Search

Nanotechnology is associated with the development of particles in the nano-size range that can be used in a wide range of applications in the medical field. It has gained more importance in the pharmaceutical research field particularly in drug delivery, as it results in enhanced therapeutic drug performance, improved drug solubility, targeted drug delivery to the specific sites, minimized side effects, and prolonged drug retention time in the targeted site. To date, the application of nanotechnology continues to offer several benefits in the treatment of various chronic diseases and results in remarkable improvements in treatment outcomes. The use of nano-based delivery systems such as liposomes, micelles, and nanoparticles in pulmonary drug delivery have shown to be a promising strategy in achieving drug deposition and maintained controlled drug release in the lungs. They have been widely used to minimize the risks of drug toxicity in vivo. In this review, recent advances in the application of nano- and micro-based delivery systems in pulmonary drug delivery for the treatment of various pulmonary diseases, such as lung cancer, asthma, and chronic obstructive pulmonary disease, are highlighted. Limitations in the application of these drug delivery systems and some key strategies in improving their formulation properties to overcome challenges encountered in drug delivery are also discussed.

Background: Epithelial-Mesenchymal Transition (EMT) and its reverse Mesenchymal- Epithelial Transition (MET) are essential for tumor cells metastasis. However, the effect of epigenetic modifications on this transition is unclear. Objective: We aimed to explore the key histone modifications and hub genes of EMT/MET during Colorectal Cancer (CRC) metastasis. Method: The differentially expressed genes and differentially histone modified genes were identified. Based on the histone modification features, the up- and down-regulated genes were predicted by Random Forest algorithm. Through protein-protein interaction network and Cytoscape analysis, the hub genes with histone modification changes were selected. GO, KEGG and survival analyses were performed to confirm the importance of the hub genes. Results: It was found that H3K79me3 plays an important role in EMT/MET. And the 200-300bp and 400-500bp downstream of TSS may be the key regulatory regions of H3K79me3. Moreover, we found that the expression of the hub genes was down-regulated in EMT and then up-regulated in MET. And the changes of the hub genes expression were consistent with the changes of H3K79me3 signal in the specific regions of the genome. Finally, the hub genes KRT8 and KRT18 were involved in the metastasis process and were significantly related to the survival time. Conclusion: H3K79me3 may be crucial for EMT/MET, and the hub genes KRT8 and KRT18 may be the key genes in this process.

We extracted, purified, and characterized three neutral and three acidic polysaccharides from the roots, stems, and leaves of

Purpose: To investigate whether hydrogen-oxygen (67%–33%) therapy could improve the postoperative pulmonary function, recovery, complications, inflammatory reactions, and oxidative stress in patients undergoing lung surgery.Methods: We performed a prospective, randomized, single-blind, controlled clinical trial between December 2020 and December 2021. Eligible patients received either a lobectomy or sublobar resection. Postoperatively, they had 2-hour hydrogen-oxygen therapy (group H) or oxygen therapy (group C) daily, for three consecutive days. The pulmonary functions, recovery, pain intensity, oxygen saturation, inflammatory cytokines, and anti-oxidative markers were documented.Results: A total of 66 patients were analyzed, with 33 patients in each group. Both groups had decreased postoperative pulmonary functions, but group H had significantly better postoperative pulmonary functions than group C (forced vital capacities were 1.4±0.5 and 1.0±0.4 L and forced expiratory volumes in the first second were 1.1±0.3 and 0.9±0.3 L in group H and C, respectively (both PConclusion: Hydrogen-oxygen therapy could improve postoperative pulmonary functions, decrease pain intensity, accelerate recovery, and shorten the length of the hospital stay in patients who have undergone lung resection, which may be related to its anti-inflammatory and anti-oxidative effects. Trial registration: The Chinese Clinical Trial Registry (registration number ChiCTR2100042101)，the date of registration was January,13,2021.

The migration model of the (n, 0) zigzag SWNT is established on the basis of Mathiessen’s law to calculate carrier mobility, which are the foundation for performance analysis of electroluminescence light emission. The split-gate technique is used to create p-and n-doped regions in the single-walled carbon nanotube (SWNT) arrays that are separated by a gap with a width of several microns. The LED devices based on SWNT arrays using split-gate technique are fabricated and tested by using an optical measurement system. Compared to the LED with the central gate, the split-gate SWNT LED has enhanced the light generation efficiency of the intrinsic SWNT array segment by decreasing the potential barrier across the junction of the intrinsic SWNT array segment. The results demonstrate the luminescent principle of LED based on SWNT array in theoretical simulation and device measurement.

Prostate cancer (PCa) is the second most frequently diagnosed solid tumor and the fifth leading cause of cancer mortality among men worldwide. The prostate specific antigen (PSA) test for PCa remains controversial. Therefore, the development of more effective non-invasive biomarkers for PCa is necessary. The present study evaluated the diagnostic value of microRNA (miR)-20b-5p in PCa. Tissue miR-20b-5p expression levels and their correlation with clinical parameters were assessed using The Cancer Genome Atlas (TCGA) datasets, and the diagnostic value of the miR-20b-5p expression levels in PCa tissues was assessed using receiver operating characteristic curve analysis. Reverse transcription-quantitative PCR (RT-qPCR) was used to assess the relative expression levels of miR-20b-5p in PCa tissues compared with benign prostate hyperplasia (BPH) tissues. In addition, miR-20b-5p expression levels in PCa cell lines and non-tumorigenic prostate epithelial cells were compared. In this study, exosomes were extracted from the prostatic fluid as a source of liquid biopsy for the detection of PCa. The prostatic fluid exosomal miR-20b-5p expression levels between patients with PCa and the biopsy-negative patients were compared, and the diagnostic efficiency of prostatic fluid exosomal miR-20b-5p expression levels in PCa was compared with PSA and with the European Randomized Study of Screening for Prostate Cancer (ERSPC) risk calculator. The mechanism by which miR-20b-5p may function in PCa was assessed using bioinformatic analysis and validation experiments. miR-20b-5p was expressed at a markedly higher level in PCa tissues compared with normal prostate tissues with high diagnostic efficiency (area under the curve: 0.826). The expression levels of miR-20b-5p were also significantly higher in PCa tissues compared with BPH tissues; similarly, miR-20b-5p was more highly expressed in PCa cells compared with non-tumorigenic prostate epithelial cells. Prostatic fluid exosomal miR-20b-5p expression levels in patients with PCa were significantly higher compared with confirmed to be biopsy-negative, and the diagnostic performance of miR-20b-5p was superior to PSA and ERSPC risk calculator. The results of RT-qPCR and western blotting following transfection of DU145 cells with miR-20b-5p mimics and inhibitor showed that miR-20b-5p reduced the expression of retinoblastoma-associated protein 1 (RB1). Therefore, RB1 may be a significant target gene for miR-20b-5p. In conclusion, the present study demonstrated that miR-20b-5p was upregulated in PCa at the tissue and cellular levels, as well as in prostatic fluid exosomes. Therefore, miR-20b-5p may be a promising early diagnostic biomarker for PCa and an important tool to guide the decision-making of prostate biopsy.

Disulfiram (DSF) is an FDA-approved anti-alcoholic drug that has recently proven to be effective in cancer treatment. However, the short half-life in the bloodstream and the metal ion-dependent antitumor activity significantly limited the further application of DSF in the clinical field. To this end, we constructed a silk fibroin modified disulfiram/zinc oxide nanocomposites (SF/DSF@ZnO) to solubilize and stabilize DSF, and, more importantly, achieve pH triggered Zn2+ release and subsequent synergistic antitumor activity. The prepared SF/DSF@ZnO nanocomposites were spherical and had a high drug loading. Triggered by the lysosomal pH, SF/DSF@ZnO could induce the rapid release of Zn2+ under the acidic conditions and caused nanoparticulate disassembly along with DSF release. In vitro experiments showed that cytotoxicity of DSF could be enhanced by the presence of Zn2+, and further amplified when encapsulated into SF/DSF@ZnO nanocomposites. It was confirmed that the significantly amplified cytotoxicity of SF/DSF@ZnO was resulted from pH-triggered Zn2+ release, inhibited cell migration, and increased ROS production. In vivo study showed that SF/DSF@ZnO nanocomposites significantly increased the tumor accumulation and prolonged the retention time. In vivo antitumor experiments in the xenograft model showed that SF/DSF@ZnO exerted the highest tumor-inhibition rate among all the drug treatments. Therefore, this exquisite study established silk fibroin-modified disulfiram/zinc oxide nanocomposites, SF/DSF@ZnO, where ZnO not only acted as a delivery carrier but also served as a metal ion reservoir to achieve synergistic antitumor efficacy. The established DSF nanoformulation displayed excellent therapeutic potential in future cancer treatment.

Glycogen synthase kinase 3 (Gsk3) α and β are both constitutively active and inhibited upon stimulation by N-terminal serine phosphorylation. Although roles of active Gsk3 in liver ischemia reperfusion injury (IRI) have been well appreciated, whether Gsk3 N-terminal serine phosphorylation has any functional significance in the disease process remains unclear. In a murine liver partial warm ischemia model, we studied Gsk3 N-terminal serine mutant knock-in (KI) mice and showed that liver IRI was decreased in Gsk3αS21A but increased in Gsk3βS9A mutant KI mice. Bone marrow chimeric experiments revealed that the Gsk3α, but not β, mutation in liver parenchyma protected from IRI, and both mutations in bone marrow–derived cells exacerbated liver injuries. Mechanistically, mutant Gsk3α protected hepatocytes from inflammatory (TNF-α) cell death by the activation of HIV-1 TAT-interactive protein 60 (TIP60)–mediated autophagy pathway. The pharmacological inhibition of TIP60 or autophagy diminished the protection of the Gsk3α mutant hepatocytes from inflammatory cell death in vitro and the Gsk3α mutant KI mice from liver IRI in vivo. Thus, Gsk3 N-terminal serine phosphorylation inhibits liver innate immune activation but suppresses hepatocyte autophagy in response to inflammation. Gsk3 αS21, but not βS9, mutation is sufficient to sustain Gsk4 activities in hepatocytes and protect livers from IRI via TIP60 activation.

Farnesoid X receptor (FXR) is the nuclear receptor of bile acids and is involved in innate immune regulation. FXR agonists have been shown to protect multiple organs from inflammatory tissue injuries. Because liver expresses high levels of FXR, we explored the potential therapeutic benefits and underlying mechanisms of pharmacologic FXR activation in a murine model of partial liver warm ischemia. Pretreatment of mice with FXR agonist 3-(2,6-dichlorophenyl)-4-(3'-carboxy-2-chlorostilben-4-yl)oxymethyl-5-isopropylisoxazole (GW4064) attenuated liver ischemia/reperfusion injuries (IRIs) in wild-type but not FXR knockout mice. Posttreatment with GW4064 facilitated liver recovery from IRI. Mechanistically, Kupffer cells (KCs) expressed much higher levels of FXR than bone marrow-derived macrophages (BMMs). Pretreatment of KCs but not BMMs with GW4064 resulted in lower tumor necrosis factor α but higher interleukin-10 expressions following toll-like receptor stimulation. FXR-targeted gene small heterodimer partner (SHP) was critical for the regulation of KC response by GW4064. In vivo, the depletion of KCs but not cluster of differentiation (CD) 11b+ cells or knockdown of SHP diminished the immune regulatory effect of GW4064 in liver IRI. Thus, FXR activation protects liver from IRI by up-regulating SHP in KCs to inhibit the liver proinflammatory response.

Traditional bioelectrochemical systems (BESs) coupled with stripping units for ammonia recovery suffer from an insufficient supply of electron acceptors due to the low solubility of oxygen. In this study, we proposed a novel strategy to efficiently transport the oxidizing equivalent provided at the stripping unit to the cathode by introducing a highly soluble electron mediator (EM) into the catholyte. To validate this strategy, we developed a new kind of iron complex system (tartrate-EDTA-Fe) as the EM. EDTA-Fe contributed to the redox property with a midpoint potential of -0.075 V (vs. standard hydrogen electrode, SHE) at pH 10, whereas tartrate acted as a stabilizer to avoid iron precipitation under alkaline conditions. At a ratio of the catholyte recirculation rate to the anolyte flow rate (R

Psoriasis is a common chronic immune-mediated skin disease characterized by hyperproliferation and aberrant differentiation of keratinocytes and massive infiltration of inflammatory immune cells. Recent studies showed that Signal Transducer and Activator of Transcription 3 (STAT3), which plays an important role in cell survival, proliferation, differentiation, angiogenesis, and immune responses, is constitutively activated in epidermal keratinocytes of human psoriatic skin lesions. In addition, STAT3 promotes the differentiation and expansion of T cells and facilitates cytokine production, thereby exacerbating the condition of psoriasis. Alantolactone (ALT) is a sesquiterpene lactone compound that could selectively suppress STAT3 activation, but its effectiveness and application in psoriasis treatment have not been determined. In this study, we developed ALT loaded chitosan/hyaluronic acid nanoparticles (CHALT), and investigated its therapeutic potential for psoriasis therapy. CHALT effectively abrogated the hyperproliferation by inducing ROS-mediated apoptosis with loss of mitochondrial membrane potential, and also inhibited IL-6-induced STAT3 signaling activation and inflammatory reaction in HaCaT cell line. In an Imiquimod (IMQ)-induced psoriasis model, the topical treatment of psoriasis lesions with CHALT effectively attenuated the STAT3 hyperactivation within keratinocytes and ameliorated the symptoms of psoriasis. In addition, it was found that CHALT restricted the recruitment of immune cells. These results indicated that ALT-based nanoformulation CHALT holds great potential for psoriasis therapy.

Background A major discrepancy between clinical and most experimental settings of liver ischemia-reperfusion injury (IRI) is the allogenicity. Methods In the current study, we first established a murine model of allogeneic orthotopic liver transplantation with extended cold ischemia time (18 h). Roles of CD4 T cells in the pathogenesis of IRI in liver allografts were determined using a depleting anti-CD4 antibody. The clinical relevance of CD4 as a marker of liver IRI was analyzed retrospectively in 55 liver transplant patients. Results CD4 depletion in both donors and recipients resulted in the most effective protection of liver allografts from IRI, as measured by serum transaminase levels and liver histology. CD4 depletion inhibited IR-induced intragraft neutrophil/macrophage infiltration and proinflammatory gene expressions. Quantitative reverse-transcriptase polymerase chain reaction analysis of human liver biopsies (2 h postreperfusion) revealed that posttransplant, rather than pretransplant, CD4 transcript levels correlated positively with proinflammatory gene expression profile. When we divided patients into subgroups according to intragraft CD4 levels, the high CD4 cohort developed a more severe hepatocellular damage than that with low CD4 levels. Conclusions CD4 T cells play a key pathogenic role in IRI of allogeneic liver transplants, and intragraft CD4 levels in the early postreperfusion phase may serve as a potential biomarker and therapeutic target to ameliorate liver IRI and improve orthotopic liver transplantation outcomes.

Hu JC, Wang Q, Jiang LX, et al. Onco Targets Ther. 2018;11:6259–6269. The Editor and Publisher of OncoTargets and Therapy wish to retract the published article. Concerns were raised regarding the alleged duplication of images in Figure 3 and Figure 5. The authors responded to our queries but were unable to provide an explanation for the alleged image duplication and were unable to verify their original data and have therefore agreed to retract the article. Our decision-making was informed by our policy on publishing ethics and integrity and the COPE guidelines on retraction. The retracted article will remain online to maintain the scholarly record, but it will be digitally watermarked on each page as “Retracted”. This retraction relates to this paper

Islet transplantation has been considered the most promising therapeutic option with the potential to restore the physiological regulation of blood glucose concentrations in type 1 diabetes treatment. However, islets suffer from oxidative stress and nonspecific inflammation in the early stage of transplantation, which attributed to the leading cause of islet graft failure. Our previous study reported that bilirubin exerted antioxidative and anti-inflammatory effects on hypothermic preserved islets, which inspire us to utilize bilirubin to address the survival issue of grafted islets. However, the application of bilirubin for islet transplantation is limited by its poor solubility and fast clearance. In this study, we designed a supramolecular carrier (PLCD) that could improve the solubility of bilirubin and slowly release bilirubin to protect islets after cotransplantation. PLCD was synthesized by conjugating activated β-cyclodextrin (β-CD) to the side chain of ε-polylysine (PLL) and acted as a carrier to load bilirubin via host-guest interactions. The constructed bilirubin supramolecular system (PLCD-BR) significantly improved the solubility and prolonged the action time of bilirubin. In vitro results confirmed that PLCD-BR coculture substantially enhanced the resistance of islets to excessive oxidative stress and proinflammatory stimulation and maximumly maintained the islet function. In vivo, PLCD could prolong drug duration at the transplant site, and the localized released bilirubin could protect the islets from oxidative stress and suppress the production of inflammatory cytokines. Crucially, islet transplantation with PLCD-BR significantly extended the stable blood glucose time of diabetic mice and produced a faster glucose clearance compared to those cotransplanted with free bilirubin. Additionally, immunohistochemical analysis showed that PLCD-BR had superior antioxidative and anti-inflammatory abilities and beneficial effects on angiogenesis. These findings demonstrate that the PLCD-BR has great potentials to support successful islet transplantation.

BACKGROUND Organ-associated pseudosarcomatous myofibroblastic proliferation (PMP) is a very rare disorder. In the urogenital tract, PMP preferentially involves the urinary bladder; kidney involvement is rare. Here, we report a rare case of PMP with ossification in the lower pole of the kidney, which mimics urothelial carcinoma or an osteogenic tumor. CASE SUMMARY A Chinese man was admitted to our hospital due to intermittent hematuria for more than 1 mo. Enhanced renal computed tomography revealed a mass in the left renal pelvis and upper ureter. The preoperative clinical diagnosis was renal pelvic carcinoma, determined by imaging examination and biopsy. After a standard preparation for surgery, the patient underwent retroperitoneoscopic radical nephroureterectomy. The operative findings were an extensive renal tumor (6 cm × 4.5 cm × 4.5 cm) invading the lower pole of the kidney and upper ureter. The final pathological diagnosis was organ-associated PMP with ossification. After 6-mo follow-up, no recurrence or metastasis was found. CONCLUSION This case of PMP was unusual for its mimicking renal pelvic carcinoma in imaging examinations, making biopsy necessary.

Extracellular matrix (ECM) stiffness has profound effects on the regulation of cell functions. DNA methylation is an important epigenetic modification governing gene expression. However, the effects of ECM stiffness on DNA methylation remain elusive. Here, it is reported that DNA methylation is sensitive to ECM stiffness, with a global hypermethylation under stiff ECM condition in mouse embryonic stem cells (mESCs) and embryonic fibroblasts compared with soft ECM. Stiff ECM enhances DNA methylation of both promoters and gene bodies, especially the 5' promoter regions of pluripotent genes. The enhanced DNA methylation is functionally required for the loss of pluripotent gene expression in mESCs grown on stiff ECM. Further experiments reveal that the nuclear transport of DNA methyltransferase 3-like (DNMT3L) is promoted by stiff ECM in a protein kinase C α (PKCα)-dependent manner and DNMT3L can be binding to Nanog promoter regions during cell-ECM interactions. These findings unveil DNA methylation as a novel target for the mechanical sensing mechanism of ECM stiffness, which provides a conserved mechanism for gene expression regulation during cell-ECM interactions.

High-power solid-state lasers with good beam quality are attracting great attention on account of their important applications in industry and military. However, the thermal effects generated in the laser host materials seriously limit power scaling and degrade the beam quality. Thermal lensing and thermally induced wavefront deformation are the main causes of the beam quality deterioration. Here we investigate the performance of a zero thermal expansion (ZTE) solid-state laser gain material. In a proof-of-principle experiment, an ${a}$-cut rod ${\rm Nd}\!:\!{{\rm YAlO}_3}$ (Nd:YAP) perovskite crystal is chosen to be the gain medium for ZTE around 180 K. The laser performance spanning the temperature range from 80 to 290 K is studied. The maximum output power and minimum threshold pump power were obtained at a temperature of 180 K. Moreover, the measured thermal focal power and peak-to-valley value of the wavefront distortion also reach a minimum at this temperature, an additional benefit from the crystal's ZTE coefficient. We envisage that these results will open a new route towards the development of high-power and high-beam-quality lasers through the use of ZTE gain materials.

To improve the linear range of measurement, a restrictor is usually added to the main flow channel of a capillary-tube-type thermal mass flowmeter. However, as the linear range of the flowmeter increases, the singularity will occur in the low mass flow velocity section of the flowmeter calibration data, which will lead to a significant decrease in the measurement accuracy in this section. To address this issue, first, this paper developed a microelectromechanical system (MEMS) thermal gas flowmeter based on the principle of capillary-tube-type thermal mass flow. Then, the effect of the bypass ratio on its performance was further investigated using quantitative analysis and was verified using Fluent numerical analysis. In addition, to explain the singularity, the bypass ratio-sensitivity relationship model was built. Based on this model, the bypass ratio can be changed by adjusting the restrictor parameters to optimize the performance of the MEMS thermal gas flowmeter. Moreover, six numerical simulation models of restrictors with different aperture diameters and aperture numbers were designed. The numerical analysis results show that within a certain range of aperture diameters and aperture numbers, the singularity is more easily weakened when the aperture diameter decreases or the aperture number increases. Finally, the restrictor with the optimum aperture number and suitable aperture diameter was selected as the test model for calibration, and the goodness of fit R2 of the calibration results is improved from 0.9937 to 0.9972, the singularity in the low mass flow velocity section is significantly weakened, and the sensitivity is improved.

Acute kidney injury (AKI) is a common pathological process that is globally associated with a high morbidity and mortality rate. The underlying AKI mechanisms include over-produced reactive oxygen species (ROS), inflammatory cell infiltration, and high levels of inflammatory mediators. Bilirubin is an endogenous compound with antioxidant, anti-inflammatory and anti-apoptotic properties, and could, therefore, be a promising therapeutic candidate. Nanotechnology-mediated therapy has emerged as a novel drug delivery strategy for AKI treatment. In this study, we report a hyaluronic acid (HA) coated e-polylysine-bilirubin conjugate (PLBR) nanoparticle (nHA/PLBR) that can selectively accumulate in injured kidneys and alleviate the oxidative/inflammatory-induced damage. The in vitro study revealed that nHA/PLBR has good stability, biocompatibility, and exhibited higher antioxidant as well as anti-apoptotic effects when compared to nPLBR or bilirubin. The in vivo study showed that nHA/PLBR could target and accumulate in the injured kidney, effectively relieve oxidative stress and inflammatory reactions, protect the structure and function of the mitochondria, and more importantly, inhibit the apoptosis of tubular cells in an ischemia/reperfusion-induced AKI rat model. Therefore, nHA/PLBR has the capacity to enhance specific biodistribution and delivery efficiency of bilirubin, thereby providing better treatment for AKI in the future.