pH-responsive CuS/DSF/EL/PVP nanoplatform alleviates inflammatory bowel disease in mice via regulating gut immunity and microbiota.

The clinical treatment of inflammatory bowel disease (IBD) is challenging. We developed copper sulfate (CuS)/disulfiram (DSF)/methacrylic acid-ethyl acrylate copolymer (EL)/polyvinylpyrrolidone (PVP) nanoplatform (CuS/DSF/EL/PVP) and evaluated its efficiency for treating IBD. After oral administration, the pH-sensitive EL protected the CuS/DSF/EL/PVP against degradation by acidic gastric juices. Once the colon was reached, EL was dissolved, releasing DSF and Cu2+. Further, the main in vivo metabolite of DSF can bind to Cu2+ and form copper (II) N, N-diethyldithiocarbamate (CuET), which significantly alleviated acute colitis in mice. Notably, CuS/DSF/EL/PVP outperformed CuS/EL/PVP and DSF/EL/PVP nanoplatforms in reducing colonic pathology and improving the secretion of inflammation-related cytokines (such as IL-4 and IL-10) in the colonic mucosa. RNA-seq analysis revealed that the nanoplatform reduced colonic inflammation and promoted intestinal mucosal repair by upregulating C-type lectin receptor (CLR)-related genes and signaling pathways. Furthermore, CuS/DSF/EL/PVP showed potential for improving colitis Th1/Th17 cells through innate immunity stimulation, down-regulation of inflammatory cytokines, and upregulation of anti-inflammatory cytokines. Additionally, the intervention with CuS/DSF/EL/PVP led to increased intestinal flora diversity, decreased Escherichia-Shigella abundance, and elevated levels of short-chain fatty acid (SCFA)-producing bacteria Prevotella, Lactobacillus, and Bifidobacterium, indicating their potential to modulate the dysregulated intestinal flora and suppress inflammation. STATEMENT OF SIGNIFICANCE: Our study introduces the CuS/DSF/EL/PVP nanoplatform as a therapeutic strategy for treating inflammatory bowel disease (IBD). This approach demonstrates significant efficacy in targeting the colon and alleviating acute colitis in mice. It uniquely modulates gut immunity and microbiota, exhibiting a notable impact on inflammation-related cytokines and promoting intestinal mucosal repair. The nanoplatform's ability to regulate gut flora diversity, combined with its cost-effective and scalable production, positions it as a potentially transformative treatment for IBD, offering new avenues for personalized medical interventions.

Bilobalide attenuates lipopolysaccharide­induced HepG2 cell injury by inhibiting TLR4­NF­κB signaling via the PI3K/Akt pathway.

Inflammation is involved in the pathological process underlying a number of liver diseases. Bilobalide (BB) is a natural compound from Ginkgo biloba leaves that was recently demonstrated to exert hepatoprotective effects by inhibiting oxidative stress in the liver cancer cell line HepG2. The anti-inflammatory activity of BB has been reported in recent studies. The major objective of the present study was to investigate whether BB could attenuate inflammation-associated cell damage. HepG2 cells were cultured with lipopolysaccharide (LPS) and BB, and cell damage was evaluated by measuring cell viability using MTT assay. The activity of the NF-κB signaling pathway was assessed by measuring the levels of IκBα, NF-κB p65, phosphorylated (p)-IκBα, p-p65, p65 DNA-binding activity and inflammatory cytokines IL-1ß, IL-6 and TNF-α. A toll-like receptor (TLR)4 inhibitor (CLI-095) was used to detect the involvement of TLR4 in cell injury caused by LPS. In addition, the PI3K/Akt inhibitor LY294002 was applied to explore the involvement of the PI3K/Akt axis in mediating the effects of BB. The results demonstrated that LPS induced HepG2 cell injury. LPS also elevated the levels of p-IκBα, p-p65, p65 DNA-binding activity and inflammatory cytokines. However, CLI-095 significantly attenuated the LPS-induced cell damage and inhibited the activation of NF-κB signaling. BB also dose-dependently attenuated the LPS-induced cell damage, activation of NF-κB signaling and TLR4 overexpression. Furthermore, it was observed that LY294002 diminished the cytoprotective effects of BB on cell injury, TLR4 expression and NF-κB activation. These findings indicated that BB could attenuate LPS-induced inflammatory injury to HepG2 cells by regulating TLR4-NF-κB signaling.

Dhx15 regulates zebrafish intestinal development through the Wnt signaling pathway.

DEAH-box helicase 15 (DHX15) is ATP-dependent RNA helicase which is known for its role in RNA metabolism. Recent studies reported DHX15 involves in the intestinal immunity. However, the role of DHX15 (or RNA helicase) in intestinal development is poorly understood. Here, we revealed an unidentified role for dhx15 in regulating zebrafish intestinal development. We found the profound intestinal defects in dhx15 knockout zebrafish. Decreased proliferation and increased apoptosis of the intestine cells were observed when dhx15 were deleted. Further RNA genome wide analysis and qRT-PCR analysis showed the Wnt signaling pathway is down-regulated in the dhx15 knockout zebrafish. Thus, we concluded that dhx15 regulates zebrafish intestinal development through the Wnt signaling pathway. Here, we provided new insights into the role of dhx15 in intestinal development beyond its well-characterized role in intestinal immunity.

Injectable wound dressing based on carboxymethyl chitosan triple-network hydrogel for effective wound antibacterial and hemostasis.

Currently, hydrogels are widely studied for wound dressings. However, wound healing is often hindered by bacterial infection. In this study, in situ cross-linked carboxymethyl chitosan (CMCS)/oxidized dextran (OD)/poly-γ-glutamic acid (γ-PGA) (COP) hydrogel was prepared for antimicrobial and hemostasis of diffuse wounds. In the COP hydrogel, γ-PGA was able to drain the surface moisture of the wound to enhance the surface adhesion. Moreover, γ-PGA could concentrate blood by absorbing plasma, and CMCS could electrostatically adsorb negative RBCs. The antibacterial properties of CMCS and OD endowed the COP hydrogel with certain antibacterial effects. In the inhibition zone experiment, an obvious inhibition zone appeared around the COP hydrogel. In vivo studies showed that the COP hydrogel significantly inhibited bacterial growth and promoted wound healing. In the rat tail diffuse hemorrhage wound model, the COP hydrogel showed superior hemostasis ability. Therefore, the multifunctional COP hydrogel is expected to find different applications in wound hemostasis and healing.

Protective role of vitamin B6 against mitochondria damage in Drosophila models of SCA3.

Polyglutamine (polyQ)-mediated mitochondria damage is one of the prime causes of polyQ toxicity, which leads to the loss of neurons and the injury of non-neuronal cells. With the discovery of the crucial role of the gut-brain axis and gut microbes in neurological diseases, the relationship between visceral damage and neurological disorders has also received extensive attention. This study successfully simulated the polyQ mitochondrial damage model by expressing 78 or 84 polyglutamine-containing Ataxin3 proteins in Drosophila intestinal enterocytes. In vivo, polyQ expression can reduce mitochondrial membrane potential, mitochondrial DNA damage, abnormal mitochondrial morphology, and loose mitochondrial cristae. Expression profiles evaluated by RNA-seq showed that mitochondrial structural genes and functional genes (oxidative phosphorylation and tricarboxylic acid cycle-related) were significantly down-regulated. More importantly, Bioinformatic analyses demonstrated that pathological polyQ expression induced vitamin B6 metabolic pathways abnormality. Active vitamin B6 participates in hundreds of enzymatic reactions and is very important for maintaining mitochondria's activities. In the SCA3 Drosophila model, Vitamin B6 supplementation significantly suppressed ECs mitochondria damage in guts and inhibited cellular polyQ aggregates in fat bodies, indicating a promising therapeutic strategy for the treatment of polyQ. Taken together, our results reveal a crucial role for the Vitamin B6-mediated mitochondrial protection in polyQ-induced cellular toxicity, which provides strong evidence for this process as a drug target in polyQ diseases treatment.

The impact of polystyrene microplastics on cardiomyocytes pyroptosis through NLRP3/Caspase-1 signaling pathway and oxidative stress in Wistar rats.

The extensive existing of microplastics (MPs) in the ecosystem have increased considerable attention concerning their potential adverse effects, the toxicities and the underlying mechanism of MPs are still scarce. To explore the effect of MPs on cardiac tissue in Wistar rats and unravel the mechanism of pyroptosis and oxidative stress in the process of cardiomyocytes injury, 32 male Wister rats were divided into control group and three model groups, which were exposed to 0.5 mm PS MPs at 0.5, 5 and 50 mg/L for 90 days. Results revealed that MPs could damage cardiac structure and function with impaired mitochondria integrity, as well as increased levels of creatine kinase-MB and cardiac troponinI (cTnI). Moreover, MPs administration triggered oxidative stress as indicated by increased levels of malondialdehyde and decreased activity of superoxide dismutase, glutathione peroxidase and catalase. Treatment with MPs resulted in apoptosis and pyroptosis as evidenced by increasing expressions of interleukin (IL)-1ß, IL-18. Additionally, MPs were shown to induce the NOD-like receptor protein 3 inflammasomes activation in cardiac tissue, enabling activation of Caspase-1-dependent signaling pathway induced by inflammatory stimuli resulting from oxidative stress. In summary, these results illustrated that pyroptosis played a vital role in polystyrene MPs-induced cardiotoxicity, which might be helpful to understand the mechanism of cardiac dysfunction and induced by MPs.

Evaluation of a deep learning-based computer-aided diagnosis system for distinguishing benign from malignant thyroid nodules in ultrasound images.

PURPOSE: Computer-aided diagnosis (CAD) systems assist in solving subjective diagnosis problems that typically rely on personal experience. A CAD system has been developed to differentiate malignant thyroid nodules from benign thyroid nodules in ultrasound images based on deep learning methods. The diagnostic performance was compared between the CAD system and the experienced attending radiologists. METHODS: The ultrasound image dataset for training the CAD system included 651 malignant nodules and 386 benign nodules while the database for testing included 422 malignant nodules and 128 benign nodules. All the nodules were confirmed by pathology results. In the proposed CAD system, a support vector machine (SVM) is used for classification and fused features which combined the deep features extracted by a convolutional neural network (CNN) with the hand-crafted features such as the histogram of oriented gradient (HOG), local binary patterns (LBP), and scale invariant feature transform (SIFT) were obtained. The optimal feature subset was formed by selecting these fused features based on the maximum class separation distance and used as the training sample for the SVM. RESULTS: The accuracy, sensitivity, and specificity of the CAD system were 92.5%, 96.4%, and 83.1%, respectively, which were higher than those of the experienced attending radiologists. The areas under the ROC curves of the CAD system and the attending radiologists were 0.881 and 0.819, respectively. CONCLUSIONS: The CAD system for thyroid nodules exhibited a better diagnostic performance than experienced attending radiologists. The CAD system could be a reliable supplementary tool to diagnose thyroid nodules using ultrasonography. Macroscopic features in ultrasound images, such as the margins and shape of thyroid nodules, could influence the diagnostic efficiency of the CAD system.

A clinical investigation treating different types of fibroids identified by MRI-T2WI imaging with ultrasound guided high intensity focused ultrasound.

Clinical data from 172 cases of uterine fibroids with different appearances on MRI-T2WI and accepted ultrasound guided high intensity focused ultrasound (USgHIFU) treatment were retrospectively analyzed. This study aimed to evaluate the clinical safety and efficacy of ablating different types of fibroids, classified by T2-weighted magnetic resonance imaging (MRI-T2WI). Based on MRI-T2WI signal intensities, uterine fibroids were classified as three types: hypointensive (52 cases), isointensive (64 cases) and hyperintensive (56 cases). Evaluation parameters including treatment time, ablation efficiency, percentage non-perfused volume, fibroid reduction rate, adverse reactions, symptom severity scores (SSS) and re-intervention rate were assessed from 3 months to 1 year. The percentage non-perfused volume and ablation efficiency of hyperintensive uterine fibroids were lower than those of isointensive and hypointensive uterine fibroids. All fibroids shrunk and the SSS continued to reduce at 3 and 6 months after treatment respectively. At 12-month postoperative assessments, hypointensive fibroids continued to shrink, while the isointensive fibroids enlarged but remained smaller than pre-treatment. The incident rate of postoperative Society of Interventional Radiology B-class (SIRB-class) adverse events showed no significant differences. The re-interventional rate of hyperintensive fibroids was higher than in isointensive and hypointensive groups. USgHIFU ablation of all types of fibroids were safe and effective.

Value of Ultrasonographic Features for Assessing Malignant Potential of Complex Cystic Breast Lesions.

OBJECTIVES: To assess the value of ultrasonography (US) features for determining the malignant potential of complex cystic lesions. METHODS: Seventy-nine complex cystic lesions were reviewed retrospectively. They were classified into four types according to US features in type I, the masses have a thick outer wall, thick internal septa, or both; in type II, the masses are an intracystic type with one or more discrete solid mural lesions within a cyst; in type III, the masses contain mixed cystic and solid components and are at least 50% cystic portion in a mass; in type IV, there are predominantly (at least 50%) solid masses with eccentric or central cystic foci. Positive predictive values were calculated for all types. RESULTS: The frequency of malignancy was higher among type III and IV lesions than among the other two types. Lesions with a diameter greater than or equal to 20 mm, margins not circumscribed, resistance index greater than or equal to 0.7, and axillary abnormal nodes had a high probability of malignancy. CONCLUSIONS: US is an important adjunct to evaluate the malignant potential of complex cystic lesions.

Pinoresinol Diglucoside Alleviates oxLDL-Induced Dysfunction in Human Umbilical Vein Endothelial Cells.

Atherosclerotic cardiovascular diseases are the leading causes of morbidity and mortality worldwide. Deposition of oxidized low-density lipoprotein (oxLDL) is one of the initiators and promoters of atherosclerosis. Eucommia lignans were shown to possess antihypertensive effects. This study aimed to investigate the effects of pinoresinol diglucoside (PD), a Eucommia lignan, on oxLDL-induced endothelial dysfunction. HUVECs were treated with oxLDL and/or PD followed by assessing radical oxygen species (ROS), apoptosis, nitrogen oxide (NO), malondialdehyde (MDA), and superoxide dismutase (SOD) activity with specific assays kits, mRNA levels with quantitative real-time polymerase chain reaction (PCR), and protein levels with western blot. PD abolished oxLDL-induced ROS and MDA production, apoptosis, upregulation of lectin-like oxidized LDL recptor-1 (LOX-1), intercellular Adhesion Molecule 1 (ICAM-1), and nuclear factor kappa-light-chain-enhancer of activated B-cells (NF-κB), and activation of p38MAPK (mitogen-activated protein kinases)/NF-κB signaling. Meanwhile, PD alleviated oxLDL-caused inhibition of SOD activity, eNOS expression, and NO production. These data demonstrated that PD was effective in protecting endothelial cells from oxLDL-caused injuries, which guarantees further investigation on the clinical benefits of PD on cardiovascular diseases.

Poly (ADP-ribose) synthetase inhibitor has a heart protective effect in a rat model of experimental sepsis.

UNLABELLED: The aim of this study is to investigate whether PARP inhibitor could reduce cell apoptosis and injury in the heart during sepsis. MATERIALS AND METHODS: 60 healthy male Sprague-Dawley (SD) rats were randomly divided into 4 groups---sham group, modal group, 3-AB pretreatment group and 3-AB treatment group, 15 rats per group. The cecal ligation and puncture (CLP) model of sepsis was used. The following were determined--levels of malondialdehyde (MDA), ATP and nicotinamide adenine dinucleotide (NAD+), expression of PARP, Bcl-2, Bax, cytochrome C and caspase 3 activity in the myocardium tissue, levels of serum creatine kinase muscle brain (CK-MB) fraction and troponin I. RESULTS: Histological and molecular analyses showed that myocardial cells apoptosis were associated with mitochondria injury, with an increase in the amount of PARP and a decrease in ATP and NAD+ levels in model group. In addition, the levels of Bax, cytochrome C and caspase 3 activity, serum levels of CK-MB and troponin I increased, but levels of Bcl-2 significantly decreased. Inhibition of PARP upregulated the levels of ATP, NAD + and Bcl-2, and significantly reduced the activation of PARP and caspase 3, decreased the levels of MDA, cytochrome C, CK-MB and troponin I. As a result, apoptosis in the heart was attenuated. CONCLUSION: These results indicate that PARP activation may be involved in apoptosis in the heart induced by sepsis and 3-AB could improve it.

Liquid-solid phase-inversion PLGA implant for the treatment of residual tumor tissue after HIFU ablation.

BACKGROUND: HIFU has been shown to be a more suitable alternative for the treatment of primary solid tumors and metastatic diseases than other focal heat ablation techniques due to its noninvasive and extracorporeal nature. However, similar to other focal heat ablation techniques, HIFU is still in need of refinements due to tumor recurrence. METHODS: In this work, we investigated the effectiveness of an adjunct treatment regimen using doxorubicin (DOX)-loaded, injectable, in situ-forming, and phase-inverting PLGA as the second line of defense after HIFU ablation to destroy detrimental residual tumors and to prevent tumor recurrence. All of the statistical analyses were performed using the Statistical Package for the Social Sciences 18.0 (SPSS, Inc., Chicago, IL, USA), and p<0.05 was considered statistically significant. All of the results are presented as the means ± STDEV (standard deviation). For multiple comparisons, ANOVA (differences in tumor volumes, growth rates, apoptosis, proliferation indexes, and Bcl-2 and Bax protein levels) was used when the data were normally distributed with homogenous variance, and rank sum tests were used otherwise. Once significant differences were detected, Student-t tests were used for comparisons between two groups. RESULTS: Our results revealed that DOX diffused beyond the ablated tissue regions and entered tumor cells that were not affected by the HIFU ablation. Our results also show that HIFU in concert with DOX-loaded PLGA led to a significantly higher rate of tumor cell apoptosis and a lower rate of tumor cell proliferation in the areas beyond the HIFU-ablated tissues and consequently caused significant tumor volume shrinkage (tumor volumes:0.26±0.1,1.09±0.76, and 1.42±0.9 cm3 for treatment, sham, and no treatment control, respectively). CONCLUSIONS: From these results, we concluded that the intralesional injection of DOX-loaded PLGA after HIFU ablation is significantly more effective than HIFU alone for the treatment of solid tumors.

Forearm bone mineral density measurement with different scanning positions: a study in right-handed Chinese using dual-energy X-ray absorptiometry.

The purpose of our study was to determine whether different scanning positions influence forearm bone mineral density (BMD) measurements and to evaluate the association between forearm BMDs in different scanning positions and those of other skeleton sites. The study population consisted of 30 right-handed healthy Chinese volunteers. BMD was measured with GE Lunar Prodigy at the left forearm in both sitting and supine positions, and at lumbar spine and the right femur. All subjects received repeated measurements in the same day (repositioning), and the average of repeated BMD results was used for analysis. The BMD precision errors of the nondominant forearm in the sitting and supine positions varied from 1.13% to 2.46%. There were no statistically significant differences between BMD precision errors for each region of interest (ROI) between sitting and supine positions (all the p values were greater than 0.05). When comparing BMDs on the same side in the sitting position with those in the supine position, there were significant differences at both the 1/3 radius level and in the total radius (p<0.05). The BMD values at these ROIs obtained in the supine position were lower than those in the routine sitting position. The BMDs of the ultradistal radius in the both 2 different scanning positions were significantly associated with lumbar spine and femoral neck BMD, respectively. The total radius BMD in the different positions was associated with the BMD of the femoral neck. A change in body scanning position from sitting to supine will significantly influence forearm BMD results.

The pilot study of DXA assessment in chinese HIV-infected men with clinical lipodystrophy.

The aim of this study was to evaluate human immunodeficiency virus (HIV)-infected patient's body composition changes by dual-energy X-ray absorptiometry (DXA) and to analyze factors associated with lipodystrophy (LD). Total-body composition was measured by DXA in HIV-infected men and healthy men. HIV-infected men were divided into LD patients and non-LD patients according to whether they were complicated with LD. Healthy men were selected as controls. Fat mass (FM) of HIV-infected patients correlated negatively with the duration of HIV infection and with the duration of highly active antiretroviral therapy regimen (r(s)=-0.448 and -0.563; p=0.032 and 0.000, respectively). Multiple linear regression results showed that FM had positive correlation with weight and bone mineral content (BMC) and had negative correlation with lean mass (LM). Total body and regional FMs were found to be significantly different among LD patients, non-LD patients, and controls-the lowest in LD patients and the highest in controls (p<0.05). Total body, trunk, and leg BMCs of LD patients were lower than those of controls (p<0.05). Lumbar bone mineral density of LD patients was lower than that of non-LD patients and controls (p=0.04 and 0.007). LM of LD patients was higher than that of non-LD patients, and trunk LM had statistical difference between the 2 groups (p=0.003). Applying DXA to assess HIV-infected patient's body composition changes could provide objective information for physicians to prevent LD and osteoporosis.