Tumor Supplying Artery Injection of Liposome@Sunitinib Could Effectively Inhibit the Progression of Kidney Tumor.

Renal cell carcinoma (RCC) is one of the most common malignancies in the urinary system and is not sensitive to chemotherapy or radiotherapy in its advanced stages. Sunitinib is recommended as a first-line target drug for unresectable and metastatic RCC by targeting tyrosine kinase-related signaling pathways, but its therapeutic effect is unsatisfactory. Recently, nanomaterials have shown great prospects in the medical field because of their unique physicochemical properties. Particularly, liposomes are considered as ideal drug delivery systems due to their biodegradability, biocompatibility, and ideal drug-loading efficiency. Considering that tumor supplying artery injection can directly distribute drugs into tumor tissues, in this study, liposomes were employed to encapsulate water-insoluble sunitinib to construct the liposome@sunitinib (Lipo@Suni) complex, so that the drug could directly target and distribute into tumor tissue, and effectively trapped in tumor tissues after tumor supplying artery injection for the advantage of the physicochemical properties of liposomes, thereby achieving a better therapeutic effect on advanced RCC. Here, we found that compared with the peripheral intravenous administration, trans-renal arterial administration increases the content and prolongs the retention time of liposomes in tumor tissues; accordingly, more sunitinib is dispersed and retained in tumor tissues. Ultimately, trans-renal arterial administration of Lipo@Suni exerts a better suppressive effect on RCC progression than peripheral intravenous administration, even better than the conventional oral administration of sunitinib.

Engineered Exosomes Loaded with miR-563 Inhibit Lung Cancer Growth.

The malignancy of lung cancer (LC) is serious in the world. Exosomes are well-known natural nanovesicles, which are reported to have the potential to carry functional miRNAs as natural carriers and deliver chemotherapeutic drugs. However, the safety and functions of the engineered exosomes for delivering miRNA for the treatment of LC remain to be evaluated. In this study, we found that miR-563 is related to lung cancer from GeneCard database. RT-qPCR and in situ hybridization (ISH) were used to assess miR-563 expression in clinical samples. We prepared and verified the engineered exosomes loaded with miR-563 both in vitro and in vivo. In vitro, flow cytometry, Western blot, and other experimental methods were performed to evaluate the antitumor effect of miR-563 loaded exosomes. In in vivo, the LC mouse model was used to observe the effect of the prepared exosomes. The safety of using this exosomes was accessed by liver function test, hematological analysis, and H&E staining in major organs of the mice. Our findings indicated that the miR-563 loaded engineered exosomes inhibit the A549 cells growth in vitro, by inhibiting the tumor cell proliferation, migration, and invasion and promoting apoptosis. In in vivo, these engineered exosomes were enriched in tumor tissue after injecting to LC model mice and impacted tumor tissue by inhibiting the tumor volume and tumor weight. Importantly, our study indicated that miR-563 loaded engineered exosomes have the potential for clinical application for LC treatment with acceptable safety profiles. Our findings indicate a novel potential therapeutic target for lung cancer patients by miR-563 loaded engineered exosomes.

Vacancies on 2D transition metal dichalcogenides elicit ferroptotic cell death.

Sustainable developments of nanotechnology necessitate the exploration of structure-activity relationships (SARs) at nano-bio interfaces. While ferroptosis may contribute in the developments of some severe diseases (e.g., Parkinson's disease, stroke and tumors), the cellular pathways and nano-SARs are rarely explored in diseases elicited by nano-sized ferroptosis inducers. Here we find that WS2 and MoS2 nanosheets induce an iron-dependent cell death, ferroptosis in epithelial (BEAS-2B) and macrophage (THP-1) cells, evidenced by the suppression of glutathione peroxidase 4 (GPX4), oxygen radical generation and lipid peroxidation. Notably, nano-SAR analysis of 20 transition metal dichalcogenides (TMDs) disclosures the decisive role of surface vacancy in ferroptosis. We therefore develop methanol and sulfide passivation as safe design approaches for TMD nanosheets. These findings are validated in animal lungs by oropharyngeal aspiration of TMD nanosheets. Overall, our study highlights the key cellular events as well as nano-SARs in TMD-induced ferroptosis, which may facilitate the safe design of nanoproducts.

Radial extracorporeal shock wave promotes the enhanced permeability and retention effect to reinforce cancer nanothermotherapeutics.

Since most cancer nanomedicine relies on the enhanced permeability and retention (EPR) effect to eradicate tumors, strategies that are able to promote nanoparticle (NP) delivery and extravasation are presupposed to elevate the EPR effect for more effective cancer therapeutics. However, nanothermotherapeutics still suffers from limited drug delivery into tumor sites, for even though numerous efforts have been made to enhance the selective tumor targeting of NPs. In this study, we uncovered that radial extracorporeal shock wave therapy (rESWT), an important approach in physical therapy that has been overlooked in cancer treatment in the past, can largely improve the EPR-dependent tumor uptake of NPs. We here defined the optimal low dosage and desirable combinatory manner for rESWT in driving NP accumulation towards tumors. Two underlying biophysical mechanisms responsible for the rESWT-enhanced EPR effect were proposed. On one hand, rESWT-conducted compressive and tensile forces could relieve high intra-tumoral pressure; on the other hand, rESWT-induced cavitation bubbles could directly distend and disrupt tumor blood vessels. All these together synergistically promoted vessel vasodilation, tumor perfusion and NP extravasation. Further experiments revealed that the combinatory therapeutics between rESWT and nanothermotherapeutics greatly improved the tumor-killing efficacy. Thus, our findings open a new path to improve EPR-mediated drug delivery with the assistance of rESWT.

Radial extracorporeal shock wave therapy promotes osteochondral regeneration of knee joints in rabbits.

Radial extracorporeal shock wave therapy (rESWT) has been proven to be effective for nonunion fractures. It was, thus, hypothesized that it may be used as a supplement therapy to promote osteochondral regeneration when combined with a scaffold previously prepared by our research group. In the present study, to verify this hypothesis, New Zealand white adult rabbits were anaesthetized and divided into three groups, as follows: Untreated control group, in which full-thickness cylindrical osteochondral defects were created without repairing; scaffold group, in which rabbits were implanted with the scaffolds; scaffold plus rESWT group, in which rabbits were implanted with scaffolds and then treated with rESWT at 2 weeks post-surgery. At 6 and 12 weeks after surgery, the animals were sacrificed. Nitric oxide (NO) levels in the synovial cavity of the knee joints were measured by the Griess method. In addition, macroscopic observation and the gross score according to the International Cartilage Repair Society (ICRS) histological scoring system were determined. Histological evaluation was also performed by hematoxylin-eosin and Safranin O/fast green staining. The results demonstrated that both the scaffold and scaffold plus rESWT treatments significantly reduced NO levels in the synovial cavity at 6 weeks after surgery (P<0.05), whereas no significant difference was observed at 12 weeks after surgery. The ICRS scores of the scaffold and scaffold plus rESWT groups were significantly higher in comparison with those in the control group (P<0.05), and rESWT further increased these scores at 12 weeks after surgery (P<0.05). Histological results revealed that osteochondral regeneration was improved after treatment with scaffold or scaffold plus rESWT, with the latter displaying better results. These data suggested that rESWT improved the osteochondral regeneration when applied in combination with the scaffold, and that one of the underlying mechanisms may involve the reduction of NO in the synovial fluid. Therefore, rESWT may be a useful treatment for knee osteochondral regeneration.

Bio-transformation of Graphene Oxide in Lung Fluids Significantly Enhances Its Photothermal Efficacy.

Rationale: Graphene oxide (GO) has shown great promises in biomedical applications, such as drug delivery and thermotherapeutics, owing to its extraordinary physicochemical properties. Nonetheless, current biomedical applications of GO materials are premised on the basis of predesigned functions, and little consideration has been given to the influence of bio-transformation in the physiological environment on the physicochemical properties and predesigned functionalities of these materials. Hence, it is crucial to uncover the possible influence on GO's physicochemical properties and predesigned functionalities for better applications. Methods: Bio-transformed GOs were characterized by X-ray diffraction (XRD) spectra, Raman spectra, X-ray photoelectron spectroscopy (XPS) and Fourier transform infrared transmission (FT-IR) spectra. The morphologies of various GO materials were assessed via transmission electron microscopy (TEM), scanning electron microscopy (SEM) and atomic force microscopy (AFM) images. The photothermal (PTT) performance of different GO materials in vitro and in vivo were measured using 808 nm laser at a power density of 2 W/cm2. The PTT efficacy was determined using transplanted 4T1 cells-derived breast tumors in mice. Results: Bio-transformation of GO in the lung (a main target organ for GO to localize in vivo) can induce dramatic changes to its physicochemical properties and morphology, and consequently, its performances in biomedical applications. Specifically, GO underwent significant reduction in two simulated lung fluids, Gamble's solution and artificial lysosomal fluid (ALF), as evidenced by the increase of C/O ratio (the ratio of C content to O content) relative to pristine GO. Bio-transformation also altered GO's morphology, characterized by sheet folding and wrinkle formation. Intriguingly, bio-transformation elevated the PTT performance of GO in vitro, and this elevation further facilitated PTT-based tumor-killing efficacy in tumor cells in vitro and in a mouse model with transplanted tumors. Bio-transformation also compromised the interaction between drug with GO, leading to reduced drug adsorption, as tested using doxorubicin (DOX). Conclusions: Transformation in Gamble's solution and ALF resulted in varied degrees of improved performances of GO, due to the differential effects on GO's physicochemical properties. Our findings unveiled an overlooked impact of GO bio-transformation, and unearthed a favorable trait of GO materials in thermotherapeutics and drug delivery in the lung microenvironment.

Understanding the adsorptive interactions of arsenate-iron nanoparticles with curved fullerene-like sheets in activated carbon using a quantum mechanics/molecular mechanics computational approach.

The prevalence of global arsenic groundwater contamination has driven widespread research on developing effective treatment systems including adsorption using various sorbents. The uptake of arsenic-based contaminants onto established sorbents such as activated carbon (AC) can be effectively enhanced via immobilization/impregnation of iron-based elements on the porous AC surface. Recent suggestions that AC pores structurally consist of an eclectic mix of curved fullerene-like sheets may affect the arsenic adsorption dynamics within the AC pores and is further complicated by the presence of nano-sized iron-based elements. We have therefore, attempted to shed light on the adsorptive interactions of arsenate-iron nanoparticles with curved fullerene-like sheets by using hybridized quantum mechanics/molecular mechanics (QMMM) calculations and microscopy characterization. It is found that, subsequent to optimization, chemisorption between HAsO42- and the AC carbon sheet (endothermic process) is virtually non-existent - this observation is supported by experimental results. Conversely, the incorporation of iron nanoparticles (FeNPs) into the AC carbon sheet greatly facilitates chemisorption of HAsO42-. Our calculation implies that iron carbide is formed at the junction between the iron and the AC interface and this tightly chemosorbed layer prevents detachment of the FeNPs on the AC surface. Other aspects including electronic structure/properties, carbon arrangement defects and rate of adsorptive interaction, which are determined using the Climbing-Image NEB method, are also discussed.

Estrogen contributes to regulating iron metabolism through governing ferroportin signaling via an estrogen response element.

Ferroportin (FPN) is the only known iron exporter in mammalian cells, and is universally expressed in most types of cells. FPN signaling plays a crucial role in maintaining iron homeostasis through governing the level of intracellular iron. Serum iron storage is conversely related with the estrogen level in the female bodies, and women in post-menopause are possibly subjected to iron retention. However, the potential effects of estrogen on iron metabolism are not clearly understood. Here, FPN mRNA transcription in all selected estrogen receptor positive (ER+) cells was significantly reduced upon 17ß-estradiol (E2) treatment; and this inhibitory effect could be attenuated by ER antagonist tamoxifen. Likewise, in murine bone marrow-derived macrophages (BMDMs), FPN reduction with elevated intracellular iron (reflected by increased ferritin) was observed in response to E2; however, ferritin level barely responded to E2 in FPN-null BMDMs. The observation of inhibition of FPN mRNA expression was not replicated in ER(-) cells upon E2. A functional estrogen response element (ERE) was identified within the promoter of FPN, and this ERE was responsible for the suppressive effect of E2 on FPN expression. Moreover, ovariectomized (OVX) and sham-operated (SHAM) mice were used to further confirm the in vitro finding. The expression of hepatic FPN was induced in OVX mice, compared to that in the SHAM mice. Taken together, our results demonstrated that estrogen is involved in regulating FPN expression through a functional ERE on its promoter, providing additional insights into a vital role of estrogen in iron metabolism.

Hepcidin deficiency undermines bone load-bearing capacity through inducing iron overload.

Osteoporosis is one of the leading disorders among aged people. Bone loss results from a number of physiological alterations, such as estrogen decline and aging. Meanwhile, iron overload has been recognized as a risk factor for bone loss. Systemic iron homeostasis is fundamentally governed by the hepcidin-ferroportin regulatory axis, where hepcidin is the key regulator. Hepcidin deficiency could induce a few disorders, of which iron overload is the most representative phenotype. However, there was little investigation of the effects of hepcidin deficiency on bone metabolism. To this end, hepcidin-deficient (Hamp1(-/-)) mice were employed to address this issue. Our results revealed that significant iron overload was induced in Hamp1(-/-) mice. Importantly, significant decreases of maximal loading and maximal bending stress were found in Hamp1(-/-) mice relative to wildtype (WT) mice. Moreover, the levels of the C-telopeptide of type I collagen (CTX-1) increased in Hamp1(-/-) mice. Therefore, hepcidin deficiency resulted in a marked reduction of bone load-bearing capacity likely through enhancing bone resorption, suggesting a direct correlation between hepcidin deficiency and bone loss. Targeting hepcidin or the pathway it modulates may thus represent a therapeutic for osteopenia or osteoporosis.

HSPC111 governs breast cancer growth by regulating ribosomal biogenesis.

UNLABELLED: Activation of c-Myc plays a decisive role in the development of many human cancers. As a transcription factor, c-Myc facilitates cell growth and proliferation by directly transcribing a multitude of targets, including rRNAs and ribosome proteins. However, how to elucidate the deregulation of rRNAs and ribosome proteins driven by c-Myc in cancer remains a significant challenge and thus warrants close investigation. In this report, a crucial role for the HSPC111 (NOP16) multiprotein complex in governing ribosomal biogenesis and tumor growth was determined. It was discovered that enhanced HSPC111 expression paralleled the upregulation of c-Myc and was directly regulated by c-Myc in breast cancer cells. Knockdown of HSPC111 dramatically reduced the occurrence of tumorigenesis in vivo, and largely restrained tumor cell growth in vitro and in vivo. In stark contrast, HSPC111 overexpression significantly promoted tumor cell growth. Biochemically, it was demonstrated that RNA 3'-phosphate cyclase (RTCD1/RTCA) interacted with HSPC111, and RTCD1 was involved in the HSPC111 multiprotein complex in regulating rRNA production and ribosomal biogenesis. Moreover, HSPC111 and RTCD1 synergistically modulated cell growth and cellular size through commanding rRNA synthesis and ribosome assembly coupled to protein production. Finally, overall survival analysis revealed that concomitant upregulation of HSPC111 and RTCD1 correlated with the worst prognosis in a breast cancer cohort. IMPLICATIONS: Inhibition of HSPC111-dependent ribosomal biosynthesis and protein synthesis is a promising therapeutic strategy to diminish breast cancer tumor progression.

Childhood bronchial tuberculosis: report of one case and literature review.

OBJECTIVE: To explore the early diagnosis of childhood bronchial tuberculosis (BTB). METHODS: The clinical data of a 9-year-old boy with long-term chronic cough were retrospectively analyzed, and the relevant literature was reviewed. RESULTS: The pediatric patient was suspected to be with bronchial asthma due to long-term chronic cough, and was confirmed to be with "nasopharyngeal tuberculosis" during surgery. Purified protein derivative (PPD) (5 IU) showed moderately positive results. Chest X-ray showed the atelectasis of left lower lobe, which was suspected to be caused by bronchial tuberculosis. Chest CT and three-dimensional airway reconstruction showed atelectasis of left lower lobe, increased air volume of the left upper lung, left deviation of the mediastinum, bronchiolitis obliterans in the left lower lobe, and narrowing of the left upper lobe bronchus, suggesting the presence of bronchial tuberculosis. The bronchoscopy showed necrosis of the left main bronchus and mucosal congestion and edema, and then bronchial tuberculosis was confirmed. In addition to the systemic anti-TB treatment, transluminal interventions including local drug injection and balloon angioplasty under bronchoscope were applied routinely and achieved good effectiveness. CONCLUSIONS: Patients with long-term chronic cough should be cautiously managed in clinical settings. Examinations including PPD test, chest CT, three-dimensional airway reconstruction, and bronchoscopy should be performed as early as possible to confirm the potential existence of bronchial tuberculosis. Meanwhile, appropriate interventional treatment under bronchoscopy should be promptly applied to provide optimal protection of bronchi and lung, restore the damaged lung function, and minimize the complications.

Characteristics and oil sorption effectiveness of kapok fibre, sugarcane bagasse and rice husks: oil removal suitability matrix.

The characteristics and water/oil sorption effectiveness ofkapok fibre, sugarcane bagasse and rice husks have been compared. The three biomass types were subjected to field emission scanning electron microscopy-energy dispersive X-ray spectroscopy and surface tension analyses for liquid-air and oil-water systems were conducted. Both kapok fibre and sugarcane bagasse exhibit excellent oil sorption capabilities for diesel, crude, new engine and used engine oils as their oil sorption capacities all exceed 10 g/g. The synthetic sorbent exhibits oil sorption capacities comparable with sugarcane bagasse, while rice husks exhibit the lowest oil sorption capacities among all the sorbents. Kapok fibre shows overwhelmingly high oil-to-water sorption (O/W) ratios ranging from 19.35 to 201.53 while sugarcane bagasse, rice husks and synthetic sorbent have significantly lower O/W ratios (0.76-2.69). This suggests that kapok fibre is a highly effective oil sorbent even in well-mixed oil-water media. An oil sorbent suitability matrix is proposed to aid stakeholders in evaluating customized oil removal usage of the natural sorbents.

Lipopolysaccharide pretreatment protects against ischemia/reperfusion injury via increase of HSP70 and inhibition of NF-κB.

It has been reported that pretreatment of rats with lipopolysaccharide (LPS) increases myocardial functional recovery in ischemia/reperfusion (I/R) hearts. However, the mechanisms by which LPS induces cardioprotection against I/R injury have not been fully elucidated. In this study, we pretreated rats with LPS (1.0 mg/kg) 24 h before they were subjected to I/R injury, and then examined the roles of heat shock protein-70 (HSP70) and nucleus factor-κB (NF-κB) in LPS-induced cardioprotection. We observed that pretreatment with low-dose LPS resulted in significantly increased levels of HSP70 in the myocardium, which could dramatically inhibit NF-κB translocation and reduce degradation of inhibitory κB. Inhibition of NF-κB, in turn, attenuated release of inflammatory cytokines (tumor necrosis factor-α, interleukin (IL)-1ß, and IL-6) and reduced apoptosis of myocardium and infarct area following I/R injury. Moreover, HSP70 could ameliorate oxidative stress following I/R injury. To further investigate whether increase of HSP70 might be responsible for protection of the myocardium against I/R injury, we co-administered the HSP70 inhibitor, quercetin, with LPS before I/R injury. We found that LPS-induced cardioprotection was attenuated by co-administration with quercetin. Herein, we concluded that increased levels of HSP70 through LPS pretreatment led to inhibition of NF-κB activity in the myocardium after I/R injury. Our results indicated that LPS-induced cardioprotection was mediated partly through inhibition of NF-κB via increase of HSP70, and LPS pretreatment could provide a means of reducing myocardial I/R injury.