Embodying Temporality in Response Efficacy: How Coping Appraisal Promotes Preventive Behavioral Engagement During the Ongoing Pandemic.

This study heightens the understanding of response efficacy as a determinant of engagement in preventive behavior during the ongoing COVID-19 pandemic. To achieve a more nuanced conceptualization of response efficacy, this study proposes and examines a time-based coping appraisal framework, drawing upon a part of the extended parallel process model (EPPM). The current study investigates how the temporality of coping response message features work in generating social distancing behavioral intentions and explicates the role of anticipated emotions in this motivational process. Results of the experimental study (N = 584) indicate that proximal future framed coping response message (vs. distant future message) led to greater response efficacy, which in turn led to greater anticipated guilt and pride, and by extension increased social distancing behavioral intentions. Mediation analyses also demonstrated the indirect effects of the temporality conditions (proximal future-oriented message vs. distant future-oriented message) on social distancing intentions through response efficacy, anticipated guilt, and anticipated pride. The theoretical and practical implications of this study are discussed.

Functional Characterization of the GNAT Family Histone Acetyltransferase Elp3 and GcnE in Aspergillus fumigatus.

Post-translational modifications of chromatin structure by histone acetyltransferase (HATs) play a pivotal role in the regulation of gene expression and diverse biological processes. However, the function of GNAT family HATs, especially Elp3, in the opportunistic human pathogenic fungus Aspergillus fumigatus is largely unknown. To investigate the roles of the GNAT family HATs Elp3 and GcnE in the A. fumigatus, we have generated and characterized individual null Δelp3 and ΔgcnE mutants. The radial growth of fungal colonies was significantly decreased by the loss of elp3 or gcnE, and the number of asexual spores (conidia) in the ΔgcnE mutant was significantly reduced. Moreover, the mRNA levels of the key asexual development regulators were also significantly low in the ΔgcnE mutant compared to wild type (WT). Whereas both the Δelp3 and ΔgcnE mutants were markedly impaired in the formation of adherent biofilms, the ΔgcnE mutant showed a complete loss of surface structure and of intercellular matrix. The ΔgcnE mutant responded differently to oxidative stressors and showed significant susceptibility to triazole antifungal agents. Furthermore, Elp3 and GcnE function oppositely in the production of secondary metabolites, and the ΔgcnE mutant showed attenuated virulence. In conclusion, Elp3 and GcnE are associated with diverse biological processes and can be potential targets for controlling the pathogenic fungus.

NTRK oncogenic fusions are exclusively associated with the serrated neoplasia pathway in the colorectum and begin to occur in sessile serrated lesions.

Neurotrophic tropomyosin receptor kinase (NTRK) gene fusions are emerging tissue-agnostic drug targets in malignancies including colorectal carcinomas (CRCs), but their detailed landscape in the context of various colorectal carcinogenesis pathways remains to be investigated. In this study, pan-tropomyosin receptor kinase (TRK) protein expression was assessed by immunohistochemistry (IHC) in retrospectively collected colorectal epithelial tumor tissues, including 441 CRCs [133 microsatellite instability-high (MSI-high) and 308 microsatellite stable (MSS)] and 595 premalignant colorectal lesions (330 serrated lesions and 265 conventional adenomas). TRK-positive cases were then subjected to next-generation sequencing and/or fluorescence in situ hybridization to confirm NTRK rearrangements. TRK IHC positivity was not observed in any of the MSS CRCs, conventional adenomas, traditional serrated adenomas, or hyperplastic polyps, whereas TRK positivity was observed in 11 of 58 (19%) MLH1-methylated MSI-high CRCs, 4 of 23 (17%) sessile serrated lesions with dysplasia (SSLDs), and 5 of 132 (4%) sessile serrated lesions (SSLs). The 11 TRK-positive MSI-high CRCs commonly harbored CpG island methylator phenotype-high (CIMP-high), MLH1 methylation, BRAF/KRAS wild-type, and NTRK1 or NTRK3 fusion (TPM3-NTRK1, TPR-NTRK1, LMNA-NTRK1, SFPQ-NTRK1, ETV6-NTRK3, or EML4-NTRK3). Both NTRK1 or NTRK3 rearrangement and BRAF/KRAS wild-type were detected in all nine TRK-positive SSL(D)s, seven of which demonstrated MSS and/or CIMP-low. TRK expression was selectively observed in distorted serrated crypts within SSLs and was occasionally localized at the base of serrated crypts. NTRK fusions were detected only in SSLs of patients aged ≥50 years, whereas BRAF mutation was found in younger age-onset SSLs. In conclusion, NTRK-rearranged colorectal tumors develop exclusively through the serrated neoplasia pathway and can be initiated from non-dysplastic SSLs without BRAF/KRAS mutations prior to full occurrence of MSI-high/CIMP-high. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Effects of Individuals' Cultural Orientations and Trust in Government Health Communication Sources on Behavioral Intentions During a Pandemic: A Cross-Country Study.

Public health messages disseminated by trusted government authorities are likely to have more influence over individuals' intentions and behaviors. However, individuals worldwide have different levels of trust in government authorities, which leads to varying levels of compliance intentions. Additionally, these trust levels may vary during major public crises, such as pandemics. Based on a COVID-19 pandemic communication survey (N = 3,065) disseminated throughout six countries (Australia, Finland, Italy, South Korea, Sweden, and the United States), this study examined the association among trust in distinct government sources, cultural orientations, and health behavioral intentions. Findings indicated that trust in official health communication sources at four governmental levels (i.e. national government, the head of the national government, the national health authority, and the chief representative of the national health authority) was related to vaccination intentions and other behavioral compliance intentions (i.e. willingness to prevent COVID-19 infection in other ways). Meanwhile, these direct associations were mediated by the cultural orientations of power distance and uncertainty avoidance. Findings also revealed that the direct association of trust in government sources and the indirect relationship through the above cultural orientations varied by country. This study offers insight into the important role of credible sources and individuals' cultural orientations in the domain of health communication aimed at influencing behavioral intentions.

Schwann cell O-GlcNAcylation promotes peripheral nerve remyelination via attenuation of the AP-1 transcription factor JUN.

Schwann cells (SCs), the glia of the peripheral nervous system, play an essential role in nerve regeneration. Upon nerve injury, SCs are reprogrammed into unique "repair SCs," and these cells remove degenerating axons/myelin debris, promote axonal regrowth, and ultimately remyelinate regenerating axons. The AP-1 transcription factor JUN is promptly induced in SCs upon nerve injury and potently mediates this injury-induced SC plasticity; however, the regulation of these JUN-dependent SC injury responses is unclear. Previously, we produced mice with a SC-specific deletion of O-GlcNAc transferase (OGT). This enzyme catalyzes O-GlcNAcylation, a posttranslational modification that is influenced by the cellular metabolic state. Mice lacking OGT in SCs develop a progressive demyelinating peripheral neuropathy. Here, we investigated the nerve repair process in OGT-SCKO mutant mice and found that the remyelination of regenerating axons is severely impaired. Gene expression profiling of OGT-SCKO SCs revealed that the JUN-dependent SC injury program was elevated in the absence of injury and failed to shut down at the appropriate time after injury. This aberrant JUN activity results in abnormalities in repair SC function and redifferentiation and prevents the timely remyelination. This aberrant nerve injury response is normalized in OGT-SCKO mice with reduced Jun gene dosage in SCs. Mechanistically, OGT O-GlcNAcylates JUN at multiple sites, which then leads to an attenuation of AP-1 transcriptional activity. Together, these results highlight the metabolic oversight of the nerve injury response via the regulation of JUN activity by O-GlcNAcylation, a pathway that could be important in the neuropathy associated with diabetes and aging.

Topical Application of Aronia melanocarpa Extract Rich in Chlorogenic Acid and Rutin Reduces UVB-Induced Skin Damage via Attenuating Collagen Disruption in Mice.

Aronia melanocarpa, a black chokeberry, contains high levels of phenolic acids and polyphenolic flavonoids and displays antioxidative and anti-inflammatory effects. Through high-performance liquid chromatography for extracts from Aronia melanocarpa, we discovered that the extract contained chlorogenic acid and rutin as major ingredients. In this study, we examined the protective effects of the extract against ultraviolet B- (UVB)-induced photodamage in the dorsal skin of institute of cancer research (ICR) mice. Their dorsal skin was exposed to UVB, thereafter; the extract was topically applied once a day for seven days. Photoprotective properties of the extract in the dorsal skin were investigated by clinical skin severity score for skin injury, hematoxylin and eosin staining for histopathology, Masson's trichrome staining for collagens. In addition, we examined change in collagen type I and III, and matrix metalloproteinase (MMP)-1 and MMP-3 by immunohistochemistry. In the UVB-exposed mice treated with the extract, UVB-induced epidermal damage was significantly ameliorated, showing that epidermal thickness was moderated. In these mice, immunoreactivities of collagen type I and III were significantly increased, whereas immunoreactivities of MMP-1 and 3 were significantly decreased compared with those in the UVB-exposed mice. These results indicate that treatment with Aronia melanocarpa extract attenuates UV-induced photodamage by attenuating UVB-induced collagen disruption: these findings might be a result of the chlorogenic acid and rutin contained in the extract. Based on the current results, we suggest that Aronia melanocarpa can be a useful material for developing photoprotective adjuvant.

Dysregulation of NAD+ Metabolism Induces a Schwann Cell Dedifferentiation Program.

The Schwann cell (SC) is the major component of the peripheral nervous system (PNS) that provides metabolic and functional support for peripheral axons. The emerging roles of SC mitochondrial function for PNS development and axonal stability indicate the importance of SC metabolism in nerve function and in peripheral neuropathies associated with metabolic disorders. Nicotinamide adenine dinucleotide (NAD+) is a crucial molecule in the regulation of cellular metabolism and redox homeostasis. Here, we investigated the roles of NAD+ metabolism in SC functions in vivo by mutating NAMPT, the rate-limiting enzyme of NAD+ biosynthesis, specifically in SCs. NAMPT SC knock-out male and female mice (NAMPT SCKO mice) had delayed SC maturation in development and developed hypomyelinating peripheral neuropathy without axon degeneration or decreased SC survival. JUN, a master regulator of SC dedifferentiation, is elevated in NAMPT SCKO SCs, suggesting that decreased NAD+ levels cause them to arrest at an immature stage. Nicotinic acid administration rescues the NAD+ decline and reverses the SC maturation defect and the development of peripheral neuropathy, indicating the central role of NAD+ in PNS development. Upon nicotinic acid withdrawal in adulthood, NAMPT SCKO mice showed rapid and severe peripheral neuropathy and activation of ERK/MEK/JUN signaling, which in turn promotes SC dedifferentiation. These data demonstrate the importance of NAD+ metabolism in SC maturation and nerve development and maintenance and suggest that altered SC NAD+ metabolism could underlie neuropathies associated with diabetes and aging.SIGNIFICANCE STATEMENT In this study, we showed that Schwann cell differentiation status is critically dependent on NAD+ homeostasis. Aberrant regulation of NAD+ biosynthesis via NAMPT deletion results in a blockade of Schwann cell maturation during development and severe peripheral neuropathy without significant axon loss. The phenotype can be rescued by supplementation with nicotinic acid; however, withdrawal of nicotinic acid leads to Schwann cell dedifferentiation, myelination defects, and death. These results provide new therapeutic possibilities for peripheral neuropathies associated with NAD+ decline during aging or diabetes.

Medical Drama Viewing and Healthy Lifestyle Behaviors: Understanding the Role of Health Locus of Control Beliefs and Education Level.

The present study advances the understanding of how medical drama viewing influences healthy lifestyle behaviors (e.g., smoking, exercising, and consuming vegetables) by examining the role of the health locus of control (HLOC) beliefs and education level. An analysis of nationally representative data reveals that watching medical dramas is positively associated with chance and powerful others' HLOC beliefs. In addition, healthy lifestyle behaviors are positively associated with the internal HLOC belief and are negatively associated with the chance and powerful others' HLOC beliefs. Research findings demonstrate that there are indirect effects of medical drama viewing on these behaviors via chance and powerful others' HLOC beliefs. The indirect effect through the powerful others' HLOC belief is also contingent on the education level. The implications for the role of HLOC beliefs and education level in terms of the effects of medical dramas on health-promoting behaviors are discussed.

Effects of Message Framing on Influenza Vaccination: Understanding the Role of Risk Disclosure, Perceived Vaccine Efficacy, and Felt Ambivalence.

The current study examined the effects of framing in promotional health messages on intention to vaccinate against seasonal influenza virus. The findings of an experimental study (N = 86) indicated that exposure to both benefits and side effects of vaccination (gain-framed with risk disclosure message) led to lower intention to receive the flu vaccine. This relationship was mediated by both perceived vaccine efficacy and felt ambivalence in a serial order, revealing the underlying psychological mechanisms important for understanding health-related behaviors. Theoretical implications of constructing sub-framed messages are discussed and the concept of second-order framing is introduced.

Time-Course Changes and New Expressions of MIP-3α and Its Receptor, CCR6, in the Gerbil Hippocampal CA1 Area Following Transient Global Cerebral Ischemia.

Macrophage inflammatory protein-3α (MIP-3α) and its sole receptor, CCR6, play pivotal roles in neuroinflammatory processes induced by brain ischemic insults. In this study, we investigated transient ischemia-induced changes in MIP-3α and CCR6 protein expressions in the hippocampal CA1 area following 5 min of transient global cerebral ischemia (tgCI) in gerbils. Both MIP-3α and CCR6 immunoreactivities were very strongly expressed in pyramidal neurons of the CA1 area from 6 h to 1 day after tgCI and were hardly shown 4 days after tgCI. In addition, strong MIP-3α immunoreactivity was newly expressed in astrocytes 6 h after tgCI. These results indicate that tgCI causes apparent changes in MIP-3α and CCR6 expressions in pyramidal neurons and astrocytes in the hippocampal CA1 area and suggest that tgCI-induced changes in MIP-3α and CCR6 expressions might be closely associated with neuroinflammatory processes in brain ischemic regions.

Brain ischemic preconditioning protects against moderate, not severe, transient global cerebral ischemic injury.

Ischemic preconditioning (IPC) in the brain increases ischemic tolerance to subsequent ischemic insults. In this study, we examined whether IPC protects neurons and attenuates microgliosis or not in the hippocampus following severe transient global cerebral ischemia (TCI) in gerbils. Gerbils were assigned to 8 groups; 5- and 15-min sham operated groups, 5-min and 15-min TCI operated groups, IPC plus 5- and 15-min sham operated groups, and IPC plus 5- and 15-min TCI operated groups. IPC was induced by subjecting animals to 2-min transient ischemia 1 day before 5-min TCI for a typical transient ischemia and 15-min TCI for severe transient ischemia. Neuronal damage was examined by cresyl violet staining and Fluoro-Jade B histofluorescence staining. In addition, microglial activation was examined using immunohistochemistry for Iba-1 (a marker for microglia). Delayed neuronal death and microgliosis was found in the CA1 alone in the 5-min TCI operated group at 5 days post-ischemia, and, in the 15-min TCI operated group, neuronal death and microgliosis was shown in all CA areas (CA1-3) and the dentate gyrus. IPC displayed neuroprotection and attenuated microglial activation in the 5-min TCI operated group. However, in the 15-min TCI operated group, IPC did not show neuroprotection and not attenuate microglial activation. Our present findings indicate that IPC hardly protect against severe transient cerebral ischemic injury.

Schwann Cell O-GlcNAc Glycosylation Is Required for Myelin Maintenance and Axon Integrity.

UNLABELLED: Schwann cells (SCs), ensheathing glia of the peripheral nervous system, support axonal survival and function. Abnormalities in SC metabolism affect their ability to provide this support and maintain axon integrity. To further interrogate this metabolic influence on axon-glial interactions, we generated OGT-SCKO mice with SC-specific deletion of the metabolic/nutrient sensing protein O-GlcNAc transferase that mediates the O-linked addition of N-acetylglucosamine (GlcNAc) moieties to Ser and Thr residues. The OGT-SCKO mice develop tomaculous demyelinating neuropathy characterized by focal thickenings of the myelin sheath (tomacula), progressive demyelination, axonal loss, and motor and sensory nerve dysfunction. Proteomic analysis identified more than 100 O-GlcNAcylated proteins in rat sciatic nerve, including Periaxin (PRX), a myelin protein whose mutation causes inherited neuropathy in humans. PRX lacking O-GlcNAcylation is mislocalized within the myelin sheath of these mutant animals. Furthermore, phenotypes of OGT-SCKO and Prx-deficient mice are very similar, suggesting that metabolic control of PRX O-GlcNAcylation is crucial for myelin maintenance and axonal integrity. SIGNIFICANCE STATEMENT: The nutrient sensing protein O-GlcNAc transferase (OGT) mediates post-translational O-linked N-acetylglucosamine (GlcNAc) modification. Here we find that OGT functions in Schwann cells (SCs) to maintain normal myelin and prevent axonal loss. SC-specific deletion of OGT (OGT-SCKO mice) causes a tomaculous demyelinating neuropathy accompanied with progressive axon degeneration and motor and sensory nerve dysfunction. We also found Periaxin (PRX), a myelin protein whose mutation causes inherited neuropathy in humans, is O-GlcNAcylated. Importantly, phenotypes of OGT-SCKO and Prx mutant mice are very similar, implying that compromised PRX function contributes to the neuropathy of OGT-SCKO mice. This study will be useful in understanding how SC metabolism contributes to PNS function and in developing new strategies for treating peripheral neuropathy by targeting SC function.

Changes in Urinary Angiotensinogen Associated with Deterioration of Kidney Function in Patients with Type 2 Diabetes Mellitus.

Urinary angiotensinogen (AGT) is potentially a specific biomarker for the status of the intrarenal renin-angiotensin system (RAS) in patients with diabetes mellitus. We explored whether changes in urinary AGT excretion levels were associated with the deterioration of kidney function in type 2 diabetes patients with preserved kidney function. Urinary baseline AGT levels were measured in 118 type 2 diabetic patients who were not taking RAS blockers and who had estimated glomerular filtration rates (eGFRs) ≥ 60 mL/min/1.73 m². A total of 91 patients were followed-up for 52 months. Changes in urinary levels of AGT (ΔAGT) were calculated by subtracting urinary AGT/creatinine (Cr) at baseline from urinary AGT/Cr after 1 year. ΔAGT was significantly inversely correlated with annual eGFR change (ß = -0.29, P = 0.006; ß = -0.37, P = 0.001 after adjusting for clinical factors). RAS blockers were prescribed in 36.3% of patients (n = 33) during follow-up. The ΔAGT values were lower in the RAS blockers users than in the non-RAS blockers users, but the differences were not statistically significant (7.37 ± 75.88 vs. 22.55 ± 57.45 µg/g Cr, P = 0.081). The ΔAGT values remained significantly correlated with the annual rate of eGFR change (ß = -0.41, P = 0.001) in the patients who did not use RAS blockers, but no such correlation was evident in the patients who did. ΔAGT is inversely correlated with annual changes in eGFR in type 2 diabetes patients with preserved kidney function, particularly in RAS blocker-naïve patients.

Regulation of blood glucose level by kainic acid in mice: involvement of glucocorticoid system and non-NMDA receptors.

Kainic acid (KA) is a well-known excitatory neurotoxic substance. In the present study, effects of KA-injected intraperitoneally (i.p.), intracerebroventricularly (i.c.v.) or intrathecally (i.t.) on the blood glucose level were investigated in ICR mice. We found that KA administered intraperitoneally (i.p.), intracerebroventricularly (i.c.v.) or intrathecally (i.t.) increased the blood glucose and corticosterone levels, suggesting that KA-induced hyperglycemia appeared to be due to increased blood corticosterone level. In support of this finding, adrenalectomy causes a reduction of KA-induced hyperglycemia and neuronal cell death in CA3 regions of the hippocampus. In addition, pretreatment with i.c.v. or i.t. injection of CNQX (6-cyano-7-nitroquinoxaline-2, 3-dione; a non-NMDA receptor blocker) attenuated the i.p. and i.c.v. administered KA-induced hyperglycemia. KA administered i.c.v. caused an elevation of the blood corticosterone level whereas the plasma insulin level was reduced. Moreover, i.c.v. pretreatment with CNQX inhibited the decrease of plasma insulin level induced by KA i.c.v. injection, whereas the KA-induced plasma corticosterone level was further enhanced by CNQX pretreatment. Our results suggest that KA administered systemically or centrally produces hyperglycemia. A glucocorticoid system appears to be involved in KA-induced hyperglycemia. Furthermore, central non-N-methyl-D-aspartate receptors may be responsible for KA-induced hyperglycemia.

The activation of α2-adrenergic receptor in the spinal cord lowers sepsis-induced mortality.

The effect of clonidine administered intrathecally (i.t.) on the mortality and the blood glucose level induced by sepsis was examined in mice. To produce sepsis, the mixture of D-galactosamine (GaLN; 0.6 g/10 ml)/lipopolysaccharide (LPS; 27 µg/27 µl) was treated intraperitoneally (i.p.). The i.t. pretreatment with clonidine (5 µg/5 µl) increased the blood glucose level and attenuated mortality induced by sepsis in a dose-dependent manner. The i.t. post-treatment with clonidine up to 3 h caused an elevation of the blood glucose level and protected sepsis-induced mortality, whereas clonidine post-treated at 6, 9, or 12 h did not affect. The pre-treatment with oral D-glucose for 30 min prior to i.t. post-treatment (6 h) with clonidine did not rescue sepsis-induced mortality. In addition, i.t. pretreatment with pertussis toxin (PTX) reduced clonidine-induced protection against mortality and clonidine-induced hyperglycemia, suggesting that protective effect against sepsis-induced mortality seems to be mediated via activating PTX-sensitive G-proteins in the spinal cord. Moreover, pretreatment with clonidine attenuated the plasma tumor necrosis factor α (TNF-α) induced by sepsis. Clonidine administered i.t. or i.p. increased p-AMPKα1 and p-AMPKα2, but decreased p-Tyk2 and p-mTOR levels in both control and sepsis groups, suggesting that the up-regulations of p-AMPKα1 and p-AMPKα2, or down-regulations of p-mTOR and p-Tyk2 may play critical roles for the protective effect of clonidine against sepsis-induced mortality.

Effect of D-glucose feeding on mortality induced by sepsis.

Sepsis is the life-threatening response to infection which can lead to tissue damage, organ failure, and death. In the current study, the effect of orally administered D-glucose on the mortality and the blood glucose level induced by D-Galactosamine (GaLN)/lipopolysaccharide (LPS)-induced sepsis was examined in ICR mice. After various amounts of D-glucose (from 1 to 8 g/kg) were orally fed, sepsis was induced by injecting intraperitoneally (i.p.) the mixture of GaLN /LPS. Oral pre-treatment with D-glucose dose-dependently increased the blood glucose level and caused a reduction of sepsis-induced mortality. The oral post-treatment with D-glucose (8 g/kg) up to 3 h caused an elevation of the blood glucose level and protected the mortality observed in sepsis model. However, D-glucose post-treated at 6, 9, or 12 h after sepsis induction did not affect the mortality and the blood glucose level induced by sepsis. Furthermore, the intrathecal (i.t.) pretreatment once with pertussis toxin (PTX; 0.1 µg/5 ml) for 6 days caused a reduction of D-glucose-induced protection of mortality and hyperglycemia. Furthermore, once the hypoglycemic state is continued up to 6 h after sepsis initiated, sepsis-induced mortality could not be reversed by D-glucose fed orally. Based on these findings, it is assumed that the hypoglycemic duration between 3 and 6 h after the sepsis induction may be a critical time of period for the survival. D-glucose-induced protective effect against sepsis-induced mortality appears to be mediated via activating PTX-sensitive G-proteins in the spinal cord. Finally, the production of hyperglycemic state may be critical for the survival against the sepsis-induced mortality.

Phospholipase A2 inhibits cisplatin-induced acute kidney injury by modulating regulatory T cells by the CD206 mannose receptor.

Previously, we found that Foxp3-expressing CD4(+) regulatory T (Treg) cells attenuate cisplatin-induced acute kidney injury in mice and that bee venom and its constituent phospholipase A2 (PLA2) are capable of modulating Treg cells. Here we tested whether PLA2 could inhibit cisplatin-induced acute kidney injury. As a result of treatment with PLA2, the population of Treg cells was significantly increased, both in vivo and in vitro. PLA2-injected mice showed reduced levels of serum creatinine, blood urea nitrogen, renal tissue damage, and pro-inflammatory cytokine production upon cisplatin administration. These renoprotective effects were abolished by depletion of Treg cells. Furthermore, PLA2 bound to CD206 mannose receptors on dendritic cells, essential for the PLA2-mediated protective effects on renal dysfunction. Interestingly, PLA2 treatment increased the secretion of IL-10 in the kidney from normal mice. Foxp3(+)IL-10(+) cells and CD11c(+)IL-10(+) cells were increased by PLA2 treatment. The anticancer effects of repeated administrations of a low dose of cisplatin were not affected by PLA2 treatment in a tumor-bearing model. Thus, PLA2 may prevent inflammatory responses in cisplatin-induced acute kidney injury by modulating Treg cells and IL-10 through the CD206 mannose receptor.

Drosophila Golgi membrane protein Ema promotes autophagosomal growth and function.

Autophagy is a self-degradative process in which cellular material is enclosed within autophagosomes and trafficked to lysosomes for degradation. Autophagosomal biogenesis is well described; however mechanisms controlling the growth and ultimate size of autophagosomes are unclear. Here we demonstrate that the Drosophila membrane protein Ema is required for the growth of autophagosomes. In an ema mutant, autophagosomes form in response to starvation and developmental cues, and these autophagosomes can mature into autolysosomes; however the autophagosomes are very small, and autophagy is impaired. In fat body cells, Ema localizes to the Golgi complex and is recruited to the membrane of autophagosomes in response to starvation. The Drosophila Golgi protein Lva also is recruited to the periphery of autophagosomes in response to starvation, and this recruitment requires ema. Therefore, we propose that Golgi is a membrane source for autophagosomal growth and that Ema facilitates this process. Clec16A, the human ortholog of Ema, is a candidate autoimmune susceptibility locus. Expression of Clec16A can rescue the autophagosome size defect in the ema mutant, suggesting that regulation of autophagosome morphogenesis may be a fundamental function of this gene family.

Effect of sulfonylureas administered centrally on the blood glucose level in immobilization stress model.

Sulfonylureas are widely used as an antidiabetic drug. In the present study, the effects of sulfonylurea administered supraspinally on immobilization stress-induced blood glucose level were studied in ICR mice. Mice were once enforced into immobilization stress for 30 min and returned to the cage. The blood glucose level was measured 30, 60, and 120 min after immobilization stress initiation. We found that intracerebroventricular (i.c.v.) injection with 30 µg of glyburide, glipizide, glimepiride or tolazamide attenuated the increased blood glucose level induced by immobilization stress. Immobilization stress causes an elevation of the blood corticosterone and insulin levels. Sulfonylureas pretreated i.c.v. caused a further elevation of the blood corticosterone level when mice were forced into the stress. In addition, sulfonylureas pretreated i.c.v. alone caused an elevation of the plasma insulin level. Furthermore, immobilization stress-induced insulin level was reduced by i.c.v. pretreated sulfonylureas. Our results suggest that lowering effect of sulfonylureas administered supraspinally against immobilization stress-induced increase of the blood glucose level appears to be primarily mediated via elevation of the plasma insulin level.

Pertussis toxin administered spinally induces a hypoglycemic effect on normal and diabetic mice.

BACKGROUND/AIMS: To show whether intrathecal (i.t.) treatment with pertussis toxin (PTX) produces a hypoglycemic effect in ICR, db/db and streptozotocin-treated mice. METHODS: The blood glucose level (BGL) was measured after i.t. treatment with PTX, AB5 toxins and PTX subunits. Insulin or leptin levels were measured after PTX injection. The effect of PTX on the BGL was examined in adrenalectomized (ADX) mice. Glucose transporter (GLUT) levels were determined by Western blotting. RESULTS: PTX attenuated the elevated BGL in the D-glucose-fed model in a long-term manner. Heat-labile toxin (HLT), HLT subunit B or Shiga toxin, which belong to the AB5 toxins, administered i.t. did not affect the BGL. PTX A protomer (PTX-A) or PTX B oligomers (PTX-B) injected i.t. did not have an effect on the BGL as well. However, combined treatment with PTX-A and PTX-B subunits caused a hypoglycemic effect. The leptin level was gradually reduced by PTX for up to 6 days, without affecting the insulin level. PTX administered i.t. significantly decreased the BGL further in ADX mice. Moreover, GLUT-2 (hypothalamus and pituitary gland), GLUT-4 (muscle) and GLUT-3 (adrenal gland) expression levels were increased, whereas GLUT-1 (brain cortex, liver, muscle and spinal cord), GLUT-2 (liver) and GLUT-3 (brain cortex and pituitary gland) expression levels were decreased. DISCUSSION: Our data suggest that PTX administered spinally produces a hypoglycemic effect in a long-term manner, and PTX-induced hypoglycemia appears to be mediated by the reduction in activity of the glucocorticoid system. Furthermore, PTX may modulate the insulin level during hypoglycemia. Among GLUTs, GLUT-4 in muscle, GLUT-2 in the liver, hypothalamus and pituitary gland as well as GLUT-1 in the adrenal gland may be responsible for PTX-induced hypoglycemia.