Adenosine A2A receptor blockade prevents cisplatin-induced impairments in neurogenesis and cognitive function.

Chemotherapy-induced cognitive impairment (CICI) has emerged as a significant medical problem without therapeutic options. Using the platinum-based chemotherapy cisplatin to model CICI, we revealed robust elevations in the adenosine A2A receptor (A2AR) and its downstream effectors, cAMP and CREB, by cisplatin in the adult mouse hippocampus, a critical brain structure for learning and memory. Notably, A2AR inhibition by the Food and Drug Administration-approved A2AR antagonist KW-6002 prevented cisplatin-induced impairments in neural progenitor proliferation and dendrite morphogenesis of adult-born neurons, while improving memory and anxiety-like behavior, without affecting tumor growth or cisplatin's antitumor activity. Collectively, our study identifies A2AR signaling as a key pathway that can be therapeutically targeted to prevent cisplatin-induced cognitive impairments.

Comparison of perfusion values after percutaneous transluminal angioplasty according to the severity of ischaemia in the diabetic foot.

Percutaneous transluminal angioplasty (PTA) is now more frequently used to improve tissue perfusion in ischemic diabetic feet. However, there are concerns about its feasibility and effectiveness in severely ischaemic feet. This study aimed to compare the perfusion values after PTA according to the ischaemic degree of diabetic feet. This study included 133 ischaemic diabetic feet. The foot transcutaneous oxygen pressure (TcPO2 ) and toe pressure were measured before the procedure and every second postoperative week for 6 weeks. The patients were divided into three groups according to ischaemic severity on the basis of TcPO2 and toe pressures. In the "severely ischaemic" group, the TcPO2 increased from 7.5 ± 4.9 to 40.3 ± 11.3 mm Hg (5.4-fold) 6 weeks after the PTA (P < 0.001). The toe pressure increased from 8.5 ± 8.8 to 42.2 ± 19.3 mm Hg (5.0-fold, P < 0.001). In the "mild" group, the TcPO2 increased from 35.4 ± 2.5 to 41.8 ± 12.4 mm Hg (1.2-fold, P = 0.003), and the toe pressure increased from 45.7 ± 12.3 to 54.3 ± 31.3 mm Hg (1.2-fold, P > 0.05). Results of the "intermediate" group were in between. The most severely ischaemic group had the most dramatic increase of tissue perfusion after PTA. As such, PTA can be an effective method for increasing tissue perfusion even in the severely ischaemic diabetic feet.

Alternative Choices for Anterolateral Thigh Flaps Lacking Suitable Perforators: A Systematic Review.

BACKGROUND: The anterolateral thigh (ALT) flap has become a predominant option in the field of reconstruction. However, some difficulties in harvesting flap exist due to the anatomical variability of the perforators. Reports have provided solutions for unreliable perforators. Although numerous cases that showed successful conversion to tensor fasciae latae (TFL) flap or anteromedial thigh (AMT) flap have been reported in the literature, none fully addresses the reliability of the perforators that have been described to date. Therefore, we conducted a systematic literature review to compare the reliability of the TFL flap with that of the AMT flap when an ALT flap perforator is not suitable. METHODS: A systematic review of the MEDLINE, PubMed, and Cochrane Library electronic databases was performed to compare the characteristics of TFL and AMT flap perforators. RESULTS: A total of 13 articles were included for review. The mean number of TFL perforators varied from 1.41 to 3.17 per thigh. The mean number of AMT perforators was between 0.59 and 1.3 per thigh. The cumulative assessment of the clinical and anatomical studies showed 456 perforators in 180 TFL flaps (mean, 2.53) and 145 perforators in 162 AMT flaps (mean, 0.90). The mean pedicle length of the TFL and AMT flaps ranged from 7.0 to 9.59 cm and from 7.4 to 11.0 cm, respectively. The mean perforator diameter was similar in both flaps. CONCLUSION: Currently available literature suggests that the TFL flap may be a more reliable alternative when adequate perforators are not found for ALT flap harvest.

Evaluation of the Efficacy of Highly Hydrophilic Polyurethane Foam Dressing in Treating a Diabetic Foot Ulcer.

OBJECTIVE: To demonstrate the efficacy of a highly hydrophilic polyurethane foam dressing in the treatment of diabetic ulcers. BACKGROUND: Diabetic foot ulcers often pose a difficult treatment problem. Polyurethane foam dressings have been used worldwide to accelerate wound healing, but only a few clinical studies demonstrate the effect of foam dressing on the healing of diabetic ulcers. METHODS: Medical records of 1342 patients with diabetic ulcers who were admitted and treated at the authors' institution were reviewed. A total of 208 patients met the study's inclusion criteria. Of these 208 patients, 137 were treated with a highly hydrophilic polyurethane foam dressing, and 71 were treated with saline gauze (control group). Except for the application of polyurethane foam dressing, the treatment method was identical for patients in both groups. The wound healing outcomes of the 2 groups were compared. RESULTS: Complete wound healing occurred in 87 patients (63.5%) in the polyurethane foam dressing group and in 28 patients (39.4%) in the control group within 12 weeks (P < .05, X test). The mean percentage of wound area reduction in both groups was statistically significant (P < .05, Mann-Whitney U test). The mean time required for complete closure in patients who achieved complete healing within 12 weeks was 6.2 (SD, 3.4) weeks and 7.3 (SD, 2.6) weeks in the polyurethane foam dressing and control groups, respectively (P < .05, Mann-Whitney U test). CONCLUSION: These results indicate that the highly hydrophilic polyurethane foam dressing may provide an effective treatment strategy for diabetic foot ulcers.

Influence of Negative-Pressure Wound Therapy on Tissue Oxygenation in Diabetic Feet.

OBJECTIVE: Negative-pressure wound therapy (NPWT) has become a common wound care treatment modality for a variety of wounds. Several previous studies have reported that NPWT increases blood flow in the wound bed. However, NPWT might decrease tissue oxygenation in the wound bed because the foam sponge of NPWT compresses the wound bed under the influence of the applied negative pressure. Adequate tissue oxygenation is an essential consideration during diabetic foot management, and the foot is more sensitive to ischemia than any other region. Furthermore, the issue as to whether NPWT reduces or increases tissue oxygenation in diabetic feet has never been correctly addressed. The aim of this study was to evaluate the influence of NPWT on tissue oxygenation in diabetic feet. PARTICIPANTS: Transcutaneous partial oxygen pressures (TcPO2) were measured to determine tissue oxygenation levels beneath NPWT dressings on 21 feet of 21 diabetic foot ulcer patients. DESIGN: A TcPO2 sensor was fixed at the tarsometatarsal area of contralateral unwounded feet. A suction pressure of -125 mm Hg was applied until TcPO2 reached a steady state. The TcPO2 values for diabetic feet were measured before, during, and after NPWT. MAIN RESULTS: The TcPO2 levels decreased significantly after applying NPWT in all patients. Mean TcPO2 values before, during, and after therapy were 44.6 (SD, 15.2), 6.0 (SD, 7.1), and 40.3 (SD, 16.4) mm Hg (P < .01), respectively. CONCLUSION: These results show that NPWT significantly reduces tissue oxygenation levels in diabetic feet.

Corosolic Acid Exhibits Anti-angiogenic and Anti-lymphangiogenic Effects on In Vitro Endothelial Cells and on an In Vivo CT-26 Colon Carcinoma Animal Model.

We describe the anti-angiogenic and anti-lymphangiogenic effects of corosolic acid, a pentacyclic triterpenoid isolated from Cornus kousa Burg. A mouse colon carcinoma CT-26 animal model was employed to determine the in vivo anti-angiogenic and anti-lymphangiogenic effects of corosolic acid. Corosolic acid induced apoptosis in CT-26 cells, mediated by the activation of caspase-3. In addition, it reduced the final tumor volume and the blood and lymphatic vessel densities of tumors, indicating that it suppresses in vivo angiogenesis and lymphangiogenesis. Corosolic acid inhibited the proliferation and tube formation of human umbilical vein endothelial cells and human dermal lymphatic microvascular endothelial cells. In addition, corosolic acid decreased the proliferation and migration of human umbilical vein endothelial cells stimulated by angiopoietin-1. Pretreatment with corosolic acid decreased the phosphorylation of focal adhesion kinase (FAK) and ERK1/2, suggesting that corosolic acid contains anti-angiogenic activity that can suppress FAK signaling induced by angiopoietin-1.

Improved Neural Inductivity of Size-Controlled 3D Human Embryonic Stem Cells Using Magnetic Nanoparticles.

Background: To improve the efficiency of neural development from human embryonic stem cells, human embryoid body (hEB) generation is vital through 3-dimensional formation. However, conventional approaches still have limitations: long-term cultivation and laborious steps for lineage determination. Methods: In this study, we controlled the size of hEBs for ectodermal lineage specification using cell-penetrating magnetic nanoparticles (MNPs), which resulted in reduced time required for initial neural induction. The magnetized cells were applied to concentrated magnetic force for magnet-derived multicellular organization. The uniformly sized hEBs were differentiated in neural induction medium (NIM) and suspended condition. This neurally induced MNP-hEBs were compared with other groups. Results: As a result, the uniformly sized MNP-hEBs in NIM showed significantly improved neural inductivity through morphological analysis and expression of neural markers. Signaling pathways of the accelerated neural induction were detected via expression of representative proteins; Wnt signaling, dopaminergic neuronal pathway, intercellular communications, and mechanotransduction. Consequently, we could shorten the time necessary for early neurogenesis, thereby enhancing the neural induction efficiency. Conclusion: Overall, this study suggests not only the importance of size regulation of hEBs at initial differentiation stage but also the efficacy of MNP-based neural induction method and stimulations for enhanced neural tissue regeneration.

Cultured meat with enriched organoleptic properties by regulating cell differentiation.

Research on cultured meat has primarily focused on the mass proliferation or differentiation of muscle cells; thus, the food characteristics of cultured meat remain relatively underexplored. As the quality of meat is determined by its organoleptic properties, cultured meat with similar sensory characteristics to animal-derived meat is highly desirable. In this study, we control the organoleptic and nutritional properties of cultured meat by tailoring the 2D differentiation of primary bovine myoblasts and primary bovine adipose-derived mesenchymal stem cells on gelatin/alginate scaffolds with varying stiffness. We assess the effect of muscle and adipose differentiation quality on the sensory properties of cultured meat. Thereafter, we fabricate cultured meat with similar sensory profiles to that of conventional beef by assembling the muscle and adipose constructs composed of highly differentiated cells. We introduce a strategy to produce cultured meat with enriched food characteristics by regulating cell differentiation with scaffold engineering.

Preconditioning with Substance P Restores Therapeutic Efficacy of Aged ADSC by Elevating TNFR2 and Paracrine Potential.

Aging leads to a decline in stem cell activity by reducing the repopulation rate and paracrine potential, ultimately diminishing efficacy in vivo. TNF-α can exert inflammatory and cell death actions via Erk by binding to TNFR-1, and survival and tissue repair actions via Akt by binding to TNFR-2. Aged cells are reported to have insufficient expression of TNFR-2, indicating that aged adipose-derived stem cells (ADSCs-E) lack the ability for cell survival and immune control compared to young ADSCs (ADSCs-Y). This study aims to assess the preconditioning effect of SP on the response of ADSCs-E to inflammation. ADSCs-E were treated with SP and then exposed to a high dose of TNF-α for 24 h. Consequently, ADSC-E exhibited weaker viability and lower TNFR2 levels compared to ADSC-Y. In response to TNF-α, the difference in TNFR2 expression became more pronounced in ADSC-E and ADSC-Y. Moreover, ADSC-E showed a severe deficiency in proliferation and paracrine activity. However, preconditioning with SP significantly enhanced the viability of ADSCs-E and also restored TNFR2 expression and paracrine potential, similar to ADSC-Y under inflammatory conditions. Our findings support the idea that preconditioning with SP has the potential to restore the cellular function of senescent stem cells before transplantation.

High protein-containing new food by cell powder meat.

Demand for a new protein source to replace meat is increasing to solve various issues such as limited resources and food shortages. Diverse protein sources are being developed, but alternative proteins such as plants or insects need to improve people's perceptions and organoleptic properties. Therefore, cell-based meat research is intensively conducted, and most studies are aimed at scale-up and cost-down via the research of scaffolds and culture media. Here, we proposed a new food by cell powder meat (CPM), which has a high protein content and a meaty flavor. The powder was manufactured 76% more cost-effectively with less serum than the conventional culture medium and without 3D scaffold. Due to its comprehensive characteristics, the potential applicability of CPM in the cell-based meat industry could be expected.

The selective cyclooxygenase-2 inhibitor NS398 ameliorates cisplatin-induced impairments in mitochondrial and cognitive function.

Chemobrain is a condition that negatively affects cognition in cancer patients undergoing active chemotherapy, as well as following chemotherapy cessation. Chemobrain is also known as chemotherapy-induced cognitive impairment (CICI) and has emerged as a significant medical contingency. There is no therapy to ameliorate this condition, hence identification of novel therapeutic strategies to prevent CICI is of great interest to cancer survivors. Utilizing the platinum-based chemotherapy cisplatin in an investigative approach for CICI, we identified increased expression of cyclooxygenase-2 (COX-2) and prostaglandin E2 (PGE2) in the adult mouse hippocampus, and in human cortical neuron cultures derived from induced pluripotent stem cells (iPSCs). Notably, administration of NS398, a selective COX-2 inhibitor, prevented CICI in vivo without negatively affecting the antitumor efficacy of cisplatin or potentiating tumor growth. Given that dysfunctional mitochondrial bioenergetics plays a prominent role in CICI, we explored the effects of NS398 in cisplatin-induced defects in human cortical mitochondria. We found that cisplatin significantly reduces mitochondrial membrane potential (MMP), increases matrix swelling, causes loss of cristae membrane integrity, impairs ATP production, as well as decreases cell viability and dendrite outgrowth. Pretreatment with NS398 in human cortical neurons attenuated mitochondrial dysfunction caused by cisplatin, while improving cell survival and neurite morphogenesis. These results suggest that aberrant COX-2 inflammatory pathways may contribute in cisplatin-induced mitochondrial damage and cognitive impairments. Therefore, COX-2 signaling may represent a viable therapeutic approach to improve the quality of life for cancer survivors experiencing CICI.

Recombinant canstatin inhibits angiopoietin-1-induced angiogenesis and lymphangiogenesis.

We describe the effect of recombinant canstatin, the NC1 domain of the α2 chain of Type IV collagen, on suppression of angiogenesis and lymphangiogenesis both in vitro and in vivo. Recombinant canstatin produced from stably transformed Drosophila S2 cells reduced the expression of angiopoietin-1 in hypoxia mimetic agent, CoCl(2) -treated CT-26 cells. Recombinant canstatin inhibited proliferation, tube formation and migration of human angiopoietin-1 (rhAngpt-1)-treated human umbilical vein endothelial cells (HUVEC) and lymphatic endothelial cells (LEC). Recombinant canstatin suppressed the expression of Tie-2 and vascular endothelial growth factor-3 (VEGFR-3) transcripts in rhAngpt-1-treated HUVEC and LEC, respectively. The inhibitory effect of recombinant canstatin on tumor growth was also investigated using a heterotopic CT-26 colon carcinoma animal (BALB/c mice) model. Recombinant canstatin reduced the final volume and weight of tumors, and blood and lymphatic vessel densities of tumors, which were evaluated by CD-31 and LYVE-1 immunostaining. Immunohistochemical analysis showed that recombinant canstatin dramatically reduced the expression of angiopoietin-1 in CT-26 colon carcinoma-induced tumor, but not the expression of VEGF-C. Tie-2 and VEGFR-3 expressions were also reduced in recombinant canstatin-treated tumors. These results indicate that recombinant canstatin has anti-tumoral activities against CT-26 colon carcinoma cells. Recombinant canstatin reduces the expression of angiopoietin-1 in hypoxia-induced CT-26 cells and inhibits the angiogenic and lymphangiogenic signaling induced by angiopoietin-1. Recombinant canstatin probably inhibits angiogenesis and lymphangiogenesis via suppression of the integrin-dependent FAK signaling induced by angiopoietin-1/Tie-2 and/or VEGFR-3.

3-O-acetyloleanolic acid induces apoptosis in human colon carcinoma HCT-116 cells.

The cytotoxic effect of 3-O-acetyloleanolic acid, an oleanolic acid derivative isolated from the seeds of Vigna sinensis K., was investigated in human colon carcinoma HCT-116 cells. 3-O-acetyloleanolic acid dose-dependently inhibited the viability of HCT-116 cells. Apoptosis was characterized by detection of cell surface annexin V and sub-G1 apoptotic cell populations. The number of immunostained cells with annexin V-FITC was increased after treatment with 3-O-acetyloleanolic acid. The sub-G1 cell population was also increased. Expression of TRAIL-mediated apoptosis signaling-related death receptor DR5 was increased in 3-O-acetyloleanolic acid-treated HCT-116 cells. Activation of caspase-8 and caspase-3, critical mediators of extrinsic apoptosis signaling, was also increased by 3-O-acetyloleanolic acid. The results indicate that 3-O-acetyloleanolic acid induces apoptosis in HCT-116 cells mediated by an extrinsic apoptosis signaling cascade via up-regulation of DR5.

Synthesis of double-layered rotavirus-like particles using internal ribosome entry site vector system in stably-transformed Drosophila melanogaster.

We established a bicistronic expression system using an encephalomyocarditis virus (EMCV)-derived internal ribosomal entry site (IRES) element to generate stably transformed Drosophila melanogaster Schneider 2 (S2) cells expressing human rotavirus Wa capsid proteins, VP2 and VP6, for the synthesis of VP2/6 double-layered virus-like particle (DVLP). The EMCV-derived IRES permitted bicistronic translation of recombinant VP6. Recombinant VP2 and VP6 were detected in extracellular fractions of stably transformed S2 cells. A wheel-like DVLP (diam ~ 50-55 nm) with short spikes was produced from the extracellular fraction of stably transformed S2 cells. A bicistronic expression system using an EMCV-derived IRES element can thus be used to express two proteins of interest in stably transformed S2 cells. The bi-or tri-cistronic expression of recombinant VP2/6/7 using stably transformed S2 cells can also be used to produce rotavirus VLPs.

Nicotinamide Mononucleotide Prevents Cisplatin-Induced Cognitive Impairments.

Chemotherapy-induced cognitive impairment (CICI) is often reported as a neurotoxic side effect of chemotherapy. Although CICI has emerged as a significant medical problem, meaningful treatments are not currently available due to a lack of mechanistic understanding underlying CICI pathophysiology. Using the platinum-based chemotherapy cisplatin as a model for CICI, we show here that cisplatin suppresses nicotinamide adenine dinucleotide (NAD+) levels in the adult female mouse brain in vivo and in human cortical neurons derived from induced pluripotent stem cells in vitro. Increasing NAD+ levels through nicotinamide mononucleotide (NMN) administration prevented cisplatin-induced abnormalities in neural progenitor proliferation, neuronal morphogenesis, and cognitive function without affecting tumor growth and antitumor efficacy of cisplatin. Mechanistically, cisplatin inhibited expression of the NAD+ biosynthesis rate-limiting enzyme nicotinamide phosphoribosyl transferase (Nampt). Selective restoration of Nampt expression in adult-born neurons was sufficient to prevent cisplatin-induced defects in dendrite morphogenesis and memory function. Taken together, our findings suggest that aberrant Nampt-mediated NAD+ metabolic pathways may be a key contributor in cisplatin-induced neurogenic impairments, thus causally leading to memory dysfunction. Therefore, increasing NAD+ levels could represent a promising and safe therapeutic strategy for cisplatin-related neurotoxicity. SIGNIFICANCE: Increasing NAD+ through NMN supplementation offers a potential therapeutic strategy to safely prevent cisplatin-induced cognitive impairments, thus providing hope for improved quality of life in cancer survivors. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/81/13/3727/F1.large.jpg.

Recombinant canstatin inhibits tumor growth in an orthotopic AT-84 oral squamous cell carcinoma model.

The inhibitory effect of recombinant canstatin on tumor growth was investigated using an orthotopic oral squamous cell carcinoma (AT-84 cells) animal (C3H/HeN) model. Recombinant canstatin from stably transfected Drosophila S2 cells was purified to homogeneity using a simple one-step Ni NTA affinity fractionation. In our oral cancer model, the final volume and weight of tumors in groups treated with purified canstatin were both reduced to 44% of values for a control group treated with PBS. Blood or lymphatic vessel densities of tumors in the canstatin-treated group were reduced to 72% and 44% of control group values, respectively. Recombinant canstatin at 20 microg/ml effectively inhibited tube formation in HUVEC and lymphatic endothelial cells. Our results show that recombinant canstatin has anti-tumoral effects against primary oral squamous cell carcinoma.

Genetic Inhibition of sFRP3 Prevents Glial Reactivity in a Mouse Model of Accelerated Aging.

PURPOSE: Aging is the most significant risk factor for neurodegenerative disorders that are typified by cognitive deficits. Our recent work utilizing BubR1 hypomorphic (BubR1H/H) mice, an accelerated aging model, has revealed that genetic inhibition of the endogenous Wnt pathway inhibitor secreted frizzled related protein 3 (sFRP3) plays a neuroprotective role. Neuroinflammation has been suggested as a pathological hallmark of age-related neurodegeneration mediating cognitive impairment. However, whether sFRP3 inhibition has a neuroprotective effect on neuroinflammatory gliosis in BubR1H/H mice is unknown. METHODS: To investigate neuroprotection from aging-related neuroinflammation by sFRP3 in vivo, we generated double Bub R1H/H;sfrp3 knockout mice and performed immunohistological analysis with cell type-specific markers for astrocytes (glial fibrillary acidic protein), and microglia (ionized calcium-binding adapter molecule 1). Given that the hippocampus is a brain structure critical for learning and memory, and is uniquely affected in aging-related neurodegeneration, we evaluated morphological changes on astrocytes and microglia via confocal imaging. RESULTS: We demonstrate that BubR1H/H mice exhibit significantly increased levels of astrogliosis and an increased trend of microglial activation in the hilus and molecular layer of the young adult hippocampus, thus suggesting that BubR1 insufficiency accelerates glial reactivity. Importantly, our results further show that genetic inhibition of sFRP3 significantly recovers the astrogliosis and microglial activation observed in BubR1H/H mice, suggesting a critical neuroprotective role for sFRP3 in age-related neuroinflammation. CONCLUSION: Our findings suggest that sFRP3 inhibition may represent a novel therapeutic strategy for neurodegeneration.

sFRP3 inhibition improves age-related cellular changes in BubR1 progeroid mice.

Wnt signaling is a well-known molecular pathway in age-related pathogenesis and therapy of disease. While prior studies have mainly focused on Wnt ligands or Wnt activators, the in vivo functions of naturally secreted Wnt inhibitors are not clear, especially in brain aging. Using BubR1H/H mice as a novel mouse model of accelerated aging, we report that genetic inhibition of sFRP3 restores the reduced body and brain size observed in BubR1H/H mice. Furthermore, sFRP3 inhibition ameliorates hypomyelination in the corpus callosum and rescues neural progenitor proliferation in the hippocampal dentate gyrus of BubR1H/H mice. Taken together, our study identifies sFRP3 as a new molecular factor that cooperates with BubR1 function to regulate brain development, myelination, and hippocampal neurogenesis.

A new lignan glycoside from the fruits of Cornus kousa Burg.

A new lignan glycoside, (7'S, 8'R)-dihydrodehydrodiconiferyl alcohol-4'-O-beta-D-xylopyranoside (1), named cornuskoside A, was isolated from the fruits of Cornus kousa. The structure of the compound was determined by spectroscopy, including FABMS, UV, IR, (1)H-and 13C-NMR, DEPT and 2D-NMR (COSY, HSQC, and HMBC). This new lignan glycoside, along with its aglycone, (7'S, 8'R)-dihydrodehydrodiconiferyl alcohol (3), and another lignan with a similar skeleton, (-)-balanophonin (2), which have been previously isolated from this plant, were evaluated for cytotoxicity in human cancer cell lines such as HeLa, MCF-7, SK-MEL-5, and SK-OV-3. Compounds 2 and 3 showed cytotoxicity against HeLa [IC50 = 29.1 microM (2), 45.5 microM (3)], MCF-7 [IC50 = 29.2 microM (2), 28.2 microM (3)], SK-MEL-5 [IC50 = 31.3 microM (2), 32.3 microM (3)], and SK-OV-3 [IC50 = 33.4 microM (2), 43.4 microM (3)] cell lines.

BubR1 Insufficiency Impairs Affective Behavior and Memory Function in Mice.

PURPOSE: Although aging causes functional declines in cognition, the molecular mechanism underlying these declines remains largely unknown. Recently, the spindle checkpoint kinase budding uninhibited by benzimidazole-related 1 (BubR1) has emerged as a key determinant for age-related pathology in various tissues including brain. However, the neurobehavioral impact of BubR1 has not been explored. In this study, we investigated the role of BubR1 in behavioral function. METHODS: To investigate the neurobiological functions of BubR1 in vivo, we utilized transgenic mice harboring BubR1 hypomorphic alleles (BubR1H/H mice), which produce low amounts of BubR1 protein, as well as mice that have specific knockdown of BubR1 in the adult dentate gyrus. To assess anxiety-like behavior, the above groups were subjected to the elevated plus maze and the light-dark test, in addition to utilizing the tail-suspension and forced-swim test to determine depression-like behavior. We used novel object recognition to test for memory-related function. RESULTS: We found that BubR1H/H mice display several behavioral deficits when compared to wild-type littermates, including increased anxiety in the elevated-plus maze test, depression-like behavior in the tail suspension test, as well as impaired memory function in the novel object recognition test. Similar to BubR1H/H mice, knockdown of BubR1 within the adult dentate gyrus led to increased anxiety-like behavior as well as depression-like behavior, and impaired memory function. CONCLUSION: Our study demonstrates a requirement of BubR1 in maintaining proper affective and memory-related behavioral function. These results suggest that a decline in BubR1 levels with advanced age may be a crucial contributor to age-related hippocampal dysfunction.