Retraction of "Effect of C-phycocyanin on HDAC3 and miRNA-335 in Alzheimer's disease".

[This retracts the article DOI: 10.1515/tnsci-2020-0101.].

Differential expression of microRNAs in diapause and non-diapause gonads of Aspongopus chinensis Dallas (Hemiptera: Dinidoridae): implications for reproductive control.

Aspongopus chinensis Dallas, 1851 (Hemiptera: Dinidoridae), an edible and medicinal insect, usually found in China and Southeast Asia, offers substantial potential for various applications. The reproductive cycle of this particular insect occurs annually because of reproductive diapause, leading to inadequate utilization of available natural resources. Despite its considerable ecological importance, the precise mechanisms underlying diapause in A. chinensis are not yet well understood. In this study, we conducted an analysis of comparing the microRNA (miRNA) regulation in the diapause and non-diapause gonads of A. chinensis and identified 303 differentially expressed miRNAs, among which, compared with the diapause group, 76 miRNAs were upregulated and 227 miRNAs downregulated. The results, regarding the Enrichment analysis of miRNA-targeted genes, showed their involvement in several essential biological processes, such as lipid anabolism, energy metabolism, and gonadal growth. Interestingly, we observed that the ATP-binding cassette pathway is the only enriched pathway, demonstrating the capability of these targeted miRNAs to regulate the reproductive diapause of A. chinensis through the above essential pathway. The current study provided the role of gonadal miRNA expression in the control of reproductive diapause in A. chinensis, the specific regulatory mechanism behind this event remained unknown and needed more investigation.

Combining Bone Collagen Material with hUC-MSCs for Applicationto Spina Bifida in a Rabbit Model.

Spina bifida is one of the neural tube defects, with a high incidence in human birth defects, which seriously affects the health and quality of life of patients. In the treatment of bone defects, the source of autologous bone is limited and will cause secondary damage to the patient. At the same time, since the bone tissue in animals needs to play a variety of biological functions, its complex structure cannot be replaced by a single material. The combination of mechanical materials and biological materials has become a common choice. Human umbilical cord mesenchymal stem cells (hUC-MSCs) have the advantages of easy access, rapid proliferation, low immunogenicity, and no ethical issues. It is often used in the clinical research of tissue regeneration and repair. Therefore, in this study, we established a spina bifida model using Japanese white rabbits. This model was used to screen the best regenerative repair products for congenital spina bifida, and to evaluate the safety of regenerative repair products. The results showed that the combination of hUC-MSCs with collagen material had better regeneration effect than collagen material alone, and had no negative impact on the health of animals. This study provides a new idea for the clinical treatment of spina bifida, and also helps to speed up the research progress of regenerative repair products.

Combining Bone Collagen Matrix with hUC-MSCs for Application to Alveolar Process Cleft in a Rabbit Model.

BACKGROUND: Most materials used clinically for filling severe bone defects either cannot induce bone re-generation or exhibit low bone conversion, therefore, their therapeutic effects are limited. Human umbilical cord mesenchymal stem cells (hUC-MSCs) exhibit good osteoinduction. However, the mechanism by which combining a heterogeneous bone collagen matrix with hUC-MSCs to repair the bone defects of alveolar process clefts remains unclear. METHODS: A rabbit alveolar process cleft model was established by removing the bone tissue from the left maxillary bone. Forty-eight young Japanese white rabbits (JWRs) were divided into normal, control, material and MSCs groups. An equal volume of a bone collagen matrix alone or combined with hUC-MSCs was implanted in the defect. X-ray, micro-focus computerized tomography (micro-CT), blood analysis, histochemical staining and TUNEL were used to detect the newly formed bone in the defect area at 3 and 6 months after the surgery. RESULTS: The bone formation rate obtained from the skull tissue in MSCs group was significantly higher than that in control group at 3 months (P < 0.01) and 6 months (P < 0.05) after the surgery. The apoptosis rate in the MSCs group was significantly higher at 3 months after the surgery (P < 0.05) and lower at 6 months after the surgery (P < 0.01) than those in the normal group. CONCLUSIONS: Combining bone collagen matrix with hUC-MSCs promoted the new bone regeneration in the rabbit alveolar process cleft model through promoting osteoblasts formations and chondrocyte growth, and inducing type I collagen formation and BMP-2 generation.

Active bone material containing modified recombinant human bone morphogenetic protein-2 induces bone regeneration in rabbit spina bifida.

This study focuses on spina bifida, which is a high incidence among the current clinical manifestations of human birth defects. Because in the treatment of bone defects, the source of autologous bone is limited and it is easy to cause secondary injury to the patient. At the same time, since the bone tissue in animals needs to perform a variety of biological functions, its complex structure cannot be replaced by a single material. Therefore, in this study, we used Japanese white rabbits to establish an animal model similar to human congenital spina bifida. The established animal model is used to screen the best regenerative repair products for the treatment of congenital spondylolisthesis defects, and to evaluate the safety of regenerative repair products. The results show that bone morphogenetic protein (BMP)-2 combined with collagen material has a better regeneration effect than collagen material alone, and it did not negatively affect the health of animals. This study is not only suitable for the screening of large-scale biomaterials, accelerating the research progress of regenerative repair products, but also conducive to the research on the mechanism of regeneration and repair of various materials.

Smurf participates in Helicoverpa armigera diapause by regulating the transforming growth factor-ß signaling pathway.

Diapause, an important strategy used by insects to avoid adverse environments, is regulated by various cell signaling pathways. The results of our previous studies demonstrated that the transforming growth factor-ß (TGF-ß) signaling pathway regulated pupal diapause in Helicoverpa armigera, which was accompanied by downregulation of proteins in TGF-ß signaling. However, to date the mechanism underlying this phenomenon remains unknown. Here, we cloned the E3 ubiquitin ligases gene Smurf. In vitro experiments showed that Smurf directly bound to TGF-ß receptor type I (TGFßRI) and Smad2. Overexpressing Smurf promoted ubiquitination of TGFßRI and Smad2, thereby downregulating their protein levels. Conversely, silencing of the Smurf gene suppressed ubiquitination of TGFßRI and Smad2 thereby increasing their protein levels. Results from in vivo co-immunoprecipitation assays revealed that the binding of Smurf to TGFßRI or Smad2 was stronger in diapause pupae than in nondiapause pupae. Injection of Smurf inhibitor A01 into diapause pupae markedly upregulated expression of TGFßRI and Smad2 proteins, leading to resumption of development in diapause pupae. Taken together, these findings suggested that ubiquitin ligase E3 Smurf participated in H. armigera diapause by regulating TGF-ß signaling, and thus could be playing a crucial role in insect diapause.

Triggering Receptor Expressed on Myeloid Cells 2 Protects Dopaminergic Neurons by Promoting Autophagy in the Inflammatory Pathogenesis of Parkinson's Disease.

Parkinson's disease is a neurodegenerative disorder with an inflammatory response as the core pathogenic mechanism. Previous human genetics findings support the view that the loss of TREM2 function will aggravate neurodegeneration, and TREM2 is one of the most highly expressed receptors in microglia. However, the role of TREM2 in the inflammatory mechanism of PD is not clear. In our study, it was found both in vivo and in vitro that the activation of microglia not only promoted the secretion of inflammatory factors but also decreased the level of TREM2 and inhibited the occurrence of autophagy. In contrast, an increase in the level of TREM2 decreased the expression of inflammatory factors and enhanced the level of autophagy through the p38 MAPK/mTOR pathway. Moreover, increased TREM2 expression significantly decreased the apoptosis of dopaminergic (DA) neurons and improved the motor ability of PD mice. In summary, TREM2 is an important link between the pathogenesis of PD and inflammation. Our study provides a new view for the mechanism of TREM2 in PD and reveals TREM2 as a potential therapeutic target for PD.

Chromosomal-Level Genome Assembly of a True Bug, Aspongopus chinensis Dallas, 1851 (Hemiptera: Dinidoridae).

The true bug, Aspongopus chinensis Dallas, 1851 (Hemiptera: Dinidoridae), is a fascinating insect with prolonged diapause and medicinal properties but also a notorious pest. However, because of the lack of genomic resources, an in-depth understanding of its biological characteristics is lacking. Here, we report the first genome assembly of A. chinensis anchored to 10 pseudochromosomes, which was achieved by combining PacBio long reads and Hi-C sequencing data. This chromosome-level genome assembly was 1.55 Gb in size with a scaffold N50 of 156 Mb. The benchmarking universal single-copy ortholog (BUSCO) analysis of the assembly captured 96.6% of the BUSCO genes. A total of 686,888,052 bp of repeat sequences, 18,511 protein-coding genes, and 1,749 noncoding RNAs were annotated. By comparing the A. chinensis genome with that of 8 homologous insects and 2 model organisms, 213 rapidly evolving gene families were identified, including 83 expanded and 130 contracted gene families. The functional enrichment of Gene Ontology and KEGG pathways showed that the significantly expanded gene families were primarily involved in metabolism, immunity, detoxification, and DNA/RNA replication associated with stress responses. The data reported here shed light on the ecological adaptation of A. chinensis and further expanded our understanding of true bug evolution in general.

Repair of alveolar cleft bone defects in rabbits by active bone particles containing modified rhBMP-2.

Objective: A model of alveolar cleft phenotype was established in rabbits to evaluate the effect of active bone particles containing modified rhecombinant human BMP-2 on the repair of the alveolar cleft. Methods: 2-month-old Japanese white rabbits were selected and randomly divided into four groups: normal, control, material and BMP groups. Blood biochemical analysis, skull tomography (microfocus computerized tomography), and histological and immunohistochemical staining analysis of paraffin sections were performed 3  and 6 months after operation. Results: Both types of collagen particles showed good biocompatibility and promoted bone regeneration. The effect of active bone particles on bone repair and regeneration was better than that of bone collagen particles. Conclusions: Active bone particles containing modified rhecombinant human BMP-2 can be used for incisors regeneration.

MicroRNA-3473b regulates the expression of TREM2/ULK1 and inhibits autophagy in inflammatory pathogenesis of Parkinson disease.

Parkinson disease (PD) is a neurodegenerative disease characterized by selective loss of dopaminergic (DA) neurons in the midbrain. The regulatory role of a variety of microRNAs in PD has been confirmed, and our study is the first to demonstrate that miR-3473b is involved in the regulation of PD. In vitro, an miR-3473b inhibitor can inhibit the secretion of inflammatory factors (TNF-α and IL-1ß) in moues microglia cell line (BV2) cells induced by lipopolysaccharide (LPS) and promote autophagy in BV2 cells. In vivo, miR-3473b antagomir can inhibit the activation of substantia nigra pars compacta (SNpc) microglia of C57BL/6 mice induced by 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and promote autophagy. Deletion of TREM2, one of the most highly expressed receptors in microglia, leads to the occurrence and development of PD. ULK1 is a component of the Atg1 complex. Deletion of ULK1 aggravates the pathological reaction of PD. TREM2 and ULK1 are predicted potential targets of miR-3473b by Targetscan. Then, the results of our experiments indicate that transfection with a miR-3473b mimic can inhibit the expression of TREM2 and ULK1. Data from a double luciferase experiment indicate that the 3'-UTR of TREM2, but not ULK1, is the direct target of miR-3473b. Then we aim to investigate the regulation of TREM2 and ULK1 in PD. We found that the expression of p-ULK1 was significantly increased via up-regulation of TREM2. The increased expression of p-ULK1 can promote autophagy and inhibit the expression of inflammatory factors. The regulation of ULK1 by miR-3473b may be accomplished indirectly through TREM2. Thus, miR-3473b may regulate the secretion of proinflammatory mediators by targeting TREM2/ULK1 expression to regulate the role of autophagy in the pathogenesis of inflammation in Parkinson's disease, suggesting that mir-3473b may be a potential therapeutic target to regulate the inflammatory response in PD.

Active bone material containing modified recombinant human bone morphogenetic protein 2 induces bone regeneration in the alveolar process cleft in rabbits.

The clinical application of most materials used to fill severe bone defects is limited owing to the insufficient ability of such materials to induce bone regeneration over a long repair period. The purpose of this study was to establish a model for the alveolar process cleft in rabbits to evaluate the effect of active bone material in bone defect repair. The active bone material used in this study is a new bone repair material composed of a heterogeneous collagen membrane implanted with modified recombinant human bone morphogenetic protein 2. This proposed active bone material can specifically bind to collagen. Twenty-four young Japanese white rabbits (JWRs) were selected and randomly divided into four groups (normal, control, material, and bone morphogenetic protein groups). The alveolar process cleft model was established by removing an equal volume bone at the left maxillary position. Blood samples were collected from the JWRs 3 and 6 months after the surgery to evaluate the biocompatibility of the active bone materials. Subsequently, the skull model was established, and the appearance was observed. Imaging methods (including X-ray examination and micro-computerized tomography scanning), tissue staining, and immunohistochemistry were employed for the evaluation. The bone collagen material and active bone material exhibited high biocompatibility. In addition, the ability of the active bone material to induce bone repair and regeneration was higher than that of the bone collagen material. The active bone material exhibited satisfactory bone regeneration performance in rabbits, indicating its potential as an active material for repairing congenital alveolar process clefts in humans.

Effect of C-phycocyanin on HDAC3 and miRNA-335 in Alzheimer's disease.

BACKGROUND: Amyloid-beta (Aß) plaque deposits and neurofibrillary tangles containing tau proteins are the key pathognomonic manifestations of Alzheimer's disease (AD). Lack of holistic drugs for AD has reinvigorated enthusiasm in the natural product-based therapies. In this study, our idea to decipher the beneficial effects of C-phycocyanin (CPC) in the management of AD is buoyed by its multifaceted and holistic therapeutic effects. METHODS: We evaluated the effect of CPC treatment on epigenetic factors and inflammatory mediators in a mouse with oligomeric Aß1-42-induced AD. Besides, the cognitive function was evaluated by the spatial memory performance on a radial arm maze. RESULTS: The results showed cognitive deficit in the mice with AD along with upregulated HDAC3 expression and diminished miRNA-335 and brain-derived neurotrophic factor (BDNF) expressions. In addition, inflammation was provoked (manifested by increased interleukins (IL)-6 and IL-1ß) and neuronal apoptosis was accelerated (indicated by increased Bax, caspase-3, and caspase-9 along with decreased Bcl2) in the hippocampus of the mice with AD. Interestingly, CPC treatment in the mice with AD improved spatial memory performance and decreased the perturbations in the epigenetic and inflammatory biofactors. CONCLUSION: These results underscore that mitigation of inflammation via regulation of epigenetic factors might be the key pathway underlying the ameliorative effect of CPC against the aberrations in AD. Our findings provide the rationale for considering CPC as a viable therapeutic option in the management of AD.

Repair of alveolar cleft bone defects by bone collagen particles combined with human umbilical cord mesenchymal stem cells in rabbit.

BACKGROUND: Alveolar cleft is a type of cleft lip and palate that seriously affects the physical and mental health of patients. In this study, a model of the alveolar cleft phenotype was established in rabbits to evaluate the effect of bone collagen particles combined with human umbilical cord mesenchymal stem cells (HUC-MSCs) on the repair of alveolar cleft bone defects. METHODS: A model of alveolar clefts in rabbits was established by removing the incisors on the left side of the upper jaw bone collagen particles combined with HUC-MSCs that were then implanted in the defect area. Blood biochemical analysis was performed 3 months after surgery. Skull tissues were harvested for gross observation, and micro-focus computerised tomography (micro-CT) analysis. Tissues were harvested for histological and immunohistochemical staining. The experiments were repeated 6 months after surgery. RESULTS: Bone collagen particles and HUC-MSCs showed good biocompatibility. Bone collagen particles combined with HUC-MSCs were markedly better at inducing bone repair and regeneration than bone collagen particles alone. CONCLUSIONS: Combining HUC-MSCs with bone collagen particles provides a simple, rapid and suitable method to fill a bone defect site and treat of alveolar cleft bone defects.

Adipose-derived mesenchymal stem cell transplantation promotes adult neurogenesis in the brains of Alzheimer's disease mice.

In the present study, we transplanted adipose-derived mesenchymal stem cells into the hippocampi of APP/PS1 transgenic Alzheimer's disease model mice. Immunofluorescence staining revealed that the number of newly generated (BrdU(+)) cells in the subgranular zone of the dentate gyrus in the hippocampus was significantly higher in Alzheimer's disease mice after adipose-derived mesenchymal stem cell transplantation, and there was also a significant increase in the number of BrdU(+)/DCX(+) neuroblasts in these animals. Adipose-derived mesenchymal stem cell transplantation enhanced neurogenic activity in the subventricular zone as well. Furthermore, adipose-derived mesenchymal stem cell transplantation reduced oxidative stress and alleviated cognitive impairment in the mice. Based on these findings, we propose that adipose-derived mesenchymal stem cell transplantation enhances endogenous neurogenesis in both the subgranular and subventricular zones in APP/PS1 transgenic Alzheimer's disease mice, thereby facilitating functional recovery.

Stimuli responsive elastin-like polypeptides and applications in medicine and biotechnology.

Elastin-like polypeptides (ELPs) are artificial biopolymers composed of the pentapeptide repeat Val-Pro-Gly-Xaa-Gly. They are a class of stimuli responsive biopolymers exhibiting an inverse temperature transition, which are particularly attractive in biological applications. In this paper, the methods of synthesizing ELPs and the applications in medicine and biotechnology such as purification of fusion proteins, drug delivery, and tissue engineering are reviewed. In addition, further perspective will be presented.

Intracerebral transplantation of adipose-derived mesenchymal stem cells alternatively activates microglia and ameliorates neuropathological deficits in Alzheimer's disease mice.

Recent studies suggest that transplantation of mesenchymal stem cells might have therapeutic effects in preventing pathogenesis of several neurodegenerative disorders. Adipose-derived mesenchymal stem cells (ADSCs) are a promising new cell source for regenerative therapy. However, whether transplantation of ADSCs could actually ameliorate the neuropathological deficits in Alzheimer's disease (AD) and the mechanisms involved has not yet been established. Here, we evaluated the therapeutic effects of intracerebral ADSC transplantation on AD pathology and spatial learning/memory of APP/PS1 double transgenic AD model mice. Results showed that ADSC transplantation dramatically reduced ß-amyloid (Aß) peptide deposition and significantly restored the learning/memory function in APP/PS1 transgenic mice. It was observed that in both regions of the hippocampus and the cortex there were more activated microglia, which preferentially surrounded and infiltrated into plaques after ADSC transplantation. The activated microglia exhibited an alternatively activated phenotype, as indicated by their decreased expression levels of proinflammatory factors and elevated expression levels of alternative activation markers, as well as Aß-degrading enzymes. In conclusion, ADSC transplantation could modulate microglial activation in AD mice, mitigate AD symptoms, and alleviate cognitive decline, all of which suggest ADSC transplantation as a promising choice for AD therapy. This manuscript is published as part of the International Association of Neurorestoratology (IANR) supplement issue of Cell Transplantation.

Huperzine A promotes hippocampal neurogenesis in vitro and in vivo.

Huperzine A (Hup A) is a lycopodium alkaloid from Huperzia serrata, which has been used as a therapeutic agent in several neurological disorders. Despite the diverse pharmacological activities Hup A has, its role in hippocampal neurogenesis remains to be established. This study showed that Hup A not only promoted the proliferation of cultured mouse embryonic hippocampal neural stem cells (NSCs), but also increased the newly generated cells in the subgranular zone (SGZ) of the hippocampus in adult mice. Furthermore, the in vitro findings indicated that low concentrations of Hup A stimulated the proliferation of cultured NSCs, whereas extremely high concentration of it decreased the cell proliferation. Hup A activated mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) signaling pathway, which was a well-known regulator of biological processes including cell proliferation and differentiation. ERK inhibitor dramatically inhibited the proliferative effect of Hup A on NSCs. Administration of Hup A to adult mice significantly enhanced the cell proliferation in dentate gyrus of hippocampus, and increased the remaining newborn cells 4 weeks after the drug administration. Moreover, the newly generated BrdU(+)/NeuN(+) neurons were also increased by Hup A treatment. These findings suggest a novel role of Hup A in neurogenesis and provide a new insight into its therapeutic effects in neurological disorders via a neurogenesis-related mechanism.

Positive charge of chitosan retards blood coagulation on chitosan films.

In this study, a series of chitosan films with different protonation degrees were prepared by deacidification with NaOH aqueous or ethanol solutions. The films were then used as a model to investigate the effects of the positive charge of chitosan on blood coagulation. The results showed that the positive charge of chitosan acted as a double-edged sword, in that it promoted erythrocyte adhesion, fibrinogen adsorption, and platelet adhesion and activation, but inhibited activation of the contact system. In contrast to prevailing views, we found that the positive charge of chitosan retarded thrombin generation and blood coagulation on these films. At least two reasons were responsible for this phenomenon. First, the positive charge inhibited the contact activation, and second, the positive charge could not significantly promote the activation of non-adherent platelets in the bulk phase during the early stage of coagulation. The present findings improve our understanding of the events leading to blood coagulation on chitosan films, which will be useful for the future development of novel chitosan-based hemostatic devices.

Protective effect of edaravone against Alzheimer's disease-relevant insults in neuroblastoma N2a cells.

Oxidative stress has been demonstrated to be involved in the pathogenesis of Alzheimer's disease (AD). Thus, antioxidant therapy may represent a promising avenue for the treatment of AD. Edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one) is a potent free radical scavenger and has been shown to provide neuroprotection in both animal models of cerebral ischemia and stroke patients. In the present study, we investigated the protective effect of edaravone against AD-relevant insults in neuroblastoma N2a cells and explored the potential mechanisms involved. N2a/Swe.Δ9 cells were used as the AD model cells, which exhibited reduced cell viability, increased apoptosis and oxidative stress as well as decreased mitochondrial membrane potential compared with N2a/Wt cells. All of these phenotypes were significantly reversed by edaravone treatment. Edaravone treatment significantly elevated cell viability, reduced apoptotic rate, attenuated oxidative stress and improved mitochondrial membrane potential in N2a/Swe.Δ9 cells. Furthermore, edaravone treatment inhibited mitochondria-dependent apoptosis pathways in N2a/Swe.Δ9 cells through decreasing the Bax/Bcl-2 ratio, attenuating cytochrome c release and suppressing the activation of caspase-3. These results demonstrate that edaravone provides neuroprotection in an AD-related in vitro model and therefore, may be a potential complement for AD therapy.

Mitochondrial modulation of store-operated Ca(2+) entry in model cells of Alzheimer's disease.

Mitochondrial malfunction and calcium dyshomeostasis are early pathological events considered as important features of the Alzheimer's disease (AD) brain. Recent studies have suggested mitochondrion as an active regulator of Ca(2+) signaling based on its calcium buffering capacity. Herein, we investigated the mitochondrial involvement in the modulation of store-operated calcium entry (SOCE) in neural 2a (N2a) transgenic AD model cells. Results showed that SOCE was significantly depressed in N2a cells transfected with wild-type human APP695 (N2a APPwt) compared with empty vector control (N2a WT) cells. Pharmacological manipulation with mitochondrial function blockers, such as FCCP, RuR, or antimycin A/oligomycin, could inhibit mitochondrial calcium handling, and then impair SOCE pathway in N2a WT cells. Furthermore, mitochondria of N2a APPwt cells exhibited more severe swelling in response to Ca(2+), which is an indication of mitochondrial membrane permeability transition (MPT), than the wild-type controls. Additionally, treatment with cyclosporin A, a potent inhibitor of cyclophilin D, which can block MPT, could significantly restore the attenuated SOCE in N2a APPwt cells. Therefore, inhibition of cyclophilin D might be a therapeutic strategy for Alzheimer's disease.