Modulating cell stiffness for improved vascularization: leveraging the MIL-53(fe) for improved interaction of titanium implant and endothelial cell.

Vascularization plays a significant role in promoting the expedited process of bone regeneration while also enhancing the stability and viability of artificial bone implants. Although titanium alloy scaffolds were designed to mimic the porous structure of human bone tissues to facilitate vascularization in bone repair, their biological inertness restricted their broader utilization. The unique attribute of Metal-organic framework (MOF) MIL-53(Fe), known as "breathing", can facilitate the efficient adsorption of extracellular matrix proteins and thus provide the possibility for efficient interaction between scaffolds and cell adhesion molecules, which helps improve the bioactivity of the titanium alloy scaffolds. In this study, MIL-53(Fe) was synthesized in situ on the scaffold after hydrothermal treatment. The MIL-53(Fe) endowed the scaffold with superior protein absorption ability and preferable biocompatibility. The scaffolds have been shown to possess favorable osteogenesis and angiogenesis inducibility. It was indicated that MIL-53(Fe) modulated the mechanotransduction process of endothelial cells and induced increased cell stiffness by promoting the adsorption of adhesion-mediating extracellular matrix proteins to the scaffold, such as laminin, fibronectin, and perlecan et al., which contributed to the activation of the endothelial tip cell phenotype at sprouting angiogenesis. Therefore, this study effectively leveraged the intrinsic "breathing" properties of MIL-53 (Fe) to enhance the interaction between titanium alloy scaffolds and vascular endothelial cells, thereby facilitating the vascularization inducibility of the scaffold, particularly during the sprouting angiogenesis phase. This study indicates that MIL-53(Fe) coating represents a promising strategy to facilitate accelerated and sufficient vascularization and uncovers the scaffold-vessel interaction from a biomechanical perspective.

A black phosphorus nanosheet-based RNA delivery system for prostate cancer therapy by increasing the expression level of tumor suppressor gene PTEN via CeRNA mechanism.

BACKGROUND: Prostate cancer (PCa) has a high incidence in men worldwide, and almost all PCa patients progress to the androgen-independent stage which lacks effective treatment measures. PTENP1, a long non-coding RNA, has been shown to suppress tumor growth through the rescuing of PTEN expression via a competitive endogenous RNA (ceRNA) mechanism. However, PTENP1 was limited to be applied in the treatment of PCa for the reason of rapid enzymatic degradation, poor intracellular uptake, and excessively long base sequence to be synthesized. Considering the unique advantages of artificial nanomaterials in drug loading and transport, black phosphorus (BP) nanosheet was employed as a gene-drug carrier in this study. RESULTS: The sequence of PTENP1 was adopted as a template which was randomly divided into four segments with a length of about 1000 nucleotide bases to synthesize four different RNA fragments as gene drugs, and loaded onto polyethyleneimine (PEI)-modified BP nanosheets to construct BP-PEI@RNA delivery platforms. The RNAs could be effectively delivered into PC3 cells by BP-PEI nanosheets and elevating PTEN expression by competitive binding microRNAs (miRNAs) which target PTEN mRNA, ultimately exerting anti-tumor effects. CONCLUSIONS: Therefore, this study demonstrated that BP-PEI@RNAs is a promising gene therapeutic platform for PCa treatment.

Synergistic effect of hierarchical topographic structure on 3D-printed Titanium scaffold for enhanced coupling of osteogenesis and angiogenesis.

The significance of the osteogenesis-angiogenesis relationship in the healing process of bone defects has been increasingly emphasized in recent academic research. Surface topography plays a crucial role in guiding cellular behaviors. Metal-organic framework (MOF) is an innovative biomaterial with nanoscale structural and topological features, enabling the modulation of scaffold physicochemical properties. This study involved the loading of varying quantities of UiO-66 nanocrystals onto alkali-heat treated 3D-printed titanium scaffolds, resulting in the formation of hierarchical micro/nano topography named UiO-66/AHTs. The physicochemical properties of these scaffolds were subsequently characterized. Furthermore, the impact of these scaffolds on the osteogenic potential of BMSCs, the angiogenic potential of HUVECs, and their intercellular communication were investigated. The findings of this study indicated that 1/2UiO-66/AHT outperformed other groups in terms of osteogenic and angiogenic induction, as well as in promoting intercellular crosstalk by enhancing paracrine effects. These results suggest a promising biomimetic hierarchical topography design that facilitates the coupling of osteogenesis and angiogenesis.

Improving osteoinduction and osteogenesis of Ti6Al4V alloy porous scaffold by regulating the pore structure.

Titanium alloy scaffolds with a porous structure have attracted much attention in bone defect repair. However, which pore structure is more beneficial to bone defect repair is controversial. In the present research, the Ti6Al4V alloy porous scaffolds with gradient pore sizes were designed and fabricated. The microstructure characterization, tests of mechanical properties, and in vitro and in vivo experiments have been performed to systematically evaluate the effect of pore size on osteoinduction and osteogenesis. The results revealed that the contact angle with water, compressive strength, and elastic modulus of the Ti6Al4V alloy porous scaffolds decreased gradually with the increase of pore size. However, there were obvious drops when the pore size of the porous scaffold was around 600 µm. As the pore size increased, the proliferation and integrin ß1 of RAW 264.7 macrophages seeded on Ti6Al4V alloy porous scaffolds increased at first, reaching a maximum value at a pore size of around 600 µm, and then decreased subsequently. The proliferation, integrin ß1, and osteogenic gene-related expressions of Bone marrow mesenchymal stem cells (BMSCs) seeded on Ti6Al4V alloy porous scaffolds with different pore sizes all exhibited similar variations which rose with increased pore size firstly, obtaining the maximum value at pore size about 600 µm, and then declined. The in vivo experiments confirmed the in vitro results, and the Ti6Al4V alloy porous scaffold with a pore size of 600 µm possessed the better capability to induce new bone formation. Therefore, for the design of Ti6Al4V alloy with a regular porous scaffold, the surface morphology, porosity, strength, and elastic modulus should be considered systematically, which would determine the capability of osteoinduction and osteogenesis.

Low-dose graphene oxide promotes tumor cells proliferation by activating PI3K-AKT-mTOR signaling via cellular membrane protein integrin αV.

Along with the increasing production and application of graphene oxide (GO), its environmental health and safety (EHS) risks have become a global concern. Numerous studies have investigated the biosafety and toxicity mechanisms associated with GO, however, the majority of previous studies were based on its direct toxic dose, which could not reflect the realistic state of environmental exposure of GO with an indirect toxic dose (low dose). Meanwhile, the effects of low-dose GO on the progression of tumors are still unclearly. Herein, we found that GO can promote multiple types of tumor cell proliferation under its low-dose treatment. Moreover, the lateral size of GO has no obvious distinction on its promoting effect on tumor proliferation. The mechanistic investigation revealed that low-dose GO treatment increased the expression level of integrin αV protein, a cell membrane receptor, and further lead to the constitutively activated PI3K/AKT/mTOR signaling pathway and promoted mitotic progression. Collectively, these findings increased our understanding of the detrimental effects of GO in promoting tumor proliferation, as well as improved our biosafety assessment at its realistic exposure doses.

HSP90s are required for hypocotyl elongation during skotomorphogenesis and thermomorphogenesis via the COP1-ELF3-PIF4 pathway in Arabidopsis.

Light and temperature are two key environmental signals that share several molecular components that, in turn, regulate plant growth. Darkness and high ambient temperatures promote skoto- and thermomorphogenesis, including stem elongation. Heat shock proteins 90 (HSP90s) facilitate the adaptation of organisms to various adverse environmental stimuli. Here, we showed that HSP90s are required for hypocotyl elongation during both skoto- and thermomorphogenesis. When HSP90s activities are impaired by the knockdown of HSP90s expression or the application of HSP90 inhibitors, the expression levels and protein abundance of PHYTOCHROME-INTERACTING FACTOR 4 (PIF4) markedly decreased. EARLY FLOWERING 3 (ELF3) deficiency was resistant to the inhibition of HSP90s activities. Furthermore, HSP90s interacted with and destabilized ELF3. In the CONSTITUTIVE PHOTOMORPHOGENIC 1 (COP1) mutant, the changes in endogenous PIF4 and ELF3 protein levels caused by the inhibition of HSP90s activities were abolished. HSP90s enhanced the interaction between COP1 and ELF3, reduced ELF3 functional effects on PIF4 and modulated hypocotyl elongation during skoto- and thermomorphogenesis. Our results indicated that HSP90s participate in light and temperature signalling via the COP1-ELF3-PIF4 module to regulate hypocotyl growth in changing environments.

Tree Size Influences Leaf Shape but Does Not Affect the Proportional Relationship Between Leaf Area and the Product of Length and Width.

The Montgomery equation predicts leaf area as the product of leaf length and width multiplied by a correction factor. It has been demonstrated to apply to a variety of leaf shapes. However, it is unknown whether tree size (measured as the diameter at breast height) affects leaf shape and size, or whether such variations in leaf shape can invalidate the Montgomery equation in calculating leaf area. Here, we examined 60 individual trees of the alpine oak (Quercus pannosa) in two growth patterns (trees growing from seeds vs. growing from roots), with 30 individuals for each site. Between 100 and 110 leaves from each tree were used to measure leaf dry mass, leaf area, length, and width, and to calculate the ellipticalness index, ratio of area between the two sides of the lamina, and the lamina centroid ratio. We tested whether tree size affects leaf shape, size, and leaf dry mass per unit area, and tested whether the Montgomery equation is valid for calculating leaf area of the leaves from different tree sizes. The diameters at breast height of the trees ranged from 8.6 to 96.4 cm (tree height ranged from 3 to 32 m). The diameter at breast height significantly affected leaf shape, size, and leaf dry mass per unit area. Larger trees had larger and broader leaves with lower leaf dry mass per unit area, and the lamina centroid was closer to the leaf apex than the leaf base. However, the variation in leaf size and shape did not negate the validity of the Montgomery equation. Thus, regardless of tree size, the proportional relationship between leaf area and the product of leaf length and width can be used to calculate the area of the leaves.

Biotransformation of graphene oxide within lung fluids could intensify its synergistic biotoxicity effect with cadmium by inhibiting cellular efflux of cadmium.

Graphene oxide (GO) has been widely studied and applied in numerous industrial fields and biomedical fields for its excellent physical and chemical properties. Along with the production and applications of GO persist increasing, the environmental health and safety risk (EHS) of GO has been widely studied. However, previous studies almost focused on the biotoxicity of pristine GO under a relatively high exposure dose, without considering its transformation process within environmental and biological mediums. Meanwhile, its secondary toxicity or synergistic effects have not been taken seriously. Here, two different kinds of artificial lung fluids were adopted to incubate pristine GO to mimic the biotransformation process of GO in the lung fluids. And, we explored that biotransformation within the artificial lung fluids could significantly change the physicochemical properties of GO and could enhance its biotoxicity. To reveal the synergistic effects of GO and toxic metal ions, we uncovered that GO could enhance the intracellular content of metal ions by inhibiting the efflux function of ATP binding cassette (ABC) transporters which are distributed on the cellular membrane, and artificial lung fluids incubation of GO could enhance this synergistic effect. Finally, toxic metal ions induced a series of toxic reactions through oxidative stress response and promoted cell death. Moreover, consistent with the results of in vitro experiments, the lungs of mice exposed to GOs combined with Cd exhibited significant inflammation and oxidative stress compared with Cd treatment alone, and it was more remarkable within the mice which were treated with bio-transformed GOs. In summary, this study explored the impact and mechanism of biotransformation of GO in the lung fluids on the synergistic and secondary effects between GO and metal ions.

Circ_SETD3 regulates gefitinib sensitivity and tumor progression by miR-873-5p-dependent regulation of APPBP2 in non-small cell lung cancer.

Previous data have shown the prominent clinical efficacy of gefitinib in non-small cell lung cancer (NSCLC) patients. However, its therapeutic efficacy is limited because of the development of gefitinib resistance. This research is designed to investigate the role of circRNA SET domain containing 3, actin histidine (circ_SETD3) in the sensitivity of NSCLC to gefitinib. The expression of circ_SETD3, microRNA-873-5p (miR-873-5p) and amyloid protein-binding protein 2 (APPBP2) was detected by qRT-PCR. Protein expression was determined by western blot analysis or immunohistochemistry assay. The half-maximal inhibitory concentration of gefitinib was determined by 3-(4,5-Dimethylthazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Cell proliferation was investigated by 5-Ethynyl-29-deoxyuridine (EdU), cell colony formation and MTT assays. Cell apoptosis was analyzed by Annexin V-fluorescein isothiocyanate and propidium iodide double staining assay. Transwell assay was employed to evaluate cell migration and invasion. Additionally, the binding relationship between miR-873-5p and circ_SETD3 or APPBP2 was predicted by starbase online database, and identified by a dual-luciferase reporter assay. Further, circ_SETD3 silencing-mediated effect on tumor sensitivity to gefitinib in vivo was confirmed by xenograft mouse model experiment. Circ_SETD3 and APPBP2 expression were upregulated, while miR-873-5p was downregulated in gefitinib-resistant NSCLC tissues and cells compared with gefitinib-sensitive NSCLC tissues or cells. Reduced expression of circ_SETD3 repressed gefitinib resistance, proliferation, migration and invasion, but induced apoptosis of gefitinib-resistant NSCLC cells. Additionally, circ_SETD3 modulated gefitinib sensitivity and tumor development by binding to miR-873-5p. APPBP2 upregulation attenuated miR-873-5p-mediated gefitinib sensitivity and NSCLC progression. Furthermore, circ_SETD3 absence improved tumor sensitivity to gefitinib in vivo. Circ_SETD3 knockdown improved gefitinib sensitivity and repressed NSCLC cell malignancy via miR-873-5p/APPBP2 axis, which provides a theoretical basis for using circ_SETD3-based therapeutic strategies to improve NSCLC sensitivity to gefitinib.

[Application of preputial endoscopy in the treatment of phimosis].

OBJECTIVE: To explore the application value of preputial endoscopy in the treatment of phimosis. METHODS: The clinical data were obtained on 58 cases of phimosis with an obvious narrow ring at the prepuce mouth and unable to reveal the glans penis when pushed up, which were treated in hour department from October 2018 to May 2020. The patients underwent preputial endoscopic examination followed by circumcision (group A, n = 30) or simple circumcision (group B, n = 28). A ureteroscope was used for preputial endoscopy, and the foreign matter removed with forceps to prepare for later circumcision. Under surface anesthesia, the ureteroscope was entered into the preputial cavity to observe the intactness and smoothness of the right, left and anterior walls and the frenulum side, as well as possible bleeding, tumor or hypospadias. RESULTS: Preputial endoscopy was successfully performed in all the 30 cases, which revealed 1 case of adhesive integration of the inner preputial lamina to the glans, 1 case of hypospadias, 2 cases of preputial adhesion and 2 cases of glans hemorrhage. Pathological biopsy confirmed penile cancer in 1 of the 6 cases. Lateral wall hemorrhage was found in 4 cases, preputial stones in 3, which was removed with foreign matter forceps, and preputial infection in 5 cases, which was treated by intrapreputial irrigation and antibiotic anti-inflammation therapy. The preputial endoscopic examinations lasted (6.52 ± 2.03) min. The operation time was significantly shorter in group A than in B (ï¼»37.81 ± 4.09ï¼½ vs ï¼»48.04 ± 5.48ï¼½ min, P < 0.01), and so were the postoperative pain duration (ï¼»110.74 ± 22.09ï¼½ vs ï¼»121.43 ± 26.80ï¼½ min, P < 0.01) and postoperative recovery time (ï¼»7.96 ± 1.83ï¼½ vs ï¼»12.04 ± 3.28ï¼½ d, P < 0.01). CONCLUSIONS: Preputial endoscopy is a safe and efficient method for the diagnosis and treatment of phimosis, with the advantages of simple operation, short examination time and less intraoperative pain, making essential preparations for subsequent circumcision.

Propofol Suppresses Gastric Cancer Progression by Regulating circPDSS1/miR-1324/SOX4 Axis.

BACKGROUND: Propofol is a common intravenous anesthetic that exerts an antitumor role in human cancers. Circular RNAs (circRNAs) play crucial roles in the progression of various cancers. However, the relationship between propofol and circRNA decaprenyl diphosphate synthase subunit 1 (circPDSS1) in gastric cancer (GC) remains unclear. METHODS: Cell proliferation was evaluated by Cell Counting Kit-8 (CCK-8), colony formation, and 5-ethynyl-2'-deoxyuridine (EdU) assays. Cell migration and invasion were assessed by transwell assay. Cell apoptosis was determined by flow cytometry. All protein levels were detected by Western blot assay. The expression levels of circPDSS1, microRNA-1324 (miR-1324), and SRY-box transcription factor 4 (SOX4) mRNA were determined by quantitative real-time PCR (qRT-PCR). The interaction between miR-1324 and circPDSS1 or SOX4 was confirmed by dual-luciferase reporter and RNA pull-down assays. The mice xenograft model was established to investigate the role of propofol and circPDSS1 in vivo. RESULTS: Propofol inhibited cell proliferation, migration and invasion and induced apoptosis in GC cells, which could be reversed by upregulating circPDSS1. MiR-1324 was a target of circPDSS1, and circPDSS1 promoted cell proliferation, migration and invasion and reduced apoptosis in propofol-treated cells by sponging miR-1324. Moreover, SOX4 was a direct target of miR-1324, and miR-1324 exerted anticancer role by targeting SOX4 in propofol-treated cells. CircPDSS1 acted as a sponge of miR-1324 to regulate SOX4 expression. Additionally, circPDSS1 overexpression weakened the anticancer role of propofol in vivo. CONCLUSION: Propofol exerted anticancer role in GC through regulating circPDSS1/miR-1324/SOX4 axis, indicating that propofol might be an effective therapeutic medicine for GC treatment.

Clinical Application of Cytokines in Cancer Immunotherapy.

Cytokines are key components of the immune system and play pivotal roles in anticancer immune response. Cytokines as either therapeutic agents or targets hold clinical promise for cancer precise treatment. Here, we provide an overview of the various roles of cytokines in the cancer immunity cycle, with a particular focus on the clinical researches of cytokine-based drugs in cancer therapy. We review 27 cytokines in 2630 cancer clinical trials registered with ClinicalTrials.gov that had completed recruitment up to January 2021 while summarizing important cases for each cytokine. We also discuss recent progress in methods for improving the delivery efficiency, stability, biocompatibility, and availability of cytokines in therapeutic applications.

Contrast-enhanced Ultrasound (CEUS) vs contrast-enhanced computed tomography for multilocular cystic renal neoplasm of low malignant potential: A retrospective analysis for diagnostic performance study.

Multilocular cystic renal neoplasm of low malignant potential (MCRNLMP) might be benefited from nephron-sparing surgery. Contrast-enhanced computed tomography is used for the diagnosis of MCRNLMP but contrast-enhanced ultrasound has lack of nephrotoxicity and several advantages over contrast-enhanced computed tomography and contrast-enhanced magnetic resonance. The purpose of the study was to compare diagnostic parameters of preoperative contrast-enhanced ultrasound against contrast-enhanced computed tomography for the detection of MCRNLMP in patients who faced curative surgery for complex cystic renal mass.Data regarding contrast-enhanced ultrasound, contrast-enhanced computed tomography, and clinicopathological results of 219 patients who underwent curative surgery for complex cystic renal mass (Bosniak classification III or IV) were retrospectively collected and analyzed. Bosniak classification for imaging modality and the 2016 WHO criteria for clinic pathology were used for detection of MCRNLMP.Contrast-enhanced ultrasound, contrast-enhanced computed tomography, and clinicopathology were detected 68, 66, and 67 as a MCRNLMP respectively. Contrast-enhanced ultrasound and contrast-enhanced computed tomography had 30.37% and 29.27% sensitivities for the detection of MCRNLMP. While 60% and 50% specificities respectively. Bosniak classification III (P = .045) and lower mean Hounsfield unit (P = .049) were associated with the prevalence of MCRNLMP. Contrast-enhanced computed tomography was detected 6 and 7, while contrast-enhanced ultrasound detected 3 and 2 complex cystic renal mass as false positive and false negative MCRNLMP respectively. A contrast-enhanced ultrasound had 0.011 to 1.0 diagnostic confidence and contrast-enhanced computed tomography had 0.045 to 0.983 diagnostic confidence for decision making of nephron-sparing surgeries.Contrast-enhanced ultrasound may have better visualization of MCRNLMP than contrast-enhanced computed tomography.Level of Evidence: III.