{"case_id":"PICO-V2-001","abstract_text":"SHIP represses lung inflammation and inhibits mammary tumor metastasis in BALB/c mice . SH2-containing-inositol-5′-phosphatase ( SHIP ) is a negative regulator of the phosphatidylinositol-3-kinase pathway in hematopoietic cells and limits the development of leukemias and lymphomas . The potential role of SHIP in solid tumor development and metastasis remains unknown . While SHIP restricts the aberrant development of myeloid cells in C57BL/6 mice , there are conflicting reports regarding the effect of SHIP deletion in BALB/c mice with important consequences for determining the influence of SHIP in different model tumor systems . We generated SHIP−/− BALB/c mice and challenged them with syngeneic non-metastatic 67NR or metastatic 4T1 mammary tumors . We demonstrate that SHIP restricts the development , alternative-activation , and immunosuppressive function of myeloid cells in tumor-free and tumor-bearing BALB/c mice . Tumor-free SHIP−/− BALB/c mice exhibited pulmonary inflammation , myeloid hyperplasia , and M2-polarized macrophages and this phenotype was greatly exacerbated by 4T1 , but not 67NR , tumors . 4T1-bearing SHIP−/− mice rapidly lost weight and died from necrohemorrhagic inflammatory pulmonary disease , characterized by massive infiltration of pulmonary macrophages and myeloid-derived suppressor cells that were more M2-polarized and immunosuppressive than wild-type cells . Importantly , while SHIP loss did not affect primary tumor growth , 4T1-bearing SHIP−/− mice had 7.5-fold more metastatic tumor cells in their lungs than wild-type mice , consistent with the influence of immunosuppressive myeloid cells on metastatic growth . Our findings identify the hematopoietic cell-restricted protein SHIP as an intriguing target to influence the development of solid tumor metastases , and support development of SHIP agonists to prevent the accumulation of immunosuppressive myeloid cells and tumor metastases in the lungs to improve treatment of metastatic breast cancer ."}
{"case_id":"PICO-V2-002","abstract_text":"TNF-Like Weak Inducer of Apoptosis Aggravates Left Ventricular Dysfunction after Myocardial Infarction in Mice . Background . TNF-like weak inducer of apoptosis ( TWEAK ) has recently been shown to be potentially involved in adverse cardiac remodeling . However , neither the exact role of TWEAK itself nor of its receptor Fn14 in this setting is known . Aim of the Study . To analyze the effects of sTWEAK on myocardial function and gene expression in response to experimental myocardial infarction in mice . Results . TWEAK directly suppressed the expression of PGC-1α and genes of oxidative phosphorylation ( OXPHOS ) in cardiomyocytes . Systemic sTWEAK application after MI resulted in reduced left ventricular function and increased mortality without changes in interstitial fibrosis or infarct size . Molecular analysis revealed decreased phosphorylation of PI3K/Akt and ERK1/2 pathways associated with reduced expression of PGC-1α and PPARα . Likewise , expression of OXPHOS genes such as atp5O , cycs , cox5b , and ndufb5 was also reduced . Fn14 −/− mice showed significantly improved left ventricular function and PGC-1α levels after MI compared to their respective WT littermates ( Fn14 + /+ ) . Finally , inhibition of intrinsic TWEAK with anti-TWEAK antibodies resulted in improved left ventricular function and survival . Conclusions . TWEAK exerted maladaptive effects in mice after myocardial infarction most likely via direct effects on cardiomyocytes . Analysis of the potential mechanisms revealed that TWEAK reduced metabolic adaptations to increased cardiac workload by inhibition of PGC-1α ."}
{"case_id":"PICO-V2-003","abstract_text":"Negative legacy of obesity . Obesity promotes excessive inflammation , which is associated with senescence-like changes in visceral adipose tissue ( VAT ) and the development of type 2 diabetes ( T2DM ) and cardiovascular diseases . We have reported that a unique population of CD44hi CD62Llo CD4 + T cells that constitutively express PD-1 and CD153 exhibit cellular senescence and cause VAT inflammation by producing large amounts of osteopontin . Weight loss improves glycemic control and reduces cardiovascular disease risk factors , but its long-term effects on cardiovascular events and longevity in obese individuals with T2DM are somewhat disappointing and not well understood . High-fat diet (HFD)-fed obese mice were subjected to weight reduction through a switch to a control diet . They lost body weight and visceral fat mass , reaching the same levels as lean mice fed a control diet . However , the VAT of weight reduction mice exhibited denser infiltration of macrophages , which formed more crown-like structures compared to the VAT of obese mice kept on the HFD . Mechanistically , CD153 + PD-1 + CD4 + T cells are long-lived and not easily eliminated , even after weight reduction . Their continued presence maintains a self-sustaining chronic inflammatory loop via production of large amounts of osteopontin . Thus , we concluded that T-cell senescence is essentially a negative legacy effect of obesity ."}
{"case_id":"PICO-V2-004","abstract_text":"STAT1 is a sex‐specific tumor suppressor in colitis‐associated colorectal cancer . The interferon‐inducible transcription factor STAT1 is a tumor suppressor in various malignancies . We investigated sex‐specific STAT1 functions in colitis and colitis‐associated colorectal cancer ( CRC ) using mice with specific STAT1 deletion in intestinal epithelial cells ( STAT1∆IEC ) . Male but not female STAT1∆IEC mice were more resistant to DSS‐induced colitis than sex‐matched STAT1flox/flox controls and displayed reduced intraepithelial infiltration of CD8 + TCRαβ+ granzyme B+ T cells . Moreover , DSS treatment failed to induce expression of T‐cell‐attracting chemokines in intestinal epithelial cells of male but not of female STAT1∆IEC mice . Application of the AOM‐DSS protocol for induction of colitis‐associated CRC resulted in increased intestinal tumor load in male but not in female STAT1∆IEC mice . A sex‐specific stratification of human CRC patients corroborated the data obtained in mice and revealed that reduced tumor cell‐intrinsic nuclear STAT1 protein expression is a poor prognostic factor in men but not in women . These data demonstrate that epithelial STAT1 is a male‐specific tumor suppressor in CRC of mice and humans ."}
{"case_id":"PICO-V2-005","abstract_text":"Pulmonary influenza A virus infection leads to suppression of the innate immune response to dermal injury . The innate immune system is responsible for many important functions in the body including responding to infection , clearing cancerous cells , healing wounds , and removing foreign substances . Although many of these functions happen simultaneously in life , most laboratory studies of the innate immune response focus on one activity . How the innate immune system responds to concurrent insults in different parts of the body is not well understood . This study explores the impact of a lung infection on the cutaneous wound healing process . We used two complimentary models of injury : the excisional tail wound and subcutaneous implantation of polyvinyl alcohol ( PVA ) sponges . These models allow for assessment of the rate of closure and measurement of cellular and cytokine responses during acute wound healing , respectively . When mice with these healing wounds were infected with influenza A virus ( IAV ) in the lung there was a delay in wound healing . The viral lung infection suppressed the innate immune response in a healing wound , including cellular infiltrate , chemokines , growth factors , and cytokines . However , there was not a global immune suppression as there was an increase in inflammation systemically in mice with both infection and healing wounds compared to mice with only wounds or IAV infection . In addition , the lung immune response was largely unaffected indicating that responding to a lung infection is prioritized over a healing wound . This study introduces the concept of immune triage , in that when faced with multiple insults the immune system prioritizes responses . This paradigm likely applies to many situations that involve the innate immune system , and understanding how the innate immune system handles multiple insults is essential to understanding how it can efficiently clear pathogens while responding to other inflammatory events ."}
{"case_id":"PICO-V2-006","abstract_text":"The Enhancing Effects of Hyperbaric Oxygen on Mouse Skin Carcinogenesis . The effects of hyperbaric oxygen ( HBO ) on mouse skin two-stage chemical carcinogenesis were examined . Six-week-old inbred CD-1 female mice were divided into the following five groups : group 1 , normoxia and application of 25 nmol 7,12-dimethylbenz[a]anthracene ( DMBA ) and 8.5 nmol 12-O-tetradecanoylphorbol-13-acetate ( TPA ) ( n=19 ) ; group 2 , HBO and DMBA/TPA ( n=21 ) ; group 3 , HBO and DMBA/acetone ( n=3 ) ; group 4 , normoxia and acetone ( n=3 ) ; and group 5 , non-treatment group ( n=5 ) . HBO was started at the same time as DMBA . Mice were euthanized at 23 weeks after the start of the experiment . Mice in group 2 showed the occurrence of tumors at 8 weeks after the beginning of the experiment , while the occurrence of tumors in mice in group 1 was observed beginning at 9 weeks . There was a difference in occurrence among low-grade papillomas , high-grade papillomas and SCCs in both groups 1 and 2 by the χ2-test at end of the experiment ( p<0.05 ) . The Ki-67 labeling indices of tumors revealed that the percentages of positive cells in low-grade papillomas in groups 1 and 2 were 15.27 ± 2.54 % and 29.67 ± 2.82 % , respectively ( p<0.01 ) . The results suggested that the tumors in group 2 , which was treated with HBO , were more progressive than those in group 1 , which was not treated with HBO . In this study , HBO accelerated tumor cell proliferation and advanced tumor progression in skin carcinogenesis by DMBA/TPA ."}
{"case_id":"PICO-V2-007","abstract_text":"Knockout of Cyclophilin-D Provides Partial Amelioration of Intrinsic and Synaptic Properties Altered by Mild Traumatic Brain Injury . Mitochondria are central to cell survival and Ca2 + homeostasis due to their intracellular buffering capabilities . Mitochondrial dysfunction resulting in mitochondrial permeability transition pore ( mPTP ) opening has been reported after mild traumatic brain injury ( mTBI ) . Cyclosporine A provides protection against the mPTP opening through its interaction with cyclophilin-D ( CypD ) . A recent study has found that the extent of axonal injury after mTBI was diminished in neocortex in cyclophilin-D knockout ( CypDKO ) mice . Here we tested whether this CypDKO could also provide protection from the increased intrinsic and synaptic neuronal excitability previously described after mTBI in a mild central fluid percussion injury mice model . CypDKO mice were crossed with mice expressing yellow fluorescent protein ( YFP ) in layer V pyramidal neurons in neocortex to create CypDKO/YFP-H mice . Whole cell patch clamp recordings from axotomized ( AX ) and intact ( IN ) YFP+ layer V pyramidal neurons were made 1 and 2 days after sham or mTBI in slices from CypDKO/YFP-H mice . Both excitatory post synaptic currents ( EPSCs ) recorded in voltage clamp and intrinsic cellular properties , including action potential ( AP ) , afterhyperpolarization ( AHP ) , and depolarizing after potential ( DAP ) characteristics recorded in current clamp were evaluated . There was no significant difference between sham and mTBI for either spontaneous or miniature EPSC frequency , suggesting that CypDKO ameliorates excitatory synaptic abnormalities . There was a partial amelioration of intrinsic properties altered by mTBI . Alleviated were the increased slope of the AP frequency vs. injected current plot , the increased AP , AHP and DAP amplitudes . Other properties that saw a reversal that became significant in the opposite direction include the current rheobase and AP overshoot . The AP threshold remained depolarized and the input resistance remained increased in mTBI compared to sham . Additional altered properties suggest that the CypDKO likely has a direct effect on membrane properties , rather than producing a selective reduction of the effects of mTBI . These results suggest that inhibiting CypD after TBI is an effective strategy to reduce synaptic hyperexcitation , making it a continued target for potential treatment of network abnormalities ."}
{"case_id":"PICO-V2-008","abstract_text":"Effect of edaravone in diabetes mellitus-induced nephropathy in rats . Edaravone , a synthetic-free radical scavenger , has been reported to reduce ischemia-reperfusion-induced renal injury by improving tubular cell function , and lowering serum creatinine and renal vascular resistance . The present study investigated the effect of edaravone in diabetes mellitus-induced nephropathy in rats . A single administration of streptozotocin ( STZ , 55 mg/kg , i.p . ) was employed to induce diabetes mellitus in rats . The STZ-administered diabetic rats were allowed for 10 weeks to develop nephropathy . Mean body weight , lipid alteration , renal functional and histopathology were analysed . Diabetic rats developed nephropathy as evidenced by a significant increase in serum creatinine and urea , and marked renal histopathological abnormalities like glomerulosclerosis and tubular cell degeneration . The kidney weight to body weight ratio was increased . Moreover , diabetic rats showed lipid alteration as evidenced by a signifi ca nt increase in serum triglycerides and decrease in serum high-density lipoproteins . Edaravone ( 10 mg/kg , i.p . , last 4-weeks ) treatment markedly prevented the development of nephropathy in diabetic rats by reducing serum creatinine and urea and preventing renal structural abnormalities . In addition , its treatment , without significantly altering the elevated glucose level in diabetic rats , prevented diabetes mellitus-induced lipid alteration by reducing serum triglycerides and increasing serum high-density lipoproteins . Interestingly , the renoprotective effect of edaravone was comparable to that of lisinopril ( 5 mg/kg , p.o , 4 weeks , standard drug ) . Edaravone prevented renal structural and functional abnormalities and lipid alteration associated with experimental diabetes mellitus . Edaravone has a potential to prevent nephropathy without showing an anti-diabetic action , implicating its direct renoprotection in diabetic rats ."}
{"case_id":"PICO-V2-009","abstract_text":"Engraftment of Human Glioblastoma Cells in Immunocompetent Rats through Acquired Immunosuppression . Transplantation of glioblastoma patient biopsy spheroids to the brain of T cell-compromised Rowett ( nude ) rats has been established as a representative animal model for human GBMs , with a tumor take rate close to 100 % . In immunocompetent littermates however , primary human GBM tissue is invariably rejected . Here we show that after repeated passaging cycles in nude rats , human GBM spheroids are enabled to grow in the brain of immunocompetent rats . In case of engraftment , xenografts in immunocompetent rats grow progressively and host leukocytes fail to enter the tumor bed , similar to what is seen in nude animals . In contrast , rejection is associated with massive infiltration of the tumor bed by leukocytes , predominantly ED1 + microglia/macrophages , CD4 + T helper cells and CD8 + effector cells , and correlates with elevated serum levels of pro-inflammatory cytokines IL-1β , IL-18 and TNF-α . We observed that in nude rat brains , an adaptation to the host occurs after several in vivo passaging cycles , characterized by striking attenuation of microglial infiltration . Furthermore , tumor-derived chemokines that promote leukocyte migration and their entry into the CNS such as CXCL-10 and CXCL-12 are down-regulated , and the levels of TGF-β2 increase . We propose that through serial in vivo passaging in nude rats , human GBM cells learn to avoid and or/ suppress host immunity . Such adapted GBM cells are in turn able to engraft in immunocompetent rats without signs of an inflammatory response ."}
{"case_id":"PICO-V2-010","abstract_text":"Differential Alterations in the Expression of Neurotransmitter Receptors in Inner Retina following Loss of Photoreceptors in rd1 Mouse . Loss of photoreceptors leads to significant remodeling in inner retina of rd1 mouse , a widely used model of retinal degeneration . Several morphological and physiological alterations occur in the second- and third-order retinal neurons . Synaptic activity in the excitatory bipolar cells and the predominantly inhibitory amacrine cells is enhanced . Retinal ganglion cells ( RGCs ) exhibit hyperactivity and aberrant spiking pattern , which adversely affects the quality of signals they can carry to the brain . To further understand the pathophysiology of retinal degeneration , and how it may lead to aberrant spiking in RGCs , we asked how loss of photoreceptors affects some of the neurotransmitter receptors in rd1 mouse . Using Western blotting , we measured the levels of several neurotransmitter receptors in adult rd1 mouse retina . We found significantly higher levels of AMPA , glycine and GABAa receptors , but lower levels of GABAc receptors in rd1 mouse than in wild-type . Since GABAa receptor is expressed in several retinal layers , we employed quantitative immunohistochemistry to measure GABAa receptor levels in specific retinal layers . We found that the levels of GABAa receptors in inner plexiform layer of wild-type and rd1 mice were similar , whereas those in outer plexiform layer and inner nuclear layer combined were higher in rd1 mouse . Specifically , we found that the number of GABAa-immunoreactive somas in the inner nuclear layer of rd1 mouse retina was significantly higher than in wild-type . These findings provide further insights into neurochemical remodeling in the inner retina of rd1 mouse , and how it might lead to oscillatory activity in RGCs ."}
{"case_id":"PICO-V2-011","abstract_text":"Objective Assessment of Endogenous Collagen In Vivo during Tissue Repair by Laser Induced Fluorescence . Collagen , a triple helical protein with the primary role of mechanical function , provides tensile strength to the skin , and plays a pivotal task in tissue repair . During tissue regeneration , collagen level increases gradually and therefore , monitoring of such changes in vivo by laser induced fluorescence was the main objective behind the present study . In order to accomplish this , 15 mm diameter excisional wounds were created on six to eight week old Swiss albino mice . The collagen deposition accelerated upon irradiation of single exposure of 2 J/cm2 He-Ne laser dose immediately after wounding was recorded by laser induced autofluorescence in vivo along with un-illuminated and un-wounded controls . Autofluorescence spectra were recorded for each animal of the experimental groups on 0 , 5 , 10 , 30 , 45 and 60 days post- wounding , by exciting the granulation tissue/skin with 325 nm He-Cd laser . The variations in the average collagen intensities from the granulation tissue/skin of mice were inspected as a function of age and gender . Further , the spectral findings of the collagen synthesis in wound granulation tissue/ un-wounded skin tissues were validated by Picro-Sirius red- polarized light microscopy in a blinded manner through image analysis of the respective collagen birefringence . The in vivo autofluorescence studies have shown a significant increase in collagen synthesis in laser treated animals as compared to the un-illuminated controls . Image analysis of the collagen birefringence further authenticated the ability of autofluorescence in the objective monitoring of collagen in vivo . Our results clearly demonstrate the potential of laser induced autofluorescence in the monitoring of collegen synthesis during tissue regeneration , which may have clinical implications ."}
{"case_id":"PICO-V2-012","abstract_text":"Citrus ichangensis Peel Extract Exhibits Anti-Metabolic Disorder Effects by the Inhibition of PPARγ and LXR Signaling in High-Fat Diet-Induced C57BL/6 Mouse . Obesity is a common nutritional disorder associated with type 2 diabetes , cardiovascular diseases , dyslipidemia , and certain cancers . In this study , we investigated the effects of Citrus ichangensis peel extract ( CIE ) in high-fat ( HF ) diet-induced obesity mice . Female C57BL/6 mice were fed a chow diet or an HF diet alone or supplemented with 1 % w/w CIE for 8 weeks . We found that CIE treatment could lower blood glucose level and improve glucose tolerance . In the HF + CIE group , body weight gain , serum total cholesterol ( TC ) and low-density lipoprotein cholesterol ( LDL-c ) levels , and liver triglyceride ( TG ) and TC concentrations were significantly ( P < 0.05 ) decreased relative to those in the HF group . To elucidate the mechanism of CIE on the metabolism of glucose and lipid , related genes expression in liver were examined . In liver tissue , CIE significantly decreased the mRNA expression levels of peroxisome proliferator-activated receptor γ ( PPARγ ) and its target genes , such as fatty acid synthase ( FAS ) and acyl-CoA oxidase ( ACO ) . Moreover , CIE also decreased the expression of liver X receptor ( LXR ) α and β which are involved in lipid and glucose metabolism . These results suggest that CIE administration could alleviate obesity and related metabolic disorders in HF diet-induced obesity mice through the inhibition of PPARγ and LXR signaling ."}
{"case_id":"PICO-V2-013","abstract_text":"Impaired Recovery from Influenza A/X-31(H3N2 ) Infection in Mice with 8-Lipoxygenase Deficiency . Lipoxygenase-derived lipid mediators can modulate inflammation and are stimulated in response to influenza infections . We report an effect of 8-lipoxygenase ( ALOX8 ) on the recovery of mice after infection with Influenza virus X31 . We compared the responses of 3- and 6-month-old mice with a deletion of ALOX8 ( ALOX8−/− ) to influenza infections with those of age-matched littermate wild-type mice ( ALOX8+/+ ) . The duration of illness was similar in 3-month-old ALOX8−/− and ALOX8+/+ mice . However , the 6-month-old ALOX8−/− mice showed a prolonged state of illness compared with ALOX8+/+ mice , as evidenced by reduced body temperatures , reduced locomotor activities , and delayed weight recovery . Although residual viral RNA in the lungs at day 10 post-inoculation was significantly influenced by the age of the ALOX8−/− mice , there were no significant differences between ALOX8−/− and ALOX8+/+ mice within the same age groups . The levels of cytokines interleukin 6 ( IL-6 ) and keratinocyte chemoattractant ( KC ) differed significantly between 6-month-old ALOX8−/− and ALOX8+/+ mice 10 days after viral inoculation . Our data suggest that ALOX8 deficiency in mice leads to impaired recovery from influenza infection in an age-dependent manner ."}
{"case_id":"PICO-V2-014","abstract_text":"Significance of the Tks4 scaffold protein in bone tissue homeostasis . The main driver of osteoporosis is an imbalance between bone resorption and formation . The pathogenesis of osteoporosis has also been connected to genetic alterations in key osteogenic factors and dysfunction of bone marrow mesenchymal stem/stromal cells ( BM-MSCs ) . Tks4 ( encoded by the Sh3pxd2b gene ) is a scaffold protein involved in podosome organization . Homozygous mutational inactivation of Sh3pxd2b causes Frank-ter Haar syndrome ( FTHS ) , a genetic disease that affects bone tissue as well as eye , ear , and heart functions . To date , the role of Tks4 in adult bone homeostasis has not been investigated . Therefore , the aim of this study was to analyze the facial and femoral bone phenotypes of Sh3pxd2b knock-out ( KO ) mice using micro-CT methods . In addition to the analysis of the Sh3pxd2b-KO mice , the bone microstructure of an FTHS patient was also examined . Macro-examination of skulls from Tks4-deficient mice revealed craniofacial malformations that were very similar to symptoms of the FTHS patient . The femurs of the Sh3pxd2b-KO mice had alterations in the trabecular system and showed signs of osteoporosis , and , similarly , the FTHS patient also showed increased trabecular separation/porosity . The expression levels of the Runx2 and osteocalcin bone formation markers were reduced in the bone and bone marrow of the Sh3pxd2b-KO femurs , respectively . Our recent study demonstrated that Sh3pxd2b-KO BM-MSCs have a reduced ability to differentiate into osteoblast lineage cells ; therefore , we concluded that the Tks4 scaffold protein is important for osteoblast formation , and that it likely plays a role in bone cell homeostasis ."}
{"case_id":"PICO-V2-015","abstract_text":"Protective Effects of Nintedanib against Polyhexamethylene Guanidine Phosphate-Induced Lung Fibrosis in Mice . Nintedanib ( NDN ) , a tyrosine kinase inhibitor , has been shown to have anti-tumor , anti-inflammatory , and anti-fibrotic effects in several reports . We investigated the protective effects of NDN against polyhexamethylene guanidine phosphate ( PHMG ) -induced lung fibrosis in mice . The following three experimental groups were evaluated : ( 1 ) vehicle control ; ( 2 ) PHMG ( 1.1 mg/kg ) ; and ( 3 ) PHMG & NDN ( 60 mg/kg ) . PHMG induced pulmonary inflammation and fibrosis by intratracheal instillation in mice . In contrast , NDN treatment effectively alleviated the PHMG induced lung injury , and attenuated the number of total cells and inflammatory cells in the bronchoalveolar lavage fluid , including the fibrotic histopathological changes , and also reduced the hydroxyproline content . NDN also significantly decreased the expression of inflammatory cytokines and fibrotic factors , and the activation of the NLRP3 inflammasome in lung tissues . These results suggest that NDN may mitigate the inflammatory response and development of pulmonary fibrosis in the lungs of mice treated with PHMG ."}
{"case_id":"PICO-V2-016","abstract_text":"Metabolic Changes in Skin Caused by Scd1 Deficiency : A Focus on Retinol Metabolism . We previously reported that mice with skin-specific deletion of stearoyl-CoA desaturase-1 ( Scd1 ) recapitulated the skin phenotype and hypermetabolism observed in mice with a whole-body deletion of Scd1 . In this study , we first performed a diet-induced obesity experiment at thermoneutral temperature ( 33 ° C ) and found that skin-specific Scd1 knockout ( SKO ) mice still remain resistant to obesity . To elucidate the metabolic changes in the skin that contribute to the obesity resistance and skin phenotype , we performed microarray analysis of skin gene expression in male SKO and control mice fed a standard rodent diet . We identified an extraordinary number of differentially expressed genes that support the previously documented histological observations of sebaceous gland hypoplasia , inflammation and epidermal hyperplasia in SKO mice . Additionally , transcript levels were reduced in skin of SKO mice for genes involved in fatty acid synthesis , elongation and desaturation , which may be attributed to decreased abundance of key transcription factors including SREBP1c , ChREBP and LXRα . Conversely , genes involved in cholesterol synthesis were increased , suggesting an imbalance between skin fatty acid and cholesterol synthesis . Unexpectedly , we observed a robust elevation in skin retinol , retinoic acid and retinoic acid-induced genes in SKO mice . Furthermore , SEB-1 sebocytes treated with retinol and SCD inhibitor also display an elevation in retinoic acid-induced genes . These results highlight the importance of monounsaturated fatty acid synthesis for maintaining retinol homeostasis and point to disturbed retinol metabolism as a novel contributor to the Scd1 deficiency-induced skin phenotype ."}
{"case_id":"PICO-V2-017","abstract_text":"Role of D3 dopamine receptors in modulating neuroanatomical changes in response to antipsychotic administration . Clinical research has shown that chronic antipsychotic drug ( APD ) treatment further decreases cortical gray matter and hippocampus volume , and increases striatal and ventricular volume in patients with schizophrenia . D2-like receptor blockade is necessary for clinical efficacy of the drugs , and may be responsible for inducing these volume changes . However , the role of other D2-like receptors , such as D3 , remains unclear . Following our previous work , we undertook a longitudinal study to examine the effects of chronic ( 9-week ) typical ( haloperidol ( HAL ) ) and atypical ( clozapine ( CLZ ) ) APDs on the neuroanatomy of wild-type ( WT ) and dopamine D3-knockout ( D3KO ) mice using magnetic resonance imaging ( MRI ) and histological assessments in a sub-region of the anterior cingulate cortex ( the prelimbic [ PL ] area ) and striatum . D3KO mice had larger striatal volume prior to APD administration , coupled with increased glial and neuronal cell density . Chronic HAL administration increased striatal volume in both WT and D3KO mice , and reduced PL area volume in D3KO mice both at trend level . CLZ increased volume of the PL area of WT mice at trend level , but decreased D3KO PL area glial cell density . Both typical and atypical APD administration induced neuroanatomical remodeling of regions rich in D3 receptor expression , and typically altered in schizophrenia . Our findings provide novel insights on the role of D3 receptors in structural changes observed following APD administration in clinical populations ."}
{"case_id":"PICO-V2-018","abstract_text":"Differential Effects of Dietary Oils on Emotional and Cognitive Behaviors . Several dietary oils have been used preventatively and therapeutically in the setting of neurological disease . However , the mechanisms underlying their influence on brain function and metabolism remain unknown . It was investigated whether 3 types of dietary oils affected emotional behaviors in mice . Wild-type ( WT ) mice and sialyltransferase ST3Gal IV-knockout ( KO ) mice , which exhibit increased emotional and cognitive behaviors , were fed diets containing 20 % dietary oils from post-weaning to adulthood . Mice were fed pellets made from control feed AIN93 G powder containing 18 % fish oil , soybean oil , or a mixture of 1-palmitoyl-2-oleoyl-3-palmitoyl glycerol ( POP ) and 1-stearoyl-2-oleoyl-3-stearoyl glycerol ( SOS ) , plus 2 % soybean oil . Once mice reached adulthood , they were subjected to fear conditioning test to measure cognitive anxiety and forced swim test to measure depression . WT mice fed the POP-SOS diet showed a 0.6-fold decrease in percent freezing with contextual fear compared with WT mice fed the control diet . KO mice fed the fish oil diet showed a 1.4-fold increase in percent freezing with contextual fear compared with KO mice fed the control diet . These findings indicate that response to contextual fear was improved in WT mice that consumed POP-SOS but aggravated in KO mice that consumed fish oils . Furthermore , KO mice showed a 0.4-fold decrease in percent freezing in response to tone fear when they were fed POP-SOS diet compared to a control diet . Thus , POP-SOS diet reduced tone fear level of KO mice until the same level of WT mice . Finally , KO mice fed the soybean oil diet showed a 1.7-fold increase in immobility in the forced swim test compared to KO mice fed the control diet . Taken together , oil-rich diets differentially modulate anxiety and depression in normal and anxious mice . Oils rich in saturated fatty acids may alleviate anxiety more strongly than other oils ."}
{"case_id":"PICO-V2-019","abstract_text":"Derlin-1 Deficiency Is Embryonic Lethal , Derlin-3 Deficiency Appears Normal , and Herp Deficiency Is Intolerant to Glucose Load and Ischemia in Mice . Accumulation of unfolded or misfolded proteins in the endoplasmic reticulum ( ER ) causes a cellular condition called ER stress . To overcome ER stress , unfolded proteins are eliminated by an ER-associated degradation ( ERAD ) system . To explore the physiological requirements for ERAD-related membrane proteins in mammals , we generated Derlin-1– , Derlin-3– , and Herp-deficient mice by gene targeting . Complete loss of Derlin-1 caused embryonic lethality at around E7–E8 ( early somite stages ) . In contrast , Derlin-3– and Herp-deficient mice were born alive with the expected Mendelian frequency , and were superficially indistinguishable from wild-type mice . However , in the Derlin-3– and Herp-deficient mouse organs , the expression levels of ERAD-related proteins were affected under both normal and ER stress conditions ; specific effects differed among the organs . Degradation of ERAD substrates was reduced in the Herp-deficient liver , and Herp-deficient mice exhibited impaired glucose tolerance and vulnerability to brain ischemic injury , both of which are known to be implicated in ER stress . Our findings indicate that ERAD or uncharacterized functions involving Derlin-1 are essential in early embryonic development . Derlin-3– and Herp-deficient mice may become useful model animals for investigations of the physiological contribution of ERAD under stressful or pathological conditions ."}
{"case_id":"PICO-V2-020","abstract_text":"Activation of Pregnane X Receptor by Pregnenolone 16 α-carbonitrile Prevents High-Fat Diet-Induced Obesity in AKR/J Mice . Pregnane X receptor ( PXR ) is known to function as a xenobiotic sensor to regulate xenobiotic metabolism through selective transcription of genes responsible for maintaining physiological homeostasis . Here we report that the activation of PXR by pregnenolone 16α-carbonitrile ( PCN ) in AKR/J mice can prevent the development of high-fat diet-induced obesity and insulin resistance . The beneficial effects of PCN treatment are seen with reduced lipogenesis and gluconeogenesis in the liver , and lack of hepatic accumulation of lipid and lipid storage in the adipose tissues . RT-PCR analysis of genes involved in gluconeogenesis , lipid metabolism and energy homeostasis reveal that PCN treatment on high-fat diet-fed mice reduces expression in the liver of G6Pase , Pepck , Cyp7a1 , Cd36 , L-Fabp , Srebp , and Fas genes and slightly enhances expression of Cyp27a1 and Abca1 genes . RT-PCR analysis of genes involved in adipocyte differentiation and lipid metabolism in white adipose tissue show that PCN treatment reduces expression of Pparγ2 , Acc1 , Cd36 , but increases expression of Cpt1b and Pparα genes in mice fed with high-fat diet . Similarly , PCN treatment of animals on high-fat diet increases expression in brown adipose tissue of Pparα , Hsl , Cpt1b , and Cd36 genes , but reduces expression of Acc1 and Scd-1 genes . PXR activation by PCN in high-fat diet fed mice also increases expression of genes involved in thermogenesis in brown adipose tissue including Dio2 , Pgc-1α , Pgc-1β , Cidea , and Ucp-3 . These results verify the important function of PXR in lipid and energy metabolism and suggest that PXR represents a novel therapeutic target for prevention and treatment of obesity and insulin resistance ."}