D-mannose alleviates intervertebral disc degeneration through glutamine metabolism.

BACKGROUND: Intervertebral disc degeneration (IVDD) is a multifaceted condition characterized by heterogeneity, wherein the balance between catabolism and anabolism in the extracellular matrix of nucleus pulposus (NP) cells plays a central role. Presently, the available treatments primarily focus on relieving symptoms associated with IVDD without offering an effective cure targeting its underlying pathophysiological processes. D-mannose (referred to as mannose) has demonstrated anti-catabolic properties in various diseases. Nevertheless, its therapeutic potential in IVDD has yet to be explored. METHODS: The study began with optimizing the mannose concentration for restoring NP cells. Transcriptomic analyses were employed to identify the mediators influenced by mannose, with the thioredoxin-interacting protein (Txnip) gene showing the most significant differences. Subsequently, small interfering RNA (siRNA) technology was used to demonstrate that Txnip is the key gene through which mannose exerts its effects. Techniques such as colocalization analysis, molecular docking, and overexpression assays further confirmed the direct regulatory relationship between mannose and TXNIP. To elucidate the mechanism of action of mannose, metabolomics techniques were employed to pinpoint glutamine as a core metabolite affected by mannose. Next, various methods, including integrated omics data and the Gene Expression Omnibus (GEO) database, were used to validate the one-way pathway through which TXNIP regulates glutamine. Finally, the therapeutic effect of mannose on IVDD was validated, elucidating the mechanistic role of TXNIP in glutamine metabolism in both intradiscal and orally treated rats. RESULTS: In both in vivo and in vitro experiments, it was discovered that mannose has potent efficacy in alleviating IVDD by inhibiting catabolism. From a mechanistic standpoint, it was shown that mannose exerts its anti-catabolic effects by directly targeting the transcription factor max-like protein X-interacting protein (MondoA), resulting in the upregulation of TXNIP. This upregulation, in turn, inhibits glutamine metabolism, ultimately accomplishing its anti-catabolic effects by suppressing the mitogen-activated protein kinase (MAPK) pathway. More importantly, in vivo experiments have further demonstrated that compared with intradiscal injections, oral administration of mannose at safe concentrations can achieve effective therapeutic outcomes. CONCLUSIONS: In summary, through integrated multiomics analysis, including both in vivo and in vitro experiments, this study demonstrated that mannose primarily exerts its anti-catabolic effects on IVDD through the TXNIP-glutamine axis. These findings provide strong evidence supporting the potential of the use of mannose in clinical applications for alleviating IVDD. Compared to existing clinically invasive or pain-relieving therapies for IVDD, the oral administration of mannose has characteristics that are more advantageous for clinical IVDD treatment.

piRNA mmu_piR_037459 suppression alleviated the degeneration of chondrocyte and cartilage.

OBJECTIVE: Osteoarthritis (OA) is a prevalent chronic degenerative joint ailment. Its primary pathological characteristics encompass degeneration of articular cartilage, inflammation of the synovium, and alterations in the subchondral bone proximate to the cartilage. Chondrocytes, as the sole cell type within articular cartilage, assume a crucial role in upholding the dynamic equilibrium between anabolic and catabolic processes within the extracellular matrix of articular cartilage. IL-1ß stands as a pivotal inflammatory factor that instigates cartilage degeneration. piRNA, categorized as a subset of brief non-coding RNAs spanning nucleotide lengths of 26-31nt, assumes a significant regulatory role in cellular function. METHODS: Small RNA sequencing and quantitative PCR (qPCR) were employed to investigate the impact of the inflammatory factor IL-1ß on piRNA expression within chondrocytes. The regulation of mmu_piR_037459 expression in chondrocytes was achieved using piRNA mimics and inhibitors. Additionally, collagen II expression was assessed through both qPCR and Western blot analysis. Chondrocyte apoptosis was evaluated via flow cytometry and clonogenesis assays. To assess the influence of mmu_piR_037459 on osteoarthritis, a mouse model of anterior cruciate ligament transection (ACLT) was established. Furthermore, the regulatory effect of mmu_piR_037459 on USP7 was investigated using bioinformatics and a luciferase reporter gene assay. RESULTS: mmu_piR_037459 inhibited the expression of collagen II in chondrocytes, inhibited the proliferation of chondrocytes, and promoted the apoptosis of chondrocytes. mmu_piR_037459 affected the function of chondrocytes by regulating the expression of USP7. Inhibition of mmu_piR_037459 expression could promote chondrocyte proliferation, inhibit chondrocyte apoptosis, and alleviate the degeneration of OA cartilage. CONCLUSIONS: This study suggests that mmu_piR_037459 maybe a new therapeutic targets and strategies for the treatment of OA.

Nanozymes With Osteochondral Regenerative Effects: An Overview of Mechanisms and Recent Applications.

With the discovery of the intrinsic enzyme-like activity of metal oxides, nanozymes garner significant attention due to their superior characteristics, such as low cost, high stability, multi-enzyme activity, and facile preparation. Notably, in the field of biomedicine, nanozymes primarily focus on disease detection, antibacterial properties, antitumor effects, and treatment of inflammatory conditions. However, the potential for application in regenerative medicine, which primarily addresses wound healing, nerve defect repair, bone regeneration, and cardiovascular disease treatment, is garnering interest as well. This review introduces nanozymes as an innovative strategy within the realm of bone regenerative medicine. The primary focus of this approach lies in the facilitation of osteochondral regeneration through the modulation of the pathological microenvironment. The catalytic mechanisms of four types of representative nanozymes are first discussed. The pathological microenvironment inhibiting osteochondral regeneration, followed by summarizing the therapy mechanism of nanozymes to osteochondral regeneration barriers is introduced. Further, the therapeutic potential of nanozymes for bone diseases is included. To improve the therapeutic efficiency of nanozymes and facilitate their clinical translation, future potential applications in osteochondral diseases are also discussed and some significant challenges addressed.

Chitosan based macromolecular hydrogel loaded total glycosides of paeony enhances diabetic wound healing by regulating oxidative stress microenvironment.

Oxidative stress microenvironment caused by reactive oxygen species (ROS) accumulation seriously hinders wound healing in diabetes, which brings great burden to global health. Various wound dressings on the market focus on delivering active substances to promote wound healing in diabetes. However, the complex pathological microenvironment of diabetic wounds often leads to the inactivation of delivery factors, which often leads to treatment failure, and thus, emerging therapeutic approaches are urgently needed. In this study, a macromolecular hydrogel synthesized by crosslinking N-carboxyethyl chitosan, hyaluronic acid-aldehyde, and adipic acid dihydrazide, with self-healing and injectable abilities was used to deliver total glycosides of paeony (TGP). The TGP incorporated hydrogel could obviously induce fibroblasts proliferation and secretion of various extracellular matrix proteins and growth factors, induce migration and angiogenesis of vein endothelial cells, and enhance macrophages polarization to M2 phenotype by eliminating accumulated ROS. In diabetic wound models, the ROS-scavenging hydrogel efficiently enhanced proliferation, re-epithelialization, collagen deposition, as well as angiogenesis in the wound area. Besides, the dressing induced the macrophages polarization from M1 phenotype (pro-inflammatory) to M2 phenotype (anti-inflammatory) and decreased the levels of inflammatory cytokines, thereby enhancing the diabetic wound healing. The wounds treated with TGP incorporated hydrogel almost completely healed 16 days after treatment. However, the residual wound areas in the groups of Con, INTRA, and Gel are 55.2 ± 4.6 %, 33.7 ± 6.5 %, and 34.9 ± 6.1 % on the 16th day, respectively. This hydrogel with pathological microenvironment improvement ability affords a novel therapeutic strategy for enhancing healing of chronic diabetic wound.

Bioprinted constructs that simulate nerve-bone crosstalk to improve microenvironment for bone repair.

Crosstalk between nerves and bone is essential for bone repair, for which Schwann cells (SCs) are crucial in the regulation of the microenvironment. Considering that exosomes are critical paracrine mediators for intercellular communication that exert important effects in tissue repair, the aim of this study is to confirm the function and molecular mechanisms of Schwann cell-derived exosomes (SC-exos) on bone regeneration and to propose engineered constructs that simulate SC-mediated nerve-bone crosstalk. SCs promoted the proliferation and differentiation of bone marrow mesenchymal stem cells (BMSCs) through exosomes. Subsequent molecular mechanism studies demonstrated that SC-exos promoted BMSC osteogenesis by regulating the TGF-ß signaling pathway via let-7c-5p. Interestingly, SC-exos promoted the migration and tube formation performance of endothelial progenitor cells. Furthermore, the SC-exos@G/S constructs were developed by bioprinting technology that simulated SC-mediated nerve-bone crosstalk and improved the bone regeneration microenvironment by releasing SC-exos, exerting the regulatory effect of SCs in the microenvironment to promote innervation, vascularization, and osteogenesis and thus effectively improving bone repair in a cranial defect model. This study demonstrates the important role and underlying mechanism of SCs in regulating bone regeneration through SC-exos and provides a new engineered strategy for bone repair.

Fullerenol inhibits tendinopathy by alleviating inflammation.

Tendinopathy is a common disease in orthopaedics, seriously affecting tendon functions. However, the effects of non-surgical treatment on tendinopathy are not satisfactory and surgical treatments possibly impair the function of tendons. Biomaterial fullerenol has been proved to show good anti-inflammatory effects on various inflammatory diseases. For in vitro experiments, primary rat tendon cells (TCs) were treated by interleukin-1 beta (IL-1ß) combined with aqueous fullerenol (5, 1, 0.3 µg/mL). Then inflammatory factors, tendon-related markers, migration and signaling pathways were detected. For in vivo experiments, rat tendinopathy model was constructed by local injection of collagenase into Achilles tendons of rats and fullerenol (0.5, 1 mg/mL) was locally injected 7 days after collagenase injection. Inflammatory factors and tendon-related markers were also investigated. Fullerenol with good water-solubility showed excellent biocompatibility with TCs. Fullerenol could increase expression of tendon-related factors (Collagen I and tenascin C) and decrease expression of inflammatory factors (matrix metalloproteinases-3, MMP-3, and MMP-13) and reactive oxygen species (ROS) level. Simultaneously, fullerenol slowed the migration of TCs and inhibited activation of Mitogen-activated protein kinase (MAPK) signaling pathway. Fullerenol also attenuated tendinopathy in vivo, including reduction of fiber disorders, decrease of inflammatory factors and increase of tendon markers. In summary, fullerenol is a promising biomaterial that can be used to treat tendinopathy.

Regeneration of Humeral Head Using a 3D Bioprinted Anisotropic Scaffold with Dual Modulation of Endochondral Ossification.

Tissue engineering is theoretically thought to be a promising method for the reconstruction of biological joints, and thus, offers a potential treatment alternative for advanced osteoarthritis. However, to date, no significant progress is made in the regeneration of large biological joints. In the current study, a biomimetic scaffold for rabbit humeral head regeneration consisting of heterogeneous porous architecture, various bioinks, and different hard supporting materials in the cartilage and bone regions is designed and fabricated in one step using 3D bioprinting technology. Furthermore, orchestrated dynamic mechanical stimulus combined with different biochemical cues (parathyroid hormone [PTH] and chemical component hydroxyapatite [HA] in the outer and inner region, respectively) are used for dual regulation of endochondral ossification. Specifically, dynamic mechanical stimulus combined with growth factor PTH in the outer region inhibits endochondral ossification and results in cartilage regeneration, whereas dynamic mechanical stimulus combined with HA in the inner region promotes endochondral ossification and results in efficient subchondral bone regeneration. The strategy established in this study with the dual modulation of endochondral ossification for 3D bioprinted anisotropic scaffolds represents a versatile and scalable approach for repairing large joints.

Polydopamine-coated 3D-printed ß-tricalcium phosphate scaffolds to promote the adhesion and osteogenesis of BMSCs for bone-defect repair: mRNA transcriptomic sequencing analysis.

Cellular bioactivity and tissue regeneration can be affected by coatings on tissue-engineered scaffolds. Using mussel-inspired polydopamine (PDA) is a convenient and effective approach to surface modification. Therefore, 3D-printed ß-tricalcium phosphate (ß-TCP) scaffolds were coated with PDA in this study. The effects of the scaffolds on the adhesion and osteogenic differentiation of seeded bone marrow mesenchymal stem cells (BMSCs) in vitro and on new-bone formation in vivo were investigated. The potential mechanisms and related differential genes were assessed using mRNA sequencing. It was seen that PDA coating increased the surface roughness of the 3D-printed ß-TCP scaffolds. Furthermore, it prompted the adhesion and osteogenic differentiation of seeded BMSCs. mRNA sequencing analysis revealed that PDA coating might affect the osteogenic differentiation of BMSCs through the calcium signaling pathway, Wnt signaling pathway, TGF-beta signaling pathway, etc. Moreover, the expression of osteogenesis-related genes, such as R-spondin 1 and chemokine c-c-motif ligand 2, was increased. Finally, both the 3D-printed ß-TCP scaffolds and PDA-coated scaffolds could significantly accelerate the formation of new bone in critical-size calvarial defects in rats compared with the control group; and the new bone formation was obviously higher in the PDA-coated scaffolds than in ß-TCP scaffolds. In summary, 3D-printed ß-TCP scaffolds with a PDA coating can improve the physicochemical characteristics and cellular bioactivity of the scaffold surface for bone regeneration. Potential differential genes were identified, which can be used as a foundation for further research.

Three-dimensional bioprinted BMSCs-laden highly adhesive artificial periosteum containing gelatin-dopamine and graphene oxide nanosheets promoting bone defect repair.

The periosteum is a connective tissue membrane adhering to the surface of bone tissue that primarily provides nutrients and regulates osteogenesis during bone development and injury healing. However, building an artificial periosteum with good adhesion properties and satisfactory osteogenesis for bone defect repair remains a challenge, especially using three-dimensional (3D) bioprinting. In this study, dopamine was first grafted onto the molecular chain of gelatin usingN-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride andN-hydroxysuccinimide (NHS) to activate the carboxyl group and produce modified gelatin-dopamine (GelDA). Next, a methacrylated gelatin, methacrylated silk fibroin, GelDA, and graphene oxide nanosheet composite bioink loaded with bone marrow mesenchymal stem cells was prepared and used for bioprinting. The physicochemical properties, biocompatibility, and osteogenic roles of the bioink and 3D bioprinted artificial periosteum were then systematically evaluated. The results showed that the developed bioink showed good thermosensitivity and printability and could be used to build 3D bioprinted artificial periosteum with satisfactory cell viability and high adhesion. Finally, the 3D bioprinted artificial periosteum could effectively enhance osteogenesis bothin vitroandin vivo. Thus, the developed 3D bioprinted artificial periosteum can prompt new bone formation and provides a promising strategy for bone defect repair.

Thermosensitive hydrogel loaded with concentrated growth factors promote bone repair in segmental bone defects.

Treating critical-size bone defects beyond the body's self-healing capacity is a challenging clinical task. In this study, we investigate the effect of concentrate growth factors (CGFs) loaded Poloxamer 407 hydrogel on the viability and osteogenic differentiation potential of bone marrow mesenchymal stem cells (BMSCs) and reconstruction of critical-size bone defects. In vitro, this CGFs-loaded thermosensitive hydrogel can significantly promote proliferation, maintain cell viability, and induce osteogenic differentiation of BMSCs by up-regulating the mineralization and alkaline phosphatase (ALP) activity, as well as gene markers, including runt-related transcription factor-2 (Runx-2), type I collagen (Col-1), osteocalcin (OCN), as well as osteopontin (OPN). In vivo, Micro-CT radiography analysis and histological detection demonstrated that the CGFs-loaded hydrogel significantly induced bone healing and reconstructed the medullary cavity structure in critical-size bone defect models. In conclusion, this strategy of transplantation of CGFs-loaded hydrogel promoted bone regeneration and prevented bone nonunion, so as to provide basis for clinical treatment for repairing critical-size bone defects.

3D bioprinting of osteon-mimetic scaffolds with hierarchical microchannels for vascularized bone tissue regeneration.

The integration of three-dimensional (3D) bioprinted scaffold's structure and function for critical-size bone defect repair is of immense significance. Inspired by the basic component of innate cortical bone tissue-osteons, many studies focus on biomimetic strategy. However, the complexity of hierarchical microchannels in the osteon, the requirement of mechanical strength of bone, and the biological function of angiogenesis and osteogenesis remain challenges in the fabrication of osteon-mimetic scaffolds. Therefore, we successfully built mimetic scaffolds with vertically central medullary canals, peripheral Haversian canals, and transverse Volkmann canals structures simultaneously by 3D bioprinting technology using polycaprolactone and bioink loading with bone marrow mesenchymal stem cells and bone morphogenetic protein-4. Subsequently, endothelial progenitor cells were seeded into the canals to enhance angiogenesis. The porosity and compressive properties of bioprinted scaffolds could be well controlled by altering the structure and canal numbers of the scaffolds. The osteon-mimetic scaffolds showed satisfactory biocompatibility and promotion of angiogenesis and osteogenesisin vitroand prompted the new blood vessels and new bone formationin vivo. In summary, this study proposes a biomimetic strategy for fabricating structured and functionalized 3D bioprinted scaffolds for vascularized bone tissue regeneration.

Restoration of dystrophin expression in mice by suppressing a nonsense mutation through the incorporation of unnatural amino acids.

Approximately 11% of monogenic diseases involve nonsense mutations that are caused by premature termination codons. These codons can in principle be read-through via the site-specific incorporation of unnatural amino acids to generate full-length proteins with minimal loss of function. Here we report that aminoacyl-tRNA-synthase-tRNA pairs specific for the desired unnatural amino acids can be used to read through a nonsense mutation in the dystrophin gene. We show partial restoration of dystrophin expression in differentiated primary myoblasts (from a mdx mouse model and a patient with Duchenne muscular dystrophy), and restoration of muscle function in two mouse models: mdx mice, via viral delivery of the engineered tRNA-synthase-tRNA pair intraperitoneally or intramuscularly and of the associated unnatural amino acid intraperitoneally; and mice produced by crossing mdx mice and transgenic mice with a chromosomally integrated pair, via intraperitoneal delivery of the unnatural amino acid. The incorporation of unnatural amino acids to restore endogenous protein expression could be explored for therapeutic use.

Developments and Opportunities for 3D Bioprinted Organoids.

Organoids developed from pluripotent stem cells or adult stem cells are three-dimensional cell cultures possessing certain key characteristics of their organ counterparts, and they can mimic certain biological developmental processes of organs in vitro. Therefore, they have promising applications in drug screening, disease modeling, and regenerative repair of tissues and organs. However, the construction of organoids currently faces numerous challenges, such as breakthroughs in scale size, vascularization, better reproducibility, and precise architecture in time and space. Recently, the application of bioprinting has accelerated the process of organoid construction. In this review, we present current bioprinting techniques and the application of bioinks and summarize examples of successful organoid bioprinting. In the future, a multidisciplinary combination of developmental biology, disease pathology, cell biology, and materials science will aid in overcoming the obstacles pertaining to the bioprinting of organoids. The combination of bioprinting and organoids with a focus on structure and function can facilitate further development of real organs.

IL1RN Polymorphisms Are Associated with a Decreased Risk of Esophageal Cancer Susceptibility in a Chinese Population.

BACKGROUND: Recent evidence suggested that IL1RN (interleukin-1 receptor antagonist) polymorphisms increased the susceptibility to cancers. The present study aimed to evaluate whether IL1RN was related to esophageal cancer susceptibility in a Northwest Han Chinese population. METHODS: The case-control study was conducted on 384 esophageal cancer patients and 499 healthy controls. We successfully genotyped four SNPs distributed in IL1RN. The Gene Expression Profiling Interactive Analysis (GEPIA) database was used to observe the expression of IL1RN in esophageal cancer tissues and normal tissues. RegulomeDB and HaploReg v4.1 were used to calculate possible functional effects of the polymorphisms. We also used genetic models to detect any potential association between IL1RN variants and esophageal cancer risk. RESULTS: In our study, rs3181052 was associated with a reduced risk of esophageal cancer in the codominant (odds ratio [OR] = 0.70, 95% confidence interval [CI] 0.52-0.93, p = 0.040), the dominant (OR = 0.75, 95% CI 0.57-0.99, p = 0.041), and the overdominant (OR = 0.71, 95% CI 0.54-0.93, p = 0.012) model. The rs452204 was associated with a 0.76-fold (OR = 0.76, 95% CI 0.58-0.99; p = 0.043) decreased esophageal cancer risk under the overdominant model without adjustment. We also found that rs3181052 had a negative effect on esophageal cancer under the overdominant model (OR = 0.72, 95% CI 0.53-0.97, p = 0.033) adjusted for age and gender. In stratified analyses by age >55 years, rs3181052 reduced the risk of esophageal cancer in the dominant and overdominant models. In addition, rs315919 had a remarkable influence on esophageal cancer risk in females, while the association was not significant between rs3181052 and esophageal cancer risk in males. CONCLUSIONS: Our study provided the first evidence that IL1RN rs3181052, rs452204, and rs315919 are correlated with a decreased risk of esophageal cancer in a Northwest Han Chinese population. These findings may be useful for the development of early prognostics for esophageal cancer. However, further larger studies on different ethnic populations are warranted to verify these findings.

The impact of genetic variants in IL1R2 on cervical cancer risk among Uygur females from China: A case-control study.

BACKGROUND: Disordered inflammation and immune response is an acknowledged risk factor for cervical cancer development. Interleukin-1 receptor type 2 (IL1R2) is a decoy receptor for IL-1 cytokines and involved in host inflammatory and immune progression which could lead to the lesion and neoplasia of cervix. In this study, we aimed to evaluate the relationships between IL1R2 polymorphisms and cervical cancer risk in Uygur females from China. METHODS: In this case-control study, genotypes of six selected variants (rs11674595, rs4851527, rs719250, rs3218896, rs3218977, and rs2072472) distributed in IL1R2 were detected among 247 cervical cancer patients and 286 healthy controls with the usage of an Agena MassARRY method. Furthermore, Genetic models and haplotype analyses were conducted to estimate the associations of IL1R2 polymorphisms with cervical cancer risk. RESULTS: After statistical analyses, rs719250 (odd ratio [OR] = 1.436, 95% confidence interval [95% CI] = 1.079-1.911, p = 0.013) and rs3218896 (OR = 1.552, 95% CI = 1.080-2.229, p = 0.017) showed obvious evidence in correlation to cervical cancer susceptibility owing to the surviving significant differences between cases and controls in allele model. Genetic model analyses also revealed significant associations of rs719250 and rs3218896 with cervical cancer risk in the codominant model, the dominant model and the log-additive model even after adjustment for age (p < 0.05). Moreover, haplotype "T/A" of rs11674595/rs4851527 (adjusted OR = 0.73, 95% CI = 0.54-0.98, p = 0.037) and "T/C" of rs719250/rs3218896 (adjusted OR = 1.61, 95% CI = 1.10-2.36, p = 0.015) exhibited protective and risky effects for Uygur individuals on cervical cancer development, respectively. CONCLUSION: Our data first shed the new light on the associations of IL1R2 polymorphisms with cervical cancer susceptibility among Uygur females. These results are supposed to facilitate the tumorigenesis genetic research among Chinese minorities.

The relationship between apolipoprotein E gene ε2/ε3/ε4 polymorphism and breast cancer risk: a systematic review and meta-analysis.

OBJECTIVE: We conducted a systematic review and meta-analysis aiming to assess the relationship between apolipoprotein E (APOE) gene ε2/ε3/ε4 polymorphism and breast cancer risk. METHODS: Yun-Long Liu and Hao-Min Zhang independently completed literature retrieval and data collection, and statistical analyses were performed by Stata. Individual odds ratio (OR) and 95% confidence interval (CI) were pooled in a random-effects model using the DerSimonian-Laird method. Heterogeneity was evaluated by I (2) statistic at a significance level of 50%. Publication bias was assessed by Egger's test. RESULTS: Eleven articles including 2,074 breast cancer patients and 2,372 controls were summarized. Using the most common allele ε3 as a reference, the ε2 (OR =0.87, 95% CI =0.72-1.05, P=0.154, I (2)=0.0%) and ε4 (OR =1.07, 95% CI =0.80-1.42, P=0.654, I (2)=71.8%) alleles were not found to be significantly associated with breast cancer risk in the overall analyses. Subgroup analyses revealed that the comparison of allele ε4 with ε3 was significant in Asians (OR =1.58, 95% CI =1.17-6.32, P=0.003, I (2)=12.1%) and in studies that used the restriction fragment length polymorphism (RFLP) genotyping method (OR =1.27; 95% CI =1.01-1.61, P=0.045, I (2)=34.3%), and was marginally significant in hospital-based studies (OR =1.33; 95% CI =0.98-1.79, P=0.065, I (2)=30.2%), without heterogeneity. Moreover, the presence of the ε2 allele was significantly associated with breast cancer in small studies (total sample size <500) (OR =0.73, 95% CI =0.54-1.00, P=0.052, I (2)=0.0%) without heterogeneity. The Egger's test indicated low probabilities of publication bias. CONCLUSION: We observed a significant association between APOE gene ε4 allele and breast cancer risk in Asian populations. Moreover, the findings of our subgroup analyses suggest that source of controls, genotyping platform, and sample size might be the potential causes of heterogeneity.

Durable Microstructured Surfaces: Combining Electrical Conductivity with Superoleophobicity.

In this study, electrically conductive and superoleophobic polydimethylsiloxane (PDMS) has been fabricated through embedding Ag flakes (SFs) and Ag nanowires (SNWs) into microstructures of the trichloroperfluorooctylsilane (FDTS)-blended PDMS elastomer. Microstructured PDMS surfaces became conductive at the percolation surface coverage of 3.0 × 10(-2) mg/mm(2) for SFs; the highest conductivity was 1.12 × 10(5) S/m at the SFs surface coverage of 6.0 × 10(-2) mg/mm(2). A significant improvement of the conductivity (increased 3 times at the SNWs fraction of 11%) was achieved by using SNWs to replace some SFs because of the conductive pathways from the formed SNWs networks and its connections with SFs. These conductive fillers bonded strongly with microstructured FDTS-blended PDMS and retained surface properties under the sliding preload of 8.0 N. Stretching tests indicated that the resistance increased with the increasing strains and returned to its original state when the strain was released, showing highly stretchable and reversible electrical properties. Compared with SFs embedded surfaces, the resistances of SFs/SNWs embedded surfaces were less dependent on the strain because of bridging effect of SNWs. The superoleophobicity was achieved by the synergetic effect of surface modification through blending FDTS and the microstructures transferred from sand papers. The research findings demonstrate a simple approach to make the insulating elastomer to have the desired surface oleophobicity and electrical conductivity and help meet the needs for the development of conductive devices with microstructures and multifunctional properties.

Berberine regulates neurite outgrowth through AMPK-dependent pathways by lowering energy status.

As a widely used anti-bacterial agent and a metabolic inhibitor as well as AMP-activated protein kinase (AMPK) activator, berberine (BBR) has been shown to cross the blood-brain barrier. Its efficacy has been investigated in various disease models of the central nervous system. Neurite outgrowth is critical for nervous system development and is a highly energy-dependent process regulated by AMPK-related pathways. In the present study, we aimed to investigate the effects of BBR on AMPK activation and neurite outgrowth in neurons. The neurite outgrowth of primary rat cortical neurons at different stages of polarization was monitored after exposure of BBR. Intracellular energy level, AMPK activation and polarity-related pathways were also inspected. The results showed that BBR suppressed neurite outgrowth and affected cytoskeleton stability in the early stages of neuronal polarization, which was mediated by lowered energy status and AMPK activation. Liver kinase B1 and PI3K-Akt-GSK3ß signaling pathways were also involved. In addition, mitochondrial dysfunction and endoplasmic reticulum stress contributed to the lowered energy status induced by BBR. This study highlighted the knowledge of the complex activities of BBR in neurons and corroborated the significance of energy status during the neuronal polarization.

MnTM-4-PyP modulates endogenous antioxidant responses and protects primary cortical neurons against oxidative stress.

AIMS: Oxidative stress is a direct cause of injury in various neural diseases. Manganese porphyrins (MnPs), a large category of superoxide dismutase (SOD) mimics, shown universally to have effects in numerous neural disease models in vivo. Given their complex intracellular redox activities, detailed mechanisms underlying the biomedical efficacies are not fully elucidated. This study sought to investigate the regulation of endogenous antioxidant systems by a MnP (MnTM-4-PyP) and its role in the protection against neural oxidative stress. METHODS: Primary cortical neurons were treated with MnTM-4-PyP prior to hydrogen peroxide-induced oxidative stress. RESULTS: MnTM-4-PyP increased cell viability, reduced intracellular level of reactive oxygen species, inhibited mitochondrial apoptotic pathway, and ameliorated endoplasmic reticulum function. The protein levels and activities of endogenous SODs were elevated, but not those of catalase. SOD2 transcription was promoted in a transcription factor-specific manner. Additionally, we found FOXO3A and Sirt3 levels also increased. These effects were not observed with MnTM-4-PyP alone. CONCLUSION: Induction of various levels of endogenous antioxidant responses by MnTM-4-PyP has indispensable functions in its protection for cortical neurons against hydrogen peroxide-induced oxidative stress.

Confined growth of poly(butylene succinate) in its miscible blends with poly(vinylidene fluoride): morphology and growth kinetics.

The morphology and confined crystallization behavior of poly(butylene succinate) (PBS) in miscible poly(vinylidene fluoride) (PVDF)/PBS blends has been studied using differential scanning calorimetry (DSC) and optical and atomic force microscopy (OM and AFM). It was found that PBS crystal lamellae nucleated and grew confined inside the matrix of PVDF spherulites. Crystallized PBS domains grow with an ellipsoidal outline within PVDF spherulites formed at a relatively high PVDF crystallization temperature (T(c,PVDF)), while circular domains, engulfing several PVDF spherulites, are seen when growing in the PVDF spherulites created at lower T(c,PVDF). The growth kinetics of PBS confined in the PVDF matrix was investigated under various conditions. The growth rate of PBS (G(PBS)) increases with decreasing crystallization temperature and increasing PBS content under a given PVDF crystallization temperature (T(c,VDF)). For T(c,PVDF) above 145 °C, G(PBS) decreases with T(c,PVDF) for both 50:50 and 30:70 PVDF/PBS blends. However, for T(c,PVDF) below 145 °C, 50:50 and 30:70 PVDF/PBS blends exhibit the opposite G(PBS) trend; that is, G(PBS) for the 50:50 blend decreases with decreasing T(c,PVDF), while for the 30:70 PVDF/PBS blend G(PBS) increases with decreasing T(c,PVDF). It is shown that this behavior cannot be associated with the effect of crossing the boundary of smaller PVDF spherulites formed at a lower temperature. Rather, the behavior appears to be related to the interleaving growth of PBS lamellae among PVDF lamellae or between bundles of PVDF lamellae (fibrils), as in situ AFM observation shows. It is found that the interconnectedness of the molten pockets within the PVDF spherulites, which depends on the PVDF crystallization temperature, is an important factor determining the growth kinetics of PBS confined within the PVDF scaffold.