Human Placenta Hydrolysate Promotes Liver Regeneration via Activation of the Cytokine/Growth Factor-Mediated Pathway and Anti-oxidative Effect.

Liver regeneration is a very complex process and is regulated by several cytokines and growth factors. It is also known that liver transplantation and the regeneration process cause massive oxidative stress, which interferes with liver regeneration. The placenta is known to contain various physiologically active ingredients such as cytokines, growth factors, and amino acids. In particular, human placenta hydrolysate (hPH) has been found to contain many amino acids. Most of the growth factors found in the placenta are known to be closely related to liver regeneration. Therefore, in this study, we investigated whether hPH is effective in promoting liver regeneration in rats undergoing partial hepatectomy. We confirmed that cell proliferation was significantly increased in HepG2 and human primary cells. Hepatocyte proliferation was also promoted in partial hepatectomized rats by hPH treatment. hPH increased liver regeneration rate, double nucleic cell ratio, mitotic cell ratio, proliferating cell nuclear antigen (PCNA), and Ki-67 positive cells in vivo as well as interleukin (IL)-6, tumor necrosis factor alpha (TNF-α), and hepatocyte growth factor (HGF). Moreover, Kupffer cells secreting IL-6 and TNF-α were activated by hPH treatment. In addition, hPH reduced thiobarbituric acid reactive substances (TBARs) and significantly increased glutathione (GSH), glutathione peroxidase (GPx), and superoxide dismutase (SOD). Taken together, these results suggest that hPH promotes liver regeneration by activating cytokines and growth factors associated with liver regeneration and eliminating oxidative stress.

A 13-week repeated-dose oral toxicity and bioaccumulation of aluminum oxide nanoparticles in mice.

Because of an increase in the commercial applications of manufactured nanoparticles, the issue of potential adverse health effects of nanoparticles following intended or unintended exposure is rapidly gaining attention. In this study, we evaluated the toxicity of aluminum oxide nanoparticles (AlNPs, rod-type, 1.5, 3, and 6 mg/kg) after oral administration to mice for 13 weeks. Compared with the control group, the consumption of diet and drinking water and body weight gain decreased in the group treated with AlNPs. The group treated with 6 mg/kg AlNPs also showed a marked elevation in the count of white blood cells that associated with a significant decrease and increase to the proportion of eosinophils and lymphocytes, respectively. In addition, the secretion of IL-6 and monocyte chemotactic protein-1 increased in a dose-dependent manner in the treated groups. Furthermore, AlNPs showed the highest accumulation in the liver and kidneys compared with the control group, increased the lactate dehydrogenase level in the blood, and induced the development of a pathological lesion in the liver and kidneys. Taken together, we suggest that the target organs of rod-type AlNPs may be the liver, kidneys and the immune system, and the not-observed adverse effect level may be lower than 6 mg/kg.

Toxic response of graphene nanoplatelets in vivo and in vitro.

With the development of nanotechnology, myriad types of novel materials have been discovered at the nanoscale, among which the most interesting material is graphene. However, the toxicity data available on graphene are extremely limited. In this study, we explored toxic response of commercially available graphene nanoplatelets (GNPs) in vivo and in vitro. The GNPs used in this study had a high surface area and feature considerably few defects. In mice, GNPs (2.5 and 5 mg/kg) remained in the lung until 28 days after a single instillation, and the secretion of inflammatory cytokines reached the maximal level at Day 14 and then decreased over time. In vitro study using BEAS-2B cells, a human bronchial epithelial cell line, GNPs located within autophagosome-like vacuoles 24 h after exposure. The GNPs (2.5, 5, 10, and 20 µg/mL) also dose-dependently reduced cell viability, which was accompanied by an increase in the portion of cells in the subG1 and S phases. Moreover, the GNPs down-regulated the generation of reactive oxygen species, suppressed ATP production, caused mitochondria damage, and elevated the levels of autophagy-related proteins. Based on these results, we suggest that GNPs provoked a subchronic inflammatory response in mice and that GNPs induced autophagy accompanying apoptosis via mitochondria damage in vitro.

Tumor Stroma as a Therapeutic Target for Pancreatic Ductal Adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis owing to its desmoplastic stroma. Therefore, therapeutic strategies targeting this tumor stroma should be developed. In this study, we describe the heterogeneity of cancer-associated fibroblasts (CAFs) and their diverse roles in the progression, immune evasion, and resistance to treatment of PDAC. We subclassified the spatial distribution and functional activity of CAFs to highlight their effects on prognosis and drug delivery. Extracellular matrix components such as collagen and hyaluronan are described for their roles in tumor behavior and treatment outcomes, implying their potential as therapeutic targets. We also discussed the roles of extracellular matrix (ECM) including matrix metalloproteinases and tissue inhibitors in PDAC progression. Finally, we explored the role of the adaptive and innate immune systems in shaping the PDAC microenvironment and potential therapeutic strategies, with a focus on immune cell subsets, cytokines, and immunosuppressive mechanisms. These insights provide a comprehensive understanding of PDAC and pave the way for the development of prognostic markers and therapeutic interventions.

Synergistic Renoprotective Effect of Melatonin and Zileuton by Inhibition of Ferroptosis via the AKT/mTOR/NRF2 Signaling in Kidney Injury and Fibrosis.

According to recent evidence, ferroptosis is a major cell death mechanism in the pathogenesis of kidney injury and fibrosis. Despite the renoprotective effects of classical ferroptosis inhibitors, therapeutic approaches targeting kidney ferroptosis remain limited. In this study, we assessed the renoprotective effects of melatonin and zileuton as a novel therapeutic strategy against ferroptosis-mediated kidney injury and fibrosis. First, we identified RSL3-induced ferroptosis in renal tubular epithelial HK-2 and HKC-8 cells. Lipid peroxidation and cell death induced by RSL3 were synergistically mitigated by the combination of melatonin and zileuton. Combination treatment significantly downregulated the expression of ferroptosis-associated proteins, 4-HNE and HO-1, and upregulated the expression of GPX4. The expression levels of p-AKT and p-mTOR also increased, in addition to that of NRF2 in renal tubular epithelial cells. When melatonin (20 mg/kg) and zileuton (20 mg/kg) were administered to a unilateral ureteral obstruction (UUO) mouse model, the combination significantly reduced tubular injury and fibrosis by decreasing the expression of profibrotic markers, such as α-SMA and fibronectin. More importantly, the combination ameliorated the increase in 4-HNE levels and decreased GPX4 expression in UUO mice. Overall, the combination of melatonin and zileuton was found to effectively ameliorate ferroptosis-related kidney injury by upregulating the AKT/mTOR/ NRF2 signaling pathway, suggesting a promising therapeutic strategy for protection against ferroptosis-mediated kidney injury and fibrosis.

Novel Herbal Therapeutic YH23537 Improves Clinical Parameters in Ligature-Induced Periodontal Disease Model in Beagle Dogs.

Currently, available medicine does not satisfy the clinical unmet needs of periodontal disease. Therefore, novel drugs with improved efficacy profiles are needed. We previously demonstrated that YH14642, water extracts of Notoginseng Radix and Rehmanniae Radix Preparata, improved probing depths in double-blind phase II clinical trial. However, it still has hurdles for commercialization due to the low efficiency of active compound extraction. To resolve this issue, we developed YH23537 through process optimization to extract active compounds efficiently while still achieving the chemical profile of YH14642. In this study, we investigated the therapeutic effects of YH23537 compared with YH14642 using a canine model of ligature-induced periodontitis. Human gingival fibroblast (hGF) cells were treated with various concentrations of YH23537 or YH14642 with lipopolysaccharide (LPS) for 24 hr. IL-6 and IL-8 levels in the conditioned media were determined using Luminex. Sixteen 3-year-old male beagle dogs had their teeth scaled and polished using a piezo-type ultrasonic scaler under general anesthesia and brushed once daily for the following 2 weeks. Two weeks after the scaling procedure, the left upper second premolar (PM2), third premolar (PM3), and fourth premolar (PM4) as well as the left lower PM3, PM4, and first molar (M1) were ligated with silk-wire twisted ligatures. The dogs were fed with soft moistened food to induce periodontitis for 8 weeks, and the ligatures were then removed. YH23537 and YH14642 were administered for 4 weeks, and clinical periodontal parameters such as plaque index (PI), gingival index (GI), probing depth (PD), clinical attachment level (CAL), and bleeding on probing (BoP) were determined before and 1, 2, 3, and 4 weeks after treatment. YH23537 inhibited IL-6 and IL-8 secretion in a dose-dependent manner in hGF cells stimulated with LPS. The IC50 values for YH23537 were 43 and 54 µg/ml for IL-6 and IL-8, respectively, while the values for YH14642 were 104 and 117 µg/ml, respectively. In the animal study, clinical parameters including GI, PD, CAL, and BoP were significantly increased after 8 weeks of ligature-induced periodontitis. The YH23537 300 and YH23537 900 mg groups had significant improvements in CAL from 1 to 4 weeks after treatment in comparison to the placebo group. GR values in the YH23537 900 mg group were decreased throughout the treatment period. GI values were also reduced significantly after 4-week treatment with 300 and 900 mg of YH23537. YH23537 at 300 mg doses showed comparable efficacy for CAL and GR with 1,000 mg of YH14642. YH23537 showed therapeutic efficacy against periodontitis in dogs, mediated by anti-inflammatory effects. These findings indicate that YH23537 has the potential for further development as a new drug for patients suffering from periodontal disease.

Vactosertib, TGF-ß receptor I inhibitor, augments the sensitization of the anti-cancer activity of gemcitabine in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) exhibits a pronounced extracellular matrix (ECM)-rich response, which is produced by an excessive amount of transforming growth factor ß (TGF-ß), resulting in tumor progression and metastasis. In addition, TGF-ß signaling contributes to rapidly acquired resistance and incomplete response to gemcitabine. Recently, selective inhibitors of the TGF-ß signaling pathway have shown promise in PDAC treatment, particularly as an option for augmenting responses to chemotherapy. Here, we investigated the synergistic anticancer effects of a small-molecule TGF-ß receptor I kinase inhibitor (vactosertib/EW-7197) in the presence of gemcitabine, and its mechanism of action in pancreatic cancer. Vactosertib sensitized pancreatic cancer cells to gemcitabine by synergistically inhibiting their viability. Importantly, the combination of vactosertib and gemcitabine significantly attenuated the expression of major ECM components, including collagens, fibronectin, and α-SMA, in pancreatic cancer compared with gemcitabine alone. This resulted in potent induction of mitochondrial-mediated apoptosis, gemcitabine-mediated cytotoxicity, and inhibition of tumor ECM by vactosertib. Additionally, the combination decreased metastasis through inhibition of migration and invasion, and exhibited synergistic anti-cancer activity by inhibiting the TGF-ß/Smad2 pathway in pancreatic cancer cells. Furthermore, co-treatment significantly suppressed tumor growth in orthotopic models. Therefore, our findings demonstrate that vactosertib synergistically increased the antitumor activity of gemcitabine via inhibition of ECM component production by inhibiting the TGF-ß/Smad2 signaling pathway. This suggests that the combination of vactosertib and gemcitabine may be a potential treatment option for patients with pancreatic cancer.

Classification of Mouse Lung Metastatic Tumor with Deep Learning.

Traditionally, pathologists microscopically examine tissue sections to detect pathological lesions; the many slides that must be evaluated impose severe work burdens. Also, diagnostic accuracy varies by pathologist training and experience; better diagnostic tools are required. Given the rapid development of computer vision, automated deep learning is now used to classify microscopic images, including medical images. Here, we used a Inception-v3 deep learning model to detect mouse lung metastatic tumors via whole slide imaging (WSI); we cropped the images to 151 by 151 pixels. The images were divided into training (53.8%) and test (46.2%) sets (21,017 and 18,016 images, respectively). When images from lung tissue containing tumor tissues were evaluated, the model accuracy was 98.76%. When images from normal lung tissue were evaluated, the model accuracy ("no tumor") was 99.87%. Thus, the deep learning model distinguished metastatic lesions from normal lung tissue. Our approach will allow the rapid and accurate analysis of various tissues.

Comparative analysis of imaging diagnostic models for tubular basophilia and mineralization of kidney.

BACKGROUND: Now that it is possible to efficiently classify and save tissue images of laboratory animals using whole-slide imaging, many diagnostic models are being developed through transfer learning with Convolutional Neural Network (CNN). In this study, transfer learning was performed to gain toxicopathological knowledge using CNN models such as InceptionV3 and Xception. For the classification of tubular basophilia and mineralization, two representative background lesions that commonly occur in toxicological studies, accuracies of diagnosis were compared using MobileNetV2, Xception and InceptionV3. For the simultaneous detection of the two lesions, the accuracy was analysed using You Only Look Once version 4 (YOLOv4). RESULTS: The accuracy of the classification models was as follows: MobileNetV2 (epoch 50, accuracy: 98.57%) > Xception (epoch 70, accuracy: 97.47%) > InceptionV3 (epoch 70, accuracy: 89.62%). In the case of object detection, the accuracy of YOLOv4 was 98.62% at epoch 3000. CONCLUSIONS: Among the classification models, MobileNetV2 had the best accuracy despite applying a lower epoch than InceptionV3 and Xception. The object detection model, YOLOv4, accurately and simultaneously diagnosed tubular basophilia and mineralization, with an accuracy of 98.62% at epoch 3000.

Discovery of a novel NUAK1 inhibitor against pancreatic cancer.

The novel (nua) kinase family 1 (NUAK1) is an AMPK-related kinase and its expression is associated with tumor malignancy and poor prognosis in several types of cancer, suggesting its potential as a target for cancer therapy. Therefore, the development of NUAK1-targeting inhibitors could improve therapeutic outcomes in cancer. We synthesized KI-301670, a novel NUAK1 inhibitor, and assessed its anticancer effects and mechanism of action in pancreatic cancer. It effectively inhibited pancreatic cancer growth and proliferation, and induced cell cycle arrest, markedly G0/G1 arrest, by increasing the expression of p27 and decreasing expression of p-Rb and E2F1. Additionally, the apoptotic effect of KI-301670 was observed by an increase in cleaved PARP, TUNEL-positive cells, and annexin V cell population, as well as the release of cytochrome c via the loss of mitochondrial membrane potential. KI-301670 inhibited the migration and invasion of pancreatic cancer cells. Mechanistically, KI-301670 effectively inhibited the PI3K/AKT pathway in pancreatic cancer cells. Furthermore, it significantly attenuated tumor growth in a mouse xenograft tumor model. Our results demonstrate that a novel NUAK1 inhibitor, KI-301670, exerts anti-tumor effects by directly suppressing cancer cell growth by affecting the PI3K/AKT pathway, suggesting that it could be a novel therapeutic candidate for pancreatic cancer treatment.

A novel DDR1 inhibitor enhances the anticancer activity of gemcitabine in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is an extracellular matrix (ECM)-rich carcinoma, which promotes chemoresistance by inhibiting drug diffusion into the tumor. Discoidin domain receptor 1 (DDR1) increases tumor progression and drug resistance by binding to collagen, a major component of tumor ECM. Therefore, DDR1 inhibition may be helpful in cancer therapeutics by increasing drug delivery efficiency and improving drug sensitivity. In this study, we developed a novel DDR1 inhibitor, KI-301690 and investigated whether it could improve the anticancer activity of gemcitabine, a cytotoxic agent widely used for the treatment of pancreatic cancer. KI-301690 synergized with gemcitabine to suppress the growth of pancreatic cancer cells. Importantly, its combination significantly attenuated the expression of major tumor ECM components including collagen, fibronectin, and vimentin compared to gemcitabine alone. Additionally, this combination effectively decreased mitochondrial membrane potential (MMP), thereby inducing apoptosis. Further, the combination synergistically inhibited cell migration and invasion. The enhanced anticancer efficacy of the co-treatment could be explained by the inhibition of DDR1/PYK2/FAK signaling, which significantly reduced tumor growth in a pancreatic xenograft model. Our results demonstrate that KI-301690 can inhibit aberrant ECM expression by DDR1/PYK2/FAK signaling pathway blockade and attenuation of ECM-induced chemoresistance observed in desmoplastic pancreatic tumors, resulting in enhanced antitumor effect through effective induction of gemcitabine apoptosis.

Lidocaine enhances the efficacy of palbociclib in triple-negative breast cancer.

The use of anesthetics in the surgical resection of tumors may influence the prognosis of cancer patients. Lidocaine, a local anesthetic, is known to act as a chemosensitizer and relieve pain in some cancers. In addition, palbociclib, a potent cyclin-dependent kinase (CDK) 4/6 inhibitor, has been approved for chemotherapy of advanced breast cancer. However, recent studies have revealed the acquired resistance of breast cancer cells to palbociclib. Therefore, the development of combination therapies that can extend the efficacy of palbociclib or delay resistance is crucial. This study investigated whether lidocaine would enhance the efficacy of palbociclib in breast cancer. Lidocaine synergistically suppressed the growth and proliferation of breast cancer cells by palbociclib. The combination treatment showed an increased cell cycle arrest in the G0/G1 phase by decreasing retinoblastoma protein (Rb) and E2F1 expression. In addition, it increased apoptosis by loss of mitochondrial membrane potential as observed by increases in cytochrome c release and inhibition of mitochondria-mediated protein expression. Additionally, it significantly reduced epithelial-mesenchymal transition and PI3K/AKT/GSK3ß signaling. In orthotopic breast cancer models, this combination treatment significantly inhibited tumor growth and increased tumor cell apoptosis compared to those treated with a single drug. Taken together, this study demonstrates that the combination of palbociclib and lidocaine has a synergistic anti-cancer effect on breast cancer cells by the inhibition of the PI3K/AKT/GSK3ß pathway, suggesting that this combination could potentially be an effective therapy for breast cancer.

Subchronic inhalation toxicity of gold nanoparticles.

BACKGROUND: Gold nanoparticles are widely used in consumer products, including cosmetics, food packaging, beverages, toothpaste, automobiles, and lubricants. With this increase in consumer products containing gold nanoparticles, the potential for worker exposure to gold nanoparticles will also increase. Only a few studies have produced data on the in vivo toxicology of gold nanoparticles, meaning that the absorption, distribution, metabolism, and excretion (ADME) of gold nanoparticles remain unclear. RESULTS: The toxicity of gold nanoparticles was studied in Sprague Dawley rats by inhalation. Seven-week-old rats, weighing approximately 200 g (males) and 145 g (females), were divided into 4 groups (10 rats in each group): fresh-air control, low-dose (2.36 × 104 particle/cm3, 0.04 µg/m3), middle-dose (2.36 × 105 particle/cm3, 0.38 µg/m3), and high-dose (1.85 × 106 particle/cm3, 20.02 µg/m3). The animals were exposed to gold nanoparticles (average diameter 4-5 nm) for 6 hours/day, 5 days/week, for 90-days in a whole-body inhalation chamber. In addition to mortality and clinical observations, body weight, food consumption, and lung function were recorded weekly. At the end of the study, the rats were subjected to a full necropsy, blood samples were collected for hematology and clinical chemistry tests, and organ weights were measured. Cellular differential counts and cytotoxicity measurements, such as albumin, lactate dehydrogenase (LDH), and total protein were also monitored in a cellular bronchoalveolar lavage (BAL) fluid. Among lung function test measurements, tidal volume and minute volume showed a tendency to decrease comparing control and dose groups during the 90-days of exposure. Although no statistically significant differences were found in cellular differential counts, histopathologic examination showed minimal alveoli, an inflammatory infiltrate with a mixed cell type, and increased macrophages in the high-dose rats. Tissue distribution of gold nanoparticles showed a dose-dependent accumulation of gold in only lungs and kidneys with a gender-related difference in gold nanoparticles content in kidneys. CONCLUSIONS: Lungs were the only organ in which there were dose-related changes in both male and female rats. Changes observed in lung histopathology and function in high-dose animals indicate that the highest concentration (20 µg/m3) is a LOAEL and the middle concentration (0.38 µg/m3) is a NOAEL for this study.

26-Week carcinogenicity study of di-isodecyl phthalate by dietary administration to CB6F1-rasH2 transgenic mice.

This study examined the carcinogenic potential of di-isodecyl phthalate (DIDP) in rasH2 mice. DIDP was administered to 15 rasH2 mice/gender/group at dietary levels of 0, 0.1, 0.33, or 1% and 15 wild-type mice/gender/group at dietary levels of 0 and 1% for 26 weeks. Non-neoplastic changes were observed in the liver (parenchymal inflammation, fatty changes, diffuse hepatocyte hypertrophy with eosinophilic granules and focal necrosis) and kidneys (tubular basophilia and tubular hyperplasia) after administration of DIDP in the rasH2 and wild-type mice. In the neoplastic lesions, there were a higher number of hepatocellular adenomas in the male rasH2 mice receiving 1% DIDP, compared with the findings in the liver of control rasH2 mice or wild-type mice. The incidence of hepatocellular adenomas in the 0.1, 0.33, and 1% DIDP exposed rasH2 mice was 7% (1/15), 7% (1/15), and 33% (5/15), respectively. This study adds a set of results for an additional test chemical for the performance of the rasH2 short-term transgenic model to the existing database of 3 compounds (WY-14643, DEHP, and clofibrate) tested in the ILSI/HESI ACT project.

Size-dependent tissue kinetics of PEG-coated gold nanoparticles.

Gold nanoparticles (AuNPs) can be used in various biomedical applications, however, very little is known about their size-dependent in vivo kinetics. Here, we performed a kinetic study in mice with different sizes of PEG-coated AuNPs. Small AuNPs (4 or 13nm) showed high levels in blood for 24h and were cleared by 7days, whereas large (100nm) AuNPs were completely cleared by 24h. All AuNPs in blood re-increased at 3months, which correlated with organ levels. Levels of small AuNPs were peaked at 7days in the liver and spleen and at 1month in the mesenteric lymph node, and remained high until 6months, with slow elimination. In contrast, large AuNPs were taken up rapidly ( approximately 30min) into the liver, spleen, and mesenteric lymph nodes with less elimination phase. TEM showed that AuNPs were entrapped in cytoplasmic vesicles and lysosomes of Kupffer cells and macrophages of spleen and mesenteric lymph node. Small AuNPs transiently activated CYP1A1 and 2B, phase I metabolic enzymes, in liver tissues from 24h to 7days, which mirrored with elevated gold levels in the liver. Large AuNPs did not affect the metabolic enzymes. Thus, propensity to accumulate in the reticuloendothelial organs and activation of phase I metabolic enzymes, suggest that extensive further studies are needed for practical in vivo applications.

Carcinogenicity study of 3-monochloropropane-1, 2-diol (3-MCPD) administered by drinking water to B6C3F1 mice showed no carcinogenic potential.

3-Monochloropropane-1, 2-diol (or 3-chloro-1,2-propanediol, 3-MCPD) is a well-known food processing contaminant found in a wide range of foods and ingredients. It has been classified as non-genotoxic carcinogen but its carcinogenic potential in the rodents has been controversial. The carcinogenicity to B6C3F1 mice by drinking water administration was assessed over a period of 104 weeks. Three groups, each comprising 50 male and 50 female mice received 3-MCPD at dosages of 30, 100 or 300 ppm up to Day 100 and 200 ppm onward (4.2, 14.3 and 33.0 mg/kg for males; 3.7, 12.2, and 31.0 mg/kg for females), were allocated. Survival was good, with at least 80% of males and 72% of females in each group surviving 104 weeks. Body weights and body weight gain were decreased in males and females receiving 200 ppm. Water and food consumptions of both sexes at 300/200 ppm were lowered. Emaciated or crouching position was observed for animals of both sexes exposed to 200 ppm. There were some differences in hematology and serum biochemistry compared with controls, although there was no histopathological evidence to support those changes. Histopathological examination did not reveal any neoplastic or non-neoplastic findings attributable to treatment with 3-MCPD. It is concluded that drinking water administration of 3-MCPD for 104 weeks revealed no evidence of carcinogenic potential.

SRIS: Saliency-Based Region Detection and Image Segmentation of COVID-19 Infected Cases.

Noise or artifacts in an image, such as shadow artifacts, deteriorate the performance of state-of-the-art models for the segmentation of an image. In this study, a novel saliency-based region detection and image segmentation (SRIS) model is proposed to overcome the problem of image segmentation in the existence of noise and intensity inhomogeneity. Herein, a novel adaptive level-set evolution protocol based on the internal and external functions is designed to eliminate the initialization sensitivity, thereby making the proposed SRIS model robust to contour initialization. In the level-set energy function, an adaptive weight function is formulated to adaptively alter the intensities of the internal and external energy functions based on image information. In addition, the sign of energy function is modulated depending on the internal and external regions to eliminate the effects of noise in an image. Finally, the performance of the proposed SRIS model is illustrated on complex real and synthetic images and compared with that of the previously reported state-of-the-art models. Moreover, statistical analysis has been performed on coronavirus disease (COVID-19) computed tomography images and THUS10000 real image datasets to confirm the superior performance of the SRIS model from the viewpoint of both segmentation accuracy and time efficiency. Results suggest that SRIS is a promising approach for early screening of COVID-19.

ANGPTL4 exacerbates pancreatitis by augmenting acinar cell injury through upregulation of C5a.

Pancreatitis is the inflammation of the pancreas. However, little is known about the genes associated with pancreatitis severity. Our microarray analysis of pancreatic tissues from mild and severe acute pancreatitis mice models identified angiopoietin-like 4 (ANGPTL4) as one of the most significantly upregulated genes. Clinically, ANGPTL4 expression was also increased in the serum and pancreatic tissues of pancreatitis patients. The deficiency in ANGPTL4 in mice, either by gene deletion or neutralizing antibody, mitigated pancreatitis-associated pathological outcomes. Conversely, exogenous ANGPTL4 exacerbated pancreatic injury with elevated cytokine levels and apoptotic cell death. High ANGPTL4 enhanced macrophage activation and infiltration into the pancreas, which increased complement component 5a (C5a) level through PI3K/AKT signaling. The activation of the C5a receptor led to hypercytokinemia that accelerated acinar cell damage and furthered pancreatitis. Indeed, C5a neutralizing antibody decreased inflammatory response in LPS-activated macrophages and alleviated pancreatitis severity. In agreement, there was a significant positive correlation between C5a and ANGPTL4 levels in pancreatitis patients. Taken together, our study suggests that targeting ANGPTL4 is a potential strategy for the treatment of pancreatitis.

Acute toxicity and pharmacokinetics of 13 nm-sized PEG-coated gold nanoparticles.

In general, gold nanoparticles are recognized as being as nontoxic. Still, there have been some reports on their toxicity, which has been shown to depend on the physical dimension, surface chemistry, and shape of the nanoparticles. In this study, we carry out an in vivo toxicity study using 13 nm-sized gold nanoparticles coated with PEG (MW 5000). In our findings the 13 nm sized PEG-coated gold nanoparticles were seen to induce acute inflammation and apoptosis in the liver. These nanoparticles were found to accumulate in the liver and spleen for up to 7 days after injection and to have long blood circulation times. In addition, transmission electron microscopy showed that numerous cytoplasmic vesicles and lysosomes of liver Kupffer cells and spleen macrophages contained the PEG-coated gold nanoparticles. These findings of toxicity and kinetics of PEG-coated gold nanoparticles may have important clinical implications regarding the safety issue as PEG-coated gold nanoparticles are widely used in biomedical applications.

Pulmonary toxicity and kinetic study of Cy5.5-conjugated superparamagnetic iron oxide nanoparticles by optical imaging.

Recent advances in the development of nanotechnology and devices now make it possible to accurately deliver drugs or genes to the lung. Magnetic nanoparticles can be used as contrast agents, thermal therapy for cancer, and be made to concentrate to target sites through an external magnetic field. However, these advantages may also become problematic when taking into account safety and toxicological factors. This study demonstrated the pulmonary toxicity and kinetic profile of anti-biofouling polymer coated, Cy5.5-conjugated thermally cross-linked superparamagnetic iron oxide nanoparticles (TCL-SPION) by optical imaging. Negatively charged, 36 nm-sized, Cy5.5-conjugated TCL-SPION was prepared for optical imaging probe. Cy5.5-conjugated TCL-SPION was intratracheally instilled into the lung by a non-surgical method. Cy5.5-conjugated TCL-SPION slightly induced pulmonary inflammation. The instilled nanoparticles were distributed mainly in the lung and excreted in the urine via glomerular filtration. Urinary excretion was peaked at 3 h after instillation. No toxicity was found under the concentration of 1.8 mg/kg and the half-lives of nanoparticles in the lung and urine were estimated to be about 14.4+/-0.54 h and 24.7+/-1.02 h, respectively. Although further studies are required, our results showed that Cy5.5-conjugated TCL-SPION can be a good candidate for use in pulmonary delivery vehicles and diagnostic probes.