Dominant activities of fear engram cells in the dorsal dentate gyrus underlie fear generalization in mice.

Over-generalized fear is a maladaptive response to harmless stimuli or situations characteristic of posttraumatic stress disorder (PTSD) and other anxiety disorders. The dorsal dentate gyrus (dDG) contains engram cells that play a crucial role in accurate memory retrieval. However, the coordination mechanism of neuronal subpopulations within the dDG network during fear generalization is not well understood. Here, with the Tet-off system combined with immunostaining and two-photon calcium imaging, we report that dDG fear engram cells labeled in the conditioned context constitutes a significantly higher proportion of dDG neurons activated in a similar context where mice show generalized fear. The activation of these dDG fear engram cells encoding the conditioned context is both sufficient and necessary for inducing fear generalization in the similar context. Activities of mossy cells in the ventral dentate gyrus (vMCs) are significantly suppressed in mice showing fear generalization in a similar context, and activating the vMCs-dDG pathway suppresses generalized but not conditioned fear. Finally, modifying fear memory engrams in the dDG with "safety" signals effectively rescues fear generalization. These findings reveal that the competitive advantage of dDG engram cells underlies fear generalization, which can be rescued by activating the vMCs-dDG pathway or modifying fear memory engrams, and provide novel insights into the dDG network as the neuronal basis of fear generalization.

Comparative Efficacy of Colchicine and Intensive Low-density Lipoprotein Cholesterol Lowering in Patients with Atherosclerotic Diseases receiving Statins: A Network Meta-analysis of Randomized Controlled Trials.

AIMS: Adding intensive low-density lipoprotein cholesterol (LDL-C)-lowering agents or colchicine to statin has been shown to result in additional cardiovascular benefits for patients with atherosclerotic cardiovascular diseases (ASCVD). We aimed to compare the efficacy and safety of these supplementary agents in patients with ASCVD receiving statin. METHODS: We performed a systematic review and frequentist network meta-analysis of randomized controlled trials. The primary efficacy endpoint was the main adverse cardiovascular event (MACE), and the secondary efficacy endpoints were myocardial infarct, stroke, coronary revascularization, cardiovascular death, and all-cause mortality, respectively. The safety endpoints were treatment discontinuation and non-cardiovascular death. We obtained estimates for efficacy outcomes and safety endpoints and presented these estimates as risk ratio (RR) with 95% confidence intervals. We ranked the comparative efficacy and safety of all drugs with P-scores. RESULTS: Seventeen trials totaling 85,823 participants treated with colchicine (5926 participants), intensive LDL-C lowering (37,854 participants) via proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, Niemann-Pick C1-like 1 protein (NPC1L1) inhibitor or ATP citrate lyase (ACL) inhibitor, or statin alone (42,043 participants) were included. Colchicine was associated with a greater reduction in the risk of MACE (RR 0.72, 0.69-0.91), stroke (RR 0.55, 0.33-0.92), and coronary revascularization (RR 0.73, 0.60-0.90) compared with NPC1L1 inhibitor, and it provided a larger reduction in the risk of MACE (RR 0.79, 0.69-0.91) compared to PCSK9 inhibitor. However, colchicine was associated with increased risk of non-cardiovascular death compared with NPC1L1 inhibitor (RR 1.48, 1.04-2.10) and PCSK9 inhibitor (RR 1.57, 1.08-2.27). Although no regimen prolonged survival, colchicine had worse performance on non-cardiovascular death and all-cause mortality. CONCLUSIONS: In patients with ASCVD receiving statin, colchicine seems to be more effective than intensive LDL-C-lowering therapy with PCSK9 inhibitor or NPC1L1 inhibitor for cardiovascular prevention. However, using colchicine as an alternative to intensive LDL-C-lowering therapy may need to be weighed against the cardiovascular benefits and the potential harms of higher non-cardiovascular death. TRIAL REGISTRATION: PROSPERO Identifier: CRD42023441385.

LPS stimulation stabilizes HIF-1α by enhancing HIF-1α acetylation via the PARP1-SIRT1 and ACLY-Tip60 pathways in macrophages.

Hypoxia and inflammatory mediators stabilize hypoxia-inducible factor (HIF)-1α through posttranslational modifications, such as phosphorylation and succinylation. Here, we identified sirtuin 1 (SIRT1) and 60 kDa Tat-interactive protein (Tip60)-mediated acetylation as another critical posttranslational modification that regulates HIF-1α protein stability under lipopolysaccharide (LPS) stimulation. Mechanistically, DNA damage induced by excessive reactive oxygen species (ROS) activated poly (ADP-ribose) polymerase 1 (PARP1) to consume oxidized nicotinamide adenine dinucleotide (NAD+ ). Correspondingly, SIRT1 activity was decreased with the decline in NAD+ levels, resulting in increased HIF-1α acetylation. LPS also activated the ATP-citrate lyase (ACLY)-Tip60 pathway to further enhance HIF-1α acetylation. Acetylation contributed to HIF-1α stability and exacerbated LPS-induced inflammation. Thus, inhibiting HIF-1α stability by decreasing its acetylation could partly alleviate LPS-induced inflammation. In conclusion, we revealed the mechanism by which LPS stabilized HIF-1α by increasing its acetylation via the PARP1-SIRT1 and ACLY-Tip60 pathways in fish macrophages. This study may provide novel insights for manipulation of HIF-1α acetylation as a therapeutic strategy against inflammation from the perspective of acetylation in vertebrates.

Yokoyama procedure for cyclic strabismus with axial high myopia:a case report.

BACKGROUND: It is a very rare form of ocular motility characterized by alternating strabismus and orthotropia. We report a patient with a 48-h cycle of esohypotropia associated with axial high myopia that resolved by Yokoyama procedure. CASE PRESENTATION: A 43-year-old female patient who underwent left medial rectus muscle recession and lateral rectus muscle resection elsewhere due to highly myopic strabismus 2 years ago. The patient experienced a recurrence of left esohypotropia 12 months after undergoing surgery, exhibiting a 48-hour cycle. The cycle is one full day of esohypotropia and one day of orthotropia. The patient exhibited a case of high myopia in the left eye, characterized by a diopter measurement of -24.00DS and an eye axis measurement of 28.43 mm. Orbital CT showed supertemporal dislocation of the posterior portion of the elongated globe out from the muscle cone. Based on these observations, we performed Yokoyama procedure by uniting the muscle bellies of the superior rectus(SR) and lateral rectus (LR) muscles to restoring the dislocated globe back into the muscle cone. CONCLUSIONS: When cyclic strabismus is combined with axial high myopia, the Yokoyama procedure was effective and cycles are successfully terminated without overcorrection on no squint days. The purpose of this procedure is to put the dislocated globe back into its muscle cone by uniting the muscle bellies of the superior rectus and lateral rectus.

HCN2 Channels in the Ventral Hippocampal CA1 Regulate Nociceptive Hypersensitivity in Mice.

Chronic pain is a significant health problem worldwide. Recent evidence has suggested that the ventral hippocampus is dysfunctional in humans and rodents, with decreased neuronal excitability and connectivity with other brain regions, parallel pain chronicity, and persistent nociceptive hypersensitivity. But the molecular mechanisms underlying hippocampal modulation of pain remain poorly elucidated. In this study, we used ex vivo whole-cell patch-clamp recording, immunofluorescence staining, and behavioral tests to examine whether hyperpolarization-activated cyclic nucleotide-gated channels 2 (HCN2) in the ventral hippocampal CA1 (vCA1) were involved in regulating nociceptive perception and CFA-induced inflammatory pain in mice. Reduced sag potential and firing rate of action potentials were observed in vCA1 pyramidal neurons from CFA-injected mice. Moreover, the expression of HCN2, but not HCN1, in vCA1 decreased in mice injected with CFA. HCN2 knockdown in vCA1 pyramidal neurons induced thermal hypersensitivity, whereas overexpression of HCN2 alleviated thermal hyperalgesia induced by intraplantar injection of CFA in mice. Our findings suggest that HCN2 in the vCA1 plays an active role in pain modulation and could be a promising target for the treatment of chronic pain.

Selective Reductive Coupling of Vinyl Azaarenes and Alkynes via Photoredox Cobalt Dual Catalysis.

A visible light-induced Co-catalyzed highly regio- and stereoselective reductive coupling of vinyl azaarenes and alkynes has been developed. Notably, Hünig's base together with simple ethanol has been successfully applied as the hydrogen sources instead of commonly used Hantzsch esters in this catalytic photoredox reaction. This approach has considerable advantages for the straightforward synthesis of stereodefined multiple substituted alkenes bearing an azaarene motif, such as excellent regioselectivity (>20 : 1 for >30 examples) and stereoselectivity (>20 : 1 E/Z), broad substrate scope and good functional group compatibility under mild reaction conditions, which has been utilized in the concise synthesis of natural product monomorine I. A reasonable catalytic reaction pathway involving protolysis of the cobaltacyclopentene intermediate has been proposed based on the mechanistic studies.

Regio- and Stereoselective Reductive Coupling of Alkynes and Crotononitrile.

A new regio- and stereoselective reductive coupling of alkynes and crotononitrile has been developed via visible light organophotoredox cobalt dual catalysis. A variety of enantioenriched homoallylic nitriles bearing a stereodefined trisubstituted alkene have been easily synthesized with good to excellent regio- (up to >20:1 rr), stereo- (>20:1 E/Z), and enantioselectivity (up to 98% ee) control under mild conditions. The corresponding nitrile products were smoothly converted into various chiral building blocks. Remarkably, a simple organic base together with water have been utilized as hydrogen sources in this photoinduced reductive reaction.

Docosahexaenoic Acid Ameliorates the Toll-Like Receptor 22-Triggered Inflammation in Fish by Disrupting Lipid Raft Formation.

BACKGROUND: Although dietary DHA alleviates Toll-like receptor (TLR)-associated chronic inflammation in fish, the underlying mechanism is not well understood. OBJECTIVES: This study aimed to explore the role of Tlr22 in the innate immunity of large yellow croaker and investigate the anti-inflammatory effects of DHA on Tlr22-triggered inflammation. METHODS: Head kidney-derived macrophages of croaker and HEK293T cells were or were not pretreated with 100 µM DHA for 10 h prior to polyinosinic-polycytidylic acid (poly I:C) stimulation. We executed qRT-PCR, immunoblotting, and lipidomic analysis to examine the impact of DHA on Tlr22-triggered inflammation and membrane lipid composition. In vivo, croakers (12.03 ± 0.05 g) were fed diets containing 0.2% [control (Ctrl)], 0.8%, and 1.6% DHA for 8 wk before injection with poly I:C. Inflammatory genes expression and rafts-related lipids and protein expression were measured in the head kidney. Data were analyzed by ANOVA or Student t test. RESULTS: The activation of Tlr22 by poly I:C induced inflammation, and DHA diminished Tlr22-targeted inflammatory gene expression by 56-73% (P ≤ 0.05). DHA reduced membrane sphingomyelin (SM) and SFA-containing phosphatidylcholine (SFA-PC) contents, as well as lipid raft marker caveolin 1 amounts. Furthermore, lipid raft disruption suppressed Tlr22-induced Nf-κb and interferon h activation and p65 nuclear translocation. In vivo, expression of Tlr22 target inflammatory genes was 32-64% lower in the 1.6% DHA group than in the Ctrl group upon poly I:C injection (P ≤ 0.05). Also, the 1.6% DHA group showed a reduction in membrane SM and SFA-PC contents, accompanied by a decrease in caveolin 1 amounts, compared with the Ctrl group. CONCLUSIONS: The activation of Tlr22 signaling depends on lipid rafts, and DHA ameliorates the Tlr22-triggered inflammation in both head kidney and head kidney-derived macrophages of croaker partially by altering membrane SMs and SFA-PCs that are required for lipid raft organization.

Endoplasmic reticulum stress induces hepatic steatosis by transcriptional upregulating lipid droplet protein perilipin2.

Previous studies have shown that endoplasmic reticulum (ER) stress contributes to hepatic steatosis in several manners. However, how lipid droplet (LD) proteins participate in this process has rarely been reported. In the present study, ER stress was induced at both in vitro and in vivo levels with tunicamycin in large yellow croaker (Larimichthys crocea). Effects of LD protein perilipin2 (PLIN2) on hepatic lipid accumulation and lipoprotein transport under normal physiological condition and ER stress were then explored using dsRNA mediated knockdown. Subsequently, the transcriptional regulation of plin2 expression by transcription factors generated in the unfolded protein response (UPR) was determined by dual-luciferase reporter assays, chromatin immunoprecipitation and electrophoretic mobility-shift assay. We demonstrated that ER stress could promote LDs accumulation and inhibit lipoprotein transport by transcriptionally upregulating PLIN2 in liver. Among the transcription factors generated by UPR, spliced X-box binding protein1 can directly upregulated the expression of plin2, whereas C/EBP homologous protein can upregulate the expression of plin2 through peroxisome proliferator activated-receptor α. These results revealed that the LD protein PLIN2 played an important role in ER stress-induced hepatic steatosis, which might be a novel mechanism explaining hepatic steatosis triggered by ER stress.

Nutritional programming of large yellow croaker (Larimichthys crocea) larvae by dietary vegetable oil: effects on growth performance, lipid metabolism and antioxidant capacity.

The nutritional status experienced in the early development of life plays a vital role in the long-term metabolic state of the individual, which is known as nutritional programming. The present study investigated the long-term effects of vegetable oil (VO) nutritional programming during the early life of large yellow croaker. First, larvae were fed either a fish oil (FO) diet or a VO diet for 30 d. Subsequently, under the same conditions, all fish were fed a commercial diet for 90 d and thereafter challenged with an FO or VO diet for 30 d. The results showed that growth performance was significantly lower in larvae fed the VO diet than in those in fed the FO diet in the stimulus phase. Notably, VO nutritional history fish showed lower levels of liver lipids liver total triglycerides and serum nonesterified free fatty acids than the FO nutritional history fish when juveniles were challenged with the VO diet, which was consistent with the expression of lipogenesis-related genes and proteins. Moreover, the VO nutritional history fish showed lower liver damage and higher antioxidant capacity than FO nutritional history fish when challenged with the VO diet. In summary, this study showed that a short VO stimulus during the early life stage of large yellow croaker, had a long-term effect on lipid metabolism and the antioxidant system. Specifically, VO nutritional programming had a positive effect on alleviating abnormal lipid deposition on the liver, liver damage, and the reduction of hepatic antioxidant capacity caused by a VO diet.

Lysophosphatidylcholine acyltransferase 3 (LPCAT3) mediates palmitate-induced inflammation in macrophages of large yellow croaker (Larimichthys crocea).

LPCAT3, a subtype of lysophosphatidylcholine acyltransferases, is a key enzyme in phosphatidylcholine remodeling pathway and plays a significant role in mediating inflammatory response in mammals. However, its inflammatory function in fish has yet to be discovered. Herein, this study aimed to investigate its role in inflammation in Larimichthys crocea. We analyzed the coding sequence of Larimichthys crocea LPCAT3 (Lc-LPCAT3) and explored the effect of Lc-LPCAT3 on palmitate (PA)-induced inflammation. We found that in macrophage cell line of Larimichthys crocea, the mRNA expression of Lc-lpcat3 was upregulated by PA with the elevated pro-inflammatory genes expression, including il1ß, il6, il8, tnfα and ifnγ. Next, the role of Lc-LPCAT3 in inflammation induced by PA was further investigated. Results showed that knockdown of Lc-LPCAT3 mitigated PA-induced pro-inflammatory genes mRNA expression, including il1ß, il8, tnfα and ifnγ, in which JNK signaling pathway was involved. In contrast, overexpression of Lc-LPCAT3 induced pro-inflammatory genes expression including il1ß, tnfα and ifnγ. Furthermore, several transcription factors with negative regulation of Lc-LPCAT3 promoter activity were discovered including LXRα, RXRα, PPARα, PPARγ, CEBPα, CEBPß, CEBPδ, SREBP1 and SREBP2, and SREBP1 had the strongest regulatory effect. In conclusion, we first discovered that fish LPCAT3 participated in PA-induced inflammation, and targeting SREBP1 might be an effective coping strategy.

MG53 represses high glucose-induced inflammation and angiogenesis in human retinal endothelial cells by repressing the EGR1/STAT3 axis.

BACKGROUND: Diabetic retinopathy (DR) is a vascular complication of diabetes mellitus that leads to visual injury and blindness. Both angiogenesis and inflammation play an important role in the pathogenesis of DR. Here we aimed to explore the mechanisms of mitsugumin 53 (MG53) in ameliorating the dysfunction induced by high glucose (HG) in humans retinal microvascular endothelial cells (HRECs). METHODS: HRECs were subjected to HG in the presence or absence of MG53 overexpression. The effect of MG53 on cell viability and inflammatory response in HG-treated HRECs was measured using the Cell Counting Kit-8 and ELISAs, respectively. Expression of MG53, EGR1, p-STAT3, FGF2, TGFB1, and Angiopoietin-1 in HG-treated HRECs was quantified by western blot or quantitative real-time polymerase chain reaction. RESULTS: HG significantly downregulated MG53 in HRECs, which reduced cell viability while inducing angiogenesis and inflammatory response. Upregulation of MG53 reversed these effects of HG. MG53 directly interacted with EGR1 and repressed its expression, which decreased phosphorylation of STAT3 and downregulated FGF2, TGFB1, and Angiopoietin-1. EGR1 up-regulation or STAT3 activation antagonized the protective effects of MG53. CONCLUSION: MG53 alleviates HG-induced dysfunction in HRECs by repressing EGR1/STAT3 signaling. Thereby MG53 may have therapeutic potential in DR.

Sulforaphane alleviates LPS-induced inflammatory injury in ARPE-19 cells by repressing the PWRN2/NF-kB pathway.

BACKGROUND: Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly population and its pathogenesis has been associated with inflammatory damage to retinal pigment epithelial (RPE) cells. Here, we explored the ability of sulforaphane to protect ARPE-19 cells from lipopolysaccharide (LPS)-induced inflammatory injury and elucidated the underlying molecular mechanism. METHODS: Cell viability, apoptosis, inflammation, PWRN2 expression, nuclear transcription factor-kappa B (NF-kB) activity, and the interaction between PWRN2 and the IkBa protein were assessed in RPE cells under- or over-expressing PWRN2 that had been treated with LPS and sulforaphane. RESULTS: Overexpression of PWRN2 in LPS-treated cells promoted NF-kB activation by interacting with IkBa, thus reducing cell viability. In contrast, PWRN2 downregulation repressed LPS-induced NF-kB activation and apoptosis in RPE cells. Similarly, sulforaphane downregulated PWRN2 and inhibited NF-kB activation in a concentration-dependent manner. Conversely, PWRN2 overexpression or NF-kB upregulation weakened the anti-inflammatory effects of sulforaphane. CONCLUSION: Our results suggest that sulforaphane protects RPE cells from LPS-induced inflammatory injury by suppressing the PWRN2/NF-kB pathway.

Comparison of the prognostic value of SYNTAX score and clinical SYNTAX score on outcomes of Chinese patients underwent percutaneous coronary intervention.

BACKGROUND: Previous studies have validated the capability of SYNTAX score (SS) and clinical SYNTAX score (CSS) in the prediction of clinical outcomes in patients who have undergone PCI; however, studies on comparison of these two scoring systems in Chinese population have been sparse. METHODS: To study the ability of SS and CSS in prediction of clinical outcomes of Chinese patients underwent percutaneous coronary intervention (PCI). We retrospectively calculated SS and CSS for 547 Chinese patients from a single center who underwent PCI. Patients were stratified into tertiles according to their SS and CSS. We compared the 2-year clinical outcomes in these patients stratified separately by SS and CSS tertiles. RESULTS: The incidence of major adverse cardiac and cerebro-vascular events (MACCE) was the highest in patients with SSHIGH (13.5%), comparing to 6.8% in SSMED and 0% in SSLOW (p < 0.0001). The Cox multivariable analysis showed that the SS and CSS were both strong independent predictors for MACCE [1.100 (1.069-1.133), 1.017 (1.010-1.025), both p < 0.0001]. The receiver operating characteristic (ROC) curves showed the areas-under-the-curves for all-cause death by CSS was slightly larger comparing to SS but not significantly (AUC SS, 0.64; AUC CSS, 0.71; p = 0.23). CONCLUSION: We concluded that both the SS and CSS were capable of risk stratification of clinical outcomes in all-comers population as well as in low and moderate risk Chinese patients undergoing PCI with CSS showing slightly better advantage.

Characterization of antiviral immune response induced by poly(I:C) in macrophages of farmed large yellow croaker (Larimichthys crocea).

Fish tend to rely more on their innate immunity to executing defense against viral infection by inducing antiviral gene production. However, the expression pattern and underlying mechanism of fish antiviral responses have yet to be fully defined. In the present study, an in vitro viral infection model was established by exposing head kidney-derived macrophages of large yellow croaker to virus analog, poly(I:C). Transcriptome analysis indicated that poly(I:C) appeared to induce potent antiviral activity featuring dominant interferon a3 (IFNa3) expression through activation of toll-like receptors (TLRs)/TIR-domain-containing adapter-inducing interferon-ß (TRIF) and retinoic acid-inducible gene I-like receptors (RLRs)/mitochondrial antiviral signaling protein (MAVS) pathways. Inhibition of nuclear factor κB (NF-κB) and stimulator of interferon genes (STING)/interferon regulatory factor 3 (IRF3) pathways diminished the expression of IFNa3. Mechanistically, transcription factors including p65 and IRF3 could promote expression of IRF3, and activated IRF3 alone further increased the transcriptional activity of IFNa3. We also characterized the promoter of IFNa3 with direct IRF3 binding site which was sufficient to render the transcription of IFNa3. This effect was attenuated after deletion or mutation of the IRF3 binding sites. Taken together, our findings illustrate the distinct transcriptional profiling of fish macrophages triggered by poly(I:C). Also, this work provides new insights into the molecular mechanism underpinning coordinated activation of pathogen recognition and signaling transduction in the antiviral responses of non-model fish species.

Molecular cloning and the involvement of IRE1α-XBP1s signaling pathway in palmitic acid induced - Inflammation in primary hepatocytes from large yellow croaker (Larimichthys crocea).

Apart from mitigating endoplasmic reticulum (ER) stress, vast studies have demonstrated the crucial role of inositol-requiring transmembrane kinase and endonuclease 1α (IRE1α) - spliced X-box binding protein 1 (XBP1s) signaling pathway in inflammatory response in mammals. In addition, palmitic acid (PA)-induced inflammation has been verified in large yellow croaker (Larimichthys crocea). However, whether the IRE1α-XBP1s signaling pathway is involved in inflammatory response caused by PA remains poorly studied in fish. The present study was aimed at elucidating the role of the IRE1α-XBP1s signaling pathway in inflammatory response induced by PA in primary hepatocytes from large yellow croaker. In the present study, the full-length cDNA of ire1α and xbp1s were cloned and comprised 3793 bp and 1789 bp with an open reading frame of 3279 bp and 1170 bp, encoding 1093 and 390 amino acids, respectively. IRE1α protein possessed a protein kinase and endoribonuclease domain and XBP1s protein possessed a basic-leucine zipper domain. The IRE1α protein and XBP1s protein located to the ER membrane and nucleus respectively. The ire1α and xbp1s were widely transcribed in various tissues with the higher level in intestine, liver, adipose and head kidney. The ER stress-inducing agent tunicamycin (Tm) and PA treatment significantly activated the IRE1α-XBP1s signaling pathway and increased the pro-inflammatory genes expression including tumor necrosis factor α (tnfα), interleukin 6 (il-6) and interleukin 1ß (il-1ß) (P < 0.05). When KIRA6, the IRE1α kinase inhibitor, was used to block the IRE1α-XBP1s signaling pathway, the Tm and PA-induced pro-inflammatory genes expression was significantly suppressed (P < 0.05). These data indicated that the IRE1α-XBP1s signaling pathway was involved in the PA-induced inflammatory response in large yellow croaker.

Effect of replacement of dietary fish oil with four vegetable oils on prostaglandin E2 synthetic pathway and expression of inflammatory genes in marine fish Larimichthys crocea.

As a lipid mediator with important immune function, prostaglandin E2 (PGE2) has been widely studied in mammals, whereas its synthetic pathway and immune function in fish have yet to be fully studied. To investigate the regulation of PGE2 synthetic pathway and inflammatory genes expression by dietary different oils and the underlying relationship, a 10-week feeding experiment and an immune challenge were carried out in marine fish Larimichthys crocea. Replacement of dietary fish oil (FO) with four vegetable oils (VO), including soybean oil, linseed oil, palm oil, and olive oil, all reduced PGE2 levels, and the decrease of arachidonic acid (ARA, substrate for PGE2) could account for this decline. Meanwhile, the expression of PGE2 synthesis related genes was basically upregulated, which seemed to be a feedback regulation, but it cannot compensate the deficiency of ARA. In addition, mRNA expression of inflammatory genes, including interleukin (IL)-1ß, IL-6, tumor necrosis factor (TNF)α and interferon (IFN)γ was all upregulated in four VO groups compared with FO group, which was the opposite of PGE2 levels. To verify the inflammatory regulation of PGE2, an immune challenge was conducted, and PGE2 alleviated LPS-induced expression of inflammatory genes, including IL-6, TNFα and IFNγ, and the similar downregulation of toll-like receptor (TLR) genes expression revealed that TLR signaling pathway participated in the anti-inflammatory regulation of PGE2. In conclusion, replacement of dietary FO with four VO (lack of ARA) reduced the levels of PGE2 that could alleviate LPS-induced inflammatory genes expression via TLR signaling pathway, which could be one of the reasons that VO induced inflammation in marine fish.

Inhibitory effect of ultrasonic stimulation on the voltage-dependent potassium currents in rat hippocampal CA1 neurons.

BACKGROUND: Transcranial ultrasonic stimulation is a novel noninvasive tool for neuromodulation, and has high spatial resolution and deep penetration. Although it can increase excitation of neurons, its effects on neuron are poorly understood. This study was to evaluate effect of ultrasonic stimulation (US) on neurons in vitro. In this paper, the effect of US on the excitability and voltage-dependent [Formula: see text] currents of CA1 pyramidal neurons in the rat hippocampus was studied using patch clamp. RESULTS: Our results suggest that US increased the spontaneous firing rate and inhibited transient outward potassium current ([Formula: see text]) and delayed rectifier potassium current ([Formula: see text]. Furthermore, US altered the activation of [Formula: see text] channels, inactivation and recovery properties of [Formula: see text] channels. After US, the [Formula: see text] activation curves significantly moved to the negative voltage direction and increased its slope factor. Moreover, the data showed that US moved the inactivation curve of [Formula: see text] to the negative voltage and increased the slope factor. Besides, US delayed the recovery of [Formula: see text] channel. CONCLUSIONS: Our data indicate that US can increase excitation of neurons by inhibiting potassium currents. Different US decreased the voltage sensitivity of [Formula: see text] activation differentially. Moreover, the more time is needed for US to make the [Formula: see text] channels open again after inactivating. US may play a physiological role by inhibiting voltage-dependent potassium currents in neuromodulation. Our research can provide a theoretical basis for the future clinical application of ultrasound in neuromodulation.

High percentage of dietary palm oil suppressed growth and antioxidant capacity and induced the inflammation by activation of TLR-NF-κB signaling pathway in large yellow croaker (Larimichthys crocea).

A 70-day feeding trial was conducted to investigate the effects of dietary fish oil (FO) replaced by palm oil (PO) on growth, biochemical and antioxidant response as well as inflammatory response in the liver of large yellow croaker (initial weight 15.87 ±â€¯0.14 g). Four iso-proteic and iso-lipidic experimental diets were formulated with 0% (the control group), 33.3%, 66.7% and 100% FO replaced by PO. Fish fed the diet with 100% PO showed significantly lower growth performance than the control group. As expected, the contents of C16:0, C18:1n-9 and C18:2n-6 were increased with increasing dietary PO levels. There were remarkable increases in total cholesterol (TC) and low-density lipoprotein-cholesterol (LDL-C) levels in fish fed the diet with 100% PO compared to the control group. Moreover, dietary PO significantly increased activities of plasma alanine transaminase (ALT) and aspartate aminotransferase (AST) in fish fed the diet with 100% PO compared to the control group. The total antioxidant capacity (T-AOC) and the activity of catalase (CAT) in plasma were significantly decreased in fish fed the diet with 100% PO compared to the control group, and meanwhile no significant differences were found in T-AOC and CAT activity in fish fed diets with no more than 66.7% PO. Fish fed the diet with 100% PO exerted significantly higher toll like receptors (TLRs) and myeloid differentiation factor (MyD88) mRNA expression levels than the control group. The IFNγ, IL-1ß and TNFα mRNA expressions were increased with increasing dietary PO levels. The increase of pro-inflammatory gene expression may be due to the activation of NF-κB signaling as the ratio of nucleus p65 to total p65 protein was elevated with the increase of dietary PO levels. These results showed that relatively higher PO levels in diets suppressed the growth and antioxidant capacity as well as induced the inflammatory response by activating TLR-NF-κB signaling pathway in juvenile large yellow croaker.