preventing Cd from entering plant roots. Furthermore, soil availability Cd was most affected by soil fractionation, whereas Cd concentrations in wheat tissues had the greatest effect on grain Cd accumulation. These results provide a key basis for the safe and sustainable application of nanoparticles and indicate that type and concentration should be fully considered when selecting nanomaterials to control Cd stress.

Application of CuNPs and AMF alleviates arsenic stress by encompassing reduced arsenic uptake through metabolomics and ionomics alterations in Elymus sibiricus

Recent studies have exhibited a very promising role of copper nanoparticles (CuNPs) in mitigation of abiotic stresses in plants. Arbuscular mycorrhizae fungi (AMF) assisted plants to trigger their defense mechanism against abiotic stresses. Arsenic (As) is a non-essential and injurious heavy-metal contaminant. Current research work was designed to elucidate role of CuNPs (100, 200 and 300 mM) and a commercial inoculum of Glomus species (Clonex® Root Maximizer) either alone or in combination (CuNPs + Clonex) on physiology, growth, and stress alleviation mechanisms of E. sibiricus growing in As spiked soils (0, 50, and 100 mg Kg− 1 soil). Arsenic induced oxidative stress, enhanced biosynthesis of hydrogen peroxide, lipid peroxidation and methylglyoxal (MG) in E. sibiricus. Moreover, As-phytotoxicity reduced photosynthetic activities and growth of plants. Results showed that individual and combined treatments, CuNPs (100 mM) as well as soil inoculation of AMF significantly enhanced root growth and shoot growth by declining As content in root tissues and shoot tissues in As polluted soils. E. sibiricus plants treated with CuNPs (100 mM) and/or AMF alleviated As induced phytotoxicity through upregulating the activity of antioxidative enzymes such as catalase (CAT) and superoxide dismutase (SOD) besides the biosynthesis of non-enzymatic antioxidants including phytochelatin (PC) and glutathione (GSH). In brief, supplementation of CuNPs (100 mM) alone or in combination with AMF reduced As uptake and alleviated the As-phytotoxicity in E. sibiricus by inducing stress tolerance mechanism resulting in the improvement of the plant growth parameters.

Accumulation of Per- and Polyfluoroalkyl Substances (PFAS) in Coastal Sharks from Contrasting Marine Environments: The New York Bight and The Bahamas.

Per- and polyfluoroalkyl substances (PFAS) enter the marine food web, accumulate in organisms, and potentially have adverse effects on predators and consumers of seafood. However, evaluations of PFAS in meso-to-apex predators, like sharks, are scarce. This study investigated PFAS occurrence in five shark species from two marine ecosystems with contrasting relative human population densities, the New York Bight (NYB) and the coastal waters of The Bahamas archipelago. The total detected PFAS (∑PFAS) concentrations in muscle tissue ranged from 1.10 to 58.5 ng g-1 wet weight, and perfluorocarboxylic acids (PFCAs) were dominant. Fewer PFAS were detected in Caribbean reef sharks (Carcharhinus perezi) from The Bahamas, and concentrations of those detected were, on average, ∼79% lower than in the NYB sharks. In the NYB, ∑PFAS concentrations followed: common thresher (Alopias vulpinus) > shortfin mako (Isurus oxyrinchus) > sandbar (Carcharhinus plumbeus) > smooth dogfish (Mustelus canis). PFAS precursors/intermediates, such as 2H,2H,3H,3H-perfluorodecanoic acid and perfluorooctanesulfonamide, were only detected in the NYB sharks, suggesting higher ambient concentrations and diversity of PFAS sources in this region. Ultralong-chain PFAS (C ≥ 10) were positively correlated with nitrogen isotope values (δ15N) and total mercury in some species. Our results provide some of the first baseline information on PFAS concentrations in shark species from the northwest Atlantic Ocean, and correlations between PFAS, stable isotopes, and mercury further contextualize the drivers of PFAS occurrence.

An Improved Postprocessing Method to Mitigate the Macroscopic Cross-Slice B0 Field Effect on R2* Measurements in the Mouse Brain at 7T

The MR transverse relaxation rate, R2*, has been widely used to detect iron and myelin content in tissue. However, it is also sensitive to macroscopic B0 inhomogeneities. One approach to correct for the B0 effect is to fit gradient-echo signals with the three-parameter model, a sinc function-weighted monoexponential decay. However, such three-parameter models are subject to increased noise sensitivity. To address this issue, this study presents a two-stage fitting procedure based on the three-parameter model to mitigate the B0 effect and reduce the noise sensitivity of R2* measurement in the mouse brain at 7T. MRI scans were performed on eight healthy mice. The gradient-echo signals were fitted with the two-stage fitting procedure to generate R2corr_t*. The signals were also fitted with the monoexponential and three-parameter models to generate R2nocorr* and R2corr*, respectively. Regions of interest (ROIs), including the corpus callosum, internal capsule, somatosensory cortex, caudo-putamen, thalamus, and lateral ventricle, were selected to evaluate the within-ROI mean and standard deviation (SD) of the R2* measurements. The results showed that the Akaike information criterion of the monoexponential model was significantly reduced by using the three-parameter model in the selected ROIs (p = 0.0039–0.0078). However, the within-ROI SD of R2corr* using the three-parameter model was significantly higher than that of the R2nocorr* in the internal capsule, caudo-putamen, and thalamus regions (p = 0.0039), a consequence partially due to the increased noise sensitivity of the three-parameter model. With the two-stage fitting procedure, the within-ROI SD of R2corr* was significantly reduced by 7.7–30.2% in all ROIs, except for the somatosensory cortex region with a fast in-plane variation of the B0 gradient field (p = 0.0039–0.0078). These results support the utilization of the two-stage fitting procedure to mitigate the B0 effect and reduce noise sensitivity for R2* measurement in the mouse brain.

The usefulness of determining plasma and tissue concentrations of phosphorodiamidate morpholino oligonucleotides to estimate their efficacy in Duchenne muscular dystrophy patients.

Currently four kinds of phosphorodiamidate morpholino oligomers (PMOs) such as viltolarsen have been approved for the treatment of Duchenne muscular dystrophy (DMD); however, it is unclear whether human efficacy can be estimated using plasma concentrations. This study summarizes the tissue distribution of viltolarsen in mice and cynomolgus monkeys and evaluates the relationship between exposure and efficacy based on exon skipping. In the tissue distribution studies, all muscles in DMD model mice showed higher concentrations of viltolarsen than those in wild-type mice and cynomolgus monkeys, and the concentrations in skeletal muscle were correlated with the exon-skipping efficiency in mice and cynomolgus monkeys. In addition, a highly sensitive bioanalytical method using liquid chromatography with tandem mass spectrometry shows promise for determining plasma concentrations up to a later time point, and the tissue (muscle)/plasma concentration ratio (Kp) in DMD model mice was shown to be useful for predicting changes in pharmacodynamic (PD) markers in humans. Our results suggest that pharmacokinetic (PK)/PD analysis can be conducted by using the human PK profile or Kp values and skipping efficiency in DMD model mice. This information will be useful for the efficient and effective development of PMOs as therapeutic agents. Significance Statement We compare that plasma and tissue concentrations with the efficiency of exon skipping for viltolarsen as an example phosphorodiamidate morpholino oligomers in skeletal and cardiac muscle of mice and cynomolgus monkeys for pharmacokinetics/pharmacodynamics (PK/PD) analysis. Our results suggest that PK/PD analysis can be conducted by using the human PK profile or Kp values and skipping efficiency in DMD model mice.

General toxicity and screening of reproductive and developmental toxicity following bioaccumulation of oral-dosed perfluorooctanoic acid: Loss of the Golgi apparatus

Despite its widespread use as a stabilizer across various industries over the past several decades, the health effects of chronic exposure to PFOA are still unclear. We administered PFOA by oral gavage (0, 12.5, 50, and 200 μg/day/mouse, eight groups) to male and female mice for six months. Body weight gain decreased with dose accompanied by increased liver weight, and PFOA altered liver damage-related-blood biochemical indicators and induced pathological lesions, including hepatocellular hypertrophy, cholangiofibrosis, and centrilobular hepatocellular vacuolation. Loss of the Golgi apparatus, formation of lamellar body-like structures, and lipid accumulation were observed in the liver of PFOA-treated mice. We also cohabited five pairs of male and female mice for the last ten days of administration, dosed PFOA to dam up to 28 days after birth, and investigated effects on reproduction and development. The survival rate of pups and the sex ratio of surviving mice decreased significantly at the highest dose. PFOA tissue concentration increased with the dose in the parent mice's liver and the pups' blood and brain. Taken together, we suggest that PFOA primarily affects the liver and reproduction system and that disturbance in lipid metabolism and Golgi's structural stability may be involved in PFOA-induced toxicity.

Comprehensive Assessment of Drug Kinetics, Neurotoxicity, and Safety of Sirolimus-Eluting Intracranial Stents in Canine Basilar Artery.

Sirolimus-eluting stents (SESs) have shown promise in treating intracranial atherosclerosis but concerns about potential neurotoxicity due to prolonged drug release exist. The aim of this study was to comprehensively assess the safety of SES, with a focus on neurotoxicity. Stents (1.50 × 7 or 12 mm) were implanted into the basilar arteries of 154 Labrador Retrievers (weighing >25 kg and aged older than 1 year) divided into 4 groups: baer-metal stent, polymer-coated stent, standard-dose SES (sirolimus dose: 71 μg), and high-dose SES group (sirolimus dose: 284 μg). Pharmacokinetic analysis was conducted using liquid chromatography-mass spectrometry on blood and tissue samples, and analysis of brain tissue was performed with 5 different special stains and immunohistochemistry protocols to assess axonal degeneration, vacuolization, astrocyte proliferation, microglial activation, or widespread neurodegeneration. In the standard-dose SES group, the stent released 10.56% of the drug on day 1 and 95.41% on day 28 postimplantation. In the high-dose SES group, corresponding figures were 40.20% on day 1 and 98.08% on day 28. Systemic drug concentration consistently remained below 1.5 ng/mL throughout the study. Arterial tissue concentration reached its peak at day 28 days in the standard-dose group and at 7 days in the high-dose group. Importantly, the brain and related tissue concentrations remained below 0.4 µg/g in both standard-dose and high-dose SES groups, peaking on day 21 in the standard-dose group and day 1 in the high-dose group. The detailed 180-day safety assessment revealed no adverse effects on the brain, even at high sirolimus doses in the SES group. This study provides robust evidence supporting the long-term pharmacokinetic safety of SESs in the context of intracranial interventions for high-grade intracranial atherosclerosis. The results adequately alleviate concerns related to neurotoxicity and substantiate the feasibility of using these stents as a therapeutic choice in neurosurgery.