Engineered Cytokine-Primed Extracellular Vesicles with High PD-L1 Expression Ameliorate Type 1 Diabetes.

Type 1 diabetes (T1D), which is a chronic autoimmune disease, results from the destruction of insulin-producing ß cells targeted by autoreactive T cells. The recent discovery that mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) function as therapeutic tools for autoimmune conditions has attracted substantial attention. However, the in vivo distribution and therapeutic effects of MSC-EVs potentiated by pro-inflammatory cytokines in the context of T1D have yet to be established. Here, it is reported that hexyl 5-aminolevulinate hydrochloride (HAL)-loaded engineered cytokine-primed MSC-EVs (H@TI-EVs) with high expression of immune checkpoint molecule programmed death-legend 1 (PD-L1) exert excellent inflammatory targeting and immunosuppressive effects for T1D imaging and therapy. The accumulated H@TI-EVs in injured pancreas not only enabled the fluorescence imaging and tracking of TI-EVs through the intermediate product protoporphyrin (PpIX) generated by HAL, but also promoted the proliferative and anti-apoptotic effects of islet ß cells. Further analysis revealed that H@TI-EVs exhibited an impressive ability to reduce CD4+ T cell density and activation through the PD-L1/PD-1 axis, and induced M1-to-M2 macrophage transition to reshape the immune microenvironment, exhibiting high therapeutic efficiency in mice with T1D. This work identifies a novel strategy for the imaging and treatment of T1D with great potential for clinical application.

Primed 3D injectable microniches enabling low-dosage cell therapy for critical limb ischemia.

The promise of cell therapy for repair and restoration of damaged tissues or organs relies on administration of large dose of cells whose healing benefits are still limited and sometimes irreproducible due to uncontrollable cell loss and death at lesion sites. Using a large amount of therapeutic cells increases the costs for cell processing and the risks of side effects. Optimal cell delivery strategies are therefore in urgent need to enhance the specificity, efficacy, and reproducibility of cell therapy leading to minimized cell dosage and side effects. Here, we addressed this unmet need by developing injectable 3D microscale cellular niches (microniches) based on biodegradable gelatin microcryogels (GMs). The microniches are constituted by in vitro priming human adipose-derived mesenchymal stem cells (hMSCs) seeded within GMs resulting in tissue-like ensembles with enriched extracellular matrices and enhanced cell-cell interactions. The primed 3D microniches facilitated cell protection from mechanical insults during injection and in vivo cell retention, survival, and ultimate therapeutic functions in treatment of critical limb ischemia (CLI) in mouse models compared with free cell-based therapy. In particular, 3D microniche-based therapy with 10(5) hMSCs realized better ischemic limb salvage than treatment with 10(6) free-injected hMSCs, the minimum dosage with therapeutic effects for treating CLI in literature. To the best of our knowledge, this is the first convincing demonstration of injectable and primed cell delivery strategy realizing superior therapeutic efficacy for treating CLI with the lowest cell dosage in mouse models. This study offers a widely applicable cell delivery platform technology to boost the healing power of cell regenerative therapy.

Influential Factors of the Indeterminate Results Tested by QuantiFERON-TB Gold In-Tube (QFT-IT) Assay for Diagnosing TB Infection in HIV-Infected Patients.

BACKGROUND: QuantiFERON-TB Gold In-Tube test (QFT-IT) is a recommended method for diagnosing TB in HIV-infected patients. However, the rate of indeterminate results is higher than that in HIV-uninfected patients. Our previous study showed that the CD4 cell count was an important influential factor for the indeterminate results of QFT-IT. Whether other influential factors affect the QFT-IT results was unclear. METHODS: In this paper, 98 HIV-infected patients with suspected TB infection were enrolled and the plasma of peripheral blood was collected for QFT-IT. The relationship between the CD4 T-cell count, lymphocyte count, lymphocyte percentage, and the results of QFT-IT were analyzed. RESULTS: All patients who have the clinical symptoms of TB including fever and productive cough and were later confirmed by other assays including the sputum culture and chest radiography (n = 8) tested as QFT-positive (positive rate 100%). The other 90 patients without clinical symptoms tested as negative (n = 51), indeterminate (n = 33), and positive (n = 6). The lymphocyte count and the lymphocyte percentage as well as the CD4 T-cell count were significant higher in the positive group and negative group than in the indeterminate group (p < 0.05, for all). CONCLUSIONS: The QFT-IT could be a potential, simple, and feasible method for diagnosing and screening TB in HIV-infected patients. In addition, the CD4 T-cell count, the lymphocyte count, and the lymphocyte percentage were influential factors of the indeterminate results of QFT-IT.

Correction: Chen et al. Multifunctional Injectable Hydrogel Loaded with Cerium-Containing Bioactive Glass Nanoparticles for Diabetic Wound Healing. Biomolecules 2021, 11, 702.

The authors would like to replace Figure 4A of the following published paper [...].

Establishment and validation of a novel integrin-based prognostic gene signature that sub-classifies gliomas and effectively predicts immunosuppressive microenvironment.

The integrin family members play a key role in cancer immunomodulation and prognosis. We comprehensively analyzed the expression patterns and clinical significance of integrin family-related genes in gliomas. A total of 2293 gliomas from the Cancer Genome Atlas (TCGA), Chinese Glioma Genome Atlas (CGGA) and Gliovis platform were enrolled for analyses. Twenty-six integrin coding genes showed different expression patterns between glioma and normal brain tissues. We screened an integrin family-related gene signature (ITGA5, ITGA9, ITGAE, ITGB7 and ITGB8) that showed independent prognostic value and sub-classified gliomas into different prognostic and molecular clusters, further composed an integrin-based risk score model associated with glioma malignant clinical features, overall survival (OS), and immune microenvironment alterations. Besides, glioma patients with high-risk scores showed chemotherapeutic resistance and more immune cells infiltration as well as high immune checkpoints expression. Concurrently, we also revealed that high-risk score group presented resistance to T cell-mediated cancer killing process and lower rates of response to immune checkpoint blockade (ICB) treatment. In conclusion, our study identified a valuable integrin gene signature that predicted gliomas OS effectively, and sub-classified them into different phenotypes and accompanied with immunological changes, possibly acted as a biomarker for ICB treatment.

Kinases in cerebral cavernous malformations: Pathogenesis and therapeutic targets.

Cerebral cavernous malformations (CCMs) are low-flow, hemorrhagic vascular lesions of the central nervous system of genetic origin, which can cause stroke-like symptoms and seizures. From the identification of CCM1, CCM2 and CCM3 as genes related to disease progression, molecular and cellular mechanisms for CCM pathogenesis have been established and the search for potential drugs to target CCM has begun. Broadly speaking, kinases are the major group signaling in CCM pathogenesis. These include the MEKK3/MEK5/ERK5 cascade, Rho/Rock signaling, CCM3/GCKIII signaling, PI3K/mTOR signaling, and others. Since the discovery of Rho/Rock in CCM pathogenesis, inhibitors for Rho signaling and subsequently other components in CCM signaling were discovered and applied in preclinical and clinical trials to ameliorate CCM progression. This review discusses the general aspects of CCM disease, kinase-mediated signaling in CCM pathogenesis and the current state of potential treatment options for CCM. It is suggested that kinase target drug development in the context of CCM might facilitate and meet the unmet requirement - a non-surgical option for CCM disease.

Sr/Ba substitution induced higher thermal stability far red-emitting Ba1-ySryLaLiWO6:Mn4+ phosphors for plant growth applications.

A series of red-emitting BaLaLiWO6:Mn4+ (BLLW:Mn4+) phosphors were successfully synthesized by a high-temperature solid-state reaction method. The crystal structure and luminescence properties of the obtained samples were systematically investigated. The emission spectra exhibited a deep red emission band peaking at 716 nm with a full width at half-maximum (FWHM) of 44 nm under 340 nm excitation. The optimal Mn4+ molar concentration was about 1.2%. In addition, the luminescence mechanism was analyzed using a Tanabe Sugano energy level diagram. With the substitution of Sr for Ba, there was a red shift in the emission spectrum and a blue shift in the excitation spectrum. The emission intensity of BLLW:1.2%Mn4+ at 150 °C was about 22% of the initial value at room temperature. In contrast, the emission intensity of SrLaLiWO6:1.2%Mn4+ still maintained 79% of the initial emission intensity at room temperature at 150 °C. This was due to the fact that with the substitution of Sr for Ba, the W-O bond length gradually decreases, which gradually enhanced the crystal field strength of Mn4+.

Release of STK24/25 suppression on MEKK3 signaling in endothelial cells confers cerebral cavernous malformation.

Loss-of-function mutations in cerebral cavernous malformation (CCM) genes and gain-of-function mutation in the MAP3K3 gene encoding MEKK3 cause CCM. Deficiency of CCM proteins leads to the activation of MEKK3-KLF2/4 signaling, but it is not clear how this occurs. Here, we demonstrate that deletion of the CCM3 interacting kinases STK24/25 in endothelial cells causes defects in vascular patterning during development as well as CCM lesion formation during postnatal life. While permanent deletion of STK24/25 in endothelial cells caused developmental defects of the vascular system, inducible postnatal deletion of STK24/25 impaired angiogenesis in the retina and brain. More importantly, deletion of STK24/25 in neonatal mice led to the development of severe CCM lesions. At the molecular level, a hybrid protein consisting of the STK kinase domain and the MEKK3 interacting domain of CCM2 rescued the vascular phenotype caused by the loss of ccm gene function in zebrafish. Our study suggests that CCM2/3 proteins act as adapters to allow recruitment of STK24/25 to limit the constitutive MEKK3 activity, thus contributing to vessel stability. Loss of STK24/25 causes MEKK3 activation, leading to CCM lesion formation.

Identification of a five-gene signature deriving from the vacuolar ATPase (V-ATPase) sub-classifies gliomas and decides prognoses and immune microenvironment alterations.

Aberrant expression of coding genes of the V-ATPase subunits has been reported in glioma patients that can activate oncogenic pathways and result in worse prognosis. However, the predictive effect of a single gene is not specific or sensitive enough. In this study, by using a series of bioinformatics analyses, we identified five coding genes (ATP6V1C2, ATP6V1G2, TCIRG1, ATP6AP1 and ATP6AP2) of the V-ATPase that were related to glioma patient prognosis. Based on the expression of these genes, glioma patients were sub-classified into different prognosis clusters, of which C1 cluster performed better prognosis; however, C2 cluster showed more malignant phenotypes with oncogenic and immune-related pathway activation. The single-cell RNA-seq data revealed that ATP6AP1, ATP6AP2, ATP6V1G2 and TCIRG1 might be cell-type potential markers. Copy number variation and DNA promoter methylation potentially regulate these five gene expressions. A risk score model consisted of these five genes effectively predicted glioma prognosis and was fully validated by six independent datasets. The risk scores also showed a positive correlation with immune checkpoint expression. Importantly, glioma patients with high-risk scores presented resistance to traditional treatment. We also revealed that more inhibitory immune cells infiltration and higher rates of "non-response" to immune checkpoint blockade (ICB) treatment in the high-risk score group. In conclusion, our study identified a five-gene signature from the V-ATPase that could sub-classify gliomas into different phenotypes and their abnormal expression was regulated by distinct mechanisms and accompanied with immune microenvironment alterations potentially act as a biomarker for ICB treatment.

T cell immune regulator 1 is a prognostic marker associated with immune infiltration in glioblastoma multiforme.

Glioma is the most common primary brain tumor and glioblastoma multiforme (GBM) is the most malignant brain glioma with the worst prognosis. T cell immune regulator 1 (TCIRG1) constitutes the V0a3 subunit of vacuolar ATPase (V-ATPase), and the function of V-ATPase in malignant tumors, such as breast cancer, melanoma and hepatocellular carcinoma, has been reported. However, the effect of the TCIRG1 subunit on GBM remains to be fully elucidated. mRNA levels of TCIRG1 in different cancer types and the corresponding normal tissues were extracted from the Oncomine and Tumor Immune Estimation Resource (TIMER) databases. The Gene Expression Omnibus (access number: GSE16011), the Chinese Glioma Genome Atlas and The Cancer Genome Atlas were used to investigate the mRNA level of TCIRG1 in glioma. Protein level validation in glioma was performed using western blotting. The Database for Annotation, Visualization and Integrated Discovery was used to analyze Gene Ontology (GO) categories for genes correlated with TCIRG1 in GBM. Protein-protein interaction (PPI) networks and module analyses were performed using Cytoscape software and the MCODE plugin. The correlation between tumor immune cell infiltration and TCIRG1 expression was explored using the TIMER database. Additionally, the correlation between TCIRG1 and the gene signature of immune infiltration was explored through TIMER and Gene Expression Profiling Interactive Analysis. External validation of TCIRG1 expression according to immune signatures in GBM was performed using the GSE16011 dataset with the GlioVis online tool. It was found that TCIRG1 expression was increased in GBM and numerous malignant tumors and may serve as a biomarker of the mesenchymal subtype of GBM. GO category analysis of positively correlated genes revealed that TCIRG1 was correlated with the immune response in GBM. PPI network and module analyses also supported the potential function of TCIRG1 in the local immune response. The expression of TCIRG1 was associated with various immune markers. It was therefore speculated that TCIRG1 is associated with glioma malignancy and may be a marker of unfavorable prognosis in patients with GBM, and it could be regarded as a prognostic biomarker and an indicator of immune infiltration in GBM.

Poly (γ-glutamic acid)/chitooligo-saccharide/papain hydrogel prevents hypertrophic scar during skin wound healing.

Hypertrophic scar, a common skin disorder typically caused by deep burns or scald were usually treated via surgical resection, laser irradiation, and drugs. However, all the approaches were always companied with complications and devastatingly subjected to relapse, which indicated the urgently need of an effective treatment method. In this project, a new hydrogel composed of Poly (γ-glutamic acid) (γ-PGA), Chitooligo-saccharide, and Papain was developed via crosslinker (EDC&NHS), and characterized with good porously three-dimensional network structure, good water absorption, and mechanical properties. Besides, G/C/P hydrogel facilitated cell adhesion and inhibited excessive proliferation of fibroblasts, which indicated the potential of in vivo application. After applied onto skin wound healing in vivo on a rabbit ear skin wound model, G/C/P hydrogel inhibited excessive collagen deposition and the generation of hyperplastic scars effectively during wound healing. The hydrogel described here provide a new platform for regeneration field and hold great promise for solving serious skin disorder.

Thrombospondin-1 is a prognostic biomarker and is correlated with tumor immune microenvironment in glioblastoma.

Glioblastoma (GBM) is the most common malignant brain tumor and the most aggressive type of glioma, characterized by strong invasive potential and rapid recurrence despite severe treatment methods, such as maximal tumor resection followed by chemotherapy and radiotherapy. Thrombospondin-1 (THBS1) was first discovered in platelets and subsequent studies have indicated its functions in the development of several cancers, including breast cancer, melanoma, gastric cancer, cervical cancer and GBM. However, to the best of our knowledge, the expression profiles of THBS1 in GBM subtypes remain unknown, and the underlying mechanism by which THBS1 expression is regulated, and its effect on the local immune response in GBM, remains unclear. The present study used public datasets from The Cancer Genome Atlas, the Chinese Glioma Genome Atlas, the Gene Expression Omnibus, the Ivy Glioblastoma Atlas Project, Tumor Immune Estimation Resource, Estimation of STromal and Immune cells in MAlignant Tumor tissues using Expression data and the Human Protein Atlas to investigate the prognostic value of THBS1 and its expression profiles, as well as its correlation with the local immune response in GBM. The results demonstrated that THBS1 was a biomarker of the pathological malignancy of glioma, and predicted the mesenchymal subtype of GBM. Furthermore, DNA methylation of THBS1 may be an important mechanism by which THBS1 expression is regulated in GBM. The hypomethylation or overexpression of THBS1 predicted an unfavorable prognosis in patients with GBM. Additionally, THBS1 was correlated with immune and inflammatory responses in GBM. Thus, the findings of the present study provide insight into the potential value of THBS1 in the treatment of GBM.

Pentoxifylline Enhances Antioxidative Capability and Promotes Mitochondrial Biogenesis in D-Galactose-Induced Aging Mice by Increasing Nrf2 and PGC-1α through the cAMP-CREB Pathway.

Aging is a complex phenomenon associated with oxidative stress and mitochondrial dysfunction. The objective of this study was to investigate the potential ameliorative effects of the phosphodiesterase inhibitor pentoxifylline (PTX) on the aging process and its underlying mechanisms. We treated D-galactose- (D-gal-) induced aging mice with PTX and measured the changes in behavior, degree of oxidative damage, and mitochondrial ultrastructure and content as well as the expression of nuclear factor erythroid 2-related factor 2- (Nrf2-) mediated antioxidant genes and peroxisome proliferator-activated receptor-gamma coactivator 1-alpha- (PGC-1α-) dependent mitochondrial biogenesis genes. The results demonstrated that PTX improved cognitive deficits, reduced oxidative damage, ameliorated abnormal mitochondrial ultrastructure, increased mitochondrial content and Nrf2 activation, and upregulated antioxidant and mitochondrial biogenesis gene expression in the hippocampus of wild-type aging mice. However, the above antiaging effects of PTX were obviously decreased in the brains of Nrf2-deficient D-gal-induced aging mice. Moreover, in hydrogen peroxide-treated SH-SY5Y cells, we found that cyclic adenosine monophosphate (cAMP) response element-binding protein (CREB) and Nrf2/PGC-1α act in a linear way by CREB siRNA transfection. Thus, PTX administration improved the aging-related decline in brain function by enhancing antioxidative capability and promoting mitochondrial biogenesis, which might depend on increasing Nrf2 and PGC-1α by activating the cAMP-CREB pathway.

TGase-mediated cell membrane modification and targeted cell delivery to inflammatory endothelium.

Targeted cell delivery to lesion sites via minimally invasive approach remains an unmet need in regenerative medicine to endow controlled cell distribution and minimized side-effects. Current cell modification approaches to improve cell delivery tend to have adverse effects on cellular phenotype and functionality. Here, we rationally developed a facile and mild cell modification and targeted delivery strategy leveraging endogenous tissue transglutaminase (TGase) expressed on the surface of MSCs (Mesenchymal Stem Cells) and inflammatory endothelial cells (ECs). Cell modification by functional peptides was accomplished simply via TGase catalyzed cross-linking with naturally-expressed MSCs membrane proteins (e.g. Annexin II), without detectable disturbance of cellular viability and functionality. The modified functional peptides could facilitate adhesion of MSCs to inflammatory ECs (with up-regulated TGase expression compared with normal ECs) in vitro, as demonstrated by a one-fold increase of the MSC-EC adhesion force measured by atomic force microscopy (AFM) and by targeted delivery of modified MSC to inflammatory ECs in a flow chamber assay. When transplanted in vivo, modified MSCs demonstrated a dramatic increase in targeted efficiency to inflammatory endothelium compared with non-modified MSCs in both mice ear inflammation and acute/chronic liver injury models. The cell membrane modification strategy and targeted cell delivery mechanism described here can be readily extended for empowering cell engineering and cell therapy with multifaceted functionalities to combat refractory diseases.

Multifunctional Injectable Hydrogel Loaded with Cerium-Containing Bioactive Glass Nanoparticles for Diabetic Wound Healing.

Diabetic foot wound healing is a major clinical problem due to impaired angiogenesis and bacterial infection. Therefore, an effective regenerative dressing is desiderated with the function of promoting revascularization and anti-bacteria. Herein, a multifunctional injectable composite hydrogel was prepared by incorporation of the cerium-containing bioactive glass (Ce-BG) into Gelatin methacryloyl (GelMA) hydrogel. The Ce-BG was synthesized by combining sol-gel method with template method, which maintained spherical shape, chemical structure and phase constitution of bioactive glass (BG). The Ce-BG/GelMA hydrogels had good cytocompatibility, promoted endothelial cells migration and tube formation by releasing Si ion. In vitro antibacterial tests showed that 5 mol % CeO2-containing bioactive glass/GelMA (5/G) composite hydrogel exhibited excellent antibacterial properties. In vivo study demonstrated that the 5/G hydrogel could significantly improve wound healing in diabetic rats by accelerating the formation of granulation tissue, collagen deposition and angiogenesis. All in all, these results indicate that the 5/G hydrogel could enhance diabetic wound healing. Therefore, the development of multifunctional materials with antibacterial and angiogenic functions is of great significance to promote the repair of diabetic wound healing.

Serine Incorporator 2 (SERINC2) Expression Predicts an Unfavorable Prognosis of Low-Grade Glioma (LGG): Evidence from Bioinformatics Analysis.

Serine Incorporator 2 (SERINC2) is a transmembrane protein that incorporates serine into membrane lipids. The function of SERINC2 in tumors has been reported, but the role of SERINC2 in gliomas is not fully understood. RNA-sequencing data from The Cancer Genome Atlas (TCGA) (530 cases of low-grade glioma (LGG) and 173 cases of glioblastoma multiforme (GBM)) and microarray data from Gene Expression Omnibus (GEO) (Accession No. GSE16011, 284 cases gliomas were included) were acquired. Bioinformatics analysis was performed as the primary method to examine the function of SERINC2 and its correlated genes in glioma. SERINC2 was highly expressed in GBM compared with LGG and normal brain tissues. Elevated SERINC2 expression predicted shorter 5-, 10-, and 15-year overall survival (OS) of LGG patients and isocitrate dehydrogenase-1 (IDH-1) mutation-type LGG patients but had no effect on the OS of GBM patients. Cox regression analysis showed that SERINC2 was an independent factor in LGG OS. Methylation analysis found that 13 CpG methylation sites (methylation450k) correlated with SERINC2 expression in LGG. The mRNA expression level of SERINC2 was significant lower in the DNA deletion group than in the intact and amplification groups. A total of 390 copositive and 244 conegative correlation genes with SERINC2 were obtained from LGG in TCGA-LGG and GSE16011. Gene ontology (GO) category and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses showed that the copositive correlation genes were primarily enriched in the mitotic process and cell cycle. Combining the results from the protein-protein interaction (PPI) network of SERINC2 correlation genes and CytoHubba led to the selection of 10 hub genes (CDC20, FN1, AURKB, AURKA, KIF2C, BIRC5, CCNB2, UBE2C, CCNA2, and CENPE). OncoLnc analysis confirmed that high expression levels of these hub genes were associated with poor OS in LGG. Our results suggested that aberrant SERINC2 expression existed in glioma and that its expression might be a potential prognostic marker in LGG patients. CDC20, FN1, AURKB, AURKA, KIF2C, BIRC5, CCNB2, UBE2C, CCNA2, and CENPE may be potential biomarkers and therapeutic targets for LGG.

Poly(N-Isopropyl-Acrylamide)/Poly(γ-Glutamic Acid) Thermo-Sensitive Hydrogels Loaded with Superoxide Dismutase for Wound Dressing Application.

INTRODUCTION: Chronic trauma repair is an important issue affecting people's healthy lives. Thermo-sensitive hydrogel is injectable in situ and can be used to treat large-area wounds. In addition, antioxidants play important roles in promoting wound repair. METHODS: The purpose of this research was to prepare a novel thermo-sensitive hydrogel-poly(N-isopropyl-acrylamide)/poly(γ-glutamic acid) (PP) loaded with superoxide dismutase (SOD) to improve the effect for trauma treatment. The micromorphology of the hydrogel was observed by scanning electron microscope and the physical properties were measured. The biocompatibility of hydrogel was evaluated by MTT experiment, and the effect of hydrogel on skin wound healing was evaluated by in vivo histological staining. RESULTS: Gelling behavior and differential scanning calorimeter outcomes showed that the PP hydrogels possessed thermo-sensitivity at physiological temperature and the phase transformation temperature was 28.2°C. The high swelling rate and good water retention were conducive to wound healing. The activity of SOD in vitro was up to 85% at 10 h, which was advantageous to eliminate the superoxide anion. MTT assay revealed that this hydrogel possessed good biocompatibility. Dressings of PP loaded with SOD (SOD-PP) had a higher wound closure rate than other treatments in vivo in diabetic rat model. DISCUSSION: The SOD-PP thermo-sensitive hydrogels can effectively promote wound healing and have good application prospects for wound repair.

Potentials of sandwich-like chitosan/polycaprolactone/gelatin scaffolds for guided tissue regeneration membrane.

Periodontal disease is a common complication and conventional periodontal surgery can lead to severe bleeding. Guided tissue regeneration (GTR) membranes favor periodontal regrowth, but they still have limitations, such as improper biodegradation, poor mechanical property, and no effective hemostatic property. To overcome these shortcomings, we generated unique multifunctional scaffolds. A chitosan/polycaprolactone/gelatin sandwich-like construction was fabricated by electrospinning and lyophilization. These composite scaffolds showed favorable physicochemical properties, including: appropriate porosity (<50%), pore size (about 10 µm) and mechanical stability (increasing with more PCL), good swelling and hydrophilicity. Appropriate degradation rates were approved by degradability analysis in vitro and in vivo, which resembled tissue regeneration process more closely. As shown in cell viability assay, cell attachment assay and Sirius red staining, we knew that the scaffolds had good biocompatibility, did not adversely affect cell ability for attachment, and induced high levels of collagen secretion. Experiments of blood clotting measurement in vitro showed that composite scaffolds were capable of accelerating blood clotting and could realize effective hemostasis. The results from subcutaneous implantation revealed the scaffolds had strong cell barrier effects and protection from external cell invasion. In summary, our multifunctional composite scaffolds showed optimised structure, enhanced regenerative capabilities, and serve as a basis for approaches to improve GTR designs for periodontal regeneration.

Pentoxifylline enhances antioxidative capability and promotes mitochondrial biogenesis for improving age-related behavioral deficits.

Pentoxifylline (PTX) is a non-specific phosphodiesterase inhibitor with pleiotropic effects that is routinely used to treat peripheral vascular disease. In this study, we tested whether PTX could also counteract the detrimental effects of aging in the brain. To accomplish that, we treated aged rats with PTX and measured resulting behavioral alterations as well as changes in dopaminergic neurochemical levels, oxidative balance markers, mitochondrial function, nuclear factor erythroid 2-related factor 2 (Nrf2), peroxisome proliferator activated receptor-gamma coactivator 1-alpha (PGC-1α) and downstream gene expression, and cyclic adenosine monophosphate (cAMP) content in the brain. The results demonstrated that PTX improved motor and cognitive deficits and restored levels of dopamine and its metabolites in the brains of aged rats. PTX also reduced malondialdehyde levels and increased the GSH/GSSG ratio, mitochondrial ATP, nuclear Nrf2, and cAMP levels, and upregulated PGC-1α, nuclear respiratory factor 1, and mitochondrial transcription factor A expression in the substantia nigra and hippocampus of aged rats. Thus, increased nuclear Nrf2 levels and upregulation of PGC-1α, which enhance antioxidative capability and promote mitochondrial biogenesis, may be responsible for PTX-induced amelioration of behavioral deficits in aged rats.

Testosterone propionate activated the Nrf2-ARE pathway in ageing rats and ameliorated the age-related changes in liver.

The present study aimed to evaluate the protective efficacy of testosterone propionate (TP) on age-related liver changes via activation of the nuclear factor erythroid 2-related factor 2-antioxidant response element (Nrf2-ARE) pathway in aged rats. Aged rats received subcutaneous injections of TP (2 mg/kg/d, 84 days). Oxidative stress parameters and the expression levels of signal transducer and activator of transcription 5b (STAT5b), Kelch-like ECH associating protein-1 (Keap1), Nrf2, haem oxygenase-1 (HO-1) and NAD(P)H: quinone oxidoreductase-1 (NQO1) in liver tissues were examined to check whether the Nrf2-ARE pathway was involved in the age-related changes in liver. Our results showed that TP supplementation alleviated liver morphology, liver function and liver fibrosis; improved oxidative stress parameters; and increased the expression of STAT5b, Nrf2, HO-1 and NQO-1 and decreased the expression of Keap1 in the liver tissues of aged rats. These results suggested that TP increased the expression of STAT5b, and then activated the Nrf2-ARE pathway and promoted antioxidant mechanisms in aged rats. These findings may provide new therapeutic uses for TP in patients with age-related liver changes.