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Background: Urinary tract infections (UTIs) are common bacterial infections, primarily caused by uropathogenic Escherichia coli (UPEC), leading to significant health issues and economic burden. Although antibiotics have been effective in treating UPEC infections, the rise of antibiotic-resistant strains hinders their efficacy. Hence, identifying novel bacterial targets for new antimicrobial approaches is crucial. Bacterial factors required for maintaining the full virulence of UPEC are the potential target. MepM, an endopeptidase in E. coli, is involved in the biogenesis of peptidoglycan, a major structure of bacterial envelope. Given that the bacterial envelope confronts the hostile host environment during infections, MepM's function could be crucial for UPEC's virulence. This study aims to explore the role of MepM in UPEC pathogenesis. Results: MepM deficiency significantly impacted UPEC's survival in urine and within macrophages. Moreover, the deficiency hindered the bacillary-to-filamentous shape switch which is known for aiding UPEC in evading phagocytosis during infections. Additionally, UPEC motility was downregulated due to MepM deficiency. As a result, the mepM mutant displayed notably reduced fitness in causing UTIs in the mouse model compared to wild-type UPEC. Conclusions: This study provides the first evidence of the vital role of peptidoglycan endopeptidase MepM in UPEC's full virulence for causing UTIs. MepM's contribution to UPEC pathogenesis may stem from its critical role in maintaining the ability to resist urine- and immune cell-mediated killing, facilitating the morphological switch, and sustaining motility. Thus, MepM is a promising candidate target for novel antimicrobial strategies. [ABSTRACT FROM AUTHOR]

Background: PTEN loss has been identified in various tumor types and is linked to unfavorable clinical outcomes. In addition to PTEN mutation, multiple mechanisms contribute to PTEN loss during tumor development. However, the natural selection process of PTEN-deficient tumor cells remains unclear. Here, we aimed at further elucidating the role of PTEN-L in tumor progression. Methods: PTEN knockout cell lines were generated using CRISPR/Cas9 technology. Ni-NTA affinity column chromatography was employed for PTEN-L purification. Tumor cell metastasis was evaluated in murine models and observed using the IVIS Spectrum Imaging System. RNA-sequencing, western blotting, PCR, flow cytometry, and cell proliferation assays were employed to investigate tumor cell dormancy and related mechanisms. Results: The chemotherapeutic drugs, cisplatin, paclitaxel, and doxorubicin, induced tumor cells to secrete PTEN-long (PTEN-L), which shields PTEN-deficient tumor cells from chemotherapy-induced apoptosis better than it shields PTEN-intact cells. Further investigation revealed that PTEN-L treatment induced dormancy in PTEN-null tumor cells, characterized by an increase in p16 and p27 levels, cell-cycle arrest, reduced cell proliferation, and enhanced DNA repair. Furthermore, PTEN-L treatment selectively promoted the accumulation and growth of PTEN-null tumor cells in the lungs of C57BL/6J mice, while evading immune surveillance. Mechanistically, PTEN-L induced dormancy in PTEN-null tumor cells by activating the p38 signaling pathway. Addition of a p38 inhibitor effectively reversed dormancy and growth of PTEN-deficient tumor cells in the lungs. We also demonstrated that PTEN expression played a pivotal role in determining the outcome of PTEN-L-mediated antitumor therapy. Conclusions: In summary, PTEN-L was identified as a potent inducer of dormancy in PTEN-deficient tumor cells, which increased their efficient selection within the tumor microenvironment. [ABSTRACT FROM AUTHOR]

Background: Chlorogenic acid (CHA) has been shown to have substantial biological activities, including anti-inflammatory, antioxidant, and antitumor effects. However, the pharmacological role of CHA in neuroblastoma has not yet been assessed. Neuroblastoma is a type of cancer that develops in undifferentiated sympathetic ganglion cells. This study aims to assess the antitumor activity of CHA against neuroblastoma and reveal its mechanism of action in cell differentiation. Methods: Be(2)-M17 and SH-SY5Y neuroblastoma cells were used to confirm the differentiation phenotype. Subcutaneous and orthotopic xenograft mouse models were also used to evaluate the antitumor activity of CHA. Seahorse assays and metabolomic analyses were further performed to investigate the roles of CHA and its target ACAT1 in mitochondrial metabolism. Results: CHA induced the differentiation of Be(2)-M17 and SH-SY5Y neuroblastoma cells in vivo and in vitro. The knockdown of mitochondrial ACAT1, which was inhibited by CHA, also resulted in differentiation characteristics in vivo and in vitro. A metabolomic analysis revealed that thiamine metabolism was involved in the differentiation of neuroblastoma cells. Conclusions: These results provide evidence that CHA shows good antitumor activity against neuroblastoma via the induction of differentiation, by which the ACAT1-TPK1-PDH pathway is involved. CHA is a potential drug candidate for neuroblastoma therapy. [ABSTRACT FROM AUTHOR]

Influenza A virus (IAV) can cause high morbidity and mortality globally every year. Myriad host kinases and their related signaling pathways are involved in IAV infection, and the important role of the c-Jun N-terminal kinase signaling pathway during infection has been demonstrated. SP600125, an inhibitor of c-Jun N-terminal kinase, was found in our previous study to suppress IAV replication in vitro. In this study, we established a mouse model of H1N1 IAV infection and treated the mice with SP600125 to study its protective effect. The results showed that SP600125 treatment reduced the pulmonary inflammatory response, lung injury, and pulmonary viral load and increased the survival rate of H1N1-infected mice. Our data confirm the crucial role of c-Jun N terminal kinase in H1N1 virus replication and inflammatory responses in vivo. Hence, we speculate that SP600125 has a potential antiviral therapeutic benefit against IAV infection. [ABSTRACT FROM AUTHOR]

Rodent fur mite infestation is a persistent and intractable problem in laboratory rodent colonies, due to insensitive diagnostics, unrepresentative samples for testing and improper sentinel system. Myocoptes musculinus (COP), Myobia musculi (MOB) and Radfordia affinis (RDA) have been reported in laboratory mouse colonies. To improve the sensitivity and efficiency of fur mite detection, COP-specific PCR and MOB/RDA-specific PCR assays were developed to detect and differentiate these fur mites, with the existence of a rodent housekeeping gene. The COP-specific PCR and the MOB/RDA-specific PCR could specifically detect COP and MOB/RDA at as low as 10 copies, respectively. In comparison of the specific PCRs with traditional methods (pluck test, tape test and pelt exam) for fur mite diagnosis, 31 rodents and 17 cage environment samples were evaluated. In screening for the infestation status of various fur mites on individual animals, the specific PCR assays showed distinctly higher sensitivity and accuracy (100% and 100%) than those of the traditional methods (sensitivity: 25–80%, accuracy: 83.9–96.8%). Interestingly, by using cage wipe environmental samples, the specific PCR assays exhibited 100% sensitivity and accuracy in the fur mite detection and differentiation. The COP-specific and MOB/RDA-specific PCR assays developed in this study could be reliable alternatives for routine pathogen monitoring of laboratory mice and environments of animal facilities without animal sacrifice. [Chou C-L, Cheng Y-C, Wang MH, Wan CH, Novel PCR assays for three fur mites in naturally infected mice without animal sacrifice, Taiwan Vet J46(4):133–142, 2020.] [ABSTRACT FROM AUTHOR]

The bioactive, signaling lipid, sphingosine-1-phosphate (S1P), and its analog, fingolimod (FTY720), have previously shown neuroprotective effects against ischemic brain injury. However, the underlying mechanisms have not yet been fully clarified. The roles of autophagy in ischemic stroke are being increasingly recognized. In the present study, we sought to determine whether the S1P pathway is involved in neuronal autophagy and investigate its possible mechanisms following stroke. Interestingly, we found that FTY720 significantly attenuates infarct volumes and reduces neuronal apoptosis on days 1 and 3 post stroke, accompanied by amelioration of functional deficits. Additionally, FTY720 was found to decrease the induction of autophagosome proteins, microtubule-associated protein 1 light chain 3(LC3-II) and Beclin1, following ischemic stroke in a dose-dependent manner. Meanwhile, protein levels of the mammalian target of rapamycin (mTOR) and the 70-kDa ribosomal protein, S6 kinase1 (p70S6K), were also up-regulated in FTY720-treated animals, and the nonspecific SphK inhibitor, N,N-dimethylsphingosine (DMS), was found to cause a reverse effect. Our results indicate that modulation of the S1P signaling pathway by FTY720 could effectively decrease neuronal autophagy through the mTOR/p70S6K pathway and attenuate ischemic brain injury in mice. [ABSTRACT FROM AUTHOR]

Astilbin is a flavonoid compound derived from the rhizome of Smilax china L. The effects and possible molecular mechanisms of astilbin on potassium oxonate-induced hyperuricemia mice were investigated in this study. Different dosages of astilbin (5, 10, and 20 mg/kg) were administered to induce hyperuricemic mice. The results demonstrated that the serum uric acid (Sur) level was significantly decreased by increasing the urinary uric acid (Uur) level and fractional excretion of urate (FEUA) with astilbin, related with suppressing role in meditation of Glucose transporter 9 (GLUT9), Human urate transporter 1 (URAT1) expression and up-regulation of ABCG2, Organic anion transporter 1/3 (OAT1/3) and Organic cation transporter 1 (OCT1). In addition, kidney function parameters, including serum creatinine (Scr) and blood urea nitrogen (BUN) were restored in astilbin-treated hyperuricemic rats. Further investigation indicated that astilbin prevented the renal damage against the expression of Thioredoxin-interacting protein (TXNIP) and its related inflammation signal pathway, including NLR pyrin domain-containing 3/Nuclear factor κB (NLRP3/NF-κB), which is associated with the up-regulation of interleukin-1β (IL-1β) and interleukin-18 (IL-18), and also presented a renal protective role by suppression oxidative stress. Moreover, astilbin inhibited activation of the Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) cascade and over-expression of suppressor of cytokine signaling 3 (SOCS3) in the kidneys of potassium oxonate-induced mice. These findings provide potent evidence and therapeutic strategy for astilbin as a safe and promising compound in the development of a disease-modifying drug due to its function against hyperuricaemia and renal injury induced by potassium oxonate. [ABSTRACT FROM AUTHOR]

Problem Many researchers have demonstrated that the expression of interleukin- 17(IL-17) is higher in spontaneous abortion. However, whether Th17 cells are an independent factor in inducing abortion is not known. Method of study This study investigated the effect of exogenous recombinant IL-17 and an anti-IL-17 antibody in a normal and an abortion mouse model using flow cytometry, enzyme-linked immunosorbent assay, real-time PCR, and Western blot. Results Th17 cells and the related factors, IL-17 and RORct, were significantly upregulated in abortion mice, and Treg cells and the related factor, Foxp3, were downregulated. Intraperitoneal injection of recombinant IL (rIL)-17 induced fetal loss in a normal mouse model, and an anti-IL-17 antibody prevented fetal loss in an abortion mouse model. Conclusion This study confirmed an imbalance of the Th17/Treg paradigm in abortion mice and IL-17 as a risk factor of fetal loss. An anti-IL-17 antibody may prevent abortion. [ABSTRACT FROM AUTHOR]

Objectives To identify the protective role of sodium cromoglycate in mice during influenza virus infection. Design H5N1 virus-infected mice were treated with the mast cell stabilizer sodiumcromoglycate (SCG) to investigate its therapeutic effect. Sample The nose, trachea and lungs from mice were collected. Main outcome measures Virus replication and host responses were determined by plaque assay, quantitative PCR, immunohistochemistry, and histology. Results SCG-treated mice survived better than did PBS-treated mice after H5N1 virus infection. Mild pathological changes with fewer inflammatory cell infiltration and fewer virus antigens were observed in the nose, trachea, and lungs of SCG-treated mice on days 3 and 5 post-infection. However, no significant changes in viral load in the lungs were detected between SCG- and PBS-treated mice. Furthermore, significantly decreased expression of interleukin-6, tumor necrosis factor-a, Toll-like receptor 3, and TIR-domaincontaining adapter-inducing interferon-b was detected in the lungs of SCG-treated mice, and no higher expression of interferon-c was detected. Conclusion These results suggest that SCG has therapeutic roles in H5N1 virus-infected mice by alleviating the inflammatory response rather than inhibition of viral replication in the lungs. [ABSTRACT FROM AUTHOR]

Background. This study evaluated the impact of different doses of Astragalus polysaccharides (APS) on the functional status and phenotype of T cells during polymicrobial sepsis. Methods. On day 1 after cecal ligation and puncture, mice were treated with either saline, 100 (A100), 200 (A200), or 400 mg APS/kg body weight (BW) (A400) by an intraperitoneal injection daily for 4 days. All mice were sacrificed 5 days after the operation. Results. APS treatment reversed the sepsis-induced decrement in the T helper (Th) cell population, and the percentage of activated Th cells also increased in the spleen and Peyer’s patches. APS administration downregulated the percentages of circulating Th2 cells and regulatory T cells (Treg), and the percentage of Th17 cells in blood was upregulated in the A400 group. Weight loss and kidney injury were attenuated in the A100 and A200 groups but not in the A400 group at the end of the study. Conclusions. Treatments with 100 and 200 mg APS/kg BW reduced Treg populations and elicited a more-balanced Th1/Th2 response that consequently attenuated immunosuppression in polymicrobial sepsis. High-dose APS administration led to excessive responses of Th17 cells which may have adverse effects in sepsis-induced organ injury. [ABSTRACT FROM AUTHOR]

Currently, only tumor necrosis factor alpha (TNF-α) and interleukin family cytokines have been found to be elicited in Vibrio vulnificus (V. vulnificus)-infected animal models and humans. However, multiple other cytokines are also involved in the immune and inflammatory responses to foreign microorganism infection. Antibody array technology, unlike traditional enzyme-linked immunosorbent assay (ELISA), is able to detect multiple cytokines at one time. Therefore, in this study, we examined the proinflammatory cytokine profile in the serum and liver homogenate samples of bacterial-infected mice using antibody array technology. We identified nine novel cytokines in response to V. vulnificus infection in mice. We found that keratinocyte-derived chemokine (KC) was the most elevated cytokine and demonstrated that KC played a very important role in the V. vulnificus infection-elicited inflammatory response in mice, as evidenced by the fact that the blocking of KC by anti-KC antibody reduced hepatic injury in vivo and that KC induced by V. vulnificus infection in AML-12 cells chemoattracted neutrophils. Our findings implicate that KC may serve as a novel diagnostic biomarker and a possible therapeutic target for V. vulnificus infection. [ABSTRACT FROM AUTHOR]

Objectives: Influenza in humans is often accompanied by gastroenteritis-like symptoms such as diarrhea and abdominal pain nausea, but the underlying mechanism remains unclear. Results: Mice infected with three subtypes of respiratory influenza A virus (IAV), particularly H5N1 and H7N2, developed intestinal injury. The avian H5N1 and H7N2 IAV were detected in the small intestine, whereas the human H1N1 was not detected. Section staining with the sialic acid (SA) receptor demonstrated that the small intestine mainly expressed SA α2, 3 Gal instead of SA α2, 6 Gal which preferentially binds to avian IAV. The number of goblet and sIgA cells in the small intestine increased, whereas CD4 and CD8 T cells decreased in all infected mice except for CD8 T cells increased in H7N2 infected mice. Conclusions: Respiratory IAV infection, particularly infected by avian IAV, can cause small intestine structural damage and modify the local immune response, thereby resulting in gastroenteritis-like symptoms. [ABSTRACT FROM AUTHOR]

Alarin is a newly identified member of the galanin family of neuropeptides. Until now, research on alarin is limited compared with other members of the galanin family. Unearthing the new biological effects of alarin and its unidentified receptor(s) interests us. We previously showed that alarin has an effect on depression-like behaviors, although the underlying mechanisms are not fully clarified. The present study verified the antidepressant-like effects of alarin using the unpredictable chronic mild stresses (UCMS) paradigm, and explored the mechanism that underlies antidepressant-like effects of alarin in mice. Previous research has shown that TrkB receptor-mediated ERK and AKT signaling pathways participate in depression pathophysiology. Therefore, we aimed to explore whether alarin improved depression-like behaviors by increasing activity of ERK and AKT pathways mediated by TrkB. Results showed that alarin significantly reduced immobility time in the forced swim test and latency to feed in the novelty suppressed feeding test. In addition, decreased p-ERK/ERK and p-AKT/AKT levels in the prefrontal cortex, hippocampus, olfactory bulb, and hypothalamus induced by UCMS were reversed by intracerebroventricular injection of alarin. Results suggested that alarin increased p-ERK/ERK and p-AKT/AKT levels by acting on the TrkB receptor. To verify this hypothesis, mice were pretreated with the TrkB inhibitor K252a (or 0.1% dimethyl sulfoxide, intraperitoneally, 3 days), followed by intracerebroventricular injection of alarin. This resulted in an absence of antidepressant-like effects, as well as no activation of ERK and AKT signaling pathways. Results demonstrate that alarin may exert antidepressant-like effects by targeting TrkB receptor-mediated ERK and AKT signal systems, which could help to identify the alarin receptor. [ABSTRACT FROM AUTHOR]

Nuciferine, a major aporphine alkaloid of the leaves of Nelumbo nucifera , was found to decrease serum urate levels and improved kidney function, as well as inhibited system and renal interleukin-1β (IL-1β) secretion in potassium oxonate-induced hyperuricemic mice. Furthermore, nuciferine reversed expression alteration of renal urate transporter 1 (URAT1), glucose transporter 9 (GLUT9), ATP-binding cassette, subfamily G, membrane 2 (ABCG2), organic anion transporter 1 (OAT1), organic cation transporter 1 (OCT1), and organic cation/carnitine transporters 1/2 (OCTN1/2) in hyperuricemic mice. More importantly, nuciferine suppressed renal activation of Toll-like receptor 4/myeloid differentiation factor 88/NF-kappaB (TLR4/MyD88/NF-κB) signaling and NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome to reduce serum and renal IL-1β levels in hyperuricemic mice with renal inflammation reduction. The anti-inflammatroy effect of nuciferine was also confirmed in human proximal renal tubular epithelial cells (HK-2 cells) incubated with 4 mg/dl uric acid for 24 h. This study firstly reported the anti-hyperuricemic and anti-inflammatory effects of nuciferine by regulating renal organic ion transporters and inflammatory signaling in hyperuricemia. These results suggest that a dietary supplement of nuciferine rich in lotus leaf may be potential for the prevention and treatment of hyperuricemia with kidney inflammation. [ABSTRACT FROM AUTHOR]

C57BL/6J mice were divided into control group (C), CLA, c9t11, or t10c12 groups. CLA and t10c12 significantly increased α-tocopherol levels in the plasma and various tissues in experiment 1. The CLA and t10c12 groups also showed a significant increase in hepatic α-tocopherol transfer protein (α-TTP) levels. In experiment 2, mice were divided into control, CLA, R (rosiglitazone, a PPARγ agonist), or CLA+R groups. Vitamin E levels in the liver, epididymal fat pad, kidney, and plasma were increased by CLA, and this effect was reduced in the CLA+R group. t10,c12-CLA is the most active isomer in the CLA mixture in the regulation of tissue vitamin E status and α-TTP protein levels in mice. The increase in liver vitamin E status in CLA-fed mice is mainly due to the effect of PPARγ inhibition. [ABSTRACT FROM AUTHOR]

Highlights: [•] Acute alarin administration (i.c.v.) produced rapid antidepressant-like effects. [•] Alarin reversed depressive-like behavior induced by CUMS. [•] Alarin reduced CRH mRNA expression of brain tissue in the mice and serum CRH, CORT and ACTH levels in CUMS-treated mice. [•] Alarin increased the level of BDNF mRNA expression of brain tissue in the mice. [Copyright &y& Elsevier]

Aim:Androgen receptor (AR) antagonists have proven to be useful in the early control of prostate cancer. The aim of this study was to identify and characterize a novel β-amino-carbonyl-based androgen receptor antagonist.Methods:Different isomers of the β-amino-carbonyl compounds were obtained by chiral separation. The bioactivities of the isomers were evaluated by AR nuclear translocation, mammalian two-hybrid, competitive receptor binding and cell proliferation assays. The expression of genes downstream of AR was analyzed with real-time PCR. The therapeutic effects on tumor growth in vivo were observed in male SCID mice bearing LNCaP xenografts.Results:Compound 21 was previously identified as an AR modulator by the high-throughput screening of a diverse compound library. In the present study, the two isomers of compound 21, termed compounds 21-1 and 21-2, were characterized as partial AR agonists in terms of androgen-induced AR nuclear translocation, prostate-specific antigen expression and cell proliferation. Further structural modifications led to the discovery of a androgen receptor antagonist (compound 6012), which blocked androgen receptor nuclear translocation, androgen-responsive gene expression and androgen-dependent LNCaP cell proliferation. Four stereoisomers of compound 6012 were isolated, and their bioactivities were assessed. The pharmacological effects of 6012, including AR binding, androgen-induced AR translocation, NH2- and COOH-terminal interaction, growth inhibition of LNCaP cells in vitro and LNCaP xenograft growth in nude mice, were mainly restricted to isomer 6012-4 (1R, 3S).Conclusion:Compound 6012-4 was determined to be a novel androgen receptor antagonist with prostate cancer inhibitory activities comparable to bicalutamide both in vitro and in vivo. [ABSTRACT FROM AUTHOR]

G protein-coupled receptor 119 (GPR119) is highly expressed in pancreatic β cells and enteroendocrine cells. It is involved in glucose-stimulated insulin secretion and glucagon-like peptide-1 (GLP-1) release, thereby representing a promising target for the treatment of type 2 diabetes. Although a number of GPR119 agonists were developed, no positive allosteric modulator (PAM) to this receptor has been reported. Here we describe a high-throughput assay for screening GPR119 PAMs and agonists simultaneously. Following screening of a small molecule compound library containing 312,000 synthetic and natural product-derived samples, one potent GPR119 agonist with novel chemical structure, MW1219, was identified. Exposure of MIN6 and GLUTag cells to MW1219 enhanced glucose-stimulated insulin secretion and GLP-1 release; once-daily oral dosing of MW1219 for 6 weeks in diabetic db/db mice reduced hemoglobin A1c (HbA1c) and improved plasma glucose, insulin and GLP-1 levels; it also increased glucose tolerance. The results demonstrate that MW1219 is capable of effectively controlling blood glucose level and may have the potential to be developed as a new class of anti-diabetic agents. [ABSTRACT FROM AUTHOR]

Embryo implantation is a crucial process for successful pregnancy. To date, the mechanism of embryo implantation remains unclear. Ezrin-radixin-moesin-binding protein-50-kDa (EBP50) is a scaffold protein, which has been shown to play an important role in cancer development. Embryo implantation and cancer follow a similar progression. Thus, in this article, we utilized immunohistochemical staining and western blot analyses to examine the spatiotemporal expression and regulation of EBP50 both in the mouse uterus during embryo implantation as well as in other related models. We found that EBP50 was detected in epithelial cells in all of the groups used in our study. During the peri-implantation period, EBP50 mainly localized in apical membranes. At the implantation site (IS) on day 5 (D5) of pregnancy, EBP50 was mainly expressed in the nuclei of stroma cells, whereas from day 6 to day 8 (D6-D8) of pregnancy, the expression of EBP50 was noted in the cytoplasm of decidual cells. The expression of EBP50 was not significantly different in the pseudopregnant uterus and decreased in the uteri subjected to activation of delayed implantation. Artificial decidualization also decreased EBP50 expression. Thus, the expression levels and location were affected by active blastocysts and decidualization during the window of implantation. [ABSTRACT FROM AUTHOR]

Aim:To study the in vivo effects of Quin-C1, a highly specific agonist for formyl peptide receptor 2 (FPR2/ALX), in a mouse model of bleomycin (BLM)-induced lung injury.Methods:Male ICR mice were injected intratracheally with BLM (d 0), and intraperitoneally with Quin-C1 (0.2 mg/d) or vehicle between d 1 and d 28, during which pulmonary inflammation was monitored. A similar regimen was carried out between d 5 and d 28 to differentiate anti-inflammatory from anti-fibrotic effects. During the treatment, leukocyte numbers in bronchoalveolar lavage fluid (BALF) were counted, and FPR2/ALX transcripts, tumor necrosis factor α (TNF-α), interleukin-1β (IL-1β), the mouse keratinocyte-derived chemokine (KC), transforming growth factor β1 (TGF-β1) and C-X-C motif chemokine 10 (CXCL10) expression levels in the lung tissue were also measured. Both hydroxyproline content and histological changes were examined on d 28 to assess the severity of lung fibrosis.Results:BLM caused a significant increase in expression levels of all the selected cytokines and chemokines, as well as a thickening of the alveolar wall. Treatment with Quin-C1 significantly reduced the neutrophil and lymphocyte counts in BALF, diminished expression of TNF-α, IL-1β, KC, and TGF-β1, and decreased collagen deposition in lung tissue. The treatment also lowered the content of lung hydroxyproline. Quin-C1 did not ameliorate lung fibrosis when the treatment was started 5 d after the BLM challenge, suggesting that the protection may be attributed to its anti-inflammatory effects. Exposure to BLM or BLM plus Quin-C1 did not change the level of FPR2/ALX transcripts (mFpr1, mFpr2, and Lxa4r) in the lung tissue.Conclusion:The results demonstrate an anti-inflammatory role for Quin-C1 in bleomycin-induced lung injury, which may be further explored for therapeutic applications. [ABSTRACT FROM AUTHOR]

Abstract: Senescence-accelerated mouse prone 8 (SAMP8) has an early onset of senility and a shorter life span, providing with cognitive impairment. Contrasted with C57BL/6 mouse, which is most commonly used in the study of Parkinson''s disease (PD), SAMP8 needs shorter period of breeding and might be good candidate for the investigation of cognitive impairment in PD. Studies had shown the increase of sensibility to 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) with aging in C57BL/6 mouse. However, the sensitivity of MPTP neurotoxicity depends on the strains of animal and the exact mechanisms of the progression of PD promoted by aging is lack of consensus. Here, we showed after MPTP injection, the spontaneous activity of both young (3-month-old) and old (6-month-old) SAMP8 decreased dramatically, and the old mice required longer recovery time. Immunohistochemical and immunoblot analysis revealed that old mice displayed significant reductions in the dopaminergic neuron numbers and tyrosine hydroxylase (TH) protein. Microglia protein (CD11b) in the striatum of old mice increased more pronouncedly than that in the young mice from 24h to 3days. Inducible nitric oxide synthase (iNOS) in the striatum remarkably increased, however, no discernible difference between the two groups was found. These results suggested that the sensibility to MPTP increased with aging in SAMP8. A greater increase of microglial activation in old mice may be a possible mechanism to explain how advancing age predisposes the dopamine system to parkinsonism. The MPTP-SAMP8 model will start a new consideration for the study of PD. [Copyright &y& Elsevier]

Memory deterioration in Alzheimer's disease (AD) is thought to be underpinned by aberrant amyloid β (Aβ) accumulation, which contributes to synaptic plasticity impairment. Avenanthramide-C (Avn-C), a polyphenol compound found predominantly in oats, has a range of biological properties. Herein, we performed methanolic extraction of the Avns-rich fraction (Fr. 2) from germinated oats using column chromatography, and examined the effects of Avn-C on synaptic correlates of memory in a mouse model of AD. Avn-C was identified in Fr. 2 based on 1H-NMR analysis. Electrophysiological recordings were performed to examine the effects of Avn-C on the hippocampal long-term potentiation (LTP) in a Tg2576 mouse model of AD. Avn-C from germinated oats restored impaired LTP in Tg2576 mouse hippocampal slices. Furthermore, Avn-C-facilitated LTP was associated with changes in the protein levels of phospho-glycogen synthase kinase-3β (p-GSK3β-S9) and cleaved caspase 3, which are involved in Aβ-induced synaptic impairment. Our findings suggest that the Avn-C extract from germinated oats may be beneficial for AD-related synaptic plasticity impairment and memory decline. [ABSTRACT FROM AUTHOR]

In the present work we undertook the complete mitochondrial genome sequencing of an important glioma model inbred rat strain for the first time. The total length of the mitogenome was 16,308 bp. It harbored 13 protein-coding genes, 2 ribosomal RNA genes, 22 transfer RNA genes and 1 non-coding control region (D-loop region). The mutation events were also reported. [ABSTRACT FROM PUBLISHER]

Hepatitis B virus (HBV)-related acute-on-chronic liver failure (ACLF) has a poor prognosis with high in-hospital mortality. Hepatic and circulating inflammatory cytokines, such as fibrinogen like protein 2 (fgl2), FasL/Fas, and TNFα/TNFR1, play a significant role in the pathophysiology of ACLF. This study aimed to investigate the therapeutic effect of recombinant adenoviral vectors carrying constructed DNA code for non-native microRNA (miRNA) targeting mouse fgl2 (mfgl2) or both mFas and mTNFR1 on murine hepatitis virus (MHV)-3-induced fulminant hepatitis in BALB/cJ mice. Artificial miRNA eukaryotic expression plasmids against mfgl2, mFas, and mTNFR1 were constructed, and their inhibitory effects on the target genes were confirmed in vitro. pcDNA6.2-mFas-mTNFR1- miRNA，which expresses miRNA against both mFas and mTNFR1 simultaneously，was constructed. To construct a miRNA adenovirus expression vector against mfgl2, pcDNA6.2-mfgl2-miRNA was cloned using Gateway technology. Ad-mFas-mTNFR1- miRNA was also constructed by the same procedure. Adenovirus vectors were delivered by tail-vein injection into MHV-3-infected BALB/cJ mice to evaluate the therapeutic effect. 8 of 18 (44.4%) mice recovered from fulminant viral hepatitis in the combined interference group treated with Ad-mfgl2-miRNA and Ad-mFas-mTNFR1-miRNA. But only 4 of 18 (22.2%) mice receiving Ad-mfgl2-miRNA and 3 of 18 (16.7%) mice receiving Ad-mFas-mTNFR1- miRNA survived. These adenovirus vectors significantly ameliorated inflammatory infiltration, fibrin deposition, hepatocyte necrosis and apoptosis, and prolonged survival time. Our data illustrated that combined interference using adenovirus-mediated artificial miRNAs targeting mfgl2, mFas, and mTNFR1 might have significant therapeutic potential for the treatment of fulminant hepatitis. [ABSTRACT FROM AUTHOR]

Several secondary tropomyosin receptor kinase (TRK) mutations located in the solvent front, xDFG, and gatekeeper regions, are a common cause of clinical resistance. Mutations in the xDFG motif in particular limit sensitivity to second-generation TRK inhibitors, which represent an unmet clinical need. We designed a series of 3-pyrazolyl-substituted pyrazolo[1,5- a ]pyrimidine derivatives toward these secondary mutations using ring-opening and scaffold-hopping strategies. Compound 5n was the most potent, with IC 50 values of 2.3 nM, 0.4 nM, and 0.5 nM against TRKAG667C, TRKAF589L, and TRKAG595R, compared to selitrectinib with IC 50 values of 12.6 nM, 5.8 nM, and 7.6 nM, respectively (approximately 5.4, 14.5, and 15.2-fold increases). Furthermore, 5n displayed favorable pharmacokinetic properties and satisfactory antitumor efficacy (tumor growth inhibition of 97% at 30 mg/kg and 73% at 100 mg/kg) in TRKAWT and TRKAG667C xenograft mouse models. Collectively, 5n is a promising TRK inhibitor lead compound for overcoming clinically acquired resistance to second-generation inhibitors, particularly for resistant tumors harboring the TRKAG667C mutation in the xDFG motif. [Display omitted] • TRKA G667C mutation still limit sensitivity to the second-generation inhibitors. • A novel inhibitor 5n was rationally designed to overcome the TRKA G667C mutation. • Compound 5n displayed favorable pharmacokinetic profile and antitumor efficacy. [ABSTRACT FROM AUTHOR]

Background & Aims: Aberrant activation of the signal transducer and activator of transcription (Stat)3 and overexpression of polo-like kinase (PLK)1 each have been associated with cancer pathogenesis. The mechanisms and significance of dysregulation of Stat3 and PLK1 in carcinogenesis and cancer progression are unclear. We investigated the relationship between Stat3 and PLK1 and the effects of their dysregulation in esophageal squamous cell carcinoma (ESCC) cells. Methods: We used immunoblot, quantitative reverse-transcription polymerase chain reaction, immunochemistry, chromatin immunoprecipitation, mobility shift, and reporter assays to investigate the relationship between Stat3 and PLK1. We used colony formation, fluorescence-activated cell sorting, terminal deoxynucleotidyl transferase–mediated deoxyuridine triphosphate nick-end labeling, and xenograft tumor assays to determine the effects of increased activation of Stat3 and PLK1 in proliferation and survival of ESCC cells. Results: Stat3 directly activated transcription of PLK1 in esophageal cancer cells and mouse embryonic fibroblast cell NIH3T3. PLK1 then potentiated the expression of Stat3; β-catenin was involved in PLK1-dependent transcriptional activation of Stat3. This mutual regulation between Stat3 and PLK1 was required for proliferation of esophageal cancer cells and resistance to apoptosis in culture and as tumor xenografts in mice. Furthermore, phosphorylation of Stat3 and overexpression of PLK1 were correlated in a subset of ESCC. Conclusions: Stat3 and PLK1 control each other''s transcription in a positive feedback loop that contributes to the development of ESCC. Increased activity of Stat3 and overexpression of PLK1 promote survival and proliferation of ESCC cells in culture and in mice. [Copyright &y& Elsevier]

11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) regulates glucocorticoid action by activating glucocorticoids at the tissue level. Both genetic and pharmacologic studies suggest that 11β-HSD1 inhibition is a viable therapeutic strategy for the treatment of type 2 diabetes and metabolic syndrome. There are two sources of active glucocorticoids in the target tissue: the plasma cortisol (or corticosterone in rodents) and that produced locally by 11β-HSDI. The physiological effect is mediated by the total local glucocorticoid level in a given tissue. Due to the circadian variation of plasma glucocorticoids, the pharmacologic efficacy of 11βHSD1 inhibition may depend on the timing of inhibitor administration. In order to determine the optimal time to acheive maximum efficacy, we used a diet induced obesity (DIO) mouse model and a novel small molecule inhibitor of 11β-HSD1 from our thiazolone series. Mice were fed a high fat diet for 12 weeks, randomized on their fed blood glucose and treated with an 11β-HSD1 inhibitor for 3 weeks. This compound is potent and selective for the 11β-HSD1 enzyme from several species. One group of mice was treated at 25 mpk in the morning (AM), a second group at 25 mpk in the evening (PM) and a third group at 12.5 mpk BID. Three groups of mice were treated with vehicle following the same schedule as the 11β-HSD1 inhibitor. At the end of the treatment, a sub-group of mice from each group were challenged with a glucose tolerance test (GTT) and the rest were used for determination of lipid and insulin levels. During the GTT, glucose clearance was improved only in mice treated with the 11β-HSD1 inhibitor in the PM or BID. Fasted and fed blood glucose levels were decreased in the same groups. In conclusion, in this animal model an 11β-HSD1 inhibitor showed maximum efficacy when dosed in the PM (when the plasma corticosterone is high), Dosing in the AM, when the plasma corticosterone is low, does not appear to be important in achieving efficacy. [ABSTRACT FROM AUTHOR]

We estimated the dosimetry of 18 F-alfatide II with the method established by MIRD based on biodistribution data of mice. Six mice (three females and three males) were scanned for 160 min on an Inveon MicroPET/CT scanner after injection of 18 F-alfatide II via tail vein. Eight source organs were delineated on the CT images and their residence times calculated. The data was then converted to human using scaling factors based on organ and body weight. The absorbed doses for human and the resulting effective dose were computed by OLINDA 1.1 software. The highest absorbed doses was observed in urinary bladder wall (male 0.102 mGy/MBq, female 0.147 mGy/MBq); and the lowest one was detected in brain (male 0.0030 mGy/MBq, female 0.0036). The total effective doses were 0.0127 mSv/MBq for male and 0.0166 mSv/MBq for female, respectively. A 370-MBq injection of 18 F-alfatide II led to an estimated effective dose of 4.70 mSv for male and 6.14 mSv for female. The potential radiation burden associated with 18 F-alfatide II/PET imaging therefore is comparable to other PET examinations. [ABSTRACT FROM AUTHOR]

Amyotrophic lateral sclerosis (ALS) is a fatal and incurable disease involving motor neuron (MN) degeneration and is characterized by ongoing myasthenia and amyotrophia in adults. Most ALS patients die of respiratory muscle paralysis after an average of 3–5 years. Defective autophagy in MNs is considered an important trigger of ALS pathogenesis. Roflupram (ROF) was demonstrated to activate autophagy in microglial cells and exert protective effects against Parkinson's disease (PD) and Alzheimer's disease (AD). Therefore, our research aimed to investigate the efficacy and mechanism of ROF in treating ALS both in vivo and in vitro. We found that ROF could delay disease onset and prolong the survival of hSOD1-G93A transgenic mice. Moreover, ROF protected MNs in the anterior horn of the spinal cord, activated the AMPK/ULK1 signaling pathway, increased autophagic flow, and reduced SOD1 aggregation. In an NSC34 cell line stably transfected with hSOD1-G93A , ROF protected against cellular damage caused by hSOD1-G93A. Moreover, we have demonstrated that ROF inhibited gliosis in ALS model mice. Collectively, our study suggested that ROF is neuroprotective in ALS models and the AMPK/ULK1 signaling pathway is a potential therapeutic target in ALS, which increases autophagic flow and reduces SOD1 aggregation. [ABSTRACT FROM AUTHOR]

Abstract: Furocoumarins are a group of natural products with many biological activities. Clinical evidences have demonstrated the important contribution of furocoumarins to the toxicity of some foods and herbs. In order to assess liver and kidney toxicity of furocoumarins, male mice were orally administrated with psoralen, isopsoralen, imperatorin, isoimperatorin and xanthotoxin at 20 and 40mg/kg once daily for 28 days, respectively. No changes of food or water intake were observed in furocoumarins-treated mice. Only 40mg/kg isopsoralen reduced body weight. 40mg/kg furocoumarins altered serum activities of alanine transaminase, aspartate aminotransferase, alkaline phosphatase, and/or levels of albumin, showing hepatotoxicity. Furthermore, furocoumarins increased activity and protein expression of hepatic microsomal cytochrome P450 (CYP450) 3A11. CYP 2E1 activity and protein expression were suppressed by psoralen and isopsoralen and increased by xanthotoxin. Renal protein levels of organic cation/carnitine transporters (OCT1, OCT2 and OCTN2) and organic anion transporter 3 were increased by most furocoumarins. Renal urate transporter 1, glucose transporter 9 and multidrug resistance protein 4 were influenced by furocoumarins. These findings suggest that furocoumarins may interfere in metabolism, excretion and bioavailability of endogenous and exogenous compounds to impair liver and kidney functions mediated by affecting hepatic CYP450 and renal organic ion transport system. [Copyright &y& Elsevier]

• A novel mouse model of schizophrenia was established by MK-801 plus Cuprizone. • The novel model showed severe memory deficits, hyperactivity and anxiety disorder. • The novel model showed obvious demyelination and white matter damage. • The novel model displayed dysregulations in Fyn and NMDARs. Schizophrenia is a mental illness characterized by episodes of psychosis, apathy, social withdrawal, and cognitive impairment. White matter lesions and glutamatergic hypofunction are reported to be the key pathogeneses underlying the multiple clinical symptoms of schizophrenia. Cuprizone (CPZ) is a copper chelator that selectively injures oligodendrocytes, and MK-801 is an antagonist of the N -methyl d -aspartate (NMDA) receptor. To better mimic the psychosis and complicated pathogenesis of schizophrenia, a novel possible mouse model was established by the combination of CPZ and MK-801. After exposure to CPZ for 5 weeks, the mice received a daily intraperitoneal injection of MK-801 for 2-weeks. Behavioral changes in the mouse model were evaluated using Y-maze, object recognition, and open field tests. Pathological changes were observed by transmission electron microscopy, oil red O staining, immunohistochemistry, and western blotting. The results showed that the novel mouse model induced by CPZ plus MK-801 exhibited severe spatial and recognition memory deficits, hyperactivity, and anxiety disorder. Moreover, the mice showed obvious demyelination and white matter damage and decreased expression levels of myelin basic protein (MBP) and 2′,3′-cyclic nucleotide-3′-phosphodiesterase (CNPase) in the corpus callosum. Furthermore, the phosphorylation levels of Fyn and NMDA receptor 2B in the corpus callosum and NMDA receptor 1 in the cerebral cortex were noticeably decreased. Taken together, the novel mouse model induced by the combination of cuprizone and MK-801 showed comprehensive behavioral and neurobiological changes, which might make it a suitable animal model for schizophrenia. [ABSTRACT FROM AUTHOR]

Accumulating researches reported that particulate matter (PM2.5) is a risk factor for developing various diseases, including metabolic syndrome. Recently, inactive rhomboid protein 2 (iRhom2) was considered as a necessary modulator for shedding of tumor necrosis factor-α (TNF-α) in immune cells. TNF-α, a major pro-inflammatory cytokine, was linked to various pathogenesis of diseases, including dyslipidemia. Here, wild type (WT) and iRhom2-knockout (iRhom2 −/− ) mice were used to investigate the effects of iRhom2 on PM2.5-induced hepatic dyslipidemia. The hepatic histology, inflammatory response, glucose tolerance, serum parameters and gene expressions were analyzed. We found that long-term inhalation of PM2.5 resulted in hepatic steatosis. And a significant up-regulation of iRhom2 in liver tissues was observed, accompanied with elevated TNF-α, TNF-α converting enzyme (TACE), TNFα receptor (TNFR)2 and various inflammatory cytokines expressions. Additionally, PM2.5 treatment caused TG and TC accumulation in serum and liver, probably attributed to changes of genes modulating lipid metabolism. Intriguingly, hepatic injury and dyslipidemia were attenuated by iRhom2 −/− in mice with PM2.5 challenge. In vitro, iRhom2-knockdwon reduced TNF-α expressions and its associated inflammatory cytokines in Kupffer cells, implying that liver-resident macrophages played an important role in regulating hepatic inflammation and lipid metabolism in cells treated with PM2.5. The findings indicated that long-term PM2.5 exposure caused hepatic steatosis and dyslipidemia through triggering inflammation, which was, at least partly, dependent on iRhom2/TNF-α pathway in liver-resident macrophages. [ABSTRACT FROM AUTHOR]

Type 1 diabetes (T1D) is a metabolic disease induced by abnormal insulin secretions from damaged islet B cells. Clinical observations have shown that T1D patients are more easily infected by influenza A virus (IAV) and suffer more serious symptoms than non-T1D patients. To investigate the susceptibility of T1D mice to IAV, a T1D mouse model was built by intraperitoneal injection of diluted streptozotocin (STZ) over 5 consecutive days, followed by infection with three subtypes of IAV (H1N1/H5N1/H7N2). The T1D-infected mice showed more serious clinical symptoms and lower survival rates than the non-T1D infected mice. The hematoxylin and eosin (H&E) staining results revealed an increase in serious pathological damage to the lung and pancreas in T1D-infected mice. Immunohistochemistry results indicated higher IAV loads and a more extensive distribution of positive signals in the lungs and pancreas of T1D-infected mice than in those of non-T1D infected mice. Furthermore, according to real-time quantitative polymerase chain reaction (PCR) results, viral replication appeared to occur more easily in the lungs of T1D-infected mice. Thus, T1D-infected mice exhibited higher susceptibility to IAV than did normal mice. This study contributes a mouse model suitable for T1D research as well as valuable information about the mechanism underlying T1D patients' increased susceptibility to IAV. [ABSTRACT FROM AUTHOR]

Alzheimer’s disease (AD) is the most common age-dependent neurodegenerative disorder, characterized by a progressive dysfunction of central neurons, and senescence-accelerated mouse prone 8 (SAMP8), a spontaneous AD mouse model, appears to be an excellent model to investigate the process of AD. Previous studies have indicated that neuronal excitability is impaired in transgenic AD mice. In this study, the cognition of SAMP8 mice was tested using the passive avoidance task and Morris water maze; whole-cell current-clamp recordings were used to evaluate the neuronal excitability, including the resting membrane potential, the number of action potentials, and after-hyperpolarization; and the voltage-dependent Ca 2+ current in hippocampal slices was measured using whole-cell voltage-clamp recordings. We found that compared to the young mice, the performance in the learning and memory behavior tasks was impaired in aged mice, and the hippocampal CA1 pyramidal neurons of the aged mice showed a significantly depolarized resting membrane potential, increased numbers of action potentials after injection of depolarizing current, and increased after-hyperpolarization after the action potentials. Consistent with the above changes, the voltage-dependent Ca 2+ current was larger in aged mice than in young mice. These data suggested that the aged SAMP8 neurons were hyperexcitable, and the alterations in the voltage-dependent Ca 2+ current of aged neurons occurred in parallel to the elevation in excitability. [ABSTRACT FROM AUTHOR]

To date, we still lack an ideal strategy for designing envelope glycoprotein (Env) vaccines to elicit potent protective antibodies against HIV-1 infection. Since the human hepatitis B virus surface antigen (HBsAg) is representative of effective vaccines that can induce ideal humoral immune responses, knowledge of how it elicits antibody responses and T helper cells would be an useful reference for HIV vaccine development. We compared the characteristics of the HIV-1 Env gp120 trimer and HBsAg in antibody elicitation and induction of T follicular helper (Tfh) and memory B cells in immunized Balb/c mice. Using the strategy of protein prime-protein boost, we found that HIV-1 gp120 induced slower recall antibody responses but redundant non-specific IgG responses at early time after boosting compared to HBsAg. The higher frequency of PD-1 hi CD4 + T cells and Tfh cells that appeared at the early time point after gp120 boosting is likely to limit the development of memory B cells, memory T cells, and specific antibody recall responses. These findings regarding the different features of HIV envelope and HBsAg in T helper cell responses may provide a direction to improve HIV envelope immunogenicity. [ABSTRACT FROM AUTHOR]

Nodamura virus (NoV) lethally infects suckling mice and contains a segmented positive-strand RNA genome that encodes a potent suppressor of RNA interference (RNAi). Recent studies have demonstrated immune detection and subsequent processing of NoV dsRNA replicative intermediates by the mouse RNAi machinery. However, diverse RNA viruses, including Encephalomyocarditis virus that also triggers Dicer-dependent biogenesis of viral siRNAs in mouse cells, are targeted in mammals by RIG-I-like receptors that initiate an IFN-dependent antiviral response. Using mouse embryonic fibroblasts (MEFs) for NoV infection, here we show that MEFs derived from mice knockout for RIG-I, but not those knockout for MDA5, LGP2, TLR3 or TLR7, exhibited an enhanced susceptibility to NoV. Further studies indicate that NoV infection induced an IFN-dependent antiviral response mediated by RIG-I. Our findings suggest that RIG-I directs a typical IFN-dependent antiviral response against an RNA virus capable of suppressing the RNAi response. [ABSTRACT FROM AUTHOR]

Water-soluble superparamagnetic iron oxide nanoparticles (SPIONs) were synthesized by the thermal decomposition of iron (III) acetylacetonate (Fe(acac) 3 ) in the mixture of poly(ethylene glycol) (PEG) and poly(ethylene imine) (PEI). The average sizes of the SPIONs are in the range of 6–12 nm, which could be tuned by adjusting the synthesis temperature and molecular weight of PEI. Benefiting from the coating of hydrophilic PEG and PEI, the resulted SPIONs showed excellent colloidal stability in deionized water and other physiological buffers. The XRD patterns indicate that the obtained SPIONs are magnetite. The PEG/PEI-SPIONs exhibited high r 2 / r 1 ratio. In vivo magnetic resonance imaging (MRI) of the mouse brains after intravenous injection of the SPIONs showed their good contrast effect. Considering the facile fabrication process and excellent imaging performance of the water soluble PEG-SPIONs and PEG/PEI-SPIONs, it is believed that the SPIONs will find great potential in advanced MRI. [ABSTRACT FROM AUTHOR]

Chronic high-frequency repetitive transcranial magnetic stimulation (rTMS) is a noninvasive method to increase the excitability of neurons, and it induces long-term effects that can improve symptoms related to neurodegenerative diseases, including cognitive ability. The present study was undertaken to identify the mechanism by which rTMS improves cognitive impairments in mice. The novel object recognition test in vivo was used to evaluate the cognitive function of the mice. Whole-cell patch-clamp recordings were used to evaluate the neuronal excitability, including the resting membrane potential, the number of action potentials induced by depolarized current, after-hyperpolarization, and the voltage-dependent Ca 2+ current in hippocampal slices. We found that the aged mice showed impairments in cognitive function, and high-frequency (25 Hz) rTMS for 14 consecutive-days ameliorated the impairments. Whole-cell patch-clamp recordings showed that, compared to matured mice, the hippocampal CA1 pyramidal neurons of aged mice showed significantly hyperpolarized resting membrane potential, significantly decreased numbers of action potentials after injection of depolarizing current, and significantly increased after-hyperpolarization after an action potential. The exposure to high-frequency rTMS significantly improved the above deficits in the neuronal excitability in the aged rTMS mice. Consistent with the above changes, the exposure to high-frequency rTMS also significantly decreased the voltage-dependent Ca 2+ current of the neurons compared with the aged sham mice. These data suggested that the rTMS could improve the age-related cognitive impairment in parallel with regulating the neuronal excitability and modifying the voltage-dependent Ca 2+ channels. [ABSTRACT FROM AUTHOR]

Abstract: Adipose-derived stem cells (ADSCs) have been shown to be pluoripotent and explored for their usage in tissue engineering. Previously, we have established a cell-based approach comprised of platelet-enriched plasma and osteo-progenitor cells for treating osteoporosis in an ovariectomized-senescence-accelerated mice (OVX-SAMP8) model. In the present study, we intend to explore the feasibility of using ADSCs as a cell-based therapeutic approach for treating osteoporosis, and to examine the effects of aging on the pluoripotency of ADSCs and the efficiency of bone formation both in vitro and in vivo. Flow cytometry was used to characterize ADSCs isolated from young and aged female SAMP8 mice and showed that the highly positive expression of surface markers such as CD44 and CD105 and negative for CD34 and CD45. Therefore, to compare the aging effects on the growth kinetics and differentiation potential of young and aged ADSCs, we found that there was a significant decline in both the proliferation rate (approximately 13.3%) and osteo-differentiation potential in aged ADSC. Subsequently, young and aged ADSCs were transplanted into the bone marrow of osteoporotic mice (OVX-SAMP8) to evaluate their bone formation ability. ADSC transplants were shown effective in restoring bone mineral density in the right/left knees, femurs and spine, 4 months post-transplantation; mice which received young ADSC transplants showed significantly higher bone regeneration（an average of 24.3% of improved BMD） over those received aged ADSCs. In conclusion, these findings showed that aging impedes osteoporosis-ameliorating potential of ADSC by diminishing osteogenic signal, and that ADSC could be used as a potential cell-based therapy for osteoporosis. [Copyright &y& Elsevier]

Abstract: The envelope protein of dengue virus is involved in host cell attachment for entry and induction of protective immunity. Current efforts are focused on producing a tetravalent vaccine by mixing four monovalent vaccine components. In this work, we developed a genetic vaccine based on a novel adeno-associated viral (AAV) vector expressing the carboxy-terminal truncated envelope protein (79E) of dengue virus. The expression of the recombinant 79E protein in HEK 293 cells was confirmed by Western blot. Vectors packaged with novel AAV capsids (AAV2/8 or AAV2/rh32.33) were injected into C57BL/6 mice intramuscularly. Dengue virus antigen was produced in the mice and induced long-lasting antibody responses against the dengue virus still detectable 20 weeks after immunization. AAV2/8 vaccine induced higher anti-dengue virus antibody levels than AAV2/rh32.33 vaccine or AAV plasmid. Furthermore, the anti-dengue antibodies could neutralize homogeneous dengue virus. These results demonstrated that the AAV vaccines possessed appropriate immunogenicity and could be used for the development of an effective dengue vaccine. [Copyright &y& Elsevier]

Abstract: Recipients of influenza A (H1N1) vaccine in 1976 had an increased risk for the neurologic disorder Guillain-Barré syndrome (GBS). Anti-ganglioside antibodies, which might be associated with the development of GBS, were previously reported to be induced in mice immunized with an H1N1 vaccine of 1976 or another influenza vaccine. In this study we analyzed anti-ganglioside antibodies in human subjects infected with or vaccinated against 2009 pandemic H1N1, including eight patients diagnosed to have post-vaccination GBS. Antibodies against GM1 or another ganglioside were not detected in any subject or in vaccinated mice. Our results did not support the induction of anti-ganglioside antibodies by influenza viruses or vaccines. [Copyright &y& Elsevier]

Abstract: Streptococcus suis is an important swine pathogen responsible for a diverse range of diseases. S. suis serotype 2 (SS2) and S. suis serotype 9 (SS9) are the prevalent serotypes in diseased Chinese pigs. Little is known about SS9 virulence factors. Two strains, GZ0565 and SH040917, were isolated from a diseased pig and a healthy pig, respectively. Suppression subtractive hybridization (SSH) was used to identify SS9 virulence genes associated with pathogenicity. We identified 30 gene fragments unique to GZ0565, including stp which encodes a serine/threonine protein phosphatase known to affect the virulence and morphology of bacteria. To investigate the role of stp in pathogenesis of SS9, an isogenic stp mutant (Δstp) and a complementation strain (CΔstp) were constructed. The results demonstrated that the stp affected the expression of a few genes involving in adhesion and virulence for bacteria. The Δstp exhibited a significant decrease in HEp-2 cell adherence, compared with the wild type, and a reduced survival ratio in whole blood. The Δstp was attenuated in a CD1 murine model of infection and its LD50 values was seven-fold higher than the wild type. Our data suggest that stp is involved in the pathogenesis of SS9. [Copyright &y& Elsevier]

Abstract: The aim of this study was to develop a new diagnostic and therapeutic approach for the treatment of osteoporosis. Previously, we demonstrated that intraosseous transplantation of platelet-rich plasma (PRP) treated-osteoblast-like cells into ovariectomized senescence-accelerated mice (OVX-SAMP8) prevented the development of osteoporosis. In continuation, we aimed to explore the complex etiology of osteoporosis using this platform. An inverse relationship between bone marrow adipogenesis and osteogenesis has been suggested in the development of osteoporosis but the underlying mechanisms remain poorly described. To address these issues, we used PRP to inhibit adipocyte differentiation by promoting osteoblastic differentiation in adipocytes. In addition, a positive correlation between an increase in bone marrow adipocytes and bone loss was established. We assessed this relationship using an osteoporotic animal disease model which consisted of young (for prevention) and old (for treatment) OVX-SAMP8 mice. This animal model demonstrated that PRP treatment mainly exerted its action via promoting bone regeneration but also appeared to suppress adipogenesis within the marrow. The findings and methodology of this study could potentially be applied in the prevention and treatment of osteoporosis. [Copyright &y& Elsevier]

Abstract: In the present study, we evaluated the beneficial effect of mulberry extracts (ME), which are rich in phenolics and anthocyanins, on the induction of antioxidant enzymes and on the promotion of cognition in senescence-accelerated mice (SAMP). Six-month old SAMP8 and SAMR1 mice were fed a basal diet supplemented with 0.18% and 0.9% ME for consecutive 12 weeks. The results showed that the mice fed the ME supplement demonstrated significantly less amyloid β protein and showed improved learning and memory ability in avoidance response tests. ME-treated mice showed a higher antioxidant enzyme activity and less lipid oxidation in both the brain and liver, as compared to the control mice. Furthermore, treatment with ME decreased the levels of serum aspartate aminotransferase, alanine aminotransferase, triglyceride and total cholesterol that increase with ageing. The hepatoprotective effect of ME appeared to occur through a mechanism related to regulation of the mitogen-activated protein kinases and activation of the nuclear factor-erythroid 2 related factor 2, where the latter regulates the induction of phase 2 antioxidant enzymes and reduction of oxidative damage. Overall, supplementation of ME might be advantageous to the induction of an antioxidant defense system and for the improvement of memory deterioration in ageing animals. [Copyright &y& Elsevier]

Abstract: This article reported the synthesis and bioevaluation of two [18F] labeled benzimidazole derivatives, 4-(5-(2-[18F] fluoro-4-nitrobenzamido)-1-methyl-1H-benzimidazol-2-yl) butanoic acid ([18F] FNBMBBA, [18F]a1) and 3-(2-fluoroethyl)-7-methyl-2-propyl-3H-benzimidazole-5-carboxylic acid ([18F] FEMPBBA, [18F]b1) for PET tumor imaging. The preparation [18F] FEMPBBA was completed in 1h with overall radiochemical yield of 50–60% (without decay corrected). Biodistribution assay in S180 tumor bearing mice of both compounds were carried out, and the results are both meaningful. [18F] FEMPBBA which can be taken as a revision of [18F] FNBMBBA got an excellent result, and has significant advantages in some aspects compared with L-[18F] FET and [18F]-FDG in the same animal model, especially in tumor/brain uptake ratio. The tumor/brain uptake ratio of [18F] FEMPBBA gets to 4.81, 7.15, and 9.8 at 30min, 60min and 120min, and is much higher than that of L-[18F] FET (2.54, 2.92 and 2.95) and [18F]-FDG (0.61, 1.02, 1.33) at the same time point. The tumor/muscle and tumor/blood uptake ratio of [18F] FEMPBBA is also higher than that of L-[18F] FET at 30min and 60min. This result indicates compound [18F] FEMPBBA is a promising radiotracer for PET tumor imaging. [Copyright &y& Elsevier]

Abstract: Macranthoside B (MB) is a hederagenin saponin extracted from the flower bud of Lonicera macranthoides. In this study, we defined the anticancer effect of MB both in vitro and in vivo using cell proliferation assays and xenograft tumor growth assays. Our data indicate that MB inhibits the proliferation of various kinds of cancer cells with IC50 values in the range of 10–20μM. Moreover, the volume and weight of xenograft tumors in nude mice treated with 5mg/kgMB were decreased remarkably compared to those of the vehicle control group. Furthermore, DAPI staining and flow cytometry analysis with Annexin V/PI double staining revealed that more apoptotic cells were observed following MB treatment. In addition, degradation of PARP (poly-ADP-ribose polymerase), and activation of the caspase cascade for intrinsic pathways were observed. We also found that the expression of Bcl-2 protein decreased and the protein level of Bax increased which leading to an increase of the Bax/Bcl-2 ratio. Our results showed that MB exhibited strong anti-tumor effect and mitochondrion-mediated apoptosis induction involved in it. [Copyright &y& Elsevier]

Abstract: Neuroprotective effects of enriched environment (EE) have been well established. Recent study suggests that exposure to EE can protect dopaminergic neurons against MPTP-induced Parkinsonism. After 64 female SAMP8 mice were reared in EE and standard environment (SE) for 3 months, the effects of EE and SE were compared on behavioural change, tyrosine hydroxylase (TH) immunoreaction positive neuron and dopaminetransporter (DAT) expression in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)-treated SAMP8. EE mice showed decreased spontaneous activity compared with SE mice. But EE+MPTP mice showed less decreased spontaneous activity compared with SE+MPTP mice. Otherwise, EE mice showed increased percentage of entries into the open arms and percentage of time spent in the open arms. Furthermore, EE mice demonstrated reduced neurotoxicity, with less decreased TH mRNA and protein expression in Substantia Nigra (SN) after MPTP administration compared with SE mice. SE mice showed a 53.77% loss of TH-positive neurons, whereas EE mice only showed a 42.28% loss. Moreover, EE mice showed decreased DAT mRNA and protein expression compared with SE mice. These data demonstrate that EE can protect dopaminergic neurons against MPTP-induced neuronal damage, which suggest that the probability of developing Parkinson''s disease (PD) may be related to life environment. [Copyright &y& Elsevier]

Abstract: Application of aged animals to studies of Parkinson''s disease (PD) will be beneficial to improve the understanding of its pathogenesis. The senescence-accelerated mouse prone8 (SAMP8) mouse has an early onset of senility and a short life span, characterized by learning and memory impairment, and affective disturbance in the aging process. There is no animal currently being used as a PD model that exhibits these characteristics. Application of the SAMP8 mouse to PD research may have several merits. For the first time, we have investigated damage of the nigrostriatal system in the SAMP8 mouse induced by 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP). Male SAMP8 mice (12 weeks) were treated with four subcutaneous injections of MPTP (20mg/kg at 2h intervals): spontaneous activity decreased significantly after the third injection, and recovered 48h after the first injection. In MPTP-SAMP8 mice, the tyrosine hydroxylase (TH)-positive neuronal loss at 6h (7.06%), 24h (12.79%), 3 days (22.49%), and 8 days (42.39%), while striatal dopamine (DA) levels decreased at 6h by 79.09%, at 24h by 80.33%, at 3 days by 83.86%, and at 8 days by 80.14%. These results indicated that there were marked decreases in striatal DA levels and a loss of dopaminergic neurons in the substantia nigra, with the behavior change following shortly thereafter, in MPTP-SAMP8 mice. On the basis of the current findings, the SAMP8 mouse is also vulnerable to neurotoxic effects of MPTP. These data suggest that the SAMP8 mouse may be utilized in PD research. [Copyright &y& Elsevier]