3D skin bioprinting as promising therapeutic strategy for radiation-associated skin injuries.

Both cutaneous radiation injury and radiation combined injury (RCI) could have serious skin traumas, which are collectively referred to as radiation-associated skin injuries in this paper. These two types of skin injuries require special managements of wounds, and the therapeutic effects still need to be further improved. Cutaneous radiation injuries are common in both radiotherapy patients and victims of radioactive source accidents, which could lead to skin necrosis and ulcers in serious conditions. At present, there are still many challenges in management of cutaneous radiation injuries including early diagnosis, lesion assessment, and treatment prognosis. Radiation combined injuries are special and important issues in severe nuclear accidents, which often accompanied by serious skin traumas. Mass victims of RCI would be the focus of public health concern. Three-dimensional (3D) bioprinting, as a versatile and favourable technique, offers effective approaches to fabricate biomimetic architectures with bioactivity, which provides potentials for resolve the challenges in treating radiation-associated skin injuries. Combining with the cutting-edge advances in 3D skin bioprinting, the authors analyse the damage characteristics of skin wounds in both cutaneous radiation injury and RCI and look forward to the potential value of 3D skin bioprinting for the treatments of radiation-associated skin injuries.

Application of a derivative of human defensin 5 to treat ionizing radiation-induced enterogenic infection.

Enterogenic infection is a common complication for patients with radiation injury and requires efficient therapeutics in the clinic. Herein, we evaluated the promising drug candidate T7E21RHD5, which is a peptide derived from intestinal Paneth cell-secreted human defensin 5. Oral administration of this peptide alleviated the diarrhea symptoms of mice that received total abdominal irradiation (TAI, γ-ray, 12 Gy) and improved survival. Pathologic analysis revealed that T7E21RHD5 elicited an obvious mitigation of ionizing radiation (IR)-induced epithelial damage and ameliorated the reduction in the levels of claudin, zonula occluden 1 and occludin, three tight junction proteins in the ileum. Additionally, T7E21RHD5 regulated the gut microbiota in TAI mice by remodeling ß diversity, manifested as a reversal of the inverted proportion of Bacteroidota to Firmicutes caused by IR. T7E21RHD5 treatment also decreased the abundance of pathogenic Escherichia-Shigella but significantly increased the levels of Alloprevotella and Prevotellaceae_NK3B31, two short-chain fatty acid-producing bacterial genera in the gut. Accordingly, the translocation of enterobacteria and lipopolysaccharide to the blood, as well as the infectious inflammatory responses in the intestine after TAI, was all suppressed by T7E21RHD5 administration. Hence, this versatile antimicrobial peptide possesses promising application prospects in the treatment of IR-induced enterogenic infection.

In Vitro Cellular Activity Evaluation of the Nanoemulsion Vaccine Adjuvant Ophiopogonin D.

As a principal ingredient of vaccines, adjuvants can directly induce or enhance the powerful, widespread, innate, and adaptive immune responses associated with antigens. Ophiopogonin D (OP-D), a purified component extracted from the plant Ophiopogon japonicus, has been found to be useful as a vaccine adjuvant. The problems of the low solubility and toxicity of OP-D can be effectively overcome by using a low-energy emulsification method to prepare nanoemulsion ophiopogonin D (NOD). In this article, a series of in vitro protocols for cellular activity evaluation are examined. The cytotoxic effects of L929 were determined using a cell counting kit-8 assay. Then, the secreted cytokine levels and corresponding immune cell numbers after the stimulation and culture of splenocytes from immunized mice were detected by ELISA and ELISpot methods. In addition, the antigen uptake ability in bone marrow-derived dendritic cells (BMDCs), which were isolated from C57BL/6 mice and matured after incubation with GM-CSF plus IL-4, was observed by laser scanning confocal microscopy (CLSM). Importantly, macrophage activation was confirmed by measuring the levels of IL-1ß, IL-6, and tumor necrosis factor alpha (TNF-α) cytokines by ELISA kits after coculturing peritoneal macrophages (PMs) from blank mice with the adjuvant for 24 h. It is hoped that this protocol will provide other researchers with direct and effective experimental approaches to evaluate the cellular response efficacies of novel vaccine adjuvants.

Selenium nanoparticles alleviate ischemia reperfusion injury-induced acute kidney injury by modulating GPx-1/NLRP3/Caspase-1 pathway.

Rationale: Acute kidney injury (AKI) is a common critical illness in the clinic and currently lacks effective treatment options. Ischemia reperfusion injury (IRI) is a major pathogenic factor for AKI. Due to the deficiency of selenium (Se) in AKI patients, we intended to treat IRI-induced AKI using a Se rebalancing strategy in the present study. Methods: Sodium selenate, ascorbic acid, and bovine serum albumin (BSA) were employed to prepare nanomaterials termed Se@BSA nanoparticles (NPs) using a simple method. Experiments with human renal tubular epithelial HK-2 cells exposed to hypoxia/reoxygenation (H/R) and IRI-AKI mice were used to evaluate the therapeutic efficiency of Se@BSA NPs. Transcriptome sequencing, further molecular biology experiments, and pathologic analysis were performed to investigate the underlying mechanisms. Results: Se@BSA NPs accumulated in mouse kidneys and could be endocytosed by renal tubular epithelial cells after intravenous administration. In vitro studies showed that Se@BSA NP treatment markedly increased the levels of glutathione peroxidase (GPx)-1 and suppressed NLRP3 inflammasome activation in H/R cells, which resulted in reductions in the proteolytic cleavage of pro-Caspase-1 into active Caspase-1 and the maturation of inflammatory factors. Mouse experiments confirmed these findings and demonstrated an inspiring mitigative effect of Se@BSA NPs on IRI-induced AKI. Owing to modulation of the GPx-1/NLRP3/Caspase-1 pathway, Se@BSA NPs dramatically inhibited fibrosis formation after AKI. Conclusion: This study provides an effective therapeutic option by applying easy-to-produce Se-containing nanomaterials to remedy Se imbalance and impede inflammatory responses in the kidney, which is a promising candidate for AKI treatment.

A generic and non-enzymatic electrochemical biosensor integrated molecular beacon-like catalyzed hairpin assembly circuit with MOF@Au@G-triplex/hemin nanozyme for ultrasensitive detection of miR-721.

MicroRNAs (miRNAs) have been extensively studied as circulating biomarkers for early diagnosis and prognosis of many human diseases. However, it has been found challenging to accurately detect and quantify the trace amounts of miRNAs in biological samples. Herein, we propose a generic and non-enzymatic electrochemical strategy integrated molecular beacon-like catalyzed hairpin assembly (mCHA) circuit with MOF@Au@G-triplex/hemin nanozyme for ultrasensitive detection of miR-721 (a novel diagnostic biomarker of acute myocarditis). Nitro-functionalized MIL-101 functions as an ideal nanocatalyst and nanocarrier to facilitate efficient immobilization of G-triplex/hemin DNAzyme, to form signal probes. Tetrahedral nanostructured DNA probes self-assemble onto the Au nanoparticles/proton-functionalized graphitic carbon nitride nanosheets films, to fabricate a coordinated sensing interface. A mCHA circuit is designed to convert and amplify each target to DNA duplexes, which cause signal probes anchored on the sensing interface and produce an enhanced electrochemical signal. With the assistance of the mCHA circuit, double-amplified nanozymes and sensing interface for signal amplification, this biosensor had a low detection limit of 0.25 fM and high specificity. The proposed biosensor has been successfully used in miR-721 detection in real biological samples, which provided a promising potential method for acute myocarditis early diagnosis.

γ-Core Guided Antibiotic Design Based on Human Enteric Defensin 5.

An increase in the number of infections caused by resistant bacteria worldwide necessitates the development of alternatives to antibiotics. Human defensin (HD) 5 is an innate immune peptide with broad-spectrum antibacterial activity, but its complicated structure makes its preparation difficult. Herein, we truncated the HD5 structure by extracting the highly conserved γ-core motif. A structure-activity study showed that this motif was ineffective in killing bacteria in the absence of specific spatial conformation. Notably, after the introduction of two intramolecular disulfide bonds, its antibacterial activity was markedly improved. Glu and Ser residues were then replaced with Arg to create the derivative RC18, which exhibited stronger potency than HD5, particularly against methicillin-resistant S. aureus (MRSA). Mechanistically, RC18 bound to lipid A and lipoteichoic acid at higher affinities than HD5. Furthermore, RC18 was more efficient than HD5 in penetrating the bacterial membranes. Molecular dynamics simulation revealed that five Arg residues, Arg1, Arg7, Arg9, Arg15, and Arg18, mediated most of the polar interactions of RC18 with the phospholipid head groups during membrane penetration. In vivo experiments indicated that RC18 decreased MRSA colonization and dramatically improved the survival of infected mice, thus demonstrating that RC18 is a promising drug candidate to treat MRSA infections.

An angiotensin-converting enzyme-2-derived heptapeptide GK-7 for SARS-CoV-2 spike blockade.

The ongoing coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is a global concern and necessitates efficient drug antagonists. Angiotensin-converting enzyme-2 (ACE2) is the main receptor of SARS-CoV-2 spike 1 (S1), which mediates viral invasion into host cells. Herein, we designed and prepared short peptide inhibitors containing 4-6 critical residues of ACE2 that contribute to the interaction with SARS-CoV-2 S1. Among the candidates, a peptide termed GK-7 (GKGDFRI), which was designed by extracting residues ranging from Gly353 to Ile359 in the ligand-binding domain of ACE2, exhibited the highest binding affinity (25.1 nM) with the SARS-CoV-2 spike receptor-binding domain (RBD). GK-7 bound to the RBD and decreased SARS-CoV-2 S1 attachment to A549 human alveolar epithelial cells. Owing to spike blockade, GK-7 inhibited SARS-CoV-2 spike pseudovirion infection in a dose-dependent manner, with a half-maximal inhibitory concentration of 2.96 µg/mL. Inspiringly, pulmonary delivery of GK-7 by intranasal administration did not result in toxicity in mice. This study revealed an easy-to-produce peptide inhibitor for SARS-CoV-2 spike blockade, thus providing a promising candidate for COVID-19 treatment.

Protective effect of melatonin entrapped PLGA nanoparticles on radiation-induced lung injury through the miR-21/TGF-ß1/Smad3 pathway.

Radiation-induced lung injury (RILI) is a complication commonly found in victims suffering from nuclear accidents and patients treated with chest tumor radiotherapy, and drugs are limited for effective prevention and treatment. Melatonin (MET) has an anti-radiation effect, but its metabolic period in the body is short. In order to prolong the metabolism period of MET, we prepared MET entrapped poly (lactic-co-glycolic acid) nanoparticles (MET/PLGANPS) for the treatment of RILI. As a result, the release rate of MET/PLGANPS in vitro was lower than MET, with stable physical properties, and it caused no changes in histopathology and biochemical indicators. After 2 weeks and 16 weeks of irradiation with the dose of 15 Gy, MET and MET/PLGANPS could reduce the expression of caspase-3 proteins, inflammatory factors, TGF-ß1 and Smad3 to alleviate radiation-induced lung injury. MET/PLGANPS showed better therapeutic effect on RILI than MET. In addition, we also found that high expression of miR-21 could increase the expression levels of TGF-ß1, and inhibit the protective effect of MET/PLGANPS. In conclusion, MET/PLGANPS may alleviate RILI by inhibiting the miR-21/TGF-ß1/Smad3 pathway, which would provide a new target for the treatment of radiation-induced lung injury.

Neutrophils-derived Spink7 as one safeguard against experimental murine colitis.

The uncontrolled abnormal intestinal immune responses play important role in eliciting inflammatory bowel disease (IBD), yet the molecular events regulating intestinal inflammation during IBD remain poorly understood. Here, we describe an endogenous, homeostatic pattern that controls inflammatory responses in experimental murine colitis. We show that Spink7 (serine peptidase inhibitor, kazal type 7), the ortholog of human SPINK7, is significantly upregulated in dextran sodium sulfate (DSS)-induced murine colitis model. Spink7-deficient mice showed highly susceptible to experimental colitis characterized by enhanced weight loss, shorter colon length, higher disease activity index and increased colonic tissue destruction. Bone marrow reconstitution experiments demonstrated that expression of Spink7 in the immune compartment makes main contribution to its protective role in colitis. What's more, neutrophils are the primary sources of Spink7 in experimental murine colitis. Loss of Spink7 leads to augmented productions of multiple chemokines and cytokines in colitis. In summary, this study identifies neutrophils-derived endogenous Spink7-mediated control of chemokines/cytokines production as a molecular mechanism contributing to inflammation resolution during colitis.

Efficacy and safety of Shenyankangfu Tablet, a Chinese patent medicine, for primary glomerulonephritis: A multicenter randomized controlled trial.

BACKGROUND: Shenyankangfu Tablet (SYKFT) is a Chinese patent medicine that has been used widely to decrease proteinuria and the progression of chronic kidney disease. OBJECTIVE: This trial compared the efficacy and safety of SYKFT, for the control of proteinuria in primary glomerulonephritis patients, against the standard drug, losartan potassium. DESIGN, SETTING, PARTICIPANTS AND INTERVENTION: This was a multicenter, double-blind, randomized, controlled clinical trial. Primary glomerulonephritis patients, aged 18-70 years, with blood pressure ≤ 140/90 mmHg, estimated glomerular filtration rate (eGFR) ≥ 45 mL/min per 1.73 m2, and 24-hour proteinuria level of 0.5-3.0 g, were recruited in 41 hospitals across 19 provinces in China and were randomly divided into five groups: SYKFT, losartan potassium 50 mg or 100 mg, SYKFT plus losartan potassium 50 mg or 100 mg. MAIN OUTCOME MEASURES: The primary outcome was change in the 24-hour proteinuria level, after 48 weeks of treatment. RESULTS: A total of 735 participants were enrolled. The percent decline of urine protein quantification in the SYKFT group after 48 weeks was 8.78% ± 2.56% (P = 0.006) more than that in the losartan 50 mg group, which was 0.51% ± 2.54% (P = 1.000) less than that in the losartan 100 mg group. Compared with the losartan potassium 50 mg group, the SYKFT plus losartan potassium 50 mg group had a 13.39% ± 2.49% (P < 0.001) greater reduction in urine protein level. Compared with the losartan potassium 100 mg group, the SYKFT plus losartan potassium 100 mg group had a 9.77% ± 2.52% (P = 0.001) greater reduction in urine protein. With a superiority threshold of 15%, neither was statistically significant. eGFR, serum creatinine and serum albumin from the baseline did not change statistically significant. The average change in TCM syndrome score between the patients who took SYKFT (-3.00 [-6.00, -2.00]) and who did not take SYKFT (-2.00 [-5.00, 0]) was statistically significant (P = 0.003). No obvious adverse reactions were observed in any group. CONCLUSION: SYKFT decreased the proteinuria and improved the TCM syndrome scores of primary glomerulonephritis patients, with no change in the rate of decrease in the eGFR. SYKFT plus losartan potassium therapy decreased proteinuria more than losartan potassium therapy alone. TRIAL REGISTRATION NUMBER: NCT02063100 on ClinicalTrials.gov.

MicroRNA-34a deficiency leads to impaired wound closure by augmented inflammation in mice.

BACKGROUND: Proper inflammation resolution is critical for cutaneous wound healing and disordered inflammation resolution results in chronic nonhealing wounds. However, the cellular and molecular mechanisms for resolution of inflammation during skin wound healing are not well understood. MicroRNA-34a is regarded as one tumor suppressor with complexed immune regulatory effects, yet its role during skin wound repair is still unclear. METHODS: Circular full thickness excisional wounds were made on the dorsal skin of C57 mice and miR-34a expression pattern was examined by real time RT-PCR and in situ hybridization. The wound healing rates and histologic morphometric analysis were quantified and compared between wounds treated with antagomir-34a and autologous control antagomir-NC wounds, as well as wounds between miR-34a knockout (KO) and wild type (WT) mice. Immunohistochemistry (IHC) for both MPO and F4/80 were performed to examine the infiltrative neutrophils and macrophages in wounds from miR-34a KO and WT mice. Cytokines including IL-1ß, IL-6, TNF-α and IL-10, were detected and analyzed by real time RT-PCR during wound healing. IHC for IL-6 and p-STAT3 were quantified, and WB for p-STAT3 and IL-6R were examined in wounds of miR-34a KO and WT mice. RESULTS: We found miR-34a was significantly downregulated in the inflammatory phase and back to normal levels in the proliferative phase. Both topical knockdown wounds miR-34a levels by antagomir gel and systematic knockout miR-34a using KO mice resulted in impaired wound healing with delayed re-epithelialization and augmented inflammation. IHC results indicated that there were more residual infiltrative inflammatory cells in the proliferative phase. Moreover, over-activated IL-6/STAT3 signal pathway was identified in the wounds of miR-34a KO mice. CONCLUSIONS: Our findings reveal that miR-34a deficiency augments skin wound inflammation response and leads to impaired wound healing, which suggest that targeted inhibition of miR-34a for tissue repair/regeneration should be with serious consideration.

Reactive oxygen species-responsive dexamethasone-loaded nanoparticles for targeted treatment of rheumatoid arthritis via suppressing the iRhom2/TNF-α/BAFF signaling pathway.

Rheumatoid arthritis (RA) is an immune-mediated inflammatory disease that results in synovitis, cartilage destruction, and even loss of joint function. The frequent and long-term administration of anti-rheumatic drugs often leads to obvious adverse effects and patient non-compliance. Therefore, to specifically deliver dexamethasone (Dex) to inflamed joints and reduce the administration frequency of Dex, we developed Dex-loaded reactive oxygen species (ROS)-responsive nanoparticles (Dex/Oxi-αCD NPs) and folic acid (FA) modified Dex/Oxi-αCD NPs (Dex/FA-Oxi-αCD NPs) and validated their anti-inflammatory effect in vitro and in vivo. In vitro study demonstrated that these NPs can be effectively internalized by activated macrophages and the released Dex from NPs significantly downregulated the expression of iRhom2, TNF-α, and BAFF in activated Raw264.7. In vivo experiments revealed that Dex/Oxi-αCD NPs, especially Dex/FA-Oxi-αCD NPs significantly accumulated at inflamed joints in collagen-induced arthritis (CIA) mice and alleviated the joint swelling and cartilage destruction. Importantly, the expression of iRhom2, TNF-α, and BAFF in the joint was inhibited by intravenous injection of Dex/Oxi-αCD NPs and Dex/FA-Oxi-αCD NPs. Collectively, our data revealed that Dex-loaded ROS-responsive NPs can target inflamed joints and attenuate arthritis, and the 'iRhom2-TNF-α-BAFF' pathway plays an important role in the treatment of RA with the NPs, suggesting that this pathway may be a novel target for RA therapy.

dTMP-GH Fusion Protein Therapy Improves Survival after Radiation Injury Combined with Skin-Burn Trauma in Mice.

Exposure to ionizing radiation combined with traumatic tissue injury is an important life-threatening condition found in the civilian populations after nuclear and radiological events. The significance feature of radiation combined injury (RCI) is the severe combined effect, which makes the injury more complicated. At present, there are limited measures available to treat RCI. Here we show that a chimeric protein dTMP-GH, fusing human growth hormone (hGH) with a tandem dimer of thrombopoietin mimetic peptide (dTMP), could be an effective therapy agent for RCI in a mice model. In this study, using a RCI mouse model exposed to 60Co γ-ray photons (6.0 Gy, 0.3 Gy/min) followed by a 20% total-body-surface-area burns (henceforth called: RB-CI) was established. Administration of dTMP-GH (200 ug/kg) for 10 consecutive days beginning at 24 h after injury improved survival rate during a 30-day observation period compared with the control vehicle group. dTMP-GH treatment also showed enhanced bone marrow hematopoiesis recovery determined by peripheral blood analysis and bone marrow histopathology. Meanwhile, dTMP-GH treatment accelerated skin wound closure and mitigated ileum injury in the RCI model. These results suggest that dTMP-GH may prove to be an effective therapeutic drug for RCI.

Epitope-loaded nanoemulsion delivery system with ability of extending antigen release elicits potent Th1 response for intranasal vaccine against Helicobacter pylori.

BACKGROUND: Helicobacter pylori (H. pylori) infection remains a global public health issue, especially in Asia. Due to the emergence of antibiotic-resistant strains and the complexity of H. pylori infection, conventional vaccination is the best way to control the disease. Our previous study found that the N-acetyl-neuroaminyllactose-binding hemagglutinin protein (HpaA) is an effective protective antigen for vaccination against H. pylori infection, and intranasal immunization with the immunodominant HpaA epitope peptide (HpaA 154-171, P22, MEGVLIPAGFIKVTILEP) in conjunction with a CpG adjuvant decreased bacterial colonization in H. pylori-infected mice. However, to confer more robust and effective protection against H. pylori infection, an optimized delivery system is needed to enhance the P22-specific memory T cell response. RESULTS: In this study, an intranasal nanoemulsion (NE) delivery system offering high vaccine efficacy without obvious cytotoxicity was designed and produced. We found that this highly stable system significantly prolonged the nasal residence time and enhanced the cellular uptake of the epitope peptide, which powerfully boosted the specific Th1 responses of the NE-P22 vaccine, thus reducing bacterial colonization without CpG. Furthermore, the protection efficacy was further enhanced by combining the NE-P22 vaccine with CpG. CONCLUSION: This epitope-loaded nanoemulsion delivery system was shown to extend antigen release and elicit potent Th1 response, it is an applicable delivery system for intranasal vaccine against H. pylori.

An immunopotentiator, ophiopogonin D, encapsulated in a nanoemulsion as a robust adjuvant to improve vaccine efficacy.

As an ingredient of vaccines, adjuvants are indispensable for enhancing and directly inducing robust and extensive adaptive immune responses associated with vaccine antigens. In this study, we initially determined that a new molecular immunopotentiator, ophiopogonin D (OP-D), enhanced the antibody response to antigen. Because OP-D has certain disadvantages, including poor solubility, we next encapsulated OP-D in a nanoemulsion adjuvant (nanoemulsion-encapsulated OP-D, NOD) using low-energy emulsification methods. The NOD thus produced was small, with an average size of 76.45 nm, and exhibited good distribution (PdI value 0.16), significantly increasing the solubility of OP-D. Furthermore, NOD exhibited reduced cellular toxicity and acute toxicity. Our results showed that a fusion antigen of MRSA (HlaH35LIsdB348-465) formulated with NOD significantly improved humoral and cellular immune responses compared to those observed in the antigen/OP-D and antigen/AlPO4 groups. Compared with antigen/OP-D, the antigen formulated with NOD more effectively promoted antigen uptake by dendritic cells (DCs) and the activation of antigen-presenting cells (APCs). Moreover, the NOD-formulated antigen had ideal protective efficacy in a MRSA sepsis model by inducing more potent antibody responses and a Th1/Th17-biased CD4+ T cell immune response. Therefore, these results suggest that NOD is a promising and robust adjuvant platform for a MRSA vaccine. STATEMENT OF SIGNIFICANCE: We first identified a new powerful immunopotentiator, Ophiopogonin D, among dozens of natural products and then used nanotechnology to construct a highly efficient and low toxic adjuvant system (NOD). Our approach intersects natural medicinal chemistry, nanomaterials and immunology, revealing that a strong adjuvant activity of this adjuvant system was verified in vitro and in vivo, and the application of MRSA subunit vaccine model for survival experiments achieved a 100% protection rate. This research illustrate that NOD is a promising and robust adjuvant platform for subunit vaccines.

SRC-3 is involved in maintaining hematopoietic stem cell quiescence by regulation of mitochondrial metabolism in mice.

Quiescence maintenance is an important property of hematopoietic stem cells (HSCs), whereas the regulatory factors and underlying mechanisms involved in HSC quiescence maintenance are not fully uncovered. Here, we show that steroid receptor coactivator 3 (SRC-3) is highly expressed in HSCs, and SRC-3-deficient HSCs are less quiescent and more proliferative, resulting in increased sensitivity to chemotherapy and irradiation. Moreover, the long-term reconstituting ability of HSCs is markedly impaired in the absence of SRC-3, and SRC-3 knockout (SRC-3-/-) mice exhibit a significant disruption of hematopoietic stem and progenitor cell homeostasis. Further investigations show that SRC-3 deficiency leads to enhanced mitochondrial metabolism, accompanied by overproduction of reactive oxygen species (ROS) in HSCs. Notably, the downstream target genes of peroxisome proliferator-activated receptor-coactivators 1α (PGC-1α) involved in the regulation of mitochondrial metabolism are significantly upregulated in SRC-3-deficient HSCs. Meanwhile, a significant decrease in the expression of histone acetyltransferase GCN5 accompanied by downregulation of PGC-1α acetylation is observed in SRC-3-null HSCs. Conversely, overexpression of GCN5 can inhibit SRC-3 deficiency-induced mitochondrial metabolism enhancement and ROS overproduction, thereby evidently rescuing the impairment of HSCs in SRC-3-/- mice. Collectively, our findings demonstrate that SRC-3 plays an important role in HSC quiescence maintenance by regulating mitochondrial metabolism.

IGF-1 facilitates thrombopoiesis primarily through Akt activation.

It is known that insulin-like growth factor-1 (IGF-1) also functions as a hematopoietic factor, although its direct effect on thrombopoiesis remains unclear. In this study, we show that IGF-1 is able to promote CD34+ cell differentiation toward megakaryocytes (MKs), as well as the facilitation of proplatelet formation (PPF) and platelet production from cultured MKs. The in vivo study demonstrates that IGF-1 administration accelerates platelet recovery in mice after 6.0 Gy of irradiation and in mice that received bone marrow transplantation following 10.0 Gy of lethal irradiation. Subsequent investigations reveal that extracellular signal-regulated kinase 1/2 (ERK1/2) and Akt activation mediate the effect of IGF-1 on thrombopoiesis. Notably, Akt activation induced by IGF-1 is more apparent than that of ERK1/2, compared with that of thrombopoietin (TPO) treatment. Moreover, the effect of IGF-1 on thrombopoiesis is independent of TPO signaling because IGF-1 treatment can also lead to a significant increase of platelet counts in homozygous TPO receptor mutant mice. Further analysis indicates that the activation of Akt triggered by IGF-1 requires the assistance of steroid receptor coactivator-3 (SRC-3). Therefore, our data reveal a distinct role of IGF-1 in regulating thrombopoiesis, providing new insights into TPO-independent regulation of platelet generation.

Transdermal Vascular Endothelial Growth Factor Delivery with Surface Engineered Gold Nanoparticles.

Skin injuries caused by burns or radiation remain a serious concern in terms of clinical therapy. Because of the damage to the epidermis or dermis, angiogenesis is needed to repair the skin. Vascular endothelial growth factor (VEGF) is one of the most effective factors for promoting angiogenesis and preventing injury progression, but the delivery of VEGF to lesion sites is limited by the skin barrier. Recently, gold nanoparticle (AuNP)-mediated drug delivery into or through the epidermis and dermis has attracted much attention. However, the efficacy of the AuNP-mediated transdermal drug delivery remains unknown. In this study, gold nanoparticles were conjugated with VEGF and generated a surface by carrying negative charges, showing an ideal transdermal delivery efficacy for VEGF in wound repair. Our findings may provide new avenues for the treatment of cutaneous injuries.

Kidney Tissue Targeted Metabolic Profiling of Unilateral Ureteral Obstruction Rats by NMR.

Renal interstitial fibrosis is a common pathological process in the progression of kidney disease. A nuclear magnetic resonance (NMR) based metabolomic approach was used to analyze the kidney tissues of rats with renal interstitial fibrosis (RIF), induced by unilateral ureteral obstruction (UUO). The combination of a variety of statistical methods were used to screen out 14 significantly changed potential metabolites, which are related with multiple biochemical processes including amino acid metabolism, adenine metabolism, energy metabolism, osmolyte change and induced oxidative stress. The exploration of the contralateral kidneys enhanced the understanding of the disease, which was also supported by serum biochemistry and kidney histopathology results. In addition, the pathological parameters (clinical chemistry, histological and immunohistochemistry results) were correlated with the significantly changed differential metabolites related with RIF. This study showed that targeted tissue metabolomic analysis can be used as a useful tool to understand the mechanism of the disease and provide a novel insight in the pathogenesis of RIF.

Single step synthesis of amine-functionalized mesoporous magnetite nanoparticles and their application for copper ions removal from aqueous solution.

Amine-functionalized mesoporous superparamagnetic Fe3O4 nanoparticles with an average size of 70nm have been synthesized using a single step solvothermal method by the introduction of triethylenetetramine (TETA), a chelating agent recommended for the removal of excess copper in patients with Wilson's disease. The synthesized nanoparticles were characterized by transmission electron microscopy (TEM), X-ray diffraction (XRD), Raman spectroscopy, nitrogen adsorption/desorption isotherm, vibrating sample magnetometer (VSM), and Fourier transform infrared spectroscopy (FTIR). It is confirmed that the magnetic nanoparticles have been functionalized with TETA during the synthetic process, and the concentration of TETA is crucial for the formation of monodisperse mesoporous nanoparticles. The obtained single-crystal magnetic nanoparticles have a high magnetization, which enhances their response to external magnetic field and therefore should greatly facilitate the manipulation of the particles in practical uses. Reaction parameters affecting the formation of mesoporous structure were explored, and a possible formation mechanism involving templated aggregation and recrystallization processes was proposed. The capacity of the synthesized amine-functionalized Fe3O4 nanoparticles toward Cu(II) removal from aqueous solution was investigated. The adsorption rate of Cu(II) on amine-functionalized Fe3O4 nanoparticles followed a pseudo-second order kinetic model. The results of this study demonstrated that the amine-functionalized mesoporous superparamagnetic Fe3O4 nanoparticles could be used as an efficient adsorbent in water treatment and would also find potential application for Cu(II) removal in vivo.