Identification of hub genes in bladder transitional cell carcinoma through ceRNA network construction integrated with gene network analysis.

Bladder transitional cell carcinoma (BTCC) forms more than 90% of bladder cancer cases. It brings challenges to the early diagnosis and therapy of BTCC, due to lack of efficient screening biomarkers. We used weighted gene co-expression network analysis (WGCNA) combined competing endogenous RNA (ceRNA) network construction depending on TCGA datasets to investigate potential hub genes and regulatory pathways associated with occurrence and progression of BTCC. We further used real-time polymerase chain reaction (RT-PCR) to validate the relative expression genes correlated with BTCC. By WGCNA, the gene co-expression module with 11 genes was found corelated with BTCC tumour stage and prognosis after survival analyses. Ultimately, we put 100 highly stage-related genes into the above constructed ceRNA network and then constructed another new network. Among them, all elements in AC112721.1/LINC00473/AC128709.1-hsa-mir-195-RECK and LINC00460-hsa-mir-429-ZFPM2 axes were simultaneously corelated with overall survival. RT-PCR showed that AKAP12 was downregulated in tumour tissues. The hub genes screened out in the present study may provide ideals for further treatment on BTCC.

Identifying biomarkers of heterogeneity and transplantation efficacy in retinal pigment epithelial cells.

Transplantation of retinal pigment epithelial (RPE) cells holds great promise for patients with retinal degenerative diseases, such as age-related macular degeneration. In-depth characterization of RPE cell product identity and critical quality attributes are needed to enhance efficacy and safety of replacement therapy strategies. Here, we characterized an adult RPE stem cell-derived (RPESC-RPE) cell product using bulk and single-cell RNA sequencing (scRNA-seq), assessing functional cell integration in vitro into a mature RPE monolayer and in vivo efficacy by vision rescue in the Royal College of Surgeons rats. scRNA-seq revealed several distinct subpopulations in the RPESC-RPE product, some with progenitor markers. We identified RPE clusters expressing genes associated with in vivo efficacy and increased cell integration capability. Gene expression analysis revealed lncRNA (TREX) as a predictive marker of in vivo efficacy. TREX knockdown decreased cell integration while overexpression increased integration in vitro and improved vision rescue in the RCS rats.

[Effect of LINC00174 on the Malignant Proliferation of Multiple Myeloma Cells and Its Related Mechanism].

OBJECTIVE: To explore the biological function of LINC00174 in multiple myeloma (MM). METHODS: Real-time quantitative polymerase chain reaction (RT-qPCR) was used to detect the expressions of LINC00174 and miR-150 in peripheral blood of MM patients and MM cell lines. EdU staining and flow cytometry were used to detect the effects of LINC00174 and miR-150 on the proliferation and apoptosis of MM cells. Western blot was used to detect the expressions of proliferation marker nuclear-related antigen Ki67, apoptosis-related protein cleaved caspase-3 and transcription factor forkhead box protein P1 (FOXP1). Bioinformatics and dual-luciferase reporter assay were used to verify the targeting relationship between LINC00174 and miR-150 and the targeting relationship between miR-150 and FOXP1. RESULTS: The level of LINC00174 was significantly increased in peripheral blood of MM patients and MM cell lines (P <0.05). Compared with NC-siRNA group, the expression of LINC00174 was significantly reduced in LINC00174-siRNA group, the proliferation of U266 cells was reduced, the apoptosis rate was significantly increased, the level of Ki67 protein was reduced, and the level of cleaved caspase-3 protein was increased (all P <0.05). LINC00174 targeted regulation of the expression of miR-150. Compared with LINC00174-siRNA+NC inhibitor group, the expression of miR-150 in U266 cells in LINC00174-siRNA+miR-150 inhibitor group was significantly reduced, the cell proliferation was enhanced, the apoptosis rate was reduced, the level of Ki67 protein was increased, and the level of cleaved caspase-3 was decreased (all P <0.05). FOXP1 is the target gene of miR-150. Compared with NC mimic group, the expression of FOXP1 protein in miR-150 mimic group was significantly reduced, the cell proliferation was reduced, the apoptosis rate was significantly increased, Ki67 protein level was decreased, and the level of cleaved caspase-3 was increased. Compared with miR-150 mimic + vector group, the expression of FOXP1 protein in miR-150 mimic + pcDNA-FOXP1 group was significantly increased, the cell proliferation was enhanced, the apoptosis rate was reduced, the level of Ki67 protein was increased, and the level of cleaved caspase-3 was decreased (all P <0.05). CONCLUSION: LINC00174 promotes the proliferation of MM cells and inhibits cell apoptosis by regulating the miR-150/ FOXP1 axis.

Recent Advances in Therapeutic Modalities Against Breast Cancer-Related Lymphedema: Future Epigenetic Landscape.

Background: Lymphedema is a significant postsurgical complication observed in the majority of breast cancer patients. These multifactorial etiopathogenesis have a significant role in the development of novel diagnostic/prognostic biomarkers and the development of novel therapies. This review aims to ascertain the epigenetic alterations that lead to breast cancer-related lymphedema (BCRL), multiple pathobiological events, and the underlying genetic predisposing factors, signaling cascades pertinent to the lapses in effective prognosis/diagnosis, and finally to develop a suitable therapeutic regimen. Methods and Results: We have performed a literature search in public databases such as PubMed, Medline, Google Scholar, National Library of Medicine and screened several published reports. Search words such as epigenetics to induce BCRL, prognosis/diagnosis, primary lymphedema, secondary lymphedema, genetic predisposing factors for BRCL, conventional therapies, and surgery were used in these databases. This review described several epigenetic-based predisposing factors and the pathophysiological consequences of BCRL, which affect the overall quality of life, and the interplay of these events could foster the progression of lymphedema in breast cancer survivors. Prognosis/diagnostic and therapy lapses for treating BCRL are highly challenging due to genetic and anatomical variations, alteration in the lymphatic vessel contractions, and variable expression of several factors such as vascular endothelial growth factor (VEGF)-E and vascular endothelial growth factor receptor (VEGFR) in breast cancer survivors. Conclusion: We compared the efficacy of various conventional therapies for treating BCRL as a multidisciplinary approach. Further substantial research is required to decipher underlying signaling epigenetic pathways to develop chromatin-modifying therapies pertinent to the multiple etiopathogenesis to explore the correlation between the disease pathophysiology and novel therapeutic modalities to treat BCRL.

Clinicopathologic Profiles of Sporadic Late-Onset Nemaline Myopathy: Practical Importance of Anti-α-Actinin Immunostaining.

BACKGROUND AND OBJECTIVES: Sporadic late-onset nemaline myopathy (SLONM) is a treatable or otherwise fatal myopathy. Diagnosis of SLONM is still challenging, and no therapeutic consensus has been achieved. Here, we reported the clinicopathologic features and long-term follow-up data of SLONM in a Chinese cohort. METHODS: We performed a retrospective evaluation of clinical, pathologic, and treatment outcomes of 17 patients with SLONM diagnosed between March 1986 and April 2021 at our neuromuscular center. Immunohistochemistry (IHC) with antibodies against 5 Z-disc-associated proteins was performed in the muscle biopsies of SLONM to identify a potential pathologic marker in aid of diagnosis. In comparison, we also performed muscle IHC in patients with selective type II fiber atrophy (n = 22), neurogenic atrophy (n = 22), mitochondrial myopathy (n = 5), immune-mediated necrotizing myopathy (n = 5), and normal controls (n = 5). RESULTS: Most of the patients exhibited asymmetric limb muscles weakness (71%, 12/17) and neck extensor weakness (53%, 9/17). Immunofixation electrophoresis was performed in 11 patients, and 4 of them were identified with monoclonal gammopathy of undetermined significance (MGUS). EMG from 16 patients demonstrated a myopathic pattern with spontaneous activities in 69% (11/16) of them. Muscle MRI showed preferential involvement of paraspinal, gluteus minimus and medius, semimembranosus, and soleus muscles. Suspected nemaline bodies on modified Gomori trichrome were confirmed by IHC using anti-α-actinin antibody (100%, 17/17), anti-myotilin antibody (94%, 16/17), anti-desmin antibody (94%, 16/17), anti-α-B crystallin antibody (65%, 11/17), and anti-telethonin antibody (18%, 3/17) with various positive rates. Notably, anti-α-actinin IHC showed the highest percentage of strongly positive staining (77%, 13/17), being the only one without negative results. Moderate improvement following autologous stem cell transplantation (ASCT) was noted in 3/4 patients with MGUS; favorable outcomes were also achieved in 6/7 patients without MGUS, including 3 patients with complete recovery who were given a combined treatment of prednisone and another immunosuppressant. DISCUSSION: SLONM is a treatable myopathy with ASCT or traditional immunotherapy, especially when combined with steroids and immunosuppressants. Anti-α-actinin immunostaining is the most reliable pathologic marker to identify rod-bearing fibers, and it should be performed routinely in adult patients with undiagnosed nonnecrotic myopathies.

Modulation of MagR magnetic properties via iron-sulfur cluster binding.

Iron-sulfur clusters are essential cofactors found in all kingdoms of life and play essential roles in fundamental processes, including but not limited to respiration, photosynthesis, and nitrogen fixation. The chemistry of iron-sulfur clusters makes them ideal for sensing various redox environmental signals, while the physics of iron-sulfur clusters and its host proteins have been long overlooked. One such protein, MagR, has been proposed as a putative animal magnetoreceptor. It forms a rod-like complex with cryptochromes (Cry) and possesses intrinsic magnetic moment. However, the magnetism modulation of MagR remains unknown. Here in this study, iron-sulfur cluster binding in MagR has been characterized. Three conserved cysteines of MagR play different roles in iron-sulfur cluster binding. Two forms of iron-sulfur clusters binding have been identified in pigeon MagR and showed different magnetic properties: [3Fe-4S]-MagR appears to be superparamagnetic and has saturation magnetization at 5 K but [2Fe-2S]-MagR is paramagnetic. While at 300 K, [2Fe-2S]-MagR is diamagnetic but [3Fe-4S]-MagR is paramagnetic. Together, the different types of iron-sulfur cluster binding in MagR attribute distinguished magnetic properties, which may provide a fascinating mechanism for animals to modulate the sensitivity in magnetic sensing.

Impacts of Chemokine (C-X-C Motif) Receptor 2 C1208T Polymorphism on Cancer Susceptibility.

BACKGROUND: The CXC chemokines belong to a unique family of cytokines that participates in the progression and development of many malignant tumors. Evidence for the relationship between chemokine (C-X-C motif) receptor 2 (CXCR2) C1208T polymorphism and susceptibility to cancer remains inconsistent. METHODS: Odds ratios (ORs), 95% confidence intervals (CIs), and combined analysis were used to investigate the effect of CXCR2 variation on cancer risk. Gene Set Enrichment Analysis (GSEA) and enzyme-linked immunosorbent assay (ELISA) were also used to evaluate the expression of CXCR2 in prostate cancer (PCA). RESULTS: Across 11 case-control studies, 4,909 cases and 5,884 controls were involved in the current analysis. Individuals with a TT genotype were associated with increased risk of digestive cancer, compared to those with a TC+CC genotype (OR = 1.16, 95%CI = 1.02-1.31, P = 0.025). Individuals carrying the TT genotype had a 39% higher risk of urinary cancer than those carrying CC genotype (OR = 1.39, 95%CI = 1.04-1.87, P = 0.025). Individuals with a TT genotype showed a 56% augmented breast cancer risk, compared to those with a CC genotype (OR = 1.56, 95%CI = 1.03-2.35, P = 0.034). It was found that CXCR2 expression was downregulated in PCA. Compared with PCA subjects carrying the CC genotype, the expression of CXCR2 was decreased in patients with the TT genotype. CONCLUSIONS: The CXCR2 C1208T variation was associated with elevated risk of urinary, breast, and digestive cancer. However, the C1208T polymorphism was correlated with attenuated risk of lung cancer.

Declined expressions of vast mitochondria-related genes represented by CYCS and transcription factor ESRRA in skeletal muscle aging.

Age-related skeletal muscle deterioration (sarcopenia) has a significant effect on the elderly's health and quality of life, but the molecular and gene regulatory mechanisms remain largely unknown. It is necessary to identify the candidate genes related to skeletal muscle aging and prospective therapeutic targets for effective treatments. The age-line-related genes (ALRGs) and age-line-related transcripts (ALRTs) were investigated using the gene expression profiles of GSE47881 and GSE118825 from the Gene Expression Omnibus (GEO) database. The protein-protein interaction (PPI) networks were performed to identify the key molecules with Cytoscape, and Gene Set Enrichment Analysis (GSEA) was used to clarify the potential molecular functions. Two hub molecules were finally obtained and verified with quantitative real-time PCR (qRT-PCR). The results showed that the expression of mitochondria genes involved in mitochondrial electron transport, complex assembly of the respiratory chain, tricarboxylic acid cycle, oxidative phosphorylation, and ATP synthesis were down-regulated in skeletal muscle with aging. We further identified a primary hub gene of CYCS (Cytochrome C) and a key transcription factor of ESRRA (Estrogen-related Receptor Alpha) to be associated closely with skeletal muscle aging. PCR analysis confirmed the expressions of CYCS and ESRRA in gastrocnemius muscles of mice of different ages were significantly different, and decreased gradually with age. In conclusion, the main cause of skeletal muscle aging may be the systematically reduced expression of mitochondrial functional genes. The CYCS and ESRRA may play significant roles in the progression of skeletal muscle aging and serve as potential biomarkers for future diagnosis and treatment.

Cerebrotendinous xanthomatosis with peripheral neuropathy: a clinical and neurophysiological study in Chinese population.

BACKGROUND: Cerebrotendinous xanthomatosis (CTX) is an inborn disorder of bile acid metabolism caused by deficiency of sterol 27-hydroxylase (CYP27A1) gene. CTX-related peripheral neuropathy has rarely been discussed in Chinese population. Here, we reported 6 CTX cases and performed a literature review focused on CTX with neuropathy to summarize its clinical and neurophysiological features. METHODS: All clinical data of 6 CTX cases were collected, and 21 reported Chinese CTX patients (including this study) were reviewed and summarized. RESULTS: Clinical manifestations of 6 CTX cases showed great heterogeneity. Cognitive decline, spastic paraplegia, cerebellar ataxia and advanced bulbar palsy were common neurological disorders, often accompanied by non-neurological signs like xanthomas, cataract, diarrhea and pes cavus. Dentate nuclei hyperintensity with or without hyposignal is a valuable MRI hallmark. Pooling our patients and literature review together, peripheral neuropathy was predominant sensorimotor demyelinating type in Chinese population, with an evident length dependent pattern and increased vulnerability in motor nerves. Demyelinating and axonal degeneration tend to exist in severe neuropathy. Three novel mutations including c.1055C>A; c.432T>G; c.472T>G were identified in CYP27A1 and predicted to be pathogenic. Oral CDCA therapy could ameliorate some of the existing symptoms and provide clinical stability, but it could not cease disease progression completely. CONCLUSIONS: Our study broadens the phenotype and mutation spectrum of CTX. Patients with cognitive decline, spastic tetraparesis, cerebellar ataxia and bulbar palsy, should be highly suspicious of CTX even no xanthomas disclosed. Peripheral neuropathy was predominant sensorimotor demyelinating type in Chinese population, with mixed axonal and demyelinating type in severe cases. Three novel likely pathogenic mutations including c.1055C>A; c.432T>G; c.472T>G were identified in CYP27A1.

Stent retriever thrombectomy combined with long-term local thrombolysis for severe hemorrhagic cerebral venous sinus thrombosis.

Cerebral venous sinus thrombosis (CVST) is a rare disease associated with high disability and mortality rates. A subset of patients do not respond to standard anticoagulation therapy, leading to the progression of CVST with hemorrhagic stroke, which represents a major challenge for its treatment. Severe hemorrhagic (SH)-CVST is life-threatening due to large hematoma, edema and/or cerebral hernia. Anticoagulation or thrombolytic therapy alone may lead to further aggravation of the hematoma. Stent retriever thrombectomy combined with long-term local thrombolysis (SRT-LLT) has been used in certain centers for those refractory cases or patients with new intracranial hemorrhage. However, to date, no studies on SRT-LLT treatment specifically for SH-CVST have been performed. The aim of the present retrospective study was to specifically evaluate the effectiveness of SRT-LLT in SH-CVST. Between December 2013 and November 2018, SRT-LLT was performed at our center in 8 patients with hemorrhagic CVST who did not respond to intravenous anticoagulation. The clinical characteristics, results of the radiological evaluation, details on the surgical procedure and clinical outcomes were assessed. The patients were administered systemic intravenous anticoagulation as the initial treatment following admission. SRT-LLT was performed when their condition deteriorated with a high risk of a fatal outcome within a short time period. SRT-LLT was performed in 8 patients, with successful recanalization confirmed by angiography. In 4 of the patients, complete recanalization was achieved, whereas in the remaining 4, recanalization was partial. There were no intraoperative complications. Two patients developed rebleeding after surgery, but they all gradually recovered. There were no treatment-associated fatalities. Therefore, SRT-LLT appears to be a feasible, safe and effective option for SH-CVST and it may be used as rescue therapy for carefully selected patients with SH-CVST.

Development of a Refined Protocol for Trans-scleral Subretinal Transplantation of Human Retinal Pigment Epithelial Cells into Rat Eyes.

Degenerative retinal diseases such as age-related macular degeneration (AMD) are the leading cause of irreversible vision loss worldwide. AMD is characterized by the degeneration of retinal pigment epithelial (RPE) cells, which are a monolayer of cells functionally supporting and anatomically wrapping around the neural retina. Current pharmacological treatments for the non-neovascular AMD (dry AMD) only slow down the disease progression but cannot restore vision, necessitating studies aimed at identifying novel therapeutic strategies. Replacing the degenerative RPE cells with healthy cells holds promise to treat dry AMD in the future. Extensive preclinical studies of stem cell replacement therapies for AMD involve the transplantation of stem cell-derived RPE cells into the subretinal space of animal models, in which the subretinal injection technique is applied. The approach most frequently used in these preclinical animal studies is through the trans-scleral route, which is made difficult by the lack of direct visualization of the needle end and can often result in retinal damage. An alternative approach through the vitreous allows for direct observation of the needle end position, but it carries a high risk of surgical traumas as more eye tissues are disturbed. We have developed a less risky and reproducible modified trans-scleral injection method that uses defined needle angles and depths to successfully and consistently deliver RPE cells into the rat subretinal space and avoid excessive retinal damage. Cells delivered in this manner have been previously demonstrated to be efficacious in the Royal College of Surgeons (RCS) rat for at least 2 months. This technique can be used not only for cell transplantation but also for delivery of small molecules or gene therapies.

The Developmental Stage of Adult Human Stem Cell-Derived Retinal Pigment Epithelium Cells Influences Transplant Efficacy for Vision Rescue.

Age-related macular degeneration (AMD) is a common cause of central visual loss in the elderly. Retinal pigment epithelial (RPE) cell loss occurs early in the course of AMD and RPE cell transplantation holds promise to slow disease progression. We report that subretinal transplantation of RPE stem cell (RPESC)-derived RPE cells (RPESC-RPE) preserved vision in a rat model of RPE cell dysfunction. Importantly, the stage of differentiation that RPESC-RPE acquired prior to transplantation influenced the efficacy of vision rescue. Whereas cells at all stages of differentiation tested rescued photoreceptor layer morphology, an intermediate stage of RPESC-RPE differentiation obtained after 4 weeks of culture was more consistent at vision rescue than progeny that were differentiated for 2 weeks or 8 weeks of culture. Our results indicate that the developmental stage of RPESC-RPE significantly influences the efficacy of RPE cell replacement, which affects the therapeutic application of these cells for AMD.

Stem cell therapies for retinal diseases: recapitulating development to replace degenerated cells.

Retinal degenerative diseases are the leading causes of blindness worldwide. Replacing lost retinal cells via stem cell-based therapies is an exciting, rapidly advancing area of translational research that has already entered the clinic. Here, we review the status of these clinical efforts for several significant retinal diseases, describe the challenges involved and discuss how basic developmental studies have contributed to and are needed to advance clinical goals.

Human RPE Stem Cell-Derived RPE Preserves Photoreceptors in the Royal College of Surgeons Rat: Method for Quantifying the Area of Photoreceptor Sparing.

PURPOSE: Numerous preclinical studies have shown that transplantation of stem cell-derived retinal pigment epithelial cell (RPE) preserves photoreceptor cell anatomy in the dystrophic Royal College of Surgeons (RCS) rat. How rescue is spatially distributed over the eye, relative to the transplantation site, is less clear. To understand spatial variations in transplant efficacy, we have developed a method to measure the spatial distribution of rescued photoreceptor cells. METHODS: Human RPE Stem Cell-derived RPE (RPESC-RPE) cells were subretinally injected into RCS rat eyes. After tissue recovery and orientating the globe, a series of retinal sections were cut through the injected area. Sections were stained with DAPI (4',6-diamidino-2-phenylindole) and a number of photoreceptor nuclei were counted across the nasal-temporal and superior-inferior axes. These data were used to construct 2D maps of the area of photoreceptor cell saving. RESULTS: Photoreceptor cell preservation was detected in the injected temporal hemisphere and occupied areas greater than 4 mm(2) centered near the injection sites. Rescue was directed toward the central retina and superior and inferior poles, with maximal number of rescued photoreceptor cells proximal to the injection sites. CONCLUSIONS: RPESC-RPE transplantation preserves RCS photoreceptor cells. The photoreceptor cell contour maps readily convey the extent of rescue across the eye. The consistent alignment and quantification of results using this method allow the application of other downstream statistical analyses and comparisons to better understand transplantation therapy in the eye.

[Effect and mechanism of marrow stromal cells within cerebrospinal fluid on SOD1 transgenic mice].

OBJECTIVE: To explore the effect and mechanism of murine marrow stromal cells (MSCs) within cerebrospinal fluid (CSF) on Cu/Zn superoxide dismutase 1 (SOD1) transgenic mice. METHODS: A dose of 5×10(5) MSCs was injected into the CSF of SOD1 transgenic mice at the ages of 8, 10 and 12 weeks.Hanging wire test and motor neuron counts were used to assess disease progression of SOD1 mice. To examine the glial activation in murine lumbar spinal cord at 15 weeks of age, the sections were stained with antibody to CD11b and GFAP through immunohistochemistry.In vitro, mRNA expression of neurotrophin of MSCs was analyzed by reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: Compared with vehicle-treated mice, intrathecally transplanted MSCs enhanced motor performance and decreased motor neuron loss. An intrathecal injection of MSCs inhibited microglial (52 ± 7 vs 38 ± 7; F = 69.3, P = 0.02) and astrocyte (79 ± 9 vs 63 ± 9; F = 40.7, P = 0.03) activity in lumbar spinal cord at the age of 15 weeks of age. MSCs cultured in an inflammatory environment expressed a higher mRNA level of neurotrophin (P < 0.05). CONCLUSION: A CSF administration of MSCs has therapeutic effects on SOD1 mice. And the meditation of MSCs may be achieved through inhibiting neuroinflammation and secreting a variety of trophic factors.

Human umbilical cord mesenchymal stem cell-derived neuron-like cells rescue memory deficits and reduce amyloid-beta deposition in an AßPP/PS1 transgenic mouse model.

INTRODUCTION: Cell therapy is a potential therapeutic approach for neurodegenerative disorders, such as Alzheimer disease (AD). Neuronal differentiation of stem cells before transplantation is a promising procedure for cell therapy. However, the therapeutic impact and mechanisms of action of neuron-like cells differentiated from human umbilical cord mesenchymal stem cells in AD have not been determined. METHODS: In this study, we used tricyclodecan-9-yl-xanthogenate (D609) to induce human mesenchymal stem cells isolated from Wharton jelly of the umbilical cord (HUMSCs) to differentiate into neuron-like cells (HUMSC-NCs), and transplanted the HUMSC-NCs into an AßPP/PS1 transgenic AD mouse model. The effects of HUMSC-NC transplantation on the cognitive function, synapsin I level, amyloid ß-peptides (Aß) deposition, and microglial function of the mice were investigated. RESULTS: We found that transplantation of HUMSC-NCs into AßPP/PS1 mice improved the cognitive function, increased synapsin I level, and significantly reduced Aß deposition in the mice. The beneficial effects were associated with "alternatively activated" microglia (M2-like microglia). In the mice transplanted with HUMSC-NCs, M2-like microglial activation was significantly increased, and the expression of antiinflammatory cytokine associated with M2-like microglia, interleukin-4 (IL-4), was also increased, whereas the expression of proinflammatory cytokines associated with classic microglia (M1-like microglia), including interleukin-1ß (IL-1ß) and tumor necrosis factor-α (TNF-α), was significantly reduced. Moreover, the expression of Aß-degrading factors, insulin-degrading enzyme (IDE) and neprilysin (NEP), was increased substantially in the mice treated with HUMSC-NCs. CONCLUSIONS: HUMSC-NC transplantation decreased Aß deposition and improved memory in AßPP/PS1 mice by a mechanism associated with activating M2-like microglia and modulating neuroinflammation. Transplantation of neuron-like cells differentiated from mesenchymal stem cells might be a promising cell therapy for Alzheimer disease.

A butyrolactone derivative 3BDO alleviates memory deficits and reduces amyloid-ß deposition in an AßPP/PS1 transgenic mouse model.

Excessive extracellular deposition of amyloid- peptide (Aß) in the brain is the pathological hallmark of Alzheimer's disease (AD). Cumulative evidence indicates that autophagy is involved in the metabolism of Aß and pathogenesis of AD. However, the molecular mechanism underlying the pathogenesis of AD is not yet well defined, and there has been no effective treatment for AD. We recently found that long-term treatment with a butyrolactone derivative 3-benzyl-5-((2-nitrophenoxy) methyl)-dihydrofuran- 2(3 H)-one (3BDO) increased levels of insulin-degrading enzyme and neprilysin, suppressed autophagy via an mTOR pathway, lowered levels of Aß, and prevented AD-like cognitive deficits in the AßPP/PS1 double transgenic mouse model. Therefore, our findings suggest that 3BDO may be beneficial in the prevention and treatment of AD.

Butyrolactone derivative 3-benzyl-5-((2-nitrophenoxy) methyl)-dihydrofuran-2(3H)-one protects against amyloid-ß peptides-induced cytotoxicity in PC12 cells.

Excessive extracellular deposition of amyloid-ß peptides (Aß) is a characteristic pathologic feature of Alzheimer's disease (AD). Accumulating evidence indicates that macroautophagy is involved in the pathogenesis of AD, but the exact role of macroautophapy is still unclear. We investigated whether Aß(25-35) could cause reactive oxygen species (ROS) accumulation, decrease the activity of Na(+), K(+)-ATPase, trigger an autophagy process, and inhibit the growth of PC12 cells and examined the effect of a new autophagy modulator, butyrolactone derivative 3-benzyl-5-((2-nitrophenoxy) methyl)-dihydrofuran-2(3 H)-one (3BDO). 3BDO could block the decrease in cell viability induced by Aß(25-35) by inhibiting ROS accumulation and the decrease in activity of Na(+), K(+)-ATPase and the autophagy process. In addition, 3BDO modulated the autophagy progress via a mammalian target of rampamycin-dependent pathway. 3BDO has a protective effect against the cytotoxicity induced by Aß(25-35) and might be a promising tool for AD research.

VEGF-induced angiogenesis ameliorates the memory impairment in APP transgenic mouse model of Alzheimer's disease.

Vascular endothelial growth factor (VEGF) was investigated in the present study to see whether it could provide a therapeutic opportunity for the treatment of Alzheimer's disease (AD). PDGF-hAPP(V717I) transgenic mice were treated with VEGF or PBS by intraperitoneal injection for three consecutive days. The results showed that VEGF ameliorated the memory impairment of mice, accompanied by CD34(+) cells increasing in peripheral blood, vWF(+) vessels increasing in hippocampus, and CD34(+)/VEGFR2(+), vWF(+)/VEGFR2(+) and BrdU(+)/vWF(+) cells expressing in hippocampus. Furthermore, the level of choline acetyltransferase (ChAT) was considerably enhanced and Aß deposition was decreased in the brains of mice upon VEGF treatment. These observations suggest that VEGF should be pursued as a novel therapeutic agent for treatment of AD.

NADPH treatment decreases C6 glioma cell survival by increasing oxidative stress.

NADPH (nicotinamide adenine dinucleotide phosphate, reduced form) plays pivotal roles in antioxidation and reductive biosynthesis. However, the effect of NADPH treatment on cell survival is unknown. In this study, we determined the effect of NADPH treatment on the survival of glioma cells. Treatment of C6 glioma cells with as low as 1 µM NADPH for 24 hrs induced a significant decrease in the survival of the glioma cells, while NADPH treatment had no effect on the survival of primary astrocyte cultures. We also found that NADPH treatment increased intracellular oxidative stress. Three antioxidants and the NADPH oxidase inhibitor, apocynin, attenuated the effect of NADPH. Poly(ADP-ribose) polymerase (PARP) activation appears to be a downstream effector of the oxidative stress, since PARP inhibitors reduced the effect of NADPH. Calcium chelator, BAPTA-AM, also attenuated the effect of NADPH. Collectively, these data indicate a novel property of NADPH: NADPH decreases glioma cell survival by inducing the NADPH oxidase-dependent increase in oxidative stress and by PARP activation. These results also suggest a potential therapeutic effect of NADPH on gliomas.