The pore size of porous scaffold plays a critical role in bone regeneration, but its mechanism and optimal value remain unclear. This study investigated the effect of pore size on hydromechanical ...properties of porous scaffold and its correlation with cellular response and bone regeneration. Porous titanium scaffolds with similar porosity and different pore sizes (400, 650, 850, and 1100 μm) were fabricated by selective laser melting. Their hydromechanical properties were derived by computational fluid dynamics analysis. The MC3T3 cells were dynamic seeded and cultured on the scaffolds to evaluate the cellular response. The rabbit distal femoral condyle implantation models were used to assess the bone ingrowth. Results indicated that the permeability, flow velocity, and the inflow of fluid linearly increased with the pore size. The wall shear stress evaluated from 400 to 650 μm and then dropped. These changes induced various performances in cell penetration, adhesion, proliferation, and differentiation, and finally induced best bone ingrowth in scaffold with pore size of 650 μm. This study provided a new understanding of the effect of pore size on bone regeneration of porous scaffold from the perspective of hydromechanics and indicated the potential of combining computational simulation and laboratory experiments in future studies.
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•Increasing the pore size linearly increased the permeability, flow velocity, and inflow of fluid.•The shear stress first increased and then decreased with the increase in pore size.•The pore size significantly affected the cell penetration, adhesion, proliferation, differentiation, and bone ingrowth.•The hydromechanical properties closely correlated with the cellular response and bone regeneration
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Glioblastoma (GBM) remains the most lethal malignant tumours. Gboxin, an oxidative phosphorylation inhibitor, specifically restrains GBM growth by inhibiting the activity of F
F
ATPase complex V. ...However, its anti-GBM effect is seriously limited by poor blood circulation, the blood brain barrier (BBB) and non-specific GBM tissue/cell uptake, leading to insufficient Gboxin accumulation at GBM sites, which limits its further clinical application. Here we present a biomimetic nanomedicine (HM-NPs@G) by coating cancer cell-mitochondria hybrid membrane (HM) on the surface of Gboxin-loaded nanoparticles. An additional design element uses a reactive oxygen species responsive polymer to facilitate at-site Gboxin release. The HM camouflaging endows HM-NPs@G with unique features including good biocompatibility, improved pharmacokinetic profile, efficient BBB permeability and homotypic dual tumour cell and mitochondria targeting. The results suggest that HM-NPs@G achieve improved blood circulation (4.90 h versus 0.47 h of free Gboxin) and tumour accumulation (7.73% ID/g versus 1.06% ID/g shown by free Gboxin). Effective tumour inhibition in orthotopic U87MG GBM and patient derived X01 GBM stem cell xenografts in female mice with extended survival time and negligible side effects are also noted. We believe that the biomimetic Gboxin nanomedicine represents a promising treatment for brain tumours with clinical potential.
Small interfering RNA (siRNA) has been considered as a highly promising therapeutic agent for human cancer treatment including glioblastoma (GBM), which is a fatal disease without effective therapy ...methods. However, siRNA‐based GBM therapy is seriously hampered by a number of challenges in siRNA brain delivery including poor stability, short blood circulation, low blood–brain barrier (BBB) penetration, and tumor accumulation, as well as inefficient siRNA intracellular release. Herein, an Angiopep‐2 (Ang) functionalized intracellular‐environment‐responsive siRNA nanocapsule (Ang‐NCss(siRNA)) is successfully developed as a safe and efficient RNAi agent to boost siRNA‐based GBM therapy. The experimental results demonstrate that the developed Ang‐NCss(siRNA) displays long circulation in plasma, efficient BBB penetration capability, and GBM accumulation and retention, as well as responsive intracellular siRNA release due to the unique design of small size (25 nm) with polymeric shell for siRNA protection, Ang functionalization for BBB crossing and GBM targeting, and disulfide bond as a linker for intracellular‐environment‐responsive siRNA release. Such superior properties of Ang‐NCss(siRNA) result in outstanding growth inhibition of orthotopic U87MG xenografts without causing adverse effects, achieving remarkably improved survival benefits. The developed siRNA nanocapsules provide a new strategy for RNAi therapy of GBM and beyond.
Reduction‐responsive nanocapsules (Ang‐NCss(siRNA)) are readily prepared from interfacial polymerization with disulfide bonds as cross‐linkers, followed by target ligand Angiopep‐2 functionalization. The developed siRNA nanocapsules show small size, excellent stability, outstanding blood–brain barrier penetration, and tumor accumulation, leading to effective suppression of orthotopic glioblastoma with negligible side effects. Such an siRNA nanocapsule displays promising application potential in brain disease RNAi therapy.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Wheat straw (WS) is a potential biomass for production of monomeric sugars. However, the enzymatic hydrolysis ratio of cellulose in WS is relatively low due to the presence of lignin and ...hemicellulose. To enhance the enzymatic conversion of WS, we tested the impact of three different pretreatments, e.g. sulfuric acid (H
SO
), sodium hydroxide (NaOH), and hot water pretreatments to the enzymatic digestions. Among the three pretreatments, the highest cellulose conversion rate was obtained with the 4% NaOH pretreatment at 121 °C (87.2%). In addition, NaOH pretreatment was mainly effective in removing lignin, whereas the H
SO
pretreatment efficiently removed hemicellulose. To investigate results of pretreated process for enhancement of enzyme-hydolysis to the WS, we used scanning electron microscopy, X-ray diffraction, and Fourier transform infrared spectroscopy to analyze structural changes of raw and treated materials. The structural analysis indicated that after H
SO
and NaOH pretreatments, most of the amorphous cellulose and partial crystalline cellulose were hydrolyzed during enzymatic hydrolysis. The findings of the present study indicate that WS could be ideal materials for production of monomeric sugars with proper pretreatments and effective enzymatic base hydrolysis.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Nonalcoholic steatohepatitis (NASH) is becoming one of the leading causes of hepatocellular carcinoma (HCC). Sorafenib is the only first-line therapy for advanced HCC despite its serious adverse ...effects. Here, we report that at an equivalent of approximately one-tenth the clinical dose for HCC, sorafenib treatment effectively prevents the progression of NASH in both mice and monkeys without any observed significant adverse events. Mechanistically, sorafenib’s benefit in NASH is independent of its canonical kinase targets in HCC, but involves the induction of mild mitochondrial uncoupling and subsequent activation of AMP–activated protein kinase (AMPK). Collectively, our findings demonstrate a previously unappreciated therapeutic effect and signaling mechanism of low-dose sorafenib treatment in NASH. We envision that this new therapeutic strategy for NASH has the potential to translate into a beneficial anti-NASH therapy with fewer adverse events than is observed in the drug’s current use in HCC.
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•Low-dose sorafenib safely suppresses NASH progression in mice•Low-dose sorafenib resolves NASH in monkeys without detectable toxicities•AMPK activation is required for the therapeutic effects of sorafenib in NASH•Sorafenib activates AMPK by acting as a mitochondrial uncoupler
Jian et al. show that low-dose sorafenib safely and effectively suppressed NASH progression in both mice and monkeys. Mechanistically, induction of mitochondrial uncoupling and subsequent AMPK activation primarily underlies the therapeutic effects of sorafenib in NASH.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
BACKGROUND—Although metabolic reprogramming is critical in the pathogenesis of heart failure, studies to date have focused principally on fatty acid and glucose metabolism. Contribution of amino acid ...metabolic regulation in the disease remains understudied.
METHODS AND RESULTS—Transcriptomic and metabolomic analyses were performed in mouse failing heart induced by pressure overload. Suppression of branched-chain amino acid (BCAA) catabolic gene expression along with concomitant tissue accumulation of branched-chain α-keto acids was identified as a significant signature of metabolic reprogramming in mouse failing hearts and validated to be shared in human cardiomyopathy hearts. Molecular and genetic evidence identified the transcription factor Krüppel-like factor 15 as a key upstream regulator of the BCAA catabolic regulation in the heart. Studies using a genetic mouse model revealed that BCAA catabolic defect promoted heart failure associated with induced oxidative stress and metabolic disturbance in response to mechanical overload. Mechanistically, elevated branched-chain α-keto acids directly suppressed respiration and induced superoxide production in isolated mitochondria. Finally, pharmacological enhancement of branched-chain α-keto acid dehydrogenase activity significantly blunted cardiac dysfunction after pressure overload.
CONCLUSIONS—BCAA catabolic defect is a metabolic hallmark of failing heart resulting from Krüppel-like factor 15–mediated transcriptional reprogramming. BCAA catabolic defect imposes a previously unappreciated significant contribution to heart failure.
Nutrients are absorbed solely by the intestinal villi. Aging of this organ causes malabsorption and associated illnesses, yet its aging mechanisms remain unclear. Here, we show that aging-caused ...intestinal villus structural and functional decline is regulated by mTORC1, a sensor of nutrients and growth factors, which is highly activated in intestinal stem and progenitor cells in geriatric mice. These aging phenotypes are recapitulated in intestinal stem cell-specific Tsc1 knockout mice. Mechanistically, mTORC1 activation increases protein synthesis of MKK6 and augments activation of the p38 MAPK-p53 pathway, leading to decreases in the number and activity of intestinal stem cells as well as villus size and density. Targeting p38 MAPK or p53 prevents or rescues ISC and villus aging and nutrient absorption defects. These findings reveal that mTORC1 drives aging by augmenting a prominent stress response pathway in gut stem cells and identify p38 MAPK as an anti-aging target downstream of mTORC1.
Fatty liver syndrome (FLS) is a kind of nutritional metabolic disease in laying hens. Revealing FLS pathogenesis during the early period is what really makes sense for the prevention or nutritional ...regulation strategies. In the study, 9 healthy or naturally occurring early FLS birds were screened based on visual inspection, liver index and morphologic analysis. Liver and fresh cecal content samples were collected. Then transcriptomic and 16S rRNA technologies are applied to investigate hepatic transcriptome and cecum microbiota composition. Unpaired Student t test and some omics methods were used for statistical analysis. Results showed higher liver weight and index were found in FLS group; morphologic analysis indicated that there existed more lipid droplets in the liver of birds with FLS. Based on DESeq2 analysis, there were 229 up- and 487 down-regulated genes in the FLS group, among which most genes related to de novo fatty acid synthesis were up-regulated such as acetyl-CoA carboxylase, fatty acid synthase, stearoyl-CoA desaturase, and ELOVL fatty acid elongase 6 (ELOVL6). Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis indicated that pathways associated with lipid metabolism and liver damage were affected. 16S rRNA sequencing analysis of cecum microbiota showed that there was a significant difference between the Con and FLS groups. LEfSe analysis revealed that the relative abundance of Coprococcus, Odoribacter, Collinsella, Turicibacter, YRC22, Enterococcus, Shigella, and Bifidobacterium were down-regulated in the FLS group, whereas the abundance of Bacteroides, Mucispirillum, Butyricicoccus, Campylobacter, Akkermansia, and Clostridium were up-regulated. The KEGG enrichment from differential microbiota suggested that some metabolism-related functions were altered to some extent. Taken together, during the developmental of early fatty liver of laying hens, lipogenesis was enhanced, whereas abnormal metabolism occurs not only in lipid transportation but also in hydrolysis, which caused structural damage to the liver organ. Moreover, the dysbiosis of the cecum microbiota occurred. All of these serve as targets or provide theoretical references for the development of probiotics for fatty liver prevention in laying hens.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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