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Identification of the genomic mutation in Epha4(rb-2J/rb-2J) mice

Mohd-Zin SW, Abdullah NL, Abdullah A, Greene ND, Cheah PS, Ling KH, et al.

Genome, 2016 Jul;59(7):439-48.
PMID: 27373307 DOI: 10.1139/gen-2015-0142

The EphA4 receptor tyrosine kinase is involved in numerous cell-signalling activities during embryonic development. EphA4 has the ability to bind to both types of ephrin ligands, the ephrinAs and ephrinBs. The C57BL/6J-Epha4rb-2J/GrsrJ strain, denoted Epha4(rb-2J/rb-2J), is a spontaneous mouse mutant that arose at The Jackson Laboratory. These mutants exhibited a synchronous hind limb locomotion defect or "hopping gait" phenotype, which is also characteristic of EphA4 null mice. Genetic complementation experiments suggested that Epha4(rb-2J) corresponds to an allele of EphA4, but details of the genomic defect in this mouse mutant are currently unavailable. We found a single base-pair deletion in exon 9 resulting in a frame shift mutation that subsequently resulted in a premature stop codon. Analysis of the predicted structure of the truncated protein suggests that both the kinase and sterile α motif (SAM) domains are absent. Definitive determination of genotype is needed for experimental studies of mice carrying the Epha4(rb-2J) allele, and we have also developed a method to ease detection of the mutation through RFLP. Eph-ephrin family members are reportedly expressed as numerous isoforms. Hence, delineation of the specific mutation in EphA4 in this strain is important for further functional studies, such as protein-protein interactions, immunostaining and gene compensatory studies, investigating the mechanism underlying the effects of altered function of Eph family of receptor tyrosine kinases on phenotype.

Matched MeSH terms: Mice, Inbred C57BL
Fulltext Withaferin A inhibits adipogenesis in 3T3-F442A cell line, improves insulin sensitivity and promotes weight loss in high fat diet-induced obese mice

Khalilpourfarshbafi M, Devi Murugan D, Abdul Sattar MZ, Sucedaram Y, Abdullah NA

PLoS One, 2019;14(6):e0218792.
PMID: 31226166 DOI: 10.1371/journal.pone.0218792

The increased prevalence of obesity and associated insulin resistance calls for effective therapeutic treatment of metabolic diseases. The current PPARγ-targeting antidiabetic drugs have undesirable side effects. The present study investigated the anti-diabetic and anti-obesity effects of withaferin A (WFA) in diet-induced obese (DIO) C57BL/6J mice and also the anti-adipogenic effect of WFA in differentiating 3T3- F442A cells. DIO mice were treated with WFA (6 mg/kg) or rosiglitazone (10 mg/kg) for 8 weeks. At the end of the treatment period, metabolic profile, liver function and inflammatory parameters were obtained. Expression of selective genes controlling insulin signaling, inflammation, adipogenesis, energy expenditure and PPARγ phosphorylation-regulated genes in epididymal fats were analyzed. Furthermore, the anti-adipogenic effect of WFA was evaluated in 3T3- F442A cell line. WFA treatment prevented weight gain without affecting food or caloric intake in DIO mice. WFA-treated group also exhibited lower epididymal and mesenteric fat pad mass, an improvement in lipid profile and hepatic steatosis and a reduction in serum inflammatory cytokines. Insulin resistance was reduced as shown by an improvement in glucose and insulin tolerance and serum adiponectin. WFA treatment upregulated selective insulin signaling (insr, irs1, slc2a4 and pi3k) and PPARγ phosphorylation-regulated (car3, selenbp1, aplp2, txnip, and adipoq) genes, downregulated inflammatory (tnf-α and il-6) genes and altered energy expenditure controlling (tph2 and adrb3) genes. In 3T3- F442A cell line, withaferin A inhibited adipogenesis as indicated by a decrease in lipid accumulation in differentiating adipocytes and protein expression of PPARγ and C/EBPα. The effect of rosiglitazone on physiological and lipid profiles, insulin resistance, some genes expression and differentiating adipocytes were markedly different. Our data suggest that WFA is a promising therapeutic agent for both diabetes and obesity.

Matched MeSH terms: Mice, Inbred C57BL
Generation of induced pluripotent stem cells by a polycistronic lentiviral vector in feeder- and serum- free defined culture

Al Abbar A, Nordin N, Ghazalli N, Abdullah S

Tissue Cell, 2018 Dec;55:13-24.
PMID: 30503056 DOI: 10.1016/j.tice.2018.09.004

Induced pluripotent stem cells (iPSCs) have great potentials for regenerative medicine. However, serious concerns such as the use of the viral-mediated reprogramming strategies and exposure of iPSCs to animal products from feeder cells and serum-containing medium have restricted the application of iPSCs in the clinics. Therefore, the generation of iPSCs with minimal viral integrations and in non-animal sourced and serum-free medium is necessary. In this report, a polycistronic lentiviral vector carrying Yamanaka's factors was used to reprogram mouse fibroblasts into iPSCs in feeder- and xeno-free culture environment. The generated iPSCs exhibited morphology and self-renewal properties of embryonic stem cells (ESCs), expression of specific pluripotent markers, and potentials to differentiate into the three-major distinct specialized germ layers in vitro. The iPSCs were also shown to have the potential to differentiate into neural precursor and neurons in culture, with greater than 95% expression of nestin, Pax6 and βIII-tubulin. This body of work describes an alternative method of generating iPSCs by using polycistronic lentiviral vector that may minimize the risks associated with viral vector-mediated reprogramming and animal derived products in the culture media.

Matched MeSH terms: Mice, Inbred C57BL
Lack of methylation on transgene leads to high level and persistent transgene expression in induced pluripotent stem cells

Alhaji SY, Nordin N, Ngai SC, Al Abbar A, Mei L, Abdullah S

Gene, 2020 Oct 20;758:144958.
PMID: 32683073 DOI: 10.1016/j.gene.2020.144958

Short-lived therapeutic gene expression in mammalian cells by DNA methylation is one of the major challenges in gene therapy. In this study, we assessed the implication of DNA methylation on the duration of GFP expression in mouse embryonic stem (ES) and mouse induced pluripotent stem (iPS) cells. The cells were transduced with lentivirus (LV) carrying green fluorescent protein (GFP) driven by either human elongation factor (EF1α) or cytomegalovirus (CMV) promoter. Transduced iPS cells exhibited higher percentage of GFP+ cells with persistent mean fluorescent intensity than transduced ES cells. Analysis on the integrated copy of transgene in the population of the transduced cells demonstrated similar copy number. However, significant increase in GFP intensity following 5-azaC treatment was observed in transduced ES cells only, suggesting the influence of DNA methylation in transgene silencing. Subsequent DNA methylation analysis showed that the promoter and the GFP region of the provirus in iPS cells had negligible methylation profile compared to transduced ES cells. Interestingly, sustained transgene expression was observed upon directed differentiation of transduced iPS cells towards CD34+ CD45+ cells. Hence, this study has shown that favourable transgene activity from lentiviral transduced iPS cells was due to the lack of methylation at the proviral regions.

Matched MeSH terms: Mice, Inbred C57BL
Fulltext Liposomes derived from Mycobacterium smegmatis promote immune activation of mice bone marrow-derived dendritic cells

Mat Luwi NE, Kadir R, Mohamud R, A Garcia-Santana ML, Acevedo R, Sarmiento ME, et al.

Int J Mycobacteriol, 2020 8 31;9(3):261-267.
PMID: 32862158 DOI: 10.4103/ijmy.ijmy_82_20

Background: Tuberculosis (TB) is the leading cause of mortality due to infectious diseases. The development of new generation vaccines against TB is of paramount importance for the control of the disease. In previous studies, liposomes obtained from lipids of Mycobacterium smegmatis (LMs) demonstrated their immunogenicity and protective capacity against Mycobacterium tuberculosis in mice. To characterize the immunomodulatory capacity of this experimental vaccine candidate, in the current study, the stimulatory capacity of LMs was determined on bone marrow-derived dendritic cells (BMDCs) from mice.
Methods: LMs were obtained and incubated with mature BMDCs. The internalization of LMs by BMDCs was studied by confocal microscopy, and the LMs immune-stimulatory capacity was determined by the expression of surface molecules (CD86 and MHCII) and the cytokine production (interleukin [IL]-12, interferon-Υ, tumor necrosis factor-α, and IL-10) 24 h after exposure to LMs.
Results: The interaction of LMs with BMDCs and its internalization was demonstrated as well as the immune activation of BMDCs, characterized by the increased expression of CD86 and the production of IL-12. The LMs internalization and immune activation of BMDCs were blocked in the presence of cytochalasin, filipin III and chlorpromazine, which demonstrated that internalization of LMs by BMDCs is a key process for the LMs induced immune activation of BMDCs.
Conclusions: The results obtained support the further evaluation of LMs as a mycobacterial vaccine, adjuvant, and in immunotherapy.

Matched MeSH terms: Mice, Inbred C57BL
Fulltext Effect of postoperative corticosteroids on surgical outcome and aqueous autotaxin following combined cataract and microhook ab interno trabeculotomy

Honjo M, Yamagishi R, Igarashi N, Ku CY, Kurano M, Yatomi Y, et al.

Sci Rep, 2021 01 12;11(1):747.
PMID: 33436915 DOI: 10.1038/s41598-020-80736-w

To evaluate the effect of postoperative corticosteroids on surgical outcome and autotaxin (ATX) levels after microhook ab interno trabeculotomy combined with cataract surgery (μLOT-CS), prospective, consecutive non-randomized case series comparing outcomes of 30 eyes with primary open angle glaucoma was performed. The aqueous ATX, intraocular pressure (IOP) and glaucoma medications were monitored for 3 months postoperatively. An in-vivo mouse μLOT model was generated. In vitro, ATX and fibrotic changes induced by dexamethasone (Dex) treatment following scratch (S) in cultured human trabecular meshwork (hTM) cells were assessed by immunofluorescence, immunoenzymatic assay, and RT-qPCR. Postoperative ATX at 1 week and the number of antiglaucoma medications at 3 months were significantly lower in non-steroid group, and steroid use was the only variable significantly associated with postoperative medications at 3 months in multiregression analyses. In vitro, ATX activity was significantly upregulated in the Dex + S group, and αSMA was significantly upregulated in the Dex and Dex + S groups. Fibronectin and COL1A1 were significantly upregulated in the S group. μLOT-CS decreased IOP and medications in the overall cohort, and non-use of postoperative steroids resulted in a smaller number of postoperative medications. Limiting postoperative steroids in μLOT may minimize IOP elevation and postoperative fibrosis.

Matched MeSH terms: Mice, Inbred C57BL
Fulltext Anti-obesity and anti-inflammatory effects of synthetic acetic acid vinegar and Nipa vinegar on high-fat-diet-induced obese mice

Beh BK, Mohamad NE, Yeap SK, Ky H, Boo SY, Chua JYH, et al.

Sci Rep, 2017 07 27;7(1):6664.
PMID: 28751642 DOI: 10.1038/s41598-017-06235-7

Recently, food-based bioactive ingredients, such as vinegar, have been proposed as a potential solution to overcome the global obesity epidemic. Although acetic acid has been identified as the main component in vinegar that contributes to its anti-obesity effect, reports have shown that vinegar produced from different starting materials possess different degrees of bioactivity. This study was performed to compare the anti-obesity and anti-inflammatory effects of synthetic acetic acid vinegar and Nipa vinegar in mice fed a high-fat diet. In this work, mice were fed a high-fat diet for 33 weeks. At the start of week 24, obese mice were orally fed synthetic acetic acid vinegar or Nipa vinegar (0.08 and 2 ml/kg BW) until the end of week 33. Mice fed a standard pellet diet served as a control. Although both synthetic acetic acid vinegar and Nipa vinegar effectively reduced food intake and body weight, a high dose of Nipa vinegar more effectively reduced lipid deposition, improved the serum lipid profile, increased adipokine expression and suppressed inflammation in the obese mice. Thus, a high dose of Nipa vinegar may potentially alleviate obesity by altering the lipid metabolism, inflammation and gut microbe composition in high-fat-diet-induced obese mice.

Matched MeSH terms: Mice, Inbred C57BL
Fulltext Pineapple Vinegar Regulates Obesity-Related Genes and Alters the Gut Microbiota in High-Fat Diet (HFD) C57BL/6 Obese Mice

Mohamad NE, Yeap SK, Ky H, Liew NWC, Beh BK, Boo SY, et al.

Evid Based Complement Alternat Med, 2020;2020:1257962.
PMID: 33029159 DOI: 10.1155/2020/1257962

Obesity is a pandemic metabolic syndrome with increasing incidences every year. Among the significant factors that lead to obesity, overconsumption of high-fat food in daily intake is always the main contributor. Functional foods have shown a positive effect on disease prevention and provide health benefits, including counteracting obesity problem. Vinegar is one of the fermented functional beverages that have been consumed for many years, and different types of vinegar showed different bioactivities and efficacies. In this study, we investigated the potential effects of pineapple vinegar as an antiobesity agent on a high-fat diet- (HFD-) induced C57BL/6 obese mice. C57BL/6 mice were treated with pineapple vinegar (1 mL/kg BW and 0.08 mL/kg BW) for 12 weeks after 24 weeks of HFD incubation. Serum biochemistry profiles, antioxidant assays, qPCR, proteome profiler, and 16S metagenomic were done posttreatment. Our data showed that a high concentration of pineapple vinegar (1 mL/kg BW) treatment significantly (p < 0.05) reduced the bodyweight (∼20%), restored lipid profiles, increased the antioxidant activities, and reduced the oxidative stress. Besides, significant (p < 0.05) regulation of several adipokines and inflammatory-related genes was recorded. Through the regulation of gut microbiota, we found a higher abundance of Akkermansia muciniphila, a microbiota reported to be associated with obesity in the high concentration of pineapple vinegar treatment. Collectively, these data established the mechanism of pineapple vinegar as antiobesity in mice and revealed the potential of pineapple vinegar as a functional food for obesity.

Matched MeSH terms: Mice, Inbred C57BL
Khat (Catha edulis) upregulates lipolytic genes in white adipose tissue of male obese mice (C57BL/6J)

Alshagga MA, Mohamed Z, Seyedan A, Ebling FJP, Alshawsh MA

J Ethnopharmacol, 2020 Nov 15;262:113187.
PMID: 32730892 DOI: 10.1016/j.jep.2020.113187

ETHNOPHARMACOLOGICAL RELEVANCE: Khat (Catha edulis (Vahl) Forssk.) is a herb from the Celastraceae family (also known as qat, gaad, or mirra) that is widely-consumed in East Africa and in the Arabian peninsula. The green leaves and small stems are consumed primarily at recreational and social gatherings, and medicinally for their antidiabetic and appetite-suppression effects.
AIMS: The objectives of this study were to determine the effects of khat and its active alkaloid, cathinone, on food intake and body weight in mice maintained on a high-fat diet, and to investigate its mechanism of action in white adipose tissue and in the hypothalamus.
MATERIALS & METHOD: Adult male mice (C57BL/6J) were fed a high fat diet (HFD) for 8 weeks (n = 30), then divided into 5 groups and treated daily for a further 8 weeks with HFD + vehicle [control (HFD)], HFD + 15 mg/kg orlistat (HFDO), HFD + 200 mg/kg khat extract (HFDK200), HFD + 400 mg/kg khat extract (HFDK400) and HFD + 3.2 mg/kg cathinone (HFDCAT). Treatments were carried out once daily by gastric gavage. Blood and tissue samples were collected for biochemical, hormonal and gene expression analyses.
RESULTS: Khat extracts and orlistat treatment significantly reduced weight gain as compared to control mice on HFD, and cathinone administration completely prevented weight gain in mice fed on HFD. Khat treatment caused a marked reduction in body fat and in serum triglycerides. A dose-dependent effect of khat was observed in reducing serum leptin concentrations. Analysis of gene expression in adipose tissue revealed a significant upregulation of two lipolysis pathway genes:(adipose triglyceride lipase (PNPLA-2) and hormone-sensitive lipase (LIPE). In the hypothalamic there was a significant (P mice on an obesogenic diet through stimulation of lipolysis in white adipose tissue.

Matched MeSH terms: Mice, Inbred C57BL
Cynometra cauliflora Linn. Attenuates metabolic abnormalities in high-fat diet-induced obese mice

Seyedan A, Mohamed Z, Alshagga MA, Koosha S, Alshawsh MA

J Ethnopharmacol, 2019 May 23;236:173-182.
PMID: 30851371 DOI: 10.1016/j.jep.2019.03.001

ETHNOPHARMACOLOGICAL RELEVANCE: Cynometra cauliflora Linn. belongs to the Fabaceae family and is known locally in Malaysia as nam-nam. Traditionally, a decoction of the C. cauliflora leaves is used for treating hyperlipidemia and diabetes.
AIM OF THE STUDY: This study aims to investigate the anti-obesity and lipid lowering effects of ethanolic extract of C. cauliflora leaves and its major compound (vitexin) in C57BL/6 obese mice induced by high-fat diet (HFD), as well as to further identify the molecular mechanism underlying this action.
METHODS AND MATERIAL: Male C57BL/6 mice were fed with HFD (60% fat) for 16 weeks to become obese. The treatment started during the last 8 weeks of HFD feeding and the obese mice were treated with C. cauliflora leaf extract at 200 and 400 mg/kg/day, orlistat (10 mg/kg) and vitexin (10 mg/kg).
RESULTS: The oral administration of C. cauliflora (400 and 200 mg/kg) and vitexin significantly reduced body weight, adipose tissue and liver weight and lipid accumulation in the liver compared to control HFD group. Both doses of C. cauliflora also significantly (P ≤ 0.05) decreased serum triglyceride, LDL, lipase, IL-6, peptide YY, resistin levels, hyperglycemia, hyperinsulinemia, and hyperleptinemia compared to the control HFD group. Moreover, C. cauliflora significantly up-regulated the expression of adiponectin, Glut4, Mtor, IRS-1 and InsR genes, and significantly decreased the expression of Lepr in white adipose tissue. Furthermore, C. cauliflora significantly up-regulated the expression of hypothalamus Glut4, Mtor and NF-kB genes. GC-MS analysis of C. cauliflora leaves detected the presence of phytol, vitamin E and β-sitosterol. Besides, the phytochemical evaluation of C. cauliflora leaves showed the presence of flavonoid, saponin and phenolic compounds.
CONCLUSION: This study shows interesting outcomes of C. cauliflora against HFD-induced obesity and associated metabolic abnormalities. Therefore, the C. cauliflora extract could be a potentially effective agent for obesity management and its related metabolic disorders such as insulin resistance and hyperlipidemia.

Matched MeSH terms: Mice, Inbred C57BL
Fulltext A mouse model of weight-drop closed head injury: emphasis on cognitive and neurological deficiency

Khalin I, Jamari NL, Razak NB, Hasain ZB, Nor MA, Zainudin MH, et al.

Neural Regen Res, 2016 Apr;11(4):630-5.
PMID: 27212925 DOI: 10.4103/1673-5374.180749

Traumatic brain injury (TBI) is a leading cause of death and disability in individuals worldwide. Producing a clinically relevant TBI model in small-sized animals remains fairly challenging. For good screening of potential therapeutics, which are effective in the treatment of TBI, animal models of TBI should be established and standardized. In this study, we established mouse models of closed head injury using the Shohami weight-drop method with some modifications concerning cognitive deficiency assessment and provided a detailed description of the severe TBI animal model. We found that 250 g falling weight from 2 cm height produced severe closed head injury in C57BL/6 male mice. Cognitive disorders in mice with severe closed head injury could be detected using passive avoidance test on day 7 after injury. Findings from this study indicate that weight-drop injury animal models are suitable for further screening of brain neuroprotectants and potentially are similar to those seen in human TBI.

Matched MeSH terms: Mice, Inbred C57BL
Insights into immunopathology and triggering of apoptosis in chronic cerebral toxoplasmosis using murine models

El Saftawy EA, Shash RY, Aboulhoda BE, Arsanyos SF, Albadawi EA, Abou-Fandoud SM, et al.

Trop Biomed, 2021 Jun 01;38(2):53-62.
PMID: 33973573 DOI: 10.47665/tb.38.2.037

BACKGROUND: toxoplasmosis is a cosmopolitan protozoan disease with a wide range of neuropathology. Recent studies identified its potential association with several mental disorders e.g. schizophrenia dependable on apoptosis in their pathogenesis. We investigated value of toxoplasmosis to induce apoptosis of the neuronal cells.
METHODS: per-orally infected C57BL/6 mice with 15-20 cysts of the avirulent T. gondii Beverly strain at 9-11 weeks of age were examined 12 weeks later during parasite establishment. Distributions of the parasite's cysts and the histopathological lesions in the brains were analyzed using Image J software. Relative expression of TNF-α and iNOS of cell-mediated immunity (CMI), Bax (pro-apoptosis) and Bcl-2 (anti-apoptosis) were all assessed using immunohistochemistry.
RESULTS: higher parasite burden was seen in the forebrain with p value <= 0.05. Dramatically increased TNF-α, iNOS, and Bax expressions with Bax/Bcl-2 ratio 2.42:0.52 were reported (p value <= 0.05). The significant correlation between Bax data and different CMI biomarkers including TNF-α and i-NOS was evaluated. Interestingly, no significant correlation was seen between TNF-α, iNOS, Bax and Bcl-2 expressions and location of the parasite. However, Bax/Bcl-2 ratio was statistically correlated with CMI biomarkers and whole sample mean parasite burden, p value <= 0.05.
CONCLUSION: Chronic toxoplasmosis exhibits an immense pro-apoptotic signal on the cerebral tissues of experimental mice.

Matched MeSH terms: Mice, Inbred C57BL
Demonstration of antigenic similarities and variations in excretory/secretory antigens of Toxoplasma gondii

Rahmah N, Anuar AK

Biochem Biophys Res Commun, 1992 Aug 31;187(1):294-8.
PMID: 1520310

C57BL/6 mice were orally infected with different doses of cysts of ME49 strain of Toxoplasma gondii to produce groups of acutely and chronically infected mice. Sera were obtained at different periods post-infection. SDS-PAGE was ran with excretory/secretory antigens of ME49 and RH strains of T. gondii, followed by Western blot analyses using the above sera and anti- IgA, IgM, IgG as conjugates. The SDS-PAGE profiles of the two antigens were similar. However the antigenic bands showed variations in all blots, most evidently in IgA blots of chronic sera. IgG blots showed greatest similarities in reactive bands. In IgM blots, more common bands were shown in chronic sera than in acute sera. Variations and similarities in prominence of some bands and time of their appearance were also noted, especially in IgM and IgG blots of chronic sera. Thus antigenic variations and similarities are present in excretory/secretory products of different strains of T. gondii.

Matched MeSH terms: Mice, Inbred C57BL
Use of prednisolone to aid propagation of Toxoplasma gondii in mice

Puvanesuaran VR, Nowroji K, Sreenivasan S, Noordin R, Balakrishnan V

Eur Rev Med Pharmacol Sci, 2012 Aug;16(8):1028-32.
PMID: 22913152

AIM: To determine the usefulness of prednisolone in increasing the number of Toxoplasma (T.) gondii tachyzoites and bradyzoites in mice.
MATERIALS AND METHODS: The mice were water-fasted prior to being immunosuppressed with oral inoculation of prednisolone. Tachyzoites of 7T gondii RH strain were inoculated into mice and the number of the parasites in the intraperitoneal fluids was then determined at 96 hs post-infection. In addition, tachyzoites of T. gondii ME49 strains were orally introduced into mice and the number of brain cysts formed was observed by microscopic observation at 45 days post-infection.
RESULTS: T. gondii propagation was found to be significantly improved by introduction of the prednisolone (p = 0.0004); and the number of parasite showed positive correlation with the increment in dosage of prednisolone (r = 0.9051).
CONCLUSIONS: The use of prednisolone greatly improved the number of parasite formed in mice: both tachyzoite and cyst forms.

Matched MeSH terms: Mice, Inbred C57BL
Isolation of viable Toxoplasma gondii cysts from brain samples for oral infection

Puvanesuaran VR, Ibrahim N, Noordin R, Balakrishnan V

Eur Rev Med Pharmacol Sci, 2012 Sep;16(9):1179-83.
PMID: 23047500

AIM: A method was developed to separate contaminant-free viable Toxoplasma gondii cysts from brain samples of infected mice for molecular biology studies and reinfection.
MATERIALS AND METHODS: The mice brains were homogenized and washed with phosphate buffered saline (PBS) Tween 80 prior to fractionation using 19-22% dextran solution. Finally, the supernatant was purified by two-step membrane filtration (100-160 microm and < 10 microm) to obtain pure T. gondii cyst. The isolates were analyzed through microscopic observation, qPCR and by reinfection of new batch of mice.
RESULTS: T. gondii cysts were best isolated with 21% dextran solution and two step filtration.
CONCLUSIONS: The method was observed not to disrupt the integrity of the cysts containing bradyzoites. In addition, the isolated cysts in the filtrate were found to be contaminant-free, viable and able to infect healthy mice when introduced orally; which, mimics the natural infectivity pathway.

Matched MeSH terms: Mice, Inbred C57BL
Fulltext Mitochondrial Respiration Is Reduced in Atherosclerosis, Promoting Necrotic Core Formation and Reducing Relative Fibrous Cap Thickness

Yu EPK, Reinhold J, Yu H, Starks L, Uryga AK, Foote K, et al.

Arterioscler Thromb Vasc Biol, 2017 12;37(12):2322-2332.
PMID: 28970293 DOI: 10.1161/ATVBAHA.117.310042

OBJECTIVE: Mitochondrial DNA (mtDNA) damage is present in murine and human atherosclerotic plaques. However, whether endogenous levels of mtDNA damage are sufficient to cause mitochondrial dysfunction and whether decreasing mtDNA damage and improving mitochondrial respiration affects plaque burden or composition are unclear. We examined mitochondrial respiration in human atherosclerotic plaques and whether augmenting mitochondrial respiration affects atherogenesis.
APPROACH AND RESULTS: Human atherosclerotic plaques showed marked mitochondrial dysfunction, manifested as reduced mtDNA copy number and oxygen consumption rate in fibrous cap and core regions. Vascular smooth muscle cells derived from plaques showed impaired mitochondrial respiration, reduced complex I expression, and increased mitophagy, which was induced by oxidized low-density lipoprotein. Apolipoprotein E-deficient (ApoE-/-) mice showed decreased mtDNA integrity and mitochondrial respiration, associated with increased mitochondrial reactive oxygen species. To determine whether alleviating mtDNA damage and increasing mitochondrial respiration affects atherogenesis, we studied ApoE-/- mice overexpressing the mitochondrial helicase Twinkle (Tw+/ApoE-/-). Tw+/ApoE-/- mice showed increased mtDNA integrity, copy number, respiratory complex abundance, and respiration. Tw+/ApoE-/- mice had decreased necrotic core and increased fibrous cap areas, and Tw+/ApoE-/- bone marrow transplantation also reduced core areas. Twinkle increased vascular smooth muscle cell mtDNA integrity and respiration. Twinkle also promoted vascular smooth muscle cell proliferation and protected both vascular smooth muscle cells and macrophages from oxidative stress-induced apoptosis.
CONCLUSIONS: Endogenous mtDNA damage in mouse and human atherosclerosis is associated with significantly reduced mitochondrial respiration. Reducing mtDNA damage and increasing mitochondrial respiration decrease necrotic core and increase fibrous cap areas independently of changes in reactive oxygen species and may be a promising therapeutic strategy in atherosclerosis.

Matched MeSH terms: Mice, Inbred C57BL
Fulltext Catalpol Ameliorates Insulin Sensitivity and Mitochondrial Respiration in Skeletal Muscle of Type-2 Diabetic Mice Through Insulin Signaling Pathway and AMPK/SIRT1/PGC-1α/PPAR-γ Activation

Yap KH, Yee GS, Candasamy M, Tan SC, Md S, Abdul Majeed AB, et al.

Biomolecules, 2020 09 24;10(10).
PMID: 32987623 DOI: 10.3390/biom10101360

Catalpol was tested for various disorders including diabetes mellitus. Numerous molecular mechanisms have emerged supporting its biological effects but with little information towards its insulin sensitizing effect. In this study, we have investigated its effect on skeletal muscle mitochondrial respiration and insulin signaling pathway. Type-2 diabetes (T2DM) was induced in male C57BL/6 by a high fat diet (60% Kcal) and streptozotocin (50 mg/kg, i.p.). Diabetic mice were orally administered with catalpol (100 and 200 mg/kg), metformin (200 mg/kg), and saline for four weeks. Fasting blood glucose (FBG), HbA1c, plasma insulin, oral glucose tolerance test (OGTT), insulin tolerance test (ITT), oxygen consumption rate, gene (IRS-1, Akt, PI3k, AMPK, GLUT4, and PGC-1α) and protein (AMPK, GLUT4, and PPAR-γ) expression in muscle were measured. Catalpol (200 mg/kg) significantly (p < 0.05) reduced the FBG, HbA1C, HOMA_IR index, and AUC of OGTT whereas, improved the ITT slope. Gene (IRS-1, Akt, PI3k, GLUT4, AMPK, and PGC-1α) and protein (AMPK, p-AMPK, PPAR-γ and GLUT4) expressions, as well as augmented state-3 respiration, oxygen consumption rate, and citrate synthase activity in muscle was observed in catalpol treated mice. The antidiabetic activity of catalpol is credited with a marked improvement in insulin sensitivity and mitochondrial respiration through the insulin signaling pathway and AMPK/SIRT1/PGC-1α/PPAR-γ activation in the skeletal muscle of T2DM mice.

Matched MeSH terms: Mice, Inbred C57BL
The effect of immune status, age and genetic background on induction of oral tolerance to Actinomyces viscosus in mice

Sosroseno W, Herminajeng E, Bird P

Biomed Pharmacother, 2015 Mar;70:294-8.
PMID: 25776514 DOI: 10.1016/j.biopha.2014.12.039

The aim of the present study was to determine the effect of immune status, age and genetic background on the induction of oral tolerance to Actinomyces viscosus. Suppression of delayed type hypersensitivity (DTH) response and antigen-specific serum antibody levels could be induced in DBA/2 mice intragastrically and systemically immunized with A. viscocus, suggesting the induction of oral tolerance. In contrast, this immune suppression could be abrogated if the animals had been systemically immunized prior to the induction of oral tolerance with the same bacterium. Long-term systemic immunization prior to intragastric immunization with A. viscocus suppressed DTH response only. Cell transfer of this group of animals also suppressed DTH response in the donors, indicating the action of suppressor cells for inhibition of DTH response. Furthermore, oral tolerance to A. viscocus failed to occur in mice aged at 3 days and 1, 2, 4, 6 and 36 weeks old. Mice bearing H-2(d) haplotype were the most susceptible to oral tolerization, followed by H-2(b) and H-2(k). Therefore, the results of the presence study suggest that the induction of oral tolerance to A. viscosus in mice may be dependence on the immune status and genetic background but not age.

Matched MeSH terms: Mice, Inbred C57BL
Fulltext Basal lamina remodeling at the skeletal muscle stem cell niche mediates stem cell self-renewal

Rayagiri SS, Ranaldi D, Raven A, Mohamad Azhar NIF, Lefebvre O, Zammit PS, et al.

Nat Commun, 2018 03 14;9(1):1075.
PMID: 29540680 DOI: 10.1038/s41467-018-03425-3

A central question in stem cell biology is the relationship between stem cells and their niche. Although previous reports have uncovered how signaling molecules released by niche cells support stem cell function, the role of the extra-cellular matrix (ECM) within the niche is unclear. Here, we show that upon activation, skeletal muscle stem cells (satellite cells) induce local remodeling of the ECM and the deposition of laminin-α1 and laminin-α5 into the basal lamina of the satellite cell niche. Genetic ablation of laminin-α1, disruption of integrin-α6 signaling or blocking matrix metalloproteinase activity impairs satellite cell expansion and self-renewal. Collectively, our findings establish that remodeling of the ECM is an integral process of stem cell activity to support propagation and self-renewal, and may explain the effect laminin-α1-containing supports have on embryonic and adult stem cells, as well as the regenerative activity of exogenous laminin-111 therapy.

Matched MeSH terms: Mice, Inbred C57BL
Fulltext Pharmacologically antagonizing the CXCR4-CXCL12 chemokine pathway with AMD3100 inhibits sunlight-induced skin cancer

Sarchio SNE, Scolyer RA, Beaugie C, McDonald D, Marsh-Wakefield F, Halliday GM, et al.

J Invest Dermatol, 2014 Apr;134(4):1091-1100.
PMID: 24226205 DOI: 10.1038/jid.2013.424

One way sunlight causes skin cancer is by suppressing anti-tumor immunity. A major mechanism involves altering mast cell migration via the C-X-C motif chemokine receptor 4-C-X-C motif chemokine ligand 12 (CXCR4-CXCL12) chemokine pathway. We have discovered that pharmacologically blocking this pathway with the CXCR4 antagonist AMD3100 prevents both UV radiation-induced immune suppression and skin cancer. The majority of control mice receiving UV-only developed histopathologically confirmed squamous cell carcinomas. In contrast, skin tumor incidence and burden was significantly lower in AMD3100-treated mice. Perhaps most striking was that AMD3100 completely prevented the outgrowth of latent tumors that occurred once UV irradiation ceased. AMD3100 protection from UV immunosuppression and skin cancer was associated with reduced mast cell infiltration into the skin, draining lymph nodes, and the tumor itself. Thus a major target of CXCR4 antagonism was the mast cell. Our results indicate that interfering with UV-induced CXCL12 by antagonizing CXCR4 significantly inhibits skin tumor development by blocking UV-induced effects on mast cells. Hence, the CXCR4-CXCL12 chemokine pathway is a novel therapeutic target in the prevention of UV-induced skin cancer.

Matched MeSH terms: Mice, Inbred C57BL

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